Pregnancy

Introduction

Donald R. Mattison

1

Over the past decade, attention to clinical therapeutics has grown substantially from many different directions, including the important in uences of gender differences and pregnancy [1–3]. Despite these advances there is increasing concern that discovery and development of new drugs for these important populations is lagging [4–9]. At the same time, recognition has grown that select populations are excluded from the drug development process, especially women and children [5, 10–12]. One consequence of this failure to speci cally develop drugs for maternal and child health is to dissociate therapeutic opportu- nities for women and children from the drugs and treatments currently available. This distancing of women and children from drug development and therapeutic knowledge produces a host of clinical challenges for the concerned practitioner. In the absence of suf cient therapeutic knowledge, appropriate dos- ing is not known [13–17]. Without understanding of appropriate dosing, the clinician does not know if the dose recommended on the product label will produce the desired drug concentration at the site of action – or if the concentration produced will be above or below the needed concentration, producing toxicity or inadequate response, respectively. Similarly, without thoughtful therapeutic development in women and children it is not known if differences in pharmacodynamics will produce different treat- ment goals and needs for monitoring effectiveness and safety [14, 18–21].

A consequence of the failure to develop drugs for use in pregnancy is that most drugs are not tested for use during pregnancy [4, 22]; consequently, labeling, which may include exten- sive information about fetal safety [10, 23], includes nothing about dosing, appropriate treatment, ef cacy, or maternal safety [3–5, 10, 11, 22, 23]. Yet these are concerns of health care providers consid- ering treatment during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in

2 Introduction

adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treat- ment? Clearly treatment of depression poses risks for both mother and fetus, as does stopping treatment [24–26]. This is also the case with respect to in uenza during pregnancy [13, 27, 28]. All com- bined, the state of therapeutics during pregnancy underscores the continued tension that exists between maternal–placental–fetal health and maternal quality of life during pregnancy and the lack of critical study of “gestational therapeutics”. This book hopes to address many of these imbalances.

Medical and health care providers caring for women during pregnancy have many excellent resources describing the safety of medications for the fetus [10, 23]. However, none of these references provide information on appropriate dosing as well as the ef cacy of the various medications used during pregnancy for maternal/placental therapeutics. We are all familiar with the potential/actual costs, nancial and psychosocial, of having treatments which produce developmental toxicity – however, how many of us ever think critically about the costs of having inadequate therapeutic options to treat the major diseases of pregnancy; growth restriction, pregnancy loss, preeclampsia/ eclampsia. Where we have effective treatments for maternal disease – infection, depression, diabetes, hypertension – we are recognizing that continuation of treatment during pregnancy carries bene t for mother, placenta, and baby. In the end what is important for the mother, baby, and family is the appropriate balancing of bene t and risk – as indeed is the important bal- ancing for all clinical therapeutics [11, 12]. This book provides medical and health professionals involved in the care of preg- nant women with contemporary information on clinical phar- macology for pregnancy. It covers an overview of the impact of pregnancy on drug disposition, summarizing current research about the changes of pharmacokinetics and pharmacodynamics during pregnancy. This is followed by speci c sections on the treatment, dosing and clinical effectiveness of medications dur- ing pregnancy, providing health care providers with an essential reference on how to appropriately treat women with medica- tions during pregnancy. At one level the question is simple – how to treat, how to monitor for bene t and risk, how to know if treatment is successful? This book was developed to explore that question for women during pregnancy. The book is meant to be a guide to clinicians who care for women during pregnancy – we hope the busy clinician and student of obstetrics will nd this a useful guide.

1 Introduction 3

References

[1] Zajicek A, Giacoia GP. Obstetric clinical pharmacology: coming of age. Clin Pharmacol Ther 2007;81(4):481–2.

[2] Schwartz JB. The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther 2007;82(1):87–96.

[3] Kearns GL, Ritschel WA, Wilson JT, Spielberg SP. Clinical pharmacology: a discipline called to action for maternal and child health. Clin Pharmacol Ther 2007;81(4):463–8.

[4] Malek A, Mattison DR. Drug development for use during pregnancy: impact of the placenta. Expert Rev Obstet Gynecol 2010;5(4):437–54.

[5] Thornton JG. Drug development and obstetrics: where are we right now? J Matern Fetal Neonatal Med 2009;22(suppl. 2):46–9.

[6] Woodcock J, Woosley R. The FDA critical path initiative and its in uence on new drug development. Annu Rev Med 2008;59:1–2.

[7] The PME. Drug development for maternal health cannot be left to the whims of the market. PLoS Med 2008;5(6):e140.

[8] Hawcutt DB, Smyth RL. Drug development for children: how is pharma tackling an unmet need? IDrugs 2008;11(7):502–7.

[9] Adams CP, Brantner VV. Estimating the cost of new drug development: is it really $802 million? Health Aff 2006;25(2):420–8.

[10] Lo WY, Friedman JM. Teratogenicity of recently introduced medications in human pregnancy. Obstet Gynecol 2002;100(3):465–73.

[11] Fisk NM, Atun R. Market failure and the poverty of new drugs in maternal health. PLoS Med 2008;5(1):e22.

[12] Thornton J. The drugs we deserve. BJOG 2003;110(11):969–70.
[13] Beigi RH, Han K, Venkataramanan R, Hankins GD, Clark S, Hebert MF, et al. Pharmacokinetics of oseltamivir among pregnant and nonpregnant women.

Am J Obstet Gynecol 2011;204(6 Suppl. 1):S84–8.
[14] Rothberger S, Carr D, Brateng D, Hebert M, Easterling TR. Pharmacodynamics

of clonidine therapy in pregnancy: a heterogeneous maternal response impacts

fetal growth. Am J Hypertens 2010;23(11):1234–40.
[15] Eyal S, Easterling TR, Carr D, Umans JG, Miodovnik M, Hankins GD, et al.

Pharmacokinetics of metformin during pregnancy. Drug Metab Dispos

2010;38(5):833–40.
[16] Hebert MF, Ma X, Naraharisetti SB, Krudys KM, Umans JG, Hankins GD,

et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009;85(6):607–14.

[17] Andrew MA, Easterling TR, Carr DB, Shen D, Buchanan ML, Rutherford T, et al. Amoxicillin pharmacokinetics in pregnant women: modeling and simu- lations of dosage strategies. Clin Pharmacol Ther 2007;81(4):547–56.

[18] Na-Bangchang K, Manyando C, Ruengweerayut R, Kioy D, Mulenga M, Miller GB, et al. The pharmacokinetics and pharmacodynamics of atova- quone and proguanil for the treatment of uncomplicated falciparum ma- laria in third-trimester pregnant women. Eur J Clin Pharmacol 2005;61(8): 573–82.

[19] Hebert MF, Carr DB, Anderson GD, Blough D, Green GE, Brateng DA, et al. Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum. J Clin Pharmacol 2005;45(1):25–33.

1 Introduction

4 References

[20] Meibohm B, Derendorf H. Pharmacokinetic/pharmacodynamic studies in drug product development. J Pharm Sci 2002;91(1):18–31.

[21] Lu J, P ster M, Ferrari P, Chen G, Sheiner L. Pharmacokinetic-pharmacodynamic modelling of magnesium plasma concentration and blood pressure in preeclamp- tic women. Clin Pharmacokinet 2002;41(13):1105–13.

[22] Feghali MN, Mattison DR. Clinical therapeutics in pregnancy. J Biomed Biotechnol 2011; 2011:783528.

[23] Adam MP, Polifka JE, Friedman JM. Evolving knowledge of the teratogenicity of medications in human pregnancy. Am J Med Genet C Semin Med Genet 2011;157(3):175–82.

[24] Markus EM, Miller LJ. The other side of the risk equation: exploring risks of untreated depression and anxiety in pregnancy. J Clin Psychiatry 2009;70(9):1314–5.

[25] Marcus SM, Heringhausen JE. Depression in childbearing women: when depression complicates pregnancy. Prim Care 2009;36(1):151–65; ix.
[26] Marcus SM. Depression during pregnancy: rates, risks and consequences –

Motherisk Update 2008. Can J Clin Pharmacol 2009;16(1):e15–22.
[27] Mirochnick M, Clarke D. Oseltamivir pharmacokinetics in pregnancy: a

commentary. Am J Obstet Gynecol 2011;204(6 Suppl. 1):S94–5.
[28] Greer LG, Leff RD, Rogers VL, Roberts SW, McCracken Jr GH, Wendel Jr GD, et al. Pharmacokinetics of oseltamivir according to trimester of pregnancy.

Am J Obstet Gynecol 2011;204(6 Suppl. 1):S89–93.

Physiologic Changes During 2 Pregnancy

Luis D. Pacheco, Maged M. Costantine, Gary D.V. Hankins

. 2.1  Physiologic changes during pregnancy 5

. 2.2  Cardiovascular system 6

. 2.3  Respiratory system 7

. 2.4  Renal system 8

. 2.5  Gastrointestinal system 10

. 2.6  Hematologic and coagulation systems 11

. 2.7  Endocrine system 12

. 2.8  Summary 14

2.1 Physiologic changes during pregnancy

Human pregnancy is characterized by profound anatomic and physiologic changes that affect virtually all systems and organs in the body. Many of these changes begin in early gestation. Understanding of pregnancy adaptations is vital to the clini- cian and the pharmacologist as many of these alterations will have a signi cant impact on pharmacokinetics and pharma- codynamics of different therapeutic agents. A typical example of the latter involves the increase in glomerular ltration rate leading to increased clearance of heparins requiring the use of higher doses during pregnancy. The present chapter discusses the most relevant physiologic changes that occur during human gestation.

6 2.2 Cardiovascular system 2.2 Cardiovascular system

Profound changes in the cardiovascular system characterize human pregnancy and are likely to affect the pharmacokinetics of different pharmaceutical agents. Table 2.1 summarizes the main cardiovascular changes during pregnancy. Cardiac output (CO) increases by 30–50% during pregnancy secondary to an increase in both heart rate and stroke volume [1]. Most of the increase occurs early in pregnancy, such that by the end of the rst trimes- ter 75% of such increment has already occurred. CO plateaus at 28–32 weeks and afterwards remains relatively stable until the delivery period [2]. As CO increases, pregnant women experience a signi cant decrease in both systemic and pulmonary vascular resistances [1]. Systemic vascular resistance decreases in early pregnancy, reaching a nadir at 14–24 weeks. Subsequently, vas- cular resistance starts rising, progressively approaching the pre- pregnancy value at term [1]. Blood pressure tends to fall toward the end of the rst trimester and then rises again in the third tri- mester to pre-pregnancy levels [3]. Physiologic hypotension may be present between weeks 14 and 24 and likely this is due to the decrease in the systemic vascular resistance described previously.

Maternal blood volume increases in pregnancy by 40–50%, reaching maximum values at 32 weeks [4]. Despite the increase in blood volume, central lling pressures like the central venous

Table 2.1 Summary of cardiovascular changes during pregnancy

Variable

Change

Mean arterial pressure Central venous pressure

Pulmonary arterial occlusion pressure

Systemic vascular resistance Pulmonary vascular resistance Heart rate

Stroke volume Colloid osmotic pressure

Hemoglobin concentration

No signi cant change No change No change

Decreased by 21% (nadir at 14–24 weeks) Decreased by 34%

Increased (approaches 90 beats/minute at rest during the third trimester)

Increases to a maximum of 85 mL at 20 weeks of gestation

Decreased by 14% (associated with a decrease in serum osmolarity noticed as early as the rst trimester of pregnancy)

Decreased (maximum hemodilution is achieved at 30–32 weeks)

 

2 Physiologic changes during pregnancy 7

and pulmonary occlusion pressures remain unchanged secondary to an increase in compliance of the right and left ventricles [5].

The precise etiology of the increase in blood volume is not clearly understood; however, increased mineralocorticoid activity with water and sodium retention does occur [6]. Production of ar- ginine vasopressin (resulting in increased water absorption in the distal nephron) is also increased during pregnancy and thought to contribute to hypervolemia. Secondary hemodilutional anemia and a decrease in serum colloid osmotic pressure (due to a drop in albumin levels) ensue.

The latter physiological changes could have theoretical impli- cations on pharmacokinetics. The increase in blood volume, in- creased capillary hydrostatic pressure, and decrease in albumin concentrations would be expected to increase signi cantly the volume of distribution of hydrophilic substances. Highly protein bound compounds may display higher free levels due to decreased protein binding availability.

2.3 Respiratory system

The respiratory system undergoes both mechanical and functional changes during pregnancy. Table 2.2 summarizes these changes.

The sharp increase in estrogen concentrations during pregnancy leads to hypervascularity and edema of the upper respiratory mu- cosa [7]. These changes result in an increased prevalence of rhi- nitis and epistaxis in pregnant individuals. Theoretically, inhaled medications such as steroids used in the treatment of asthma could be more readily absorbed in the pregnant patient. Despite this theoretical concern, there is no evidence of increased toxic- ity with the use of these agents during pregnancy. Mainly driven by progesterone, minute ventilation increases by 30–50% second- ary to an increase in tidal volume. Respiratory rate remains un- changed during pregnancy [8]. The increase in ventilation results in an increase in the arterial partial pressure of oxygen (PaO2) to 101–105mmHg and a diminished arterial partial pressure of car- bon dioxide (PaCO2), with normal values of PaCO2 during preg- nancy of 28–31 mmHg. This decrement allows for a gradient to ex- ist between the PaCO2 of the fetus and the mother so that carbon dioxide can diffuse freely from the fetus into the mother through the placenta and then be eliminated through the maternal lungs.

The normal maternal arterial blood pH in pregnancy is between 7.4 and 7.45, consistent with a mild respiratory alkalosis. The latter is partially corrected by an increased renal excretion of bicarbonate,

2 Physiologic Changes During Pregnancy

8 2.4 Renal system
Table 2.2 Summary of respiratory changes during pregnancy

Variable

Change

Tidal volume

Respiratory rate Minute ventilation

Partial pressure of oxygen

Partial pressure of carbon dioxide

Arterial pH Vital capacity

Functional residual capacity

Total lung capacity

Increased by 30–50% (increase starts as early as the rst trimester)

No change

Increased by 30–50% (increase starts as early as the rst trimester)

Increased (increase starts as early as the rst trimester) Decreased (decrease starts as early as the rst trimester)

Slightly increased (increase starts as early as the rst trimester) No change

Decreased by 10–20% (predisposes pregnant patients to hypoxemia during induction of general anesthesia)

Decreased by 4–5% (maximum diaphragmatic elevation happens during the third trimester of pregnancy)

 

rendering the normal serum bicarbonate between 18 and 21 meq/L during gestation [9]. As pregnancy progresses, the increased intra- abdominal pressure (likely secondary to uterine enlargement, bowel dilation, and third-spacing of uids to the peritoneal cavity second- ary to decreased colloid-osmotic pressure) displaces the diaphragm upward by 4–5cm leading to alveolar collapse in the bases of the lungs. Bibasilar atelectasis results in a 10–20% decrease in the func- tional residual capacity and increased right to left vascular shunt [10, 11]. The decrease in expiratory reserve volume is coupled with an increase in inspiratory reserve volume; as a result no change is seen in the vital capacity [10].

Changes in respiratory physiology may impact pharmacokinet- ics of certain drugs. Topical drugs administered into the naso- pharynx and upper airway could be more readily available to the circulation as local vascularity and permeability are increased. As discussed earlier, the latter assumption is theoretical and no evi- dence of increased toxicity from inhaled agents during pregnancy has been demonstrated.

2.4 Renal system

Numerous physiologic changes occur in the renal system during pregnancy. These changes are summarized in Table 2.3.

2 Physiologic changes during pregnancy 9 Table 2.3 Summary of renal changes during pregnancy

Variable

Change

Renal blood ow

Glomerular ltration rate

Serum creatinine

Renin–angiotensin– aldosterone system

Total body water

Ureter–bladder muscle tone

Urinary protein excretion

Serum bicarbonate

Increased by 50%. Increase noticed as early as 14 weeks of gestation Increased by 50%. Increase noticed as early as 14 weeks of gestation

Decreased (normal value is 0.5–0.8 mg/dL during pregnancy)

Increased function leading to sodium and water retention noticed from early in the rst trimester of pregnancy

Increased by up to 8 liters. Six liters gained in the extracellular space and 2 liters in the intracellular space

Decreased secondary to increases in progesterone. Smooth muscle relaxation leads to urine stasis with increased risk for urinary tract infections

Increased secondary to elevated ltration rate. Values up to 260 mg of protein in 24 hours are considered normal in pregnancy

Decreased by 4–5 meq/L. Normal value in pregnancy is 18–22 meq/L (24 meq/L in non-pregnant individuals)

 

The relaxing effect of progesterone on smooth muscle leads to dilation of the urinary tract with consequent urinary stasis, predis- posing pregnant women to infectious complications.

The 50% increase in renal blood ow during early pregnancy leads to a parallel increase in the glomerular ltration rate (GFR) of approximately 50%. This massive elevation in GFR is present as early as 14 weeks of pregnancy [12]. As a direct consequence, serum values of creatinine and blood urea nitrogen will decrease. A serum creatinine above 0.8 mg/dL may be indicative of underly- ing renal dysfunction during pregnancy.

Besides detoxi cation, one of the most important functions of the kidney is to regulate sodium and water metabolism. Progester- one favors natriuresis while estrogen favors sodium retention [13]. The increase in GFR leads to more sodium wasting; however, the latter is counterbalanced by an elevated level of aldosterone which reabsorbs sodium in the distal nephron [13]. The net balance dur- ing pregnancy is one of avid water and sodium retention leading to a signi cant increase in total body water with up to 6 liters of uid gained in the extracellular space and 2 liters in the intracel- lular space. This “dilutional effect” leads to a mild decrease in both serum sodium (concentration of 135–138meq/L) and serum os- molarity (normal value in pregnancy ~280mOsm/L) [14]. In the non-pregnant state, normal serum osmolarity is 286–289mOsm/L with a concomitant normal serum sodium concentration of

2 Physiologic Changes During Pregnancy

10 2.5 Gastrointestinal system

135–145meq/L. Changes in renal physiology have profound reper- cussions on drug pharmacokinetics. Agents cleared renally are ex- pected to have shorter half-lives and uid retention is expected to increase the volume of distribution of hydrophilic agents. A typical example involves lithium. Lithium is mainly cleared by the kidney and during the third trimester of pregnancy clearance is doubled compared to the non-pregnant state [15]. Not all renally cleared medications undergo such dramatic increases in excretion rates (digoxin clearance is only increased by 30% during the third trimes- ter of pregnancy).

2.5 Gastrointestinal system

The gastrointestinal tract is signi cantly affected during preg- nancy secondary to progesterone-mediated inhibition of smooth muscle motility [16]. Table 2.4 summarizes these changes.

Gastric emptying and small bowel transit time are considerably prolonged. The increase in intra-gastric pressure (secondary to delayed emptying and external compression from the gravid uter- us) together with a decrease in resting muscle tone of the lower esophageal sphincter favors gastroesophageal regurgitation. Of note, recent studies have shown that gastric acid secretion is not affected during pregnancy [17].

Table 2.4 Summary of gastrointestinal changes during pregnancy

Variable

Change

Gastric emptying time

Gastric acid secretion Liver blood ow

Liver function tests

Bowel/gallbladder motility

Pancreatic function enzymes (amylase, lipase)

Prolonged, increasing the risk of aspiration in pregnant women. Intra-gastric pressure is also increased

Unchanged

Unchanged in the hepatic artery; however, more venous return in the portal vein has been documented with ultrasound Doppler studies

No change during pregnancy except for alkaline phosphatase (increases in pregnancy secondary to placental contribution)

Decreased, likely secondary to smooth muscle relaxation induced by progesterone

Unchanged

 

2 Physiologic changes during pregnancy 11

Con icting data exist regarding liver blood ow during preg- nancy. Recently, with the use of Doppler ultrasonography, in- vestigators found that blood ow in the hepatic artery does not change during pregnancy but portal venous return to the liver was increased [18]. Most of the liver function tests are not altered. Spe- ci cally, serum transaminases, billirubin, lactate dehydrogenase, and gamma-glutamyl transferase are all unaffected by pregnancy. Serum alkaline phosphatase is elevated secondary to production from the placenta and levels two to four times higher than that of non-pregnant individuals may be seen [19]. Other liver products that are normally elevated include serum cholesterol, brinogen, and most of the clotting factors, ceruloplasmin, thyroid binding globulin, and cortisol binding globulin. The increase in all these proteins is likely estrogen mediated [19]. Also mediated by proges- terone, gallbladder motility is decreased, rendering the pregnant woman at increased risk for cholelitiasis. The latter changes will clearly affect pharmacokinetics of orally administered agents, with delayed absorption and onset of action as a result. Antimalarial agents undergo signi cant changes at the gastrointestinal level dur- ing pregnancy that could decrease their therapeutic ef cacy [20].

2.6 Hematologic and coagulation systems

Pregnancy is associated with increased white cell count and red cell mass. The rise in white cell count is thought to be related to increased bone marrow granulopoeisis and may make a diagnosis of infection dif cult sometimes; however, it is usually not asso- ciated with signi cant elevations in immature forms like bands. On the other hand, the 30% increase in red cell mass is thought to be secondary to increase in renal erythropoietin production, and may be induced by placental hormones. This occurs simul- taneously with a much higher (around 45%) increase in plasma volume leading to what is referred to as “physiologic anemia” of pregnancy which peaks early in the third trimester (30–32 weeks) [21, 22]. This hemodilution is thought to confer maternal and fe- tal survival advantage as the patient will lose a more dilute blood during delivery, and the decreased blood viscosity improves uter- ine perfusion, while the increase in red cell mass serves to opti- mize oxygen transport to the fetus. To that account, patients with preeclampsia, despite having uid retention, suffer from reduced intravascular volume (secondary to diffuse endothelial injury with resultant third-spacing) which makes them less tolerant to peripartum blood loss [23, 24].

2 Physiologic Changes During Pregnancy

12 2.7 Endocrine system Table 2.5 Hemoglobin values during pregnancy

12 weeks 12.2 28 weeks 11.8 40 weeks 12.9

Pregnancy is associated with changes in the coagulation and brinolytic pathways that favor a hypercoagulable state. Plasma levels of brinogen, clotting factors (VII, VIII, IX, X, XII), and von Willebrand factor increase during pregnancy leading to a hy- percoagulable state. Factor XI decreases and levels of prothrom- bin and factor V remain the same. Protein C is usually unchanged but protein S is decreased in pregnancy. There is no change in the levels of anti-thrombin III. The brinolytic system is suppressed during pregnancy as a result of increased levels of plasminogen activator inhibitor (PAI-1) and reduced plasminogen activator levels. Platelet function remains normal in pregnancy. Routine coagulation screen panel will show values around normal. This hypercoagulable state predisposes the pregnant patient to high- er risk of thromboembolism; however, it is also thought to offer survival advantage in minimizing blood loss after delivery [25]. Tables 2.5 and 2.6 summarize some of the most relevant changes discussed previously.

2.7 Endocrine system

Pregnancy is de ned as a “diabetogenic” state. Increased insulin resistance is due to elevated levels of human placental lactogen, progesterone, estrogen, and cortisol. Carbohydrate intolerance that occurs only during pregnancy is known as gestational diabe- tes. Most gestational diabetes patients are managed solely with a modi ed diet. Approximately 10% of patients will require phar- macological treatment, mainly in the form of insulin, glyburide, or even metformin. Available literature suggests that glyburide and metformin may be as effective as insulin for the treatment of ges- tational diabetes.

Pregnancy is associated with higher glucose levels following a carbohydrate load. By contrast, maternal fasting is characterized by accelerated starvation, increased lipolysis, and faster depletion of liver glycogen storage [26]. This is thought to be related to the

Gestational age

Mean hemoglobin value (g/dL)

 

2 Physiologic changes during pregnancy 13 Table 2.6 Summary of hematological changes during pregnancy

Variable

Change

Fibrinogen level

Factors VII, VIII, IX, X Von Willebrand factor Factors II and V

Clotting times (prothrombin and activated partial thromboplastin times)

Protein C, anti-thrombin III Protein S

Plasminogen activator inhibitor White blood cell count

Platelet count

Increased (elevation starts in the rst trimester of pregnancy and peaks during the third trimester)

Increased Increased No change No change

No change

Decreased. Free antigen levels above 30% in the second trimester and 24% in the third trimester are considered normal during pregnancy

Levels increase 2–3 times leading to a decrease in brinolytic activity

Elevated. This increase results in a “left shift” with granulocytosis. Increase peaks at 30 weeks of gestation. During labor may see values of 20,000–30,000/mm3

No change

 

increased insulin resistance state of pregnancy induced by placen- tal hormones such as human placental lactogen. Pancreatic β-cells undergo hyperplasia during pregnancy resulting in increased insu- lin production leading to fasting hypoglycemia and postprandial hyperglycemia. All of these changes facilitate placental glucose transfer, as the fetus is primarily dependent on maternal glucose for its fuel requirements [27].

Leptin is a hormone primarily secreted by adipose tissues. Maternal serum levels of leptin increase during pregnancy and peak during the second trimester. Leptin in pregnancy is also pro- duced by the placenta.

On the other hand, the thyroid gland faces a particular chal- lenge during pregnancy. Due to the hyperestrogenic milieu, thyroid binding globulin (the major thyroid hormone binding protein in serum) increases by almost 150% from a pre-pregnancy concen- tration of 15–16 mg/L to 30–40 mg/L in mid-gestation. This forces the thyroid gland to increase its production of thyroid hormones to keep their free fraction in the serum constant [28, 29]. The increase in thyroid hormones production occurs mostly in the rst half of gestation and plateaus around 20 weeks until term. Other

2 Physiologic Changes During Pregnancy

14 2.8 Summary
Table 2.7 Summary of endocrine changes during pregnancy

Variable

Change

Free T4 and T3 levels Total T4 and T3 levels

Thyroid stimulating hormone (TSH)

Total cortisol levels Free serum cortisol

Unchanged

Increased secondary to increased levels of thyroid binding globulin (TBG) induced by estrogen. This elevation begins as early as 6 weeks and plateaus at 18 weeks of pregnancy

Decreases in the rst half of pregnancy and returns to normal in the second half of gestation. During the rst 20 weeks of pregnancy, a normal value is between 0.5 and 2.5 mIU/L

Increased, mainly driven by increased liver synthesis of cortisol binding globulin (CBG)

Increased by 30% in pregnancy

 

factors that in uence thyroid hormones (TH) status in pregnancy include minor thyrotropic action of human chorionic gonadotro- pin hormone (hCG), higher maternal metabolic rate as pregnancy progresses, in addition to increase in transplacental transport of TH to the fetus early in pregnancy, inactivity of placental type III monodeionidase (which converts T4 to reverse T3), and in mater- nal renal iodine excretion. Although the free fraction of T4 and T3 concentrations declines somewhat during pregnancy (but remains within normal values), these patients remain clinically euthyroid [28, 29]. Thyroid stimulating hormone (TSH) decreases during the rst half of pregnancy secondary to a negative feedback from peripheral thyroid hormones secondary to thyroid gland stimula- tion by hCG. During the rst half of pregnancy, the upper limit of normal value of TSH is 2.5mIU/L (as compared to 5mIU/L in the non-pregnant state).

Serum cortisol levels are increased during pregnancy. Most of this elevation is secondary to increased synthesis of cortisol binding globulin (CBG) by the liver. Free cortisol levels are also increased by 30% during gestation. The endocrine changes during pregnancy are summarized in Table 2.7.

2.8 Summary

Pregnancy is associated with profound changes in human physiol- ogy. Virtually every organ in the body is affected and the clinical consequences of these changes are signi cant. Unfortunately, our knowledge of how these changes affect the pharmacokinetics and

2 Physiologic changes during pregnancy 15

pharmacodynamics of therapeutic agents is still very limited. Fu- ture research involving pharmacokinetics of speci c agents dur- ing pregnancy is desperately needed.

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2 Physiologic Changes During Pregnancy

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[21] Pritchard JA. Changes in the blood volume during pregnancy and delivery. Anesthesiology 1965;26:393–9.

[22] Peck TM, Arias F. Hematologic changes associated with pregnancy. Clin Obstet Gynecol 1979;22:785–98.

[23] Letsky EA. Erythropoiesis in pregnancy. J Perinat Med 1995;23:39–45.
[24] Koller O. The clinical signi cance of hemodilution during pregnancy. Obstet

Gynecol Surv 1982;37:649–52.
[25] Hehhgren M. Hemostasis during pregnancy and puerperium. Hemostasis

1996;26:244–7.
[26] Boden G. Fuel metabolism in pregnancy and in gestational diabetes mellitus.

Obstet Gynecol Clin North Am 1996;23:1–10.
[27] Phelps R, Metzger B, Freinkel N. Carbohydrate metabolism in pregnancy.

XVII. Diurnal pro les of plasma glucose, insulin, free fatty acids, triglycer- ides, cholesterol, and individual amino acids in late normal pregnancy. Am J Obstet Gynecol 1981;140:730–6.

[28] Glinoer D. The regulation of thyroid function in pregnancy: pathways of endo- crine adaptation from physiology to pathology. Endocr Rev 1997;18:404–33.

[29] Glinoer D. What happens to the normal thyroid during pregnancy? Thyroid 1999;9(7):631–5.

Impact of Pregnancy on 3 Maternal Pharmacokinetics
of Medications

Mary F. Hebert

. 3.1  Introduction 17

. 3.2  Effects of pregnancy on pharmacokinetic parameters 18

. 3.3  Summary 34

3.1 Introduction

Variability in drug ef cacy and safety is multi-factorial. Both the pharmacokinetics (how the body handles the drug) and the phar- macodynamics (how the body responds to the drug) play signi – cant roles in drug ef cacy and safety. This chapter will discuss the effects of pregnancy on medication pharmacokinetics.

The physiologic changes that occur during pregnancy result in marked changes in the pharmacokinetics for some medications. Whether or not the physiologic changes will result in clinically signi cant pharmacokinetic changes for an individual medication depends on many factors. The discussion of these factors will be the focus of this chapter. Generally speaking, pharmacokinetic changes are most important clinically for medications with nar- row therapeutic ranges. The therapeutic range includes all the con- centrations above the minimum effective concentration, but less than the maximum tolerated concentration (Figure 3.1A and B). Medications such as cyclosporine, tacrolimus, lithium, lamotrig- ine, gabapentin, levetiracetam, phenytoin, digoxin, vancomycin, and the aminoglycosides are examples of narrow therapeutic range drugs. These are medications for which the concentrations needed for therapeutic bene t are very close to those that result in toxicity.

18 3.2 Effects of pregnancy on pharmacokinetic parameters

 

Figure 3.1 A: Stereotypic oral concentration–time curve. The upper horizontal solid line represents the maximum tolerated concentration and the lower horizontal solid line represents the minimum effective concentration. The therapeutic range for this drug, represented by the vertical double-sided arrow, includes all the concentrations between the minimum effective concentration and the maximum tolerated concentration. B: Stereotypic oral concentration–time curve with the shaded area depicting the area under the concentration–time curve, which is a measure of total drug exposure.

For these agents, small changes in drug concentrations can lead to inef cacy if the concentrations decrease or intolerable toxicity if the concentrations increase. Typically, when drug interactions, dis- ease states or conditions alter the concentration–time pro le for a medication, if no changes have occurred in the pharmacodynamics, the patient’s dosage is adjusted to keep the concentrations similar to those prior to the altered state or similar to those for the popula- tion in which the drug has been approved. This dosage adjustment is done to maintain concentrations within the therapeutic range. For narrow therapeutic range medications, even a 25% change in drug concentration can be considered clinically signi cant. In con- trast, for most medications, which have wide therapeutic ranges, small changes in pharmacokinetics have little to no clinical effect. However, given the magnitude of some of the pharmacokinetic changes that occur during pregnancy in which there can be two- to six-fold changes in drug exposure (Figure 3.2A), even medications that have wide therapeutic ranges can be clinically affected.

3.2 Effects of pregnancy on pharmacokinetic parameters

A change in pharmacokinetics for a medication can result in the need to change dosage. As described above, altered concentrations during pregnancy can result in the need for higher (Figure 3.2A)

3 Impact of pregnancy on maternal pharmacokinetics 19

 

Figure 3.2 A: Concentration–time curves for a CYP2D6 substrate during pregnancy represented by the solid line and in the same subject 3 months postpartum represented by the dotted line. The increase in metabolism that occurs during pregnancy results in two- to six-fold lower AUC for CYP2D6 substrates during pregnancy than in the non-pregnant state in patients given the same dose. B: Concentration–time curves for a CYP1A2 substrate during pregnancy represented by the solid line and in the same subject 10 days postpartum represented by the dotted line. The inhibition of metabolism that occurs during pregnancy results in a higher AUC for CYP1A2 substrates during pregnancy than in the non-pregnant state.

or lower (Figure 3.2B) drug dosage to maintain concentrations within the therapeutic range. The changes in medication phar- macokinetics during pregnancy in some cases are so great that altered medication selection should be considered. For example, oral metoprolol concentrations are two- to four-fold lower during pregnancy than in the non-pregnant state [1, 2]. Given the magni- tude and variability in metoprolol concentrations during pregnan- cy, for those patients that require a beta blocker, selecting another agent such as atenolol, which is renally eliminated, should be con- sidered. Even with the changes in renal function that are expected during pregnancy, atenolol will give much more consistent and reliable drug concentrations in pregnant patients than metoprolol [1–3]. Although there are fetal risks with the utilization of beta blockers during pregnancy, such as intrauterine growth restriction, if a beta blocker is required during pregnancy, selecting an agent that will consistently and reliably achieve the desirable therapeu- tic effect requires consideration of pharmacokinetic changes in medication selection.

The following sections will discuss the commonly estimated pharmacokinetic parameters, their application and how they might

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

20 3.2 Effects of pregnancy on pharmacokinetic parameters

be altered by pregnancy. The actual calculation of these parameters will not be discussed in this chapter. However, the reader is referred to the many publications that discuss in detail the mathematical equations used to determine the pharmacokinetic parameters [4, 5].

3.2.1 Extraction ratio

Extraction ratio (ER) is the fraction of drug that is removed from the blood or plasma as it crosses the eliminating organ (e.g. liver or kidney). Knowing whether a drug has a high (ER >0.7; e.g. morphine, metoprolol, verapamil), intermediate (ER 0.3–0.7; e.g. codeine, midazolam, nifedipine, metformin, cimetidine) or low (ER <0.3; e.g. phenytoin, indomethacin, cyclosporine, amoxicil- lin, digoxin, atenolol) extraction ratio is important in predicting which factors, such as intrinsic clearance, protein binding, and/or blood ow, will alter the pharmacokinetic parameters for the drug.

3.2.2 Area under the concentration–time curve (AUC)

The area under the concentration–time curve is a measure of the overall systemic drug exposure (Figure 3.1B). Since we rarely can measure the drug concentration at the site of action (e.g. brain, lung or heart), blood, plasma or serum concentrations are typical- ly used to determine systemic drug exposure. The AUC is depen- dent on the dose, clearance, and bioavailability of the drug. For some medications, AUC is the key determinant of medication ef – cacy and safety; while for other medications, either the maximum concentration and/or minimum concentration are better corre- lated with outcomes. For low extraction ratio drugs (both oral and intravenous administration), an increase in enzyme activity and/or a decrease in plasma protein binding will lead to a lower total drug AUC with changes in blood ow having no effect. For high hepatic extraction ratio, intravenously administered drugs, a decrease in blood ow will increase the total AUC; whereas, enzyme activity and protein binding have no effect on the total AUC. For high hepatic extraction ratio, orally administered drugs, the decrease in clearance caused by a decrease in blood ow is equal to the decrease in bioavailability such that changes in blood ow have no effect on oral AUC. However, increased enzyme activity or decreased plasma protein binding will decrease the total AUC through their effect on oral bioavailability.

3.2.3 Bioavailability

Bioavailability is the fraction of the dose administered that reaches the systemic circulation unchanged. Sometimes, the bioavailability

3 Impact of pregnancy on maternal pharmacokinetics 21

term is used to encompass both the rate and extent of absorp- tion from the site of administration to the systemic circulation. For orally administered drugs, the bioavailability is affected by the amount of drug that is absorbed across the intestinal epithelium as well as rst pass metabolism as the drug crosses the intestine and liver on its way to the systemic circulation. An increase or decrease in bioavailability directly impacts the oral AUC or total drug expo- sure. For low hepatic extraction ratio drugs, bioavailability is not affected by enzyme activity, hepatic blood ow or protein binding. In contrast, for high hepatic extraction ratio drugs, bioavailability is decreased by an increase in enzyme activity, decreased hepatic blood ow and/or a decrease in plasma protein binding. In addi- tion to the above described changes in enzyme activity, protein binding and blood ow which can alter medication pharmaco- kinetics, other physiologic changes that occur during pregnancy which might in uence the bioavailability of drugs include: gastric acidity, gastrointestinal transit time, and hypertrophy of duodenal villi, which can alter drug absorption [6–9].

3.2.4 Clearance

Clearance is a parameter used to describe how well the body can metabolize or eliminate drug. The clearance directly affects total drug exposure as well as average steady state drug concentrations and is utilized to determine maintenance dosage. There are three major determinants of hepatic drug clearance: hepatic blood ow, protein binding, and the intrinsic activity of hepatic drug metab- olizing enzymes. Hepatic blood ow plays an important role in determining the hepatic clearance of drugs, particularly those with high extraction ratios. Physiologic, pathologic, and drug-induced changes in hepatic blood ow can alter the systemic clearance and oral bioavailability of many important therapeutic agents, re- sulting in changes in patient response. For high hepatic extraction ratio drugs, clearance is directly affected by hepatic blood ow such that an increase in blood ow will increase clearance. The rate-limiting step for metabolism of high hepatic extraction ratio drugs is the delivery of the drug to the liver. Visualizing this pro- cess in which everything that is delivered to the eliminating organ, such as the liver, will be cleared from the body can be helpful. This process will proceed so that the faster the drug is delivered to the eliminating organ, the faster the drug is eliminated from the body.

In contrast, for low extraction ratio drugs, the rate-limiting step is not blood ow; therefore, a change in organ blood ow does not alter clearance. Instead, clearance is affected by the enzyme activity and protein binding, such that an increase in enzyme activity or a decrease in protein binding will increase the drugs’

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

22 3.2 Effects of pregnancy on pharmacokinetic parameters

total clearance. For intermediate extraction ratio drugs, clearance will be dependent on changes in enzyme activity, protein binding, and organ blood ow.

3.2.5 Protein binding

As described above, plasma protein binding can affect the phar- macokinetics of medications. There are multiple issues to con- sider with regards to protein binding of medications. Some of the plasma proteins are known to be altered both in normal preg- nancy as well as pathologic conditions [10]. In normal pregnancy, albumin concentrations decrease on average by approximately 1% at 8 weeks, 10% at 20 weeks, and 13% at 32 weeks [11]. In preg- nant patients with pathologic conditions, albumin concentrations can be substantially lower. Changes in albumin concentrations are important for many medications (e.g. phenytoin, valproic acid, car- bamazepine). Other plasma proteins such as α-1-acid glycoprotein are involved in binding of drugs like betamethasone, bupivacaine, lopinavir, and lidocaine. Plasma α-1-acid glycoprotein has been reported to be 52% lower in late pregnancy (30–36 weeks’ gesta- tion) than postpartum (2 to 13 weeks) [12]. In addition, some agents (e.g. cyclosporine, tacrolimus) concentrate within the red blood cells. For these agents, binding might be altered as a result of anemia during pregnancy. Hematocrits are known to fall during normal pregnancy by 2% at 8 weeks and 4% at 20–32 weeks [11]. Some medications, disease states or conditions during pregnancy can lead to severe anemia, which would be expected to have a much greater effect on binding of these medications.

Drug binding is important for many reasons. The rst reason is that the unbound drug is in equilibrium with the site of action and is therefore considered the active moiety as well as being able to cross membranes including the placenta. Unbound drug will cause not only bene cial effects, but also potentially toxic effects. For drugs that are highly bound to albumin, such as phe- nytoin, these changes in albumin during pregnancy can be associ- ated with alterations in protein binding. Yerby et al. reported a signi cant increase in the percent of unbound phenytoin during the second and third trimesters of pregnancy as well as labor and delivery as compared to the pre-pregnancy state [13]. This is par- ticularly important clinically because phenytoin is a highly protein bound drug with a narrow therapeutic range, which undergoes therapeutic drug monitoring.

The second reason is that understanding protein binding is critical in the interpretation of total drug concentrations. For phenytoin, when interpreting total drug concentrations, knowing

3 Impact of pregnancy on maternal pharmacokinetics 23

whether protein binding has been altered or not is critical. Figure 3.3A illustrates that the total concentration for the drug in plasma is measured to be 10, and the unbound concentration is 1. In contrast, in Figure 3.3B the total drug concentration is 5, but the unbound concentration is still 1. In this example, although the total concentration is reduced in half, since the unbound concen- tration is still the same, no dosage adjustment should be made clinically because the active form of the drug (unbound concen- tration) is the same. This would be expected to occur if there was a change in protein binding and no change in enzyme activity, leading to a change in total clearance, but no change in unbound clearance. This scenario can occur with phenytoin, in which the total drug concentration is lower but no dosage adjustment is needed because the unbound concentration has not changed.

An alternate situation could occur in which there is no change in total clearance, but a change in protein binding, leading to no change in total drug concentration, but an increase in unbound drug concentration and toxicity. So it is critical in the case of high- ly bound drugs with narrow therapeutic ranges either to measure the unbound concentration or to mathematically account for the changes in protein binding if total concentrations are measured, such as in pregnant patients with low albumin concentrations. If protein binding is not accounted for and the total drug con- centration is measured in a patient with an increase in the fraction unbound, when there is no change in unbound clearance, the

Figure 3.3 A: Drug with a total plasma concentration of 10, unbound concentration of 1, and bound concentration of 9. It is the unbound drug that is in equilibrium with the bound drug and is available to cross membranes and get to the site of action. B: Drug with a total plasma concentration of 5, unbound concentration of 1, and bound concentration of 4. Although the total drug concentrations are 50% in B compared to the example in A, in both cases, the unbound or active form of the drug are the same. A and B are adapted with permission from gures included in reference (4).

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

24 3.2 Effects of pregnancy on pharmacokinetic parameters

total concentration will be lower but the dosage should not be adjusted. If the clinician does not account for the altered protein binding and increases the dose, the patient might develop drug toxicity.

The physiologic changes that occur during pregnancy can trans- late into changes in multiple pharmacokinetic parameters that can alter the interpretation of drug concentrations. For example, you often have changes in both protein binding and unbound clearance during pregnancy, as is the case with phenytoin. These patients require consideration of both factors in interpreting the implications of total phenytoin concentrations. It is important to note that not all highly protein bound drugs have increased percent unbound during pregnancy. Some highly protein bound drugs such as midazolam and glyburide have little to no change in protein binding during pregnancy, but signi cant changes in their clearance [10, 14].

3.2.6 Organ blood ow

Changes in hepatic and renal blood ows can alter drug clearance. As described above, changes in organ blood ow are particularly important for high extraction ratio drugs. During pregnancy, car- diac output is markedly increased, which potentially can increase organ blood ow. On average, during normal pregnancies, car- diac output has been reported to be 35% increased in the second trimester and 40% increased in the third trimester as compared to postpartum [15]. One would suspect that the increased car- diac output during pregnancy may result in changes in hepatic blood ow. In non-septic critically ill patients, there is a good correlation (r=0.92) between cardiac output and effective hepat- ic blood ow [16]. In an animal model of reduced cardiac out- put, there was an associated decrease in portal venous ow [17]. Unfortunately, there is limited information available evaluating the effects of pregnancy on hepatic blood ow. Nakai et al. [18] stud- ied the effects of pregnancy on hepatic arterial and portal venous blood ows during the rst trimester of pregnancy (n = 13), second trimester (n=25), third trimester (n=29), and in non- pregnant women (n=22). They found an increase in total liver blood ow (2.98 ± 1.13 L/min, p < 0.05) and portal vein blood ow (1.92 ± 0.83 L/min, p < 0.05) during the third trimester of pregnan- cy as compared to the non-pregnant women (1.82±0.63L/min and 1.25±0.46L/min, respectively). Rudolf et al. [19] reported indocyanine-green clearance in 16 women with hyperemesis grav- idarum with all but one subject within the upper limit of normal. Robson et al. [20] found no change in hepatic blood ow in 12

3 Impact of pregnancy on maternal pharmacokinetics 25

women at 12–14 weeks’, 24–26 weeks’, and 36–38 weeks’ gesta- tion as compared to 10–12 weeks after delivery. Probst et al. [21] conducted a study in seven healthy pregnant women during labor and delivery and compared them to non-pregnant controls. They found that hepatic blood ow was decreased to 70% of the control value during labor. All of the studies were underpowered and in most cases did not have the pregnant women serve as their own control. At this point, it is unclear whether hepatic blood ow is increased or unchanged during pregnancy.

In contrast, pregnancy is associated with increased renal ltra- tion, creatinine clearance, and renal clearance of drugs [3, 10, 22, 23]. During normal pregnancy, effective renal plasma ow increases on average 50–85%, with a corresponding 50% increase in glomerular ltration rate [24, 25]. Because the estimated tubu- lar extraction ratio for metformin is moderately high, the gesta- tional changes in the metformin’s net secretory clearance can in part be explained by enhanced renal plasma ow [26].

3.2.7 Intrinsic clearance

The intrinsic clearance generally refers to the liver’s inherent ability to metabolize drug. It is a term used to describe enzyme activity and is independent of protein binding and hepatic blood ow.

3.2.8 Metabolism

Drug metabolism is the conversion of one chemical structure to another. The formation of metabolites often occurs via drug me- tabolizing enzymes. There are many drug metabolizing enzymes involved in both phase I (e.g. CYP3A4, CYP3A5, CYP2D6, CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CY- P2A6, CYP2B6, esterases, epoxide hydrolase, dihydropyrimidine dehydrogenase, alcohol dehydrogenase) and phase II (e.g. UDP glucuronyltransferase, sulfotransferase, methyltransferase, N-acetyltransferase, catechol-O-methyltransferase, thiopurine S-methyltransferase, histamine methyltransferase, glutathione S-transferase) metabolism. Phase I metabolism usually precedes phase II metabolism, but not always. Phase I reactions typically include: oxidation, reduction, hydrolysis, cyclization and decy- clization reactions. Phase II reactions involve conjugation with glucuronic acid, sulfate, glutathione or amino acids. Occasionally, there is back conversion of metabolites to the parent compound. For some medications that are administered as inactive com- pounds (prodrugs), metabolism is necessary to convert the drug to active compound.

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

26 3.2 Effects of pregnancy on pharmacokinetic parameters

As described above, many different drug metabolizing enzymes exist. The enzyme involved in the metabolism of a drug is depen- dent on the chemical structure of the agent. For some medica- tions, only one enzyme is involved in the metabolism. For other drugs, multiple enzymes with differing af nities are involved in the formation of the metabolites. One method that has been used to evaluate the effects of pregnancy on drug metabolizing enzymes is to use probe substrates as markers for enzyme activ- ity. A probe substrate is a drug that is primarily metabolized by a single enzyme. The drug is administered and a pharmacokinetic study is completed. From this, drug clearance, urinary excretion of metabolite, metabolite formation clearance, area under the concentration–time curve or metabolite to parent concentration ratio are used as surrogate markers for enzyme activity. The dis- cussion below will describe the effects of pregnancy on key drug metabolizing enzymes.

3.2.8.1 CYP3A

CYP3A is responsible for the metabolism of more drugs than any other P450 enzyme. Examples of CYP3A substrates can be found in Table 3.1. Midazolam is one of the “gold standard” probes for CYP3A activity. We conducted a study evaluating the effect of pregnancy on CYP3A activity utilizing midazolam as the probe drug. Mean midazolam area under the concentration–time curve and maximum concentration were markedly lower during preg- nancy than postpartum. This corresponded to an average of 108% increase in midazolam apparent oral clearance and 123% increase in 1′-hydroxymidazolam formation clearance during pregnancy as compared to postpartum. Apparent oral unbound midazolam clearance and unbound 1′-hydroxymidazolam forma- tion clearance were on average 86% and 99% higher, respective- ly, in pregnancy than postpartum [10]. Other CYP3A substrates (dextromethorphan N-demethylation, nel navir, indinavir) have also been studied during pregnancy. N-demethylation of oral dextromethorphan was increased by 35–38% during pregnancy [27]. Similarly, nel navir was reported to have a 25–33% increase in apparent oral clearance in pregnancy [28, 29]. Interestingly, indinavir has an approximately three-fold lower average AUC in pregnancy than postpartum [30]. These data are consistent with increased CYP3A activity during pregnancy as compared to the non-pregnant state.

Because CYP3A is involved in the metabolism of many medica- tions, this nding has clinical implications for medication dosages during pregnancy. In particular, CYP3A substrates with narrow therapeutic ranges may fall below effective concentrations during

3 Impact of pregnancy on maternal pharmacokinetics 27 Table 3.1 Cytochrome P450 substrate examples

CYP3A

CYP2D6

CYP2C9

CYP2C19

CYP1A2

Alfentanil Alprazolam Amlodipine Amprenavir Buspirone Chlorpheniramine Citalopram Cyclosporine Dapsone Diltiazem Efavirenz Erythromycin Felodipine Fentanyl

Indinavir Isradipine Itraconazole Lidocaine Loratidine Methadone Midazolam Nel navir Nicardipine Nifedipine Oxycodone Simvastatin Sirolimus Tacrolimus Zolpidem

Alprenolol Amitriptyline Clomipramine Codeine Debrisoquine Dextromethorphan Doxepin Flecainide Fluoxetine Fluvoxamine Haloperidol Hydrocodone Imipramine Metoprolol Mexiletine Nortriptyline Paroxetine Promethazine Propafenone Propranolol Resperidone Thioridazine Tolterodine Venlafaxine

Diclofenac Flubiprofen Glipizide Glyburide Ibuprofen Losartan Naproxen Omeprazole Phenytoin Piroxicam Sulfamethoxazole Tolbutamide Voriconazole Warfarin

Citalopram Clopidogrel Escitalopram Esomeprazole Mephenytoin Omeprazole Proguanil Sertraline

Caffeine Clozapine Lidocaine Olanzapine Ondansetron Ramelteon Ropivacaine Theophylline Triamterene

pregnancy if dosage adjustments are not made. When CYP3A substrates are initiated during pregnancy and titrated to response, dosage reductions might be needed postpartum to avoid toxicity.

3.2.8.2 CYP2D6

CYP2D6 is responsible for the metabolism of the second highest number of drugs metabolized by P450 enzymes. Substrates for CYP2D6 can be found in Table 3.1. CYP2D6 is a particularly chal- lenging enzyme to understand and study because of its genetic polymorphism. Genetic variation for this enzyme can result in some patients having no enzyme, some having a low amount of enzyme activity with only one active allele, some having two active alleles, and some having duplicate genes. Clinically, these

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

28 3.2 Effects of pregnancy on pharmacokinetic parameters

genetic differences result in poor, extensive, and ultra metaboliz- ers for CYP2D6 substrates. Interestingly, CYP2D6 is not an induc- ible enzyme by known, classic mechanisms for enzyme induction. So the apparent increase in CYP2D6 activity described below is surprising and the mechanism by which it occurs is unknown.

Metoprolol is the “gold standard” probe for CYP2D6 activity. In a small study, oral metoprolol AUC was reported to be two- to four- fold lower during pregnancy than in the non-pregnant population [1, 2]. Other CYP2D6 substrates have also been studied during pregnancy. For example, dextromethorphan is primarily a CYP2D6 substrate (although its N-demethylation occurs via CYP3A as described above). Utilizing dextromethorphan as a CYP2D6 probe, Tracy et al. [27] reported an increase in CYP2D6 activ- ity by ~25% at 14–18 weeks’ gestation, ~35% at 24–28 weeks’ gestation, and ~50% at 36–40 weeks’ gestation. In addition, we have found clonidine to primarily be a CYP2D6 substrate [31]. The mean apparent oral clearance of clonidine is approximately 80% higher in pregnant women compared with the non-pregnant population. Of note, in the non-pregnant population, clonidine is primarily renally eliminated. However, only 36% of the cloni- dine was excreted unchanged in the urine in pregnancy compared with 59% in the non-pregnant population [32–35]. Interestingly, the increase in CYP2D6 activity during pregnancy is so great that the major pathway for elimination for clonidine switched from primarily renal to primarily metabolic.

3.2.8.3 CYP2C9

CYP2C9 is involved in the elimination of approximately 10% of the metabolized drugs from the list of top 100 drugs by US sales. Substrates for CYP2C9 can be found in Table 3.1. CYP2C9 is the primary metabolic pathway for phenytoin elimination. Because of the high protein binding for phenytoin, when considering phe- nytoin as a probe for CYP2C9, utilizing free phenytoin clearance is important given the known changes in phenytoin protein bind- ing during pregnancy. CYP2C9 activity as measured by free phe- nytoin clearance is increased ~1.5-fold during all three trimesters of pregnancy as compared to the pre-pregnant state [13].

Glyburide is another agent that is metabolized by CYP2C9, although CYP3A and CYP2C19 are also involved in its metabo- lism in vitro [36–38]. In vivo, glyburide appears to be a CYP2C9 substrate in the non-pregnant population [39–42]. At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnant compared to non-pregnant women [14]. The large ges- tational increase in unbound glyburide CL/F and unbound for- mation clearance of the primary metabolite 4-trans OH-glyburide

3 Impact of pregnancy on maternal pharmacokinetics 29

(>two-fold increase) suggest that higher dosages may be needed during pregnancy. The gestational increase in unbound glyburide CL/F most likely re ects induction of CP2C9 and CYP3A, since these activities have been previously shown to be increased (and CYP2C19 activity decreased) during pregnancy [10, 13, 43].

3.2.8.4 CYP1A2

CYP1A2 is involved in the metabolism of fewer drugs than the enzymes previously discussed. However, some agents that are substrates for CYP1A2 are being used more and more frequently during pregnancy, such as ondansetron (Table 3.1). A commonly used probe substrate for CYP1A2 activity is caffeine. The activ- ity of CYP1A2 as determined by caffeine clearance is reported to be decreased by approximately 30% at 14–18 weeks’ gestation, 50% at 24–28 weeks’ gestation, and 70% at 36–40 weeks’ gesta- tion [27]. The apparent decrease in CYP1A2 activity potentially could result in increased toxicity for CYP1A2 substrates. This is in contrast to the effect seen with CYP3A, CYP2D6, and CYP2C9, which all have markedly increased activities during pregnancy and potentially will result in decreased drug ef cacy.

3.2.8.5 CYP2C19

Substrates for CYP2C19 can be found in Table 3.1. Similar to CYP1A2, CYP2C19 activity appears to be inhibited during preg- nancy. The ratio of proguanil to cycloguanil has been utilized as a probe for CYP2C19 activity. Although no signi cant changes are seen in CYP2C19 activity during pregnancy in poor metaboliz- ers, in extensive metabolizers there is a doubling in the plasma ratio of proguanil to cycloguanil 6 hours after dosing when com- paring women in their third trimester of pregnancy to women 2 months postpartum, suggesting a decrease in CYP2C19 activity in late pregnancy [43]. In light of these data, monitoring for medica- tion toxicity and perhaps lower dosages for CYP2C19 substrates during pregnancy warrants consideration.

3.2.8.6 UGT1A4

UDP glucuronyltransferase 1A4 (UGT1A4) is a non-P450 enzyme involved in phase 2 metabolism. UGT1A4 metabolizes agents to gluc- uronide conjugates. There are many substrates for UGT1A4 such as amitriptyline, doxepin, imipramine, lamotrigine, and promethazine [44, 45]. The increase in UGT1A4 activity starts in the rst trimester of pregnancy and is reported to return to pre-pregnancy baseline by 2–3 weeks postpartum. The clearance of lamotrigine has been reported to increase by 65% during pregnancy [46]. The increase in clearance translates to lower concentrations during pregnancy and

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

30 3.2 Effects of pregnancy on pharmacokinetic parameters

potential for a decrease in ef cacy. Consistent with this, an increase in seizure frequency during pregnancy along with a decrease in la- motrigine concentration to dose ratio by ~50% between 11 weeks’ gestation and term has been reported [47].

3.2.9 Renal

Almost one-third of the medication on the top 100 drugs list by US sales is primarily eliminated by the kidneys. During normal pregnancy, creatinine clearance increases by 45% at 9 weeks’ gestation, and peaks in the mid-second trimester at 150–160% of non-pregnant values. In some women, clearances will decline over the last 6 weeks of pregnancy. Occasionally, creatinine clear- ance will return to the non-pregnant state over the last 3 weeks of pregnancy [22, 23]. Pregnancy has been reported to induce chang- es in tubular secretion of endogenous compounds such as glucose and amino acids [24]. Understanding and accounting for changes in kidney function during pregnancy is important for optimizing dosage for renally eliminated medications.

3.2.9.1 Filtration

Changes in renal ltration as measured by creatinine clearance during pregnancy have been associated with changes in the re- nal clearance of many medications [3, 10, 26, 48]. In some, but not all, cases these changes will require dosage adjustments dur- ing pregnancy. For example, changes in digoxin concentrations during pregnancy often require dosage adjustments to maintain therapeutic concentrations. On average, digoxin renal clear- ance increases 61% during pregnancy compared to 6–10 weeks postpartum [10]. There is a good correlation (r=0.8) between creatinine clearance and digoxin renal clearance [10]. Even though digoxin also has an active transport component to its renal elimination, the change in creatinine clearance appears to be a good surrogate marker for the expected change in digoxin renal clearance during pregnancy due to the large fraction of digoxin renal clearance accounted for by ltration compared to net secretion [10].

Metformin is eliminated almost entirely unchanged in the urine. In mid- and late pregnancy, metformin renal clearance increases on average by 49 and 29%, respectively, compared to 3–4 months postpartum. The change in renal clearance parallels the 29 and 21% increase in creatinine clearance during mid- and late preg- nancy reported in the same study [26]. There are currently not enough data to determine if dosage increases for metformin are needed during pregnancy.

3 Impact of pregnancy on maternal pharmacokinetics 31

Atenolol is another drug that is primarily eliminated unchanged in the urine. Pregnancy as compared to 3 months postpartum results in signi cant increases in creatinine clearance, 42 and 50% in the second and third trimesters, respectively, and in atenolol renal clearance, 38 and 36% in the second and third trimesters, respectively. There is a very good correlation (r=0.7) between creatinine clearance and atenolol renal clearance [3]. However, changes in atenolol renal clearance during pregnancy do not translate into clinically signi cant changes in apparent oral clear- ance and therefore dosage adjustments are not necessary based on pharmacokinetic changes. However, changes in hemodynam- ics and pharmacodynamics over the course of gestation may result in the need for dosage adjustments for atenolol during pregnancy.

3.2.9.2 Secretion/Reabsorption

P-glycoprotein and organic anion transporter polypeptides

Digoxin has been considered the “gold standard” probe for P-glycoprotein activity because it mediates secretion of digoxin across the apical membrane of the renal tubular epithelium [49, 50]. However, other renal transporters are also involved in the net secretion of digoxin. There is evidence that digoxin is a substrate for organic anion transporter polypeptides (OATPs) [51, 52]. Hu- man OATP4C1 (SLCO4C1) plays a primary role in the transport of digoxin on the basolateral membrane of the kidney [53]. Thus, digoxin renal tubular secretion appears to be a serial transport process mediated by P-glycoprotein and OATP. Although glomer- ular ltration rate increases during pregnancy, this increase does not completely explain the increased renal clearance of digoxin. Digoxin secretion clearance was 120% higher during pregnancy as compared to postpartum. Unbound digoxin secretion clearance was higher (on average 107%) during pregnancy than postpartum [10]. The doubling of digoxin net renal secretion clearance is con- sistent with an increase in P-glycoprotein renal activity, but may also be explained by an increase in renal OATP activity during pregnancy.

Organic anionic transporter, oligopeptide transporters

The transporters involved in renal transport of amoxicillin are still being worked out. In vivo studies with amoxicillin and pro- benecid (inhibitor of the renal organic anion transport system) have shown that the renal clearance of amoxicillin is signi cantly reduced by probenecid, suggesting that amoxicillin is a substrate for an organic anion transporter [54]. The oligopeptide transport- ers hPepT1 and hPepT2 are located on the apical membrane of the proximal tubule and are involved in reabsorption of endogenous

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

32 3.2 Effects of pregnancy on pharmacokinetic parameters

peptides [55]. Amoxicillin is an inhibitor and substrate for hPepT2 transport with a lower af nity for hPepT1 [56]. In both the sec- ond and third trimesters of pregnancy, the renal clearance and net renal secretion of amoxicillin are increased by more than 60 and 50%, respectively [48]. Renal secretion makes up more than half of the renal clearance for amoxicillin. The change in net renal secretion clearance may be a result of increased renal secretion, inhibition of reabsorption or both.

Organic cation transporters, multidrug and toxic compound extrusion transporter, and plasma monoamine transporter Metformin is a substrate for OCTs, including OCT1, OCT2, the multidrug and toxic compound extrusion transporter (MATE) [57], and the plasma membrane monoamine transporter (PMAT) [58]. In humans, OCT2 plays an important role in metformin renal clear- ance [59–61]. Several studies in vitro and in animal species suggest that Oct2 expression and activity in the kidney can be regulated by the steroid hormones [62–64]. Metformin secretion clearance was on average 45 and 38% higher in mid- and late pregnancy than postpartum [26]. Metformin renal clearance correlates well with creatinine clearance (r=0.8), but even better with its net tubular secretion clearance (r=0.97), which is not surprising given metfor- min’s high secretory clearance [26]. The increase in metformin net secretory clearance could in part be a result of upregulation in the renal tubular transport (i.e. OCT2 activity). Further research is nec- essary to determine which transporters are affected by pregnancy and the mechanism underlying these changes.

pH-dependent changes in secretion and reabsorption

Although the tendency is to assume that all drugs that are pre- dominantly eliminated by the kidneys in the non-pregnant popu- lation will remain as such in the pregnant population, this is not always the case. For example, clonidine is a drug that is ~65% eliminated unchanged in the urine in the non-pregnant popula- tion with dosage adjustment recommendations for patients with renal disease. Therefore, it is reasonable to assume that the increase in creatinine clearance expected during pregnancy would increase the renal clearance of clonidine. However, even though the patients in our study had an increase in creatinine clearance during pregnancy, there was no change in clonidine renal clear- ance and a poor correlation (r=0.26) between clonidine renal clearance and creatinine clearance. In fact, the primary pathway for elimination of clonidine during pregnancy switches from renal to metabolic. The explanation for the discrepancy between changes in creatinine clearance and clonidine renal clearance during

3 Impact of pregnancy on maternal pharmacokinetics 33

pregnancy is related to the chemical properties of clonidine. Cloni- dine’s pKa is 8.05, which resulted in a strong correlation (r=0.82, p<0.001) between clonidine renal clearance, corrected for GFR, and urine pH (range 5.8–7.5) [32]. This example is a reminder that it is dif cult to predict the effects of pregnancy on the pharmacoki- netics of medications and that each medication requires evaluation.

3.2.10 Volume of distribution

Volume of distribution is not a physical space, but rather an ap- parent one. Volume of distribution is the apparent volume needed to account for the total amount of drug in the body if the drug was evenly distributed throughout the body and in the same concentration as the site of sample collection such as peripheral venous plasma. Some drugs (e.g. tolbutamide, phenytoin, genta- micin, warfarin) are known to have small volumes of distribution (0.1–1L/kg) while others (e.g. meperidine, propranolol, digoxin) are known to have large volumes of distribution (1–10 L/kg). The volume of distribution for a drug affects the difference between peak and trough concentrations at steady state or maximum con- centrations for single intravenous bolus dosing. The volume of distribution can be used to determine the loading dose needed to achieve a certain concentration.

There are many physiologic changes that occur during preg- nancy that can result in altered volume of distribution for medica- tions. For example, the recommended total weight gain during a singleton pregnancy depends on the BMI and stature of the preg- nant woman, but ranges from 6 to 18kg. Despite the recommen- dations, many women will exceed these weight gain guidelines. Of the weight gained, approximately 62% will be water, 30% will be fat, and 8% will be protein. Blood volume typically increases 30–45% and peaks between 28 and 34 weeks’ gestation. Total body water increases 6–8 liters during pregnancy and peaks at term [65]. Increases in the volume of distribution for a medica- tion will not alter the average steady state concentration, but will result in lower peak and higher trough concentrations. Apparent volume of distribution is dependent on the drug’s lipid or water solubility, plasma protein binding as well as tissue binding. Met- formin has a larger apparent oral volume of distribution during pregnancy than in women 3–4 months postpartum [26].

3.2.11 Half-life

Half-life is the time it takes for the drug concentration to be reduced in half and is useful in determining dosing frequen- cy. Half-life is dependent on both clearance and volume of

3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

34 3.3 Summary

distribution, such that a decrease in clearance, as might be seen with a CYP1A2 or CYP2C19 substrate, or an increase in volume of distribution will prolong the half-life and lead to a longer dos- age interval. Medications with increased clearance (e.g. CYP3A, CYP2D6 or CYP2C9 substrates or those eliminated by the kid- neys) or decreased volume of distribution will have shorter half- lives and require more frequent dosing. Since half-life is dependent on both clearance and volume of distribution, if there is a similar increase in both clearance and volume, there will be no change in the half-life for the drug as is the case for midazolam and meto- prolol [1, 2, 10]. Although the changes in renal function during pregnancy are small relative to the magnitude of change seen with some of the hepatic enzymes, altered renal function can change the pharmacokinetics of some medications. We found that both renally eliminated drugs, atenolol and amoxicillin, have shorter half-lives during the second and third trimesters of pregnancy compared to the same women 3 months postpartum, although these changes were relatively small [3, 48]. In contrast, metfor- min, which is also eliminated by the kidneys, has a longer half-life in the second trimester of pregnancy than women 3–4 months postpartum, re ecting the increase in volume of distribution seen during pregnancy [26].

3.3 Summary

There is a tremendous amount of variability in patient response to medications during pregnancy. In part, this variability can be explained by changes in pharmacokinetics. The medication’s chemical and pharmacokinetic characteristics in uence the type of effect pregnancy can have on drug handling and response. Changes in protein binding are most important for highly pro- tein bound drugs and should be taken into account when inter- preting total drug concentrations. Hepatic blood ow will affect the hepatic clearance of high extraction ratio drugs. Medications that are eliminated by the kidneys as well as those metabolized by CYP3A, CYP2D6, CYP2C9, and UGT are likely to undergo increased clearance during pregnancy. Those metabolized by CYP1A2 and CYP2C19 might have decreased clearance during pregnancy. The physiologic changes that occur during pregnancy can have signi cant impact on medication pharmacokinetics, dosage, and selection. Taking into account the pharmacokinet- ic changes that occur during pregnancy will help to minimize the variability in patient response. This approach is particularly

3 Impact of pregnancy on maternal pharmacokinetics 35

important for medications with narrow therapeutic ranges. Phar- macokinetic changes should be taken as only one component in determining optimum medication selection and dosage.

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3 Impact of Pregnancy on Maternal Pharmacokinetics of Medications

Medications and the 4 Breastfeeding Mother

Cheston M. Berlin, Jr.

. 4.1  Medication use by the breastfeeding mother 41

. 4.2  Clinical pharmacology of drug transfer into breast
milk 42

. 4.3  During delivery 42

. 4.4  General anesthesia 43

. 4.5  Epidural anesthesia 44

. 4.6  Galactogogues 45

. 4.7  Immediate postpartum period 45

. 4.8  Pain 46

4.9 4.10

4.11 4.12

4.13

4.14 4.15

Methadone 47

Resumption of pre- pregnancy medications 47

Psycho- and neurotropic drugs 48

Drugs not to give to the nursing mother
postpartum 49

Oral contraceptives
(OCPs) 49

Summary 50

Where to nd
information 50

4.1 Medication use by the breastfeeding mother

Mothers may need medication both during and after preg- nancy. In both cases it is important not only to protect the infant, but also to provide the mother with necessary drug treatment. The infant may be born having been exposed to maternal medication during gestation. It is important to re- member, in addition to drug exposure of the infant during breastfeeding, that previous exposure during pregnancy may potentiate any adverse effects during lactation. This would

42 4.3 During delivery

especially be true in the immediate postnatal period, but for some drugs, the window of adverse reactions in the infant may be longer (e.g. antidepressants).

4.2 Clinical pharmacology of drug transfer into breast milk

The determining factors for the transport of drugs from maternal circulation to the alveolar lumen in the mammary cell are: [1] mo- lecular weight, [2] binding to maternal plasma proteins, [3] lipid solubility, and [4] degree of ionization. Drugs which are trans- ferred most rapidly and/or in the highest amount are those with high lipid solubility, no electrical charge, low molecular weight, and low or no binding to maternal plasma proteins. There are four diffusion mechanisms for drug transfer into the mammary cell al- veolar lumen: transcellular, intercellular, passive and inophore (transfer of polar compounds bound to carrier proteins) [1]. Tran- scellular diffusion probably accounts for most drug transfer. The intercellular diffusion route, which avoids the interior of the cell, may account for the appearance in milk of high molecular weight compounds such as immunoglobulins (from maternal plasma) and monoclonal antibody drugs such as etanercept (Enbrel®, molecu- lar weight 52,000). High molecular weight compounds do appear in milk. Most obvious are antibodies from maternal plasma. Many of the newer pharmacological agents are high molecular weight entities such as monoclonal antibodies. For drugs like etanercept, the amount appearing in milk is extremely small (2–5ng/mL) compared to the maternal serum level of 1450 to 2000ng/mL [2]. Such a small amount of a protein is most likely pharmacologically inactive both because of the extremely small dose, and also be- cause of lack of absorption from the infant’s gastrointestinal tract. Because virtually all drugs of a molecular weight below 200 or 300 daltons will cross into milk, the dose that the child receives (con- centration×volume) is usually pharmacologically insigni cant. For most drugs, less than 1–2% of the maternal dose is potentially available to be excreted into breast milk [3].

4.3 During delivery

The obvious concern in this period of time is the type and anes- thesia/analgesia that the mother may have received. This drug

4 Medications and the breastfeeding mother 43

exposure may delay the onset of lactogenesis, may affect the mother’s mentation and ability to nurse, and the infant may show effects from transplacental transfer that interfere with latch and ingestion. An important concept is that regardless of the type of anesthesia and/or analgesia used after delivery, the amount of any agent potentially transferred to the infant would be less than the amount transferred during labor and delivery via the placenta.

4.4 General anesthesia 4.4.1 Volatile anesthetic agents

There are very little data on the concentration of these com- pounds in human milk. This is due to rapid washout after admin- istration and by the time the mother wakens to nurse her infant, her plasma levels are very low or absent.

4.4.1.1 Halothane

There are no published reports measuring the amount of halo- thane in milk after general anesthesia to the mother. It has been reported that patients can exhale measurable amounts of halo- thane for 11 to 20 days after anesthesia [4]. A female anesthesi- ologist had levels of 2 ppm of halothane in her milk after working in an operating room for up to 5 hours [5]. Because of this obser- vation, it is reasonable to assume that it would appear in the milk of a mother administered halothane for a cesarean section or any post-delivery complication.

4.4.1.2 Des urane and sevo urane

These two inhalation anesthetic agents are highly uorinat- ed and not very soluble in fat and other peripheral tissues. Thus induction and recovery are rapid. Although there are no reports of measurement of these two compounds in milk, the levels are very likely to be low or absent because of very low fat solubility.

4.4.2 Intravenous anesthetic agents

4.4.2.1 Ketamine

There are no reports of the measurement of ketamine in the milk of postpartum women. The half-life of ketamine is about 3 hours, so that permitting a mother to breastfeed several

4 Medications and the Breastfeeding Mother

44 4.5 Epidural anesthesia
hours after delivery would expose the infant to extremely small

amounts of this drug.

4.4.2.2 Propofol

This drug is a lipid and must be administered to the mother via a lipid emulsion. The half-life of the drug is about 2 hours. The amounts found in milks are very low – usually 1mg/L of milk or less [6]. Such low amounts would be unlikely to be absorbed by the nursing infant.

4.4.2.3 Etomidate

Concentrations of etomidate in milk are very low (less than 1mg/L) and absent 4 hours after administration. Maternal half- life is about 3 hours [7].

4.4.2.4 Thiopental

Concentrations of thiopental in milk are usually 2 mg/dL or less depending on the time of sampling after intravenous adminis- tration to the mother. Serum concentrations usually decline to less than 1 mg/dL after 4 hours from the last dose [7]. One study compared the excretion of thiopental in both breastfed and non-breastfed infants and found no difference in the amount excreted [8]. It is unlikely that the breastfed infant would re- ceive a signi cant amount of thiopental by the time lactation is established. This drug has been the subject of much debate because of its use as a component in lethal injection for capital punishment. It has not been manufactured in the USA since 2009 and its importation from foreign suppliers is a source of litigation.

4.4.3 A general statement

It is interesting to speculate on whether initial dif culty in breastfeeding (especially poor latch) may be due to residual general anesthetics (either inhalation or intravenous) in breast milk. It is safe for mother (and infant) to start or resume breast- feeding as soon as she emerges from a general anesthetic agent [9, 10].

4.5 Epidural anesthesia

The usual anesthetic agents employed in epidural anesthesia are bupivacaine or ropivacaine. The opioid fentanyl is frequently

4 Medications and the breastfeeding mother 45

added to the injection uid. These local anesthetic agents provide rapid onset of pain relief and when used in the usual concentrations do not cause signi cant loss of muscle power. They are both highly bound to maternal plasma protein and hence transfer to milk is limited. Two recent, prospective, ran- dom allocated studies did not show any appreciable difference in breastfeeding between groups receiving epidural anesthesia with a local anesthetic and/or with fentanyl [11, 12]. There was a suggestion that women receiving only meperidine did have a lower rate of successful breastfeeding. Chang and Heaman reported on 53 women receiving either ropivacaine or bupiva- caine for an average infusion time of 3.5 hours. There was no ef- fect on neurobehavior including breastfeeding when compared to a group that received no anesthesia [13]. Both of these local anesthetic agents are poorly, if at all, absorbed from the gastro- intestinal tract, so that even if a small amount was present in milk, the infant should not be affected. Rosen and Lawrence studied 83 mother–child pairs and found no difference between breastfed and bottle-fed infants on the ability to feed or initial weight loss [14].

4.6 Galactogogues

Several drugs and many dietary supplements have been tried to improve lactation both in initiation of milk formation and increase in milk supply. There are no studies which can con- rm that any of these substances are effective [15, 16]. Mothers should be advised not to use dietary supplements as both their purity and ef cacy are not established. There is no substitute for lactation support by the physician, the hospital, and a lactation consultant.

4.7 Immediate postpartum period

During the immediate postpartum period, the major concerns for drug administration to the mother are: [1] pain relief, [2] resump- tion of medications for chronic conditions that may have been interrupted by pregnancy, and [3] treatment of newly diagnosed conditions.

4 Medications and the Breastfeeding Mother

46 4.8 Pain 4.8 Pain

For immediate postpartum pain relief (cesarean section, epi- siotomy), acetaminophen or a nonsteroidal anti-in ammatory drug may be suf cient if appropriate dosing is used. There have been recent concerns over the use of higher doses of acetamin- ophen for chronic therapy particularly when associated with the use of alcoholic beverages. Should acetaminophen or NSAIDs (nonsteroidal anti-in ammatory drugs) provide insuf cient pain control, a switch to a narcotic would be appropriate.

4.8.1 Morphine

Regardless of route of administration to the mother (oral, intrave- nous, epidural, intrathecal) the amount of morphine and its active metabolite, morphine-6-glucuronide, transferred in milk is very small and unlikely to cause symptoms in the infant except pos- sibly in the very young term or premature infant. As an example, mothers given 4mg of morphine epidurally had peak milk levels of 82mcg/L. If the morphine was given parenterally (5–15mg), the peak level was 500mcg/L [17]. The half-life of morphine is about 3 hours (adult), so if the mother waited 3 hours after any dose of morphine, the level in milk would be quite low and most likely have no clinical effect.

4.8.2 Codeine

The active metabolites of codeine are morphine and the morphine metabolite morphine-6-glucuronide. The enzyme systems respon- sible for this metabolism are: CYP2D for codeine and UGT2B7 for morphine, codeine-6-gluronide, and morphine-6-glucuronide. Both of these systems are subject to genetic variation. Some pa- tients are ultrarapid metabolizers of codeine and produce higher levels of morphine and active metabolites in a very short period of time after administration. These increased levels will produce increased side effects, especially drowsiness and central nervous system depression in both the mother and nursing child [18, 19]. One death has been reported from morphine poisoning [18]. It would be prudent to avoid using codeine in the immediate postpartum period and perhaps never in breastfeeding moth- ers regardless of the infant’s age. Older infants, especially those receiving solid foods in addition to breast milk, may not have signi cant symptoms even though their mothers are ultrafast metabolizers [19].

4 Medications and the breastfeeding mother 47 4.8.3 Meperidine

Meperidine does appear in milk and in infant plasma after the ad- ministration of the drug for cesarean section and also for postpar- tum pain management [20, 21]. The infant’s plasma level was found to be 1.4% of the maternal plasma level [20]. Meperidine given postpartum for pain control does produce decreased alertness in 3- to 4-day-old infants compared to equivalent doses of morphine [21, 22]. Hodgkinson et al. using the Early Neonatal Neurobehav- ioral Scale showed a suppression of most of the 13 items (including alertness, rooting, and sucking) on the rst and second postpartum days. The effects were dose related [23]. Morphine appears to be the preferred opioid for intra- and postpartum pain.

4.8.4 Hydrocodone

Hydrocodone is metabolized to the more active metabolite hydromorphone and both are excreted into breast milk. If the daily dosage is limited to 30 mg per day, it is unlikely to affect the established nursing infant [24, 25]. The estimated median opiate dose to which the infant might be exposed is 0.7% of the thera- peutic dosage for older infants.

There has been much concerned expressed over the potential toxicity of opioids delivered to the infant through breastfeeding. Adverse events are usually associated with high maternal dose in very young infants.

4.9 Methadone

Women who have been on methadone during pregnancy for narcotic addiction should be encouraged to breastfeed and con- tinue to take methadone [26]. Babies who nurse from mothers on methadone have both a slower onset and less severe neonatal abstinence syndrome. They also have less need for pharmacologi- cal treatment of the abstinence syndrome [27]. Concentrations of methadone are low in breast milk: 21–314ng/mL [28]. Only about 1–3% of the maternal dose is excreted into milk [29]. These infants will still require very close observation in the hospital and after discharge to monitor possible withdrawal symptoms.

4.10 Resumption of pre-pregnancy medications

With the possible exception of psychotropic drugs, almost all medications for acute and chronic maternal conditions are safe

4 Medications and the Breastfeeding Mother

48 4.11 Psycho- and neurotropic drugs

for the breastfeeding infant. Adverse reactions in the infant to ma- ternal drug administration are very rare and usually con ned to infants under the age of 2 months [30, 31]. Anderson et al. found 100 reports of adverse reactions in several database searches from 1966 to 2002 [30]. None were considered de nitely related to the drug used, 53 were possibly related, and 47 were probably related. There were three deaths among the 100 infants; one was a sudden infant death syndrome. These reports were before the concern about the use of codeine in mothers of very young infants. Only 4% of the reports were in infants older than 6 months of age. Information on approximately 1000 drugs is on the LactMed website [32] (see below).

4.11 Psycho- and neurotropic drugs

4.11.1 Antidepressants, antipsychotics, anxiolytics, antiepileptics, drugs for attention de cit hyperactivity disorder

These drugs are grouped together because they target the brain; the pharmacodynamic action of these compounds involves al- terations of neurotransmitters within the central nervous system. These alterations may be in the amount of neurotransmitter, sensi- tivity of the receptor on the neuron, or number of active receptors. These drugs include antidepressants, antipsychotics, tranquilizers, antiepilepsy drugs, and drugs to treat attention de cient hyperac- tivity disorder. These compounds may be transmitted during both pregnancy and lactation. This group of drugs is perhaps the most signi cant challenge to the physician caring for the mother; she needs the drug or drugs, but what of the effect or effects on the infant? Since they all act by in uencing transmitter function and since central nervous system receptors are developing in the fetus and young infant, will there be permanent effects on neurodevel- opment? The evidence is far from complete; long-term studies are not available. Limited information suggests that the effect of these compounds on long-term development may not be signi cant or at the most dif cult to measure because of so many variables such as genetic background, and social and economic status [33]. It is impossible to separate drug effect during breastfeeding from effect due to exposure during pregnancy. The important information to be given to the mother is: [1] all of these drugs if measured in breast milk do appear, [2] the amount in milk is very small and frequently the drug does not appear in infant plasma, and [3] long- term studies (over childhood and adolescence) are not available.

4 Medications and the breastfeeding mother 49

It appears that the sensitive period for exposure and adverse ef- fects may be within the rst weeks and months.

The antidepressants are of special interest for obstetricians be- cause of the well-known incidence of depression during pregnancy as well as in the postpartum period. As many as 18–20% of women may experience depression either during pregnancy or during the rst 3 months after delivery [34, 35]. Most of the antidepressants currently in use are members of the selective serotonin uptake inhibitors (SSRI) class. They all have prolonged half-lives of 15 to 36 hours [36]. Several of the SSRIs also have active metabolites ( uoxetine, sertraline) which may extend pharmacological action for a further 4–16 days. There is a neonatal withdrawal syndrome associated with the use of SSRIs. These symptoms can vary from infant to infant and usually consist of dif culty feeding, jitteriness, tremor, sneezing, and sleep dif culties [37]. Symptoms are usually mild and subside within 2 weeks [38].

4.12 Drugs not to give to the nursing mother postpartum

This list is quite small and would include:

• drugs of abuse (cocaine, heroin);

• several of the beta blocking agents such as atenolol and sotalol. These have a high percentage of maternal dose excreted and symptoms have been reported in the nursing infant [39];

• lithium – signi cant blood levels (from 11 to 56% of mater- nal levels) reported in nursing infants [40]. Twenty-four infants reported nursed without dif culty; four infants reported with symptoms (all under 2 months of age) [41];

• amiodarone – 3.5 to 45% of the maternal dose may be excreted in milk [42]. This drug contains 39% iodine and may interrupt thyroid function. The half-life in adults is 100 days [43]. Infant serum levels can be 25% of maternal serum levels [44].

4.13 Oral contraceptives (OCPs)

There have been two concerns with the use of oral contraceptives in the breastfeeding woman: quality and quantity of milk produced.

4 Medications and the Breastfeeding Mother

50 4.15 Where to nd information

The quality of milk does not seem to vary between mothers not tak- ing OCPs and mothers taking a variety of OCPs. There have been many studies showing decreased milk supply especially with the older high dose estrogen compounds and especially with starting in the rst few weeks after delivery. Progestins seem not to inhibit lactation as much as the estrogen compounds do. The Academy of Breastfeeding Medicine places progestin-only compounds as a sec- ond choice for contraception and estrogen contraceptives as the third choice [45]. The rst choices are: LAM (Lactational Amen- orrhea Method), natural family planning, barrier contraception, and intrauterine devices. Mothers wishing to use LAM should be referred to a physician or lactation consultant for advice on how to use LAM. When used correctly it is 98% effective [46].

4.14 Summary

Important lessons for any drug that may be transferred in breast milk to the infant are: neonates up to 2 weeks of age are particu- larly susceptible to toxicity; most adverse reports are in infants less than 2 months of age; there is a dose (maternal) response (infant) relationship; there are signi cant interindividual varia- tions in drug response; and both maternal and infant pharmaco- genetics play a critical response in drug toxicity [47].

Finally, precise analytic methods have identi ed compounds in such extremely small (e.g. nanograms per liter of milk) amounts that it will be dif cult to correlate with biological measures.

4.15 Where to nd information

The most up-to-date, comprehensive and authoritative infor- mation is to be found in LactMed [32]. This is a website of the National Library of Medicine, TOXNET (Toxicology Data Net- work). Approximately 1000 drugs including herbal preparations are referenced; the information is peer reviewed, evidence based, and updated frequently during each year. LactMed can be ac- cessed with a mobile device. The LactMed app for iPhone/iPod Touch and Android can be downloaded at: http://toxnet.nlm.nih. gov/help/lactmedapp.htm. Another source is Briggs et al. which also offers detailed information about the use of drugs during pregnancy [48].

4 Medications and the breastfeeding mother 51

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[2] Berthelsen BG, Fjeldsoe-Nielsen H, Nielsen CT, Hellmuth E. Etanercept con- centrations in maternal serum, umbilical cord serum, breast milk and child serum during breastfeeding. Rheumatology 2010;49:2225–7.

[3] Bennett PH, Notarianni LJ. Risk from drugs in breast milk; an analysis by rela- tive dose. Br J Clin Pharmacol 1996;42:673–4.

[4] Corbett TH, Ball GL. Respiratory excretion of halothane after clinical and occupational exposure. Anesthesiology 1973;39:342–5.

[5] Cote CJ, Kenepp NB, Reed SB, Strobel GE. Trace concentrations of halothane in human breast milk. Br J Anaesth 1976;48:541–3.

[6] http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?/temp/~SrnBRA:1 (propofol). [7] Esener Z, Sarihasan B, Guven H, Ustun E. Thiopentone and etomidate con- centrations in maternal and umbilical plasma, and in colostrum. Br J Anaesth

1992;69:586–8.
[8] Morgan DJ, Beamiss CG, Blackman GL, Paull JD. Urinary excretion of

placentally transferred thiopentone by the human neonate. Dev Pharmacol

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1999;15:185–94.
[10] Montgomery A, Hale TW, Academy of Breastfeeding Medicine Protocol

Committee. ABM Clinical Protocol #15: analgesia and anesthesia for the

breastfeeding mother. Breastfeed Med 2006;1:271–7.
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Effect of labor epidural analgesia with and without fentanyl on infant breast- feeding: a prospective, randomized, double-blind study. Anesthesiology 2005;103:1211–7.

[12] Wilson MJ, MacArthur C, Cooper GM, Bick D, Moore PA, Shennan A, et al. Epidural analgesia and breastfeeding: a randomised controlled trial of epi- dural techniques with and without fentanyl and a non-epidural comparison group. Anaesthesia 2010;65:145–53.

[13] Chang ZM, Heaman MI. Epidural analgesia during labor and delivery: effects on the initiation and continuation of effective breastfeeding. J Hum Lact 2005;21:305–14.

[14] Rosen AR, Lawrence RA. The effect of epidural anesthesia on infant feeding. J Univ Roch Med Ctr 1994;6:3–7.

[15] Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Pro- tocol #9: use of galactogogues in initiating or augmenting the rate of maternal milk secretion ( rst revision January 2011). Breastfeed Med 2011;6:41–9.

[16] Anderson PO, Valdes V. A critical review of pharmaceutical galactagogues. Breastfeed Med 2007;2:229–42.

[17] Feilberg VL, Rosenborg D, Broen Christensen C, Mogensen JV. Excretion of morphine in human breast milk. Acta Anaesthesiol Scand 1989;33:426–8.

[18] Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:33–5.

4 Medications and the Breastfeeding Mother

52 References

[19] Madadi P, Ross CJD, Hayden MR, Carleton BC, Gaedigk A, Leeder SJ, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case–control study. Clin Pharmacol Ther 2009;85:31–5.

[20] Al-Tamimi Y, Ilett KF, Paech MJ, O’Halloran SJ, Hartman PE. Estimation of infant dose and exposure to pethidine and norpethidine via breast milk follow- ing patient-controlled epidural pethidine for analgesia post caesarean delivery. Int J Obstet Anesth 2011;20:28–34.

[21] Wittels B, Scott DT, Sinatra RS. Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study. Anesthesiology 1990;73:864–9.

[22] Wittels, B., Glosten, BT., Faure, E.A., Moawad, A.H., Ismail, M., Hibbard, J., et al. Postcesarean analgesia with both epidural morphine and intravenous patient-controlled analgesia: neurobehavioral outcomes among nursing neo- nates. Anesth Analg 1997;85:600–6.

[23] Hodgkinson R, Bhatt M, Wang CN. Double-blind comparison of the neurobe- havior of neonates following the administration of different doses of meperi- dine to the mother. Canad Anaesth Soc J (Can J Anesth) 1978;25:405–41.

[24] Sauberan JB, Anderson PO, Lane JR, Ra e S, Nguyen N, Rossi SS, et al. Breast milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain. Obstet Gynecol 2011;117:611–7.

[25] Anderson PO, Sauberan JB, Lane JR, Rossi SS. Hydrocodone excretion into breast milk: the rst two reported cases. Breastfeed Med 2007;2:10–4.

[26] Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical Protocol #21: guidelines for breastfeeding and the drug-dependent woman. Breastfeed Med 2009;4:225–8.

[27] Abdel-Latif ME, Pinner J, Clews S, Cooke F, Lui K, Oei J. Effects of breast milk on the severity and outcome of neonatal abstinence syndrome among infants of drug-dependent mothers. Pediatrics 2007;117:e1163–1169.

[28] Jansson LM, Choo R, Harrow C, Velez M, Schroeder JR, Lowe R, et al. Metha- done maintenance and long-term lactation. J Hum Lact 2007;23:184–90.
[29] http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?/temp/~nMXQon:1 (metha-

done).
[30] Anderson PO, Pochop SL, Manoguerra AS. Adverse drug reactions in breast-

fed infants: less than imagined. Clin Pediatr 2003;42:325–40.
[31] Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breastfed infants exposed to maternal medi-

cation. Am J Obstet Gynecol 1993;168:1393–9.
[32] LactMed (drugs and lactation database). http://toxnet.nlm.nih.gov/cgi-

bin/sis/htmlgen?LACT

[33] Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, et al. Child development following exposure to tricyclic antidepressants or uox- etine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159:1889–95.

[34] Marcus SM. Depression during pregnancy: rates, risks, and consequences – motherisk update 2008. Can J Clin Pharmacol 2009;16:e15–22.

[35] Gavin NI, Gaynes BN, Lohr KN, Meltzer-Brody S, Gartlehner G, Swinson T. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol 2005;106:1071–83.

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[36] Davanzo R, Copertino M, De Cunto A, Minen F, Amaddeo A. Antidepressant drugs and breastfeeding: a review of the literature. Breastfeed Med 2011;6:89–98. [37] Monk C, Fitelson EM, Werner E. Mood disorders and their pharmacologi- cal treatment during pregnancy: is the future child affected?. Pediatr Res

2011;69:3R–10R.
[38] Moses-Kolko EL, Bogen D, Bregar A, Uhl K, Levin B, Wisner KL. Neonatal

signs after late in utero exposure to serotonin reuptake inhibitors: literature

review and implications for clinical applications. JAMA 2005;293:2372–83. [39] Atkinson H, Begg EJ. Concentrations of beta-blocking drugs in human milk. J

Pediatr 1990;116:156.
[40] Viguera AC, Newport DJ, Ritchie J, Stowe Z, Whit eld T, Mogielnicki J,

et al. Lithium in breast milk and nursing infants: clinical implications. Am J

Psychiatry 2007;164:342–5.
[41] http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?/temp/~r7lQ4W:1 (lithium). [42] http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?/temp/~yGm4ch:1 (amioda-

rone).
[43] Basaria S, Cooper DS. Amiodarone and the thyroid. Am J Med 2005:118,

706–714.
[44] McKenna WJ, Harris L, Rowland E, Storey G, Holt D. Amiodarone therapy

during pregnancy. Am J Cardiol 1983;51:1231–3.
[45] Academy of Breastfeeding Medicine Protocol Committee. ABM Clinical

Protocol #13: contraception during breastfeeding. Breastfeed Med 2006;

1:43–50.
[46] Labbok MH, Hight-Laukaran V, Peterson AE, Fletcher V, von Hertzen H,

Van Look PFA. Multicultural study of the lactational amenorrhea method (LAM): I. ef cacy, duration, and implications for clinical application. Contra- ception 1997;55:327–36.

[47] Berlin Jr CM, Paul IM, Vesell ES. Safety issues of maternal drug therapy during breastfeeding. Clin Pharmacol Ther 2009;85:20–2.

[48] Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins; 2011.

4 Medications and the Breastfeeding Mother

Fetal Drug Therapy

Erik Rytting and Mahmoud S. Ahmed

5

. 5.1  Introduction 55

. 5.2  Indications for fetal therapy 56

. 5.3  Strategies to achieve fetal drug therapy 61

. 5.4  Special considerations 65

Acknowledgments 66

5.1 Introduction

When drugs are prescribed during pregnancy, most often the intention is to treat a condition affecting maternal health. Care- ful attention is placed on the appropriate selection of medication and dose to reduce transplacental drug transport and minimize any consequences of fetal drug exposure. However, this chapter focuses on the administration of drugs intended to treat medical conditions af icting the fetus, rather than the mother. In order to achieve therapeutic drug concentrations in the fetus, efforts are made to circumvent the placenta’s function as a barrier. In this case, it is imperative to reduce maternal exposure to medication that she does not need and which might even adversely affect her well-being.

The rst section of this chapter will discuss a number of medical indications for which fetal drug therapy might be war- ranted. As the focus is on pharmacological therapy, the reader is referred to other sources for details regarding other fetal medical

56 5.2 Indications for fetal therapy

interventions, such as prenatal repair of myelomeningocele [1], blood transfusions to treat fetal anemia [2], and others [3].

The second part of the chapter will describe strategies for fetal drug delivery, including transplacental transfer following mater- nal administration, direct fetal injection, gene therapy, stem cell transplantation, and nanomedicine. The chapter will conclude with a brief discussion of the ethics associated with this challeng- ing subject (see also Chapter 8 which discusses the ethics of clinical pharmacology in pregnancy).

5.2 Indications for fetal therapy

Table 5.1 lists some common indications for fetal therapy and details regarding these conditions are provided below (see also Table 5.2). Nevertheless, as this table is not an exhaustive list, this section will identify a number of additional settings where fetal drug therapy may be bene cial.

Among the most common pharmacological interventions for fetal therapy is the administration of antenatal corticosteroids to promote fetal lung maturation in anticipation of preterm delivery. Dexamethasone and betamethasone are the most common drugs prescribed for this purpose, which has demonstrated clinically signi cant reductions in respiratory distress syndrome, neonatal mortality, cerebroventricular hemorrhage, necrotizing enteroco- litis, intensive care admission, and systemic infections in the rst 48 hours of life [4, 5].

Fetal cardiac arrhythmias affect 1% of pregnancies [6]. Although intermittent extrasystoles can be common and may not require

Table 5.1 Examples of indications for fetal drug therapy and medications used

Indication for fetal drug therapy

Medications

Cardiac arrhythmias

Endocrinological disorders

Congenital adrenal hyperplasia Fetal thyroid disorders

Hematological disorders

Alloimmune thrombocytopenia Erythrocyte alloimmunization

Lung maturation

Digoxin, ecainide, sotalol

Dexamethasone Levothyroxine

Gamma globulin Anti-D immunoglobulin

Dexamethasone, betamethasone

 

5 Fetal drug therapy 57 Table 5.2 Pharmacokinetic considerations for some medications used in fetal drug therapy

(see Table 5.1)

Drug

Typical dosing

Notes

References

Digoxin

Flecainide

Sotalol

Dexamethasone (for lung maturation)

Betamethasone

Levothyroxine

Gamma globulin

Anti-D immunoglobulin

Dexamethasone (for congenital adrenal hyperplasia)

0.5 mg bid for two days, then 0.25–0.75 mg/day

100 mg, tid or qid

80–160 mg, bid or tid

6 mg, four intramuscular doses, 12 hours apart

12 mg, two intramuscular doses, 24 hours apart

Case studies report intraamniotic doses ranging from 50–800 mcg (median dose 250 mcg), every 1–4 weeks

1–2 g/kg/week IV, depending on risk

1500 IU as a single intramuscular injection at 28 weeks of gestation

20 mcg/kg/day based on pre-pregnancy body weight, divided in three doses

Therapeutic concentration 1.0–2.5 ng/mL; fetal/maternal ratio: 0.3–1.3; hydrops reduces placental transfer; substrate for P-glycoprotein

Therapeutic concentration 0.2–1.0 mcg/mL; fetal/maternal ratio: 0.5–1.0; crosses placenta even in the presence of hydrops

Therapeutic concentration 2–7 mcg/mL (atrial utter); fetal/ maternal ratio 1.0 ± 0.5

Fetal/maternal ratio ranged from 0.20 (50 min after dose) to 0.44 (after 265 min); a fraction is metabolized in the placenta to the inactive 11-ketosteroid

Fetal/maternal ratio: 0.28 ± 0.04; a fraction is metabolized in the placenta to the inactive 11-ketosteroid

Concurrent dose reduction of maternal antithyroid drugs may be necessary; it may be advisable to start with a low dose (150 mcg), then increase if necessary; cordocentesis should be limited

Prednisone is often used in combination

A two-dose regimen consisting of either 500 or 1250 IU each at 28 weeks and 34 weeks may be more effective in maintaining suf cient anti-D levels at term

See notes on dexamethasone above

[66–74]

[66, 73, 75–79]

[66, 78, 80–87] [88–92]

[93–97]

[15, 98–101]

[102] [103–105]

[11]

5 Fetal Drug Therapy

58 5.2 Indications for fetal therapy

treatment, sustained fetal arrhythmias demand vigorous attention because this can lead to hydrops within 48 hours, a condition with poor prognosis [6–9]. Hydrops can impair transplacental trans- port, thereby necessitating fetal injection of medication [9]. The most common fetal arrhythmias are supraventricular tachycardia, atrial utter, and severe bradyarrhythmia associated with com- plete heart block. Drugs used to treat fetal tachycardia include digoxin, ecainide, sotalol, procainimide, propranolol, amioda- rone, and adenosine; questions remain regarding the use of ste- roids and sympathomimetics for bradycardia caused by heart block [7]. Attentive monitoring of response to most antiarrhyth- mic drugs is needed due to narrow therapeutic margins, and co- administration of digoxin and verapamil may cause fetal death [10]. Maternal side effects to fetal antiarrhythmic therapy include palpitations, second degree atrioventricular block, Wenckebach phenomenon, and hypotension [10].

Congenital adrenal hyperplasia is most often due to a 21-hy- droxylase de ciency (CYP21A2) [8]. Decreased cortisol production results in excess androgen synthesis, which causes virilization of female genitalia. A survey of 13 countries demonstrated an over- all incidence of 1 in 15,000 births, but the rate is as high as 1 in 282 births among Yupik Eskimos [11]. In utero treatment with dexamethasone reduces the abnormal levels of androgens, and this therapy prevents the devastating consequences of wrong sex assignment in affected females. Differentiation of external geni- talia occurs between 7 and 12 weeks of gestation, so therapy in at-risk pregnancies must begin earlier, preferably by the 5th week [11]. Cell-free DNA testing provides non-invasive determination of fetal sex at 7 weeks of gestation, thereby enabling rapid discon- tinuation of dexamethasone for male fetuses [12, 13]. Chorionic villus sampling (CVS) can be performed at 10–12 weeks, at which point therapy can be halted for unaffected females [11]. Dexa- methasone treatment (three times daily) will continue throughout pregnancy for an affected female fetus. Maternal side effects of fetal dexamethasone therapy include edema, striae, excess weight gain, Cushingoid facial features, facial hair, glucose intolerance, hypertension, gastrointestinal problems, and emotional irritability [8, 11, 14].

Congenital hypothyroidism, which affects approximately 1 out of every 4500 pregnancies, is usually a secondary condition caused by treatment of maternal hyperthyroidism, such as Graves’ disease [8]. Fetal goiter can interfere with fetal swallowing and lead to polyhydramnios and premature rupture of membranes. Further- more, fetal goiter can cause tracheal compression and asphyxia at birth [8, 15]. Fetal hypothyroidism can be successfully treated with

5 Fetal drug therapy 59

levothyroxine. Levothyroxine is administered via intraamniotic injection due to its low transplacental transfer [8, 15].

Fetal hematological disorders that can be treated include alloimmune thrombocytopenia and erythrocyte alloimmuniza- tion. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) has an incidence rate of 1 in 1500 and is caused by a maternal an- tibody-mediated response against a fetal platelet-speci c antigen; this may lead to intracranial hemorrhage in utero [16]. Women at risk for a pregnancy with FNAIT are usually only identi ed after having a previous child with the disorder, but maternal adminis- tration of intravenous gamma globulin can successfully increase fetal platelet counts [8, 16]. Erythrocyte alloimmunization – the reaction of maternal antibodies with fetal erythrocyte antigens – can lead to hemolysis, fetal anemia, and hydrops fetalis [8]. The use of prophylactic anti-D immunoglobulin in Rh-negative women carrying an Rh-positive fetus can reduce the need for intrauterine blood transfusions to treat alloimmune hemolytic disease [17]. It should be noted that there are other types of red-cell alloimmuni- zation besides anti-RhD without prophylactic immune globulins yet available [18].

In addition to the aforementioned indications, there are a num- ber of fetal conditions for which experimental therapeutics are in various stages of testing. Polyhydramnios (excess amniotic uid) affects approximately 1% of pregnancies, of which 55% are idio- pathic and 25% are related to fetal diabetes [6, 19]. Amnioreduc- tion and indomethacin administration have been investigated for polyhydramnios therapy, but not as randomized controlled trials [19]. Indomethacin likely decreases fetal urine production, with minor maternal side effects [6]. While some therapeutic options for intrauterine growth restriction currently under investigation require further study and randomized controlled trials to establish ef cacy [20], it is clear that smoking cessation lowers rates of low birth weight and preterm birth [21]. Injection of picibanil into the pleural cavity for pleurodesis appears promising for the treat- ment of early second trimester, non-hydropic fetal chylothorax [22, 23]. Digoxin and furosemide have been injected into fetal in- travascular space to treat idiopathic non-immune hydrops fetalis [24], and infection-induced non-immune hydrops fetalis has been treated with transplacental antiviral or antibiotic therapy [25]. Fetal malignancies are rarely diagnosed in utero [26], but this may represent a future area of potential fetal chemotherapy. There are also several examples of maternal prescriptions with direct or indirect fetal bene t, including tocolytics preventing preterm birth, penicillin to treat syphilis [6], spiramycin for toxoplasmosis [6], antibiotics before delivery to reduce neonatal sepsis [27], and

5 Fetal Drug Therapy

60 5.2 Indications for fetal therapy

 

5 Fetal drug therapy 61 the reduction of maternal–fetal HIV transmission rates by the use

of highly active antiretroviral therapy [28].
5.3 Strategies to achieve fetal drug therapy

5.3.1 Transplacental drug transfer

Many medications intended for the fetus are administered to the mother, with a portion of the dose crossing the placenta and reach- ing the fetal circulation. Although this method of drug delivery can cause maternal side effects, it is often preferred over the invasive- ness and risks associated with direct fetal injection. To understand this process, it is important to provide a brief introduction to the role of human placenta as a functional barrier (see Figure 5.1).

Human placenta is a tissue of fetal origin localized at the interface between the maternal and fetal circulations. During gestation, pla- cental functions include those of several organs in the newborn/ adult. For example, the placenta is responsible for exchange of gases, uptake of nutrients from the maternal circulation, elimina- tion of waste products, and the biosynthesis of speci c hormones (steroids and proteins) that regulate autocrine and/or paracrine functions. Taken together, placental functions begin by ensuring implantation, supporting normal fetal organogenesis and develop- ment, and maintaining a healthy pregnancy until parturition.

In the early 20th century, the human placenta had been viewed as a barrier similar to the blood–brain barrier but with the role to “protect” the fetus from exposure to xenobiotics and envi- ronmental toxins. The thalidomide-induced birth defects of the

Figure 5.1 Mechanisms of maternal–fetal transfer. A: Overview of human placental morphology showing fetal vessels from the umbilical cord branching into villous trees, which are bathed by maternal blood entering the placenta via spiral arteries. Trophoblast cells on the surface of the villous structures separate the maternal blood in the intervillous space from the fetal circulation, as highlighted in B. B: Cellular components of a placental villus, wherein multinucleated syncytiotrophoblast cells are formed by fusion of the precursor cytotrophoblast cells. The trophoblast cells and the fetal vascular endothelial cells are separated by basal lamina. Several transport mechanisms within the trophoblast cell layer are highlighted in C. C: Transport mechanisms in trophoblast cells, with different molecules represented by different shapes. Passive diffusion is governed by the concentration gradient of any compound (xenobiotic or intermediary metabolite). Two types of carrier-mediated transport (uptake and ef ux) involve transport proteins that span the phospholipid bilayer of the cell membrane. The biotransformation of molecules by metabolizing enzymes is also represented [59–65].

  

5 Fetal Drug Therapy

62 5.3 Strategies to achieve fetal drug therapy

1960s shattered that concept and provided evidence for differ- ences in transplacental transfer of compounds between placentas of human and other mammals. Currently, it is assumed that small molecules (<1000Da, which includes most current medications) can freely cross the placenta between the maternal and fetal circu- lations by simple diffusion. However, the bidirectional transfer of compounds between the maternal and fetal circulations across the placenta by simple diffusion does not preclude the simultaneous involvement of two other transport processes, namely, facilitated diffusion and active transport [29, 30].

The transfer of a drug by either one of the two processes is mediated by a protein that is usually selective for a particular compound or group of compounds. The rst process is facili- tated diffusion and does not require metabolic energy where the transfer of the compound occurs down a concentration gradient until steady state equilibrium is reached. The second process is active transport, which is unidirectional, requires metabolic en- ergy, and can transport compounds against a concentration gradi- ent. For example, uptake transporters in the apical membrane are responsible for the transfer of many nutrients from the maternal to fetal circulation [31]. On the other hand, ef ux transporters (such as P-glycoprotein, breast cancer resistant protein, and mul- tidrug resistant associated proteins) are responsible for the extru- sion of compounds from the fetal to maternal circulation [32]. Ef ux transporters are crucial for decreasing fetal exposure to xe- nobiotics and each one of them is responsible for the extrusion of a diverse number of drugs.

Several trophoblast tissue metabolic enzymes are responsible for the placental biotransformation of drugs [33, 34]. Placental enzymes are occasionally identical to those in the liver, but in most cases their activity is ≤10% of the hepatic enzymes. One placental enzyme, CYP19/aromatase, which is known for its role in steroidogenesis, is also involved in the placental biotransfor- mation of xenobiotics [35], thus catalyzing reactions which are performed by other hepatic enzymes that have not been identi ed in the placenta [36, 37]. For example, CYP3A4 is involved in the hepatic biotransformation of many drugs, but its activity in pla- centa has not been detected.

Thus, placental metabolic enzymes and ef ux transporters de ne the human placenta as a functional barrier that regulates transplacental transport of drugs. The activities of these proteins are subject to regulation at the transcription and translational lev- els. Their activities vary widely between individuals and in the same individual with gestational age [38–41]. In terms of maxi- mizing the transplacental transfer of maternally administered

5 Fetal drug therapy 63

medications intended for fetal drug therapy, substrates of uptake transporters are more likely to reach therapeutic levels in the fe- tal circulation. Drugs which are substrates for ef ux transporters and/or metabolizing enzymes, on the other hand, are more likely to result in maternal side effects, as higher doses will be necessary to reach therapeutic drug levels in the fetal circulation.

5.3.2 Direct fetal injection

Ultrasound-guided injections can be introduced into the umbili- cal cord, amniotic uid, intravenously, or into speci c fetal tis- sues [2]. Such an approach may be advantageous when hydropic conditions or the chemical nature of the therapeutic agent limit its transplacental transfer [2, 4]. Nevertheless, there are important disadvantages to consider. Not only can fetal movement make the initial injection challenging, but it may also cause the needle to dislodge [27, 42]. The overall risk of fetal loss by CVS or amnio- centesis is 0.5–1% [17]. When repeated injections are necessary, the risks of infection and fetal death are multiplied [2, 4].

5.3.3 Gene therapy

Fetal gene therapy could prove bene cial for a number of diseases, including cystic brosis, hemophilia, intrauterine growth restric- tion, Duchenne muscular dystrophy, and β-thalassemia [43]. The fetal period may present a unique window of opportunity for gene therapy and access to an expanding population of stem cells which may not be possible after birth. The comparative immaturity of the fetal immune system may allow for a circumvention of the type of immune response that would limit transgene expression. Further- more, presentation of a vector to fetal thymus could induce lifelong tolerance to antigen, thereby enabling repeated injections of that same vector after birth, if necessary [43, 44]. Nevertheless, current utility is hampered by the selection of an appropriate vector and a series of unknown risks, such as increased chance of fetal loss upon injection during the rst trimester, induction of preterm la- bor, infection, immune reaction, interference with normal fetal de- velopment, insertional mutagenesis, germline integration, and the chance that maternal harm may affect future pregnancies [43, 44].

5.3.4 Stem cell transplantation

Diseases where in utero stem cell transplantation might prove bene cial include hemoglobinopathies, immunode ciencies, and inborn errors of metabolism [45]. As proposed for gene therapy, it has been anticipated that a naive fetal immune system would

5 Fetal Drug Therapy

64 5.3 Strategies to achieve fetal drug therapy

readily accept stem cell transplantation, but to date, such therapy has only been realized in fetuses with immunode ciencies that might facilitate engraftment [45, 46]. Sources of stem cells in- clude maternal bone marrow, paternal bone marrow, fetal liver, and amniotic uid [46, 47]. An advantage of using stem cells from amniotic uid is eliminating the need for a donor source. Intra- peritoneal injection of transduced amniotic uid stem cells appears to be a promising strategy [47, 48].

5.3.5 Nanoparticles

Nanoparticles present a number of advantages for drug delivery, including sustained drug release promoting reduced dosing fre- quency and improved patient compliance, the potential for ef – cient drug targeting by passive and/or active targeting approaches, protection of therapeutic payload, and improved bioavailability for certain compounds. Besides traditional small-molecule drugs, nanoparticles can also be used to deliver peptides, proteins, genes, siRNA, and vaccines [49]. Examples of nanoparticles developed for drug delivery include liposomes, solid lipid nanoparticles, polymeric nanoparticles, polymeric micelles, and dendrimers. Multifunctional nanoparticles – combining both drug delivery and biomedical diagnostic imaging – have also gained recent attention as “theranostic” tools [50].

Targeted nanoparticle-based drug delivery systems offer the po- tential to increase the amount of drug reaching the fetus, thereby reducing the side effects associated with unnecessary maternal drug exposure. Ex vivo dual perfusion of human placental lob- ule is a representative model of in vivo placental transport and metabolism. To date, this model has been used with a few sets of nanoparticles to elucidate the effects of particle composition, size, and charge on the placental transfer of nanoparticles. Small, anionic liposomes increased the transplacental transport of thy- roxine, with reduced metabolism to rT3 [51]. Although PEGylated gold nanoparticles 15–30nm in size were not transferred from the maternal circuit to the fetal circuit [52], minimal transplacen- tal transport of a uorescent fourth-generation polyamidoamine dendrimer (5–6nm, fetal-to-maternal ratio of 0.073±0.02) was reported [53]. Polystyrene beads with sizes up to 240nm crossed the placenta, and higher fetal-to-maternal ratios were reported for 50–80nm-sized particles [54]. These studies show that particle size is not the only determinant for transfer. This should not be surprising because macromolecules such as IgG and vitamin B12 can cross the placenta by carrier-mediated mechanisms, but the transport of other macromolecules such as heparin is negligible

5 Fetal drug therapy 65

[53]. Due to their size, most nanoparticles are unlikely to pass through tight junctions or trophoblastic pores [55], but nanopar- ticles for fetal therapy could take advantage of receptors in the placenta, such as FcR, for receptor-mediated cellular entry [56]. Future developments in placental nanoparticle research must also include assessment of fetal safety to ensure improved drug delivery without adverse effects [55].

5.4 Special considerations

Maternal drug therapy during pregnancy requires balancing mater- nal bene t versus fetal risk, but in the case of drug therapy intend- ed for the fetus, we must weigh maternal risks against potential fetal bene ts. Despite the potential of a fetal medication causing maternal side effects, transplacental therapy is often preferred to avoid certain risks associated with fetal injections. In one extreme example of an attempted fetal intracardiac injection, the needle overshot its target, passed through to the other side of the fetal heart, and resulted in a severe adverse effect for the mother [57].

Although it is anticipated that targeted therapies would require lower doses and potentially lessen the resultant maternal side ef- fects, the appropriate dose will need to be identi ed. Fetal drug therapy is associated with different pharmacokinetics than would be expected in adults or children. Compared to an adult, the fetus has more extracellular water, less fat, less metabolic enzyme activ- ity, a lower renal secretion rate, less gastrointestinal absorption, and fetal brain receives a higher percentage of cardiac output [2, 10]. Furthermore, drug elimination is altered due to amniotic recycling [2].

Finally, the ethics of fetal drug therapy must be considered. De- pending on gestational age, lung maturity, the availability of neo- natal facilities, and maternal preference, in some instances, early delivery may be seen as an alternative to fetal therapies carrying high risk [7]. The risks and potential bene ts of each disease are unique, and the recommendations of Noble and Rodeck serve as excellent guidelines [58]; it is important that the mother can give informed consent, meaning that she understands all the possible outcomes of each intervention. Protocols for fetal drug therapy must be approved by a research ethics committee. Invasive ther- apy must have a high probability of saving life or preventing dis- ease; risks to fetal health must be minimized; and risks to maternal health must be negligible. Alongside the mother’s right to consent is her right to refuse, and supportive counseling should be made

5 Fetal Drug Therapy

66 References

available to the family [58]. As if pregnancy and childbirth weren’t challenging enough, it is inspiring to see the sacri ces of pregnant women participating in clinical trials, enduring undeserved side effects, and undergoing invasive procedures in order to offer their children more hope for a better future.

Acknowledgments

The authors wish to thank Sanaalarab Al Enazy for her assis- tance with Figure 5.1 and Wayne Snodgrass for helpful sugges- tions. E.R. is supported by a research career development award (K12HD052023: Building Interdisciplinary Research Careers in Women’s Health Program, BIRCWH) from the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Develop- ment (NICHD), and the Of ce of the Director (OD), National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the of cial views of the NIAID, NICHD, OD, or the National Institutes of Health.

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. [81]  Erkkola R, Lammintausta R, Liukko P, Anttila M. Transfer of propranolol and sotalol across the human placenta. Their effect on maternal and fetal plasma renin activity. Acta Obstet Gynecol Scand 1982;61:31–4.

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5 Fetal drug therapy 71

. [86]  Oudijk MA, Michon MM, Kleinman CS, Kapusta L, Stoutenbeek P, Viss- er GH, et al. Sotalol in the treatment of fetal dysrhythmias. Circulation 2000;101:2721–6.

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5 Fetal Drug Therapy

72 References

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Treating the Placenta: an 6 Evolving Therapeutic Concept

Michael D. Reed and Donald R. Mattison

. 6.1  Introduction 73

. 6.2  The placenta as the therapeutic target: the past 74

. 6.3  The placenta: therapeutic targets 77

. 6.4  The placenta as a therapeutic target today 80

. 6.5  The placenta as a therapeutic target in the future 83

Conclusions 84

6.1 Introduction

Generally, from the perspective of clinical pharmacology, one thinks of the placenta as the passage from mother to fetus or the reverse [1–4]. With few exceptions it is generally not thought of as the tar- get for therapy. However, we believe that as our understanding of placental function grows and as the science and application of obstetric-based clinical pharmacology broadens, the placenta may become an important therapeutic target for the mother, the fetus, or both. Clinically important diseases where such a strategy is em- ployed today include the prevention of vertical HIV-1 virus trans- mission from mother to fetus and in the treatment of malaria where the placenta serves as an important reservoir of the malaria parasite. In this chapter we critically review what is known about placental functions and its modulations throughout gestation and how pla- cental processes can and might be manipulated for therapeutic gain.

74 6.2 The placenta as the therapeutic target: the past 6.2 The placenta as the therapeutic target:

the past

An early example of targeting placental function for therapeu- tic purposes that was both unsuccessful as well as resulting in unexpected tragic consequences is the experience with diethyl- stilbestrol (DES). The DES experience highlights the importance of the need for a good understanding of the disease process, drug pharmacodynamics and acute, chronic and generational toxicity before undertaking widespread drug-based manipulation of the maternal, placental, and/or fetal compartments [5]. Diethylstil- bestrol is a synthetic estrogen structurally similar to estradiol with potent estrogen-like activity that is rarely used today. From the 1940s to ~1971 DES was commonly used for the prevention of spontaneous abortions. An innovative randomized controlled tri- al conducted at the Chicago Lying-In Hospital demonstrated that DES was actually not able to prevent pregnancy loss, and may have actually led to missed abortion [6]. Unknown at the time but recently described, DES bene cial clinical effects are most likely a result of the drug’s positive effects on placentation and tropho- blast stem cell differentiation [7]. Unfortunately, pharmacologic DES use maternally results in a high incidence of teratogenic effects on the reproductive tracts of males and females and the subsequent development of vaginal clear-cell adenocarcinoma in women of childbearing age [6–8]. Many environmental chemicals and pollutants either as the intact compound or metabolite can also have similar or unique devastating negative consequences on the mother, the placenta, and/or the fetus [5] complicating our assessment of individual compounds during pregnancy. These and many other tragic experiences underscore the importance of care- ful study of mother–fetal bene t–risk pro les of drugs intended to treat the placenta.

6.2.1 Placental function

The placenta provides a link between the mother and fetus, me- tabolizing and transferring nutrients for growth and development of the fetus as well as for its own growth and development. Meta- bolic waste products generated in the fetus or placenta are elimi- nated by transfer into the maternal circulation. A unique function of the placenta is its role as an endocrine organ producing steroid and protein hormones. These characteristics must be considered in thinking about treating the placenta – to enhance therapeutic success in placental, fetal or maternal disease. A detailed descrip- tion of placental anatomy, physiology, and gestational maturation

6 Treating the placenta: an evolving therapeutic concept 75

are addressed in Chapter 5. However for completeness we pro- vide a brief overview of those anatomic and physiologic functions important to understanding therapeutic targeting of placental function for maternal and fetal health.

Brie y, fetal and maternal circulations are separated by placen- tal tissue that changes throughout pregnancy; anatomically, the surface area over which maternal–fetal exchange occurs increases and the distance between maternal and fetal blood decreases. Mor- phologically, the syncytiotrophoblast layer is reduced in thickness and the cytotrophoblast becomes discontinuous as gestation pro- gresses. Changes in the villous structure are also observed, with an increasing number of microvilli facilitating exchange between mother and fetus. These villi and the syncytiotrophoblast layer permit the maternal and fetal circulations to be in close contact while providing a transport barrier between the two circulations [1, 9, 10].

In human placenta the syncytiotrophoblast arises from the fusion of cytotrophoblast cells, forming a syncytium over the sur- face of the placenta facing the maternal blood. The plasma mem- branes of the syncytiotrophoblast are polarized; the brush border membrane in direct contact with maternal blood and the basal membrane facing the fetal circulation. The brush border mem- brane possesses a microvillus structure that effectively ampli es the surface area, whereas the basal membrane lacks this structure.

Anatomic differences between species in the number of tro- phoblast layers and connection between maternal and fetal tis- sues result in species-speci c variation in placental function that in uences data gathered during the preclinical stages of drug development. The human placenta is unique in its villous struc- ture. Factors such as diffusion, electrical potential across the placenta, magnitude of maternal and fetal blood ows, and differ- ences in metabolism, transport proteins, and other mechanisms for exchange between maternal and fetal circulations should be considered as the placental transfer and metabolism of drugs var- ies dramatically among differing species. Discordant results for maternal–fetal drug disposition between humans and many ani- mal species are often noted due to these anatomical differences in placental morphology and function [9–11]. The thalidomide tragedy was the most important event to dispel the erroneous belief that the placenta was a barrier and spawned regulation for controlled, animal-based preclinical teratology studies [11–13]. These anatomical and physiological differences can also lead to false implications for teratogenic effect(s). The widely used drugs diazepam and salicylates were shown to induce teratogenic effects in animals with no increased risk of any such effects in humans.

6 Treating the Placenta: an Evolving Therapeutic Concept

76 6.2 The placenta as the therapeutic target: the past

The previously widely used and therapeutically effective drug Benedictine (doxylamine plus pyridoxine) was shown in animal studies to cause cardiac and limb defects leading to enormous liti- gation and ultimately withdrawal from the US market though no increase in human teratogenic effects have been described [13], and this drug combination remains the most effective interven- tion for treating pregnancy associated nausea and vomiting (see Chapter 12). These misleading and sometimes erroneous ndings are directly attributable to the interspecies differences that exist in placental structure and function. Despite these disparities and the need for better mechanisms for screening possible placental toxins or teratogens, animal screening remains the best process today [11].

Drugs for treatment of placental disease should be concentrat- ed within the placenta with little access to, and toxicity for, moth- er or fetus. Drugs developed for treatment of the mother should have minimal transport to fetal circulation and minimal impact on placental and fetal health. Drugs for treatment of fetal dis- eases should have unhindered access to the fetal circulation with minimal adverse impact on mother or placenta [1, 14].

6.2.2 Placental transport mechanisms

The syncytiotrophoblast, the outermost layer of the human pla- centa, is the main site of exchange for drugs and metabolites, nutrients, waste products, and gases between the maternal and fe- tal circulations. Ef cient transfer of nutrients, gases, electrolytes, and solutes across the placenta is essential for fetal growth and development. There are several mechanisms by which transfer occurs, and depending on the mechanism of transfer the direction may be toward the maternal or fetal circulation.

As noted in Chapter 5 the placenta performs a multitude of important, complex, simultaneous functions at a differing func- tional capacity that changes as gestation progresses. Drugs may transfer from the maternal to fetal compartments via simple pas- sive diffusion, facilitated diffusion, active transport, ltration or pinocytosis. The physiochemical characteristics of a drug sub- stantially in uence its maternal–fetal disposition pro le. Struc- tural modi cations of a proposed drug’s physical and chemical characteristics including molecular weight/size, degree of ioniza- tion at physiologic and pathophysiologic pH linked to water/lipid solubility and af nity for membrane transporters and drug metab- olizing enzymes represent just a few of a multitude of targets for drug therapy. Xenobiotics with a molecular weight of <600 daltons can usually transfer across the placenta via passive diffusion

6 Treating the placenta: an evolving therapeutic concept 77

whereas compounds of 1000+ daltons, e.g. heparin and insulin, cross very poorly. With a small, highly lipid soluble, low plasma protein bound drug, its transfer across the placenta will primar- ily be dependent upon maternal and fetal blood ow combined with involvement, if any, of a membrane transporter. Important to the treatment of placental-based disorders (see below, e.g. ma- laria) a drug may have high af nity for placental tissue and bind to and/or accumulate within the syncytiotrophoblast [15]. Depend- ing upon the inherent physiochemical characteristics of a drug, it may be released into the fetal circulation or be released back into maternal circulation without reaching the fetal compartment. The rates of these transfer processes can be very different than the individual or combined maternal or fetal clearance rates of the drug [1–5, 9, 10, 15–19].

6.3 The placenta: therapeutic targets

As noted above, the placenta is a multifunctional dynamic organ continuously evolving throughout gestation with the sole purpose of maintaining maternal–fetal homeostasis up to the time of op- timal pre-programmed delivery of the newborn infant. The many perturbations that occur with each of these processes during gestation heighten the complexity of effectively targeting one or more functions as a therapeutic target [20]. Nevertheless, as our understanding of maternal–fetal physiology and pathophysiology increases in concert with advances in digital technology fostering more sophisticated patient monitoring and safer anatomical ma- nipulation, therapeutic targeted strategies are a reality now and will continue to expand. With respect to possible therapeutics, enzymes capable of metabolizing (CYPs) or conjugating drugs (transferases) as well as uni- and bi-directional transporters facili- tating or preventing drug movement from one location to another are ripe for pharmacologic manipulation to maximize maternal or fetal therapeutics [16, 19–25]. Similarly, a drug development plan focused on an analog’s structure–activity relationship linked to speci c manipulations of its physiochemical characteristics will foster safer and more effective therapy [1–4, 16, 18].

Tables 6.1, 6.2 and 6.3, respectively, outline placental expression of known CYPs, enzymes involved in conjugation and cellular transporters relative to gestational age that are active in maternal– fetal homeostasis. The overall in uence of these placental-based processes on xenobiotic disposition must be considered in total with the functional activity of the mother and the fetus. Changes

6 Treating the Placenta: an Evolving Therapeutic Concept

78 6.3 The placenta: therapeutic targets

in the functional capacity and activity of these processes impor- tant to drug disposition occur between the mother, placenta, and fetus throughout gestation. In general, fetal tissue activity of these processes increases whereas placental activity decreases with ges- tation such that at birth, placental metabolic activity is minimal [23]. This gestational ontogeny may be the basis for much of the con icting data regarding placental drug disposition that exist in current literature. For example, the energy-dependent ef ux pla- cental transporter Pgp is of little importance in term placenta but very important during earlier stages of gestation in preventing xenobiotic access to the fetal compartment. This ontogenic pat- tern through gestation is very important to the rate and extent of digoxin placental transfer for the treatment of fetal arrhythmias (see Chapter 5) [22].

It is conceivable if not inevitable that drugs will be developed that function as a pure antagonist, i.e. high af nity with no in- trinsic activity, which occupies a speci c placental transporter, enzyme or other target antagonizing its effects. Such a compound could be used alone or in combination with other therapeutic compounds with the sole purpose of blocking drug transfer into the fetal compartment thus leading to maternal drug accumula- tion, or conversely, to block back transfer from the fetal compart- ment to maternal circulation leading to drug accumulation or persistence in the fetal compartment. Such a strategy is employed today with digoxin for fetal arrhythmias where Pgp inhibitors

Table 6.1 Placental expression of cytochrome P450 enzymes involved in drug metabolism

Placental maturity

Speci c enzyme

CYP1A1 CYP1A2 CYP2C8/9/19 CYP2D6 CYP2E1 CYP3A4-7

First trimester Term Inducible

R, P, A A, P, R Yes R A, P Yes R ND Yes R ND Yes A, R A, P*, R* Yes P, R P* R Yes

CYP – Cytochrome P450 isozyme. A – Activity; ND – No substantive activity/excesses detected; P – Protein; R – mRNA. *CYP2E1 has only been detected in the term placenta of heavy ethanol-consuming mothers. Adapted from reference 23.

6 Treating the placenta: an evolving therapeutic concept 79 Table 6.2 The expression of cellular transporter proteins in human placenta

Placenta

Transporter

First trimester

Second trimester

Third trimester

ABCB1 ABCB4 ABCC1 ABCC2 ABCC3 ABCC4 ABCC5 ABCC6 ABCC10 ABCC11 ABCG2 NET
SERT OCT1 OCT2 OCT3 OCTN1 OCTN2 OAT1 OAT4 OATP1A2 OATP1B1 OATP281 OATP3A1 OATP4A1

R, P R, P R, P, A R NA R
R NA R, P, A R, P R, P R, P

R NA R, P, A NA NA R, P
R R R, P, A NA NA NA NA NA NA NA NA R

R, P R, P R, P, A NA NA R, A NA NA R, P, A NA NA R, A NA NA R

R NA R, P, A NA NA NA NA NA R, P, A NA NA NA

P NA R, P
R NA R
R NA ND
P P R, P, A R NA R

R NA R, P

A – Activity; NA – Data not available; ND – Not detected; NET – Noradrenalin transporter; OAT – Organic anion transporter; OATP – Organic anion transporting polypeptide; OCT – Organic cation transporter; P –Protein; R – mRNA; SERT – 5-HT.
Adapted from reference 23.

6 Treating the Placenta: an Evolving Therapeutic Concept

80 6.4 The placenta as a therapeutic target today
Table 6.3 Therapeutic agents that are substitutes for P-glycoprotein and/or breast cancer

resistance protein

Cyclosporine Digoxin Erythromycin Indenavir Levo exacin Morphine Phenobarbital Phenytoin Ritonavir Saquinavir Veropamil

Glyburide Methotrexate Sulfated estrogens Zidovudine

Pgp

BCRP

 

Pgp – P-glycoprotein; BCRP – Breast cancer resistance protein. Adapted from reference 18.

(e.g. verapamil) are coadministered to enhance fetal compartment digoxin concentrations [22]. As noted above, this strategy is of variable success but clearly dependent upon the fetus’s gestational age [22].

6.4 The placenta as a therapeutic target today 6.4.1 Diabetes during pregnancy

Poorly or uncontrolled diabetes during pregnancy has been clearly shown to markedly increase maternal and fetal risk for a spectrum of untoward effects, many that are serious and attenuated or prevented with effective therapy [9, 26]. However, a major concern in the selection of drug therapy for maternal diabetes is strictly preventing fetal hypoglycemia [9, 17, 27–29]. The design of drug therapy for optimal treatment of maternal diabetes is a case study for the contemporary targeting of the placenta for successful therapeutics. In this case the target is exploiting the known in uences the placenta has on drug distri- bution and overall maternal disposition to limit fetal exposure [9, 17, 27, 29].

6 Treating the placenta: an evolving therapeutic concept 81

The best example of manipulation of maternal and placental function to in uence drug disposition for optimal maternal thera- peutics is the story of glibenclamide (Glyburide) [9, 17, 27, 29]. Glibenclamide (GBC) is an oral hypoglycemic drug that stimu- lates the pancreatic beta cells to secrete insulin and is often used to treat diabetes, including diabetes during pregnancy. This par- ticular drug dosing strategy capitalized on the known in uences of drug protein binding, maternal drug clearance rate, and af nity for placental–fetal transporters to achieve the desired therapeutic effect. Glibenclamide is highly bound to maternal plasma pro- teins (primarily albumin) to the extent of 99.8%. This extensive degree of drug binding to circulating maternal plasma protein substantially reduces the amount of free active drug available for placental transfer. Augmenting this effect is the drug’s relative short maternal elimination half-life (t{1/2}), minimizing the dura- tion of time the free GBC is present in maternal circulation for transplacental transfer. A third and extremely important charac- teristic of GBC is the drug’s af nity as a substrate for multiple ef ux proteins, P-glycoprotein (Pgp), multidrug resistant protein 1 (MRP1), 2 (MRP2) or 3 (MRP3) and breast cancer resistant protein (BCRP). Very recent data suggest that GBC may be pref- erentially transported from the fetal to the maternal circulations by BCRP [9, 15, 18]. When all three of these characteristics are combined, with the latter probably the most important to lim- iting drug access to the fetal compartment, highly effective and safe maternal therapeutic regimens can be constructed with easily achieved drug structure–activity relationships targeted at speci c maternal and placental function.

6.4.2 Malaria in pregnancy

Malaria during pregnancy is a medical as well as public health concern owing to maternal (anemia, fever, cerebral infection, hy- poglycemia, and death), placental, fetal (abortion, stillbirth, and congenital infection), and neonatal (prematurity, growth restric- tion, infection, and death) effects [14, 30, 31]. Therapy has been complicated by the emergence and rapid spread of drug resis- tance, necessitating combination therapy. In addition, malaria and HIV can be found in the same populations and interact to the detriment of the mother, placenta, and fetus [31, 32]. Finally, of special relevance are the interactions between malaria and the placenta, as placental malaria may be asymptomatic until adverse pregnancy outcome [33–35].

Drug development for malaria in pregnancy encounters two signi cant obstacles: malaria is a disease of developing countries and af icts women during pregnancy [30, 31, 36, 37]. Existing

6 Treating the Placenta: an Evolving Therapeutic Concept

82 6.4 The placenta as a therapeutic target today

treatments are poorly characterized with respect to pharmacoki- netics, pharmacodynamics, safety, and ef cacy yet the tools for studying the existing drugs and new drug development are readily available. Further complicating this scenario is the fact that Plas- modium falciparum, the most common human malarial species, manifests differently in pregnant women than in non-pregnant women. In pregnant women P. falciparum expresses a different antigen variant to that found in non-pregnant women. Malaria- infected red blood cells possess adhesive proteins on their surface which appear to interact with chondroitin sulfate on the placental surface [34]. These and other cellular perturbations lead to in- fected erythrocytes preferentially accumulating in the intervillous space of the placenta resulting in a thickening of the trophoblast basement membrane. This later event appears to be an adaptive mechanism in response to the enormous amount of secreted cy- tokines released in response to the infection. The thickened tro- phoblast basement membrane damages the syncytiotrophoblastic surface of chorionic villi [35] leading to the negative maternal and fetal consequences associated with this parasitic disease. Thus, an effective therapeutic strategy must not only focus on parasite eradication at the placental and peripheral levels but might con- currently target antagonism of select chemokines and cytokines elevated with placental malaria [35].

6.4.3 HIV-1 infection in pregnancy

As noted above, referring to the placenta as a “barrier”, the placen- tal barrier has been discouraged for decades and for the most part falsely. This myth has been dispelled for many decades [1, 3, 12]. For some, however, the placenta does serve as a barrier to fetal transmission of viruses. Cytomegalovirus easily crosses the syncy- tiotrophoblast to the fetus whereas the HIV-1 virus crosses very poorly. In untreated HIV-1 infected mothers more than 90% of their offspring will be HIV-1 negative re ecting the maternal and placental focus of the infection [28]. Mother-to-child transmission of HIV-1 can be reduced to <1% with the use of antiviral drugs dur- ing pregnancy and in the neonate. The most common antiretrovi- ral drug used to prevent maternal-to-child HIV-1 transmission is zidovudine – in 1994 maternal zidovudine (ZDV) monotherapy was clearly shown to decrease maternal-to-child HIV-1 transmission by two thirds [39]. Zidovudine is metabolized to its active moiety in the placenta and inhibits HIV-1 replication within placental cells [38].

The exact mechanism(s) of HIV-1 transmission in utero is poor- ly understood but the role of the placenta as the primary target

6 Treating the placenta: an evolving therapeutic concept 83

is clear. Histological examination of term placentas from HIV-1 positive women revealed HIV-1 infection in syncytiotrophoblast, cytotrophoblast, and villous endothelial cells. Similar histological examination of placenta at 16 weeks revealed syncytiotrophoblast and cytotrophoblast infection whereas chorionic villi were rarely involved [38]. All these data combined underscore the importance of the placenta as the primary therapeutic target for the preven- tion of mother-to-child transmission of HIV-1 infection. Further supporting this contention is the data showing increased expres- sion of human beta defensins, a natural defense mechanism in the maternal–fetal interface, in HIV-1 seropositive mothers [40].

Like malarial infection during pregnancy many factors in u- ence the ef cacy of maternal HIV therapy in preventing mother-to- child transmission. Understanding and accounting for the changes in drug pharmacokinetics during pregnancy (see Chapter 3) is of paramount importance to the ef cacy and safety of maternal and fetal drug therapy. Although the placenta is well perfused, inad- equate prevention, the development of HIV-1 drug resistance or drug-induced toxicity can occur if maternal antiretroviral drug dose regimens do not account for the changes in drug disposition observed throughout gestation. Sub-therapeutic antiviral drug tis- sue and uid concentrations can lead to inadequate fetal preven- tion and/or the development of HIV-1 drug resistance whereas too large doses may increase the risk of maternal and/or fetal toxicity.

6.5 The placenta as a therapeutic target in the future

The ideal drug for maternal therapy would be an agent that nei- ther reaches the fetal compartment nor alters maternal physiology suf ciently to adversely affect placental function. Similarly, the ideal maternally administered drug targeting the fetal compart- ment would have no negative maternal or placental effects. To our knowledge this “ideal” drug does not yet exist – but soon “they” will. Furthermore, a drug may be maternally administered to the mother to inhibit or stimulate individual or multiple placental functions to achieve the desired therapeutic goal.

The value of nanosized materials as a method for drug delivery, and more speci cally targeting speci c anatomic site delivery, is gaining considerable interest. The number of nanoparticle polymer constructs supporting the engineering of compounds with novel

6 Treating the Placenta: an Evolving Therapeutic Concept

84 6.5 The placenta as a therapeutic target in the future

physical and chemical characteristics has increased dramatically over the last decade [41]. Based on the ability to manufacture nanosized compounds (e.g. drugs) of speci c size, charge, and dis- integration characteristics it is not surprising that the maternal– placental–fetal compartments are speci c targets for ongoing re- search [41–43]. We envision that nanotechnology will foster the development of a number of speci c compounds that target spe- ci c placental characteristics, i.e. targeting speci c maternal sites, speci c placental sites, and/or fetal compartment penetration and binding to speci c fetal sites [41–43]. However, before these bene ts are fully realized the methodical study of placental nano- pharmaceuticals will provide tremendous insight into placental anatomy and physiology [43]. Advances in placental imaging, par- ticularly of transport mechanisms [44] and other functions, should augment the rate at which such new therapies are realized.

Lastly, the genomics of placental function will further expand the therapeutic armamentarium for speci c placental diseases and functions [45, 46]. Genetic technology has impacted greatly on the ability to detect perinatal genetic disorders and their susceptibility at multiple time points during gestation [45]. Pharmacogenomics in reproductive and perinatal medicine is in its infancy [46]. Although a few clinically useful drugs in perinatal medicine contain phar- macogenetic information in their of cial labeling, the relevance to contemporary perinatal care is extremely limited. Pharmacogenom- ics of placental receptors, transporters, enzymes, and other func- tions will be exploited for therapeutic purposes. As such, placental epigenetics are of great interest with respect to the treatment of pla- cental disease as well as possible manipulation of the fetal compart- ment by using the placenta as the “gateway to the fetus” [47]. Much more information serving to de ne speci c therapeutic targets is being described at a faster and faster rate as advances continue to occur in our technical capabilities. A recent example of such ad- vances described differential expression of several human placental proteins between lean and obese pregnant women that could lead to a number of therapeutic strategies targeting many maternal, pla- cental, and fetal perturbations [48]. This is just the beginning.

Conclusions

The placenta is the most important structure to the health and viability of the mother and the fetus and for fetal development up to delivery. Nevertheless, the majority of therapeutic strategies used during pregnancy today focus on manipulation of the placenta

6 Treating the placenta: an evolving therapeutic concept 85

for maternal or fetal therapeutics. Increasing information de nes the importance of therapies directed at, or focused on, the placenta for maternal–fetal health. Advances in molecular biology, tech- nology, imaging, and genomics are among just a few avenues that are fostering a much better understanding of placental anatomy, physiology, maturation, and pathophysiology and serving as the foundations for effective treatment of the placenta.

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6 Treating the Placenta: an Evolving Therapeutic Concept

What is Suf cient Evidence to 7 Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

Gabrielle Constantin, Gabriel Shapiro, Nils Chaillet and William D. Fraser

. 7.1  Introduction 89

. 7.2  Evidence, equipoise, and the ethical considerations
in deciding whether to conduct a trial 91

. 7.3  Why are failure rates so high for pregnancy drug trials
compared to other therapeutic areas? 92

. 7.4  Role of phase 2 trials 95

. 7.5  How to improve success rates 96

. 7.6  Learning from experience – the example of antioxidants and preeclampsia 97

Conclusions and recommendations 99

7.1 Introduction

Randomized controlled trials (RCT) are the gold standard for the evaluation of a new drug or technology. From the perspective of in- dustry, trials are a key component in the process of obtaining regula- tory approval and a “successful” or “positive” trial is one that moves the drug further down the pipeline from rst-in-human studies to- ward registration. Failure of a drug to complete this process is not

90 7.1 Introduction

uncommon and many drugs fail at the level of the phase 3 trial. During a 10-year period (1991–2000) for 10 large US and European pharmaceutical companies, the overall “success rate” was 11%. The rate of success for trials in Women’s Health was the lowest across sectors (less than 5%) [1]. Strand and Jobe [2] have noted the large number of negative trials in perinatal medicine and suggest that the situation requires a critical analysis.

Negative trials have a variety of costs, including nancial as well as the exposure of participants to the potential toxicity of unproven experimental treatments without associated bene ts. As well, there are “opportunity costs”, as only a limited number of trials can be conducted at a given time. On the other hand, “negative trials give us important information about biologic and pathologic processes, and help us avoid ineffective therapies. They lead us from one path of investigation and point us in new direc- tions. However, the large number of negative trials in the perinatal area does illustrate that we have poor preliminary information on which to base trials and little insight into what interventions may be bene cial” ([2], p. 348).

Over the last several decades, there has been a dearth of trials of new drugs conducted during pregnancy. Most of those that are conducted are investigator led, as pharmaceutical compa- nies have focused their efforts elsewhere. The limited funding that is available is from government agencies. This creates an urgent need to “get it right”: to invest in the evaluation of treat- ments for which there is a high probability of success. This begs the question: Can reasons for the failure of seemingly promising pregnancy drug trials be identi ed? In this review, examples of negative trials are provided and the degree and quality of evi- dence which served as the rationale for conducting these trials is explored. In doing so, we suggest that there is a great deal of variation regarding the level of evidence that is deemed suf- cient to move forward with a phase 3 trial. We posit that we can learn from negative trials in order to be able to improve study design, to better select research questions and outcomes, and to better select among the various potential candidates for phase 3 trials.

In fact, the evidence required to justify the decision to conduct a phase 3 RCT in the area of maternal–fetal medicine has not been adequately de ned. The main objective of this review is to propose criteria that may be applied by investigators and by fund- ing agencies to assess if there is suf cient evidence to proceed to a phase 3 trial. In addition, we will attempt to identify risk factors for failure of phase 3 trials.

7 What is suf cient evidence to justify a multicenter phase 91

7.2 Evidence, equipoise, and the ethical considerations in deciding whether to

conduct a trial

“A trial with methodological weaknesses is both a waste of resources and unethical” ([3], p. 141). The same could be said of a trial based on insuf cient evidence.

A clinical trial is “warranted if there is suf cient but not de nitive evidence that the intervention to be assessed would have a favorable risk–bene t ratio in the population to be enrolled” ([4], p. 165). Equipoise is an ethical standard, and it was proposed to identify scenarios where conducting an RCT would be unethi- cal. Some authors take equipoise to be suf cient justi cation for a trial. However, this should not be the case. Equipoise is a neces- sary but not suf cient prerequisite to justify a trial. Phase 3 trials are costly and as such the number that can be conducted is limited – far fewer than the number of current and potential treatment approaches that could be tested. When the scienti c community gives the green light for a given trial, they are in some ways “say- ing no” to others, as funds are limited and not every clinical ques- tion warrants its own trial.

A sharpened de nition of equipoise has been proposed as “a state of genuine agnosticism or con ict in the expert medical community about the net preferred medically established pro- cedure for the condition under study” [5]. Physician-researchers and members of institutional review boards (IRBs) “[…] have the responsibility to evaluate the extent to which a proposed random- ized clinical trial solves a state of agnosticism or a knowledge con ict in the expert medical community” [5].

As stated by Strand and Jobe “large RCTs (phase 3) are per- formed to con rm preliminary information that suggests that a treatment or intervention will result in a clinically important improvement in outcomes for patients. The major roles of the large multicenter RCT are to verify the primary hypothesis, better quantify the magnitude of the clinical effect, better de ne poten- tial risks because of the increased numbers of patients exposed to intervention, and establish if the intervention can be translated to clinical practice” ([2], p. 343). The hypothesis for a trial “usu- ally arises from a scienti c rationale and early empirical evidence, sometimes including information from laboratory or animal studies” ([6], p. 519). It is important to note that the decision to conduct a phase 3 trial requires not only empirical evidence, but a sound biological rationale and well conducted phase 2 studies.

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

92 7.3 Why are failure rates so high for pregnancy drug trials 7.2.1 Summarizing the evidence

A phase 3 trial is only warranted after the available evidence has been reviewed and assessed, usually through a meta-analysis. The proposed RCT must add to the existing knowledge base; thus, it is important to establish what information is missing from the cur- rent knowledge base so that the trial can be designed to ll these knowledge gaps. A thorough understanding of the available evi- dence is key to formulating the appropriate research question, in assessing the target population, in estimating the effect size, and in assessing feasibility.

“If available evidence is reliable and already provides a de ni- tive answer, there is no need for a study, although there may be a need for a study in a speci c target group or a larger study to re- ne therapeutic strategies or de ne optimal ‘dosage’” ([3], p. 141). The philosophical question arises as to what constitutes suf cient evidence to consider that a treatment is ef cacious. If the estimate derived from a number of small trials shows a signi cant effect, de- spite none of the individual trials showing a statistically signi cant effect, what conclusion should be drawn? Is an additional large RCT justi ed? This question is even more dif cult to address given that studies have underlined the discrepancy between the ndings of meta-analyses and the largest trials of the same therapy [7, 8].

A trial is warranted when there is “equipoise”, that is when there is a “reasonable” balance between an existing treatment (or, in some cases, placebo when no effective treatment is available) and the experimental treatment. This is a delicate balance between the presence of insuf cient evidence to justify a trial (in which case more preliminary/elementary research is needed) and a state of overabundance where an additional trial would not be ethically acceptable. Different IRBs can disagree markedly on the same pro- tocol as to their opinion as to the presence or absence of equipoise [4]. This may re ect variations in the expertise on the IRB. As well, it re ects the absence of guidelines regarding what is evidence of suf cient quality to justify a trial.

7.3 Why are failure rates so high for pregnancy drug trials compared to other therapeutic areas?

An investigation into risk factors for failure of phase 3 trials may be informative in developing a set of criteria to be met to justify the decision to conduct such a trial. The stepwise process of drug

7 What is suf cient evidence to justify a multicenter phase 93

development seen in most major therapeutic areas such as car- diology and neurosciences is not frequently applied in develop- ment of drugs for use in pregnancy. Because few new drugs are developed speci cally for obstetrical use, the process for “obstet- rical drug development” is essentially “a repurposing” [9]. “For diseases with large populations eligible for therapy, drug devel- opment occurs through systematic searches for targets that can alter disease progression, and testing candidate drugs for ef cacy, safety and pharmacokinetic characteristics in vitro and in animals (preclinical studies), followed by human studies if preclinical studies are successful. This research produces stepwise submis- sion of data to a regulatory agency…for consideration of the drug for marketing with a speci c disease indication and approach for a speci c population (e.g. age, sex, race/ethnicity) as supported by the regulatory submission and described in the product label [4–6]. Unfortunately, drug development for women during preg- nancy…is not addressed by a structured search for targets and therapeutic molecules [13–17]” ([9], p. 437) The lack of a system- atic approach could very well be responsible for the lower success rates of obstetrical drug trials.

Following a selective review of a number of negative perinatal trials, Strand and Jobe ([2], p. 343) suggested reasons for failure to validate the primary hypothesis. In general, the rationale for negative trials was frequently based on the ndings of small trials or a meta-analysis of multiple small trials which were not meth- odologically robust. “The weak preliminary information together with limited numbers of patients, problematic primary outcomes and a poor understanding of the biology of neonatal diseases has limited the ability to reliably design trials with positive outcomes” ([2], p. 343). A single small trial has the potential for alpha error and publication bias. On the other hand, other perinatal trials that were based on more compelling evidence have also yielded nega- tive results ([2], p. 346). In some cases, changes in clinical care may have negated any bene t. Strand and Jobe [2] have noted that hypotheses may be based on a poor or erroneous understand- ing of the underlying biology of the targeted condition. Treatments that involve a failure or impossibility of blinding open the door to bias. Studies may be underpowered to detect small but clinically important differences. “Center effect” or variations across centers, particularly in the case of complex interventions, may dilute the effect and reduce power to detect a difference.

Gordion et al. [10] examined “attrition rates” (a failure of a new therapy to continue down the drug pipeline) in 656 phase 3 drug trials from a range of treatment areas undertaken between 1990 and 2002 by large pharmaceutical companies. Of these,

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

94 7.3 Why are failure rates so high for pregnancy drug trials

42% failed during phase 3. The causes of failure for 73 of the failed phase 3 trials (the only ones where enough public data were available to perform an analysis) were identi ed as ef cacy, safety problems, and “lack of differentiation”. An additional study [1] found very similar results. “The major causes of attrition…were lack of ef cacy (accounting for approximately 30% of failures) and safety (toxicology and clinical safety accounting for a further approximately 30%)” ([1], p. 712). Gordion et al. [10] found “50 percent of the drugs failed in phase III because they could not be proved effective: the trials could not demonstrate that the drugs were more medically effective than the placebo” (lack of differ- entiation). This is surprising given that demonstrating ef cacy is, after all, a primary objective of phase 2 trials. Among the remain- ing drugs that failed, 31% posed safety concerns. “An additional 19 percent were found to be neither safer (i.e. given similar ef – cacy, failure to demonstrate superior safety versus an active com- parator) nor more effective (i.e. given similar safety pro le, failure to demonstrate superior ef cacy versus active comparator) than drugs currently on the market” ([10], p. 2).

A few factors have been identi ed which help to explain fail- ure to show ef cacy. “The less established the drug’s mechanism and the less objective the endpoints, the higher the drug’s risk of failure.” Drugs combining the two higher-risk factors – novel mechanisms and less objective endpoints – failed 70% of the time, compared with 25% for drugs with known mechanisms and more objective endpoints ([10], p. 4). Studies of drugs involving novel mechanisms may involve hypothesized effects rather than proven effects.

How do we assess the plausibility of an effect of a drug involv- ing a novel mechanism? Malek and Mattison’s [9] criteria for the identi cation of promising pharmaceuticals for use in the perina- tal period can be adapted to assist in considering the appropriate- ness of a drug proposed for the treatment of a perinatal condition as well as the selection of dose. The following questions should be addressed: [1] Among the classes of molecules that have po- tential ef cacy [for] treating the condition of interest (maternal, placental or fetal condition), is the proposed molecule the best choice? Are preclinical pregnancy models of the disease pro- cesses available to help guide evaluation of the molecule prior to use in humans? [2] Among the classes of molecules avail- able, is the molecule proposed preferable for pharmacokinetic, pharmacodynamic, safety or ef cacy reasons? [3] In designing clinical trials, how will the results of dose nding and treatment be evaluated? Are therapeutic concentrations de ned in media that can be sampled (e.g. maternal urine, blood, exhaled breath or

7 What is suf cient evidence to justify a multicenter phase 95

amniotic uid)? Do pharmacokinetics and pharmacodynamics change [occur] across the course of pregnancy and how will that alter dosing and therapeutic end points monitored? [4] How will the clinical trial monitor drug toxicity or adverse events, and over what period of time will those potential adverse events be monitored? “Drug development should spring from our under- standing of the maternal, placental or fetal disease we intend to treat, recognizing that there may be sites of drug activity (toxicity) away from the therapeutic targets” [9].

Lack of objectivity of endpoints in phase 2 precursor studies is another reason for failure of phase 3 studies. Trials with less objective endpoints at phase 2 failed approximately 10% more often than those with more objective endpoints [10]. An endpoint was considered objective if it could be measured with diagnostic tests whose results could be “easily reproduced, or with a scale that was both professionally measured and widely used” ([10], p. 3) Endpoints were considered less objective “if they relied on less easily reproducible measurements, uncommonly used scales, or self-reporting by patients” ([10], p. 3).

7.4 Role of phase 2 trials

Testing the biological activity, dosage, and safety pro le of the drug in question requires thoroughness. An important risk factor for failure in phase 3 is a phase 2 clinical trial that has not been done or that has been poorly conducted. The goal of phase 2 trials is to determine if a pharmacological activity can be measured by a number of objective or subjective endpoints and how well this activity compares to that of a placebo or active control. Determi- nation of drug dose and the collection of information pertinent to the design of a phase 3 program are other goals. Safety remains a strong component of phase 2 programs. Serious toxicities may be observed for the rst time in a phase 2 trial.

In the area of critical care, many large clinical studies are based on “small pilot investigations with inadequate phase 2 trial data, and on limited mechanistic data…” ([11], p. S124). The same can be said of some large perinatal trials.

“A successful Phase 2 program should have established that the candidate drug has ‘activity’ in the indication tested and the target population of interest. A well-run Phase 2 program would also have provided information about the appropriate dose for the piv- otal studies and provided an estimate for the sample size required for the Phase 3 trials. The team must then decide if the drug meets

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

96 7.5 How to improve success rates

the ‘desirability quotient’ for further development…” ([12], p. 6). To quote Retzios: “We can divide de ciencies in the Phase 2 clini- cal trials in the following categories: (a) inadequate design; (b) endpoints with a tenuous connection to clinical-bene t-based Phase 3 endpoints; and (c) improper execution. These categories are not mutually exclusive; a failed program may span a number of them” ([12], p. 7).

7.5 How to improve success rates

It is possible to build a framework for improved trial success cen- tered on avoiding the above-identi ed risk factors for failure by systematically establishing and adhering to rigorous prerequisites for a trial. Many therapeutic areas boast higher success rates for phase 3 trials compared to obstetrics [1]. Success rates in obstet- rics can be improved by drawing from strategies used in other clinical areas.

Failure at the phase 3 stage to demonstrate safety and ef ca- cy frequently stems from inadequate understanding of underly- ing biological mechanisms and insuf cient evidence from earlier stage clinical trials. Experimental medicine paradigms must be strengthened in obstetrics to improve the ability to predict and af- fect clinical outcomes. Funding bodies must improve ef ciency in the overall scheduling and planning of clinical trials, with a suf – ciently strong focus on proof-of-concept clinical trials in the early stages of drug development to justify larger later-stage studies. Fi- nally, more predictive animal models must be used in the develop- ment of therapeutic agents for obstetrical populations [1]. While animal models play a signi cant role in perinatology research, their utility in the drug development process has been to some ex- tent hampered by limited understanding of underlying biological processes in pregnancy. In addition, differences between human pregnancy and that in other animals present particular challenges in obstetrical research.

Small treatment effects can be of major clinical importance, and phase 3 trials must be adequately powered to detect such ef- fects. Small but clinically important effects have been observed in phase 3 trials in other therapeutic areas. For example, the MRC/BHF Heart Protection Study of more than 20,000 high-risk individuals demonstrated a reduction in all-cause mortality from 14.7 to 12.9% (p=0.0003) and in coronary death from 6.9 to 5.7% (p=0.0005). Statin trials such as this have led to substantial changes in clinical care, despite showing smaller absolute effect

7 What is suf cient evidence to justify a multicenter phase 97

sizes (1.8 and 1.2% for all-cause mortality and coronary death, respectively) than nonsigni cant effects found in smaller trials from other therapeutic areas [2].

Frameworks for improved trial success based on identi ed risk factors for failure have been proposed and utilized in several branches of medicine. A useful example comes from the area of critical care. Like obstetrics, critical care has suffered from mul- tiple negative phase 3 trials. McAuley et al. [11] have proposed a stepwise approach to justify phase 3 RCTs in critical care in order to enhance the likelihood of positive results. The construction of this framework stemmed from an increasing recognition of the need to improve clinical trials in the area of critical care, a need that has not yet been saliently recognized in obstetrics.

The stepwise approach to justify phase 3 trials in critical care holds several valuable lessons for obstetrics. For example, one as- pect common to pregnancy complications and critical care injuries is the heterogeneity of causes for a given condition. Accordingly, outcome de nitions must be suf ciently speci c and clinical trials designed to account for, or in some cases minimize, heterogeneity of the study population (appropriate patient selection). Also, phase 3 trials often fail to achieve planned sample size due to poor re- cruitment or high attrition rates. Effective recruitment and follow- up strategies may require a stronger commitment from funding bodies and study leaders.

7.6 Learning from experience – the example of antioxidants and preeclampsia

In addition to examining challenges faced in other clinical areas and drawing on their successes, we can learn from our own ex- perience. A powerful and potent opportunity for such re ection can be found by examining the failure of phase 3 clinical trials to demonstrate effectiveness of antioxidants in the prevention of preeclampsia.

Oxidative stress is believed to play a role in a number of clinical disorders in obstetrics, including preeclampsia, a major contribu- tor to maternal mortality and maternal and perinatal morbidity. There is a substantial body of evidence linking oxidative stress to preeclampsia, although it remains uncertain whether this is a primary or a secondary phenomenon.

In 1999, Chappell et al. [13] reported the results of a phase 2 trial of the effects of the prophylactic administration of anti- oxidant vitamins C and E in pregnant women. Women with risk

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

98 7.6 Learning from experience – the example of antioxidants

factors for preeclampsia were included in the trial, the most fre- quent being a positive screen on uterine artery Doppler. The trial was stopped before the full sample size could be achieved, as the proportion of women experiencing preeclampsia, as observed in an interim analysis, was reduced in the active treatment group. In fact, a biochemical indicator of endothelial dysfunction (PAI- 1:PAI-2), and not preeclampsia, was the major endpoint of this phase 2 trial. However, the relationship of this marker to clinical disease was unclear. Furthermore, at the time that the study was initiated, little information was available as to whether the doses of vitamins C and E administered were those most likely to pro- duce an antioxidant effect.

Thus, while the ndings of this phase 2 study were exciting, it suffered from those limitations that placed subsequent phase 3 studies at high risk of failure: absence of data on dose- nding, un- certain mechanism of action, and high risk of alpha error due to early stopping of the phase 2 trial. Subsequently, nine large mul- ticenter trials, including patients at high risk of preeclampsia and those where nulliparity was the only identi ed risk factor, were conducted to assess the role of vitamins C and E in the prevention of preeclampsia [14]. All yielded negative results. One of the trials was led by the senior author of the current chapter (WDF), and was stopped before recruitment was completed due to concerns raised in the intercurrent reporting of a separate trial about possi- ble effects of the intervention on the risk of low birth weight [15].

Could this have been avoided? In retrospect, given the limi- tations of the initial phase 2 study, the most prudent approach might have been simply to attempt to replicate the ndings using a rigorous design and predesigned stopping rules, while collect- ing more data on possible biological mechanisms. Or, at the very least, through international collaboration, could a single trial have been conducted rather than separate trials in Canada, the UK, the US, Australia, and Brazil?

The decision to conduct phase 3 studies in such a context should be based on a cross-disciplinary consensus, involving both basic scientists and clinical trialists. From a global perspective, in order to optimize the use of scarce resources, international exper- tise and collaboration should be brought to bear on prioritizing research questions, so that only studies meeting the most rigorous criteria at the phase 2 level are given priority for phase 3 research.

The result of this “cumulative” failure has been that even those who have been longstanding leaders and supporters of clinical research in preeclampsia expressed a skepticism regarding the impact of large trials. “Thus for over a decade now, many large and expensive multicentre randomized trials have failed to show

7 What is suf cient evidence to justify a multicenter phase 99

signi cant reductions in the incidence of preeclampsia, or, when positive results occurred, the signi cance was small and the num- ber to treat large” ([16], p. 1119).

Conclusions and recommendations

As we have demonstrated in this chapter, one of the problems we are faced with is an absence of clear criteria about what con- stitutes suf cient evidence to move forward with a phase 3 ob- stetrical drug trial. The lack of systematic criteria is of signi cant concern because of the high stakes entailed by these studies: large well-conducted RCTs are expensive, time consuming, and a strain on nite resources [17]. Obstetrical trials also draw from a limited pool of patients. A negative phase 3 trial that could have been avoided with improved planning constitutes a signi cant waste of resources. Yet another crucial issue highlighted in this chapter is the absence in the scienti c literature of the recognition of the need to establish such systematic criteria in the rst place.

In order to be justi ed, phase 3 trials require rigorous phase 2 studies that [1] have been rigorously conducted from a method- ological perspective; [2] demonstrate some measure of ef cacy on unequivocal endpoints – either the disorder itself or on a marker that has been con rmed to be part of disease pathophysiology; and [3] when a new molecule is introduced, or when a medica- tion is repurposed for an indication other than that for which it was initially intended, the mechanism of action should be clearly understood. Phase 2 studies should also produce a suf cient dem- onstration of safety and should determine the adequate dosage most likely to provide clinical bene t.

To compile and assess the phase 2 evidence on novel thera- peutic agents, studies must be evaluated using carefully executed systematic reviews that suf ciently take into account the potential for publication bias and type I error in individual studies. In cases where phase 2 trials were not conducted with adequate statistical rigor or when results are statistically questionable, “promising” ndings should be replicated with further phase 2 studies rather than moving prematurely to a phase 3 trial. When meta-analyses and RCTs on a subject are contradictory, careful consideration must be taken to ensure that the decision on whether to move ahead with a phase 3 study is based on a complete review of all available data.

Several steps can be taken to improve consistency in the IRB review of obstetrics trials. Summarizing and assessing the existing

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

100 References

evidence base on novel therapeutic agents is a complex task requir- ing time and skill. It is essential that funding agencies be equipped with the necessary expertise and resources to make such decisions. Investigators can help by including in phase 3 RCT proposals a demonstration of robust phase 2 evidence and a known biological mechanism of action.

Further collaboration between both basic science and clinical trial researchers across centers, as well as open dialogue between all experts in the eld, could go a long way in optimizing the use of scarce resources in the area of obstetrical drug trials. For this reason, we urge all researchers active in this discipline to par- ticipate in evaluating and critiquing the studies published by their peers. Critical review of small or preliminary studies should make clear their merits and faults; this would undoubtedly aid in iden- tifying promising avenues for further research and minimizing the risk for failure of any subsequent trials.

References

[1] Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3:711–5.

[2] Strand M, Jobe AH. The multiple negative randomized controlled trials in perinatology: why? Semin Perinatol 2003;27(4):343–50.

[3] Morley R, Farewell V. Methodological issues in randomized controlled trials. Semin Neonatol 2000;5(2):141–8.

[4] Stark AR, Tyson JE, Hibberd PL. Variation among institutional review boards in evaluating the design of a multicenter randomized trial. J Perinatol 2010;30:163–9.

[5] van der Graaf R, van Delden JJ. Equipoise should be amended, not abandoned. Clin Trials 2011;2011(8):408–16.

[6] Field D, Elbourne D. The randomized controlled trial. Curr Paediatrics 2003;14:519–24.

[7] Villar J, Carroli G, Belizan JM. Predictive ability of meta-analyses of random- ized controlled trials. Lancet 1995;345(8952):772–6.

[8] LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 1997;337(8):536–42.

[9] Malek A, Mattison DR. Drug development for use during pregnancy: impact of the placenta. Expert Rev Obstet Gynecol 2010;5(4): 437–354.

[10] Gordian M, Singh N, Zemmel R, Elias T. (2006). Why products fail in phase III. IN VIVO 2006;24:49-54.

[11] McAuley DF, O’Kane C, Grif ths MJ. A stepwise approach to justify phase III randomized clinical trials and enhance the likelihood of a positive result. Crit Care Med 2010;38(10 suppl.):S523–7.

7 What is suf cient evidence to justify a multicenter phase 101

[12] Retzios A. Why do so many phase III clinical trials fail? Bay Clinical R&D Services 2009; Retrieved from http://www.adrclinresearch.com/Pages/WhyP ivotalClinicalTrialsFail_abstract.aspx.

[13] Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occur- rence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;354:810–6.

[14] Rumbold A, Duley L, Crowther CA, Haslam RR. Antioxidants for preventing pre-eclampsia. Cochrane Database Syst Rev 2008;1:CD004227.

[15] Fraser WD. International trial of antioxidant for the prevention of preeclamp- sia. http://controlled-trials.com.

[16] Lindheimer MD, Sibai BM. Antioxidant supplementation in pre-eclampsia. Lancet 2006;367(9517):1119–20.

[17] Chan JK, Ueda SM, Sugiyama VE, Stave CD, Shin JY, Monk BJ, et al. Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success? J Clin Oncol 2008;26(9):1511–8.

7 What is Suf cient Evidence to Justify a Multicenter Phase 3 Randomized Controlled Trial in Obstetrics?

Ethics of Clinical 8 Pharmacology Research
in Pregnancy

Marvin S. Cohen

Questions for further discussion 111

There is no need for ethics in a world free from con icts. In clini- cal research there is, however, one inherent con ict. Research subjects are at risk of incurring multiple harms without any guar- anteed direct bene t. Instead they are exposed to variable risks solely for the possible bene ts to themselves or to future genera- tions in the form of generalizable knowledge. In 1979 the federal government commissioned the Belmont commission to recom- mend ways to guarantee safe and ethically sound research [1]. Their report canonized three principles of ethical research. The rst principle of bene cence demands that all risks be minimized and proportionate to bene ts, while the second principle of re- spect for autonomy should be ful lled with a rigorous informed consent process. Justice, the third principle de ned in the Bel- mont report, directed that all factions of society share equally the bene ts and risks of research. Federal regulations establishing in- stitutional review boards (IRBs) and review policies were enacted to ensure the implementation of these recommendations [2].

Yet, despite this effort to encourage safe and ethical research, studies on the speci c effects of most drugs during pregnancy are lacking [3]. The Cochrane report on psychopharmacologi- cal agents in pregnancy recently bemoaned the sorry state of our knowledge of prescribing and using these agents in pregnant pa- tients [4]. Anyone who is pregnant or whose loved one is preg- nant has witnessed the consternation of not knowing whether to continue using these medicines or not. The occasional headache or upper respiratory infection can be a cause for hours of soul searching about whether the pregnant woman should take over- the-counter medications.

104 8 Ethics of clinical pharmacology research in pregnancy

In 2009 the Hastings Center published a paper that demonstrat- ed continuing biases among both medical professionals and the media about the risks of pregnancy. CT scans are rarely prescribed to pregnant patients with abdominal pain even though the risk of misdiagnosing an appendicitis is much greater than the risk of the exposure of the pregnant patient or the fetus to the radiation dose of a CT scan [5].

An online search for drugs that are safe during pregnancy re- peatedly nds that even the best sites use language that can easily be understood to discourage the use of any medications during pregnancy. For example, the website “E-medicine” has this sen- tence in its introduction to the chapter on teratology and drug use during pregnancy: “Because any medication can present risks in pregnancy, and because not all risks are known, the safest preg- nancy-related pharmacy is as little pharmacy as possible” [6]. The same article notes that while some studies quote the frequency of drug-related fetal complications at 1–3% the article authors could nd no evidence to corroborate this number.

Table 8.1 summarizes the conditions that need to be satis ed to guarantee an ethical study.

Ethical research requires clinical equipoise. In order to begin a clinical research project there must be a lack of a scienti c consen- sus for the optimal therapeutic option for a particular diagnosis. In other words, for a given clinical situation no speci c treatment has been shown to be preferable among various alternatives. Usu- ally one positive study is not enough to alter the clinical equipoise of the physician. Only after a number of studies have shown the same result can a therapy be considered a true advance.

Table 8.1 Necessary conditions for ethical clinical research [7]

Generates useful knowledge that has social bene t Previous theoretical and animal studies have indicated a high chance of a positive result A demonstrated need to include human subjects in order to ensure scienti c validity Clinical equipoise of both the researcher and subject

A favorable risk–bene t ratio
An equitable selection process of subjects
A thorough, informed consent process Independent review, authorization and follow-up of the study design, protocols and results Opportunity for subjects to withdraw at any time Protocols for secure handling of all data and personal identifying information Prompt noti cation and treatment of all complications

 

8 Ethics of clinical pharmacology research in pregnancy 105

Clinical equipoise should also be clear to the research subject. If the potential subject enrolls in the study because she believes she will get optimal treatment, there is a risk that she will mistake the research study for a proven treatment. This mistake is called the therapeutic misconception. In many studies the clinical re- searcher may be part of the clinical team treating the patient. It is easy for a patient to assume that her treating physician would only want the best treatment for her and therefore agreeing to par- ticipate in the study is the best treatment. This is the therapeutic misconception since in reality there is no “best treatment”.

Ensuring a favorable risk–bene t ratio requires a detailed un- derstanding of both the risks and bene ts of a study. The bene ts of research participation to the individual include direct bene ts to the subjects from possible exposure to new and improved ther- apies. Indirect bene ts include more access to the medical team, a promise of hope, and the psychological bene ts of being a Good Samaritan. Reimbursements and minimal payments are also an acceptable bene t if provided at a level that is not unduly coercive to disadvantaged populations. The risks of research participation include the complications of the medical procedures and of the experimental therapy itself, the inconveniences of multiple visits, and the possible violation of privacy.

The necessary components of a rigorous informed consent pro- cess are delineated in Table 8.2.

What differentiates research on pregnant patients from any other clinical study? With pregnancy we have two subjects instead of one; mother and fetus. The risks and bene ts of the research must be balanced for both of these patients. However, the fetus is clear- ly not able to give consent to this calculation. It is, therefore, the joint responsibility of the mother and the researcher to guard the interests of the pre-viable fetus, but it is the mother who must give her informed consent to participate in the study.

Drs Chervenak and McCullough have published extensively on the ethics of research with pregnant subjects. Their suggestions are a productive way to work through the ethical issues surrounding

Table 8.2 Necessary components of informed consent [8]

Competency Disclosure Absence of coercion Choice Authorization

 

8 Ethics of Clinical Pharmacology Research in Pregnancy

106 8 Ethics of clinical pharmacology research in pregnancy

research with pregnant subjects. They understand the fetus to have dependent moral status [9, 10]. Accordingly, the pre-viable fetus has moral status only because the mother has decided to bring the baby to a live birth. This moral status is therefore conferred by the mother and could be withdrawn at any time before viability. It is the mother that must consider the research risks and bene ts to the dependent fetus as well as her own risks and bene ts. This approach expresses respect for the pregnant patient’s autonomy as she is authorized to give consent. It protects both the fetus and mother from undue harm since possibilities of harm to both enti- ties are taken into account. It ensures the woman’s active involve- ment in her care without interference by others. Finally, it supports her personal freedom of choice within the therapeutic milieu.

Federal regulations and case law agree with this approach. Part B of these regulations mandates that only the mother needs to give informed consent to participate in research that may bene t either herself as a pregnant subject or both herself and the fetus [11]. (Phase I studies where there is no bene t to the mother or researcher will be considered below.) The regulations make an exception for research that only bene ts the fetus, in which case the federal regulations stipulate that an attempt must be made to obtain paternal consent. Some drugs that may be studied are given in pregnancy for the sole bene t of the fetus. These include steroids for fetal lung maturity and digoxin for fetal tachycardia. One example of such research that bene ts only the fetus is a study to determine the ef cacy of Flecainide as an alternative to digoxin for fetal supraventricular tachycardia [12]. Both the ob- stetric community and many women’s groups are disputing the inclusion of paternal consent in this type of research by impugn- ing the autonomous rights of the pregnant women.

In the past the pregnant patient has been excluded from most drug-related research. In 1977 the FDA (Food and Drug Adminis- tration) issued “General Considerations for the Clinical Evaluation of Drugs” [13]. These regulations excluded all women of child- bearing potential from participating in phase 1 and early phase 2 studies. The FDA in 1993 attempted to remedy this situation by issuing more liberal guidelines dedicated to include all populations in research projects [14]. However, as we have seen above there is still a lack of pharmacological research on pregnant subjects.

In dedicating a section in the federal regulations to pregnant women, in addition to other populations such as children and prisoners, the government may have dangerously strengthened the idea that pregnant women are a vulnerable population. It is true that pregnant subjects can be considered a special subset because they have responsibilities to both fetus and themselves.

8 Ethics of clinical pharmacology research in pregnancy 107

But it must be clearly stated, “Being pregnant does not by itself result in diminished decision-making capacity” [15]. Grouping pregnant patients with vulnerable populations unnecessarily ob- scures this fact. This unfortunate label is one reason IRBs are unduly hesitant to approve research involving pregnant women.

Ethical research including pregnant patients is generally under- stood to require balancing the risks and bene ts to the patient and fetus. But Brody rightly pointed out that Part B as written requires us only to minimize the risks [16]. It does not mention balanc- ing risks and bene ts. Minimizing risks can be accomplished by a stepwise process beginning with adequate animal studies done only on drugs that have a sound theoretical basis for assuming their safety and ef cacy. Those drugs that have been shown to be safe and promising in animals should then be studied in non-preg- nant humans to minimize the risk to pregnant women. Only after this should studies include pregnant women. In addition many drugs have been in wide clinical usage without reports of serious or frequent side effects in pregnant patients, although they have never been formally studied in pregnancy. These drugs should be the rst drugs of a certain class to be studied in pregnant subjects. In 2005 the European Medicines Agency’s (EMEA) Guideline on the Exposure to Medicinal Products During Pregnancy encour- aged the systematic collection of data on complications in these drugs as a way of increasing our knowledge where randomized double blind studies are lacking [17]. Pharmacokinetics studies of these drugs can also be done with minimal risk as they would have been prescribed for the patient even without the study.

Studies such as phase 1 inquiries with no therapeutic bene t require the more stringent criterion of minimal risk to the fetus because there is no direct bene t to either the mother or fetus in these studies. But this concept of “minimal risk” can be ambigu- ous. Minimal risks are de ned in the federal regulations as the risks which research subjects accept while performing their daily activities [2]. These risks might include the danger of being hit by a car when crossing the street or drowning when swimming in the sea. But should these be daily risks of a generic person? Or perhaps it should be a sick person who clearly experiences greater daily risks from hospitalization or treatment? In general the daily risks incurred by the speci c subject should be used in determin- ing minimal risk, as this is the most stringent criterion.

The process of informed consent with a pregnant subject should be very vigorous since including a pregnant woman in research involves two subjects. Many of the decisions affecting a pre-viable fetus may be irrevocable. The subject must be able to articulate her understanding of the risk–bene t calculations for both herself and

8 Ethics of Clinical Pharmacology Research in Pregnancy

108 8 Ethics of clinical pharmacology research in pregnancy

her fetus. A written record of this understanding is preferable, as it will insure that the subject has made the necessary determinations. Regulations regarding pregnant teens are governed by individ- ual states. Every researcher must be familiar with the standards applicable in her region. In most instances one parent of the ado- lescent research subject must give consent while the adolescent herself should articulate her understanding and consent to the

research project.
Unforeseen complications may arise during the research pro-

tocol that may necessitate decisions about termination of the pregnancy. The research team should not be involved in these decisions. Instead, the primary care provider should be consulted. This possibility is a good reason to include the patient’s primary physician at the earliest stages of the consent process.

There have been many recent disclosures of serious misconduct in research due to apparent con icting interests of the researchers [18, 19]. Although such deviations have not yet been reported in pharmacologic research in pregnant patients, this probably is a result of the paucity of such studies. Con ict of interest in research occurs when the researcher, who is entrusted with the public trust, is unduly tied to secondary interests that compromise his primary trust. The primary responsibilities of researchers must be the best interests of the research subject and the scienti c validity of the study. This is self-evident, yet research is being compromised because it seems that fortune and fame are unquenchable human drives that can cloud the judgment of anyone, including academic scientists [20]. A desire for academic promotion and recognition is another exam- ple of the stumbling blocks that all of us must be wary of. The old adage of “publish or perish” that has been replaced by “get funded or get red” creates a very competitive academic climate.

A study from 2003 published in JAMA [21] found that over 25% of academic researchers had nancial relationships with in- dustry. The same study found that industry-sponsored research sometimes used awed control arms, and that the published con- clusions tended to be overwhelmingly positive. Although no di- rect connection was found, the inference was made that privately funded research can be biased towards reporting positive results.

Even the appearance of con ict of interest can taint many sub- jects’ willingness to enroll in a study. They may ask, “Why should I put myself at risk when only the researcher stands to materially bene t from my sacri ce?”

To minimize con icts of interests and to ful ll our duty to re- spect our subjects, disclosure of all pertinent nancial interests is now mandated [22]. It is hoped that by openly acknowledg- ing possible con icts the researcher will be more focused on his

8 Ethics of clinical pharmacology research in pregnancy 109

primary responsibilities, and the subject will be better informed about her total exposure to risks. These con icts must be dis- closed to the IRB and through their reporting to the sponsoring institutions and to the NIH (National Institutes of Health) or FDA if appropriate. The same standards of disclosure also apply when publishing research results. In general you should disclose anything you feel uncomfortable revealing to the subject, institu- tion, or company.

Protecting the personal health information (PHI) of patients and research subjects is a major concern in this age of electronic data. See Table 8.3 [23].

Preventing PHI from being made public without consent dem- onstrates respect for personhood. More practically it can avert the multiple harms that breaches of privacy can cause. These harms include economic loss, social embarrassment, psychological dam- age, and legal complications.

Successful strategies can minimize breaches of privacy. It is im- portant to choose an innocuous study name. Stringent protocols to code electronic data and secure all paper data and electronic storage must be implemented. Staff should undergo ongoing train- ing including instructions to limit oral communication about indi- vidual subjects’ private spaces.

In the case of a breach of privacy, the subjects must be im- mediately informed and the breach reported to the supervising authorities.

This chapter reviewed the ethical issues surrounding clini- cal research with pregnant subjects. The principles of bioethics applicable to research are bene cence, autonomy, and justice. Researchers must minimize the risks to both the mother and the fetus. Pregnant women must consider not only their own risks and

Table 8.3 PHI (1)

Names
Addresses more speci c than state
Social security numbers
Medical record number
Health plan registration
Telephone and fax numbers
Email addresses
Web addresses Any other information that can be used to identify an individual

 

8 Ethics of Clinical Pharmacology Research in Pregnancy

110 References

bene ts, but also the risks and bene ts of their fetus. Con ict of interest must be minimized and privacy protections guaranteed. Finally, it is important to emphasize that any methodology or sys- tem can only hope to minimize the inherent ethical challenges of our human endeavors. The only guarantee of proper ethical conduct in a clinical research study is the virtuous and ethical behavior of the researcher.

References

[1] HHS, editor. Belmont Report: Ethical Principles and Gudelines for the Protec- tion of Human Subjects of Research. U.S. Government; 1979.

[2] Department of Health and Human Services. 45 CFR Part 46. Final regulations amending basic HHS policy for the protection of human research subjects. Federal Register 1981;46(16):8366–91.

[3] Macklin R. Enrolling pregnant women in biomedical research. Lancet 2010; 375:632–3.

[4] Frank E, Novick D, Kupfer D. Beyond the question of placebo controls: ethical issues in psychopharmacological drug studies. Psychopharmacology 2003;171:19–26.

[5] Lyerly AD, Mitchell LM, Armstrong EM, et al. Risk and the pregnant body. Hastings Cent Rep 2009;39:34–42.

[6] Scheinfeld NS. Teratology and drug use during pregnancy. Emedicine medscape 2011.

[7] Emanuel EJ, Wendler D, Grady C. An ethical framework for biomedical research. In: Emanuel EJ, Grady C, Crouch RA, Lie RK, Miller FG, Wendler D, editors. The Oxford Textbook of Clinical Research Ethics. New York: Oxford University Press; 2008.

[8] Lo B. Ethical Issues in Clinical Research: A Practical Guide. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.

[9] Chervenak FA, McCullough LB. A comprehensive ethical framework for fetal research and its application to fetal surgery for spina bi da. Am J Obstet Gynecol 2002;187:10–4.

[10] McCullough LB, Coverdale JH, Chervenak FA. A comprehensive ethical framework for responsibly designing and conducting pharmacologic research that involves pregnant women. Am J Obstet Gynecol 2005;193:901–7.

[11] HHS, editor. Code of Federal Regulations TITLE 45 Public Welfare Part 46. 2009.

[12] Allan LD, Chita SK, Sharland GK. Flecainide in the treatment of fetal tachy- cardias. Br Heart J 1991;65:46–8.

[13] Food and Drug Administration. General Considerations for the Clinical Evalu- ation of Drugs. Washington, DC: U.S. Government Printing Of ce; 1977. [14] Merkatz RB, Temple R, Sobel S. Women in clinical trials of new drugs – a

change in food and drug administration policy. N Engl J Med 1993;329:292–6. [15] Brody BA. Research on the vulnerable sick. In: Khan JP, Mastroanni A, Sugarman J, editors. Beyond Consent: Seeking Justice in Research. New

York: Oxford University Press; 1998. p. 32–46.

8 Ethics of clinical pharmacology research in pregnancy 111

[16] Brody B. The Ethics of Biomedical Research: An International Perspective. New York: Oxford University Press; 1998.

[17] Guideline on the Exposure to Medicinal Products During Pregnancy: Need for Post-Authorisation Data (Agency, E.M., ed.), London. 2005.

[18] Stolbeberg S. The biotech death of Jesse Gelsinger. New York Times. New York: New York Times Corporation; 1999.

[19] Dealy H. Did regulators fail over selective serotonin reuptake inhibitors. Br J Med 2006;333:92–5.

[20] Hampson LA, Bekelman JE, Gross CP. Empirical data on con icts of interest. In: Emanuel EJ, Wendler D, Lie RK, Grady C, editors. The Oxford Textbook of Clinical Research Ethics. New York: Oxford University Publishing; 2008.

[21] Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a re ection of treatment effect or adverse events? JAMA 2003;290:921–8.

[22] Responsibility of applicants for promoting objectivity in research for which PHS funding is sought (Health, N.I. o., ed.). U.S. Government Printing Of ce. [23] HHS, editor. HIPAA privacy rule: information for researchers. U.S. Govern-

ment; 2007.

Questions for further discussion

1. A woman prefers a certain treatment for cosmetic reasons but without any scienti c evidence that proves better ef cacy or fewer complications. Is this still a state of clinical equipoise?

2. How can we assure that the informed consent process is in- dividualized to the needs of each subject if there is a uniform consent process and form?

3. Should researchers be prohibited from owning stock in phar- maceutical companies?

8 Ethics of Clinical Pharmacology Research in Pregnancy

Pharmacogenomics 9 in Pregnancy

David M. Haas and David A. Flockhart

. 9.1  Pharmacogenomics 113

. 9.2  Genetics and polymorphisms 115

. 9.3  Genes that in uence pharmacokinetic variability 116

. 9.4  The current state of pharmacogenetic testing 118

. 9.5  Potential therapeutic areas for pharmacogenomics in
pregnancy 120

. 9.6  Study designs and approaches to pharmacogenetics trials 122

9.1 Pharmacogenomics

“If it were not for the great variability among individuals, medicine might as well be a science and not an art.”

Sir William Osler, 1892

While much drug development and many clinical practice guidelines do not directly address variability in drug response, and in many cases assume that the effects of drugs on patients can gen- erally be predicted, the evidence indicates otherwise. Signi cant numbers of patients do not respond to many medications, and adverse events that accompany drug therapy often compromise the quality of life of patients, limiting compliance with therapy, and can even be fatal in rare circumstances. The reasons for this variability in drug response often lie in easily accessible clinical factors including disease severity, age, weight, gender, ethnicity

114 9.1 Pharmacogenomics

or drug–drug interactions. Other factors may also be important, however, and in situations where readily available clinical predic- tors such as these are inadequate alternative biomarkers of drug response can be used. In many situations the need for new bio- markers is urgent, perhaps most clearly in the case of diseases such as psychiatric disease or cancer, where considerable morbid- ity is incurred when therapy is ineffective or impossibly toxic for individual patients.

While improved ef cacy is clearly a goal of the new era of “personalized medicine” heralded by the development of increas- ingly sophisticated new biomarkers of drug response, the occur- rence of unanticipated adverse effects is also of great concern. It is clear that considerable damage is done to the public health by such adverse events. In the largest study of in-hospital morbid- ity published to date, the incidence of serious adverse drug reac- tions (ADRs) was 6.7%, and of fatal ADRs was 0.32%, and it was estimated that of 2 million patients 216,000 experienced serious ADRs and over 100,000 had fatal ADRs in one year, making these reactions between the fourth and sixth leading cause of death [1]. The cost was estimated at more than 100 billion dollars per year in 1994. It follows that biomarkers that can predict and also prevent adverse events would also be of great potential value.

Biomarkers of drug response in clinical practice are far from new. Tests such as the international normalized ratio (INR) used to monitor warfarin response, the presence of estrogen or proges- terone receptors on breast tumors used to guide anti-estrogenic therapy, and the testing of patients with HIV or hepatitis C for viral loads are all a routine part of daily practice that health care professionals have become comfortable with. We have learned that clinically useful biomarkers of drug response are of most value in situations where there is great variability in response, and a clear clinical decision, such as a change in drug, dose or therapeutic approach results from a test. It is equally clear that a test must have iterative value over existing easily available clinical predictors in order to be useful. For example, a test designed to predict the ef cacy of an antihypertensive agent that had less pre- dictive ability than routine measurement of blood pressure would be of little value.

The advent of genomics has brought a series of powerful new tools to this predictive science. While proteomics and metabolo- mics show great promise, it is with germline genomics, the study of the genetic sequence that we inherit from our parents, that we have the most experience. There are a number of reasons why the science of pharmacogenetics (or pharmacogenomics) appears valuable in this context. Not least among these are the simple facts

9 Pharmacogenomics in pregnancy 115

that DNA is very stable and easy to amplify, and that there exists a map of the human genome and of the international hapmap (htt p://www.genome.gov/10001688). In addition, the cost of DNA testing continues to drop dramatically.

While many de nitions of the differences between the science of pharmacogenetics and that of pharmacogenomics have been put forward, a useful distinction appears to be simply that “phar- macogenetics” refers to the study of individual candidate genes, while “pharmacogenomics” refers to the study of whole pathways of genes, and indeed the entire genome.

9.2 Genetics and polymorphisms

Genetic variation in the sequence of about 3 billion nucleotide pairs that make up our DNA comes in many forms, but the most common differences between people are in the form of single nucleotide polymorphisms (SNPs). These are single letter nucle- otide changes and they are referred to as a “polymorphism” if they occur in 1% or more of the population. This is because vari- ants that are that common tend to be stably present in a given population, whereas variants present at less than 1% tend to drift out. There are 12–15 million such variants, and they have been meticulously catalogued by the human genome project in the publicly available database called dbSNP (http://www.ncbi. nlm.nih.gov/projects/SNP/). Since SNPs are the most common and easily accessible form of variability they form the basis of the rst genome-wide association testing studies (GWAs) that have been used to test for associations between common variants in the genome and nearly every form of human pathology (http://www. genome.gov/gwastudies/).

Other important forms of variation include deletions and insertions of sequence, variable number tandem repeats of short sequences that are clustered together and oriented in the same direction [2] and copy number variation: regions of the sequence that are copied with high delity within the genome itself. It has been estimated that such regions constitute up to 12% of the entire sequence in the genome [3].

Since only about 1.5% of the human genome sequence is used for the ~24,000 genes that code for proteins in humans, we presume that not all of it is relevant to therapeutic response, and that not all of this variability has functional or clinically meaningful conse- quence. That said, large numbers of variants that in uence function via “nonsynonymous” changes in coding SNPs (cSNPs) have been

9 Pharmacogenomics in Pregnancy

116 9.3 Genes that in uence pharmacokinetic variability

found, and a growing number of functionally important variants in intronic and regulatory regions have also been identi ed [4].

The use of GWAs to identify new genetic associations between SNPs and drug response has begun and already a signi cant num- ber of important discoveries have resulted. These include the dis- covery of the SLC transporter with the muscle toxicity incurred by the use of the statin class of drugs [5], and of a gene in the IL17 pathway with the musculoskeletal toxicity associated with the use of aromatase inhibitors in patients with breast cancer [6]. It is widely appreciated that a large number of new patterns of mul- tiple genetic associations will result from this effort [7], such that tests that involve large numbers of variants organized into a pre- dictive pattern will become commonplace. The use of such pre- dictive patterns is already commonplace in breast cancer, where arrays that test for 20–100 RNA species in a tumor at once are routinely used to predict the value of chemotherapy in individual patients [8].

Within this large eld of research, our understanding of genetic factors that affect drug disposition far exceeds our understand- ing of the factors affecting response. This is in part because phar- macokinetic changes are relatively easy to measure whereas the “phenotype” of overall drug response is more complex. In addi- tion, cloning of most drug-metabolizing enzymes and drug trans- port proteins within the past 20 years combined with the genetic polymorphism information generated by the sequencing of the human genome and catalogued in dbSNP have allowed a com- prehensive characterization of variability in drug metabolism and transport. As the practice of searching for, identifying and then using determined genetic characteristics as predictors of drug effect becomes more common, it is clear that physicians, phar- macists, and nurses, the clinical community of health care provid- ers, will have to play an increasing role as the value of carefully de ned, valuable, clinical phenotypes and their individual genetic and genomic associations increases.

9.3 Genes that in uence pharmacokinetic variability

It is well recognized that pharmacokinetic variability is most apparent for drugs that are metabolized, and that the majority of this variability is in turn due to inconsistencies in the ability of enzymes in the liver and gastrointestinal tract to carry out drug metabolism. A growing body of literature also makes clear

9 Pharmacogenomics in pregnancy 117

that differences in the activity of drug transporters in the kid- ney, blood–brain barrier, liver, and at the level of individual tis- sues between people contribute signi cantly to pharmacokinetic variability [9].

In terms of metabolic variation, the key enzymes involved include the cytochrome P450 family of drug metabolizing enzymes that carry out phase 1 drug metabolism, but also the phase 2 enzymes including the enzymes that carry out acetylation, glucuronidation, sulfation, methylation, and the addition of gluta- thione, all of which increase the solubility of hydrophobic small molecules, and catalyze their removal from the body.

The rst genetic associations with drug therapy observed were those involving glucose 6 phosphate dehydrogenase (G6PDH) and sulfa drugs in African American soldiers, and in N-acetyl transfer- ase in patients taking isoniazid for tuberculosis. Since then, 50 years of research on drugs metabolized by the cytochrome P450 enzymes has clearly documented CYP2B6, CYP2C9, CYP2D6, CYP2C19, and CYP3A5 as the most important enzymes that exhibit important genetic alterations.

Cytochrome 2B6 is the primary metabolic route for the metabo- lism of drugs used in the treatment of HIV, including the NNRTIs (non-nucleoside reverse transcriptase inhibitors), nevirapine, and efavirenz [10], but also contributes importantly to the metabolism of methadone [11], of cyclophosphamide [12], and of ketamine [13]. The enzyme has reduced function in patients who carry the *6 allele [10], and this variant has been associated with reduced rates of metabolism, and higher concentrations of all these drugs.

CYP2C9 is widely recognized as the principal enzyme involved in the clearance of the active S-enantiomer of warfarin. Genetic variants that notably reduce activity result in higher S-warfarin concentrations and in turn lower required warfarin doses, and this effect was obvious even when a genome-wide association study testing thousands of genes was carried out as identi ed [14].

CYP2D6 is the most studied of the genetically variable cyto- chrome P450 enzymes. Variants that result in complete “knock- out” or loss of enzyme activity are present in 7% of Caucasian populations, and in 2–5% of African and Asian populations [15]. In addition, the *10 allelic variant that decreases, but does not eliminate, activity is present in more than 40% of Asians, and similarly the *17 allele reduces activity in 10–20% of Africans [15]. These changes result in clinically important changes in the metabolism of more than 40 drugs (www.drug-interactions.com) that include codeine [16], tamoxifen [17], a large number of the beta-blocker class of drugs that are metabolized, and the major- ity of clinically available antidepressants, including uoxetine,

9 Pharmacogenomics in Pregnancy

118 9.4 The current state of pharmacogenetic testing

paroxetine, and venlafaxine. Changes in the concentrations of these drugs and their metabolites brought about by CYP2D6 genetic variability have been intensely investigated [18], and those with venlafaxine appear to be suf cient to result in clinically sig- ni cant changes and recommendations for dosing changes [19]. A notable example of genetic variation within the CYP2D6 gene is the presence of copy number variation, such that up to 13 cop- ies of the entire gene have been shown to exist in some families, and to be passed down through the generations in a Mendelian manner [20].

CYP2C19 is also genetically variable, with loss-of-function vari- ants designated as *2 and *3 that are present in 15–30% of Asian populations, and 2–5% of Caucasians and Africans. While a large number of drugs are metabolized by this enzyme [21], it is the dominant route for the metabolism of clopidogrel to its active metabolite, and this has resulted in a huge amount of attention because of the widespread use of this drug in cardiology. Plasma glucose variability in CYP2C19 has been clearly associated with alterations in platelet function during clopidogrel therapy [22] that have been clearly associated with cardiovascular outcomes in a large number of studies, but not all [23].

Recently, important variations in the genetics of CYP3A5 that in uence concentrations of vincristine [24], cyclosporine, tacrolimus [25], and notably of nifedipine used in tocolysis [26] have been described. These variants associate with higher con- centrations of the parent drugs and result in clinically signi cant toxicities.

While these genes represent some of those most studied among pharmacogenetic “VIP” genes, recent results of GWAs studies and targeted approaches across a wide range of genes involved in speci c diseases have resulted in the development of clinical tests. An easily accessible catalogue of such genes has been col- lected by the Pharmacogenetics and Genomics Knowledge Base (PharmGKB) at http://www.pharmgkb.org

9.4 The current state of pharmacogenetic testing

Pharmacogenetic testing has the potential to aid in the diagnosis and treatment of multiple conditions. In fact, as of July 2011 there were 15 different drugs or drug classes that had commercially available pharmacogenetic tests (Table 9.1).

Several pharmacogenetic tests have risen to become the stan- dard of care in medical therapy. Patients with colon cancer are

9 Pharmacogenomics in pregnancy 119 Table 9.1 Fifteen drugs/therapies and their available pharmacogenetic tests as of July 2011

Drug/therapy

Test

Abacavir*
Cetuximab for colon cancer*
Imatinib* Chemotherapy for breast cancer (various) Carbamezepine*
Clopidogrel
Tamoxifen
Metformin
5-Fluorouracil
Clozapine
QT-interval prolonging drugs
Irinotecan Azathioprine and mercaptopurine Warfarin
Interferon

*Standard of care in some clinical settings.

HLA-B*5701
KRAS
BCR-ABL Oncotype Dx® and MammaPrint® HLA-B*1502

CYP2C19
CYP2D6
OATP3
DPYD-TYMS 2 SNPs in HLA-DQB1 FamilionTM

UGT1A1
TPMT CYP2C9 and VKCoR IL 28b

 

often treated with anti-epidermal growth factor (EGRF) mono- clonal antibody therapy in the form of cetuximab. A mutation in the KRAS gene codon 12 or 13 leads to resistance to cetux- imab therapy [27]. Thus, the American Society of Clinical Oncol- ogy (ASCO) has recommended that all patients with metastatic colorectal carcinoma who are candidates for anti-EGRF therapy should have their tumor tested for KRAS mutations. If codon 12 or 13 mutations are detected, then the patients should not receive anti-EGRF therapy as part of their treatment [27].

The cutaneous adverse drug reaction Stevens–Johnson syndrome (SJS) is a serious concern for people taking drugs such as abaca- vir and carbamazepine [28, 29]. Pharmacogenetic screening for the HLA-B*5701 can help identify those who are most at risk for developing this severe adverse drug reaction with abacavir. Carriers of this HLA-B allele should not be given abacavir. This test is now widely used for screening patients in need of abacavir to avoid SJS in the developed world [30]. In addition, HLA-B*1502 testing is becoming the standard of care for Asians prescribed carbamazepine to avoid severe cutaneous drug reactions [28].

9 Pharmacogenomics in Pregnancy

120 9.5 Potential therapeutic areas for pharmacogenomics

For those with chronic myelogenous leukemia, imatinib inhib- its the BCR-ABL-activated tyrosine kinase, interrupting signal transduction pathways that would otherwise lead to leukemic transformation. In this way, imatinib has led to impressive sur- vival bene ts in these patients [31]. However, a mutation in the BCR-ABL gene negates the bene ts of imatinib. As imatinib is an expensive therapy, pharmacogenetic testing is employed in this scenario to avoid prescribing a costly therapy that would not be as bene cial in patients with the mutation.

Commercially available pharmacogenetic testing panels such as Oncotype Dx® and MammaPrint® have been promoted for women about to undergo chemotherapy for breast cancer [32, 33]. ASCO and other organizations have included some of these tests in their guidelines as options to predict bene t, particularly from tamoxifen therapy [34]. These are examples of commercially available tests that are not yet standard of care recommendations. Other tests that similarly have data supporting their potential role for individualizing therapy are the CYP2D6 testing for tamoxifen [35, 36] or venlafaxine [19], CYP2C19 testing for clopidogrel anti- platelet therapy [23], and CYP2C9 and VKCoR testing for those starting warfarin therapy [37–39].

Other tests are available for different conditions and/or drug therapies. At the time of writing of this chapter, however, the remaining tests have not developed the cache of evidence or treatment guideline support to become commonplace in practice. However, with the advent of new pharmacogenetic tests, phar- macogenetic modeling strategies, and the need for individual- ized pharmacotherapy to avoid adverse events, pharmacogenetic testing will likely expand greatly in the next several years.

9.5 Potential therapeutic areas for pharmacogenomics in pregnancy

Most pregnant women take drugs for various conditions. Epi- demiologic studies have documented that over 90% of pregnant women take a prescription drug, with most taking more than one [40, 41]. Even after eliminating prenatal vitamins and supplemen- tal iron, over 70% of pregnant women take a prescription drug during the course of their pregnancies [41]. Many of the drugs commonly consumed by pregnant women are potential candi- dates for pharmacogenetic testing. Based on the drug metabolism pathway or receptors that serve as targets, pregnancy therapeutics may be a ripe area for pharmacogenetics.

9 Pharmacogenomics in pregnancy 121

As the cause of the majority of neonatal morbidity and mortal- ity, preterm labor is a major focus of obstetric care and research. The use of tocolytic medications to stop uterine contractions is commonplace but of varying success [42]. Many tocolytics are substrates for polymorphic drug metabolizing enzymes. Nifedip- ine is a calcium channel blocker commonly used in obstetrics to stop contraction and delay birth. Nifedipine is metabolized by the CYP3A family. Recent studies have documented that CYP3A5 polymorphisms and concomitant use of known CYP3A inhibi- tors can impact the concentration of nifedipine in maternal blood [26]. Another potential pharmacogenetic target in preterm labor therapy includes indomethacin. Indomethacin, a nonsteroidal anti-in ammatory drug used to inhibit contractions, is metabolized by the polymorphic CYP2C9 and CYP2C19 [43]. SNPs in these enzymes can affect the concentrations of these tocolytics. As these two drugs may be the better rst line agents for preterm labor [44], these pharmacogenetic implications should be further interrogated.

Depression is common in pregnant women. The selective sero- tonin reuptake inhibitors (SSRIs) are the rst line agents to treat depression and other mood disorders in pregnancy. The SSRI drugs are metabolized by many different polymorphic enzymes (Table 9.2). Depression is commonly noted to be undertreated in pregnancy. It is possible that some of the undertreatment may be due to the combination of pregnancy physiology impacting the drug concentration as well as pharmacogenetic polymorphism causing reduced drug concentrations. The impact of SNPs in these enzymes on the effectiveness of SSRI therapy is an area of active investigation [45, 46].

Table 9.2 Drug metabolizing enzymes for SSRIs

Drug

Enzymes responsible for metabolism

Fluoxetine (Prozac) Sertraline (Zoloft) Venlafaxine (Effexor) Paroxetine (Paxil) Fluvoxamine (Luvox) Buproprion (Wellbutrin, Zyban)* Citalopram (Celexa) Escitalopram (Lexapro)

CYP2D6, CYP2C9 CYP2D6, CYP2C9, CYP2B6, CYP2C19, CYP3A4 CYP2D6
CYP2D6
CYP1A2
CYP2B6
CYP3A4, CYP2C19
CYP3A4, CYP2C19

 

*Buproprion is not an SSRI but rather a serotonin-norepinephrine reuptake inhibitor

9 Pharmacogenomics in Pregnancy

122 9.6 Study designs and approaches to pharmacogenetics trials

Nausea and vomiting of pregnancy (NVP) affects up to 80% of pregnant women [47, 48]. Both mild and severe cases of NVP have a signi cant impact on the quality of a woman’s life and contribute signi cantly to health care costs and time lost from work [48, 49]. Many anti-emetic drugs are used with various mechanisms of action to counter NVP. These include vitamin B6, doxylamine, prometha- zine, metoclopramide, and ondansetron to name a few. Learning from anesthesia research, emesis and the effectiveness of anti-emetic drugs are potential pharmacogenetic targets. Ondansetron is metab- olized by CYP2D6. Extensive and ultrarapid CYP2D6 metabolizers have been linked to ondansetron failure [50]. Also, the polymorphic serotonin receptor 5-HT3 facilitates the role of serotonin as a media- tor of nausea and vomiting [51]. Variants in the 5-HT3B receptor are linked to increased nausea and vomiting due to increased response to serotonin binding [52]. 5-HT3 receptor variants are also associ- ated with the severity of NVP (personal communication, data from our center). Thus, it is possible that identifying women with receptor variants with NVP may lead providers to utilize different medication to control a woman’s NVP. The individualized treatment of NVP using pharmacogenetics is also an area of investigation.

These are just a few of the areas of drug therapy in pregnancy where pharmacogenetics may play a role [46, 53, 54]. As obstet- rics moves into the genomics era, active pharmacogenetic research to help individualize therapy is ongoing. Maximizing the bene t for the mother and minimizing the risks to both the mother and fetus are the tenets of individualized pharmacotherapy. With both a mother and fetus to consider, optimizing therapeutics in preg- nancy is pivotal. As a tool, pharmacogenetics may provide insights to help achieve maximal bene t with minimal risk.

9.6 Study designs and approaches to pharmacogenetics trials

Gathering quality trial data in pharmacogenetics is often dif cult. Genetic testing is expensive and new SNPs are discovered fre- quently. However, there are key components of pharmacogenetic analyses that can help propel the eld forward.

In general, analyses of trials focus on the mean changes in out- come measures of two or more groups. The outliers are often elimi- nated or statistically compensated for. However, in the eld of pharmacogenetics, it is often those same outliers, the subjects in the tails of the bell-shaped curve, who are the most important to analyze. The subjects who have the most robust response to a drug

9 Pharmacogenomics in pregnancy 123

or the poorest response to a drug are often the ones who may have a genetic polymorphism in the metabolic or receptor pathway that is causing this. For instance, subjects who receive no bene t from a drug may have an SNP in an enzyme like CYP2D6 that makes them an ultrarapid metabolizer and thus not enough drug is available for effect. In that case, knowing the CYP2D6 status ahead of time could lead to either increased dose or utilizing a different drug.

Prospectively obtaining genotype information in a randomized clinical trial setting is dif cult logistically. While genotyping costs are decreasing, the approach to genotyping needs to be consid- ered. Assaying for particular candidate pathway genes may be ef – cient but could miss a key contributor. Using GWA assays or full DNA sequencing may be too expensive and give extraneous data. In addition, these become analytically complex. Using a pathway- informed GWA approach may be a practical way to limit the data needed and improve the ef ciency of using the information.

Because of the expense and time needed to genotype a screen- ing population for entry into a trial, newer adaptive trial designs have been utilized to make mid-study adjustments [55]. These adjustments may be based on genotypes. For instance, halfway through a drug trial, the subjects in the study could be genotyped in a batch to save on cost. Then an interim analysis might indicate that subjects with a certain SNP did not bene t at all at current doses. An adaptive trial design can then allow for dose adjust- ments for subjects with those SNPs for the remainder of the trial. In this way, adaptive trial designs can improve the ef ciency of tri- als, allowing researchers to demonstrate effectiveness or ineffec- tiveness sooner, improving subject safety and yielding substantial time and cost savings [55].

As pharmacogenetic studies become more prevalent and the cost of genotyping is reduced, clinical trials of individualized pharmacotherapy will become more common. Up-front genotyp- ing and strati ed randomization based on genotyping are begin- ning to appear in studies. In these ways, pharmacogenomics is becoming an increasingly important tool that will be available for providers in the future for individualizing drug therapy.

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9 Pharmacogenomics in Pregnancy

10 Sarah Armstrong and Roshan Fernando

Analgesics and Anti- In ammatory, General and Local Anesthetics and Muscle Relaxants

. 10.1  Introduction 129

. 10.2  General anesthesia 130

. 10.3  Inhalational anesthetics 131

. 10.4  Intravenous anesthetics 132

. 10.5  Neuromuscular blocking agents 136

. 10.6  Regional anesthesia 137

. 10.7  Summary 141

10.1 Introduction

As with all drug use in pregnancy, the challenges of general and regional anesthesia include optimization of maternal physiologi- cal function, preservation and maintainance of utero-placental blood ow and oxygen delivery while avoiding unwanted effects of fetal exposure to drugs.

The likelihood of maternal and fetal exposure to anesthetic drugs in delivery has increased dramatically in recent years. It has been estimated that in developed countries 1–2% of pregnant women undergo anesthesia during pregnancy for surgery unrelat- ed to the pregnancy. Of these procedures, approximately 42% are performed during the rst trimester, 35% during the second, and 23% during the third [1]. Elective surgery and therefore anesthesia

130 10.2 General anesthesia

should be avoided in pregnancy if at all possible and only after the rst 6 postpartum weeks to allow resolution of the physiological changes of pregnancy. If necessary current opinion suggests that it should be delayed to the second trimester of pregnancy to reduce the risk of both teratogenicity and miscarriage although there is no rm evidence to support this approach. Emergency surgery must proceed regardless of gestational age in order to preserve the life of the mother.

Intervention rates involving the use of general or local anesthet- ics at delivery vary widely across the world. Overall epidural rates (including operative delivery and labor analgesia) are as high as 95% in some regions in the US. There is also an increasing overall rate of cesarean delivery worldwide, the highest being currently in China at around 46% in 2008 [2]. The increasing incidence of these procedures necessitates an increasing incidence of ma- ternal and fetal exposure to anesthetic drugs. For cesarean deliv- ery, regional anesthesia is more widely used and preferred where possible over general anesthesia. Regional anesthesia minimizes risks associated with general anesthesia including pulmonary as- piration of gastric contents, failed intubation, maternal awareness, maternal gastric ileus postoperatively, and fetal exposure to drugs. No studies have shown a bene cial effect on the outcome of preg- nancy after regional anesthesia compared to general anesthesia. Before the initiation of any anesthetic technique, resuscitation fa- cilities should be available for both mother and fetus.

10.2 General anesthesia

General anesthetics may be divided into intravenous and inhaled volatile anesthetics. Indications for general anesthesia in pregnan- cy are listed in Table 10.1 and include maternal disease requiring urgent surgery or cesarean delivery where regional anesthesia is not appropriate. As stated in other chapters, pharmacokinetic and

Table 10.1 Indications for general anesthesia in pregnancy

Maternal disease/trauma requiring emergency surgery unsuitable for regional technique Urgent delivery of fetus (fetal or maternal threat) Maternal refusal of regional techniques Contraindications to regional technique (e.g. coagulopathy or infection) Failed or inadequate regional technique Delivery if at risk of obstetric major hemorrhage (e.g. placenta previa or accreta)

 

10 Analgesics and anti-in ammatory, general and local 131

pharmacodynamic pro les are altered in pregnancy and drugs for general anesthesia should be titrated as a result.

The utero-placental circulation is not autoregulated and so fetal perfusion is critically dependent on maternal systolic driving pres- sure. Hypotension in general anesthesia is common, particularly due to decreased systemic vascular resistance induced by vola- tile or intravenous anesthetic agents, hypovolemia and aortocaval compression which is further exacerbated by the supine position. Obstetric patients after the rst trimester should undergo general anesthesia in the supine position with 15 degree left lateral tilt to reduce aortocaval compression by the gravid uterus and me- ticulous attention should be paid to the maintenance of maternal systolic blood pressure through the use of intravenous uids and vasopressors.

10.3 Inhalational anesthetics

The minimum alveolar concentration (MAC) of volatile agents is a term used to describe the potency of anesthetic vapors. It is de ned as the concentration that prevents movement in response to skin incision in 50% of unpremedicated subjects studied at sea level (1 atmosphere), in 100% oxygen. Hence, it is inversely re- lated to potency and the more potent the agent, the lower the MAC value.

Although it is more than 160 years since the rst use of modern anesthetic agents, the mechanism of action of volatile anesthet- ics still remains elusive [3]. Inhaled anesthetic agents are thought to act in different levels of the central nervous system with both pre- and postsynaptic effects having been found. They may disrupt synaptic transmission by interfering with the release of excitatory or inhibitory neurotransmitters from the pre-synaptic nerve ter- minal, by altering the reuptake of neurotransmitters or by chang- ing the binding of neurotransmitters to the postsynaptic receptor sites [4]. There is a high correlation between lipid solubility and anesthetic potency suggesting inhalational anesthetics have a hy- drophobic site of action and direct interaction with the neuronal plasma membrane is likely.

In pregnancy neural tissues show increased sensitivity to ef- fects of volatile anesthetics. The minimum alveolar concentration is reduced by 30% under the in uence of progesterone and en- dogenous endorphins [5, 6]. The 25% increased alveolar minute volume from the rst trimester (caused by both increases in respi- ratory rate (by 15%) and tidal volume (by 40%)) leads to a more

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

132 10.4 Intravenous anesthetics

rapid induction of general anesthesia if an inhalational induction technique were to be used. In most cases of general anesthesia in the parturient, preoxygenation with 100% oxygenation precedes rapid sequence intravenous induction with cricoid pressure to secure the airway and to reduce the likelihood of pulmonary as- piration. This is followed by maintenance with 0.5–1.0 MAC of volatile anesthetic agents in either an air/oxygen or nitrous oxide/ oxygen mix. Nitrous oxide has a rapid alveolar uptake and re- mains an important adjunct to reduce the risk of awareness dur- ing emergency cesarean delivery. Nitrous oxide if administered in high concentrations for long periods (more than 50% concen- tration for over 24 hours) has been shown to be a weak terato- gen in rodents. Studies voicing concerns regarding nitrous oxide teratogenicity are not supported in clinical practice to date [7]. Insuf cient general anesthesia or analgesia may cause awareness and substantial maternal catecholamine release which is generally considered to be more detrimental to the fetus.

The high lipid solubility and low molecular weight of all com- monly used volatile anesthetics (En urane, Iso urane, Sevo u- rane, Des urane, and Halothane) facilitate rapid transfer across the utero-placental unit to the fetus. If induction to delivery time is prolonged, it has been shown to result in lower Apgar scores in the fetus [8]. Low doses of volatile anesthetics in combination with nitrous oxide may improve uterine blood ow but may also induce uterine relaxation. After the fetus is delivered, increasing concentrations of nitrous oxide, systemic opioids, and IV oxytocin may be used to reduce the amount of volatile anesthetic required and to encourage uterine contraction. Nitrous oxide is poorly sol- uble and may be eliminated from the blood into the alveoli very rapidly. This effectively dilutes alveolar air, and available oxygen, so that when room air is inspired hypoxia may result. This “dif- fusion hypoxia” may occur in the neonate after delivery and so it would seem prudent to administer supplemental oxygen to any neonate exposed to high concentrations of nitrous oxide immedi- ately before delivery [9].

10.4 Intravenous anesthetics

Rapid sequence induction (RSI) is the administration of a potent intravenous anesthetic agent to induce unconsciousness followed by a rapidly acting neuromuscular blocking agent to achieve mo- tor paralysis for tracheal intubation. The choice and dose of in- travenous induction agent is crucial to ensure a balance between

10 Analgesics and anti-in ammatory, general and local 133

excellent intubating conditions with minimal maternal recall and high maternal blood concentrations with subsequent adverse ma- ternal hemodynamic effects and fetal transfer. The lipophilic char- acteristics of intravenous anesthetic agents enhance their transfer across the placenta.

10.4.1 Thiopentone

Thiopentone is the most extensively studied intravenous anesthet- ic agent and has been shown to be safe in obstetric patients. It is administered in a dose of 3–7 mg/kg with 4 mg/kg being generally agreed to be unlikely to lead to fetal depression while doses in excess of 7mg/kg are liable to do so [10]. Thiopentone rapidly crosses the placenta and has been detected in umbilical venous blood within 30 seconds of administration. However, as a result of rapid equilibration in the fetus thiopentone does not produce fetal neuronal levels high enough to sedate the neonate. Approximately 80% of thiopentone is protein bound and both maternal–fetal and feto-maternal transfer is strongly in uenced by maternal and fe- tal protein concentrations. High fetal–maternal ratios suggest that thiopentone is freely diffusible but many factors must be involved in placental transfer as demonstrated by a wide intersubject vari- ability in umbilical cord concentrations at delivery [1]. Some anesthesiologists use methohexital rather than thiopentone for induction of anesthesia and evidence from in vitro perfusion studies suggests rapid maternal to fetal transfer and vice versa.

10.4.2 Propofol

Propofol is now the most widely used drug in anesthetic practice and produces a rapid, smooth induction of anesthesia. It attenu- ates the cardiovascular response to laryngoscopy and intubation more effectively than barbiturates and does not appear to adverse- ly affect umbilical cord gases at delivery. Increased maternal blood ow accentuates placental tissue uptake and rapid transfer across the placenta [11]. It is highly protein bound and so placental transfer is affected by changes in plasma protein concentrations and may be increased by reduced protein concentrations in the maternal blood. There are concerns over its capacity to produce neonatal depression and provide an adequate depth of (maternal) anesthesia [12]. An additional disadvantage of propofol is a long equilibration time from administration to effect site which may prolong the time period from injection to hypnosis. In one study comparing thiopentone 5 mg/kg with propofol 2.4 mg/kg maternal electroencephalograms were studied. Fifty percent of those wom- en receiving propofol showed rapid low voltage (8–9Hz) waves

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

134 10.4 Intravenous anesthetics

on their electroencephalogram suggestive of a light plane of an- esthesia and therefore potentially awareness compared to 10% of the thiopentone group [13]. This concern regarding the failure of propofol to produce maternal anesthesia has been found in other studies [14, 15]. Some studies have shown that propofol use may result in lower Apgar scores when compared to thiopentone even at lower doses where maternal awareness is a distinct possibility. As a result there are currently no major advantages to its use over thiopentone in pregnancy [16].

10.4.3 Ketamine

This phencyclidine derivative is used in a dose of 1–2mg/kg for induction in obstetric patients in <2% of general anesthetics [17]. It has a rapid onset and provides analgesia, hypnosis, and reliable amnesia and may be useful in patients with asthma or modest hypovolemia. It rapidly crosses the placenta and a dose of 1mg/ kg appears not to be associated with an increase in uterine tone unlike larger doses. Its use is limited in preeclampsia and hyper- tension due to its sympathomimetic effects, and due to the risk of increased uterine tone and asphyxia it should not be used in the rst two trimesters. There are practical concerns regarding hallu- cinations and emergence phenomena although both are dose re- lated and are thought to occur less frequently in obstetric patients [18]. Apgar scores and umbilical cord gases appear to be similar as with other IV induction agents.

10.4.4 Etomidate

This carboxylated imidazole has been used in pregnant women who are hemodynamically unstable when it is important to main- tain baseline systolic blood pressure. However, there are currently no adequate and well-controlled studies in pregnant women. Po- tential side effects include pain on injection, postoperative nau- sea, myoclonus, and adrenal suppression. Etomidate should be used during pregnancy only if the potential bene t justi es the potential risks to the fetus.

10.4.5 Benzodiazepines

This class of drugs is rarely used as the sole anesthetic agent due to their relatively slow maternal onset and offset and neonatal depressive actions. They may be used as co-induction agents. Benzodiazepines have been associated with cleft lip and palate in animal studies but the association in humans is controversial and a single dose has not been associated with teratogenicity

10 Analgesics and anti-in ammatory, general and local 135 [19, 20]. Long-term use should be avoided due to the association

with neonatal withdrawal.

10.4.6 Systemic opioids in pregnancy

As part of general anesthesia short- and long-acting systemic opi- oids may be administered for analgesia, facilitation of intubation, and attenuation of the stress response to surgery. Placental trans- fer to the fetus of systemic opioids is passive; however, opioids have been safely used for pain relief in pregnancy for decades. As with the non-pregnant population, maternal opioid administra- tion is associated with a number of adverse side effects including nausea and vomiting, pruritis, sedation, respiratory depression, urinary retention, and constipation.

In addition neuraxial anesthesia may be contraindicated or re- fused in labor or at cesarean delivery necessitating the use of in- travenous patient-controlled analgesia using opioid drugs such as fentanyl or remifentanil. Remifentanil is a short-acting mu-opioid receptor agonist [21]. It has the advantage of a rapid onset and offset of action (context-speci c half-life of 3 minutes in both maternal and neonatal studies) being hydrolyzed by non-speci c tissue esterases and excreted in the urine. Both drugs can cause signi cant respiratory depression and thus it is mandatory that all laboring women using this technique have adequate supervision and monitoring with maternal pulse oximetry and fetal heart rate monitoring.

Meperidine intravenously results in rapid transfer across the placenta and fetal/maternal ratios may exceed 1.0 after only a couple of hours. This is thought to be due to maternal metabolism exceeding fetal metabolism of the drug [22]. It has been associated with neonatal central nervous system and respiratory depression.

Morphine also rapidly crosses the placenta (although trans- fer is membrane-limited and there appears to be a fast pla- cental washout) and has been shown to be associated with a reduction in fetal biophysical score [23]. Fentanyl is highly li- pophilic and rapidly transferred to the placenta. It has been detected in early pregnancy in both the placenta (which acts as a drug depot) and fetal brain [24]. Maternal alfentanil ad- ministration has been associated with a reduction of 1-min- ute Apgar scores despite a relatively low fetal/maternal ratio [25–26]. Maternal sufentanil administration results in a very high fetal/maternal ratio of 0.81. Human placental studies have con rmed this rapid transfer across the placenta which is in uenced by fetal pH and differences in maternal and fetal plasma protein binding [27].

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

136 10.5 Neuromuscular blocking agents
10.5 Neuromuscular blocking agents

In pregnancy individual drug metabolism is heterogeneous re ecting the separate pregnancy-related changes in each drug- metabolizing organ system. Neuromuscular blocking agents are required for general anesthesia in nearly all cases where endo- tracheal intubation is required and may be depolarizing or non- depolarizing agents. They are highly polar, fully ionized molecules that do not cross the placenta in signi cant amounts and fetal blood concentrations of muscle relaxants are 10–20% of that of maternal blood [28]. Neonatal hypotonia is rarely seen following induction of general anesthesia with muscle relaxation.

n Depolarizing muscle relaxants include suxamethonium which acts by depolarizing the plasma membrane of the skeletal muscle ber making it resistant to further stimulation by acetylcholine. It induces rapid paralysis (within 30–90s) with a short offset time (2–5min) in order to safely facilitate tracheal intubation in the presence of increased risk of aspiration as found in the second and third trimesters. It is metabolized by plasma cholinesterases.

n Non-depolarizing neuromuscular blocking agents act by com- petitively blocking the binding of acetylcholine to its postsynaptic receptors. This class of drugs includes the aminosteroids (pan- curonium, vecuronium, and rocuronium) and the benzylisoquin- olines (atracurium, doxacurium, and mivacurium). These drugs have a longer onset time (1.5–3min) and offset time (20–60min) compared to suxamethonium. The aminosteroids undergo in gen- eral a combination of hepatic and renal metabolism and excre- tion. Atracurium is broken down to inactive metabolites by ester hydrolysis (the minority) and spontaneous Hoffman degradation (the majority) to laudanosine.

The marked physiological reduction of plasma cholinesterase levels in pregnancy (by 30% from early in the rst trimester to several weeks postpartum) theoretically causes suxamethonium to have a prolonged effect. This is, however, counterbalanced by the increased maternal volume of distribution. Maternal doses of more than 300mg (recommended dose 1–2mg/kg) are required before the drug can be detected in umbilical venous blood [29]. Fetal pseudocholinesterase de ciency or repeated high doses of suxamethonium may lead to neonatal neuromuscular blockade [11, 30]. Rocuronium demonstrates an unaltered onset time at a dose of 0.6mg/kg but shows a longer duration of action in preg- nancy [31] whereas vecuronium shows a faster onset at a standard dose of 0.2 mg/kg but also an extended duration of action [32]. The advent of sugammadex, a reversal agent for rocuronium and to a

10 Analgesics and anti-in ammatory, general and local 137

lesser extent vecuronium, may herald the increased use of these drugs in obstetrics although more studies are required to estab- lish the safety of this drug in obstetrics and postpartum [33, 34]. Non-depolarizing muscle relaxants are often administered in bolus form, which may result in an increase in fetal blood concentration over time even though the transfer rates are relatively low [35].

At cesarean delivery usually only a single dose of suxametho- nium is needed but may be followed by small boluses of a short- acting, non-depolarizing neuromuscular blocking agent. For other surgery requiring neuromuscular blockade longer-acting, non- depolarizing neuromuscular blockers may be employed but time should be allowed for adequate reversal of effects. Monitoring of neuromuscular function is recommended in all cases. Magnesium sulfate is known to decrease requirements of non-depolarizing neuromuscular blockers and prolong their effects and this should be considered in cases of preeclampsia and eclampsia.

10.6 Regional anesthesia

The advantages of maternal regional anesthesia for incidental sur- gery in pregnancy, analgesia in labor and for operative or instru- mental delivery are substantial and advantages of central neuraxial blockade are listed in Table 10.2. In ltration of local anesthetic may be employed, for example in episiotomies and paracervical blocks. It should be noted that there are signi cant contraindica- tions and complications associated with regional techniques and of which the patient should be made aware when consenting for regional anesthesia.

Table 10.2 Advantages of regional anesthesia in obstetrics

Greater maternal satisfaction
Enables maternal participation Reduces catecholamines and potentially improves placental blood ow For operative anesthesia:

Reduced risk of GA (↓ maternal aspiration, ileus, awareness, ↓ fetal exposure to drugs used for general anesthesia)
Improved respiratory function
Reduced intra-operative blood loss Improved maternal bonding, earlier breastfeeding, less postnatal depression Good postoperative analgesia

Increased mobility with low-dose epidural (e.g. 0.125% bupivacaine and 2 mcg/mL fentanyl)

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

138 10.6 Regional anesthesia

Local anesthetic drugs are weak bases and exist predominantly in the ionized form at physiological pH as their pKa exceeds 7.4. Each possesses an aromatic lipophilic group and a hydrophilic group and they are classi ed as either esters or amides, the name describing the linkage between the groups. Commonly used lo- cal anesthetics in obstetrics have low molecular weight, high lipid solubility, and low ionization and include bupivacaine, levobupi- vacaine, lidocaine and ropivacaine (amides), and chloroprocaine (ester). These agents work by binding to the receptor sites of sodi- um channels, blocking ion movement across nerve cell membranes and preventing the initiation and propagation of the action poten- tial and subsequent sensory nerve transmission. Local anesthetics cross the placenta by simple diffusion. Due to a relative fetal aci- dosis there is fetal accumulation of local anesthetic (also known as “ion trapping”). Transfer to the fetus is also affected by total dose, site of administration, and use of adjuvants such as epinephrine.

Choice and concentration of local anesthetic depends on the onset time of block required, the desired indication (operative (incidental surgery or for delivery) or labor analgesia) as well as maternal and fetal conditions. Bupivacaine has a pKa of 8.1 com- pared to lidocaine’s pKa of 7.9. This means that at physiological pH bupivacaine consists of a greater fraction in the ionized form which is unable to penetrate the phospholipid membrane, resulting in a slower onset of action. The duration of action is correlated with the extent of protein binding. Those drugs that are highly protein bound will have a lower materno-fetal transfer attributed to restricted placental transfer (for example, bupivacaine is 90% protein bound compared to lidocaine’s 50%). In pregnancy altered protein binding (physiological hypoalbuminemia combined with an increase in α1-glycoprotein concentration) changes the unbound fraction of the drug and reduces the doses required and at which toxicity may occur [1]. The sensitivity of neural tissue to local anesthetics also increases and this contributes to the risk of toxicity.

The volume of the subarachnoid and epidural spaces is reduced due to compression of the inferior vena cava causing distension of the epidural venous plexus. This results in a greater risk of inad- vertent intravascular injection and leads to more extensive spread of local anesthetic in central neuraxial blockade, both of which may increase the risk of complications.

10.6.1 Bupivacaine

Bupivacaine (0.125–0.5%) is used frequently in both epidural and subarachnoid blocks – the higher the concentration, the

10 Analgesics and anti-in ammatory, general and local 139

greater the motor blockade. It has a slower onset and longer duration than lidocaine (approximately 120–180 min). Bupi- vacaine toxicity has been associated with refractory ventricular brillation leading to the isolation and commercial preparation of the S(−) enantiomer of bupivacaine, levobupivacaine. This has been shown to be less neuro- and cardiotoxic than racemic bupivacaine.

10.6.2 Lidocaine

Lidocaine has an intermediate onset time between 2-chloropro- caine and bupivacaine and concentrations of 1.5–2% are often used in epidural anesthesia. Epinephrine is often used with lido- caine as an adjunct to decrease systemic absorption, prolong the duration of the block and increase the intensity of the blockade (both sensory and motor). Without it there may be an increased risk of inadequate anesthesia and a risk of local anesthetic toxic- ity especially with additional lidocaine doses. Bicarbonate may also be used to buffer lidocaine, increasing the amount of union- ized drug and speeding its penetration into the nerve tissue. Some studies have found differences in neonatal neurobehavior follow- ing lidocaine compared to bupivacaine in epidural anesthesia but these differences have been shown to be not clinically signi cant [36, 37].

10.6.3 2-Chloroprocaine

As an ester local anesthetic, 2-chloroprocaine is rapidly metabo- lized and placental transfer is limited compared to amide local anesthetics. As a result it is used widely in the US in the situa- tion of epidural anesthesia requiring instrumental or operative delivery and a decompensating fetus as it has an extremely rapid onset (approximately 5 minutes), it is less likely to participate in ion trapping and there is less risk of toxicity. It should not be used in the subarachnoid space due to the risk of adhesive arachnoiditis.

10.6.4 Ropivacaine

This amide anesthetic has an onset intermediate between lido- caine and bupivacaine and its safety in cesarean delivery has been established. It has a duration similar to bupivacaine (120–180 min) but exhibits less cardiac toxicity as it is supplied in the S(−) enan- tiomer form. Ropivacaine may provide anesthesia and analgesia with less motor blockade when compared to bupivacaine but this may not be clinically important [38].

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

140 10.6 Regional anesthesia 10.6.5 Adjuvant opioids

The rationale behind using opioids in obstetric regional anesthe- sia is to minimize maternal systemic and fetal effects of both lo- cal anesthetics and opioids. There have been extensive numbers of both human and animal studies con rming the synergism be- tween opioids and local anesthetics in neuraxial anesthesia which may reduce the required local anesthetic dose by up to 30%. This may reduce both the risk of local anesthetic toxicity and the inci- dence of motor blockade which may be undesirable for the labor- ing parturient. Neuraxial opioids improve the quality of analgesia and are thought to exert their effects via a direct action on spinal and supraspinal opioid receptors. Dose ranges of commonly used opioids are shown below in Table 10.3.

When considering speci c opioids, fentanyl is the most com- monly used and most widely studied adjuvant opioid in obstetric anesthesia. It is a highly potent lipophilic phenylpiperidine de- rivative that rapidly binds dorsal horn receptors in the spinal cord after neuraxial administration leading to rapid analgesia within 5 minutes intrathecally and 10 minutes epidurally. Cephalad mi- gration and the incidence of central respiratory depression are reduced compared to less lipid-soluble opioids such as morphine. Sufentanil has an analgesic potency that is around ve times more potent than fentanyl and has an even more rapid onset. Early re- spiratory depression, however, may occur due to rapid systemic absorption of these drugs and the side effects are equipotent with equivalent doses of either drug. Their fast onset of action makes these opioids desirable for labor analgesia and emergency delivery but limits their use for postoperative analgesia after a single dose.

Morphine is a hydrophilic phenanthrene derivative which is ap- proximately 100 times less potent that fentanyl. It has a slower onset (15 minutes intrathecally and 30 minutes epidurally) com- pared to fentanyl and sufentanil and a signi cantly longer dura- tion of action (12–24 hours). Poor lipid solubility leads to a delay in binding to dorsal horn receptors in the spinal cord and may

Table 10.3 Dose ranges of commonly used neuraxial opioids

Opioid

Epidural dose

Intrathecal dose

Fentanyl Sufentanil Morphine Diamorphine

50–100 mcg 25–50 mcg 2.0–3.0 mg 4.0–6.0 mg

10–25 mcg 2.5–15 mcg 100–200 mcg 200–400 mcg

  

10 Analgesics and anti-in ammatory, general and local 141

contribute to the accumulation of free drug within the cerebro- spinal uid (CSF) which may migrate cranially and cause delayed respiratory depression. In both intrathecal and epidural anesthe- sia morphine has been shown to have a ceiling effect (at 100mcg intrathecally and 3.75mg epidurally) above which there is little analgesic bene t and an increased incidence of adverse effects [39, 40]. Neuraxial morphine has been shown to be as effective as fentanyl for labor and cesarean delivery analgesia and more effec- tive than fentanyl in postoperative pain relief. However, increased incidence and magnitude of side effects such as nausea, vomiting, sedation, urinary retention, respiratory depression, and pruritis when compared to fentanyl limit its effects. There is new interest currently in extended-release epidural morphine (EREM) where morphine is encapsulated in lipid foam particles which may lead to a prolonged duration of action and fewer side effects [41].

Diamorphine is a suitable alternative to intrathecal morphine and is primarily used in the United Kingdom. It is more lipophilic than morphine and therefore has a faster onset of action. Despite a short half-life in the CSF it is metabolized into its active com- ponents (morphine and 6-acetylmorphine) increasing its duration of action. Intraoperative analgesia is of similar quality to fentanyl with the additional advantage of prolonged postoperative analge- sia [42]. Side effects, however, are dose dependent with pruritis occurring in up to 90% of women after a 200 mcg dose at cesarean delivery [43].

10.6.6 Fetal effects of neuraxial opioids

Spinal and epidural opioids will diffuse into the maternal blood- stream and will be rapidly transported to the uterus. All commer- cially available opioids have low molecular weights and rapidly cross the placenta by diffusion. The risk of neonatal depression with morphine increases with reduced inter-dosing interval and with increasing dose due to higher maternal systemic morphine levels. The risk of neonatal depression with fentanyl appears less and has only been reported at very high repeated epidural doses leading to maternal systemic accumulation [44].

10.7 Summary

General anesthesia utilizes pharmacological agents to render the parturient unconscious and unaware. It requires a rapid sequence induction with neuromuscular blockade to secure the airway after

10 Analgesics and Anti-In ammatory, General and Local Anesthetics and Muscle Relaxants

142 10.7 References

the rst trimester due to the risk of aspiration. These drugs cross the placenta in varying amounts and may be implicated in neona- tal depression. Intravenous agents should be carefully titrated to minimize fetal exposure while ensuring maternal anesthesia and analgesia. In many cases regional anesthesia and analgesia may be more appropriate with less potential risk of harm to both mother and fetus.

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[25] Gin T, Ngan-Kee WD, Siu YK, Stuart JC, Tan PE, Lam KK. Alfentanil given immediately before the induction of anesthesia for elective cesarean delivery. Anesth Analg 2000;90:1167–72.

[26] Gepts E, Heytens L, Camu F. Pharmacokinetics and placental transfer of intravenous and epidural alfentanil in parturient women. Anesth Analg 1986;65:1155–60.

[27] Johnson RF, Herman N, Arney TL, Johnson HV, Paschall RL, Downing JW. The placental transfer of sufentanil: effects of fetal pH, protein binding, and sufentanil concentration. Anesth Analg 1997;84:1262–8.

[28] Ni Mhuireachtaigh R, O’Gorman DA. Anesthesia in pregnant patients for nonobstetric surgery. J Clin Anesth 2006;18:60–6.

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11 Jennifer A. Namazy and Michael Schatz

The Management of Asthma During Pregnancy

. 11.1  Introduction 145

. 11.2  Effect of pregnancy on the course of asthma 145

. 11.3  Effect of asthma on pregnancy 147

. 11.4  Asthma management 148

. 11.5  Pharmacologic therapy 149

Conclusion 153

11.1 Introduction

Asthma is one of the most common potentially serious medi- cal problems to complicate pregnancy, and may adversely affect both maternal quality of life and perinatal outcomes. Optimal management of asthma during pregnancy is thus important for both mother and baby. This chapter reviews the assessment and management of asthma in pregnant women.

11.2 Effect of pregnancy on the course of asthma

Asthma course may worsen, improve, or remain unchanged dur- ing pregnancy, and the overall data suggest that these various courses occur with approximately equal frequency. In a recent

146 11.2 Effect of pregnancy on the course of asthma

large prospective study of 1739 pregnant asthmatic women, severity classi cation (based on symptoms, pulmonary function, and medication use) worsened in 30% and improved in 23% of patients during pregnancy [1]. Asthma also appears to be more likely to be more severe or to worsen during pregnancy in women with more severe asthma before coming pregnant [2].

The course of asthma may vary by stage of pregnancy. The rst trimester is generally well tolerated in asthmatics with infrequent acute episodes. Increased symptoms and more frequent exacerba- tions have been reported to occur between weeks 17 and 36 of gestation. In contrast, asthmatic women in general tend to experi- ence fewer symptoms and less frequent asthma exacerbations dur- ing weeks 37–40 of pregnancy than during any earlier gestational period [3].

The mechanisms responsible for the altered asthma course dur- ing pregnancy are unknown. The myriad of pregnancy-associated changes in levels of sex hormones, cortisol, and prostaglandins may contribute to changes in asthma course during pregnancy. In addition, exposure to fetal antigens, leading to alterations in immune function, may predispose some pregnant asthmatics to worsening asthma [4]. Even fetal sex may play a role, with some data showing increased severity of symptoms in pregnancies with a female fetus [5].

There are additional factors that may contribute to the clinical course of asthma during pregnancy. Pregnancy may be a source of stress for many women, and this stress can aggravate asthma. Adherence to therapy can change during pregnancy with a corre- sponding change in asthma control. Most commonly observed is decreased adherence as a result of a mother’s concerns about the safety of medications for the fetus. One study found that women with asthma signi cantly decreased their asthma medication use from 5 to 13 weeks of pregnancy. During the rst trimester, there was a 23% decline in inhaled corticosteroid prescriptions, a 13% decline in short-acting beta-agonist prescriptions, and a 54% decline in rescue corticosteroid prescriptions [6].

Physician reluctance to treat may also affect the severity of asthma during pregnancy. A recent study found that less than 40% of women who classi ed themselves as “poorly controlled” reported use of a controller medication during pregnancy [7]. Another study identi ed 51 pregnant women and 500 non-preg- nant women presenting to the emergency department with acute asthma. Although asthma severity appeared to be similar in the two groups based on peak ow rates, pregnant women were signif- icantly less likely to be discharged on oral steroids (38% vs. 64%). Presumably related to this undertreatment, pregnant women were

11 The management of asthma during pregnancy 147

three times more likely than non-pregnant women to report an ongoing exacerbation 2 weeks later [8, 9].

Infections during pregnancy can certainly affect the course of gestational asthma. Some degree of decrease in cell-mediated immunity may make the pregnant patient more susceptible to viral infection, and upper respiratory tract infections have been reported to be the most common precipitants of asthma exac- erbations during pregnancy [10]. Sinusitis, a known asthma trigger, has been shown to be six times more common in preg- nant compared with non-pregnant women [11]. In addition, pneumonia has been reported to be greater than ve times more common in asthmatic than nonasthmatic women during pregnancy [12].

11.3 Effect of asthma on pregnancy

One of the largest controlled studies that have evaluated outcomes of pregnancy described 36,985 women identi ed as having asthma in the Swedish Medical Birth Registry. These outcomes were com- pared with the total of 1.32 million births that occurred during the years of the study (1984–1995). Signi cantly increased rates of preeclampsia (OR 1.15), perinatal mortality (OR 1.21), preterm births (OR 1.15), and low birth weight infants (OR 1.21), but not congenital malformations (OR 1.05), were found in pregnancies of asthmatic versus control women [13]. The risks appeared to be greater in patients with more severe asthma, which was con- rmed in a more recent Swedish Medical Birth Registry report [14]. A recent meta-analysis, derived from a substantial body of literature spanning several decades and including very large num- bers of pregnant women (over 1,000,000 for low birth weight and over 250,000 for preterm labor), indicates that pregnant women with asthma are at a signi cantly increased risk of a range of adverse perinatal outcomes including low birth weight, small for gestational age, preterm labor and delivery, and preeclampsia [15].

Mechanisms postulated to explain the possible increase in peri- natal risks in pregnant asthmatic women demonstrated in pre- vious studies have included [1] hypoxia and other physiologic consequences of poorly controlled asthma, [2] medications used to treat asthma, and [3] pathogenic or demographic factors asso- ciated with asthma but not actually caused by the disease or its treatment, such as abnormal placental function.

Several recent prospective studies [16–24] have shown that the pregnant asthmatic with mild to moderate severity can have

11 The Management of Asthma During Pregnancy

148 11.4 Asthma management

excellent maternal and fetal outcomes. In contrast, suboptimal control of asthma or more severe asthma during pregnancy may be associated with increased maternal or fetal risk [22, 25, 26].

11.4 Asthma management

The ultimate goal of asthma therapy in pregnancy is maintaining adequate oxygenation of the fetus preventing hypoxic episodes in the mother. The management of asthma can be summarized in four categories: assessment and monitoring, education of patients, control of factors contributing to severity, and pharmacologic therapy [27].

The rst step is assessment of severity (in patients not already on controller medications) or assessment of control (in patients already on controller medications). Severity is assessed in untreated patients based on the frequency of daytime and nighttime symptoms, rescue therapy use, activity limitation, and pulmonary function (ideally spirometry, minimally peak ow rate) (Table 11.1). Based on this, severity assessment controller therapy is initiated. Patients should be monitored monthly for asthma control (Table 11.2), and if not responding adequately to treatment should have their level of treatment adjusted (Table 11.3).

Table 11.1 Classi cation of asthma severity in pregnant patients*

Asthma severity

Symptom frequency

Nighttime awakening

Interference with normal activity

FEV1 or peak ow (predicted percentage of personal best)

Intermittent

Mild persistent

Moderate persistent

Severe persistent

2 days per week Twice per

None Minor limitation

Some limitation

More than 80% More than 80%

60–80% Less than 60%

or less

More than 2 days per week, but not daily

Daily symptoms

Throughout the day

month or less

More than twice per month

More than once per week

Four times per Extremely limited week or more

Abbreviation: FEV1 – forced expiratory volume in the rst second of expiration. *Data from Dumbrowski MP, Schatz M; ACOG Committee on Practice Bulletins – Obstetrics. ACOG practice bulletin: clinical management guidelines for obstetrician -gynecologists number 90, February 2008: asthma in pregnancy. Obstet Gynecol 2008;111:457–464.

11 The management of asthma during pregnancy 149 Table 11.2 Assessment of asthma control in pregnant women*

Variable

Well-controlled asthma

Asthma not well controlled

Very poorly controlled asthma

Frequency of symptoms

Frequency of nighttime awakening

Interference with normal activity

≤2 days/week ≤2 times/month

None

>2 days/week Throughout the day 1–3 times/week ≥4 times/week

Some Extreme >2 days/week Several times/day 60–80 <60

Use of short-acting β-agonist ≤2 days/week for symptoms control

FEV1 or peak ow (% of the >80 predicted or personal best
value)

Exacerbation requiring use of 0–1 in the past ≥2 in the past ≥2 in the past systemic corticosteroid (no.) 12 months 12 months 12 months

*Data from Schatz M, Dombrowski M. Asthma in pregnancy. N Engl J Med 2009;360:1862–1869.

Table 11.3 Steps of asthma therapy during pregnancy*

. 1  None –

. 2  Low dose ICS LTRA, theophylline

. 3  Medium dose ICS Low dose ICS + either LABA, LTRA or
theophylline

. 4  Medium dose ICS + LABA Medium dose ICS + LTRA or theophylline

. 5  High dose ICS + LABA –

. 6  High dose ICS + LABA + oral prednisone –

ICS – inhaled corticosteroids; LTRA – leukotriene receptor antagonists; LABA – long-acting beta-agonists. *Data from Schatz M, Dombrowski M. Asthma in pregnancy. N Engl J Med 2009;360:1862–1869.

11.5 Pharmacologic therapy

Asthma medications generally are divided into long-term control medications and rescue therapy. Long-term control medications are used for maintenance therapy to prevent asthma manifestations and include inhaled corticosteroids, cromolyn, long-acting beta- agonists, leukotriene receptor antagonists, and theophylline. Res- cue therapy, most commonly inhaled short-acting beta-agonists,

Step

Preferred controller medication

Alternative controller medication

11 The Management of Asthma During Pregnancy

150 11.5 Pharmacologic therapy

provides immediate relief of symptoms. Oral corticosteroids can either be used as a form of rescue therapy or as chronic therapy for severe persistent asthma.

11.5.1 Inhaled corticosteroids

Inhaled corticosteroids are the mainstay of controller therapy during pregnancy. Many studies have shown no increased perina- tal risks (including preeclampsia, preterm birth, low birth weight, and congenital malformations) associated with inhaled cortico- steroids [23, 28–33]. A recent study of over 4000 women who used inhaled corticosteroids during pregnancy found no increased risk of perinatal mortality associated with inhaled corticosteroid use during pregnancy [34]. Several large studies support the lack of association of inhaled corticosteroid use with total or speci c malformations [33, 35–37]. One study [38] has suggested a rela- tionship between high dose inhaled corticosteroids and total mal- formations, but confounding by severity is a possible explanation, based on the relationships between exacerbations and congenital malformations demonstrated by the same group [26].

Because it has the most published human gestational safety data, budesonide is considered the preferred inhaled cortico- steroid for asthma during pregnancy. That is not to say that the other inhaled corticosteroid preparations are unsafe. Therefore, inhaled corticosteroids other than budesonide may be continued in patients who were well controlled by these agents prior to preg- nancy, especially if it is thought that changing formulations may jeopardize asthma control. Doses of inhaled corticosteroids are categorized as low, medium, and high (Table 11.4).

11.5.2 Inhaled beta-agonists

Inhaled short-acting beta-agonists are the rescue therapy of choice for asthma during pregnancy. Inhaled albuterol is the rst-choice short-acting beta-agonist for pregnant women because it has been studied the most extensively [28], although other agents may be used if uniquely helpful or well tolerated. In one recent case–con- trol study, the use of bronchodilators during pregnancy was asso- ciated with an increased risk of gastroschisis among infants (OR, 2.1; 95% con dence interval (CI), 1.2 to 3.6) [39]. Also, in another cohort study involving 4558 women, there was an increased risk of cardiac defects exposed to bronchodilators during pregnancy (OR, 1.4; 95% CI, 1.1 to 1.7) [35]. A more recent case–control study also supported this association (OR 2.20; 95% CI, 1.05 to 4.61) [40]. However, this observation may be a result of confounding. Asthma exacerbations may be associated with both

11 The management of asthma during pregnancy 151 Table 11.4 Comparative daily doses for inhaled corticosteroids*,**

Corticosteroid

Amount

Low dose

Medium dose

High dose

Beclomethasone HFA

Budesonide

Ciclesonide

Flunisolide HFA Fluticasone HFA

Fluticasone DPI

Mometasone

40 mcg per puff 80 mcg per puff

90 mcg per inhalation 180 mcg per inhalation

80 mcg per actuation 160 mcg per actuation

80 mcg per puff

44 mcg per puff 110 mcg per puff 220 mcg per puff

50 mcg per inhalation 100 mcg per inhalation 250 mcg per inhalation

110 mcg per actuation 220 mcg per actuation

2–6 puffs 1–3 puffs

2–6 puffs 1–3 puffs

2–4 puffs 1–2 puffs

4 puffs

2–6 puffs 2 puffs 1 puff

2–6 puffs 1–3 puffs 1 puff

2 puffs 1 puff

More than 6–12 puffs More than 3–6 puffs

More than 6–12 puffs More than 3–6 puffs

More than 4–8 puffs More than 2–4 puffs

More than 4–8 puffs

– More than 2–4 puffs More than 1–2 puffs

– More than 3–5 puffs More than 1–2 puffs

3–4 puffs 2 puffs

More than 12 puffs More than 6 puffs

More than 12 puffs More than 6 puffs

More than 8 puffs More than 4 puffs

More than 8 puffs

– More than 4 puffs More than 2 puffs

– More than 5 puffs More than 2 puffs

More than 4 puffs More than 2 puffs

Abbreviations: DPI – dry powder inhaler; HFA – hydro uoroalkane. *Total daily puffs are usually divided into a twice-per-day regimen. **Data from [27] and Kelly HW Comparison of inhaled corticosteroids: an update. Ann Pharmacother 2009;43:519-27.

increased use of bronchodilators and congenital malformations. In addition, factors such as obesity or lower household socioeco- nomic status may be associated with both more severe asthma requiring more bronchodilators and congenital malformations. In general, patients should use up to two treatments of inhaled albuterol (two to six puffs) or nebulized albuterol at 20-minute intervals for most mild to moderate symptoms; higher doses can be used for severe symptom exacerbations.

The use of long-acting beta-agonists is the preferred add-on con- troller therapy for asthma during pregnancy. This therapy should be added on when patients’ symptoms are not controlled with the use of medium-dose inhaled corticosteroids. Because long-acting and

11 The Management of Asthma During Pregnancy

152 11.5 Pharmacologic therapy

short-acting inhaled beta-agonists have similar pharmacology and toxicology, long-acting beta-agonists are expected to have a safety pro le similar to that of albuterol. Two long-acting beta-agonists are available: salmeterol and formoterol. Limited observational data exist on their use during pregnancy. A possible association between long-acting beta-agonists and an increased risk of severe and even fatal asthma exacerbations has been observed in non- pregnant patients. As a result, long-acting beta-agonists are no longer recommended as monotherapy for the treatment of asthma and are available in xed combination preparations with inhaled corticosteroids. Expert panels suggest that the bene ts of the use of long-acting beta-agonists appear to outweigh the risks as long as they are used concurrently with inhaled corticosteroids [41].

11.5.3 Leukotriene modi ers

Both za rlukast and montelukast are selectiveleukotriene recep- tor antagonists indicated for the maintenance treatment of asthma. Both are pregnancy category B; however, data on the use of leukotrienereceptor antagonists during pregnancy are more limited. There is one published study, involving 96 patients, that supports their safety during pregnancy [42]. Another study of 180 montelukast-exposed pregnancies found no increase in baseline rate of major congenital malformations [43]. Montelukast is avail- able as a once daily medication with doses variable based on age. For adults, the typical dose is 10 mg daily.

11.5.4 Cromolyn and theophylline

Given the superiority of inhaled corticosteroids over cromolyn and theophylline in the prevention of asthma symptoms, the latter are considered alternative treatments for mild persistent asthma. Theophylline is also an alternative, but not preferred, add-on treatment for moderate to severe persistent asthma. Reassuring data on the use of cromolyn and theophylline in pregnant women have been published [41]. Theophylline use is also limited by its many adverse side effects and potential drug interactions result- ing in possible toxicity. Serum levels should be monitored during pregnancy and maintained between 5 and 12mcg/mL. Cromolyn is now only available as a nebulizer solution.

11.5.5 Oral corticosteroids

Some patients with severe asthma may require regular oral corti- costeroid use to achieve adequate asthma control. Oral corticoste- roids are also typically part of the discharge regimen after an acute

11 The management of asthma during pregnancy 153

asthma episode. Doses are typically 40–60 mg in a single dose or two divided doses for 3–10 days. Oral corticosteroid use has been associ- ated with an increased risk of preterm birth [23, 28] and low birth weight infants [28] in 52–185 exposed women. An increased risk of orofacial clefts was reported in a meta-analysis of case–control stud- ies [44], but this increased risk was not con rmed in a recent large cohort study [36]. Since these risks would be less than the potential risks of a severe asthma exacerbation, which include maternal or fetal mortality, oral corticosteroids are recommended when indi- cated for the management of severe asthma during pregnancy [41].

Conclusion

Asthma is a common medical problem that may worsen during pregnancy. In addition to affecting maternal quality of life, uncon- trolled asthma may lead to adverse perinatal outcomes. Aware- ness of proper treatment options for asthma during pregnancy is important for clinicians who care for pregnant patients.

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kast use during pregnancy; a multicentre, prospective, comparative study of

infant outcomes. Eur J Clin Pharmacol 2009;65:1259–64.
[44] Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, et al. Birth defects after maternal exposure to corticosteroids: prospec- tive cohort study and meta-analysis of epidemiologic studies. Teratology

2000;62:385–92.

11 The Management of Asthma During Pregnancy

Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

Caroline Maltepe, Rachel Gow and Gideon Koren

12

. 12.1  Introduction 157

. 12.2  Hyperemesis gravidarum 158

. 12.3  Etiology and risk factors 159

. 12.4  Differential diagnosis 159

. 12.5  Management of NVP and HG 160

Conclusion 167

12.1 Introduction

Nausea and vomiting of pregnancy (NVP) is a common medical condition, one that is perhaps least understood, which occurs in up to 85% of all pregnancies. The commonly used term “morning sickness” is misleading, as symptoms (nausea, retching and/or vomiting) can persist throughout the day and/or night [1–5]. The severity of NVP can range from mild to severe, beginning between 4 and 9 weeks and worsening between 7 and 12 weeks gesta- tion. Importantly, symptoms that begin after 10 weeks’ gestation should be investigated for other causes (see differential diagnosis). Typically, symptoms subside between 12 and 16 weeks; however, up to 15% of women will experience symptoms beyond 16 weeks or for the duration of their pregnancy [1–5].

NVP symptoms, whether they are mild, moderate or severe, can have a negative impact on the overall well-being of pregnant

158 12.2 Hyperemesis gravidarum

women, affecting family, work, and social life. The impact on qual- ity of life is not only physical but also emotional. Women often describe feelings of isolation, fatigue, helplessness, depression, anx- iety, frustration, dif culty coping, and irritability [6–10]. Up to 70% nd that their parenting abilities are affected, with women spend- ing less time with their children, and approximately 82% report that their usual activities are disrupted [8–9]. Furthermore, the nancial burden of NVP can be quite signi cant. In 2007, Piwko et al. reported on the weekly cost (including costs to society, the patients, and the health care system) of NVP in women with mild– severe symptoms. Total cost of NVP per woman-week with mild symptoms was $132, $355 for moderate, and $653 for severe [10].

Health care practitioners are often uncertain as to how best to treat their patients with NVP. Both patients and physicians often fear the use of pharmacological therapies during pregnancy due to the concerns of potential risks to the fetus. Physicians can con- siderably improve their patients’ quality of life, reduce the risk of both maternal and fetal complications, and hopefully prevent hos- pitalization by implementing early symptom management using counseling and evidence-based guidelines.

12.2 Hyperemesis gravidarum

Approximately 0.5–2% of women are affected by the most severe form of NVP, known as hyperemesis gravidarum (HG) [3]. HG is de ned as severe and persistent nausea and vomiting, weight loss greater than 5% of pre-pregnancy weight, dehydration, electrolyte imbalances, and nutritional de ciencies, typically requiring hos- pitalization [3, 11–13]. The following complications have been reported in women with HG: Wernicke’s encephalopathy due to vitamin B1 de ciency, coagulopathy secondary to acute vitamin K de ciency, anemia or peripheral neuropathy due to vitamin B12 and vitamin B6 de ciency, hyponatremia, renal damage, and Mallory Weiss tears [11, 13–14]. Furthermore, a study showed the recur- rence risk for hospital admission to be 29 times higher if the woman had also been hospitalized for HG in her previous pregnancy [15].

Women with HG may have more severe psychosocial morbidi- ties, including depression. In some cases, women may choose to terminate otherwise wanted pregnancies [16]. Negative maternal effects have been reported postpartum, such as longer recovery time from the pregnancy, muscle pain, and food aversions, par- ticularly with those women with extreme weight loss [17–18]. In addition, hospitalization and treatment for HG has a great

12 Guidelines for management of NVP and HG 159

nancial impact on the patient and society overall. A 2005 study found that the average cost of HG admission to hospital is $5900 per patient, with an average stay of 2.6 days [19]. A study investi- gating preemptive therapy demonstrated that initiating treatment prior to or on rst day of symptoms effectively lessened the sever- ity of symptoms and reduced the recurrence of HG [20].

12.3 Etiology and risk factors

The etiology of NVP/HG is multifactorial and still largely unclear. The most common theory is hormonal changes during the rst tri- mester of pregnancy, speci cally human chorionic gonadotropic (hCG) hormone, estrogen, and progesterone [14]. Women with multiple pregnancies will have higher hCG levels, which, in turn, often worsen symptoms of NVP. Nausea during the rst trimes- ter is also associated with gastric slow wave dysrhythmias which correlate closely with symptomatology [21]. Additionally, genetic in uences (such as familial recurrence and carrying female fetus), underlying psychological problems, liver abnormalities, other hormonal imbalances such as thyroid disorders, elevated cyto- kine levels, vitamin de ciency/ies (such as vitamin B6, B1, and K), Helicobacter pylori infection, as well as the evolutionary adap- tation theory (maternal and embryonic protection from toxins) have been proposed as part of etiology [11–14, 19, 21–24].

12.4 Differential diagnosis

When symptoms occur daily in early pregnancy, they are typically caused by NVP itself. However, when symptoms present after 10 weeks of gestation, they are almost certainly due to other causes. Many conditions related or unrelated to pregnancy can cause nausea and/or vomiting, such as gastrointestinal disorders, genitourinary tract disorders, metabolic and neurological disor- ders, drug toxicity or intolerance, psychological disorders, and pregnancy-related complications [1, 3, 11, 21, 24]. It is important to investigate for differential diagnosis (see Table 12.1), as seri- ous complications could occur if not detected. Furthermore, a thorough medical history and symptomatology must be taken, as patients may not disclose all relevant information. The presence of signs and/or symptoms, such as abdominal tenderness or pain, fever, headache, diarrhea, constipation or goiter, can also point to

12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

160 12.5 Management of NVP and HG
Table 12.1 Other contributors to nausea and vomiting* [1, 3, 11, 21, 24]

  

Central nervous system disorders

n Migraine, headache
n Tumors
n Balance disorders (e.g. Meniere’s disease,

labyrinthitis, motion sickness)
n Psychologic and psychiatric disorders

(e.g. depression, anxiety)
n I ncreased intracranial pressure (e.g.

pseudotumor cerebri, hemorrhage, hydrocephalus)

Gastrointestinal disorders

n Pancreatitis
n Gastroesophageal re ux disease n Gastroenteritis
n Hepatitis
n Appendicitis
n Intestinal obstruction
n Helicobacter pylori infection
n Irritable bowel syndrome
n Peptic ulcer disease
n Biliary tract disease
n Achalasia
n Gastroparesis
n Cholecystitis

Metabolic and endocrine disorders

n Hyperthyroidism/Hypothyroidism n Hypercalcemia
n Addison’s disease
n Diabetes mellitus

n Diabetic ketoacidosis Genitourinary tract disorders

n Uremia
n Kidney stones n Ovarian torsion n Porphyria
n Pyelonephritis

Pregnancy-related conditions

n Preeclampsia
n Acute fatty liver of pregnancy n Gestational trophoblast disease n HELLP syndrome
n Multiple pregnancies

Other

n Viral and/or bacterial infections
n Drug toxicity, intolerance or dependence

 

*Permission to adapt by the Association of Professors of Gynecology and Obstetrics.

other conditions [1]. Ultrasound can be useful to detect multiple or molar gestation, as well as gallbladder, liver, and kidney disorders. Of note, laboratory abnormalities (such as elevations of liver enzymes, bilirubin, amylase, and lipase) may be present with severe NVP/ HG and could in uence differential diagnosis [1, 3, 11].

12.5 Management of NVP and HG

The symptoms and impact of NVP and/or HG can vary among women; therefore treatment must be tailored to the individual. It is important to advise all women on dietary and lifestyle changes, non-pharmacological and pharmacological treatments. For some women, dietary and lifestyle changes may be dif cult to main- tain, non-pharmacological approaches may lack effectiveness, and therefore pharmacological approaches may be warranted.

12 Guidelines for management of NVP and HG 161 12.5.1 Dietary and lifestyle approaches

Food and odor aversions caused by pregnancy and NVP can greatly impact a woman’s daily routine and, for some, may lead to weight loss and dehydration. To reduce symptoms, common dietary strategies include eating small, frequent meals or snacks of high-carbohydrate and low-fat types every 1–2 hours to avoid an empty stomach or feelings of hunger, thus preventing low blood sugar and gastric distension [5, 25–27]. Importantly, Jednak et al. demonstrated that nausea is reduced signi cantly when ingest- ing protein-predominant meals, therefore protein (meat and/or alternatives) should be added to all meals and snacks [26]. For women who are having dif culty eating solid foods, liquid nutri- tional products may be added. It is important to drink colder u- ids between meals and snacks and to keep well hydrated [5]. See Table 12.2 for additional symptom management.

Table 12.2 Symptom management for NVP [1, 5, 25–31] Dietary

n Eating every 1–2 hr smaller portions
n Dry, salty, bland, and soft foods may help
n Add protein or its alternates to all meals and snacks (e.g. nuts, seeds, beans, dairy, nut

butters)
n Drink 20–30 min prior to and after solid foods
n Liquid intake should be 2 liters per day; colder uids, such as slushies, popsicles, ice

chips, will help maintain hydration
n Electrolytes can be added to prevent dehydration (e.g. sport drinks, vitamin waters) n To minimize bitter or metallic taste, add candies, gums and colder uids
n For constipation, increase dietary ber, such as psyllium, fruits; and, if needed, add

docusate sodium daily
n For gas and/or bloating, switch to lactose-free and, if needed, add simethicone daily or prn n For symptoms of acidity, such as burping, burning, indigestion, re ux, modify diet and, if

needed, add antacids, H2-blockers or PPIs daily or prn

Lifestyle and other

n For heightened sense of smell, try to sniff lemons, limes or oranges, ventilate the area, consume room temperature/cold meals or snacks

n Women experiencing ptyalism, advise to spit out excessive saliva and use mouthwash more frequently

n Avoid brushing teeth after eating meals or snacks
n Get plenty of sleep and rest, try not to get overly tired
n When rising, snack beforehand and try to get up slowly
n Try not to lie down after meals
n If possible, ask for help from family members or friends
n I f iron de cient, to continue with prenatal vitamins, break in half and take in divided

doses for tolerability. If not, avoid for rst trimester and switch to children’s chewable multivitamin along with folic acid; resume with prenatal vitamin after 12 weeks

  

12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

162 12.5 Management of NVP and HG 12.5.2 Treatment for acidity and indigestion

Given that symptoms of dyspepsia and/or gastroesophageal re ux disorders are common in pregnancy (affecting 40–85% of women) and that gastric dysrythmias are associated with NVP, it is impor- tant for physicians to investigate if their patients are experiencing any symptoms of acidity and/or digestive issues [28].

A 2009 study demonstrated that adding acid-reducing medica- tions (e.g. antacids, H2-receptor antagonists, and/or proton pump inhibitors) resulted in a signi cant reduction of NVP symptoms, without making changes to the antiemetic regimen [28]. Acid and indigestion have been safely treated in pregnant women using antacids, H2-blockers (such as calcium carbonate and ranitidine) and proton pump inhibitors (omeprazole more commonly used) [28–31]. Proton pump inhibitors (PPIs) have been studied in over 5000 pregnant women and have not been associated with increased risks of major malformations [30–31].

Further, many studies and a meta-analysis have shown an association between Helicobacter pylori infection and HG and/ or severe NVP [32–33]. Screening for H. pylori should be stan- dardized for all women who have a previous pregnancy with HG, or who are currently experiencing moderate to severe NVP. Subsequent treatment of H. pylori with antibiotics and PPIs may improve NVP symptoms [1, 5, 32–33].

12.5.3 Non-pharmacological approaches

With increased fear of taking medications in the pregnancy, non- pharmacological treatments offer a good alternative. Vitamin B6 and ginger are most commonly used for NVP. Vitamin B6 has been well studied and can be taken safely in pregnancy with doses up to 200mg/day [1, 5, 34]. The effectiveness of ginger has been shown in randomized trials and can be taken safely with doses of up to 1000 mg/day (dried ginger root powder equivalent) [1, 3, 5, 35]. In addition, traditional acupuncture or acupressure of the P6 (Nei- guan point) can be safely used to treat NVP. With regards to ef – cacy, data are limited [1, 3, 5, 36]. Small studies and case reports have been published using psychotherapy and medical hypnosis for the treatment of NVP [1, 37–38]. When women are experi- encing unrelenting and more severe symptoms, many researchers recommend counseling and supportive therapy [38, 39].

12.5.4 Pharmacological approaches

There are many antiemetics that have been given either as mono- therapy or polytherapy to help alleviate NVP with varying levels

12 Guidelines for management of NVP and HG 163

of safety and effectiveness [1, 3, 5]. It is important to note that all pregnancies have a 1–3% baseline risk of having a baby with a birth defect by chance alone [25]. Health care providers should assess the best course of treatment, not only based on the severity of symptoms, but also on the patient’s self-report and impact on her daily life. Importantly, many of these antiemetics have anti- cholinergic properties and therefore, if the patient reports anti- cholinergic drug reactions, modi cations in treatment regimen, dose or schedule may be needed [11–13]. Physicians should reit- erate to their patients the importance of adherence in order to sustain the management of symptoms and, upon improvement, gradually taper down their medication(s).

The Motherisk Program at the Hospital for Sick Children in Toronto has the only specialized NVP Helpline worldwide dedi- cated to counseling women and has produced an algorithm for the treatment for NVP based on best available evidence (see Figure 12.1) [5]. The combination therapy of doxylamine suc- cinate and vitamin B6 is recommended as rst-line therapy for the treatment of NVP by the Canadian and American Colleges of Obstetricians and Gynecologists [3, 40] and the Association of Professors of Gynecology and Obstetrics [1]. This formula- tion was originally known as Bendectin, which was voluntarily removed in 1983 due to concerns of teratogenicity; however, since this time many studies including two meta-analyses have con rmed its safety [41, 42]. In Canada, this medication, known as Diclectin®, is the only drug labeled for pregnancy by Health Canada due to its large safety pro le. Furthermore, the use of Diclectin® during pregnancy was not associated with any long-term effects on neurodevelopment in a 2009 study [43]. In regards to its ef cacy, a randomized placebo-controlled trial published in 2010 showed Diclectin® was effective over placebo in 280 American women [44].

Metoclopramide use in pregnancy has not been associated with increased risk of birth defects in several prospective studies [45–47]. A study published in 2009 did not show an increased risk of birth defects following rst trimester use in over 3400 women [47]. As a stomach motility agent, it may be helpful for those women also suf- fering with heartburn and indigestion. Importantly, women should be advised to eat within 30 minutes after taking metoclopramide.

Domperidone has reportedly been used to treat NVP; however, no case reports or studies have been documented [45, 46]. In 2009, a preliminary study by Choi et al. investigated 146 women unin- tentionally exposed to domperidone in early pregnancy for gas- trointestinal tract symptoms and found no increased risk of major malformations [48]. Its safety pro le is limited, but seems reassuring.

12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

164 12.5 Management of NVP and HG

 

Figure 12.1 Algorithm for treatment of NVP. (If no improvement proceed to next step.) Permission to reprint by the Association of Professors of Gynecology and Obstetrics.

Phenothiazines, such as prochlorperazine, promethazine, and chlorpromazine, are commonly used antiemetics and antipsychot- ics. With regards to NVP/HG, numerous studies have not shown an increased risk for major malformations [1, 13, 15, 56]. When used continuously into the third trimester, neonatal withdrawal, including extra-pyramidal effects, have been reported in new- borns [13].

Ondansetron is a selective serotonin 5-HT3 receptor antagonist known for its use in treating chemotherapy-related nausea and

12 Guidelines for management of NVP and HG 165

vomiting. Despite its cost and limited safety pro le, it is commonly used. Studies and case reports are available on approximately 230 women exposed to ondansetron in pregnancy, none of which have reported any increased risk of birth defects [1, 45, 49]. Of note, a stool softener may be needed, as constipation is a common side effect [1].

Droperidol is a butyrophenone tranquilizer that has been used in the treatment of hyperemesis gravidarum [45, 50, 51]. In 2001, Turcotte et al. found no differences in any pregnancy outcome between their treatment group receiving droperidol and diphen- hydramine (n=28) and the control group (n=54) [50]. In a 2003 study, Ferreira et al. looked at two different doses of droperidol combined with diphenhydramine (total n=101) and found an increase in major malformations; however, the differences were not signi cant compared to controls (n = 54) [51]. These two non- randomized, prospective studies found a reduction of nausea and vomiting symptoms following treatment.

Trimethobenzamide is an older antiemetic that is structurally similar to antihistamines and has been reported to reduce NVP symptoms. In over 1000 women exposed in pregnancy, many in the rst trimester, trimethobenzamide was not associated with increased risk of major malformations [46, 52–54].

For breakthrough relief, antihistamines such as dimenhydrinate or meclizine have been widely used in the treatment of NVP and may be taken daily or as needed until symptoms improve [1, 3, 5, 45, 55]. Numerous studies have documented their effectiveness. A meta-analysis including over 24 different studies have shown no increased risk of birth defects [46, 55].

As a last resort, corticosteroids, speci cally methylpredniso- lone, have been used in the treatment of NVP/HG, though reports of ef cacy are con icting [56–58]. They are recommended to be used after the rst trimester since corticosteroids are associated with a slight increased risk of facial clefts [56, 57]. It has been observed that the use of corticosteroids throughout pregnancy has been associated with a higher rate of preterm births and reduced birth weight [58]. Of note, it may be necessary to monitor fetal growth, as well as maternal blood pressure and blood sugar.

12.5.5 Management of HG

When a pregnant patient presents herself with persistent nausea, dehydration, uncontrollable vomiting, and/or excessive weight loss, hospitalization may be required. For most patients, symp- toms will improve with IV hydration and antiemetics. For some women who fail to respond to treatment and experience ongoing symptoms and weight loss, enteral or parenteral nutrition should

12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

166 12.5 Management of NVP and HG Table 12.3 Nutritional support of the hyperemesis patient*

Assessment

n >5% loss of pre-pregnancy body weight
n Nutrient reserves before pregnancy
n Individual physiologic needs and added requirements pregnancy
n Any disease process or current therapy that might affect nutrient requirement or nutrient

tolerance
n Clinical and laboratory ndings (urine output, peripheral pulse, temperature, skin color,

muscle strength, general fatigue, electrolyte abnormalities)

Correct Hypovolemia

(i.e. acidosis. decreased serum bicarbonate, increased serum lactate, electrolyte imbalances) n IV uid, electrolyte, and vitamin replacement
n Lactated Ringer’s solution is effective
n Large volumes of normal saline may cause hyperchloremic acidosis

Nutritional Support

Enteral: by oral or tube feeding as tolerated Parenteral: in cases of severe depletion, and/or continued gastrointestinal dysfunction n Assess patient’s status, urgency, and impact of various routes feeding
n Consider potential complications of tube feeding (e.g. aspiration, diarrhea)
n Consider consult by nutritionist/dietician
n If deciding on enteral support, identify most appropriate formula
n Consider potential complications of parenteral nutrition (e.g. catheter insertion, line

complications, septic and metabolic problems, central versus peripheral line placement);

close monitoring required
n Monitor for re-feeding syndrome (e.g. hypokalemia, hypophosphatemia,

hypomagnesemia, thiamin de ciency)

Enternal Nutrition

Liquid caloric and vitamin supplement, such as one of the following: n Meal replacement formula
n Concentrated formula for uid-restricted patients
n High-protein formula

n Elemental semi-elemental formula for patients with impaired digestion n Modular formula for boosting select macronutrients

Parenteral Nutrition**

n With high fat content solutions, calories suf cient for short-term maintenance can be provided through a peripheral vein. If intolerance to oral feeding persists more than several days, peripheral venous nutrition cannot go on as phlebitis may develop when continued for 1 to 2 weeks.

n A representative peripheral nutrition formulation, such as 63 g of amino acids, 150 g of glucose, and 100 g of fat (total 1762 kcal) with vitamins, minerals, and required electrolytes, provides a total volume of 2000 mL/day.

  

12 Guidelines for management of NVP and HG 167 Table 12.3 Nutritional support of the hyperemesis patient*—cont’d

n For patients who cannot tolerate oral feeding or for whom the vomiting appears likely to persist more than several days, high-calorie, high-glucose formulations may be required. These must be administered centrally because of the sclerosing effect of the glucose on peripheral veins.

n A representative central venous formulation can provide an adequate nutrient intake within a reasonable uid volume for as long as necessary, such as 2400 kcal/day including 100 g amino acids, within 2000 mL.

*Adapted from [59] and incorporating recommendations from [62]. **Sample formulations given. Each formulation is patient-dependent and should be calculated individually. Once a physician determines that parenteral nutrition is required, a registered dietitian experienced in TPN and medical nutrition therapy should be actively involved in patient care.

Permission to reprint by the Association of Professors of Gynecology and Obstetrics.

be considered to provide nourishment and improve well-being for both mother and fetus [1, 59–61].

Current literature suggests that enteral feedings via nasogastric, gastric or jejunostomy feeding tubes can be used to either comple- ment or replace oral feeding and has been given successfully in patients with HG [1, 59–61]. Enteral nutrition maintains gut func- tionality thus preventing atrophy. Importantly, it also seems to be more cost effective and associated with fewer risks than parenteral nutrition [1, 59–61]. However, parenteral nutrition through periph- erally inserted central catheter (PICC) line appears to be more widely accepted by hyperemetic patients. While total parenteral nutrition (TPN) has been associated with serious complications, it has been successfully used for over 30 years [61]. Interestingly, a study found a higher rate of complications among women with cen- trally inserted catheters (50%) compared to women with PICC lines (9%) [61]. Physicians should assess their patients’ nutritional needs on an individual basis. Due to a lower risk pro le, attempts should be made to use enteral over parenteral nutrition. Of importance, while the woman is improving under IV hydration, it is critical to start effective oral antiemetic therapy, to avoid cyclic readmission due to similar presentation [1, 59–61]. The nutritional support of pregnant women with HG is addressed in Table 12.3.

Conclusion

Although NVP is the most common medical condition in pregnancy, many health care practitioners are uncertain as to how best to treat

  

12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

168 References

their patients. Optimal management of NVP/HG is multidimen- sional and often complex. Treatment regimens should be designed on an individual basis and all women should be counseled on dietary management, non-pharmacological and pharmacological treatment options. Importantly, as studies have shown a high rate of recurrent symptoms, it is bene cial for women to receive early treatment to help reduce the severity of symptoms in future pregnancies, hope- fully preventing hospitalization and improving quality of life.

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. [35]  Ozgoli G, Goli M, Simbar M. Effects of ginger capsules on pregnancy, nausea and vomiting. J Altern Complement Med 2009;15(3):243–6.

. [36]  Roscoe JA, Matteson SE. Acupressure and acustimulation bands for control of nausea: a brief review. Am J Obstet Gynecol 2002;186:S244–7.

. [37]  McCormack D. Hypnosis for hyperemesis gravidarum. J Obstet Gynaecol 2010;30(7):647–53; Review.

. [38]  Lub-Moss MM, Eurelings-Bontekoe EH. Clinical experience with patients suffering from hyperemesis gravidarum (severe nausea and vomiting during pregnancy): thoughts about subtyping of patients, treatment and counseling models. Patient Educ Couns 1997;31:65–75.

. [39]  Köken G, Yilmazer M, Cosar E, Sahin FK, Cevrioglu S, Gecici O. Nausea and vomiting in early pregnancy: relationship with anxiety and depression. J Psychosom Obstet Gynaecol 2008;29(2):91–5.

. [40]  Arsenault MY, Lane CA, MacKinnon CJ, Bartellas E, Cargill YM, Klein MC, et al. The management of nausea and vomiting of pregnancy. J Obstet Gynaecol Canada 2002;24(10):817–33.

. [41]  Brent R. Bendectin and birth defects: hopefully, the nal chapter. Birth Defects Research (Part A) 2003;67:79–87.

. [42]  Lamm SH. The epidemiological assessment of the safety and ef cacy of Bend- ectin. In: Koren G, Bishai R, editors. Nausea and Vomiting of Pregnancy: State of the Art 2000. vol. I. Toronto: Motherisk 2000. p. 100–3.

. [43]  Nulman I, Rovet J, Barrera M, Knittel-Keren D, Feldman BM, Koren G. Long- term neurodevelopment of children exposed to maternal nausea and vomiting of pregnancy and diclectin. J Pediatr 2009;155:45–50.

. [44]  Koren G, Clark S, Hankins GD, Caritis SN, Miodovnik M, Umans JG, et al. Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. Am J Obstet Gynecol 2010;203(6): 571.e1–7.

. [45]  Gill SK, Einarson A. The safety of drugs for the treatment of nausea and vomit- ing of pregnancy. Expert Opin Drug Saf 2007;6(6):685–94; Review.

. [46]  Mazzotta P, Magee LA. A risk–bene t assessment of pharmacological and nonpharmacological treatments for nausea and vomiting of pregnancy. Drugs 2000;59:781–800.

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[51] Ferreira E, Bussieres JF, Turcotte V, Duperron L, Ouellet G. Case–control study comparing droperidol plus diphenhydramine in hyperemesis gravi- darum. J Pharm Technol 2003;19:349–54.

[52] Milkovich L, Van den Berg BJ. An evaluation of the teratogenicity of certain antinauseant drugs. Am J Obstet Gynecol 1976;125:244–8.

[53] Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, Mass: Publishing Sciences Group; 1977. p. 323–324, 327, 330, 437, 489.

[54] Jick H, Holmes LB, Hunter JR, Madsen S, Stergachis A. First-trimester drug use and congenital disorders. JAMA 1981;246(4):343–6.

[55] Seto A, Einarson T, Koren G. Pregnancy outcome following rst trimester exposure to antihistamines: meta-analysis. Am J Perinat 1997;14:119–24. [56] Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L,

et al. Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62(6): 385–92.

[57] Carmichael SL, Shaw GM, Ma C, Werler MM, Rasmussen SA, Lammer EJ, et al. Maternal corticosteroid use and orofacial clefts. Am J Obstet Gynecol 2007;197(6): 585.e1–7.

[58] Gur C, Diav-Citrin O, Shechtman S, Arnon J, Ornoy A. Pregnancy outcome after rst trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 2004;18:93–101.

[59] Hamaoui E, Hamaoui M. Nutritional assessment and support during preg- nancy. Gastroenterol Clin North Am 2003;32:59–121.

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12 Updated Guidelines for the Management of Nausea and Vomiting of Pregnancy and Hyperemesis Gravidarum

13 Brookie M. Best

Clinical Pharmacology of Anti-Infectives During Pregnancy

. 13.1  Antibacterial therapy 174

. 13.2  Antifungal therapy 180

. 13.3  Malaria 181

. 13.4  Tuberculosis 183

. 13.5  HIV 184

. 13.6  Antivirals 189

. 13.7  Parasitic infections 191

Serious infections can occur during pregnancy, and must be treated to prevent maternal and fetal adverse outcomes. While some antimicrobials have been studied in pregnancy, many agents have inadequate data available to evaluate safety, ef cacy, and appropriate dosing, posing a challenge for drug and dose selection. Important safety data have been summarized elsewhere [1, 2]. This chapter focuses on pharmacology and pharmacokinet- ic studies for drugs used to treat infections in pregnancy. Drug dis- position characteristics that may alter drug exposure in pregnancy should be considered in selecting a treatment regimen. For drugs that are primarily renally eliminated, clearance may increase later in pregnancy yielding lower blood concentrations of the drugs. For drugs primarily metabolized by the liver or by a combination of pathways, changes in exposure during pregnancy may or may not occur depending on the speci c enzyme systems involved.

174 13.1 Antibacterial therapy

Further, drug interactions are a major concern when treating multiple infections, such as HIV and tuberculosis. For drugs that are highly protein bound, the dilutional effect on albumin in late pregnancy may increase the free or unbound drug concentration. Finally, the duration of exposure for both the mother and the fe- tus when a drug is given during pregnancy should be considered when selecting therapy, as about ve half-lives must pass for most of the drug to be eliminated from the body. Drugs with short half- lives, whose clearance is increased during pregnancy, may need to be dosed more frequently. These alterations in disposition can be additive or antagonistic, complicating attempts to predict whether drug exposure will change signi cantly in pregnancy. Therefore, pharmacokinetic studies in pregnant women are necessary to fully understand changes in exposure and the implications for appro- priate dose selection. In the absence of pharmacokinetic studies in pregnant women, close monitoring of drug therapy is warranted, including measurement of plasma concentrations and individual optimization of doses when possible.

13.1 Antibacterial therapy

Penicillins are the antibiotics of choice during pregnancy. They are pregnancy category B, cross the placenta and small amounts are excreted in breast milk. Penicillin G and V are 45–68% and 75–89% bound to plasma proteins, respectively, are partially metabolized (<30%) to inactive metabolites, and parent drug and metabolites are excreted in the urine via tubular secretion. One pharmaco- kinetic study of a dose of 1 million international units (IU) of penicillin G intravenously (IV) every 4 hours in pregnant women concluded that this produced adequate maternal penicillin con- centrations for prophylaxis against Group B Streptococcus [3]. Current guidelines recommend an initial dose of 5 million IU, fol- lowed by 2.5–3 million IU every 4 hours [4]. Another study of a single 2.4 million IU intramuscular dose of penicillin G for pre- vention of congenital syphilis showed high variability and some sub-therapeutic concentrations; authors suggested that higher doses may need to be studied [5]. Current syphilis treatment guidelines in pregnancy recommend use of penicillins but state optimal doses are unknown [6]. A study of a single oral dose of penicillin V in both pregnant and non-pregnant (control) women demonstrated signi cantly decreased area under the concentra- tion time curve (AUC – a measure of overall exposure), shorter half-life, and increased penicillin clearance in pregnant women.

13 Clinical pharmacology of anti-infectives during pregnancy 175

The authors concluded shorter dose intervals (1 million IU every 6 hours instead of every 8 hours) or higher doses of penicillin V may be needed during pregnancy [7]. Studies of higher than standard doses have not been described.

Amoxicillin, ampicillin, dicloxacillin, and ticarcillin are all mainly eliminated via renal tubular ltration and secretion, with about 10% metabolized. Oxacillin is about half metabolized and half eliminated unchanged in the urine. Piperacillin is 10–20% excreted via bile into the feces, with the rest eliminated unchanged in the urine. Nafcillin, unlike all the other penicillins, is 60% me- tabolized, undergoes enterohepatic recirculation, and both parent and metabolites are excreted in the bile. Plasma protein binding is about 20% for amoxicillin, ampicillin, and piperacillin, is about 50% for ticarcillin, and is 70–99% for nafcillin, oxacillin, and di- cloxacillin. One study of a single oral 500mg dose of amoxicillin in pregnant women for post-exposure prophylaxis against anthrax showed increased clearance during pregnancy compared to post- partum, and concluded that anthrax preventive concentrations will not be feasible in pregnant women [8]. Studies of intrave- nous amoxicillin have recommended a dose during labor or dur- ing preterm premature rupture of membranes of 2g followed by 1g every 4 hours [9–11]. Two older reported studies of ampicil- lin pharmacokinetics following 500mg doses during pregnancy found decreased exposure and suggested increased loading doses (because of the large increase in distribution volume) were likely needed [12, 13]. Finally, two studies of piperacillin-tazobactam in pregnant women found increased clearance and distribution vol- ume during pregnancy, and suggested that higher than standard doses may be needed during pregnancy [14, 15].

Cephalosporins, pregnancy category B, can be safely used to treat various infections during pregnancy, and older agents are preferred due to more data and experience in pregnancy. Speci c doses depend on the infection site and offending microbe. They are classi ed by antibacterial activity. Example rst generation agents are: cefadroxil, cephalexin, cephradine, cephalothin, and cefazolin; second generation agents are: cefoxitin, cefatrizine, ce- fotetan, ceforanide, cefamandole, cefaclor, cefprozil, cefuroxime, and cefuroxime axetil; and third/fourth/ fth generation agents are: cefotaxime, ceftazidime, ceftriaxone, ceftizoxime, ce xime, cefditoren, cefdinir, cefpodoxime, ceftibuten, cefoperazone, ce- fepime, and ceftaroline. As a class, they all cross the placenta well [16–18], and small amounts are found in breast milk. Many are 60–90% protein bound in plasma, except for cefaclor, cephalexin, cefadroxil, cefpodoxime, cefotaxime, ceftizoxime, ceftazidime, and cefuroxime, which are less than 50% protein bound.

13 Clinical Pharmacology of Anti-Infectives During Pregnancy

176 13.1 Antibacterial therapy

For rst generation agents, one study of cephalothin in pregnant women concluded that pregnancy alterations in exposure were insigni cant and no dose changes were warranted [19]. Cepha- lothin is 10–40% metabolized, with the rest excreted unchanged in urine, while the other rst generation agents are not metabo- lized and are wholly excreted unchanged in urine. In contrast, studies of cephradine and cefazolin in pregnant women showed increased clearance and distribution volumes, decreased AUCs, and shorter half-lives, concluding that doses in pregnancy should be increased, possibly by reducing dose intervals rather than by increasing dose amounts [20, 21].

Cefuroxime, a second generation cephalosporin, has lower plasma concentrations and a shorter half-life during pregnancy compared to postpartum [18]. For cefoxitin, at 19–21 weeks’ gestation, plasma concentrations were similar to those seen in non-pregnant adults [22], while at term, clearance of cefoxitin is signi cantly increased [23]. The second generation agents are primarily excreted unchanged in the urine.

Several later generation cephalosporins have been studied in pregnant women. Cefoperazone at term showed a larger distri- bution volume, lower peak concentration, and decreased protein binding (74% vs. 88%) during pregnancy compared to non-pregnant adults, but also showed that pregnancy did not greatly affect clearance, half-life or trough concentrations [24]. Of note, unlike most other cephalosporins, cefoperazone is metabolized in the liver and excreted in the bile. Ceftazidime clearance increases and concentrations decrease throughout pregnancy compared to post- partum; clearance is primarily renal excretion of unchanged drug [22, 25]. Cefotaxime is metabolized to an active metabolite, and both parent drug and metabolite are eliminated in urine. All other cephalosporins are not appreciably metabolized, and are primarily excreted unchanged in the urine. While increased dose amounts and more frequent dosing have been proposed to attain adequate drug concentrations for many cephalosporins, pharmacokinetic studies of such increased doses are lacking.

Carbapenems imipenem-cilastatin (category C) and merope- nem (category B) cross the placenta, have low protein binding, and are excreted mainly unchanged in the urine. Breast milk pen- etration is unknown. Clearance and distribution volume of imipe- nem after a single 500mg IV dose were signi cantly increased in early and late pregnancy compared to postpartum, and increased doses may be needed in pregnancy [26]. No pharmacokinetic studies of meropenem in pregnancy are reported. Carbacefems aztreonam and loracarbef pharmacokinetics have not been stud- ied in pregnancy either. Loracarbef is 25% protein bound, is not

13 Clinical pharmacology of anti-infectives during pregnancy 177

metabolized, and is excreted unchanged in the urine. Placental and breast milk penetration are unknown. Aztreonam is about 60% protein bound and is mainly eliminated unchanged in the urine, with 6–16% metabolized. It crosses the placenta well [27], and breast milk penetration is unknown. Beta-lactamase inhibitors, given in combination with penicillins or cephalosporins, include sulbactam, tazobactam, and clavulanic acid. All are pregnancy category B, and are about 30% protein bound. Sulbactam and tazobactam cross the placenta and undergo some metabolism while most of the drug is excreted unchanged in urine. Both have signi cantly decreased exposure during pregnancy [14, 28]. For clavulanic acid, half is metabolized, half is excreted in urine, and low amounts cross the placenta [29].

Macrolides, such as erythromycin, azithromycin, and clarithro- mycin, are used to treat various infections in pregnant women. Placental concentrations are less than 7% of maternal concentra- tions [30, 31]. Erythromycin breast milk concentrations are about 50% of maternal concentrations, and it is compatible with breast- feeding. It is 73–81% protein bound, is a substrate and inhibitor of both cytochrome P450 (CYP) 3A4 and permeability glycoprotein (Pgp), concentrates in bile and liver, and is excreted in the bile. Clarithromycin is also a substrate and inhibitor of CYP3A4 and Pgp, while azithromycin is not metabolized and has no effect on CYP enzymes. Penetration of azithromycin or clarithromycin into breast milk is unknown, and both have low protein binding. One pharmacokinetic study of azithromycin found increased distri- bution volume but unchanged AUC and elimination half-life in pregnant versus non-pregnant women, suggesting standard doses should be appropriate in pregnancy [32].

Vancomycin is used for Gram-positive bacterial infections. It is category B, administered intravenously, widely distributed, 55% protein bound and excreted renally. It crosses the placenta at con- centrations similar to maternal concentrations [33]. It is excreted in breast milk; infants would likely not absorb vancomycin, but their gut ora may be altered. Data in pregnancy are limited, so use should be reserved for serious infections. Other polypeptides, colistin, polymyxin B, and teicoplanin, have even fewer data re- garding use in pregnancy, and should only be used for compelling indications.

Chloramphenicol is well absorbed and widely distributed, is 60% bound to plasma proteins, with higher placental than maternal con- centrations [34]. It is hepatically glucuronidated, and is a potent CYP3A4 and 2C19 inhibitor. Due to neonatal toxicity, “gray baby syndrome” and agranulocytosis, use during pregnancy, especially near term, should be avoided unless absolutely necessary.

13 Clinical Pharmacology of Anti-Infectives During Pregnancy

178 13.1 Antibacterial therapy

Tetracyclines, including oxytetracycline, tetracycline, demeclo- cycline, methacycline, doxycycline, and minocycline, are preg- nancy category D, and should not be used in pregnancy due to strong binding to developing teeth and bones. Tetracycline and doxycycline are enterohepatically recirculated and eliminated mainly in feces (doxycycline) or urine (tetracycline). Minocycline is partially hepatically metabolized. These agents chelate cations, cross the placenta, and penetrate into breast milk, but are consid- ered compatible with breastfeeding. No pharmacokinetic studies in pregnancy have been reported.

Lincomycin and clindamycin, pregnancy category B, are hepat- ically metabolized, cross the placenta with 25–50% of maternal concentrations found in cord blood, and cross into breast milk but are considered compatible with breastfeeding. Clindamycin, given at 900 mg every 8 hours for Group B Streptococcus, was evaluated in pregnant women. The authors found that this standard dose may be sub-therapeutic [35]. Higher doses have not been studied in this population. These drugs should be avoided during preg- nancy unless other rst-line agents are ineffective or not tolerated.

Linezolid, pregnancy category C, is widely distributed, metabo- lized by both enzymatic (presumably CYP-mediated) and non- enzymatic processes, and about 30% is eliminated unchanged in the urine. It is used for Gram-positive infections. Data in preg- nancy are very limited. Placental and breast milk penetration in humans are unknown. Dalfopristin-quinupristin, pregnancy cat- egory B, is also used for Gram-positive infections. Both agents are metabolized to several active metabolites by non-CYP processes, but these agents potently inhibit CYP3A4. The parent compounds and metabolites are mainly eliminated in the feces, with 15–20% of each parent drug eliminated unchanged in the urine. Placental and breast milk transfer are unknown, and no pharmacokinetic studies in pregnancy are available.

Aminoglycosides (pregnancy category D, except spectinomycin which is B), including streptomycin, neomycin, kanamycin, ami- kacin, gentamicin, tobramycin, and netilmicin, are administered intravenously and eliminated unchanged in the urine. They cross the placenta, and may accumulate in the fetus [36, 37]. Gentamicin clearance and dose requirements are increased during pregnancy, which corresponded more with increased distribution volumes than increased renal function [38]. If used, plasma concentra- tion monitoring is necessary to individualize doses. These agents should be avoided in pregnancy unless needed for life-threatening infections because of fetal oto- and nephrotoxicity risks.

Sulfonamides, including sul soxazole, sulfadiazine, sulfa- methoxazole, sulfapyridine, sulfasalazine, and sulfadoxine (see

13 Clinical pharmacology of anti-infectives during pregnancy 179

malaria section), are generally used in combination with other antibiotics for various infections, and may be used in pregnan- cy if penicillins and cephalosporins are not effective. Near term, these drugs are pregnancy category D due to increased risk of hyperbilirubinemia in the neonate; likewise, they are contraindi- cated in nursing. They readily cross the placenta [39, 40], and most also penetrate into breast milk. Sulfonamides are hepatically acetylated, and are substrates and inhibitors of CYP2C9.

Trimethoprim, pregnancy category C, is used alone or in com- bination with sulfamethoxazole for various infections. It is exten- sively distributed, it inhibits CYP2C8, and is mostly eliminated unchanged in the urine. It is slowly transported in low concentra- tions across the placenta [39], but breast milk concentrations are higher than maternal plasma concentrations and caution should be exercised in lactating women. Trimethoprim is a second-line agent that can be used in pregnancy if rst-line agents are inef- fective. Folic acid supplementation (0.5mg daily) should be used along with trimethoprim in the rst trimester.

Fluoroquinolones, such as cipro oxacin, clina oxacin, enoxacin, gati oxacin, levo oxacin, lome oxacin, moxi oxacin, nor oxa- cin, o oxacin, spar oxacin, and trova oxacin, are pregnancy category C. Absorption of uoroquinolones is decreased with concomitant cation administration, including calcium, magne- sium, iron, and zinc. Lome oxacin, levo oxacin, nor oxacin, and o oxacin are mainly excreted unchanged in the urine. Spar oxa- cin is metabolized by CYP1A2. Grepa oxacin is glucuronidated by uridine diphosphate glucuronosyltransferase (UGT) enzymes and metabolized by CYP1A2. Moxi oxacin is glucuronidated and sulfated, but does not undergo CYP metabolism. Cipro oxa- cin is partially excreted unchanged, is partially metabolized by CYP1A2, and is an inhibitor of CYP1A2. Low amounts of qui- nolones cross the placenta [41], while much higher amounts pen- etrate into breast milk [42]. No other pharmacokinetic studies in pregnancy are available. Because of arthropathy risks, quinolones should be avoided in pregnancy and lactation unless needed for complicated, resistant infections.

Metronidazole, pregnancy category B, is used in pregnancy for treatment of symptomatic bacterial vaginosis or asymptomatic disease in women at high risk for preterm delivery. It is effective for eradication of infection, but does not decrease risk of pre- term birth [43, 44]. It is well absorbed, widely distributed includ- ing fetal [45] and breast milk concentrations as high as maternal concentrations [46–48], and is both oxidized and glucuronidated in the liver by unknown enzymes. Pharmacokinetic studies in early pregnancy and at term showed 15–30% reductions in AUC

13 Clinical Pharmacology of Anti-Infectives During Pregnancy

180 13.2 Antifungal therapy

compared to historical controls [49, 50], but a recent study in 20 pregnant women taking 500mg twice daily for 3 days showed weight-corrected exposure was similar in different stages of preg- nancy and to reported values in non-pregnant adults [51]. Ni- morazole, tinidazole, and ornidazole do not have enough data in human pregnancy to assess appropriate use.

Nitrofurantoin has been used in pregnancy for decades for uri- nary tract infections. It undergoes some hepatic metabolism, but is mostly concentrated unchanged in urine. Less than 1% crosses into breast milk [52], and placental exposure is also low. It is con- traindicated near term due to risk of hemolytic reactions, particu- larly in glucose-6-phosphatase dehydrogenase (G6PD) de ciency. Fosfomycin, pregnancy category B, is used as a single 3g dose for uncomplicated urinary tract infections. It is not metabolized, and is excreted unchanged in urine and feces. No pharmacokinetic studies in pregnancy have been reported. Methenamine mandel- ate and methenamine hippurate, pregnancy category C, are anti- septics used for urinary tract infections. They cross the placenta, into breast milk, and are excreted unchanged in urine. Experience in pregnancy is very limited, and they should be avoided.

Atovaquone (see malaria section) and pentamidine, pregnancy category C, are used for Pneumocystis jiroveci infections. Pent- amidine crosses the placenta in animals; breast milk penetration is unknown. Elimination is mainly renal, but several metabolites formed by unknown pathways are also present. The half-life is 2–4 weeks. Data in pregnancy are very limited, and no human pharmacokinetic studies are available.

13.2 Antifungal therapy

For treatment of fungal infections, topical therapy with older agents is considered safe in pregnancy. For topical and mucosal use, nystatin, clotrimazole, and miconazole are drugs of choice, with negligible systemic absorption. Other topical “-azoles” are second line, and other topical antifungals should be avoided due to lack of data in pregnancy. Systemic treatment with uconazole, ketoconazole, itraconazole, and miconazole should be avoided unless the indication is compelling. No pregnancy pharmacokinet- ic studies are available. Voriconazole is pregnancy category D, can cause fetal harm, and is not recommended for use in pregnancy. For treatment of vaginal candidiasis after local treatment has failed, low-dose oral uconazole (150 mg once daily) may be tried. For se- rious, disseminated fungal infections, amphotericin B is preferred.

13 Clinical pharmacology of anti-infectives during pregnancy 181

Amphotericin B is poorly absorbed and administered intrave- nously for systemic fungal infections. Its metabolism is unknown, and it is eliminated slowly with a 1- to 15-day half-life. It crosses the placenta and may be retained in placental and other tissues. Pharmacokinetics of the original or the liposomal formulations in pregnancy have not been studied. Use should be limited in pregnancy to dangerous systemic mycoses.

Flucytosine, category C, is active against Cryptococcus neofor- mans and candida species. It is widely distributed, and mostly eliminated unchanged in the urine. No pregnancy studies are available. Use during pregnancy should be reserved for severe dis- seminated fungal infection. Griseofulvin and terbina ne should not be used orally during pregnancy because data for systemic therapy during pregnancy with these agents are limited and skin mycoses do not require urgent oral treatment.

13.3 Malaria

Pregnancy increases susceptibility to, and severity of, malaria, and maternal malaria increases risks for prematurity, low birth weight, spontaneous abortion, and stillbirth. Prophylaxis and treatment medications must be tailored to the local pattern of antimalarial drug resistance [53, 54]. The goal for prophylaxis and treatment regimens is >95% ef cacy, but many regimens are associated with much lower cure rates during pregnancy; failure rates of >10 or 15% are common [55].

Chloroquine (CQ) is a drug of choice for malaria during preg- nancy if the parasite is sensitive. It has not been formally assigned a pregnancy category, but is generally considered category C. It is well absorbed orally and distributes widely throughout the body. Chloroquine crosses the placenta easily and penetrates into breast milk, delivering low infant doses of ~3%, compatible with breastfeeding [56, 57]. It is partially metabolized hepatically by CYP3A4 and 2D6, and inhibits activity of 2D6. The major metabolite desethylchloroquine (DECQ) has some activity. The half-life is 1–2 months. CQ should be given with food to mini- mize gastrointestinal upset. Pharmacokinetic studies in Tanzania and Papua New Guinea demonstrated signi cantly lower expo- sure (25–45%) to CQ and DECQ during pregnancy, suggesting higher doses may be warranted [58, 59]. A study in Thailand showed non-signi cant 11–18% exposure decreases during preg- nancy [60]. Above standard CQ doses in pregnancy have not been studied.

13 Clinical Pharmacology of Anti-Infectives During Pregnancy

182 13.3 Malaria

Proguanil (PG), pregnancy category C, alone or combined with CQ is a prophylaxis drug of choice in some regions. It is a prodrug, converted by CYP2C19 to the active compound, cyc- loguanil (CG). CYP2C19 poor metabolizers cannot make enough active metabolite for effective use. About 3% of Caucasians and 20% of Asians and Kenyans are poor metabolizers. The half-life is 12–21 hours, but longer in poor metabolizers. Four pharma- cokinetic studies in pregnant women from the western border of Thailand and Zambia all demonstrate increased clearance and reduced plasma concentrations of CG by about two-fold in pregnancy [61–64]; one study recommends increasing PG dose by 50% in late pregnancy, though no data are available for this suggested dose in pregnancy [62]. One postulated mechanism for decreased CG in late pregnancy is inhibition of CYP2C19 by estrogen. Atovaquone is often combined with PG, and exposure is approximately half in pregnant versus non-pregnant women[61, 63].

Me oquine is pregnancy category C, and is used for CQ/PG- resistant malaria. It is well absorbed and widely distributed, in- cluding penetration into breast milk. It is partially hepatically metabolized by CYP3A4, and is a substrate and inhibitor of Pgp. Elimination is very slow, mainly via bile and feces, with a half- life of 13–33 days. Two studies have reported decreased plasma me oquine concentrations during pregnancy, suggesting higher pregnancy doses need to be evaluated [65, 66].

Sulfadoxine–pyrimethamine are pregnancy category C (sulfa- doxine is category D near term due to risk of infant kernicterus), and are used in combination as a second choice antimalarial in the second and third trimesters of pregnancy. Both are widely dis- tributed and cross the placenta and into breast milk. Both are me- tabolized; sulfadoxine half-life is 200 hours while pyrimethamine is 80–123 hours. Three different pharmacokinetic studies showed 30–40% decreased sulfadoxine concentrations in pregnancy, and suggested increased doses need to be studied in pregnancy [67–69]. These same three studies con icted in respect to pyrimeth- amine, with one showing increased concentrations in pregnancy, one showing no change, and one showing decreased concentra- tions. Dapsone is also used in combination with pyrimethamine. It is well absorbed, widely distributed, and undergoes enterohe- patic recirculation. It is metabolized by CYP3A4 and 2C9, with a 30-hour half-life. Large quantities are excreted in breast milk and can cause hemolytic anemia in infants with G6PD de ciency. No pharmacokinetic studies in pregnancy have been conducted.

Quinine is pregnancy category C, and may be used for CQ- resistant malaria in pregnancy. It distributes into placenta and breast milk at 10–50% of maternal concentrations [70]; the

13 Clinical pharmacology of anti-infectives during pregnancy 183

American Academy of Pediatrics reports it as compatible with breastfeeding. It is extensively metabolized by CYP3A4 and oth- ers, may inhibit 3A4 and 2D6, and is prone to drug–drug interac- tions. Half-life is 8–21 hours. Large quinine doses are oxytoxic. Pregnancy does not signi cantly affect quinine exposure, and standard doses are recommended [71, 72].

Artemether–lumefantrine, both pregnancy category C, is a wide- ly used potent antimalarial combination. Artemether is rapidly me- tabolized by CYP3A4 to the active metabolite, dihydroartemisinin (DHA), and may induce CYP3A4/5. Lumefantrine is metabolized by CYP3A4, inhibits CYP2D6 in vitro, and has a half-life of 3–6 days. Concentrations of both are decreased in pregnancy, and lumefantrine trough concentrations fall below threshold values as- sociated with treatment failure [73–75]. Artemether and DHA con- centrations are decreased by ~50% in pregnancy [73]. Artesunate is another artemisinin derivative rapidly metabolized to DHA. DHA clearance appears increased during pregnancy [76–78]. Increased doses of artemisinin derivatives and lumfantrine are recommend- ed, but the optimum doses have not been determined.

Because of infant toxicity risks and limited data in pregnancy, primaquine should be avoided in pregnancy. Halofantrine may be necessary for some drug-resistant cases. Its absorption is poor and highly variable. It is metabolized by CYP3A4 to an active metabo- lite, and it inhibits CYP2D6. Breast milk and placental penetra- tion are unknown, and no pharmacokinetic data during pregnan- cy are available. Additional agents used as drug-resistant strains become more prevalent include clindamycin (described above), doxycyline (described above), amiodaquine, and quinacrine. The latter two are category C, and are metabolized by CYP3A4/5. No pregnancy pharmacokinetic data are available.

13.4 Tuberculosis

Treatment recommendations for tuberculosis during pregnancy are the same as in non-pregnant adults. Pregnancy does not seem to alter disease course, but untreated tuberculosis poses hazards to mothers and infants. Because of increasing resistance, multi- drug therapy is usually recommended; speci c drugs selected depend on the resistance patterns.

Isoniazid, pregnancy category C, is used for prophylaxis and treatment during pregnancy. It is widely distributed, including into placenta and breast milk. It is compatible with breastfeeding, but the infant should be supplemented with pyridoxine. It is acetylat-

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184 13.5 HIV

ed by the liver to inactive metabolites, with a half-life of 1–4 hours. It inhibits CYP1A2, 2A6, 2C9, 2C19, 2D6, and 3A4, yielding many clinically signi cant drug–drug interactions. Hepatitis from iso- niazid is more common in pregnancy, so monitoring is warranted. No pharmacokinetic studies during pregnancy are available.

Rifampicin, category C, is another drug of choice for tubercu- losis during pregnancy. It does cross the placenta and into breast milk, and prophylactic vitamin K should be administered to the mother and the infant. It is deacetylated in the liver to an active metabolite, and enterohepatically recycled, with 60% eliminated in feces via biliary excretion and 30% eliminated in the urine. It is a potent inducer of CYP3A4 and other CYP enzymes and causes numerous drug–drug interactions, often requiring dose increases of concomitant medications. No pharmacokinetic data are available in pregnant women.

Ethambutol, category B, is rst-line treatment in combination with isoniazid and rifampicin. It crosses the placenta at about 30% of maternal concentrations, and penetrates breast milk in equal concentrations to maternal plasma; no problems with breastfeeding have been reported. It is partially metabolized in the liver, with parent and metabolite excreted in both the urine and the feces, with a half-life of ~3.5 hours. Clinically important drug– drug interactions are not common. No pharmacokinetic data are available during pregnancy.

Pyrazinamide, category C, is often reserved for use in women with documented resistance to the three aforementioned rst-line agents or in women who are also HIV+. Its ability to transfer into placenta and breast milk is unknown. It is hydrolyzed in the liver to active metabolites, which are excreted in the urine, and has a 9–10- hour half-life. Clinically important drug–drug interactions are rare. Pharmacokinetic studies in pregnancy have not been reported.

Quinolones are occasionally used as second-line agents in multi- drug resistance tuberculosis; cipro oxacin is preferred. Dapsone may also be considered in speci c cases. Other agents, including aminoglycosides (causing fetal ototoxicity), para-aminosalicylic acid (causing gastrointestinal intolerance), ethionamide, prothionamide, cycloserine, rifabutine, and rifapentine (all with no pregnancy use data available), are not recommended for use during pregnancy.

13.5 HIV

Treatment for HIV is essential during pregnancy to prevent mother-to-infant transmission of the virus. Combination therapy

13 Clinical pharmacology of anti-infectives during pregnancy 185

throughout pregnancy is the standard of care in areas with suf – cient resources; more limited treatment strategies near and during labor/delivery are used in some limited-resource settings. Current perinatal treatment guidelines can be found at http://www.aidsin fo.nih.gov/guidelines [79].

Nucleoside/nucleotide reverse transcriptase inhibitors include abacavir, didanosine, emtricitabine, lamivudine, stavudine, teno- fovir, and zidovudine. The nucleosides are activated intracellular- ly and the active triphosphate nucleosides have longer half-lives than the parent drug, have low protein binding, and all but aba- cavir are eliminated renally. Abacavir is metabolized, but is not a substrate for the CYP enzyme family. Lamivudine (pregnancy category B) and zidovudine (pregnancy category C) are rst-line agents for HIV treatment in pregnancy. They have high placen- tal transfer to the fetus, readily pass into breast milk (breast milk to plasma ratios of 2.56 for lamivudine and 0.4 for zidovudine), and pharmacokinetics are not signi cantly altered by pregnancy [80, 81]. All other nucleosides are considered alternative agents for use in pregnancy. Pregnancy does not signi cantly alter the pharmacokinetics of abacavir (category C), didanosine (category B), or stavudine (category C) [82–84]. Placental transfer of aba- cavir and stavudine are high, with moderate transfer of didano- sine (cord blood to maternal plasma ratio of 0.38). Breast milk concentrations of these three agents are not known. Maternal exposure to emtricitabine and tenofovir, both pregnancy category B, is lower during the third trimester compared to postpartum, but third trimester concentrations still appear therapeutic so no dose adjustments are warranted [85, 86]. Both readily cross the placenta, but tenofovir transfer into breast milk is low while emtricitabine breast milk penetration is unknown.

First-generation non-nucleoside reverse transcriptase inhibi- tors include delavirdine (no longer available in the US), efavi- renz and nevirapine. Efavirenz, pregnancy category D, is highly protein bound (>99%), is metabolized by CYP3A4 and 2B6, and induces CYP3A4, with a terminal half-life of 40–55 hours. A small study in 13 Rwandan women showed milk to plasma con- centration ratios of 54%, and infant plasma concentrations during breastfeeding were 13% of maternal concentrations, with infant concentrations somewhat lower than concentrations targeted for treatment in adults [87]. Likewise, cord blood concentrations are about 50% of maternal concentrations at delivery [88]. Clear- ance is increased and trough concentrations are decreased during the third trimester compared to postpartum, but third trimester exposure is still high enough to be therapeutic using standard doses [88]. Efavirenz is teratogenic during embryogenesis, so use

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186 13.5 HIV

should be restricted to after the rst trimester of pregnancy. Nevi- rapine, pregnancy category B, has been used extensively and is the preferred non-nucleoside for use during pregnancy. It is 60% pro- tein bound, has a half-life with chronic dosing of 25–30 hours, is metabolized by CYP3A4 and 2B6, and induces CYP3A4 and 2B6. It readily crosses the placenta, and breast milk concentrations are 76% of maternal concentrations. Pharmacokinetics are not sig- ni cantly altered during pregnancy in studies of US women, and standard doses are recommended [89, 90]. A study in Ugandan pregnant women showed signi cantly decreased exposure dur- ing pregnancy compared to postpartum, including 67% of women falling below target trough concentrations, suggesting increased doses may be needed in some populations [91].

Second-generation non-nucleosides include rilpivirine and etra- virine. Not enough data are available during pregnancy to recom- mend use of these agents. Etravirine, pregnancy category B, is 99.9% protein bound with a terminal half-life of 41 hours, is metabolized by CYP3A4, 2C9, and 2C19, induces CYP3A4, inhibits 2C9, 2C19, and Pgp, and is subject to many drug–drug interactions. Pharmaco- kinetics were studied in four pregnant women, and showed similar concentrations in third trimester as postpartum, preliminarily sug- gesting no altered dosing is necessary in pregnancy [92]. Placen- tal transfer was approximately 33% of maternal concentrations in one woman. Rilpivirine is 99.7% protein bound, is metabolized by CYP3A4, has a half-life of 50 hours, and metabolites are excreted primarily in feces. No data regarding pharmacokinetics in preg- nancy, placental or breast milk transfer are available.

Protease inhibitors include atazanavir, darunavir, fosamprena- vir, indinavir, lopinavir, ritonavir, saquinavir, and tipranavir. All are hepatically metabolized by CYP isoenzymes, including CYP3A4, and are subject to drug–drug interactions. All except nel navir are used with low-dose ritonavir (a potent CYP3A4 inhibitor) to boost exposure to therapeutic concentrations in pregnancy. The major- ity of protease inhibitors studied to date have decreased concen- trations during pregnancy, with lowest exposure seen during the third trimester. Interestingly, early postpartum concentrations on standard doses of ritonavir-boosted lopinavir, fosamprenavir, and atazanavir are higher than seen in non-pregnant adults, so close monitoring for toxicity is warranted. Countries with routine ac- cess to therapeutic drug monitoring (TDM) will often draw trough concentrations throughout pregnancy and will adjust individual patient doses as needed to maintain troughs above recommended minimum concentrations.

Lopinavir (coformulated with ritonavir in 200mg lopina- vir/50mg ritonavir tablets) is the preferred protease inhibitor

13 Clinical pharmacology of anti-infectives during pregnancy 187

for use in pregnancy in the US [79]. It is pregnancy category C, 98–99% protein bound, metabolized by CYP3A4 with most metabolites excreted in the feces, and has a 5–6-hour half-life. Placental transfer is 20% of maternal concentrations [93], while breast milk passage is unknown. Multiple pharmacokinetic stud- ies have shown 40–60% increased lopinavir clearance during pregnancy [93, 94]. The fraction of unbound drug increases by 18% in late pregnancy, which is not enough to overcome the decrease in total exposure [95]. Some experts recommend stan- dard (400mg lopinavir/100mg ritonavir) twice daily doses dur- ing pregnancy in treatment-naive patients and increased doses (600 mg lopinavir/150 mg ritonavir twice daily) in PI-experienced patients [94], while other experts routinely increase the dose to 600mg lopinavir/150mg ritonavir twice daily in the third trimes- ter (30 weeks’ gestation), decreasing to standard dose just after delivery [93]. Once daily dosing of 800mg lopinavir/200mg rito- navir (approved in treatment-naive non-pregnant adults) is not recommended during pregnancy.

Atazanavir, pregnancy category B, is 86–89% protein bound, has a half-life of 7 hours, is extensively metabolized by CYP3A4, inhibits CYP3A4, 2C8, and UGT1A1 and is mostly excreted as metabolites in feces. Placental transfer is 10–20% of maternal concentrations, and breast milk transfer is unknown. Only when coadministered with ritonavir, is it considered an alternative agent for use in pregnant women in the US [79]. A study in 17 Italian women found no difference in pharmacokinetic parameters dur- ing pregnancy compared to postpartum with the standard dose of 300mg atazanavir and 100mg ritonavir once daily [96]. Three other studies found 21–45% decreased exposure in the third tri- mester of pregnancy compared to postpartum [97–99]. The study of mainly South African women recommended the standard dose during pregnancy despite AUC and maximum concentration de- creases because minimum concentrations were still in the thera- peutic range on the standard dose in pregnancy [97]. The P1026s study team investigated standard dose in second trimester and postpartum, and an increased dose of 400mg atazanavir/100mg ritonavir in the third trimester. The increased third trimester dose resulted in concentrations similar to those seen in non-pregnant adults [100], second trimester concentrations on standard doses were lower than typically seen in non-pregnant adults, and may be sub-therapeutic especially when coadministered with teno- fovir, while postpartum concentrations on standard doses were higher than reported in non-pregnant adults. The manufacturer recommends the standard dose in pregnancy, unless the patient is also taking either tenofovir or a histamine-2 receptor antagonist,

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188 13.5 HIV

in which case an increased dose of 400mg atazanavir/100mg ritonavir once daily should be used.

Saquinavir, pregnancy category B, combined with ritonavir is another alternative protease inhibitor for use in pregnancy [79]. It is 98% protein bound, has a half-life of 12 hours, and is a sub- strate and inhibitor of CYP3A4 and Pgp. Pharmacokinetics of old- er formulations showed decreased exposure to either saquinavir [101, 102] or ritonavir [103] during pregnancy compared to post- partum. A study of the newer 500mg tablet formulation showed saquinavir concentrations were not signi cantly different between the second and third trimesters of pregnancy and postpartum [104]. The recommended dose is 1000 mg saquinavir/100 mg ritonavir twice daily.

Two protease inhibitors recommended in some circumstanc- es during pregnancy are indinavir and nel navir [79]. Indina- vir, pregnancy category C, is 60% protein bound, a substrate of CYP3A4, UGT, and Pgp, inhibits CYP3A4 and has a 2-hour half- life. Transplacental passage is minimal, while breast milk passage is unknown. The manufacturer does not recommend use in preg- nancy because exposure is markedly decreased during pregnancy [105, 106]. If needed, only ritonavir-boosted indinavir should be used [107], at a dose of 800mg indinavir/100–200mg ritonavir twice daily [79]. For prevention of mother-to-child transmission, when treatment for the mother’s infection may not be indicated yet, nel navir may be considered in women intolerant to the other protease inhibitors. It has been extensively used in pregnant wom- en, and placental transfer is minimal while breast milk transfer is unknown. It is >98% protein bound, is a substrate of CYP3A4, 2C19, and Pgp, and inhibits CYP3A4 and Pgp. The half-life is 3.5–5 hours. Exposure is signi cantly decreased during pregnancy [108, 109], and dosing with 625mg tablets (two tablets, 1250mg twice daily, n=27) resulted in sub-therapeutic trough concentra- tions in 85% of patients [110], suggesting higher doses may be needed in pregnancy.

Darunavir, fosamprenavir, and tipranavir are not recommended agents in pregnancy due to insuf cient data [79]. Darunavir, preg- nancy category C, is 95% protein bound, is a substrate and inhibi- tor of CYP3A4, and has a 15-hour half-life when coadministered with ritonavir (as is required). A study in 31 pregnant women showed signi cantly decreased exposure during pregnancy with once or twice daily darunavir doses (800mg darunavir/100mg ritonavir once daily or 600mg darunavir/100mg ritonavir twice daily), and concluded that only twice daily doses should be used [111]. Fosamprenavir, pregnancy category C, is a phosphate ester prodrug that is rapidly converted to amprenavir in vivo. It

13 Clinical pharmacology of anti-infectives during pregnancy 189

is 90% protein bound, is extensively metabolized by CYP3A4, 2C9, 2D6, is a Pgp substrate, inhibits CYP3A4, and has a half- life of 7.7 hours. Similar to other protease inhibitors, exposure is signi cantly decreased during pregnancy when dosed as 700mg fosamprenavir/100mg ritonavir twice daily [112]. However, con- centrations on this dose during pregnancy are still higher than concentrations in non-pregnant adults taking one of the approved doses of 1400mg twice daily without ritonavir, and the standard ritonavir-boosted dose should be adequate for treatment-naive patients. Tipranavir, pregnancy category C, must be coadminis- tered with ritonavir. It is >99.9% protein bound, is a substrate for CYP3A4 and Pgp, and induces CYP3A4 and Pgp. A case re- port showed therapeutic concentrations in late pregnancy on the standard dose (500mg tipranavir/200mg ritonavir twice daily), and a cord blood to maternal concentration ratio of 0.41, higher than other protease inhibitors [113]. No other published data are available.

Raltegravir, an integrase strand transfer inhibitor classi ed as pregnancy category C, is 83% protein bound, is metabolized by UGT1A1 to a glucuronide conjugate, and is excreted in feces and urine, with a half-life of 9 hours. Placental transfer is variable but high, often with cord blood concentrations exceeding maternal concentrations [114, 115]. Breast milk transfer is unknown. Con- centrations, while altered by pregnancy and highly variable, ap- pear adequate with standard dosing [114]. Enfuvirtide, pregnancy category B, is an entry (fusion) inhibitor administered by subcu- taneous injection. It is 92% protein bound, has a 3.8-hour half- life, and is a peptide that is hydrolyzed to an inactive metabolite, and expected to be catabolized to amino acids. It does not cross the placenta [116, 117], and transfer into breast milk is unknown. Pharmacokinetic data during pregnancy are not available. Mara- viroc, another entry inhibitor classi ed as pregnancy category B, is 76% protein bound, a substrate of Pgp and CYP3A4, has a 14–18- hour half-life, and is subject to many drug–drug interactions. No information regarding maraviroc use in pregnancy is available.

13.6 Antivirals

Treatment for genital herpes is generally recommended during pregnancy to prevent neonatal herpes. Acyclovir is pregnancy category B, distributes widely in the body, crosses into the pla- centa and the breast milk at concentrations similar to or greater than maternal plasma, and is excreted unchanged in the urine

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190 13.6 Antivirals

with a short half-life of 2.5–3.3 hours. Oral bioavailability is low (10–20%). A pharmacokinetic study in pregnant women conclud- ed that 400mg orally three times daily provided appropriate con- centrations, similar to those seen in non-pregnant adults [118]. Valacyclovir, also category B, is a prodrug of acyclovir that is con- verted to acyclovir by rst pass intestinal or hepatic metabolism, with increased bioavailability (~55% acyclovir bioavailability after valacyclovir administration). A pharmacokinetic study com- paring valacyclovir 500 mg twice daily and acyclovir 400 mg three times daily found higher acyclovir exposure (approximately dou- ble) with administration of valacyclovir in pregnant women. Both were well tolerated, but insuf cient safety and ef cacy data (com- pared to acyclovir) are available to recommend use in pregnancy. Likewise, no pharmacokinetic and limited safety/ef cacy data are available for famciclovir, penciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, fomivirsen, tri uridine, or vidarabine. Use of several of these agents to treat cytomegalovirus during pregnancy should be limited to serious/severe infections.

Amantadine, rimantadine, oseltamivir, and zanamivir are used for the treatment of in uenza virus. Safety data are inadequate to determine risks of these medications in pregnancy, but mor- bidity and mortality from in uenza are higher during pregnancy, so these agents may be needed in serious infections. All four are category C. Oseltamivir is hepatically metabolized (but not by the CYP P450 system) to the active form, a carboxylate metabolite, which is excreted in urine. The half-life is 1–3 hours, and pen- etration into breast milk yields concentrations signi cantly lower than considered therapeutic in infants [119]. Two studies have evaluated pharmacokinetics in pregnant women. In 30 women, carboxylate exposure did not change signi cantly between the three trimesters of pregnancy [120]. Concentrations were above the typical viral 50% inhibitory concentrations, and the authors concluded that standard doses should be adequate in pregnan- cy. Beigi and colleagues compared 16 pregnant women to 23 non-pregnant controls, and found signi cantly lower carboxyl- ate metabolite exposure during pregnancy [121]. Given the wide therapeutic window of oseltamivir and the increasing prevalence of viral neuraminidase inhibitor resistance, these authors suggest increasing the treatment dose from 75 mg twice daily for 5 days to 75 mg three times daily in pregnant women to better approximate concentrations seen in non-pregnant patients. Pharmacokinetic studies on this increased dose have not been reported.

Amantadine is renally excreted unchanged, with an 11–15-hour half-life. It crosses the placenta and into breast milk, and is not rec- ommended in breastfeeding. Rimantadine is extensively hepatically

13 Clinical pharmacology of anti-infectives during pregnancy 191

metabolized with a half-life of 13–65 hours. Placenta and breast milk exposure are unknown. Amantadine and rimantadine are no longer rst-line agents due to high resistance, but are being used in combination with oseltamivir or zanamivir as neuraminidase inhib- itor resistance increases. Zanamivir is renally excreted unchanged with a 2.5–5-hour half-life. Small amounts cross into placenta; breast milk penetration is unknown. Pharmacokinetic data are not available for amantadine, rimantadine or zanamivir in pregnancy.

Ribavirin is pregnancy category X, and is teratogenic in ani- mals. It is used for hepatitis B and C in combination with inter- ferons (category C), and should be reserved for life-threatening infections. It is also toxic to nursing animals, and should not be used during breastfeeding.

13.7 Parasitic infections

Many parasitic infections are asymptomatic, and treatment is only indicated for severe infections during pregnancy. Meben- dazole is category C, and can be used during pregnancy if in- dicated. It is poorly absorbed and metabolized by CYP P450, but very effective within the intestine. Flubendazole is structur- ally related, with limited data available in pregnancy. Alben- dazole is a broad-spectrum anthelmintic and is category C. It is poorly bioavailable with extensive rst-pass and systemic hepatic metabolism and a 9-hour half-life. It may induce CYP1A activity and be subject to drug–drug interactions. Thiabendazole, also category C, is also extensively metabolized hepatically and is a substrate and inhibitor of CYP1A2. No data are available for use during pregnancy.

Praziquantel is category B and is a rst-line agent for schistoso- miasis treatment. It is metabolized hepatically, likely by CYP3A4, and subject to drug–drug interactions with a short half-life of 0.8–1.5 hours. Breast milk concentrations are about a quarter of maternal concentrations. No pharmacokinetic data in pregnancy are avail- able. Pyrantel is another broad-spectrum anthelmintic, category C, but is not recommended in pregnancy due to very limited preg- nancy use data available. Ivermectin and diethylcarbamazine are used to treat liriasis and onchocerciasis/onchocercosis. Data for use in pregnancy are lacking; they should only be used for compel- ling indications. Paromomycin, category C, is used for intestinal amebiasis, and is not absorbed systemically after oral ingestion. Niclosamide, category B, is used to treat tapeworm infections, and is not signi cantly absorbed from the gastrointestinal tract.

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13 Clinical Pharmacology of Anti-Infectives During Pregnancy

Chemotherapy in Pregnancy

Caroline D. Lynch, Men-Jean Lee and Giuseppe Del Priore

14

. 14.1  Introduction 201

. 14.2  Overview of chemotherapeutic agents 202

. 14.3  Alkylating agents 204

. 14.4  Anthracyclines 205

. 14.5  Plant alkaloids 206

. 14.6  Targeted therapies 208

. 14.7  Other agents 209

. 14.8  Treatment of speci c cancers 209

. 14.9  Breast cancer 210

. 14.10  Lymphoma 210

. 14.11  Leukemia 211

. 14.12  Ovarian cancer 211

. 14.13  Future fertility 212

. 14.14  Pharmacokinetics in pregnancy 212

14.1 Introduction

Cancer is the second leading cause of death in women of repro- ductive age. It is diagnosed with a frequency of 1 per 1000 preg- nant women; most commonly breast cancer followed by cervical, lymphoma, and melanoma [1]. Chemotherapy poses the greatest risks for the developing fetus early in pregnancy. Depending on the type of cancer and the stage of diagnosis, chemotherapy may need to be administered without delay, thus the recommendation for pregnancy termination. Neonatal risks of chemotherapy are reduced when administered in the second and third trimesters; however, longitudinal follow-up for low birth weight, intrauterine

202 14.2 Overview of chemotherapeutic agents

growth restriction (IUGR), and prematurity are lacking, especially regarding the neurodevelopmental effects. The ethics of the timing of delivery must balance the risk of the health of the mother and the risk to the fetus. This chapter will review the general indications for chemotherapy in pregnancy and the data surrounding the best use of the commonly prescribed chemotherapeutic agents in pregnancy.

When the fetus is exposed to the cytotoxic effects of chemotherapy during the rst trimester, the pregnancy will likely end in spontane- ous abortion, major malformations, and fetal loss [2]. Organogene- sis, the critical time of organ formation from 2 to 8 weeks following conception represents the time when the cardiac and central ner- vous system are especially susceptible to insult. However, even fol- lowing organogenesis, injury may still occur to the eyes, gonads, and central nervous and hematopoietic systems as these organ systems continue to mature over the course of a pregnancy [1]. Treatment with chemotherapy in the second and third trimester is generally thought to be safer, but can be associated with intrauterine growth restriction and low birth weight infants [2]. When treatment with chemotherapy is required, whether with single or multi-agent, the clinician must have knowledge of the optimal timing of treatment, to ensure an ef cacious and safe approach to therapy.

14.2 Overview of chemotherapeutic agents 14.2.1 Antimetabolites

Antimetabolites are characterized by their inhibitory activity during DNA or RNA synthesis. Examples include methotrexate, 5- uoro- uracil, thioguanine, cytarabine, cladribine, cladribine, udarabine, mercaptopurine, pemetrexed, and gemcitabine. Perhaps due to its long history in use as a chemotherapeutic agent, methotrexate has been used for many illnesses, including acute monocytic leu- kemia, non-Hodgkin’s lymphoma, osteosarcoma, head and neck cancer, and breast cancer [4]. It is known to be an abortifacient and a teratogen. In a review of 42 cases of methotrexate exposure, 23 cases in the rst trimester found no abnormalities [1]. Previ- ous reports noted associations with mental retardation, cranio- dystosis, hypertelorism, micrognathia, and limb deformities [3]. It is likely that there is a critical dose above which teratogenicity or spontaneous abortion occurs. Methotrexate used in low doses in rheumatologic disease has not been demonstrated to increase rates of fetal malformation or induce spontaneous abortions [5].

5-Fluorouracil was associated with multiple fetal anomalies in a patient who received chemotherapy for colon cancer begin- ning at 12 weeks’ gestation [3]. 5-Fluorouracil is often used in

14 Chemotherapy in pregnancy 203

combination with cyclophosphamide and doxorubicin for the treatment of breast cancer. Generally, it is recommended to avoid its use in the rst trimester (Figure 14.1).

Cytarabine is typically used in combination with other agents such as vincristine, tioguanine, or doxorubicin to treat acute leu- kemia. There are reports of limb malformations after rst trimester exposure, either alone or in combinations for the aforementioned agents [1, 6]. In a report of 89 cases, intrauterine fetal distress (IUFD) was noted to have occurred in 6% and neonatal deaths in two [1]. Cause of death was not identi ed in these cases. Cyta- rabine and daunorubicin were used in four cases. Cytarabine and tioguanine were used in ve of the six intrauterine fetal demises. The effects of underlying maternal leukemia may also have con- tributed to the complications [1].

A case report of 6-mercaptopurine given for treatment of acute monocytic leukemia in pregnancy during the rst trimester and again in the third trimester was associated with the birth of a premature infant but no malformations were noted [1].

As with methotrexate, much of the recent data regarding the thioprine class of chemotherapeutic agents comes from the auto- immune literature where this class of medications is commonly used as immunomodulators. Mercaptopurine has been used in combination with azathiopurine in patients with in ammatory

Figure 14.1 Selected Chemotherapeutic Agents and Mechanism of Action.

14 Chemotherapy in Pregnancy

204 14.3 Alkylating agents

bowel disease (IBD), which is estimated to affect 1.4 million Amer- icans, with a peak onset at 15–30 years of age [7]. A retrospective cohort study by Francella identi ed 15 patients who remained on 6-mercaptopurine/azathiopurine for their entire pregnancy for the treatment of IBD. The authors reported that previous data showed a 3.9% congenital anomaly rate for the aforementioned agents while their study found a 2.5% rate for one case of a con- genital anomaly, compared to 4% in the control group [8]. There was no difference in spontaneous abortion rates, major or minor malformations, neonatal infection rates or prematurity.

14.3 Alkylating agents

Alkylating agents are commonly used to treat breast cancer, acute leukocytic leukemia, and lymphoma. Cyclophosphamide is con- traindicated in the rst trimester due to signi cant malformations including absent toes, eye abnormalities, low-set ears, and cleft palate [1]. Again, much of the data surrounding the use of cyclo- phosphamide comes from the literature regarding rheumatologic diseases. A case report of a mother who was prescribed cyclophos- phamide for systemic lupus erythematosis and had exposure to the agent throughout her entire rst trimester resulted in an infant with multiple physical anomalies similar to those ndings from animal studies, raising the question of a cyclophosphamide phenotype [9]. In utero exposure during the rst trimester may be associated with the cyclophosphamide phenotype characterized as growth de ciency, developmental delay, craniosynostosis, blepharophimo- sis, at nasal bridge, abnormal ears, and distal limb defects includ- ing hypoplastic thumbs and oligodactyly. Cyclophosphamide use has been reported as safe during the second and third trimesters.

Chlorambucil has been reported to cause cleft palate, skeletal dysplasias, and renal aplasia when administered in the rst trimester [3]. A case report of a 36-year-old patient who received chlorambucil to treat her chronic lymphocytic leukemia until her pregnancy was diagnosed at 20 weeks’ gestation described no associated fetal malformations, or major abnormalities [10]. In a series of 15 pregnant patients with Hodgkin’s disease, one patient who received chemotherapy with chlorambucil during the latter half of her pregnancy delivered a full-term infant [11].

Dacarbazine is an alkalyting agent with little data in humans. In high doses, it is known to be teratogenic in rats [1]. Dacarbazine has emerged as an agent used in combination with tamoxifen, car- mustine, and cisplatin for the treatment of metastatic melanoma

14 Chemotherapy in pregnancy 205

during pregnancy. It is also used as part of the ABVD regimen for lymphoma. Dipaola et al. published a case report of a patient who received two cycles of this combination therapy for melanoma prior to delivery of her healthy infant at 30 weeks’ gestation [12]. No skeletal defects or cleft palate were observed as had been previously described with dacarbazine. The placental tissue was notable for invasion of malignant melanoma into the intervillous spaces; however, the fetus did not have metastatic disease.

Busulfan use in pregnancy was associated with no anomalies during the rst trimester [13]. It was associated with malforma- tions in two cases with second trimester use: in one case, unilat- eral renal agenesis was noted after combination of busulfan and allopurinol, and in the other case, pyloric stenosis occurred after single therapy [1].

14.4 Anthracyclines

The anthracycline agents are typically used as combination agents. A mechanism of action is by intercalating between DNA base pairs. Twenty-eight pregnancies exposed to doxorubicin and daunorubi- cin for treatment of acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin’s lymphoma, sarcoma, and breast cancer were summarized in a case series. One elective termination and two spontaneous abortions occurred; all fetuses were noted to be normal. Twenty-one pregnancies were delivered without complica- tions. At birth, one infant had transient bone marrow hypoplasia, and one set of twins presented with diarrhea and sepsis at birth. Two patients expired with the fetus in utero prior to delivery [14]. Doxorubicin had been previously cited to be associated with limb abnormalities in the rst trimester; however, it was given in combi- nation with cytarabine [1]. A case report of a spontaneous abortion at 17 weeks occurred after exposure at 13 weeks’ gestation to doxo- rubicin and vincristine for treatment of acute lymphoblastic leu- kemia (ALL). Postmortem fetal necropsy was not performed [15].

In another case, respiratory distress syndrome, neonatal sepsis, and bronchopneumonia occurred in a 31-week gestation with a birth weight of 2070 g whose mother had received doxorubicin for breast cancer at 28 weeks’ gestation. Follow-up of the offspring at 6 years of age revealed normal development [15].

Of 13 women in which epirubicin was used, three fetuses were affected. One neonatal death occurred after exposure to epirubi- cin, vincristine, and prednisone and another to epirubicin in com- bination with cyclophosphamide [15, 16]. The combination of

14 Chemotherapy in Pregnancy

206 14.5 Plant alkaloids

exposure to cyclophosphamide, epirubicin, and 5- uorouracil during the rst trimester for treatment of in ltrating ductal breast cancer resulted in limb abnormalities and micrognathia [17]. The patient electively terminated the pregnancy and the fetus was examined subsequently to con rm the ndings. Epirubicin has been the agent of choice for breast cancer in Europe where doxorubicin was typically used in the United States during pregnancy. There are inherent problems in comparative reviews of retrospective data; however, the conclusion of the authors was that the two agents, doxorubicin and epirubicin, show similar transplacental transfer rates and toxicity pro les [18].

Daunorubicin has most commonly been used in treatment of acute lymphocytic leukemia. Of 43 cases that were reviewed, IUGR occurred in ve fetuses, four suffered from transient myelo- suppression, three IUFDs occurred, two of which were notable for complications by severe preeclampsia at 29 weeks or severe maternal anemia and maternal complications from ALL [1]. The third IUFD was following combination therapy with daunorubicin, idarubicin, cytarabine, and mitoxantrone.

Though doxorubicin is typically used in advanced breast cancer in pregnancy as part of the FAC regimen (5- uorouracil, doxoru- bicin, cyclophosphamide), data surrounding its use in pregnancy are limited. Unless the patient has underlying cardiac disease, this anthracycline-containing combination [2, 9] is rst-line therapy [19].

Anthracyclines are known to be cardiotoxic in children and adults, but the in utero effects on developing fetuses are not known [20]. Meyer-Wittkopf and colleagues performed fetal echo- cardiograms every 2 weeks on a pregnant patient who was receiv- ing doxorubicin and cyclophosphamide during the second and third trimesters of pregnancy for treatment of in ltrating ductal carcinoma. Measurements of ventricles of unexposed fetuses aged 20–40 weeks were used as controls. No fetal cardiac changes were noted to suggest cardiotoxicity [21]. In a European study, 20 patients were followed throughout their pregnancy, receiving weekly epirubicin at 35mg/m2 for treatment of breast cancer at a median gestational age of 19 weeks. No major fetal malformations were noted with the exception of one case of inheritable polycys- tic kidney disease. Children were reported to be developmentally normal by reports of their parents at 2 years of age [22].

14.5 Plant alkaloids

The plant alkaloids, vincristine, vinblastine, and vinorelbine, are considered to have a higher safety pro le in pregnancy. One

14 Chemotherapy in pregnancy 207

malformation was reported in 29 patients treated during the rst trimester with combination therapy of vincristine, doxorubicin, cytarabine, and prednisone; an atrial septal defect and absent fth digit [1]. Two fetal deaths and two neonatal deaths occurred, all after combination therapy in the second and/or third trimester. Of 111 exposures to vincristine or vinblastine, nine cases of IUGR and seven cases of preterm delivery occurred [15]. Vinorelbine was administered to two subjects in combination with 5- uoro- uracil and for another patient epidoxorubicin and cyclophospha- mide due to disease progression of her breast cancer in pregnancy. The only fetal effect observed was anemia at 21 days of life, but no fetal malformations were noted [23].

14.5.1 Taxanes

Taxanes have been shown to be teratogenic in animal models, but their use in humans during pregnancy has been limited. Paclitaxel works by disruption of microtubule assembly. It has been shown to be toxic to chick, rat, and rabbit embryos when given during the critical organogenesis period [1]. The use of taxanes has emerged as important in patients with node positive breast cancer [24, 25]. A recent published case report from Clinical Breast Cancer describes a patient with invasive lobular breast cancer who received weekly paclitaxel from 19 to 33 weeks’ gestation. Fetal ultrasound was performed at 6-week intervals and labor was induced at 37 weeks due to onset of preeclampsia. The fetus was of normal weight without malformations or infection at birth [25, 26].

14.5.2 Hormonal agents

Metastatic breast cancer during pregnancy poses a challenge for the practitioner in terms of treatment options. Though it had been pre- viously held that survival was poorer for pregnant patients, when matched by stage and age with non-pregnant controls, survival is similar [27]. Research on tamoxifen in the animal literature shows epithelial changes in the neonatal period similar to those observed with diethylstilbesterol (DES). DES was used prior to tamoxifen and aromatase inhibitors for estrogen positive breast cancer. It was also used to prevent miscarriages and as estrogen replacement in estrogen-de cient states after its advent in 1938. It had signi cant adverse effects both on the women who took it and on exposed fetuses. Studies have shown that female fetuses exposed in utero show structural changes in the uterus, cervix, and upper vagina; classically, the T-shaped uteri and uterotubal anomalies that lead to repeat miscarriages [28]. There is also an increased incidence

14 Chemotherapy in Pregnancy

208 14.6 Targeted therapies

of clear cell vaginal adenocarcinoma 1/1000 exposures. The pro- posed mechanism is altered embryological Mullerian duct forma- tion due to estrogenic alterations to stromal junctions [29]. Speci c structural changes and clear cell vaginal adenocarcinoma were not reported in the literature surrounding tamoxifen use in fetuses. It is not clear if DES affects fertility; certainly structural changes may affect fertility. The teratogenicity of tamoxifen has been suggested to be species speci c and reports in humans are limited.

Treatment with aromatase inhibitors (AIs) improves survival for women with metastatic breast cancer by 10% [30]. In initial studies, AIs did not have a statistically signi cant survival bene t when com- pared to tamoxifen; however, the third generation AIs did demon- strate a survival bene t [31]. AIs are typically not given in pregnancy or in premenopausal women as peripheral inhibition of aromatase would not be able to overcome the estrogen produced by the grow- ing pregnancy or the premenopausal ovary. In the postmenopausal female, aromatase inhibitor inhibits the conversion of androgen to estrogen in the adipose tissue, as it occurs on a smaller scale.

14.6 Targeted therapies

The HER-2Neu gene has been noted to be ampli ed in 25–50% of metastatic breast cancer patients [32]. HER-2Neu gene positiv- ity is associated with a poor prognosis and decreased survival; however, it is an important for targeted therapies. Trastuztumab (Herceptin) is a targeted monoclonal antibody that binds the extracellular domain of the overexpressed HER-2Neu receptor in metastatic breast cancer patients. Herceptin is associated with reversible fetal oligohydramnios or anhydramnios [33]. In one case, a mother treated with Herceptin delivered a fetus with oli- gohydramnios, but no IUGR, and with normal lung and kidney development [33].The proposed mechanism of oligo- or anhy- dramnios is believed to be related to trastuztumab effects of vas- cular endothelial growth factor (VEGF) to inhibit amniotic uid production in the developing fetal kidney [33]. Aside from fetal oligo- or anhydramnios, no other fetal anomalies have been asso- ciated with use to date, although human data are limited. Beyond monoclonal antibody therapy, in the near future, alternative ther- apies for breast cancer may include dual inhibition of epidermal growth factor receptor (EGFR) and human epidermal growth fac- tor receptor 2 (HER-2) with lapatinib, HKI-272, and pertuzumab; antiangiogenesis agents, such as bevicizumab (to date, reports of bevicizumab in pregnancy are limited to intravitreal use for

14 Chemotherapy in pregnancy 209

neovascularization [34]); anti-mTOR effects of Temsirolimus; and anti-Hsp-90, such as 17-AAG [32].

Despite the number of new agents on the horizon, currently, standard treatment for HER-2 positive cancer consists of trastu- zumab. Caution must be taken with trastuzumab in terms of mater- nal health. It is associated with 4% cardiotoxicity when given as single agent and 27% when given in combination with anthra- cyclines [35]. The cardiotoxicity is associated with a decrease in left ventricular ejection fraction and is suspected to be reversible. Memorial Sloan Kettering has adapted guidelines for monitor- ing cardiac dysfunction during trastuzumab use; however, these guidelines would have to be adapted for pregnancy [35].

14.7 Other agents

Cisplatin and carboplatin are typically given as combination agents. They are considered to have a relatively low toxicity pro- le. An infant was exposed for 2 weeks to cisplatin, etoposide, and cytarabine during the second trimester for the treatment of mater- nal Hodgkin’s disease. Fetal jaundice, non-hemolytic anemia was observed in an otherwise normal child born at 36 weeks [15].

In another case, sensorineural hearing loss was reported in a child born with leukopenia, alopecia, and respiratory distress syn- drome at 26 weeks after the child was exposed to cisplatin only 6 days prior to delivery [1]. Complicating factors include severe prematurity of the infant and postnatal treatment with gentami- cin. A case report of a patient treated for stage IIIC ovarian cancer with paclitaxel and carboplatin beginning at 16 weeks’ gestation resulted in no fetal anomalies or complications [36].

Few case reports and little data exist on gemcitabine, bleomy- cin, mitoxantrone, dactinomycin, idarubicin, allopurinol, ritux- imab, etoposide, asparaginase, teniposide, mitoguazone, tritinoin, irinotecan, oxaliplatin, melphalan, altretamine, and erlotinib use in pregnancy due to lack of human exposures in pregnancy; thus discussion has been limited.

14.8 Treatment of speci c cancers

A summary of perinatal outcomes for 152 women who volun- tarily enrolled in the national Cancer and Pregnancy Registry between the years of 1995 and 2008 allowed for signi cant detail

14 Chemotherapy in Pregnancy

210 14.10 Lymphoma

on the effects of chemotherapy. The mean gestational age at the rst cycle of treatment was 20.1±6/2 weeks to the last treatment at 29.6±5.7 weeks. Overall, the rate of malformations was 3.8% (6/157 neonates exposed), equivalent to that of the general popu- lation [37]. Neonatal demise was observed in one case (0.7%), and an IUFD was observed in one case (0.7%). In 12 cases (7.6%), IUGR was observed. Nine cases delivered prematurly and tran- sient complications of prematurity occurred in seven infants [37].

14.9 Breast cancer

In the Cancer and Pregnancy Registry, 118 women were diagnosed with a primary breast cancer, and two with a new primary during pregnancy [37]. Most tumors in pregnancy are found to be high- grade invasive ductal carcinoma, larger than their age-matched non-pregnant controls, positive for lymphovascular invasion fol- lowing surgery, with 60–80% ER negative, and 28–58% reported to be HER-2Neu positive [39]. Most women were treated with Adria- mycin/Cytoxan with the mean gestational age of rst treatment at 20.3±5.4 weeks. The rate of congenital malformations was 3.8%, and 7.8% were small for gestational age at birth. Thirteen neonates had complications during the neonatal period involving: sepsis and anemia at birth in a prematurity infant, gastroesophageal re ux, dif- culty in feeding requiring tube feeding in three, transient tachypnea in three, hyperbilirubinemia or jaundice in three, respiratory distress syndrome in two, and apnea of prematurity in two. Death occurred in a neonate who was diagnosed with a severe rheumatologic dis- order, which resulted in her demise at 13 months of age. Long-term reports indicated no neurodevelopmental effects or leukemias.

Berry et al. reported there were no fetal anomalies or growth restriction in a cohort of 24 patients treated with cyclophospha- mide, 5- uorouracil, and doxorubicin after 12 weeks’ gestation [39]. Current treatment options typically recommend this com- bination regimen of FAC (5- uorouracil, cyclophosphamide, doxorubicin) after the rst trimester [40].

14.10 Lymphoma

Lymphoma was diagnosed in 35 patients during pregnancy; 23 were diagnosed with primary Hodgkin’s disease, two with recurrent Hodgkin’s disease and 10 with non-Hodgkin’s lymphoma. Thirty

14 Chemotherapy in pregnancy 211

of those 35 received chemotherapy during pregnancy, none during the rst trimester. In the Cancer and Pregnancy Registry, one child was born with a congenital malformation, which consisted of syndac- tyly. Two children (6.6%) were small for gestational age (<10%). An IUFD occurred at 28 weeks after CHOP chemotherapy; although an autopsy was performed, the cause of death was not identi ed [37]. One case of speech delay was reported at 4.3 years of age.

Typical regimens for lymphoma include CHOP, CHOP-R or newer reports have included the ABVD (doxorubicin, bleomycin, vinblastine dacarbazine). Dacarbazine is the least studied agent. A case report from Japan details the use of the ABVD in the sec- ond trimester, which resulted in the birth of an infant without any malformations or infections [41].

14.11 Leukemia

Three women in the Cancer and Pregnancy Registry were diag- nosed with acute leukemia in pregnancy and two received che- motherapy. Neither had low birth weights, malformations, or abnormal follow-up of the children [37].

Various combinations of chemotherapeutic agents are used. Typically, the earlier the diagnosis, the worse the prognosis for the mother and fetus; however, in these cases, treatment cannot be delayed. Fetal complications may include spontaneous abor- tion, prematurity, IUGR, and IUFD which have been theorized to be attributed to maternal anemia and disseminated intravascular coagulation (DIC) [1].

In the Cancer and Pregnancy Registry, three patients were diag- nosed with chronic myeloid leukemia during pregnancy, although only one received chemotherapy with cytarabine. She delivered a normal infant at 42 weeks without anomalies, pregnancy complica- tions, or long-term complications.

Aviles and colleagues followed 62 children treated for hemato- logic malignancies. All children were physically and neurodevel- opmentally normal by school performance standardized tests and laboratory tests showing normal tolerance of infections [42].

14.12 Ovarian cancer

Eleven women were identi ed with ovarian cancer during preg- nancy, and of those seven went on to receive chemotherapy, which

14 Chemotherapy in Pregnancy

212 Pharmacokinetics in pregnancy

neonates in the Cancer and Pregnancy Registry to carboplatin, cisplatin, etoposide, prednisone, and bleomycin. Two infants were IUGR, one child was affected with attention de cit disorder and one child was diagnosed with genetic hearing loss (both parents were carriers of the gene) [37]. Cisplatin is commonly chosen over carboplatin for ovarian cancer during pregnancy. Carboplatin has been known to cause thrombocytopenia and is less protein bound which may lead to higher rates of placental transfer [1].

Too few cases of CNS, cervical, colorectal, melanoma, and pan- creatic cancers were reported to summarize in this review.

14.13 Future fertility

Two prospective randomized controlled trials studying the use of gonadotropin-releasing hormone (GnRH) agonists during con- comitant chemotherapy for premenopausal breast cancer suggest preservation of ovarian function with return of natural menstrual function [43, 44].

14.14 Pharmacokinetics in pregnancy

To date, there have not been any pharmacokinetic studies of che- motherapeutic agents in pregnant women. Animal models have contributed to research but do not provide comprehensive details. These studies have been severly critisized for methologic aws, gnrh agonish should not be relied on to preserve fertility during chemotherapy. Much of the information regarding the chemothera- peutic agents comes from retrospective reviews and case reports. Because randomized controlled trials and pharmacokinetic stud- ies are lacking, pregnant patients receive the same weight-based doses as non-pregnant women. Pharmacokinetic studies would further the understanding of physiologic changes of pregnancy which affect drug clearance. For example, increased renal clear- ance rates and increased circulating blood volume may affect active drug concentrations. Decreased plasma albumin levels, increased levels of other circulating proteins, and increased estrogen levels may decrease drug-binding levels. Changes in gastrointestinal func- tion (which may alter absorption of oral medications) may change the active concentration of a medication as well. The volume of distribution and hepatic oxidase system may also be affected dur- ing pregnancy [1]. Elimination of a drug may also be affected by

14 Chemotherapy in pregnancy 213

the amniotic uid levels with the amniotic uid acting as a “third space” [38]. Without adequate knowledge of the pharmacokinet- ics, women may be underdosed; thus, more research is needed to understand the effects of antineoplastic medicines on the mother and the fetus [45].

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14 Chemotherapy in Pregnancy

Substance Use Disorders

James J. Nocon

15

. 15.1  Introduction 217

. 15.2  Substance use disorders de ned 218

. 15.3  Addiction de ned as a disease of the brain 219

. 15.4  The good news: the brain can recover 220

. 15.5  Pregnancy enhances recovery 221

. 15.6  Addiction in women and pregnancy 222

. 15.7  Psychiatric co-morbidity 223

. 15.8  Substances used 224

. 15.9  Screening and detection 239

. 15.10  The role of urine and meconium testing 240

. 15.11  Brief of ce screening strategies 242

. 15.12  Brief of ce interventions 245

. 15.13  Long-term care and maintenance 246

Conclusion 247

15.1 Introduction

Substance use in pregnancy of alcohol, tobacco, and other drugs (ATOD) is the single most preventable public health and social problem affecting women. Although accurate estimates of ATOD use in pregnancy are dif cult to ascertain, a national survey in 2003 revealed the prevalence to be 15.1% among young women aged 15–17 years [1]. Unfortunately, substance use in pregnancy is signi cantly under reported [2]. Admitting to the use of an ille- gal substance may lead to prosecution, incarceration, and loss of

218 15.2 Substance use disorders de ned

child custody [3]. The greater tragedy is that substance use too often goes unrecognized.

Those in the health care system often demonize pregnant addicts [4]. In one survey, 52% of physicians agreed that drug use in preg- nancy constituted child abuse [5]. In another survey, obstetrical nurses had limited knowledge of substance use and over 60% demonstrated a hostile and punitive attitude [6]. The major prob- lem is a lack of education and training, especially in the ability to screen, detect, and intervene in substance use in pregnancy. This lack of awareness gives tacit approval to the addict [7]. The American College of Obstetricians and Gynecologists addresses the ethical rationale for universal screening for at-risk drinking and illicit drug use [8]. Likewise, the American Medical Associa- tion also endorses a duty for universal screening [9].

This chapter will review the unique issues facing women and espe- cially pregnant women involved with substance use. In addition, the chapter will include data from the treatment of over 500 patients in the Prenatal Recovery Program at Wishard Memorial Hospital, Indi- anapolis, Indiana (hereinafter called the Wishard data). Wishard is a public hospital for Indianapolis and a major teaching hospital for the Indiana University School of Medicine. Demographics include approximately 3000 deliveries per year of Black (40%), White (30%), and Hispanic (30%) patients. About 95% are Medicaid funded.

15.2 Substance use disorders de ned

Addiction is actually an extremely dif cult illness to de ne and the general consensus among addiction counselors is, “I know it when I see it”, paraphrasing Potter Stewart, a former US Supreme Court Justice. It is not an issue of “weak willpower”, poor character or immorality. Rejecting this notion, a more enlightened perspec- tive has emerged as “Substance Use Disorder” (SUD) replac- ing the pejorative term “addiction” in the American Psychiatric Association (DSM-IV-TR) [10].

The DSM-IV distinguishes between substance dependence and substance abuse as follows [11]:

Substance Dependence is a pattern of substance use, leading to clinically signi cant impairment or distress, with three or more of the following, occurring at any time in the same 12 month period:

Tolerance. Withdrawal.

15 Substance use disorders 219

The substance is taken in larger amounts over a longer period than was intended.
A persistent desire or unsuccessful efforts to cut down or control use.

Inordinate time spent in acquiring the substance, use of the substance, or recovery from its effects.
Important social, occupational or recreational activities are given up or reduced.

The substance is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.

Substance Abuse is a separate diagnosis from substance dependence. It is a maladaptive pattern of substance use with one or more of the following criteria over a 1-year period:

Repeated substance use that results in an inability to ful ll obligations at home, school or work.
Repeated substance use when it could be dangerous (e.g. driv- ing a car).

Repeated substance-related legal problems, such as arrests. Continued substance use despite interpersonal or social problems that are caused or made worse by use.

15.3 Addiction de ned as a disease of the brain

The disease model of addiction is now rmly established based on overwhelming evidence that addiction is a disease of the brain, where a substance or behavior can produce a need to use drugs or behave in a compulsive manner with known adverse conse- quences [12]. It manifests as a chronic relapsing process and suc- cessful treatment is comparable to, or better than, compliance with treatment plans for hypertension or diabetes [13]. And like diabetes and hypertension, addiction is an interaction between:

The substance: alcohol, tobacco and other drugs,
The host: genetics, vulnerabilities, co-morbid disorders, and The environment: family, culture.

Continuous use of drugs changes the anatomy and physiology of brain cells, particularly in the lateral tegmental area and the nucleus accumbens [14]. PET/MRI scans have mapped the loca- tion in the brain where drugs and behaviors have their effects. Addiction depletes dopamine and the altered brain cannot manu- facture suf cient dopamine to function in a normal manner [15]. This process occurs in all addictive drugs and behaviors.

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220 15.4 The good news: the brain can recover

The pharmacological relevance of this disease model is used in the treatment of nicotine dependence. Nicotine activates the nucleus accumbens, releases dopamine and dopamine is depleted. Antidepressants that are dopamine reuptake inhibitors are effec- tive in stabilizing dopamine levels by blocking or blunting the effect of nicotine, decreasing the cravings, and enhancing smok- ing cessation. Similar antidepressants have also been used in methamphetamine treatment with good results [16].

Most recently, the American Society of Addiction Medicine (ASAM) rede ned addiction consistent with the medical and neurobiological evidence [17]. The society notes that addiction is, “a primary, chronic disease of brain reward, motivation, memory and related circuitry”. ASAM describes ve characteristics (the ABCs) in its de nition:

a. Inability to consistently Abstain;

b. Impairment in Behavioral control;

c. Craving, or increased “hunger” for drugs or rewarding
experiences;

d. Diminished recognition of signi cant problems with
one’s behaviors and interpersonal relationships; and

e. A dysfunctional Emotional response.

Moreover, the ASAM de nition holds that addiction affects emotional and cognitive behavior as well as interpersonal rela- tionships, especially with family, community, and “to things that transcend their daily experience”. This dovetails into the per- spective of addiction from 12 Step fellowships in recovery. This is termed the “relationship view”. Simply stated, if the substance use and associated behavior keeps the person from the physical and emotional attachments of those who love them, then they are addicted. Such behavior would trigger an intervention.

The ASAM de nition creates controversy because physician’s attitudes are based on physician training and current training re ects older beliefs and not the “brain disease” model [18]. Many physicians persist in holding onto the myths that treatment is not effective, it is time consuming and there are few referral services [19]. And bring- ing “spirituality” into treatment has often been viewed as less than objective. In fact, treatment works, brief interventions are effective, and spiritual models assist in motivating the patient in recovery [20].

15.4 The good news: the brain can recover

Current research indicates that recovery in the brain is medi- ated by adult stem cells, a large source of which is located by the

    

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nucleus accumbens [21]. The stem cells can migrate relatively large distances and appear to rebuild damaged circuitry. Factors found to stimulate stem cell production include physical exercise, folic acid, and reading. It is well established that folic acid supple- ments are able to prevent neural tube defects and thereby be able to repair other structural damage [22]. Thus, folic acid supple- mentation may become a new pharmacologic strategy to enhance recovery from addiction. An interesting question is whether high dose folic acid supplements can protect against and prevent fetal alcohol syndrome and its associated brain damage.

A theory for stem cell repair would assert that alcohol damages neurons and abstinence removes the stress to the CNS. Stem cells would slowly migrate from the lateral tegmental area to rebuild the damaged circuitry. In alcohol recovery it takes 8–12 months to see distinct mental changes indicating that the stem cell process is slow and that some permanent damage may persist. Another indicator of this process is the relapse rate in alcohol recovery, which is high in the rst 3 months but after 9 months of absti- nence, relapse rates drop signi cantly.

Pharmacologic therapy in alcohol recovery is well accepted. Double blind placebo-controlled studies indicate naltrexone and acamprosate have signi cantly reduced relapse rates [23]. Nal- trexone is an opioid antagonist and congener of oxymorphone and has a “blocking” effect on cravings. Acamprosate may act by interacting with glutamate and GABA neurotransmitter systems, with similar effects. These drugs and folic acid appear to have no harmful effects on the fetus and may be used in pregnancy.

15.5 Pregnancy enhances recovery

Call it maternal instinct, pregnancy clearly enhances recovery and makes a difference in long-term recovery. After 1 year of treat- ment, 65.7% of women who entered treatment while pregnant used no drugs, while only 27.7% of non-pregnant women remained drug free (p<0.0005) [24]. Likewise, in the Wishard study, dur- ing 2005, 23 women were enrolled in a treatment program that included prenatal care, individual and group counseling that con- tinued for 6 months postpartum. All 23 were positive for cocaine, THC, or opiates on their rst prenatal visit. Nineteen were nega- tive for drugs at delivery (82.6%). Of the 19, 15 remained negative 6 months postpartum (65.2% of total).

Even brief interventions have proved highly effective in treating alcohol addiction in pregnancy [25]. Most importantly, prenatal substance use intervention reduces neonatal low birth weight and

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222 15.6 Addiction in women and pregnancy

preterm delivery [26]. For example, in the Wishard population, during 2003–2004, 40 patients tested positive for cocaine at the rst prenatal visit. Treatment included prenatal care and brief indi- vidual counseling. Twenty-seven babies were meconium negative at delivery (67.5%) and had a mean birth weight of 3253.55 grams; s.d. 473.99, while 13 positive for cocaine had a mean weight of 2775.85; s.d. 466.68 (p<0.01).

It generally takes 10–14 weeks for the meconium to “clear” after cessation of cocaine use and the mechanism is unclear [27]. Thus, for a term newborn to be negative, the mother had to be drug free well before the third trimester. Early intervention clearly avoids the low birth weight effects of cocaine use in pregnancy. Brief interven- tions, using behavioral reinforcement plus brief motivational ther- apy, increases compliance with prenatal visits and results in greater abstinence, higher birth weights, and lower preterm labor [28].

15.6 Addiction in women and pregnancy

There is well-established empirical evidence supporting gender- related differences in pharmacokinetics and pharmacologic properties of psychotropic medications [29]. There is no question that males and females respond differently to many drugs. Women have much lower levels of alcohol dehydrogenase in their stomach mucosa. This results in a shorter rst-pass metabolism and more rapid intoxication in women [30]. Women have increased adverse health effects from alcohol [31]. They also have a later onset of heavy use – telescoping. This leads to a more rapid progression to dependence [32].

Women also have different psychological dynamics operating in their substance use. Defense mechanisms include self-blaming and denial styles include internalizing and rationalizing while the identity components include the caretaker and sel essness [33]. Social differences re ect the “double standard” where men are expected to be able to “hold their liquor “and women who drink are “easy”. And there is a special shame reserved for women who drink in pregnancy, i.e. “how can you do that to your baby?” This is sometimes called the shame-based approach [34].

In their own voices, psychological differences re ect shame as an internalized oppression in addiction. “I’m not worthy of recovery.” “I’m a bad person, not sick.” “I can’t tolerate my emotional pain without drugs.” “I can’t have sex without drugs.” [35] The role of shame delays diagnosis and treatment since women often use drugs and alcohol in isolation. It promotes enabling where the family often

15 Substance use disorders 223

hides the secret. Most important is the unrecognized role of trauma and PTSD. There is a strong correlation between past sexual trauma and addiction (50–80% of addicts report past sexual trauma and abuse) where women use drugs and alcohol for self-medication [36].

Hormonal differences in women may be another factor predis- posing women to addiction. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2±9.9ng/mL, which was signi cantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/mL), but there were no differences in their subjective reports of cocaine effects [37]. However, alcohol intake is associated with a higher rate of infertility [38].

There are differences in women with regard to speci c drugs. With heroin women develop dependence quicker than men [39]. Women using cocaine are more likely to use the IV route and the risk of HIV infection is greater [40]. And women are more likely to use smoking for weight control and to reduce stress [41]. Alcoholic women usually have alcoholic spouses and less spousal support [42]. Women are more likely to abuse prescription drugs, especially opioids [43]. In a related issue, women are often the only child care- givers and very few treatment programs provide child support [44].

Women are especially vulnerable to substance use. In most soci- eties, if not all, women are disempowered, pregnant women are more disempowered, and pregnant addicts are the most disem- powered. Examples would include unequal pay for equal work, unrealistic prohibitions on pregnant workers and demonizing pregnant addicts. Studies suggest that drug use is a coping strategy that some women adopt to manage this oppression [45]. In con- trast, motivational empowerment is the key to successful recovery.

15.7 Psychiatric co-morbidity

A critical aspect of the effective treatment of substance use disor- ders is to identify and treat psychiatric co-morbid disorders. Some co-morbid psychiatric problems are more common in women [46]:

n Bipolar disorders
n Panic disorder
n PTSD
n Cluster B personality disorders n Bulimia

n Depression

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224 15.8 Substances used

In addition, genetic markers have been identi ed with a num- ber of psychiatric disorders in which there is a higher incidence of substance use [47]. They include:

n Low P3 amplitude (schizophrenia, ADHD) n Conduct disorder (CD)
n Antisocial personality (ASPD)
n Decrease in dopamine receptor density (D2) n Serotonin (5-HT) systems

Pharmacologic treatment of these disorders enhances recovery from substance use and also poses additional problems for the fetus including need for treatment of the neonate in special inten- sive care units for symptoms of withdrawal [48]. This is especially true for benzodiazepines, which have a higher rate of teratogenic- ity and withdrawal, especially when combined with alcohol [49]. Risks and bene ts of pharmacologic treatment are most important when treating co-morbidity in pregnancy.

15.8 Substances used

The most frequently used substances in pregnancy are alcohol, tobacco, marijuana, cocaine, opioids, and the amphetamines [50]. Alcohol damages neurons, which results in the fetal alcohol syn- drome (FAS) and fetal alcohol spectrum disorders (FASD), which are the most common preventable causes of mental retardation. Alcohol is also associated with higher rates of stillbirth, spon- taneous abortion, and low birth weight [51]. Nicotine is associ- ated with a high incidence of miscarriage, low birth weight and preterm delivery. Alcohol and nicotine cause more fetal damage than all the other drugs combined.

Prescription opioid use has skyrocketed in the last few years [52]. The Wishard data, from 2002 to 2007, indicate that 69 of 287 patients (24%) were treated for opioid use. From 2008 through 2010, 74% of patients treated were for opioid use, especially methadone maintenance and buprenorphine maintenance. Data from the Florida Society of Addiction Medicine reveal that oxyco- done in the form of oxycontin (“oxy”) is responsible for 10 deaths in Florida per day and is the number one drug of abuse among 12–17-year-olds [53]. A awed prescription-monitoring program has created an “oxy” epidemic [54].

The following sections will describe the maternal, fetal, and newborn effects of the frequently used substances. Pharmacologi- cal treatment during pregnancy involves a number of strategies

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including detoxi cation, abstinence, maintenance, and treat- ment of co-morbid psychiatric disorders. Diet, nutrition, social service support, and 12 Step groups are essential adjuncts to pharmacologic therapy.

15.8.1 Alcohol

Alcohol is a known teratogen and there is no known safe level for use in pregnancy. Blood alcohol levels in women are higher than men after drinking similar amounts and women are more sensitive to its toxic effects; that is, they get drunk faster. This appears to be due to a lower percentage of body water and lower gastric alcohol dehydrogenase resulting in a reduced rst-pass metabolism [55].

Alcohol readily crosses the placenta and is present in amniotic uid well after the mother’s level is metabolized to zero. Alcohol damage can occur early in pregnancy before a women realizes she is pregnant. Fetal toxicity is dose related with the greatest risk occurring early in the rst trimester [56].

There are many mechanisms that result in cell death by necrosis or apoptosis including:

n Increased oxidative stress,
n Damage to mitochondria,
n Effects on glial cells,
n Impaired development and function of chemical messenger

systems,
n Transport and uptake of glucose, and n Cell adhesion [57].

In addition to cranio-facial abnormalities and mental retarda- tion associated with FAS (average IQ is 67), for children with FASD, ADHD is more likely to be earlier onset inattention subtype. These children appear to have a disturbance in brain structure, in the corpus callosum, and the response to standard psychostimulant medication can be unpredictable [58].

15.8.1.1 Pharmacologic treatment of alcohol use in pregnancy

Treatment is predicated on detoxi cation and abstinence. During detoxi cation, benzodiazepines are the drug of choice to reduce the excitatory state of the brain during withdrawal. Carbamaze- pine, an antiseizure medication, has been used extensively in Europe. It is a category D drug and may be best used in the sec- ond and third trimester [59]. Folic acid supplementation is rec- ommended with the use of carbamazepine due to an increased incidence of neural tube defects with this medication [60].

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226 15.8 Substances used

Disulferam is used to maintain abstinence. Disulferam inhibits aldehyde dehydrogenase production. Subsequent use of alcohol leads to accumulation of acetaldehyde. As a result, the patient experiences harsh symptoms including facial ushing, tachycar- dia, hypotension, nausea, and vomiting. This is a form of nega- tive reinforcement and may not be well tolerated by the pregnant alcoholic in recovery. Reports of fetal anomalies are sporadic and disulferam appears to be relatively safe [61].

Naltrexone and acamprosate have also been used to support abstinence. Naltrexone is an opiate agonist. It appears to act by blocking opiate receptor activation mediated by alcohol and one effect is to reduce craving. Acamprosate has a similar outcome and the mechanism is thought to modulate NMDA receptors in the brain [62]. There are few data regarding the use of acampro- sate in pregnancy. In most cases the risks of continued alcohol use far outweigh the risks of pharmacologic therapy in pregnancy.

15.8.2 Tobacco; nicotine

Nicotine in the form of tobacco smoke is a double-edged sword for fetal harm. Cigarette smoke contains cyanide, carbon monoxide, and a plethora of toxic hydrocarbons, which affect oxygen trans- port in the placenta. This results in spontaneous abortion, low birth weight and preterm delivery [63]. Nicotine affects umbilical blood ow, fetal cerebral artery blood ow and potentiates the effects of the smoke [64]. Smoking cessation programs are effec- tive in reducing these effects, especially if started before or early in the pregnancy [65].

Pharmacologic therapy for nicotine use is similar to alcohol focusing on detoxi cation and abstinence support. Nicotine patches, lozenges, and gums are most often used in conjunction with a smoking cessation program. Nicotine replacement treat- ment (NRT) helps prevent relapse and removes the effects of the smoke on the fetus. It appears that minimal amounts of nicotine are excreted into breast milk and that NRT can be used while breastfeeding [66]. However, it is imperative that the patient be advised not to smoke while using these methods because the com- bined dose of nicotine substantially increases fetal exposure.

Selective serotonin and dopamine reuptake inhibitors have had a modicum of success. Bupropion is the most frequently prescribed antidepressant and varenicline the most recent. Bupropion is a dopamine reuptake inhibitor and creates a blocking effect of crav- ings. Varenicline is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes. It also reduces cravings and has a blocking effect. Both may lead to neuropsychiatric symptoms in

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the mother and the physician should be aware of the black-box warnings of these agents [67].

In a survey of substance using patients in the Wishard data, about two out of every three patients continue to smoke during pregnancy. Efforts to reduce smoking have been somewhat suc- cessful. NRT is well tolerated and in selected patients, bupropion and varenicline have achieved good results. The goal is abstinence and if a patient can reduce her cigarette smoking to fewer than 10 per day, she can lower the risk of low birth weight and preterm delivery. However, even low rates of smoking are associated with some increased low birth rate [68].

15.8.3 Opiates and opioids

Opiates are alkaloids derived from the opium poppy and include morphine, codeine, and thebaine. Opioids include all opiates plus the semi-synthetics, which are derived from the alkaloids (theba- ine): hydrocodone, oxycodone, and heroin, plus the synthetics: methadone, fentanyl, Nubian, and buprenorphine. Many physi- cians use these terms interchangeably.

There has been a major shift in the approach to opiate treat- ment from detoxi cation and abstinence to maintenance. A number of factors have contributed to this shift. Relapse is high while maintenance helps prevent relapse and diseases attributed to IV drug use. Most important is that opiate withdrawal car- ries an increased risk of abruption and preterm labor. However, in selected patients, detoxi cation has been accomplished with relative safety [69]. In one retrospective study of gradual metha- done detoxi cation, there was no increased risk of preterm deliv- ery [70]. However, the relapse rate in one study was 56% after detoxi cation [71].

Opioids bind to neuro-receptors, speci cally:

n Mu: analgesia, euphoria, respiratory depression, constipation, sedation, and miosis

n Kappa: dysphoria, sedation, and psychotomimetic n Delta: unknown

The rate of excretion is faster than withdrawal. Morphine is excreted within 72 hours while withdrawal is 3–6 days. Metha- done can be excreted in 4–5 days but withdrawal is prolonged to 10–20 days. The clinical relevance is that a patient in withdrawal may have a negative urine drug screen (UDS). In addition, metha- done, hydrocodone, and oxycodone are metabolized at a more rapid rate in pregnancy. Thus, the requirement for a maintenance dose will increase. In the Wishard data, 35% of the methadone

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228 15.8 Substances used

maintenance patients required an increase of 30–50% over their initial dose to prevent withdrawal.

The major maternal risk of opioid use is respiratory depression and death. Many opioid users also use benzodiazepines, which greatly increase the risk of death. In the Wishard data, 19 of 45 (42.2%) opioid chronic pain patients tested positive for benzodiaz- epines at their rst prenatal visit. In addition, about two thirds of the patients used tobacco. The Wishard data also reveal that opioid users have a higher incidence of low birth weight and preterm labor.

Opioids were considered category B drugs with no harm noted in animal studies. Most recently, the National Birth Defects Pre- vention Study, a case–control study for infants born October 1, 1997 through December 31, 2005 in 10 states revealed that thera- peutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically signi cantly associated with:

n Conoventricular septal defects (OR, 2.7; 95% CI, 1.1–6.3),
n Atrioventricular septal defects (OR, 2.0; 95% CI, 1.2–3.6),
n Hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4–4.1), n Spina bi da (OR, 2.0; 95% CI, 1.3–3.2), and
n Gastroschisis (OR, 1.8; 95% CI, 1.1–2.9) in infants [72].

In addition, methadone maintenance was also found to be asso- ciated with ophthalmologic abnormalities including:

n Reduced acuity (95%),
n Nystagmus (70%),
n Delayed visual maturation (50%),
n Strabismus (30%),
n Refractive errors (30%), and
n Cerebral visual impairment (25%) [73].

Neonatal abstinence syndrome (NAS) is the most common effect on the fetus/neonate. The incidence is as high as 90% in methadone maintenance users and varies with the opioid used, the daily dose, length of use, and concomitant use of other drugs, especially benzodiazepines [74]. In NAS, the neonate is in acute withdrawal with an onset of hours to about 4 days. Com- mon symptoms include irritable cry, increased tone, tachypnea, sleeplessness and tremor, and treatment is based on scores from observations of psychomotor behavior [75]. Treatment consists of stabilizing the withdrawal, usually with morphine drops and then gradually decreasing the dose to detoxify the baby [76]. Pharma- cologic treatment of NAS may also use clonidine, an alpha ago- nist used to stabilize the cardiovascular system, and phenobarbital to reduce brain activity and seizures.

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There are readily observable neurobehavioral effects of opioid treatment in pregnancy. The most common observations include decreased head circumference, developmental delays, and poor ne motor coordination [77]. However, long-term effects of opi- oid treatment appear to be more dependent on home environ- ment [78]. Not surprising is that methadone-exposed infants that had delayed mental development were also raised in poor environmental conditions [79].

Maternal treatment of opioid addiction involves managing acute overdose, withdrawal, maintenance, and detoxi cation. Most com- monly, the patient presents in acute withdrawal. After she is stabilized, most are managed by maintenance with methadone or buprenor- phine and only occasionally does a patient choose detoxi cation. As more and more opioid-dependent patients are being maintained on methadone or buprenorphine, they present for their rst prenatal visit as a “methadone or buprenorphine maintenance” patient.

15.8.3.1 Opioid overdose

n Characterized by pinpoint pupils, respiratory depression, coma, and pulmonary edema.

n Establish airway.
n Inject Naloxone – repeat if long-acting opiate present, e.g.

methadone.
n Naloxone will not harm fetus.
n Treatment will precipitate a severe withdrawal.
n Will need to restart and modify an opioid dose.
n For maintenance, use methadone or buprenorphine.
n Methadone: start at 20 mg bid and increase 5–10 mg per day

until stable.
n Buprenorphine/naloxone: start at 2–4mg bid; increase by

2–4mg every 6 hours until withdrawal is abated.

15.8.3.2 Opioid withdrawal: affects major systems

n CNS – tremors, seizures.
n Metabolic – sweating, yawning.
n Vascular – hot ashes and chills.
n Respiratory – increased rate, respiratory alkalosis.
n GI – cramps, nausea, vomiting, diarrhea.
n Drug-speci c effects – methadone has a prolonged withdrawal:

10–20 days.
n Restart and modify opioid dose.
n Avoid benzodiazepines; potentiates CNS and respiratory

depression.
n Current recommendation is to avoid withdrawal during

pregnancy.

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230 15.8 Substances used

15.8.3.3 Opiate withdrawal treatment

n Initiate methadone or buprenorphine to stabilize withdrawal: may use oxycodone 10 mg q 4–6 h for up to 72 hours to stabilize patient and then switch to methadone or buprenorphine.

n Phenergan 25 mg q 4–6 h for withdrawal symptoms – best for nausea, vomiting and GI symptoms.

n Phenobarbital, 30mg tid for neurological withdrawal symptoms.

n Clonidine 0.1 mg tid – vascular withdrawal symptoms.
n Check acetaminophen levels in patients using opiate/acetamin-

ophen compounds.

15.8.3.4 Opioid detoxi cation

n Must be closely controlled. Bene ts rarely outweigh risks.
n Gradual reduction to minimize withdrawal.
n Symptomatic treatment.
n Phenergan 25 mg q 4–6 h for withdrawal symptoms – best for

nausea, vomiting, and gastrointestinal symptoms.
n Phenobarbital, 30 mg tid for neurological withdrawal symptoms. n Clonidine 0.1 mg tid – vascular withdrawal symptoms.

Preterm labor remains a major risk in overdose, withdrawal, and detoxi cation. Pharmacologic treatments for preterm labor, such as magnesium sulfate, may potentiate respiratory depres- sion in the mother and neonate. Fetal monitoring is signi cantly affected by opioids with reduced fetal activity most common [80]. Methadone will cause a higher incidence of non-reactive non- stress tests (NST), especially if given 1–3 hours before the NST [81]. The biophysical pro le is the appropriate follow-up to a non-reactive NST [82].

Intrauterine growth restriction (IUGR) is another common problem in opioid-dependent women and monitoring with ultra- sound is essential to determine prenatal management. If IUGR is identi ed, the degree of placental dysfunction is thought to be associated with changes in diastolic blood ow through the umbilical cord. Increasing resistance of diastolic ow and reduc- tion of amniotic uid are markers indicating closer surveillance and earlier intervention.

15.8.3.5 Opioid maintenance strategies: methadone and buprenorphine

Methadone maintenance has been the model for maintenance of opioid-dependent pregnant patients for many years. Contrary to popular belief, it has never been approved to treat opioid depen- dency in pregnancy. Methadone maintenance is highly regulated and can only be dispensed for opioid dependence treatment in a

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federally certi ed clinic. Thus, the patient must arrive early in the morning, receive her dose and its attendant side effects, and then carry on through her day.

Early reports found substantial bene ts from maintenance therapy, especially reduction of infectious disease and stillbirth [83]. Originally, the dosing regimen for methadone followed the practice of using the lowest possible dose to reduce the risk of NAS. Unfortunately, doses of less than 20–40mg often failed to achieve a blocking effect and led to increased preterm labor, low birth weight, and relapse [84]. Thus, it is most prudent to adjust the dose of methadone based on withdrawal symptoms and crav- ings. Up to 35% of patients will require an increase in methadone, typically in the late second and early third trimesters. Although the evidence does not support an advantage to divided doses of methadone, many patients report better tolerance and less nau- sea, which improves compliance with treatment and prenatal care [85]. If the patient experiences the typical postpartum diuresis, it is recommended to reduce the methadone dose by 20–40% shortly after delivery.

15.8.3.6 Opioid maintenance: methadone

n Encourage patient to remain on methadone during pregnancy. n Expect dose to increase up to 50% during pregnancy in about

35% of patients.
n Doses range from 50–150mg per day.
n Higher doses not associated with severity of NAS and improve

maternal compliance with prenatal care [86].
n Patient should be encouraged to breastfeed [87].
n Note: Methadone is NOT FDA approved for treatment for opi-

ate dependence in pregnancy.

Buprenorphine maintenance was rst registered to treat opiate dependence in France in 1996, and practitioners were allowed to dispense buprenorphine by prescription enabling easy access to treatment [88]. Thousands of patients underwent buprenor- phine treatment, among them an increasing number of pregnant women. An initial striking observation was that in the majority of newborns, the neonatal abstinence syndrome (NAS) was either absent or mild enough not to require treatment. A prospective French study of 34 buprenorphine-treated pregnancies revealed that only 13 had NAS, nine of which were confounded by other psychoactive drugs (benzodiazepines, opiates, and cannabis) [89]. Buprenorphine was approved for use in the United States in 2002 by an amendment to the Drug Treatment Act of 2000 [90]. The rst United States survey of a registry of over 300 mothers treated with buprenorphine reveals that buprenorphine is safe and

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232 15.8 Substances used

effective for mothers and newborns with a qualitatively and quan- titatively diminished NAS compared to methadone [91]. A com- parative study between methadone and buprenorphine con rmed improved maternal and neonatal outcomes on buprenorphine [92].

Buprenorphine is an agonist/antagonist with a high binding af nity for the Mu receptor. Thus, if the patient uses another opi- ate while on buprenorphine, she will have a minimal euphoric experience. This effect signi cantly reduces the abuse potential [93]. It is metabolized by placental aromatase to norbuprenor- phine resulting in low placental transfer. This may account for limited fetal exposure and its lower incidence of NAS [94].

Buprenorphine is marketed in the United States in two forms, buprenorphine (Subutex) and buprenorphine combined with naloxone (Suboxone). Initially, there was some concern that the buprenorphine/naloxone combination might cause an intrauter- ine withdrawal in the fetus. Hence, only buprenorphine was rec- ommended for use in pregnancy. The evidence clearly indicates that the dose of naloxone has little to no effect on the fetus [95]. Moreover, sublingual buprenorphine has been found to be safe and effective in treating NAS [96]. Small amounts of buprenor- phine are found in the breast milk. However, it has little, if any, effect on the newborn with no evidence of neonatal withdrawal when breastfeeding is discontinued [97].

15.8.3.7 Opioid maintenance: buprenorphine

n Patient must be in opioid withdrawal to start buprenorphine treatment.

n Inpatient: some recommend initiating treatment with buprenor- phine, 2–4mg sublingual by either tablet or lm.

n Increase dose by 2–4mg every 6 hours to stop withdrawal symptoms.

n Convert to buprenorphine/naloxone for outpatient use.
n Target doses range from 4 to 24mg per day.
n Most pregnant patients are stable at 8–16 mg per day in divided

doses.

15.8.3.8 Analgesia and anesthesia for opioid maintenance patients

n Epidural anesthesia for labor, delivery, and cesarean delivery is the standard.

n Spinal anesthesia for cesarean delivery.
n For acute postoperative pain, methadone and buprenorphine

patients will gain relief with doses of opiates 70% over usual

doses [98].
n Morphine is best tolerated by the largest group of patients.

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15.8.3.9 Opioid-dependent patients: a comparison of maternal and neonatal outcomes

The Wishard data re ect a long-term observational study of opi- oid-dependent patients. The study includes data from the Prenatal Recovery Clinic starting in 2002 through 2010, and includes 90 patients treated with methadone compared to 46 patients treated with buprenorphine and buprenorphine/naloxone. In addition, there are data from two other groups of opioid-dependent chronic pain patients. One group (n=31) consists of patients whose urine drug screens revealed only opiate and opiate/acetaminophen combinations for pain control while the other group (n=45) had urine drug screens that revealed multiple licit and illicit sub- stances including benzodiazepines, cocaine, and marijuana. The latter group was designated opioid “P” for poly-substance use.

The methadone group had signi cantly higher preterm deliver- ies, more low birth weight, lower birth weights, and longer length of stay (LOS) for withdrawal when compared to the buprenor- phine group. Interestingly, opioid-dependent chronic pain patients who used only opioids for pain relief had the lowest maternal and neonatal morbidity. Doses of hydrocodone and oxycodone in the latter group varied from 40 to 80mg per day.

Only nine babies of methadone-treated mothers tested positive for illicit drugs in their meconium. In a prior study in the same institution in 1999, 85% of methadone patients tested positive for an illicit substance (predominantly cocaine) in the 30 days prior to delivery [99]. It appears that a signi cant change in the treat- ment approach addressing illicit drugs resulted in substantially lower use (see Tables 15.1 and 15.2).

Opioid-dependent patients treated with buprenorphine and opioid-only-treated chronic pain patients had the lowest inci- dence of maternal and neonatal morbidity. In both groups, preterm delivery and birth weights were within the norm for non-opioid-dependent patients. The ndings strongly suggest new strategies for managing opioid-dependent patients in preg- nancy. One recommendation is to start opioid-dependent patients presenting in withdrawal on buprenorphine rather than metha- done [100]. Another is to maintain the opioid-only patient on her current regimen.

15.8.3.10 Opioid-only-dependent chronic pain patient

n Maintain current opiate regimen – avoid withdrawal (both legal to do and meets standard of care).

n Hydrocodone 5/325 or 10/325 (up to 2 tabs q 6h). n Oxycodone 5/325 or 10/325 (up to 2 tabs q 6h).
n Low rate of NAS noted with these doses.

15 Substance Use Disorders

234 15.8 Substances used
Table 15.1 Methadone vs. buprenorphine: major pregnancy outcomes

Bup. (46)1

Meth (90)2

p

Preterm delivery Low birth weight (<2500 g) Mean birth weight Positive meconium Neonatal abstinence (NAS) NAS treated Mean length of stay (days) Failed to return PP PP UDS “negative” Tobacco use (>0.5 ppd)

5 (10.9%) 27 (30%) 0.001 4 26 0.01 3079 g 2718 g 0.005 3 (6.9%) 9 (10.8%) NS

8 89 0.001 63 80 0.001 6.78 30.3 0.001 13 (28.8%) 28 (31.1%) NS 29 (63%) 59 (65.5%) NS 29 (63%) 51 (56.6%) NS

PP – postpartum. 1In the buprenorphine group there were 12 patients treated with buprenorphine and 34 treated with buprenorphine/naloxone with no differences within the groups. 2In the methadone group there were 92 babies (two sets of twins). 3Three of the NAS treated had concomitant use of benzodiazepines.

Table 15.2 Comparison of opioid-dependent chronic pain patients

Opioid (31)

Opioid P (45)*

p

Preterm delivery Low birth weight (<2500 g) Mean birth weight Positive meconium NAS treated Mean length of stay (days) Failed to return PP PP UDS “negative” Tobacco use (>0.5 ppd)

4 (12.9%) 8 (17.7%) NS
3 8 NS 3085 g 2879 g NS
0 12 (26.6%) 0.001 1 5 NS 3.3 7.8 0.01 3 13 0.01 23 (74.2%) 25 (55.5%) NS 21 (67.7%) 30 (66.6%) NS

PP – postpartum. *Opioid P – polysubstance use including benzodiazepines, cocaine, and marijuana.

n Requirement of opiate may increase. n Pain moderators may be helpful.
n Amitriptyline 50–100mg h.s.
n Gabapentin 300mg tid.

n Physical therapy – maintain mobility.

15 Substance use disorders 235

15.8.4 Fentanyl

Fentanyl is a synthetic opioid used in anesthesia and for treat- ing chronic pain. Chewing fentanyl patches is a common form of abuse. It has a high addictive potential and is one of the more common addictions among anesthesiologists. There is a high risk of fatal overdose among users. Maternal and neonatal effects and treatment are the same as other opioids.

15.8.5 Benzodiazepines

Benzodiazepines are gamma-amino-butyrate agonists used as muscle relaxants, anxiolytics, hypnotics, and anticonvulsants [101]. Unfortunately, they have a high addictive potential and are prescribed more often to women [102]. In the Wishard data, a very common scenario for woman dependent on opioids and ben- zodiazepines centers on treatment for soft tissue injuries in motor vehicle accidents. It is well established that long-term therapy leads to tolerance and dependence and should be avoided [103].

Benzodiazepines, when indicated, should be used in the lowest possible dose for the shortest time. In dependent patients, slow weaning is the treatment of choice. Maternal withdrawal can induce seizures and abrupt withdrawal can be fatal [104]. The major problem with benzodiazepines is their widespread use with other drugs, especially opioids. Although diazepam is listed as a pregnancy category D drug, it does not appear to be teratogenic, but is related to neonatal withdrawal and “ oppy infant syndrome” [105]. Lethargy has been observed in breastfed babies [106].

15.8.6 Marijuana; THC

Although marijuana is usually grouped with the hallucinogens, it deserves special attention because it is one of the most commonly used illicit substances [107]. THC is the most common substance found in urine drug screens. In the Wishard data, 40% of patients tested positive for THC at the rst prenatal visit. Fortunately, it is the easiest substance use disorder to treat with 95% of users test- ing negative at delivery.

The active substance in marijuana is delta-9-tetrahydrocannab- inol, commonly abbreviated to THC. It is derived from the plant Cannabis sativa. Its lipophilic structure allows it to accumulate in fatty tissue and remain for days before it is metabolized in the liver. Marijuana is smoked, usually as a cigarette or in water pipes (bongs) or used in small pipes called “one hitters”. Inhalation of marijuana smoke is held in the lungs for long periods and results in higher levels of carboxy hemoglobin [108].

15 Substance Use Disorders

236 15.8 Substances used

Marijuana produces a mild hallucinogenic “high” and affects major organ systems. In high doses it may precipitate psychosis. It increases blood pressure and cardiac output, compromises respi- ratory function, decreases the immune response, and is not the harmless drug it is perceived to be [109]. Low birth weight is the primary fetal effect [110]. Long-term effects have been reported and include de cits in cognitive functioning, attention, analytical skills, and problems with visual integration [111]. Prenatal expo- sure to marijuana has been associated with increased marijuana use by age 14 [112].

Treatment of marijuana substance use is best achieved with cognitive behavioral methods and motivational enhancement. Smoking cessation programs are effective. Most patients respond to simple “coercive therapy”, that is, the patient is informed if the baby tests positive for THC in the meconium, child protective services will investigate. The majority of patients test negative by the second trimester.

15.8.7 Cocaine

Cocaine is a highly addictive lipophilic alkaloid extracted from the plant Erythroxylon coca. It is generally “snorted”, smoked and less frequently injected and is a powerful dopamine, serotonin, and norepinephrine reuptake inhibitor producing a profound “high”. This effect is short lasting and users try to recapture the experience by using more of the substance more frequently. This phenomenon is called “chasing the buzz”. The rapid tolerance that develops is the basis for a rapid addictive process.

Metabolism of cocaine is primarily by plasma and liver ester- ases. In addition, it is hydrolyzed to benzoyl ecgonine, which readily appears in the urine. Meconium drug screens have a high sensitivity for detecting cocaine use [113].

Cocaine use results in intense vasoconstriction and increase in blood pressure. It also is associated with seizures, psychosis, hyperthermia, and cerebrovascular accidents. In addition, the profound cardiovascular response markedly affects uterine blood ow and leads to abruption, low birth weight, and preterm labor [114]. The so-called “crack baby syndrome” propagated in the popular press has not been validated [115]. However, cocaine use in pregnancy has been linked to microcephaly and subtle cogni- tive defects [116].

Pharmacological treatment of cocaine use includes topirimate, an anticonvulsant, and baclofen, a GABA B receptor agonist. Topira- mate raises cerebral GABA levels, facilitates GABA adrenergic neu- rotransmission, and inhibits glutamatergic activity [117]. The clinical

15 Substance use disorders 237

effect is to block the brain reward system. Topiramate is com- monly used in pregnancy with few cases of reported malforma- tions [118]. It would appear that the risk of cocaine use would outweigh the risks of topiramate use in pregnancy

Baclofen appears to act in a similar manner as topiramate in reducing cravings and substance use. However, baclofen is trans- ferred through the placenta and long-term use is associated with a neonatal abstinence syndrome and seizures [119]. Topiramate would appear to be the safer choice for treatment in pregnancy. In the Wishard study, neither of these drugs was used. Treatment was based on cognitive behavioral methods, motivational enhancement, and the “coercive approach”. At delivery, 79% of mothers testing positive for cocaine at the rst prenatal visit were negative. Child protective services were far more aggressive in removing newborns from cocaine addicted mothers than from marijuana users.

15.8.8 Stimulants: amphetamine, methamphetamine; methylphenidate; ephedra; khat

The stimulants act similarly to cocaine with dopamine, serotonin, and norepinephrine release and inhibition of uptake. The effects vary from mild euphoria to profound psychosis and violent behav- ior. They also increase blood pressure, tachycardia, and arrhyth- mias, which may create obstetrical emergencies necessitating cesarean delivery [120]. A profound withdrawal is associated with amphetamines and methamphetamines producing depression, anxiety, fatigue, paranoia, and aggression [121].

Amphetamine and methamphetamine have similar adverse effects on the fetus and neonate. Growth restriction, abruption, preterm labor, and withdrawal symptoms are common [122]. The fetus has a longer elimination half-life than the mother with higher doses remaining in the fetal brain [123]. High doses of methamphetamine in the breast milk have been associated with fatal levels in the infant [124]. Long-term effects of methamphet- amine revealed delays in cognitive skills and growth [125].

Pharmacologic treatment of amphetamine and methamphet- amine is limited in pregnancy with only a few case reports. Ran- domized, placebo-controlled, double-blind trial of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid), for the treatment of methamphetamine dependence revealed limited effects [126]. Another study evaluated gamma vinyl-GABA (GVG, vigabatrin) and demonstrated a good effect on abstinence but has not been tested in pregnancy [127].

Treatment is complicated in women because of reasons for using the amphetamines. Women use it for weight control and report

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238 15.8 Substances used

these substances increase their enjoyment of sex [128]. In addition, they improve concentration and performance and may be used as a way to cope with stress. Thus, cognitive behavioral therapy and motivational enhancement are the mainstays of treatment.

Methylphenidate is pharmacologically similar to amphet- amines. It is used in attention de cit disorders in children and has a high potential for addiction. Acute effects include tachycar- dia, irritability, and hypertension. Methylphenidate is most often obtained by diversion of a child’s prescription, thus causing harm to both parent and child. Effects on the fetus are not well known. Treatment is by gradual weaning and cognitive behavioral therapy and motivational enhancement.

Ephedra is a naturally occurring stimulant used primarily as a weight loss aid. It may cause stroke, heart attacks, and death [129]. There are few data on its use in pregnancy.

Khat is related to amphetamine and is a natural stimulant. It is used primarily in East Africa and the Arabian Peninsula [130]. The leaves are slowly chewed releasing the active substance, cathionine. It may cause low birth weight [131].

15.8.9 Hallicinogens: lysergic acid diethylamide and phencyclidine

Lysergic acid diethylamide (LSD) binds to 5-hydroxytryptamine receptors and causes vivid hallucinations. It is not associated with the onset of dependence and does not cause chromosomal dam- age [132]. The effects on pregnancy are unknown. It does pass into breast milk and should not be used while breastfeeding.

Phencyclidine (PCP) is used as a hallucinogen. It is a dissocia- tive anesthetic and acts as an N-methyl-D-aspartate antagonist at low doses causing methamphetamine-like effects and frequently violent behavior [133]. Newborns of users may present with irri- tability, poor feeding, and hypertonicity. It is readily passed into the breast milk.

15.8.10 Club drugs: MDMA; unitrazepam; gamma-hydroxybuterate; ketamine

Methylenedioxymethamphetamine, MDMA, was patented in Germany in 1912 by E. Merck of Darmstadt. Its history is murky and it is said to have been used as an appetite suppressant. Decades later, it surfaced as “ecstasy”, which often contains more volatile and toxic amphetamine-like substances [134]. Ecstasy produces highly subjective effects of stimulation, feelings of closeness, and hallucinations [135]. The drug does not appear to cause depen- dence. Adverse effects are life threatening. Night clubbers have suffered lethal hyperthermia and fatal hyponatremia secondary to

15 Substance use disorders 239

inappropriate secretion of antidiuretic hormone [136]. The typi- cal side effects are similar to amphetamines. Neurotoxicity has been reported with attendant cognitive impairment [137]. In utero exposure may lead to an increased risk of cardiovascular and skel- etal abnormalities [138].

Most people stop using ecstasy on their own. Since women who use ecstasy in pregnancy also smoke heavily, and use alcohol and other drugs, it is dif cult to determine a causal role for MDMA in newborns.

Gamma-hydroxybuterate (GHB) is a dissociative anesthetic and is used to treat narcolepsy. It is used by “clubbers” for its intoxicating effects, similar to alcohol. It has a short half-life and is often used multiple times in an evening. It has a strong addictive potential and adverse effects include acute intoxication, vomit- ing, and respiratory depression [139]. It carries a withdrawal syn- drome similar to that of benzodiazepines.

Fetal and neonatal effects are not well documented but would be expected to be similar to those of the benzodiazepines. Treat- ment for GHB addiction is similar to alcohol treatment and good success is seen with 12 Step Recovery support.

Flunitrazepam (“roo es”) is a long-acting benzodiazepine and used outside the United States for the treatment of sleep disor- ders. It is implicated as a “date-rape” drug and most often used with alcohol leading to psychomotor impairment and respiratory depression [140]. Maternal and neonatal effects are typical of the benzodiazepines. It does appear in the breast milk.

Ketamine is a dissociative anesthetic. It produces changes in perception, depersonalization, and hallucination and nds it way to clubbers by diversion from legal sources [141]. There are reports of ketamine dependence.

The effects include tachycardia, vomiting, amnesia delirium, and rhabdomyolysis [142]. Although it poses a low risk of overdose, aspiration from vomitus and sedation can be profound. Some evidence suggests it can damage the developing fetal brain [143]. Treatment of ketamine dependence would include detoxi cation, cognitive behavioral therapy, and 12 Step Recovery support.

15.9 Screening and detection

It is not dif cult to improve outcomes in pregnancy. Adequate screening and detection are essential and brief physician inter- ventions are highly effective. The Wishard data from 2002 to 2007 enrolled 274 patients in the Prenatal Recovery Program. At

15 Substance Use Disorders

240 15.10 The role of urine and meconium testing

delivery, 244 tested negative for illicit drugs. In comparison, 42 patients who tested positive for illicit drugs at the rst prenatal visit opted for routine prenatal care. Of those, 23 (55%) tested negative at delivery. These ndings indicate that detection alone motivates many patients to abstain from substance use in pregnancy.

Universal screening means that every obstetrical patient is asked about substance use at the rst prenatal or intake visit, and at least once per trimester thereafter. Thus, there is a clear dis- tinction between urine drug testing and verbal screening. When identi ed and treated:

n The rate of abstinence increases,
n Maternal and fetal complications decrease,
n Less preterm labor,
n Less growth restriction,
n Less abruption,
n Treatment is highly cost effective, and
n Reduction in preterm labor and low birth weight account for

the largest savings [144].
15.10 The role of urine and meconium testing

Both urine and meconium testing can be used to determine the prevalence in a population. In this respect, consent is not required. However, the results of urine drug screens may also carry legal jeopardy and may deter pregnant substance users from attending prenatal care. For example, in Pinellas County, Florida, prenatal urine tests were positive for alcohol or drugs in 16.3% of the medi- cally indigent and in 13.1% in the privately insured. This was not signi cantly different and there were no differences in the types of substance. Florida law, at that time, required physicians to report patients with positive tests to the authorities. Discrepancies in reporting resulted in Black women being 10 times more likely to be reported than White women [145].

Urine tests of 29,494 women presenting for delivery in 202 California hospitals revealed 6.7% tested positive for alcohol and 5.2% tested for illicit drugs [146]. In another study, the prevalence of maternal drug use revealed the problem to be much greater than previously thought. Meconium testing was performed for every other newborn in one year: 3010 subjects were studied and 1333 (44%) were positive for cocaine, morphine, or cannabinoid, while only 335 (11%) mothers admitted to illicit drug use [147]. While meconium testing is more accurate, it is far more costly and not generally used for prevalence studies.

15 Substance use disorders 241

In a comprehensive drug treatment program, urine testing serves a variety of functions. It can track drug use and enhance compliance [148]. It can also serve as a tool for positive reinforce- ment of abstinence. Contingency management is a strategy that rewards patients with negative drug screens with vouchers to use for food, clothes, and sundry items [149]. Voucher-based programs also demonstrate better compliance with prenatal care [150].

Given the high incidence of substance use in pregnancy, urine drug screens are appropriate at the rst prenatal visit, and are especially effective in revealing substance use when coupled with verbal screening [151]. Patients may be offered an “opt out” approach to the UDS:

n Inform patient that a number of routine screening tests are done in pregnancy and include blood tests, diabetes tests, genetic tests, tests for sexual infections, ultrasound, and urine tests for protein, sugar, infection, and drugs.

n Inform patient that she may “opt out” of any test.
n If patient opts out of urine drug screen, inform her that pediatri-

cians may order drug screens after the baby is born.

State laws are very liberal about what constitutes child abuse. A patient who opts out of a urine drug screen creates a reasonable basis to suspect drug use. Thus, pediatricians may legally order urine and meconium tests on the newborn without parental con- sent. The patient must be informed of this if she opts out. When informed and treated in a respectful manner, our experience has been that patients rarely drop out of care.

Obstetrical indications for a urine drug screen include:

n At each prenatal visit for any patient identi ed as a substance user.

n Any history of drug use. n Missing appointments. n Late prenatal care.
n Preterm labor.

n Third trimester bleeding – abruption. n Growth restriction.

The major limiting factor of urine drug screens is that, with few exceptions, they only reveal recent drug use. Table 15.3 indicates how long a particular drug may be detectable in the urine after typical use.

Urine drug screens must be congruent with the drug use in the area. Department of Health and Human Services guidelines for the workplace require testing of amphetamines, cannabinoids, cocaine, opiates, and phencyclidine [153]. In a prenatal treatment

15 Substance Use Disorders

242 15.11 Brief of ce screening strategies Table 15.3 Length of time substance is detectable in urine [152]

Substance

Time

Alcohol Amphetamines Barbiturates

Benzodiazepines Cocaine Marijuana

Opiates Nicotine

24 h

48 h Short acting 48 h

Long acting 7 days 72 h

72 h Single use 72 h

Chronic use 30–40 days Morphine/Heroin 72 h Methadone 96 h
Codeine Up to 10 days

3–5 days from last use

  

clinic, the drugs of choice may be different and preferences vary markedly from region to region.

Urine screens can be quanti ed for speci c drugs and this may be of signi cant value in monitoring behavior (see Table 15.4). Most urine screens only test for the free drug while many drugs are con- jugated. For example, most opioids are conjugated with glucuro- nide in order to be eliminated from the kidney. In addition, urine tests are very sensitive and will almost always bring up metabolites and even trace metabolites. Benzodiazepines break down to many metabolites, which may cause confusion in interpretation.

15.11 Brief of ce screening strategies

Every health care provider has an obligation to screen each of their pregnant and postpartum patients for substance use.

A simple “Two Item Screen” for substance use takes less than a minute and has good sensitivity and speci city. It consists of two questions [154]:

n “In the last year have you ever smoked cigarettes, drunk alco- hol or used any drugs more than you meant to?”

n “Have you felt you wanted or needed to cut down on your smoking or drinking or drug use in the last year?”

15 Substance use disorders 243 Table 15.4 Metabolites of common drugs in urine drug screens

Drug

Major metabolite

Trace metabolite

Negative cut-off in nano- grams; comments

Hydrocodone Oxycodone

Morphine Codeine Heroin

Methadone Buprenorphine Marijuana

Clonazepam

Aprazolam Diazepam

Restoril

Hydrocodone Oxycodone

Hydromorphone Codeine; morphine

6-mono-acety- morphine (6MAM)

Methadone Nor-buprenorphine Carboxy THC

Clonazepam Oxazepam*

Aprazolam; many metabolites

Nordiazepam Oxazepam Temazepam

Temazepan

Hydromorphone Oxymorphone

Hydrocodone

Nor-codeine;

Morphine; codeine

DihydroxyTHC; Hydroxyl THC

Many metabolites

Many metabolites Many metabolites

600 ng

1500–2000 ng; order opiate con rmation to detect levels less than 2000 ng

300 ng
300 ng Metabolized rapidly

300 ng. Requires separate screen

Separate screen; does not cross react

Federal cut-off is 15 ng (accounts for passive inhalation). Cut-off is 50 ng for positive test

3000 ng; not well detected, need separate screen to determine use

75 ng

*Almost all benzodiazepines metabolize to oxazepam.

In this study, two random samples of primary care patients (434 and 702 participants) aged 18 to 59 had the following results:

n “No” to each question: 7.3% chance of a current substance use disorder.

n One yes answer: 36.5% chance.
n Two positive responses had a 72.4% chance.
n Likelihood ratios were 0.27, 1.93, and 8.77, respectively.

Another practical and validated screening approach is the “4Ps Plus” method [155]. In this verbal screen, ve questions are asked:

15 Substance Use Disorders

244 15.11 Brief of ce screening strategies

n “Did either of your PARENTS have a problem with alcohol or drugs?”

n “Do any of your PEERS have a problem with alcohol or drugs?” n “Does your PARTNER have a problem with alcohol or drugs?” n “Have you ever drunk beer, wine or liquor to excess in the PAST?” n (Plus) “Have you smoked any cigarettes, used any alcohol or

any drug at any time in this PREGNANCY?”

The overall reliability for the ve-item measure was 0.62. Sev- enty-four (32.5%) of the women had a positive screen. Sensitivity and speci city were very good, at 87 and 76%, respectively. Positive predictive validity was low (36%), but negative predictive validity was quite high (97%). Of the 31 women who had a positive clinical assessment, 45% were using less than 1 day per week [156].

Numerous screening approaches have been developed for alco- hol use in women.

The T-ACE screening tool is adapted from the classic CAGE questions for alcohol use. It can be used alone or in combina- tion with the 4Ps Plus questions. If there was a positive answer to questions about Past and Current Pregnancy in the 4Ps Plus, then follow up with the T-ACE. A score of 2 or more points indicates at-risk drinking in pregnancy [157]:

n T: Tolerance: “How many drinks does it take you to feel high?” (More than 2 drinks is a positive response – score 2 points)

n A: Annoyed: “Have people annoyed you by criticizing your drinking?” (Yes – score 1 point)

n C: Cut down: “Have you ever felt you ought to cut down on your drinking?” (Yes – score 1 point)

n E: Eye opener: “Have you ever had a drink rst thing in the morning to steady your nerves or get rid of a hangover?” (Yes – score 1 point)

TWEAK is used for alcohol screening in the current pregnancy [158]:

n T: Tolerance: “How many drinks does it take you to feel high?” (More than 2 drinks is a positive response – score 2 points)

n W: Worried: “Have close friends or relatives worried or com- plained about your drinking?” (Yes – score 1 point)

n E: Eye opener: “Have you ever had a drink rst thing in the morning to steady your nerves or get rid of a hangover?” (Yes – score 1 point)

n A: Amnesia: “Has a friend or family member ever told you about things you said or did while drinking that you could not remember?” (Yes – score 1 point)

15 Substance use disorders 245 n K: Cut down: “Have you ever felt you ought to cut down on

your drinking?” (Yes – score 1 point)

With positive answers to the alcohol screens, it is imperative to ask questions about consumption:

n Consumption – “Do you have more than 1 drink a day?”
n Consumption – “Do you have more than 3 drinks per social

occasion?”
n At risk consumption:
n Consumption is >14/drinks/week or >4 drinks per occasion

(men)
n Consumption is >7/drinks/week or >3 drinks per occasion

(women)
n Document the consumption

NOTE: A positive answer to any question on any screen for substance use in pregnancy should trigger a urine drug test. Combined verbal screening and urine testing will yield the best results.

15.12 Brief of ce interventions

When the patient admits to drug use or a screen is positive, a urine drug screen is indicated. Showing the patient the laboratory report of a positive urine drug test is the most effective way to break through the denial that often accompanies substance use. A brief of ce intervention is immediately indicated. Brief of ce interventions have proven to be powerful therapeutic approaches with results comparable to more prolonged therapies [159]. If a patient does not change behavior after a brief intervention, she should be referred.

FRAMES was used in a World Health Organization study to assess brief interventions. The study evaluated heavy male drink- ers from 12 countries with obvious cultural differences in alcohol use. A brief intervention resulted in a decrease in alcohol use of 27%, compared to 7% among controls, still present 9 months after the intervention [160]. FRAMES also works well with other drug use [161].

n F – Feedback about the adverse effects of drugs or alcohol. This allows for patient education.

n R – Responsibility for a change in behavior: “Only you can decide that you want to stop using. If you do, how will your life be better?”

15 Substance Use Disorders

246 15.13 Long-term care and maintenance

n A – Advise to reduce or stop use: “For the next two weeks, stop using, and let’s see how you feel.”

n M – Menu of options: treatment; medications: “If you nd that not using for the next 2 weeks is impossible, then we should consider other options.”

n E – Empathy is central to the intervention. “I know this may be hard to do.”

n S – Self-empowerment: You can change. “I am impressed that you are considering making this change. Your strong determi- nation is going to help you succeed.”

In the FRAMES intervention, feedback follows a speci c for- mula that has universal applications. The interviewer uses four issues to clarify the situation: data, feelings, judgments, and what the interviewer wants to happen. For example, the interviewer would say the following:

n The data in your urine screen was positive for cocaine.
n I’m afraid (feeling) that if you are positive at delivery, CPS will

investigate and may put the baby in foster care.
n My opinion (judgment) is that you can stop using. n I want you to stop using now.

This four-point approach is designed to:

n Clarify the issues.
n Share feelings to enhance empathy in the relationship. n Empower the listener to act.
n Make the listener less likely to resist.

15.13 Long-term care and maintenance

Screening and detection are critical for the treatment of substance use in pregnancy. By identifying the patient, the physician can determine the appropriate path to recovery, which may include detoxi cation, pharmacologic treatment, and maintenance. Short-term interventions are designed to educate the patient and empower her to change her behavior. A number of strategies have evolved to enhance long-term abstinence or maintenance.

Motivational Enhancement Therapy (MET) is the foundation for supporting the substance user as she moves through the stages of recovery. Developed by Miller, its premise is that the respon- sibility for change rests squarely on the shoulders of the patient [162]. The approach is easy to learn and apply in prenatal care. Basic interviewing skills include the ability to express empathy,

15 Substance use disorders 247

to roll with the resistance, and to empower the patient to move through the changes occurring in her life. This approach has improved maternal and neonatal outcome in pregnancy [163].

Integrating MET with the Stages of Change approach, devel- oped by Prochaska, creates a powerful therapeutic alliance lead- ing to maintenance of recovery [164]. Prochaska describes six stages of change and it measures progress over time. The goal is to motivate the patient to move from one stage to the next, only when the patient is ready to move forward [165]. Psycho- social support for the recovering addict is critical in maintaining abstinence and preventing relapse. They also improve retention in prenatal care and substance treatment programs [166].

Conclusion

The identi cation and treatment of substance use in pregnancy is most challenging. It requires a thorough evidence-based com- mand of the pharmacologic effects of a plethora of drugs on the mother, fetus, and neonate. Most important is the ability of the physician to form a close and supportive therapeutic relationship with the patient. This relationship has a tremendous potential to convert a patient’s lifestyle into a positive and healthy life. More- over, it can in uence the well-being of her children and future generations.

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Diabetes in Pregnancy

Maisa N. Feghali, Rita W. Driggers, Menachem Miodovnik and Jason G. Umans

16

. 16.1  Introduction 257

. 16.2  Epidemiology 258

. 16.3  Classi cation 258

. 16.4  Gestational diabetes 259

. 16.5  Diabetes management in pregnancy 260

Conclusion 268

16.1 Introduction

Pregnancy imposes unique metabolic demands to provide sustained and suf cient transfer of nutrients to the growing fetus during fasting periods by ensuring adequate nutrient storage during feed- ing. Hormones produced by the feto-placental unit play a pivotal role in adjusting metabolic features to bene t both mother and fetus. However, in pregnancies complicated by diabetes mellitus (DM), its metabolic consequences for both mother and fetus can be exacerbated by the otherwise-adaptive effects of pregnancy per se [1]. The effect of DM on the fetus is determined by two factors: the intrauterine environment provided by the mother and the fetal response to it. Tight glycemic control with exogenous insu- lins led to markedly improved maternal and perinatal outcomes; more recently, oral hypoglycemics have similarly improved out- comes in women with gestational DM (GDM). Recent evidence

258 16.3 Classi cation

that directly relates even mild maternal hyperglycemia with poor perinatal outcomes highlights the importance of maternal treat- ment [2]. This chapter reviews the clinical diagnosis and effects of diabetic pregnancy with a focus on therapeutics.

16.2 Epidemiology

Pregestational DM complicates approximately 1.3% of pregnan- cies; with increasing prevalence, due principally to type 2 diabetes [3], associated with obesity and with increasing maternal age [3]. As well, new guidelines will further increase the recognition of GDM and pregestational DM by using lower glycemic thresholds (GDM: fasting ≥ 92mg/dL or 1-hour postprandial ≥180mg/dL or 2-hour postprandial ≥ 153mg/dL; Type 2 (pregestational) DM: fasting ≥126mg/dL or random glucose ≥200mg/dL or HbA1c ≥6.5%) [4]. The incidence of GDM is even greater, complicating approximately 5 to 10% of pregnancies [5] with higher rates in younger, obese women [6].

16.3 Classi cation

Outside of pregnancy, diabetes is classi ed according to its patho- physiology [7]. Broadly, type 1 DM is due to absolute insulin lack, most commonly due to immune destruction of β-cells, while type 2 DM is characterized by progressive insulin resistance, which leads initially to compensatory hyperinsulinemia, and then to defective insulin secretion as well. While treatment of type 1 DM requires insulin replacement, many type 2 DM patients will also be treated with insulin as adjunctive or primary therapy; thus, the terms insulin dependent [8] and non-insulin dependent DM [8] should no longer be used. During pregnancy, women can be cate- gorized as those who were known to have DM prior to pregnancy – pregestational or overt – and those diagnosed during pregnancy – gestational. As noted brie y above, some women who have been classi ed as having GDM must actually have had pregestational DM that had not come to clinical recognition before the more attentive medical evaluation that accompanies antenatal care; evolving de nitions will reclassify these women accordingly. The American Congress of Obstetrics and Gynecology [9] has recently shifted toward a focus on differentiating between gestational and pregestational DM, as advocated by the Expert Committee on the

16 Diabetes in pregnancy 259

Diagnosis and Classi cation of Diabetes [7] and away from the White classi cation [10], which focused on classifying women by the type and severity of diabetic target organ damage.

Pregnancy is associated with resistance to the glucose-lowering effects of insulin resulting in relative postprandial hyperglycemia. It is thought that the endocrine effects of the feto-placental unit play an important role in the development of insulin resistance during pregnancy [11, 12]. In fact, pregnant women experience less hypoglycemia in response to exogenous insulin but more fast- ing hypoglycemia than non-pregnant women [13], and normal pregnant women have exaggerated insulin responses to glucose ingestion compared to non-pregnant women [14]. It is estimated that in healthy pregnant women insulin sensitivity decreases by 40–56% during the third trimester [15].

To compensate, pregnancy is characterized by an adaptive increase in pancreatic β-cell function [16] that also leads to mater- nalpancreatichypertrophyandhyperplasia[17].GDMresultswhen insulin resistance exceeds the capacity to increase insulin secretion.

The absolute or relative insulin de ciency which characterizes type 1 and type 2 DM, respectively, precludes normal pancre- atic β-cell compensation during pregnancy, resulting in maternal hyperglycemia suf cient to impact fetal development unless ade- quate exogenous insulin is provided. Although patients with type 1 DM usually have normal insulin sensitivity when non-pregnant, the insulin resistance of pregnancy leads to a substantial (1.5- to 3-fold) increase in their insulin requirements [18]. Patients with type 2 DM have striking pregestational insulin resistance, lead- ing to insulin requirements higher than women with type 1 DM [19]. Insulin requirements increase throughout gestation, paral- leling the rise in insulin resistance; following delivery, they are decreased markedly [18].

16.4 Gestational diabetes

GDM may be mild or may present with more severe hypergly- cemia that suggests previously unrecognized overt DM. Women with GDM but without fasting hyperglycemia usually revert to euglycemia following delivery. However, they carry an ~50% risk of developing DM [20] during the rst 5 to 10 years following an affected pregnancy [21, 22]. Women with GDM appear to have underlying (though unrecognized) insulin resistance that is exac- erbated by the additive insulin resistance due to pregnancy [23]. The origin of the underlying insulin resistance has been linked,

16 Diabetes in Pregnancy

260 16.5 Diabetes management in pregnancy

in some women with GDM, to abnormal glucose transport- ers in adipocytes [24], or to polymorphisms in the region of the insulin receptor and the insulin-like growth factor 2 genes [25]; surely other speci c predisposing molecular mechanisms will be discovered. Obesity further increases insulin resistance in many women whose pregnancies are complicated by GDM [26]. Since both insulin resistance and impaired compensatory β-cell func- tion are usually required to manifest either type 2 DM or GDM, it is not surprising that maternal hyperglycemia is associated with insuf cient insulin secretion in gestational diabetics [27].

16.5 Diabetes management in pregnancy 16.5.1 Nutritional goals and exercise

Lifestyle modi cations, including both diet and exercise, remain the rst-line therapy for newly diagnosed GDM. All pregnant women with diabetes should follow a carbohydrate-restricted diet based on their ideal pre-pregnancy body weights. A diet restricted to 2000–2400kcal/day with 35% of calories from complex and high- ber carbohydrates has been shown to delay the need for hypoglycemic therapy with insulin [28, 41]. Unless otherwise con- traindicated, diet should be combined with regular exercise, such as walking 1–2 miles three times a week. A major concern is that a 2-week trial of lifestyle intervention may delay glycemic control and increase fetal risk; therefore close monitoring to enable rapid initiation of drug therapy for persisting hyperglycemia is essential.

16.5.2 Glucose monitoring and glycemic control

Monitoring of capillary blood glucose 4–6 times/day, including fasting, preprandial, and postprandial values, is central to tight management of DM during pregnancy. Treatment goals for blood glucose control are: fasting 90–99 mg/dL, 1 h postprandial <140 mg/ dL, and 2 h postprandial <120–127 mg/dL [5]. Women treated only with lifestyle modi cations or with stable and optimal glycemic control can monitor less frequently (2–4 times/day). HbA1c can aid in assessing the risk of congenital anomalies in overt diabe- tes if measured in the rst trimester while repeated measures each trimester may aid in assessment of longer-term glycemic control. In 2011 the American Diabetes Association recommended that women with HbA1c ≥6.5% be diagnosed with type 2 DM rather than GDM [29]. In euglycemic women, intermediate (5.3–6%) and high (>6%) HbA1c during the rst trimester are associated with

16 Diabetes in pregnancy 261

higher GDM risk later in pregnancy. Studies have determined that HbA1c >6% during early pregnancy is associated with increased odds of insulin use for the treatment of GDM independent of oral glucose tolerance test (OGTT) results and gestational age at the time of GDM diagnosis [30]. These results suggest that HbA1c may be used to identify women in early pregnancy who are at high risk for GDM and who develop the poorer glycemic control. The association of HbA1c and birth weight is strongest when it is mea- sured after GDM diagnosis compared to at the time of diagnosis [31, 32]. The later measurement may be a more accurate re ection of poor glycemic control during the third trimester. Tight glycemic control is essential to improve outcomes in all women, whether with severe DM, mild DM or GDM [33, 34]. Despite the variety of effective therapies for DM during pregnancy, treatment barri- ers persist. There are particular challenges to instituting insulin therapy in pregnant women with DM, in that it is important to control hyperglycemia quickly, yet opportunities for patient edu- cation and insulin titration are limited. Further, many women are reluctant to administer multiple insulin injections daily, resulting in limited adherence to treatment with poor glucose control. In addi- tion, treatment-associated hypoglycemia often limits the ability to achieve tight glucose control. Oral hypoglycemics have gained only limited popularity in clinical practice, due in part to inadequate glucose control in a signi cant fraction of women with GDM. Poor control may be due, in many cases, to irrationally slow dose titra- tion. For example, while glyburide dose is most commonly adjusted weekly, pharmacokinetic data in pregnancy suggest that its t{1/2} is decreased; steady state is therefore achieved faster and dose titra- tions should occur nearly daily if optimal glycemic control and reduction of morbidity is desired. The next section will review the pharmacology of treatment options for diabetes during pregnancy.

16.5.3 Insulin therapy

Exogenous insulin therapy attempts to use glucose monitoring- guided dose adjustment of long and short acting insulin analogs to mimic the normal pro le of insulin in response to diet and meta- bolic demands in order to maintain euglycemia. Insulin therapy is currently recommended for nearly all women with pregestational diabetes during pregnancy and for women with GDM who fail to achieve glycemic control with diet and oral hypoglycemic therapy. Insulin therapy will usually require separate insulin analogs and dosing strategies to mimic the normal basal secretion of insulin as well as the rapid and transient β-cell response to meals. In most women, essentially all nutrients are absorbed within 90min after

16 Diabetes in Pregnancy

262 16.5 Diabetes management in pregnancy

a meal and both plasma glucose and insulin return to pre-meal values within 2 h [10]. Endogenous insulin is secreted largely from the pancreas into the portal circulation with hepatic extraction of ~50% [35]. Insulin concentrations in the portal vein exceed those in arterial plasma by approximately three-fold. In healthy adults, the rate of basal insulin secretion into the portal system is ~1 unit/h. With the intake of food, the rate increases by 5–10-fold [35]. Insulin acts in the liver by prompt and ef cient inhibition of glycogenolysis [35], beginning within minutes and reaching full effect within hours [36]. Secondarily and subsequently, insu- lin inhibits hepatic gluconeogenesis, principally by decreasing release and transport of free fatty acids and precursors from fat and skeletal muscle to the liver. The effect on gluconeogenesis is usually delayed and requires more insulin than the effect on glycogenolysis, due to its peripheral sites of action [35, 37].

Insulin metabolism is, itself, altered during pregnancy, with 24 and 30% reductions in hepatic insulin extraction noted in women with type 1 DM and GDM, respectively, perhaps due to changes in hepatic blood ow [38, 39]. Placental perfusion studies show that only 1–5% of maternal insulin is transferred into fetal circula- tion, likely due to its molecular weight of ~5800Da [40]. Mater- nal insulin–antibody complexes facilitate placental transfer of insulin. Since the risk of fetal macrosomia has been linked to high levels of insulin in cord blood and amniotic uid [41], strategies to minimize maternal anti-insulin antibody production may improve fetal morbidity. Use of human insulins minimizes but may not eliminate anti-insulin antibodies [42].

Regular human insulin needs to be administered 30–45 min- utes prior to meals to control postprandial hyperglycemia, though its peak effect occurs 2–4h after injection, likely due to delayed absorption and leading, in some cases to inadequate control fol- lowed by late postprandial hypoglycemia. The delayed absorption may be due to formation of insulin molecular clusters (hexam- ers) that dissociate slowly, limiting the rate of absorption of active insulin from the subcutaneous space into the systemic circulation [43]. The inconvenience associated with injecting human insu- lin half an hour prior to a meal often leads to poor compliance and suboptimal glycemic control [44]. These limitations of regular insulin led to the development of analogs with improved charac- teristics, including short acting (SA) insulins with faster onset and clearance of long acting (LA) insulins with delayed and prolonged distribution resulting in low sustained levels. The different types of insulin used currently in pregnancy are listed in Table 16.1.

Short acting (SA) analogs attempt to mimic the rapid onset and disappearance of endogenous insulin around a meal. Lispro and

16 Diabetes in pregnancy 263 Table 16.1 Insulin analogs and pharmacokinetics

Type

Onset of action

Peak of action (hours)

Duration of action (hours)

Humalog (lispro) Novolog (aspart) Regular insulin Humulin N (NPH) Lantus (glargine) Levemir (detemir)

1–15 minutes 1 2 1–15 minutes 1 2 30–60 minutes 2 4
1–3 hours 8 8
1 hour No peak <24 3–4 hours No peak 12–24 hours

(dose dependent)

Aspart form hexamers that dissociate more rapidly so they can be administered immediately before or up to 15 minutes after start- ing meals. Their effect peaks after 1–2h with peak concentrations twice that of regular insulin [45]. Severe hypoglycemic episodes are less common with SA insulins. Circulating levels of SA insulins mirror the rise and fall in serum glucose following an oral load, leading both to better control of postprandial glucose excursion and to fewer episodes of late postprandial hypoglycemia.

Longer acting agents are needed to complement SA agents in order to mimic basal pancreatic insulin secretion, and maintain eug- lycemia without hypoglycemic episodes between meals and over- night. NPH (Neutral Protamine Hagedorn), an intermediate acting insulin, is usually administered twice daily in pregnancy to provide 24 h glycemic control in concert with prandial SA insulin. However, recent data from studies of two LA insulin analogs, glargine and detemir, may alter practice [36, 46]. The LA agents contain stabi- lized hexamers that dissociate slowly, resulting in a stable monoto- nous basal pro le decreasing the risk of fasting hypoglycemia. LA agents are associated with decreased fasting glucose, HbA1c, and nocturnal hypoglycemia [47]. When compared to NPH insulin, LA agents had similar or lower rates of maternal microvascular morbid- ity, macrosomia, and neonatal hypoglycemia [48–50]. Recent pla- cental perfusion studies using glargine and detemir demonstrated negligible placental transfer and animal studies showed rates of teratogenicity and embryotoxicity similar to human insulin [51, 52].

Besides in uencing glucose metabolism, insulin acts to alter cellular proliferation, differentiation, and cell apoptosis. At higher concentrations it promotes growth and proliferation via activation of receptors for insulin-like growth factor type I (IGF-I) [53]. Structural changes in the design of insulin analogs appear to alter its af nity

16 Diabetes in Pregnancy

264 16.5 Diabetes management in pregnancy

for IGF-1 receptors [54]. Indeed, glargine has a 6–8-fold increased af nity for IGF-1 receptors when compared to insulin in an osteo- sarcoma cell line [54]. Lispro has also been shown to have some increase in IGF-1 binding [55]. This interaction could potentially lead to increased fetal growth and other mitogenic effects, though there are no in vivo or clinical data to support these concerns. IGF-1 binding appears not to be increased for other insulin analogs.

Insulin pumps deliver insulin in a pattern that closely resembles physiologic insulin secretion and may be used safely in pregnancy. Studies have described similar safety and ef ciency as multiple injec- tion therapy with use during pregnancy [56]. A short acting insulin (either regular or lispro) is used, with 50–60% of the total daily dose (which may be calculated as described in Table 16.2) given as the basal rate and the remaining 40–50% given as pre-meal/snack boluses. Insulin pump therapy requires high patient compliance and the ability to calculate insulin requirement throughout the day.

Insulin requirements vary across trimesters and are illustrated in Table 16.2. Early in pregnancy (9–13 weeks), a decrease in insulin may be needed to adjust for decreased oral intake and vomiting. After 14 weeks of gestation, insulin requirements increase steadily (Table 16.2). Maternal obesity increases the insulin requirement by 0.1 to 0.2units/kg. Figure 16.1 illustrates a suggested protocol for insulin dosing during pregnancy and Figure 16.2 a protocol for insulin adjustment.

16.5.4 Oral hypoglycemics

Oral agents are rst-line therapy for type 2 DM outside of pregnancy [57]. They are indicated during pregnancy when diet and exercise fail to achieve treatment goals and are favored over insulin in cases with mild hyperglycemia because of quicker patient learning, lower risk for hypoglycemia, and higher compliance. In addition, since both defec- tive β-cell insulin secretion and insulin resistance are characteristics

Table 16.2 Daily insulin dose across trimesters

1–18 0.7 18–26 0.8 26–36 0.9 36–40 1 0–6 (postpartum) 0.4

Gestational period (weeks)

Total daily dose (units/kg*)

 

*Based on actual weight.

16 Diabetes in pregnancy 265

not only of type 2 DM but of GDM as well, oral agents targeting either of these pathophysiologies may bene t gravidas with DM.

Glyburide, a third generation sulfonylurea oral hypoglycemic agent, acts primarily through speci c receptors on the β-cell sur- face. Drug-receptor binding acts to close adenosine triphosphate- dependent potassium channels, resulting in cellular depolarization, calcium in ux, and translocation of insulin secretory granules to the β-cell surface. The resulting release of insulin into the portal vein rapidly suppresses hepatic glucose production and later facili- tates peripheral glucose use [58, 59]. Insulin resistance commonly diminishes as a secondary result of the reversal of hyperglycemia

Figure 16.1 Insulin protocol during pregnancy. FBS: fasting ngerstick glucose; 2hrPP: 2 h postprandial ngerstick glucose.

16 Diabetes in Pregnancy

266 16.5 Diabetes management in pregnancy

 

Figure 16.2 Insulin adjustment protocol.

[59, 60]. Because sulfonylureas rely on a preserved β-cell response, they are ineffective in patients with absent or severely diminished β-cell function, as in type 1 DM or advanced type 2 DM. Sulfonyl- ureas increase insulin secretion in direct proportion to plasma glu- cose levels from 60 to 180mg/dL, with no effect if glucose is less that 60 mg/dL [61, 62]. Despite these data, sulfonylureas, including glyburide, can still lead to symptomatic and severe hypoglycemia, most commonly in the setting of unrecognized renal insuf ciency. There is then a minimal lag time between the changes in plasma glucose and the change in insulin secretion rate [63, 64]. When given as a single agent, peak plasma glyburide concentrations are achieved within 4h and absorption is not affected by food. Its elimination t{1/2} is approximately 10h in non-pregnant adults and shorter in pregnancy due to increased clearance. While many practitioners remain concerned that glyburide could lead to neo- natal hypoglycemia, data do not support this concern [65].

A recent pharmacokinetic–pharmacodynamic (PK–PD) [66] study of glyburide in 40 women with GDM receiving glybu- ride monotherapy, and controlled for fasting glucose concentra- tion <95mg/dL, described 50% lower dose-adjusted plasma drug concentrations in pregnancy, likely due to an increase in hepatic metabolism [67]. One might expect, therefore, that dose increases, perhaps beyond those in non-pregnant labeling might overcome increased glyburide clearance, resulting in better glycemic control. However, the glyburide dose–response relationship is uncertain

16 Diabetes in pregnancy 267

and a ceiling effect may limit bene ts due to higher doses. Indeed, studies in non-pregnant patients with type 2 DM suggest little incre- mental bene t following increased doses [68, 69]. While glyburide normalized insulin secretion in women with GDM following a mixed meal in the glyburide PK–PD study, this was inadequate to compensate fully for their insulin resistance, manifest as imperfect control of postprandial hyperglycemia in those women [67]. A prior study had similarly demonstrated the challenges due to insu- lin resistance in women with GDM during insulin infusion [70]. Taken together, these results suggest that although some women with GDM may bene t from more aggressive glyburide dose titra- tion, treatment in others may be improved by the use of additional or alternative agents to improve insulin resistance.

Studies of glyburide in pregnancy describe glycemic control and pregnancy outcomes similar to those of insulin in eligible women when dosing was adjusted frequently [52, 71], starting at 2.5mg in the morning titrating to a maximum dose, based on non-pregnant package labeling, of 10mg twice a day [71]. However, almost 20% of women with GDM treated with glyburide will eventually require insulin therapy; granted this may have been due to poor dose titra- tion and switching to insulin prior to reaching maximal doses [72].

There are accepted guidelines for fasting and postprandial glucose levels in pregnancy that are associated with a decrease in neonatal morbidity [73]. However, these glycemic targets are not purely based on normalization of diabetic physiology. The discrepancy between physiology and outcome may be explained by recent data demonstrating a continuous relationship between maternal glycemic levels and neonatal outcomes [2].

It remains unclear whether the bene ts of tighter glycemic con- trol in women with GDM exceed those due to potential hypogly- cemia. Still, primary or combined therapy with agents that target insulin resistance may be especially useful in improved glycemic control in GDM.

Metformin is primarily an insulin sensitizer that reduces hepatic glucose production by suppressing gluconeogenesis [74, 75]. It may also augment peripheral glucose uptake, though this may be sec- ondary to reversal of hyperglycemia. Since it does not increase insu- lin secretion, the risk for hypoglycemia is minimal. Peak metformin plasma concentrations are achieved within 4h of oral administra- tion and administration with meals decreases drug-induced gastro- intestinal discomfort, though it decreases absorption. Metfomin’s elimination t{1/2} in non-pregnant adults is approximately 6h. Its renal clearance increases signi cantly in mid- and late gestation, in parallel with gestational increases in creatinine clearance [76]. Metformin crosses the placenta, resulting in variable fetal drug

16 Diabetes in Pregnancy

268 Conclusion

levels [76]. A study assessing 126 infants at age 18 months born to 109 mothers who conceived and continued metformin during preg- nancy found similar size and motor-social development in infants exposed to metformin compared to a non-exposed group [77].

Studies comparing metformin to insulin or glyburide describe lower rates of achieving euglycemia with metformin [78, 79]. Yet, once euglycemia was achieved, neonatal outcomes were similar to those in subjects receiving glyburide [78]. The higher rates of failure in women receiving metformin may have been due to inadequate dose adjustment to account for increased renal and total body drug clearance drug during pregnancy [76]. Metformin and insulin treat- ment each resulted in similar rates of perinatal morbidity, includ- ing metabolic abnormalities, premature birth, and birth trauma in a recent randomized trial for the treatment of GDM unresponsive to lifestyle interventions between 28 and 32 weeks’ gestation [79]. The starting dose was 500 mg once or twice daily with dose titration every 1 to 2 weeks to meet glycemic targets [79]. Women receiving both metformin and insulin had lower insulin requirements and gained less weight during pregnancy and during postpartum follow- up than those receiving insulin only [79]. In study subjects, met- formin was highly accepted and preferred over insulin [79]. These ndings highlight the potential bene ts of combination therapy with metformin, either with glyburide or insulin, and suggest that outcomes could be improved with more aggressive dose titration.

16.5.5 Postpartum metabolic management

Insulin requirements decrease immediately after delivery, when women with overt diabetes can either have their insulin dose empirically decreased by 50% or be returned to their pre-pregnancy hypoglycemic regimen. Women with GDM should be reminded about their increased risk for diabetes and the need for screening by OGTT starting at 6 to 8 weeks after delivery. Breastfeeding may improve maternal glucose levels [80]. Despite observations that support the use of combination hormonal contraceptives in women with diabetes, the American Congress of Obstetricians and Gynecologists (ACOG) recommends that their use be limited to nonsmoking, healthy women with diabetes who are younger than 35 years with no evidence of hypertension, nephropathy, reti- nopathy, or other vascular disease [9].

Conclusion

The number of pregnancies complicated by DM is increasing. Yet, the current screening and diagnostic strategies are not well aligned

16 Diabetes in pregnancy 269

with birth complications. New evidence suggests that tighter gly- cemic criteria may improve neonatal outcomes but would result in a higher rate of GDM diagnoses. The current treatment strat- egies for DM during pregnancy are limited and have not been adjusted to account for pregnancy-induced metabolic changes. Further research is needed to investigate alternative therapies and develop pregnancy-speci c treatment strategies.

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[41] Carpenter MW, Canick JA, Hogan JW, Shellum C, Somers M, Star JA. Amniotic uid insulin at 14–20 weeks’ gestation: association with later maternal glucose intolerance and birth macrosomia. Diabetes Care 2001;24:1259–63.

[42] Balsells M, Corcoy R, Mauricio D, Morales J, Garcia-Patterson A, Carreras G, et al. Insulin antibody response to a short course of human insulin therapy in women with gestational diabetes. Diabetes Care 1997;20:1172–5.

[43] Mosekilde E, Jensen KS, Binder C, Pramming S, Thorsteinsson B. Modeling absorption kinetics of subcutaneous injected soluble insulin. J Pharmacokinet Biopharm 1989;17:67–87.

[44] Zinman B. The physiologic replacement of insulin. An elusive goal. N Engl J Med 1989;321:363–70.

[45] Torlone E, Fanelli C, Rambotti AM, Kassi G, Modarelli F, Di Vincenzo A, et al. Pharmacokinetics, pharmacodynamics and glucose counterregulation follow- ing subcutaneous injection of the monomeric insulin analogue [Lys(B28), Pro(B29)] in IDDM. Diabetologia 1994;37:713–20.

[46] Price N, Bartlett C, Gillmer M. Use of insulin glargine during pregnancy: a case–control pilot study. BJOG 2007;114:453–7.

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. [48]  Negrato CA, Rafacho A, Negrato G, Teixeira MF, Araujo CA, Vieira L, et al. Glargine vs. NPH insulin therapy in pregnancies complicated by diabetes: an observational cohort study. Diabetes Res Clin Pract 2010;89:46–51.

. [49]  Fang YM, MacKeen D, Egan JF, Zelop CM. Insulin glargine compared with Neutral Protamine Hagedorn insulin in the treatment of pregnant diabetics. J Matern Fetal Neonatal Med 2009;22:249–53.

. [50]  Di Cianni G, Torlone E, Lencioni C, Bonomo M, Di Benedetto A, Napoli A, et al. Perinatal outcomes associated with the use of glargine during pregnancy. Diabet Med 2008;25:993–6.

. [51]  Kovo M, Wainstein J, Matas Z, Haroutiunian S, Hoffman A, Golan A. Pla- cental transfer of the insulin analog glargine in the ex vivo perfused placental cotyledon model. Endocr Res 2011;36:19–24.

. [52]  Torlone E, Di Cianni G, Mannino D, Lapolla A. Insulin analogs and preg- nancy: an update. Acta Diabetol 2009;46:163–72.

. [53]  Zelobowska K, Gumprecht J, Grzeszczak W. Mitogenic potency of insulin glargine. Endokrynol Pol 2009;60:34–9.

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[70] Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glu- cose metabolism during pregnancy in obese women with normal glucose toler- ance and gestational diabetes mellitus. Am J Obstet Gynecol 1999;180:903–16.

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16 Diabetes in Pregnancy

17 Thomas R. Easterling

Cardiovascular Medications in Pregnancy

. 17.1  Introduction 275

. 17.2  Cardiovascular changes in pregnancy 277

. 17.3  Cardiovascular diseases in pregnancy 279

. 17.4  Pharmacodynamics of hemodynamically active drugs in pregnancy 281

. 17.5  Fetal pharmacodynamic response to hemodynamically active
drugs 284

. 17.6  Direct fetal effects of hemodynamically active drugs 286

. 17.7  Pharmacokinetic changes in hemodynamically active drugs in pregnancy 287

Key points 291

17.1 Introduction

Women with known and unknown cardiovascular disease may experience destabilization in their condition due to physiological adaptations to pregnancy. In becoming pregnant, women accept a burden of risk to their life and health. For healthy women in the developed world, these risks are modest where maternal mortality ranges from 10 to 20 per 100,000 live births. In some parts of the developing world such as Haiti, Afghanistan, and Somalia, the lifetime risk of dying in pregnancy ranges from 1:10 to 1:20 due to high maternal mortality rates and high

276 17.1 Introduction

rates of parity. Medical complications such a severe pulmonary hypertension and advanced Marfan’s syndrome may confer a risk of death as high as 1:10. The maternal risk of hyperten- sive disease is most commonly managed by delivery of the fetus. When delivery is preterm, the burden of disease risk is trans- ferred to the neonate. By carrying a pregnancy, an individual woman af rms the inherent value of that pregnancy in her life that serves to balance the risks that she encounters in carrying the pregnancy.

Appropriate pharmacological management of maternal com- plications serves to reestablish the physiological homeostasis of a normal pregnancy with the goal of improving maternal and neonatal outcomes. Treatment is frequently associated with perceived and occasionally real risk to the fetus for the advan- tage of the mother. Errors of omission are frequently made due to perceived risk or due to a failure to balance risk. Just as maternal bene t is usually dose dependent, risks to the fetus are often dose dependent rather than absolute. Drugs with car- diovascular activity operate in a physiological environment that is altered in pregnancy. These changes are dynamic over the course of pregnancy with different trajectories depending on the point in gestation. The pharmacodynamic effect of drugs in pregnancy operates in the context of these changes and with potential impact on utero-placental perfusion impacting fetal well-being. Metabolic pathways of drug clearance and trans- port operate to limit our exposure to xenobiotics. Many of these mechanisms are signi cantly upregulated in pregnancy presumably limiting fetal exposure. In some cases, the placenta itself will operate through these mechanisms to further limit fetal exposure. After birth, neonates can potentially be exposed to maternal medications through breast milk. Appropriate pharmacological care of pregnant women with cardiovascular conditions requires an understanding of the physiological envi- ronment of pregnancy and the impact of these changes on dis- ease states; an understanding of the pharmacodynamic impact of drugs on this environment and the fetal environment; and an understanding of changes in the pharmacokinetics of drugs in pregnancy. The intent of this chapter is to offer a framework of understanding about the impact of cardiovascular medications in pregnancy. In some limited cases, there are clear data regard- ing speci c drugs to effectively inform the clinician. In many cases, however, drug-speci c data are lacking. In these cases, a framework of pharmacodynamic and pharmacokinetic effects is developed to offer clinical guidance and a basis for ongoing investigation.

17 Cardiovascular medications in pregnancy 277 17.2 Cardiovascular changes in pregnancy

Pharmacological treatment of women with cardiovascular disease will usually involve drugs that are hemodynamically active impact- ing the relationship between mean arterial pressure (MAP), car- diac output (CO), and total peripheral resistance (TPR) described by: MAP = (CO • TPR)/80. MAP is calculated from diastolic blood pressure (dBP) and systolic blood pressure (sBP): MAP= (2dBP+sBP)/3. Cardiac output is the product of stroke volume (SV) and heart rate (HR): CO=SV•HR.

Pregnancy is associated with dramatic, usually predictable, changes in maternal hemodynamics [1]. These are described in Figure 17.1. Early in the rst trimester, TPR falls which is associ- ated with a decrease in MAP and an increase in CO. As pregnancy advances CO continues to rise due to volume loading re ected in an increase in SV and an increasing HR. Near term, CO is main- tained increasingly due to an increased HR. Throughout most of pregnancy, a reduction in blood pressure is maintained despite an elevated CO by a proportionately larger reduction in TPR. Near term, BP rises to near non-pregnant levels due to an increase in TPR. These hemodynamic changes are described graphically in Figure 17.2 where CO is displayed on the x-axis and MAP on the y-axis. Isometric lines of vascular resistance allow all three vari- ables to be simultaneously displayed. Hemodynamic changes that are due to changes in TPR result in vectors of change perpen- dicular to isometric lines. Those due to changes in CO result in vectors parallel to isometric lines. In early pregnancy, hemody- namic changes are characterized by a line perpendicular to lines of resistance followed by a vector parallel to lines of resistance through mid-pregnancy and then followed by a vector perpendic- ular but due to rising TPR. Data from nulliparus women who sub- sequently developed preeclampsia result in a similar “ shhook” pattern which starts with higher MAP and CO [1]. With advanc- ing preeclampsia, these women experience a dramatic increase in resistance with worsening hypertension [2].

During labor CO is increased due to elevated HR due to dis- comfort and due to increased SV due to volume loading associ- ated with centralization of uterine blood volume due to uterine contractions [3]. Postpartum, pregnant women volume load as they mobilize extravascular volume; they remain tachycardic; TPR rises returning to non-pregnant norms [4]. These hemo- dynamic changes represent a “perfect storm” for women with vulnerable conditions such as mitral stenosis, cardiomyopathy, and pulmonary hypertension [5]. Compounding these hemody- namic changes, the normal hemodilution of pregnancy results in

17 Cardiovascular Medications in Pregnancy

278 17.2 Cardiovascular changes in pregnancy

95 80 86 80 75 70 65

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Figure 17.1 Cardiac output, mean arterial pressure, total peripheral resistance, stroke volume and heart rate derived from serial measurements in normotensive nulliparous pregnancies: mean ± sd.

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17 Cardiovascular medications in pregnancy 279

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Figure 17.2 Cardiac output vs. mean arterial pressure with total peripheral resistance represented by diagonal isometric lines. Hemodynamic changes in normotensive pregnancy are represented by a “ shhook” shaped curve lower and to the left of a second curve that describes hemodynamic changes in preeclamptic pregnancies.

reduced serum albumen concentration, reduced colloid osmotic pressure and an increased tendency towards pulmonary edema [6]. Pharmacological management of pregnant women with hemodynamically active medications requires an understand- ing of these fundamental cardiovascular changes and the tim- ing of these changes in pregnancy integrated into the desired pharmacodynamic effect.

17.3 Cardiovascular diseases in pregnancy

Hypertension is the most common cardiovascular complication in pregnancy. The spectrum of disease ranges from women with a preexisting diagnosis of chronic hypertension to preeclampsia de ned by new onset hypertension or acutely worsening chronic hypertension accompanied by proteinuria. Preeclampsia can be a life-threatening condition contributing to signi cant maternal mortality in the developing world. It can result in a broad spec- trum of maternal end-organ diseases including seizures, cerebral edema, cerebral hemorrhage, renal failure, elevated liver function

TPR 1200

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17 Cardiovascular Medications in Pregnancy

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280 17.3 Cardiovascular diseases in pregnancy

tests, hepatic rupture, hemolysis, thrombocytopenia, heart failure, and pulmonary edema. De nitive treatment requires delivery of the fetus which, when preterm, may result in signi cant neonatal morbidity and mortality. The risk of maternal seizures is substan- tially reduced by treatment with magnesium sulfate [7].

The threshold and timing for treatment of blood pressure in pregnancy remains controversial. Clearly, blood pressures above 160–170/105–110 should be treated to avoid acute cerebrovascu- lar complications. Earlier, more aggressive initiation of pharmaco- logical management decreases the risk of hypertensive crisis, but may also result in a slowing of fetal growth [8]. Early and aggres- sive treatment of hypertension in high-risk pregnancies such as those complicated by diabetic nephropathy may reduce maternal complications and the need for preterm delivery due to hyper- tension [9]. Based on meta-analysis of available antihypertensive trials, each 10mmHg reduction in MAP results in approximately 180g of decreased fetal growth [10]. The decision to treat is gen- erally a balance of the risk of uncontrolled maternal health, the risk of the potential need for preterm birth due to uncontrolled hypertension, and the risk of reduced fetal growth.

The speci c hemodynamic conditions associated with maternal hypertension may be varied and change over the course of preg- nancy. Maternal hemodynamics prior to the onset of clinical pre- eclampsia are best characterized by elevated CO and reduced TPR [1, 2]. Some women with chronic hypertension will have an elevated CO; others will be characterized by increased TPR. As preeclampsia becomes severe, TPR may dramatically increase over the course of days [2]. The hemodynamic characteristics of acute hypertension in pregnancy are associated with a differential impact on fetal growth. Increased TPR at presentation is associated with infants smaller for gestational age than those presenting with elevated cardiac output [11]. The hemodynamic effect of treatment can also impact fetal growth. If CO falls below the mean for gestational age or resis- tance rises above 1150 dyne•sec/cm5, reduced fetal growth can be expected [12]. In most clinical settings, measurements of maternal CO and TPR are not available to direct therapy. Nevertheless, an understanding of the maternal hemodynamics, the potential impact on the fetus, and the pharmacodynamic activities of speci c drugs should serve to guide empiric therapy.

Increasing numbers of young women with surgically corrected congenital heart disease are surviving to young adulthood and are choosing to have children. Mitral stenosis due to rheumatic heart disease remains common among children who grew up in condi- tions of crowding and poverty. With increased surveillance, more young women are diagnosed with hypertrophic cardiomyopathy

17 Cardiovascular medications in pregnancy 281

that is becoming one of the most common cardiac conditions seen in pregnant women. Improved medical management of dilated cardiomyopathy and pulmonary hypertension offers the potential for improved outcomes in pregnancy. The hemodynamic changes associated with normal pregnancy may hemodynamically destabi- lize a pregnant woman with cardiac disease. Volume loading will adversely affect women with mitral stenosis, dilated and hypertro- phic cardiomyopathy, and repaired congenital heart disease where the right heart is now the systemic ventricle such as a Fontan or Mustard repair. They may require diuresis to remain compensated. The acute volume loading associated with the postpartum period may be acutely destabilizing [5]. This may contribute to the high mortality rate seen postpartum in women with pulmonary hyper- tension and a failing right heart. Tachycardia results in decreased time in diastole for ow across a stenotic mitral valve.

Pharmacological control of tachycardia improves outcomes [13]. Many young women with congenital heart disease will have a tendency towards tachyarrythmia. This will worsen during preg- nancy. In some series, tachyarrythmia is the most common serious complication among pregnant women with congenital heart dis- ease. Tachyarrythmia associated with hypertrophic cardiomyopa- thy predictably worsens during pregnancy. Many of these women will bene t from pharmacological control of heart rate. Afterload reduction associated with a decrease in TPR may initially bene t women with dilated cardiomyopathy, systemic right hearts, and aortic and mitral regurgitation. However, the rise in TPR seen in the late third trimester and the acute increase in afterload expe- rienced postpartum may result in decompensation. An under- standing of the hemodynamic changes in pregnancy, the speci c vulnerabilities of individual conditions, and the pharmacody- namic impact of speci c medications will help a provider to treat preemptively to prevent decompensation rather than reacting to an acutely deteriorating maternal condition.

17.4 Pharmacodynamics of hemodynamically active drugs in pregnancy

Hemodynamically active drugs generally have primary effects on TPR, HR or SV. Changes in each of these parameters will affect CO. A reduction in vascular resistance can be induced through a number of pathways: direct action on vascular smooth mus- cle (e.g. hydralazine), inhibition of calcium channels (e.g. nife- dipine), inhibition of central adrenergic output through central

17 Cardiovascular Medications in Pregnancy

282 17.4 Pharmacodynamics of hemodynamically active drugs

alpha stimulation (e.g. clonidine), or inhibition of the angiotensin system (e.g. angiotensin converting enzyme inhibitors). A reduc- tion in CO can be achieved through either a reduction in heart rate or a reduction in stroke volume. The hemodynamic action of vasodilators can be represented as a vector in Figure 17.3 that runs perpendicular to the isometric lines of vascular resistance. A reduction in TPR results in a reduction in MAP and an increase in CO. In the upper left of the chart, changes in TPR result in relatively small changes in MAP and disproportionately large changes in CO. In the upper right portion of the chart, similar changes in TPR result in relatively small changes in CO and large changes in MAP and potentially hypotension. A reduction in CO will result in a vector of change parallel to isometric lines of resis- tance and an associated fall in MAP. On the upper left portion of the chart, lines of TPR are steep resulting in substantial changes in MAP with small changes in CO. In the upper right portion of the chart, large changes in CO are needed to lower MAP. Adding vectors, head to tail, can be used to predict the potential effects of combined drug therapy.

The pharmacodynamic effects of several individual drugs in pregnancy are plotted in Figure 17.4. Hydralazine [14] and capto- pril [15] demonstrate clear vasodilatory effects as described above.

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Figure 17.3 Cardiac output vs. mean arterial pressure with total peripheral resistance represented by diagonal isometric lines. Vectors of change associated with treatment with atenolol, furosemide, hydralazine, clonidine and captopril are represented.

                 

MAP (mmHg)

17 Cardiovascular medications in pregnancy 283

The direction of the hemodynamic vector of change of individual patients in these studies was fairly consistent as represented by the mean vector. The magnitude of effect varied. The pharmaco- dynamic effect of nifedipine has been reported in severely hyper- tensive patients. As would be expected, a reduction in MAP was associated with a fall in TPR and a rise in CO [16]. The data are not reported in a manner to permit plotting a vector. Nifedipine has been reported to signi cantly induce cerebral vasodilation that would be expected to increase cerebral perfusion pressure which is associated with adverse outcome in women with pre- eclampsia [17].

The vector for atenolol, a β-blocker, runs roughly parallel to lines of resistance but with a tendency towards increasing TPR [14]. The primary effect of a reduction in CO achieved by a reduc- tion in heart rate is blunted by a rise in stroke volume. The effect on MAP is countered to some degree by a rise in TPR. As with hydralazine and captopril, the direction of individual vectors was fairly consistent while the magnitude of the vectors varied among patients. Pharmacodynamic data in pregnancy is not available for metoprolol or propranolol, other commonly used β-blockers. One could infer similar actions from class effects from these drugs.

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Figuer 17.4 Cardiac output vs. mean arterial pressure with total peripheral resistance represented by diagonal isometric lines. Vectors representing a reduction in TPR generally run perpendicular to liners of resistance. Vectors representing a reduction in CO generally run parallel with some tendency towards increasing resistance.

                               

17 Cardiovascular Medications in Pregnancy

MAP (mmHg)

284 17.5 Fetal pharmacodynamic response to hemodynamically

The vector for furosemide, a diuretic, also runs generally paral- lel to lines of resistance and with a tendency towards increasing resistance [18]. The primary impact on reducing CO is achieved through a reduction in SV with some associated blunting of effect from a rise in HR. The pharmacodynamic effects of other diuret- ics have not been reported. Inference from class effect may again be considered.

The pharmacodynamic effects of clonidine, a central alpha ago- nist, and labetalol, a combined α- and β-blocker, are more complex [19]. Clonidine has been studied and the reported vector of change is displayed in Figure 17.4. The vector is vertical, intermediate between that expected from a vasodilator and a β-blocker. Unlike other drugs reported, a large variability of effect was observed across patients; some exhibited changes consistent with vasodilator action; others with changes consistent with beta blockade. Given its mech- anism of action, the nal effect may be dependent on the character of individual patient’s central adrenergic tone. As will be discussed below, the differences in hemodynamic effect may be relevant to the fetus. Labetalol is a combined α- and β-blocker. It is a chiral drug with two diastereomeric pairs of racemates. Two are pharmaco- logically inactive; (RR)-labetalol is a nonselective beta antagonist; (SR)-labetalol is an alpha adrenergic antagonist and operates as a vasodilator [20]. The intravenous use of the drug has a 7:1 ratio of beta:alpha effect compared to a 3:1 effect as an oral agent [21] due to differential clearance of isomers. While intravenous use usually results in a reduction in HR, oral use frequently does not.

The hemodynamic effects of some drugs in pregnancy are well described. Some generalizations of effect by class of drug are rea- sonable. An understanding of the individual effects of single drugs in the paradigm of vectors described above can assist the clinician in achieving a desired effect, particularly in the context when more than a single drug is required. In most clinical settings, pharma- codynamic response cannot be assessed with bedside measure- ments of hemodynamics. However, pharmacodynamic response to β-blockers can be assessed by change in heart rate, and response to diuretic can be assessed by change in serum beta naturetic peptide.

17.5 Fetal pharmacodynamic response to hemodynamically active drugs

The fetus can be affected directly by drugs that cross the pla- centa and then act in the fetus. Alternatively, hemodynamically active drugs can, through their actions on the mother, change

17 Cardiovascular medications in pregnancy 285

the environment of utero-placental blood ow and, in doing so, impact the fetus. Most information regarding impact on the fetus has been derived from hypertensive pregnancies.

Baseline maternal hemodynamic conditions during hyperten- sive pregnancies impact fetal growth. In a cohort of 79 women with hypertension prior to 29 weeks, those with a TPR ≥1150 dyne • sec /cm5 had, at delivery, a mean birth weight percen- tile of 18.7 compared to 38.8 among women with a TPR <1150 dyne•sec/cm5 (p=0.003) [11]. The observed reduction in growth may be the result of less favorable conditions of utero-placental perfusion associated with elevated TPR. Alternatively, reduction in growth may be the result of placental injury that in turn results in destabilization and dysregulation of maternal vascular func- tion and vasoconstriction. Superimposed on maternal baseline conditions, hemodynamically active drugs may further impact fetal growth. In a meta-analysis of antihypertensive trials, von Dadelszen et al. reported that every 10mmHg reduction in MAP resulted in a 145 g reduction in birth weight [10]. The results were not in uenced by duration of therapy or antihypertensive agent.

Reports of the impact of speci c medications are limited. Aten- olol has been the drug most broadly reported regarding the impact of fetal growth. In a small randomized trial of chronic hyperten- sion, Butters et al. reported a reduction in birth weight associated with treatment with atenolol [22]. Of particular concern were two infants that were quite small. This study was small and women were treated with doses up to 200mg per day. Patients not con- trolled with placebo were removed from the trial, 12.5% of the cohort. Follow-up after 1 year found no signi cant differences in birth weight. In a randomized trial of prehypertension char- acterized by elevated CO, the atenolol arm was associated with a reduction in birth weight compared to the placebo arm [23]. The reduction was characterized by fewer babies >4000g and more babies <3000 g. The incidence of IUGR, <10th percentile, was 4.8% in the atenolol arm and 5.2% in the placebo arm. Neither group was different from a low risk, untreated control group. The small- est babies in the atenolol group had CO lowered below the mean for gestational age. In a report of 235 women with risk factors for preeclampsia treated with atenolol, the incidence of IUGR, <10th percentile, was 19.8% [12]. IUGR was strongly associated with a history of IUGR in a prior pregnancy (p<0.001) and treatment that permitted CO to fall below the mean for gestational age or TPR to rise above 1150 dyne•sec/cm5.

The impact of clonidine on fetal growth has also been evalu- ated [19]. As reported above, the pharmacodynamic effects of clonidine are varied and probably dependent on the character of

17 Cardiovascular Medications in Pregnancy

286 17.6 Direct fetal effects of hemodynamically active drugs

an individual patient’s central adrenergic output. In this report, one-third of women experienced a primary reduction in CO when treated with clonidine. Their initial hemodynamics and demographics were similar to the others. The gestational age at birth was also comparable. Nevertheless, the average birth weight was 2555±726 compared to 2938±784 among the women who experienced a vasodilatory effect (p=0.02).

While there is no extensive data over a breadth of drugs on the impact of fetal growth, medications that impact maternal hemodynamics do seem to affect fetal growth. The work of von Dadelszen [10] suggests a broad but modest effect of lowering blood pressure on fetal growth. The experience with atenolol sug- gests that the impact is mediated by an associated reduction in CO, generally below pregnancy norms, or an elevation in TPR above pregnancy norms. This effect would be expected to be com- mon to all β-blockers and potentially to diuretics that also reduce CO. The experience with clonidine suggests that the observations made with atenolol are neither speci c to the drug itself nor spe- ci c to action at the beta receptor. The impact on fetal growth seems fundamentally related to changes in maternal hemody- namics that are re ected in changes in utero-placental perfusion. While these observations are preliminary, they offer a frame of reference regarding drug therapy.

17.6 Direct fetal effects of hemodynamically active drugs

A full review of the potential teratogenicity of hemodynami- cally active drugs is beyond the scope of this chapter. Frequently updated evaluations can be found in online databases such as Teris and Reprotox. For most medications, modest or limited data exist. That which exists is generally reassuring.

Angiotensin converting enzyme (ACE) inhibitors deserve spe- cial consideration. Substantial data suggest that the use of ACE inhibitors in the second and third trimesters is associated with a syndrome of oligohydramnios, pulmonary hypoplasia associ- ated with oligohydramnios when severe and prolonged, neona- tal oliguria and renal failure [24]. In addition fetuses have been reported with underdeveloped skull bone, presumably due to hypotension. These effects are seen most commonly with higher doses and longer administration. Small studies of low dose ther- apy have been reported without complications [24]. The renal effects are consistent with adverse impact in adults with excessive

17 Cardiovascular medications in pregnancy 287

dosing particularly in the face of renal insuf ciency. These reports have been reviewed and summarized [24]. While fewer data exist regarding risk associated with angiotensin receptor blockers, the similar mechanisms of action and complications in adults would suggest similar concerns.

Con icting reports have been published on the risks associated with ACE inhibitors in the rst trimester. A report from the Ten- nessee Medicaid data suggests a risk ratio of 2.71 (95% CI 1.72 to 4.27) associated with use in the rst trimester for major malforma- tions and a risk ratio of 3.72 (95% CI 1.89 to 7.30) for cardiovas- cular malformations [25]. This study has been criticized for the potential for serious confounders and for potential ascertainment bias in the diagnosis of fetal anomalies. A subsequent report from the Swedish national database suggests an adjusted odds ratio of 2.59 (95% CI 1.92 to 3.51) for cardiovascular defects for women taking any antihypertensive without drug speci city and no incre- mental risk associated with ACE inhibitors [26]. The authors suggest that the underlying disease, chronic hypertension and the association with obesity, insulin resistance, and diabetes represent the true risks. Given the clear bene ts of ACE inhibitors to the cardiovascular health of women outside pregnancy and the impor- tance of entering pregnancy with optimal endovascular health, withholding these medications during the preconceptional period may be harmful and result in a worse outcome in pregnancy. While a clear recommendation cannot be made, the risks associated with exposure in the rst weeks of pregnancy seem to be quite small. Risk–bene t counseling with individual patients is appropriate.

17.7 Pharmacokinetic changes in hemodynamically active drugs in pregnancy

Pregnancy is associated with clinically important changes in drug metabolism that are summarized in Chapter 3. These changes include an increase in GFR and upregulation of CYP3A, CYP2D6, and P-glycoprotein. Some drugs such as atenolol and digoxin have been speci cally studied. For others, changes in clearance can be suggested from the known mechanism of drug clearance and knowledge regarding the impact of pregnancy on that mechanism. Knowledge regarding the precise timing of changes in clearance is frequently lacking, including when, at or around conception, they begin, when the changes reach a maxi- mum, and when they completely resolve postpartum. For some drugs, a minor pathway of clearance outside pregnancy may

17 Cardiovascular Medications in Pregnancy

288 17.7 Pharmacokinetic changes in hemodynamically active drugs

become the predominant pathway in pregnancy. In some cases, the inducible minor pathways that are relevant have not been described. Examination of speci c drugs whose mechanisms of clearance are known can serve to elucidate the issues.

Digoxin may be prescribed in pregnancy to blunt a rapid ven- tricular response in women at risk for the development of atrial brillation such as those with mitral stenosis and left atrial enlargement. Digoxin has also been prescribed to treated fetuses with supraventricular tachycardia and associated fetal hydrops. To be effective in both cases, high serum levels are required. Renal clearance is increased in pregnancy 61% due in part to an increase in glomerular ltration rate. Renal secretion clearance, clearance in excess of ltration, increases by 120% attributed to an increase in P-glycoprotein activity (and possibly organic anion transporter polypeptides) [27]. To achieve therapeutic levels in the mother, digoxin must be dosed aggressively and drug lev- els monitored. P-glycoprotein is also expressed in the placenta operating as a reverse transporter limiting fetal exposure. Thus, digoxin monotherapy has had limited success in controlling fetal supraventricular tachycardia (see Chapter 5).

Atenolol is a selective β1 receptor antagonist prescribed in preg- nancy as an antihypertensive and for maternal heart rate control. Between 85 and 100% of atenolol is excreted unchanged. In preg- nancy, atenolol renal clearance is strongly correlated with creati- nine clearance. In the third trimester, renal clearance is increased by 31.5% compared with the clearance postpartum, and appar- ent oral clearance is increased by 37.5% [28]. Increased clear- ance usually requires an increase in total dose and the frequency of dosing to twice a day to achieve an equivalent and consistent effect. As discussed above, hemodynamic changes in pregnancy increase the tendency to tachycardia usually requiring an increase in dosing independent of pharmacokinetics to achieve an equiv- alent pharmacodynamic effect. Drug ef cacy can be monitored effectively by monitoring maternal heart rate. Maternal responses to needed adjustments in atenolol dosing are therefore reasonably predictable. Drug exposure to infants through breast milk from mothers taking atenolol has been studied [29]. Weight adjusted dose to the fetus ranged from 5.9 to 14.6%; serum levels in the infants were below the detection limit of the assay (10 ng/mL); no reduction in heart rate was observed compared to infants whose mothers were not taking atenolol. Information from a prior case report had been used to suggest that breastfeeding on atenolol was potentially dangerous [30]. The drug levels reported in the case report are inconsistent with levels that could be achieved through drug delivered through breast milk.

17 Cardiovascular medications in pregnancy 289

Metoprolol is also a selective β1 receptor antagonist prescribed for similar indications as atenolol. Outside pregnancy, metopro- lol is used more commonly in cardiology practice. Therefore, pregnant patients with medical complications may enter preg- nancy treated with metoprolol. Metoprolol is metabolized by CYP2D6 that is not known to be induced by pharmacological agents. In pregnancy, CYP2D6 activity is increased by 25.6% at mid-pregnancy and by 47.8% at term with considerable variabil- ity between patients presumably due to genetic polymorphisms with different activity [31]. Metoprolol apparent oral clearance is increased by 292% in the third trimester of pregnancy with signi cant variability between patients [32]. Metoprolol there- fore becomes a challenging drug to use in pregnancy. Not only is clearance increased, but maximal change in clearance is not achieved until near term and considerable variability between patients in clearance and change in clearance is observed. By monitoring heart rate, appropriate changes in dosing can be made. Total dose may need to be increased 3–4-fold to achieve an equivalent pharmacodynamic effect. Dosing frequency must be increased.

Labetalol is a combined α–β receptor antagonist. It is a chi- ral drug with two diastereomeric pairs of racemates. The (RR)- labetalol is responsible for β-blocking activity; the (SR)-labetalol is responsible for α-blocking activity. Labetalol is eliminated by glucuronidation by UDP-glucuronosyltransferase. In a small study of hypertensive pregnant women the terminal elimina- tion half-life after oral administration for the total drug has been reported to be 1.7±0.27 hours compared to 6–8 hours in non- pregnant subjects [33]. In a larger study of clearance of stereo- isomers, differences were observed depending on the route of administration [19]. With intravenous treatment, the clearance of (RR)-labetalol (β-blocking activity) and (SR)-labetalol (α-blocking activity) were equivalent (0.8 vs. 0.9 L/h/kg). When administered orally, the apparent oral clearance for (RR)-labetalol (β-blocking activity) was 1.7 times greater than clearance for the (SR)-labetalol (α-blocking activity) (2.9 vs. 4.4 L/h/kg). The increased clearance of labetalol in pregnancy requires an upward dose adjustment and more frequent dosing. This difference in clearance of stereoisomers suggests a difference in pharmacodynamic effect based on route of administration. Oral administration would be expected to have less β-blocking activity than intravenous administration. The pharma- codynamic effect can be assessed by monitoring heart rate. If a β effect is needed, oral labetalol may not be an optimal choice.

Nifedipine is a dihydropyridine calcium channel blocker. It is prescribed in pregnancy as an antihypertensive with pure

17 Cardiovascular Medications in Pregnancy

290 17.7 Pharmacokinetic changes in hemodynamically active drugs

vasodilator properties. It is also used to inhibit uterine con- tractions. Nifedipine is metabolized by CYP3A whose activity is increased in pregnancy [27]. The apparent oral clearance of midazolam, a marker for CYP3A activity, is increased by 108% in pregnancy compared to postpartum. In a small study compar- ing pregnant hypertensive women, the apparent oral clearance in pregnancy was four-fold higher than non-pregnant controls [34]. Again, the increased clearance in pregnancy requires an upward dose adjustment and more frequent dosing. Data on CYP3A and nifedipine can probably be generalized to other calcium channel blockers as substrates for CYP3A.

Sildeni l is a cGMP-speci c phosphidiesterase inhibitor used in the treatment of pulmonary hypertension. It achieves its vaso- dilatory pharmacological effect by increasing nitric oxide levels in the pulmonary arterioles. Pulmonary hypertension is a rare but lethal complication of pregnancy. Reports of maternal mortality range from 20 to 50%. Appropriate, steady-state dosing of silde- na l is of critical importance. Unlike β-blockers where pharma- codynamic effects can be monitored by heart rate, the effect of sildena l cannot be monitored at the bedside. Given the rarity and acuity of the disease in pregnancy, informative pharmaco- kinetic studies are unlikely to be performed. Sildena l metabo- lism is principally mediated by CYP3A. Based on knowledge from studies of midazolam, increased clearance of sildena l would be expected in pregnancy. Empiric upward total dose adjustment and more frequent dosing would be appropriate.

Clonidine is prescribed as an antihypertensive in pregnancy. It is a central α agonist that achieves its antihypertensive effect by decreasing central adrenergic output similar to methyldopa. As discussed above, its hemodynamic effects are variable. Outside pregnancy, 50 to 60% of the drug is excreted unchanged in the urine. In pregnant women, apparent oral clearance is increased by approximately 83% with only 36% excreted unchanged in the urine [35]. Due to these observations, human microsome studies were performed which demonstrated that clonidine was a CYP2D6 sub- strate that accounts for its increased clearance in pregnancy [35]. Again, increased clearance in pregnancy requires an upward dose adjustment and more frequent dosing. In the case of clonidine, increased CYP2D6 activity in pregnancy changed the predominant pathway of clearance in a previously undescribed pathway. Other drugs, particularly older drugs, may have previously undescribed metabolic pathways that are relevant to pregnancy.

Pregnancy is associated with important hemodynamic changes that, while well tolerated by healthy women, can result in clini- cal decompensation in the context of medical complications.

17 Cardiovascular medications in pregnancy 291

Pregnancy is also associated with clinically signi cant changes in pathways of drug clearance that impact the dosing of medi- cations used to manage cardiovascular disease and maintain cardiovascular homeostasis. To achieve the desired therapeutic effect, the clinician must establish treatment goals and recognize changes in drug metabolism that will impact the desired phar- macodynamic effects. Since maternal hemodynamics and drug metabolism change dynamically over the course of pregnancy, the treatment strategy must also be dynamic over the course of pregnancy anticipating these changes. Dosages may need to be increased; the timing of doses may need to be more frequent. In some circumstances, therapy can be based on data speci c to the circumstances. In many other cases, an understanding of classes of hemodynamic action and mechanism of drug metabolism will be needed to make more empiric decisions which then must be reevaluated for desired effect.

Key points

n Substantial changes in cardiovascular physiology occur during pregnancy that may require management through initiation of medications or changes in existing dosing.

n The pharmacodynamic changes associated with hemodynami- cally active drugs occur in the context of changing baseline conditions throughout the course of pregnancy and postpar- tum period.

n The pharmacodynamic changes associated with hemodynami- cally active drugs can impact utero-placental perfusion and therefore the welfare of the fetus.

n The pharmacokinetics of medications used in pregnancy are impacted by increased maternal GFR, upregulation of path- ways of drug metabolism such as CYP3A and CYP2D6, and upregulation of transporters such as P-glycoprotein.

n Upregulation of minor pathways of drug metabolism in preg- nancy may substantially alter primary mechanisms of drug disposition.

n Speci c information regarding pharmacokinetics and dynam- ics of speci c drugs in pregnancy may be lacking. General assumptions regarding these drugs can be made from mecha- nism of action and disposition that can then be used to guide

17 Cardiovascular Medications in Pregnancy

292 References
therapy. The effectiveness of treatment must then be con rmed

clinically.

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Antidepressants in Pregnancy

Elizabeth M. LaRusso and Marlene P. Freeman

18

. 18.1  Introduction 295

. 18.2  Effects of untreated perinatal depression on women and children 296

. 18.3  Approach to treatment 297

. 18.4  Potential risks of selective serotonin reuptake inhibitor
(SSRI) use during pregnancy 299

. 18.5  Potential risks of non-SSRI antidepressant use
during pregnancy 302

. 18.6  Potential risks of older antidepressant use during pregnancy 303

. 18.7  Anxiety 303

. 18.8  Summary 304

18.1 Introduction

Depression is common among women during pregnancy, with prevalence estimates indicating that 14–23% of pregnant women will experience a depressive disorder during pregnancy [1]. Although pregnancy is a time of increased health care utiliza- tion, pregnant women are less likely than non-pregnant women to receive psychiatric care, and a signi cant amount of women suffering from psychiatric illness during pregnancy are neither identi ed nor treated [2]. The size, complexity, and frequently inconsistent nature of the literature regarding the safety of psy- chotropic medications in pregnancy is daunting; consequently, many physicians are reluctant to manage psychiatric illness during pregnancy. Untreated maternal depression may be associated with

296 18.2 Effects of untreated perinatal depression on women

signi cant morbidity or even mortality for mother–infant pairs, and both psychiatric illness and psychotropic medication must be conceptualized as agents of fetal exposure. Prescribing psychiatric medication to pregnant women requires a complex risk–bene t calculus that balances the risks of untreated psychiatric illness to mother and fetus with the potential risks of medication use during pregnancy; ideally this process includes shared decision making between the patient and psychiatric, obstetric, and/or primary care providers. The goal of this chapter is to provide an overview of the management of depression during pregnancy and to summarize the most relevant issues impacting clinical decision making.

Symptoms of depression include depressed mood or anhedo- nia for at least a 2-week period, accompanied by symptoms that include changes in sleep, appetite, energy, concentration, psycho- motor activity, feelings of guilt or worthlessness, and/or suicidal ideation [3]. Diagnosing depression in pregnant women can be complicated by the fact that many symptoms of depression overlap with normal symptoms of pregnancy; consequently, the presence of affective symptoms such as feelings of guilt or worthlessness, anhedonia, and thoughts of suicide may more strongly support the diagnosis of depression in pregnant women. Risk factors for developing perinatal depression encompass elements of a wom- an’s genetics, hormonal/reproductive history, current stressors, and life experiences; biologic factors that have consistently been associated with increased risk include a past history of depression or premenstrual dysphoric disorder and a family history of depres- sion. Psychosocial factors, including stressful life events and lack of perceived social support, have also consistently been found to predict perinatal depression [4].

18.2 Effects of untreated perinatal depression on women and children

Untreated perinatal depression is associated with signi cant mor- bidity for mother–infant pairs via association with adverse obstetric outcomes and as a risk factor for poor maternal health, inadequate prenatal care, and postpartum depression [5, 6]. Poor nutrition, increased number of exposures to medications or herbal remedies, increased alcohol and tobacco use, and decreased compliance with prenatal care have been consistently associated with untreated psychiatric illness during pregnancy [7]. Increased rates of hyper- tension, preeclampsia, and gestational diabetes have also been associated with untreated maternal depression [8]. Data regarding

18 Antidepressants in pregnancy 297

speci c adverse obstetric outcomes resulting from untreated depres- sion during pregnancy are inconsistent. Miscarriage, fetal growth effects (low birth weight and intrauterine growth restriction), and preterm delivery have all been associated with untreated maternal depression. The strongest association appears to be with preterm birth; however, because of methodological limitations of the avail- able data, it is not currently possible to draw de nitive conclusions regarding associations between untreated maternal depression and these adverse reproductive outcomes [7–9].

In addition to the potential negative impact on pregnancy out- comes, perinatal depression is associated with disrupted mater- nal–infant bonding, increased irritability, decreased attentiveness, and decreased facial expressions in neonates [1, 10, 11]. Children and adolescents born to depressed mothers are at risk for delayed cognitive and language development, lower IQ, and increased prevalence of psychiatric and emotional problems [1, 7, 11, 12]. Depression that begins during pregnancy frequently continues or worsens after delivery.

18.3 Approach to treatment

Current guidelines created by a joint task force of the Ameri- can Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists (ACOG) recommend individual or group therapy as an initial treatment approach for pregnant women with mild to moderate depression [1]. For women who are unable to access or have not responded to evidence-based psychotherapies, who are experiencing an episode of moderate to severe depression during pregnancy, and/or who have a his- tory of recurrent severe depression or suicidality, initiation or maintenance of psychiatric medications is likely indicated [1].

It is ideal to evaluate women with a history of psychiatric ill- ness prior to pregnancy in order to generate an individualized treatment plan. However, since 50% of pregnancies in the United States are unplanned, preconception evaluation is often not fea- sible in practice [13]. Discontinuation of antidepressants during pregnancy is common and is associated with signi cant increase in relapse. In one large study, women who stopped antidepres- sants had a 68% recurrence rate of depressive symptoms as compared to 26% for women who continued their medications [14]. Frequently, patient and physician concerns about potential teratogenesis or other negative neonatal outcomes overshadow consideration of the risks associated with untreated maternal

18 Antidepressants in Pregnancy

298 18.3 Approach to treatment

psychiatric illness. This decision-making process is complicated by several factors, including varying fetal risks at different stages of gestation, inadequacy of the US Food and Drug Administra- tion (FDA) medication categorization system, and limitations of currently available data regarding the safety of antidepressants in pregnancy [1, 7].

The approach to prescribing antidepressants in pregnancy can be guided by several general principles. The goal of treatment is remission of depressive symptoms, as inadequately treated depres- sion subjects the fetus to risks associated both with maternal ill- ness and with medication exposure. Choosing a medication with an established safety pro le and a proven history of ef cacy in the patient maximizes the potential for symptom response and minimizes potential risks to the fetus. One medication at higher dose is preferred to multiple medications at lower doses in order to decrease the total number of fetal exposures; pregnant women should receive the minimal effective dose of a single antidepressant [1, 7].

Antidepressant dose requirements may increase across gesta- tion as a consequence of induction of cytochrome enzymes 3A4 and 2D6 that increase drug metabolism in the second half of pregnancy [1, 15]. Although there is a limited literature reveal- ing lowered levels of both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in many women in late pregnancy, there is wide interpersonal variability in the phar- macokinetic changes of these medications across gestation. Cur- rently, there are no evidence-based guidelines for altered dosing or therapeutic monitoring of antidepressants during pregnancy [16].

Considering the possibility of increased antidepressant metabo- lism during pregnancy, women must be monitored closely for the reemergence of depressive symptoms, especially during the third trimester. The possibility that some women may require higher doses of antidepressants in late pregnancy contradicts the clini- cal approach that advocates tapering antidepressants prior to delivery in hopes of mitigating potential adverse neonatal effects of medication use. Tapering antidepressants proximal to delivery has not been shown to decrease the potential risk of neonatal complications associated with medication use in late pregnancy [17]. Discontinuing antidepressants has been associated with sig- ni cant increase in relapse of depressive symptoms, and currently neither the APA nor ACOG recommend tapering antidepressants prior to delivery [1, 7, 14].

In addition to possible changes in antidepressant dose require- ments across gestation, optimal management of perinatal mood and anxiety disorders includes recognizing the potential for

18 Antidepressants in pregnancy 299

postpartum illness. Women who are not already engaged in psy- chotherapy should be provided with referrals to begin depression- focused psychotherapy, speci cally cognitive behavioral therapy (CBT) or interpersonal psychotherapy (IPT), both of which have been well studied for perinatal depression [16]. Supportive dynamic psychotherapy has been less well studied in pregnancy but is a reasonable approach if CBT and IPT are not available [1].

In addition to speci c considerations regarding antidepressant use in pregnancy, prescribers should be familiar with current practice guidelines for the treatment of depression in general. There is no speci c antidepressant that is better than another, and the choice of medication should be based on side effect pro- le, safety, tolerability, and previous response to medication in the individual patient [16]. Antidepressants should be started at low dose and titrated over time to effectiveness; the speed of the titration depends upon the severity of associated side effects. Frequently, patients require 4 to 8 weeks of antidepressant treat- ment prior to experiencing moderate symptom reduction. Once remission of depression has been achieved, patients with less than three prior depressive episodes should be continued on antidepressants for a minimum of 4 to 9 months prior to consid- ering discontinuation while patients with three or more episodes of major depression may require maintenance antidepressant treatment inde nitely [16]. Tapering antidepressants slowly over at least 2 weeks decreases both the risk of relapse of depres- sive illness and the severity of antidepressant discontinuation syndrome ( u-like symptoms, paresthesias, insomnia) which is associated more strongly with SSRIs with short half-lives [16, 18]. Decisions regarding tapering and discontinuation should be made in consultation with prescribing clinicians and patients should be monitored to assess for reemergence of depressive symptoms.

18.4 Potential risks of selective serotonin reuptake inhibitor (SSRI) use during pregnancy

Due to their ef cacy, tolerability, and safety pro le, SSRIs are currently among the rst-line pharmacologic treatments of major depression, and recent data suggest that up to 13% of US preg- nancies have antidepressant exposure [19]. All SSRIs, indeed all psychotropic medications, cross the placenta and are excreted in breast milk [7]. The reproductive safety of SSRIs in preg- nancy has been extensively studied. However, the data are often

18 Antidepressants in Pregnancy

300 18.4 Potential risks of SSRI use during pregnancy

contradictory and limited by several factors, including the lack of randomized controlled trials, small sample sizes and limited power of many studies, the absence of information about disease state of the mother, and the failure to control for multiple con- founding variables that impact reproductive outcomes [1]. Cur- rently available data in the major domains of reproductive toxicity will be summarized here.

18.4.1 Obstetric outcomes

Similar to untreated depression during pregnancy, miscarriage, fetal growth effects, and preterm delivery have all been incon- sistently associated with SSRI use during pregnancy [1, 9]. The APA and ACOG treatment guideline report states that currently there is not enough evidence to establish an association between SSRI use in early pregnancy and miscarriage [1]. There appears to be adequate evidence to support a true association between low birth weight and SSRI use in pregnancy; however, there is cur- rently not enough evidence to support causality, and the impact of the underlying disorder and other confounders must be consid- ered [1, 6]. Finally, a growing literature supporting an association between preterm delivery and SSRI use in pregnancy is emerging, including at least one study that attempts to control for maternal depression [1, 9]. Studies that do identify an association between preterm delivery and SSRI use in pregnancy tend to nd a small effect size, with decrease in gestational age of less than or equal to 1 week [1]. Currently it remains dif cult to differentiate whether observed adverse obstetric outcomes are related to antidepressant treatment or to depressive illness itself, and research that ade- quately controls for underlying disease state is necessary to either support or refute these associations.

18.4.2 Congenital malformations

There is a large amount of evidence supporting the conclusion that SSRIs as a group are not associated with increased risk of major congenital anomalies [1, 6, 7, 9]. There is some evidence that indi- vidual SSRIs may be associated with very low risk of minor mal- formations; however, this nding is not widely replicated [1, 6, 11, 20]. Speci c concern over paroxetine use and increased risk of congenital cardiac malformations emerged in 2005 when GlaxoS- mithKline reported a 1.5–2-fold increase in atrial and ventricular septal defects in infants exposed to paroxetine in the rst trimester. This nding prompted a change in the medication’s FDA preg- nancy rating from C to D and generated the current recommenda- tion that, if possible, paroxetine should be avoided during the rst

18 Antidepressants in pregnancy 301

trimester of pregnancy and in women contemplating pregnancy. Since 2005, other studies have not supported the association between paroxetine and cardiac malformations; however, enough uncertainty exists that avoiding rst-trimester fetal exposure to paroxetine and considering fetal echocardiography in exposed cases continues to be recommended [1, 7]. In summary, the over- whelming convergence of data suggests that the absolute risk of congenital malformations associated with SSRI use during early pregnancy, if indeed there is a risk at all, is small; consequently SSRIs are not considered to be teratogenic [1, 6, 7, 9].

18.4.3 Persistent pulmonary hypertension of the newborn (PPHN)

PPHN is a clinical syndrome characterized by failure of the normal fetal-to-neonatal circulatory transition causing right-to-left shunt- ing of blood through the ductus arteriosus and foramen ovale and subsequent neonatal hypoxia. PPHN is a rare condition: baseline population rates are 1–2 infants/1000 live births, or 0.1–0.2%. A 2006 case–control study noted an association between maternal use of SSRIs after 20 weeks of pregnancy and increased risk of PPHN, with adjusted odds ratio of approximately 6, raising the absolute risk to 6–12/1000 births [20]. Subsequent studies have revealed either lower absolute risk or no association, and no stud- ies to date have established a causal link between SSRI use in late pregnancy and PPHN [1, 7]. In December 2011, the FDA released a drug safety communication concluding that there is currently insuf cient evidence to support a potential link between SSRI use in pregnancy and PPHN and recommending that pre- scribers continue to treat depression in pregnancy according to their current clinical practice. In summary, most of the evidence suggests that there is not an association between PPHN and use of SSRIs in late pregnancy, although it has been reported. How- ever, even if this association proves to be true, the absolute risk remains quite low and there is currently no evidence that tapering SSRIs proximal to delivery decreases this potential risk.

18.4.4 Poor neonatal adaptation

Exposure to SSRIs in late pregnancy has also been associated with transient neonatal distress, including tachypnea, jitteriness, poor muscle tone, weak cry, and irritability. This symptom constellation is often termed “poor neonatal adaptation” or “withdrawal” and lasts from several hours to 2 weeks post-delivery. Poor neonatal adaptation occurs in roughly 15–30% of infants of mothers who used SSRIs in late pregnancy and symptoms are generally mild, transient, and managed by supportive care in special care nurseries.

18 Antidepressants in Pregnancy

302 18.5 Potential risks of non-SSRI antidepressant

Symptoms have been reported with all SSRIs but the highest reported rates for this syndrome occur with uoxetine and parox- etine [1, 7, 10]. It is unclear if these symptoms represent neonatal serotonin toxicity, a discontinuation phenomenon, or are the result of some as yet undiscovered mechanism, and tapering antidepres- sants towards the end of pregnancy has not been shown to decrease neonatal symptoms [17]. Future studies examining potential impact of SSRI exposure on neonates must control for the impact of maternal psychiatric illness, as behavioral symptoms such as irri- tability and decreased attentiveness have also been strongly associ- ated with poorly treated maternal depression [1, 10, 11].

18.4.5 Neurodevelopmental outcomes

The impact of prenatal antidepressant exposure on long-term cognitive, behavioral, and motor outcomes in exposed children has not been extensively investigated. Despite a general paucity of information, the available data are largely reassuring. The majority of studies show no difference in measures of intelligence, language development, or behavior between children exposed to anti- depressants in utero and unexposed controls. Two studies showed subtle delays in psychomotor development; however, these studies had signi cant methodological problems. Larger, well-designed studies with increased length of follow-up are required to either support or refute associations between in utero exposure to SSRIs and negative neurodevelopmental outcomes [11].

18.5 Potential risks of non-SSRI antidepressant use during pregnancy

Non-SSRI antidepressants include bupropion, duloxetine, mirtaz- epine, nefazodone, trazodone, and venlafaxine, and as a group they have been much less well studied than the SSRIs. Currently available data do not suggest increased risk of adverse obstet- ric outcomes, major congenital malformations, or PPHN with non-SSRI antidepressants in pregnancy. A syndrome of poor neonatal adaptation similar to that attributed to SSRIs has been consistently documented in infants born to mothers who have used non-SSRI antidepressants in late pregnancy, and virtually no information exists on long-term neurocognitive outcomes in exposed children [1, 7, 11, 20]. This general lack of negative nd- ings should be interpreted with caution as it currently re ects a paucity of data as opposed to a true absence of risk. In general,

18 Antidepressants in pregnancy 303

non-SSRI antidepressants should not be considered rst-line agents for treatment of depression during pregnancy unless there is a compelling clinical reason to use them instead of medica- tions with more established safety pro les. Such indications may include established history of ef cacy in an individual patient, lack of response or inability to tolerate SSRIs, fetal exposure to non- SSRI antidepressant in early pregnancy, or patient preference.

18.6 Potential risks of older antidepressant use during pregnancy

Tricyclic antidepressants (TCAs), the mainstay of treatment for depression prior to the introduction of SSRIs in the late 1980s, have been well studied in pregnancy; due to their side effect pro le and lethality potential in overdose they are no longer considered a rst-line treatment for depression. Similar to the SSRIs, there is con icting data regarding potential association with obstetric complications like low birth weight and preterm delivery, while most studies reveal no association with increased rates of congen- ital malformations [1, 7]. The use of TCAs in late pregnancy has been associated with transient neonatal toxicity and withdrawal symptoms including jitteriness, tachycardia, mild respiratory dis- tress, hypertonia, and irritability; currently there is no evidence of negative long-term neurobehavioral sequelae [1, 7, 12]. Mono- amine oxidase inhibitors (MAOIs) are infrequently used in mod- ern clinical practice due to their severe side effect pro le; they are essentially contraindicated during pregnancy due to increased rate of congenital anomalies in animal studies and the possibility of precipitating a hypertensive crisis if tocolytic medications are required to postpone labor.

18.7 Anxiety

Anxiety disorders such as generalized anxiety, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder may exist independently of, or co-morbid with, depressive illness. A detailed discussion of anxiety disorders during pregnancy is beyond the scope of this chapter; however, the approach to man- agement of anxiety during pregnancy is similar to that of depres- sion and SSRIs are currently considered a rst-line treatment for anxiety spectrum illness.

18 Antidepressants in Pregnancy

304 References 18.8 Summary

Depression during pregnancy is associated with signi cant risks for women and infants, and the goal of treatment should be remission. Ideal management of depressed pregnant women includes maxi- mization of non-psychopharmacologic treatments such as psycho- therapy and utilization of antidepressant medication for pregnant women with moderate to severe depressive symptoms. Optimal patient care includes an individualized treatment approach that balances the potential maternal and fetal risks of untreated depres- sion with the potential risks of antidepressant exposure. Avoiding polypharmacy, using the lowest effective dose of a medication with a history of ef cacy in the individual patient, and monitoring patient response over time are strategies that may mitigate potential risks.

References

[1] Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114(3):703–13.

[2] Vesga-Lopez O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS. Psychi- atric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry 2008;65(7):805–15.

[3] American Psychiatric Association. Diagnostic and Statistical Manual of Men- tal Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association; 2000.

[4] Miller LJ, LaRusso EM. Preventing postpartum depression. Psychiat Clin N Am 2011;34:53–65.

[5] Bonari L, Pinto N, Ahn E, Einarson A, Steiner M, Koren G. Perinatal risks of untreated depression during pregnancy. Can J Psychiatry 2004;49(11):726–34. [6] Wisner KL, Zarin DA, Holmboe ES, Appelbaum PS, Gelenberg AJ, Leonard HL, et al. Risk–bene t decision making for treatment of depression during

pregnancy. Am J Psychiatry 2000;157(12):1933–40.
[7] ACOG Practice Bulletin. Use of psychiatric medications during pregnancy and

lactation. Obstet Gynecol 2008;111(4):1001–20.
[8] Grote NK, Bridge JA, Gavin AR, Melville JL, Iyengar S, Katon WJ. A

meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction. Arch Gen Psychiatry 2010;67(10):1012–24.

[9] Wisner KL, Sit DKY, Hanusa BH, Moses-Kolko EL, Bogen DL, Hunker DF, et al. Major depression and antidepressant treatment: impact on pregnancy and neonatal outcomes. Am J Psychiatry 2009;166(5):557–66.

[10] Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA 2005;293(19):2372–83.

18 Antidepressants in pregnancy 305

[11] Gentile S, Galbally M. Prenatal exposure to antidepressant medications and neurodevelopmental outcomes: a systematic review. J Affect Disord 2011;128:1–9.

[12] Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, et al. Child development following exposure to tricyclic antidepressants or uox- etine throughout fetal life: a prospective, controlled study. Am J Psychiatry 2002;159(11):1889–95.

[13] Finer LB, Henshaw SK. Disparities in rates of unintended pregnancy in the United States, 1994 and 2001. Perspect Sex Reprod Health 2006;38:90–6.

[14] Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 2006;295(5):499–507.

[15] Sit DK, Perel JM, Helsel JC, Wisner KL. Changes in antidepressant metab- olism and dosing across pregnancy and early postpartum. J Clin Psychiatry 2008;69(4):652–8.

[16] Work Group on Major Depressive Disorder. Practice guidelines for the treatment of patients with major depressive disorder. Am J Psychiatry 2010;167(10):S9–118.

[17] Warburton W, Hertzman C, Oberlander TF. A register study of the impact of stopping third trimester selective serotonin reuptake inhibitor exposure on neonatal health. Acta Psychiatr Scand 2010;121(6):471–9.

[18] Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid ver- sus gradual discontinuation of antidepressants. Am J Psychiatry 2010;167(8): 934–41.

[19] Cooper WO, Willy ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am J Obstet Gynecol 2007;196(544):e1–5.

[20] Chambers DC, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Lyons Jones K, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 2006;354(6):579–87.

18 Antidepressants in Pregnancy

19 Courtney D. Cuppett and Steve N. Caritis

Uterine Contraction Agents and Tocolytics

19.1 Introduction 307

. 19.2  Uterine contraction agents (uterotonics) 307

. 19.3  Uterine relaxation agents (tocolytics) 316

19.1 Introduction

Human parturition is a complicated process that is not yet com- pletely understood. There are several pathways through which parturition can be initiated. The process itself begins long before “labor” can be clinically detected. Both biochemical and hor- monal factors prepare the uterus and cervix for delivery of the fetus. Physicians have long sought to identify drugs that could be used to both induce and arrest labor. Medications currently used for these purposes are referred to as uterotonics and toco- lytics, respectively. Some of these medications have additional indications such as the treatment of uterine atony or cervical ripening. Most are not FDA approved and their use in obstet- rics is considered off-label. This chapter will serve to review the indications, mechanism of action, dosing, and evidence to support the use of the most common uterotonics and tocolytics prescribed in modern obstetric practice.

19.2 Uterine contraction agents (uterotonics)

Uterotonics are by far the most common drugs administered on any labor and delivery suite. Clinically, they are used primarily for labor induction/augmentation and to control postpartum

308 19.2 Uterine contraction agents (uterotonics)

hemorrhage. All agents in this category cause uterine contraction, but each does so through a different pathway. It is important to have a working knowledge of each medication, as each can cause as much harm as good.

19.2.1 Pitocin (oxytocin)

Pitocin is one of the most potent uterotonic agents available. It is currently approved for medically indicated labor induction (i.e. premature rupture of membranes, diabetes, hypertension, preeclampsia, etc.), labor augmentation, and as an adjunctive therapy in the management of an incomplete or inevitable abortion. Additionally, Pitocin is a rst-line agent for the treat- ment of postpartum hemorrhage secondary to uterine atony or subinvolution [1].

Pitocin is a polypeptide composed of nine amino acids. It is iden- tical in structure to its endogenous counterpart, oxytocin. Pitocin stimulates uterine contractions by increasing intracellular calcium. Pitocin binds to the oxytocin receptor located on the myometrial cell membrane and stimulates phospholipase C (Figure 19.1). This

Figure 19.1 Contractant and relaxant pathways of a myometrial cell. Ptase – Phosphate kinase; MLCK – Myosin light-chain kinase; CaCAM – Calcium–calmodulin complex; CAM – Calmodulin; PLC – Phospholipase C; PIP2 – Phosphatidylinositol 4,5-biphosphate IP3 – Inositol triphosphate; Pg – Prostaglandin; Oxy – Oxytocin; SPR – Sarcoplasmic reticulum

19 Uterine contraction agents and tocolytics 309

leads to increased production of inositol triphosphate which acts to mobilize intracellular calcium by promoting release from the sarcoplasmic reticulum [2]. Binding to the oxytocin receptor also induces an in ux of extracellular calcium through nonselective, cation channels on the myometrial cell membrane [2]. Intracel- lular calcium then binds with calmodulin to form the calcium– calmodulin complex. This complex activates myosin light-chain kinase (MLCK), the key regulator of smooth muscle contractility [3]. MLCK phosphorylates myosin which in turn binds actin, ini- tiating myometrial smooth muscle contraction.

Pitocin is widely distributed throughout the extracellular uid, and has a half-life of 3–10 minutes [4–7]. Pitocin is primarily metabolized by the kidney, and it is rapidly removed from plasma. This rapid metabolism can in part be attributed to the 50% increase in glomerular ltration rate observed during pregnancy. Addition- ally, the half-life is further reduced in late pregnancy and during lactation secondary to inactivation by oxytocinase [7].

At least 4–5 half-lives are necessary for a drug administered intravenously as a continuous infusion to achieve steady state [8, 9]. Steady state is the point where the plasma concentration is stable such that the full effect of that concentration of the med- ication will be observed. This is the basis for the recommenda- tion to increase a Pitocin infusion every 40 minutes (10 minute half-life×4 half-lives). However, when infusion protocols start at 1 mU/min, a great deal of time is required to achieve a clinical response. Thus, Pitocin is typically increased at more frequent intervals with close maternal and fetal monitoring.

Currently, there is no consensus regarding the optimal dosing reg- imen for Pitocin for labor induction or augmentation. Both low and high dose protocols have been shown to be safe and effective [10]. Both meta-analysis and a randomized controlled trial report that high dose protocols with infusion increases at shorter intervals are associated with shorter labor, decreased chorioamnionitis, decreased need for cesarean section secondary to labor dystocia, and less neo- natal sepsis [11, 12]. However, these protocols are also associated with tachysystole with associated fetal heart rate changes [11, 12].

Suggested Pitocin regimens start at 0.5–6 mU/min, with increases of 1–6mU/min every 15–40 minutes. Studies have shown that infusion rates up to 6mU/min result in plasma concentrations of Pitocin similar to concentrations achieved during spontaneous labor [13]. The maximum dose of Pitocin has not been established, but most protocols do not exceed 42 mU/min [14].

Pitocin is also used as an adjunctive therapy for incomplete, inevitable, and elective abortions in the rst and second trimester. It can be administered after delivery of the placenta to aid with

19 Uterine Contraction Agents and Tocolytics

310 19.2 Uterine contraction agents (uterotonics)

uterine contraction and hemostasis. This can usually be achieved with standard postpartum Pitocin protocols (10 units in a 500cc bag of normal saline administered over 3–4 hours). High dose Pitocin protocols have been described and shown to be as effec- tive as other methods of midtrimester labor induction. One can refer to Ramsey and Owen’s review entitled “Midtrimester cervi- cal ripening and labor induction” for speci c protocols [15].

In the postpartum setting, Pitocin is considered a rst-line agent for the treatment of uterine atony. It can be administered as a bolus of 3–6 units intravenous (IV), as a continuous infu- sion of 10–40 units in 1 liter of normal saline (NS) infused at a rate adjusted to control uterine atony (range 10–80IU/1L NS, with higher doses considered safe), or as an intramuscular injection of 10 units directly into the thigh, gluteal muscle, or myometrium [16].

Pitocin is considered a pregnancy category C drug because of the potential for fetal hypoxia in the setting of uterine tachysys- tole. Appropriate precautions (i.e. administration via an infusion pump, continuous fetal and uterine monitoring, and immediate availability of obstetrician) should always be taken to ensure patient safety. Additional maternal side effects include nausea, vomiting, and hyper- or hypotension. A rare but serious mater- nal side effect is water intoxication secondary to the antidiuretic properties of Pitocin. This condition has been reported in women who received Pitocin in D5 water and/or high dose protocols (>20mU/min) for prolonged periods of time. To avoid this, it is recommended that Pitocin be administered with an isotonic saline solution, strict intake and output should be monitored, and, per product labeling, the total Pitocin dose should not exceed 30 units in a 12 hour period [1].

19.2.2 Methergine (methylergonovine)

Methergine, a semi-synthetic ergot alkaloid, is a potent uterotonic that increases the force and frequency of uterine contractions at low doses. At higher doses, methergine can increase basal uterine tone and cause uterine tetany. In obstetrics, methergine is indi- cated for the treatment of postpartum hemorrhage secondary to uterine atony or subinvolution [17].

The uterotonic properties of ergot alkaloids have been known for centuries. Their use as a labor stimulant was rst described by Adam Louicer in 1582 [18]. Although the uterine effects of ergots were discovered hundreds of years ago, the exact mechanism by which methergine causes myometrial contraction is not known. Ergot alkaloids are known to cause vasoconstriction, uterine con- tractions, and stimulation of central dopamine receptors [18].

19 Uterine contraction agents and tocolytics 311

Ergots have been shown to bind alpha adrenergic, serotonin (5-HT), and dopamine D1 receptors [19]. Based on several stud- ies, it is likely that methergine speci cally interacts with alpha adrenergic receptors on the myometrial cell (Figure 19.1). This interaction alters transmembrane calcium channel activity, caus- ing an in ux of calcium into the myometrial cell and activation of the contraction cascade [18, 20, 21].

After oral administration or intramuscular injection, methergine is rapidly absorbed and distributed throughout the plasma and extracellular uid. Approximately 25% more medication is absorbed via the intramuscular route compared to oral [17]. Methergine is metabolized by the liver and excreted in the urine. The half-life of methergine is 3.4 hours (1.5–12.7 hours) when administered intramuscularly [17].

In the setting of postpartum hemorrhage, the preferred dose and route of methergine administration is 0.2mg intramuscu- larly every 2–4 hours, for a maximum of ve doses. It can also be directly injected into the uterus; however, one should be careful to avoid intravascular administration as this has been reported to result in acute coronary vasospasm and/or myo- cardial infarction [22–24]. Alternatively, the medication can be administered orally at a dose of 0.2mg every 6–8 hours for 2–3 days (maximum of 7 days).

Methergine should be avoided by those who are pregnant, those with uncontrolled hypertension, and those with a sensi- tivity to the drug. Methergine use in postpartum women with preeclampsia should only be considered if the bene ts outweigh the risks. Common side effects include nausea, vomiting, hyper- or hypotension, and headache. Patients should be monitored closely for any adverse side effects after administration of the drug [17].

19.2.3 Prostaglandins

Prostaglandins are potent uterotonics with utility in several circumstances in obstetrics including facilitation of second trimester abortion, cervical ripening, labor induction, and the treatment of postpartum hemorrhage. For the purposes of this chapter we will focus on their effect on the uterus in the setting of postpartum hemorrhage. The prostaglandins used to treat postpartum hemorrhage include 15-methyl PGF2α (Carboprost, Hemabate), Prostin E2 (dinoprostone), and Prostaglandin E1 (Misoprostol, Cytotec).

The prostaglandins used in obstetric practice are synthetic ana- logs of endogenous prostaglandins which are cyclic, unsaturated

19 Uterine Contraction Agents and Tocolytics

312 19.2 Uterine contraction agents (uterotonics)

C20 fatty acids [25]. Prostaglandins are grouped into subtypes (A,B,C,D,E,F,G,H,I,J,K) according to the chemical substitution on the pentane ring. Speci c to obstetrics, the F subtype has two hydroxyl groups on the pentane ring and the E subtype has one keto and one hydroxyl group [25] (Figure 19.2).

O

COOH

    

HO

O

OH

  

COOH

    

HO HO

HO

OH

OH

Figure 19.2 Prostaglandin E1, Prostaglandin E2, and Prostaglandin F2α.

PGE 1

PGE 2

COOH

PGF2α

19 Uterine contraction agents and tocolytics 313

Prostaglandins cause uterine contractions by altering mem- brane permeability and increasing intracellular calcium [25–27]. They promote the formation of gap junctions, facilitating trans- mission of signals throughout the myometrium [28]. Additionally, they upregulate the expression of oxytocin receptors in the uterus which in turn promotes contractility [28] (Figure 19.1).

The synthetic prostaglandins are rapidly absorbed and dis- tributed systemically in the plasma. The half-life of endogenous prostaglandins ranges from a few seconds to minutes as they are rapidly metabolized in the lungs and liver. The synthetic prosta- glandins have much longer half-lives ranging from 2.5 to 5 minutes for Prostin E2 (dinoprostone), approximately 35 to 40 minutes for PGF2α (Hemabate, Carboprost), and 20 to 40 minutes for PGE1 (Misoprostol, Cytotec) [29–31]. All are excreted via the kidneys.

For the treatment of postpartum hemorrhage, prostaglandins are either second- or third-line agents depending on patient co- morbidities. For instance, in patients with hypertension, after oxytocin a prostaglandin would be a more appropriate second- line agent than would an ergot alkaloid. Among the various prostaglandins, the second and third generation formulations (15-methyl PGF2α and PGE1) are preferred over rst genera- tion formulations (PGE2), as the side effect pro le is somewhat improved.

15-Methyl PGF2α (Hemabate, Carboprost) is administered at a dose of 0.25mg IM (or intramyometrial) every 15–90 minutes with an eight dose (or 2mg) maximum. PGE1 (Misoprostol, Cyto- tec) is administered at a dose of 800–1000mcg and placed rec- tally. Prostin E2 (dinoprostone) can be used as a 20mg rectal or vaginal suppository (Table 19.1).

Two studies have shown rectal Misoprostol to be as effective as oxytocin for the management of the third stage of labor in the pre- vention of hemorrhage [32, 33]. However, because of the better side effect pro le and cost, Pitocin is the preferred rst-line agent.

15-Methyl PGF2α (Hemabate, Carboprost) should be avoided in patients with asthma or pulmonary disease as it can cause acute bronchoconstriction. Prostin E2 (dinoprostone) should be avoided in women with hypotension as it can acutely drop the diastolic blood pressure. There are no absolute contraindications to PGE1 (Misoprostol, Cytotec) for the treatment of postpartum hemorrhage other than sensitivity to the drug.

Common side effects of all the prostaglandins above include abdominal pain, diarrhea, nausea, vomiting, headache, paresthe- sias, fever, and shivering. The side effect pro le improves with second and third generation formulations (PGF2α and PGE1). All patients should be monitored for the development of side effects after administration of the medication.

19 Uterine Contraction Agents and Tocolytics

314 19.2 Uterine contraction agents (uterotonics)

 

Table 19.1 Uterotonics Drug

Clinical indication

Route

Dose

Frequency

Considerations

Pitocin (oxytocin)

Induction/ augmentation of labor

Intravenous

Low dose regimen: start at 0.5–1 mU/ min

Increase by 1–2 mU/ min every 15–40 min, maximum dose 42 mU/ min

Titrate to maternal response and fetal tolerance

Postpartum hemorrhage

Intravenous Intravenous Intramuscular

3–6 IU as bolus

Once Continuous Once

Monitor for hypotension, especially with IV administration

High dose regimen: start at 4–6 mU/ min

Increase by 4–6 mU/ min every 15–40 min, maximum dose 42 mU/ min

Titrate to maternal response and fetal tolerance

10–80 IU in 1L of normal saline

10 IU (thigh, gluteal, or myometrial)

19 Uterine contraction agents and tocolytics 315

      

Methergine (methylergonovine)

Postpartum hemorrhage

Intramuscular 0.2 mg Oral 0.2 mg

Can repeat dose every 2–4 hours, maximum 5 doses

Avoid in women with uncontrolled HTN. Use in women with preeclampsia or HTN should only be considered if bene ts outweigh risk

Hemabate (15-methyl PGF2α)

Postpartum hemorrhage

Can repeat dose every 15–90 minutes (maximum 8 doses or 2 mg)

Avoid in patients with asthma or pulmonary disease, can cause bronchoconstriction

Cytotec (Misoprostol, PGE1)

Postpartum hemorrhage

Intramyometrial 0.25 mg
Rectal 800–1000 mcg

Single dose Once

No absolute contraindications other than sensitivity to the drug

Dinoprostone (Prostin E2)

Postpartum hemorrhage

Rectal or vaginal 20 mg suppository

Avoid in hypotensive patients

HTN – Hypertension; CNS – Central nervous system.

19 Uterine Contraction Agents and Tocolytics

Intravenous – Intramuscular 0.25 mg

Avoid, can cause severe HTN, CNS and coronary artery vasospasm, and hemorrhage

Can repeat dose every 6–8 hours for 2–3 days (maximum 7 days)

316 19.3 Uterine relaxation agents (tocolytics) 19.2.4 Uterotonics summary

n These medications are powerful tools in an obstetrician’s arma- mentarium that can be used for both labor induction/augmen- tation and control of postpartum hemorrhage.

n All of these medications have extensive side effect pro les and the potential for maternal and/or fetal toxicity. Thus, a good understanding of their administration and dosing is essential for safe and effective use.

Uterotonics: Pitocin, methergine, and prostaglandins:

n In general, this class of medications works to promote myo- metrial contraction by increasing intracellular calcium concentrations.

n Pitocin increases intracellular calcium via the phospholipase C/IP3 pathway.

n Methergine is thought to bind to alpha adrenergic receptors on the myometrial cell and alter transmembrane calcium channel activity, resulting in calcium in ux.

n Prostaglandins not only increase intracellular calcium by alter- ing transmembrane permeability, but they also promote gap junction formation and upregulate expression of oxytocin receptors.

19.3 Uterine relaxation agents (tocolytics)

Preterm birth is a leading cause of neonatal morbidity and mor- tality worldwide. There are several pathogenic processes that can trigger uterine contractions and cervical dilation with subse- quent delivery of the preterm neonate. The goal of tocolysis is to arrest uterine contractions and prolong pregnancy to allow for administration of steroids and possibly transport to a tertiary care center. Available treatments are intended to arrest uterine con- tractility and are not necessarily geared toward the underlying pathogenic process initiating labor. It is important to acknowl- edge that studies evaluating tocolytics are limited and dif cult to analyze secondary to signi cant bias and inherent design aws. Additionally, there is a paucity of placebo-controlled trials assessing the ef cacy of these medications. Thus, the literature is somewhat limited regarding optimal tocolytic therapy and current protocols are based on the best available evidence. Pres- ently, no agent is FDA approved for this indication and all are used off-label (Table 19.2).

19 Uterine contraction agents and tocolytics 317

 

Table 19.2 Tocolytics

Drug Nifedipine

Indication* Acute tocolysis

Route

Dose

Frequency

Considerations

Terbutaline

Acute tocolysis (48–72 hours)

Subcutaneous

250 mcg every 20–30 min until contractions arrest (4 dose maximum)

Once tocolysis achieved, can repeat dose every 3–4 hours for 24–48 hours

Monitor for maternal side effects including tachycardia, ushing, dizziness, hyperglycemia, hypo-/hypertension, pulmonary edema/ARDS, and myocardial ischemia/infarction.

(48–72 hours)

Oral (short acting only)

Loading dose: 10–20 mg every 15–30 min (max 40 mg in rst hour)

10–20 mg every 6–8 hours for 48–72 hours

Monitor for maternal side effects including hypotension, ushing, nausea, headache, dizziness, anxiety, cough, and dyspnea

Acute tocolysis (48–72 hours)

Intravenous

2.5–5 mcg/min continuous infusion

Increase 2.5–5 mcg/min every 20–30 min, maximum 25 mcg/min

Titrate infusion to uterine quiescence or maternal side effects. Maternal heart rate should not exceed 120 bpm

Tachysystole Tachysystole

Subcutaneous Intravenous

250 mcg 125 mcg

Usually single dose Usually single dose

19 Uterine Contraction Agents and Tocolytics

Sublingual/oral (short and long acting)

Loading dose: 10–40 mg short acting medication sublingual

60–160 mg long acting medication daily

Maternal heart rate should not exceed 120 bpm

(Continued)

318 19.3 Uterine relaxation agents (tocolytics)

       

Table 19.2 Tocolytics—cont’d

Drug Indomethacin

Indication* Acute tocolysis

Route

Dose

Frequency

Considerations

Nitroglycerin Atosiban

Acute uterine or cervical relaxation

50–200 mcg

Can consider repeating dose after 1–4 min if inadequate response

Monitor for hypotension and uterine atony

Magnesium sulfate

Acute tocolysis (48–72 hours)

4–6 g loading dose

2–4 g/hour titrated to uterine response and maternal toxicity

Avoid in patients taking other calcium channel blockers and in patients with myasthenia gravis. Mentioned for historical purposes only, medication is not effective for tocolysis

(48–72 hours)

Oral/rectal Intravenous Intravenous Intravenous

50–100 mg loading dose

25 mg every 4–6 hours

May cause signi cant maternal GI upset. Fetal surveillance with use >48 hours

Acute tocolysis (48–72 hours)

6.75 mg bolus followed by 300 mcg/min infusion for 3 hours

100 mcg/hour for up to 45 hours

Medication not approved for use in United States

*None of the medications are FDA approved, all are used off-label. †Medication is not approved for use in United States. ‡Medication has not been shown to be effective for tocolysis.

19 Uterine contraction agents and tocolytics 319 19.3.1 Magnesium sulfate (MgSO4)

Magnesium sulfate was rst used as a tocolytic in the 1960s after it was shown to reduce uterine contractility both in vitro and in vivo [34]. Magnesium acts via extracellular and intracellular mechanisms to decrease intracellular calcium concentrations, thereby preventing the contractile response [35]. However, a large randomized controlled trial and a meta-analysis have shown it to be no better than placebo for preterm birth prevention [36, 37]. Additionally, compared to other tocolytic agents that affect intracellular calcium, magnesium has similar ef cacy but a much higher rate of drug discontinuation secondary to maternal side effects. Thus, we are mentioning this drug for historical purposes only and do not recommend its use as a tocolytic.

19.3.2 β-Adrenergic-receptor agonists

β-Adrenergic-receptor agonists have been studied extensively in several randomized controlled trials with comparisons to both placebo and other tocolytics. A meta-analysis of these studies comparing β-adrenergic-receptor agonists to placebo indicate that β-adrenergic-receptor agonists signi cantly delay delivery and reduce the incidence of preterm birth and low birth weight [38]. No signi cant decrease in perinatal/neonatal death or respiratory distress syndrome was observed. Among women who received a β-adrenergic-receptor agonist, there was a 37% reduction of pre- term birth within 48 hours (RR 0.63; 95% CI 0.53–0.75). How- ever, there was no signi cant decrease in the number of births within 7 days.

β-Adrenergic-receptor agonists work to arrest uterine contrac- tions by binding β2-adrenergic receptors on the myometrial cell (Figure 19.1). This interaction leads to increased levels of cyclic AMP which activates protein kinase. Protein kinase inactivates myosin light-chain kinase thus preventing uterine contractility [39].

Among the β-adrenergic-receptor agonists, ritodrine and ter- butaline have been the two medications most commonly used for labor inhibition. Historically, ritodrine was the only medica- tion ever to receive FDA approval for uterine tocolysis. How- ever, this medication was voluntarily removed from the US market by the manufacturer after cases of maternal death were reported in the setting of ritodrine-induced pulmonary edema [40, 41]. Currently, the only β-adrenergic-receptor agonist used in the United States for uterine tocolysis is terbutaline. Recently, the FDA issued a black box warning regarding the use of ter- butaline for tocolysis. The warning states that oral terbutaline

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320 19.3 Uterine relaxation agents (tocolytics)

should not be used for the prevention or treatment of preterm labor because it has not been shown to be effective and has the potential for serious maternal heart problems and death. Inject- able terbutaline should not be used for the prevention or pro- longed treatment (>48–72 hours) of preterm labor because of similar safety concerns [42].

Typically, terbutaline is administered for acute tocolysis intra- partum in the setting uterine tachysystole with associated fetal distress. Additionally, it can be used for uterine relaxation prior to external cephalic version and/or maternal/fetal surgery.

For preterm labor tocolysis, 250mcg of terbutaline can be administered subcutaneously every 20–30 minutes up to four doses or until tocolysis is achieved. A dose of 250mcg may then be repeated every 3–4 hours for 24–48 hours depending on uterine activity and maternal hemodynamic response [43]. For acute tocolysis in the setting of uterine tachysystole with associated fetal heart rate changes, a dose of 250mcg subcuta- neous or 125 mcg intravenous can be administered. The medi- cation should be held if the maternal heart rate is >120 beats per minute [44]. The medication is rapidly absorbed, the onset of action typically occurs within 5–15 minutes after subcutane- ous dosing. It is faster with intravenous administration. The half-life of the medication in pregnancy is 3.7 hours [45]. The majority of the medication is eliminated unchanged via the kid- ney [46].

The drug can also be administered as a constant intravenous infusion with escalating doses. The infusion is generally started at 2.5–5mcg/min; this can be increased every 20–30 minutes by 2.5–5mcg/min to a maximum dose of 25mcg/min [44, 47]. The infusion can be titrated until uterine quiescence or maternal side effects occur. Once uterine quiescence is achieved, the infusion can be reduced by 2.5–5mcg/min to the lowest dose that main- tains quiescence. Again, the maternal heart rate should not exceed 120 beats per minute.

This medication has an extensive side effect pro le includ- ing: tachycardia, ushing, nervousness, dizziness, hyperglycemia, hypokalemia, and hyperthyroidism. More serious side effects including cardiac arrhythmia, hypo-/hypertension, pulmonary edema/acute respiratory distress syndrome, and myocardial isch- emia/infarction have been reported with an incidence of 0.3–5%. Maternal death has been reported in the setting of long-term use (injectable or oral use) [40, 41]. Care should be taken when administering terbutaline to women with diabetes; terbutaline should be avoided in pregnant women with either preexisting or pregnancy-related cardiac disease.

19 Uterine contraction agents and tocolytics 321 19.3.3 Nitric oxide donors

Nitric oxide is a potent vasodilator and smooth muscle relaxant produced by a variety of cells. Nitric oxide relaxes smooth muscle via interaction with guanylyl cyclase (Figure 19.1). This interac- tion increases guanosine monophosphate (cGMP), which in turn inactivates myosin light-chain kinase leading to smooth muscle relaxation [48, 49].

Nitroglycerin (NG) is more commonly used for acute uterine relaxation in the setting of uterine inversion, or to facilitate exter- nal cephalic version, fetal delivery at the time of c-section, uterine relaxation for fetal surgery, and/or to relieve fetal head entrap- ment with vaginal breech delivery. It has been shown to be an effective uterine/cervical relaxant when administered at a dose of 100–200 mcg IV [50]. The half-life of NG is very short at 1–4 min- utes [51]. Common side effects include hypotension, ushing, and headache. One may encounter uterine atony after administration, thus, uterotonics should be readily available.

Nitroglycerin has been studied in randomized controlled trials as a tocolytic. Intravenous nitroglycerin was shown to be inferior to magnesium sulfate as a tocolytic [52]. Transdermal nitroglyc- erin was found to be superior to placebo and similar to ritodrine with respect to delaying delivery for 48 hours [53, 54]. Although nitroglycerin has been shown to delay delivery, its use as a toco- lytic is limited secondary to the potential for signi cant maternal hypotension [55].

19.3.4 Calcium channel blockers

Calcium channel blockers are commonly used as rst-line agents for acute tocolysis. Calcium channel blockers work to relax smooth muscle by directly blocking entry of calcium ions into the myometrial cell and through prevention of intracellular calcium release from the sarcoplasmic reticulum (Figure 19.1). Calcium is necessary for myosin light-chain kinase (MLCK)-mediated phosphorylation. In the absence of calcium, MLCK is inactivated resulting in myometrial relaxation [56, 57].

Nifedipine is the most common calcium channel blocker used for acute tocolysis. A systematic review of 26 randomized con- trolled trials involving 2179 women compared nifedipine to other tocolytics [58]. Compared to β-adrenergic-receptor agonists, nifedipine reduced the risk of delivery within 7 days of initiation and before 34 weeks’ gestation, and reduced the risk of respira- tory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, neonatal jaundice, and admission to the neonatal intensive care unit. There was no difference in tocolytic ef cacy

19 Uterine Contraction Agents and Tocolytics

322 19.3 Uterine relaxation agents (tocolytics)

between nifedipine and magnesium sulfate; however, there were fewer maternal adverse events associated with nifedipine. Main- tenance tocolysis with nifedipine (>48 hours) was ineffective in prolonging gestation or improving neonatal outcomes when com- pared with placebo or no treatment. To date, there have been no placebo-controlled trials studying the ef cacy and safety of nife- dipine for acute tocolysis.

The optimal dosing regimen of nifedipine for tocolysis has not been established. Numerous studies have reported that the peak serum concentration and half-life of nifedipine are signi cantly reduced, while the clearance rate is increased during pregnancy [59]. Concentrations peak in 30–60 minutes and the half-life is 1–2 hours in pregnant women (compared to 2–4 hours in non- pregnant state). Approximately 40% of the drug is inactivated by rst pass metabolism in the liver (CYP3A4); 70–80% of the metab- olites are excreted renally [59]. These alterations in the pharmaco- kinetics of nifedipine observed during pregnancy limit the duration of action to 6 hours and necessitate more frequent dosing [59].

Common dosing regimens for tocolysis include a 10–20mg loading dose of nifedipine administered orally every 15–30 min- utes for the rst hour of treatment (maximum dose of 40 mg in the rst hour). An alternate loading dose is 20 mg administered orally followed by an additional 20mg dose 90 minutes later. Mainte- nance treatment (for 48–72 hours) can be dosed at 10–20mg every 4–8 hours. The dose or frequency can be adjusted to lessen maternal side effects and achieve tocolysis. Alternatively, a combi- nation of sublingual and long acting nifedipine has also been stud- ied and shown to have similar ef cacy to intravenous ritodrine [60, 61]. This regimen consists of 10–40mg of sublingual nifedip- ine followed by 60–160mg of long acting nifedipine daily. With either strategy, we recommend limiting the maximum daily dose to 120mg per day, although others have reported using higher daily doses [62].

Common side effects include hypotension, ushing, nausea, headache, dizziness, anxiety, cough, and dyspnea. Thus, patients should be counseled and advised to monitor for symptoms. Addi- tionally, maternal blood pressure should be monitored closely as acute hypotension can result in fetal heart rate changes and lead to maternal syncope.

19.3.5 Cyclooxygenase inhibitors (COX inhibitors)

Cyclooxygenase inhibitors are commonly used in obstetrics for acute tocolysis and as an intervention for preterm cervical short- ening. COX inhibitors prevent the conversion of arachidonic acid

19 Uterine contraction agents and tocolytics 323

to prostaglandin. Prostaglandins have a signi cant role in the labor process by stimulating myometrial gap junction formation and by increasing the intracellular calcium levels [63]. Thus, COX inhibitors work to inhibit labor through the prevention of prosta- glandin formation (Figure 19.1).

The most common COX inhibitor used for tocolysis is indo- methacin. Indomethacin is typically administered as a loading dose of 50–100mg orally or rectally, followed by 25mg orally every 4–6 hours [64–66]. Oral indomethacin is rapidly absorbed and distributed systemically in the plasma with 99% being pro- tein bound [67]. The half-life of the medication is approximately 4.5 hours [67]. It is eliminated via metabolism, renal and biliary excretion [67].

Two randomized controlled trials have compared indometha- cin tocolysis to placebo [68, 69]. In the rst, 30 patients were randomized to receive either indomethacin or placebo for the treatment of preterm labor [68]. This study reported that indo- methacin was signi cantly more effective than placebo for pre- venting preterm labor during a 24-hour course of treatment (1/15 treatment failures in indomethacin group compared to 9/15 in placebo group). Although indomethacin was more effec- tive for acute preterm labor prevention, there was no signi cant difference in gestational age at delivery or neonatal outcomes between the groups. A second trial randomized 34 women to receive either indomethacin or placebo for preterm labor treat- ment [69]. The primary outcome of this study was perinatal mortality and neonatal morbidity. Indomethacin was found to be more effective than placebo for prolonging gestation for >48 hours (81% in indomethacin group compared to 56% in placebo group). Additionally, there was no difference in perinatal mor- tality or neonatal morbidity between the two groups. Additional trials have shown indomethacin to be as effective as magnesium sulfate and β-adrenergic-receptor agonists for acute tocolysis (delay delivery by 48 hours) [66, 70–72]. In all of these trials, indomethacin was better tolerated by the patient. Recently, a comparative effectiveness trial showed indomethacin to be infe- rior to nifedipine for immediate tocolysis (relief of symptoms within 2 hours), but equivalent to nifedipine for delaying deliv- ery for up to 48 hours or for 7 days [73]. Indomethacin may also be effective in prolonging pregnancy in women with a short cervix. However, data supporting this use are limited and mostly retrospective.

Long-term indomethacin use requires close fetal surveillance. Indomethacin can cause premature closure of the fetal ductus arteriosus and oligohydramnios. Neither of these complications

19 Uterine Contraction Agents and Tocolytics

324 19.3 Uterine relaxation agents (tocolytics)

has been reported in the setting of short-term tocolysis (≤48 hours) prior to 34 weeks’ gestation; however, they have been reported with long-term use [74–76]. A recent retrospective cohort study looking at 124 women who received prolonged antenatal indo- methacin reported a 6.5% rate of ductal constriction and a 7.3% rate of oligohydramnios [77].

Indomethacin is known to be a potent vasoconstrictor of fetal vessels. Indomethacin blocks the production of prostaglandins, which are necessary to maintain a patent ductus arteriosus. This can result in ductus arteriosus constriction or closure. The mecha- nism by which indomethacin causes oligohydramnios is through reduced perfusion of the fetal kidney with a subsequent decrease in fetal urine production. The reduction in perfusion is thought to be caused by suppression of renin activity and/or vasoconstriction of the renal arteries [78]. Both fetal ductus arteriosus constric- tion and oligohydramnios will typically resolve with cessation of indomethacin.

Thus, women treated with indomethacin for longer than 48 hours should have weekly fetal echocardiograms to monitor for ductal constriction/closure (between 24 and 32 weeks) and weekly ultrasound evaluation for oligohydramnios. The medica- tion should be discontinued with abnormal testing or at 30–32 weeks’ gestation, whichever occurs rst. Although early obser- vational studies also reported an increased risk of necrotizing enterocolitis and intraventricular hemorrhage with antenatal indomethacin administration, a recent meta-analysis by Loe et al. of 1621 neonates exposed to antenatal indomethacin found no increased risk of intraventricular hemorrhage, ductus arteriosus closure, necrotizing enterocolitis, or mortality [79]. The study cautiously endorsed indomethacin use for tocolysis, but called for additional, adequately powered randomized controlled trials to further clarify the controversy.

Gastrointestinal upset is a common maternal side effect of indomethacin. Thus, we recommend an H2 blocker or proton pump inhibitor for gastrointestinal prophylaxis with long-term maternal use.

19.3.6 Oxytocin receptor antagonists (atosiban)

Atosiban is not available for use in the United States. It is currently used throughout Europe for acute tocolysis. The drug itself is a selective oxytocin–vasopressin receptor antagonist that competitively inhibits oxytocin from binding to its receptors in the myometrium and decidua (Figure 19.1).

19 Uterine contraction agents and tocolytics 325

Several trials have compared atosiban to placebo or other toco- lytics. A meta-analysis of 1695 women found that compared to placebo, atosiban did not reduce the incidence of preterm birth or improve neonatal outcome [80]. One randomized controlled trial carried out in the United States reported a trend toward higher rates of fetal death in women treated with atosiban [81]. These results may have been confounded by infection and extreme pre- maturity; however, an association with atosiban could not be excluded. Thus, the United States FDA denied approval of atosi- ban for tocolysis secondary to safety concerns [82].

19.3.7 Tocolytics summary

n There is an overwhelming abundance of data regarding tocolyt- ics; however, the studies are often awed and their results are dif cult to interpret and implement in clinical practice.

n It is important to choose a tocolytic based on ef cacy and safety, and the choice at times will be patient and situation speci c (i.e. not administering indomethacin to a patient greater than 32 weeks’ gestation or adjusting the nifedipine dose for a patient with mild hypotension).

n It is important to remember appropriate fetal surveillance when indicated, especially with indomethacin administration.

Tocolytics: Magnesium sulfate, β-adrenergic-receptor agonists, nitric oxide donors, calcium channel blockers, COX inhibitors, and oxytocin receptor antagonists:

n Magnesium is thought to function as a calcium channel blocker, thereby reducing intracellular calcium and preventing myome- trial contraction.

n β-Adrenergic-receptor agonists bind β2-adrenergic receptors on the myometrial cell. This interaction leads to increased cAMP and activation of protein kinase. Protein kinase inactivates MLCK and prevents contraction.

n Nitric oxide donors relax smooth muscle via interaction with guanylyl cyclase. This leads to increase cGMP and inactivation of MLCK.

n Calcium channel blockers both directly block the entry of cal- cium ions into the myometrial cell and prevent intracellular cal- cium release from the sarcoplasmic reticulum.

n COX inhibitors prevent prostaglandin formation and thus block their contractile effects on the myometrium.

n Oxytocin receptor antagonists competitively inhibit oxytocin from binding oxytocin receptors.

19 Uterine Contraction Agents and Tocolytics

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[74] Zuckerman J, Shalev E, Gilad G, Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part I. J Perinat Med 1984;12:19–23.
[75] Dudley DK, Hardie NJ. Fetal and neonatal effects of indomethacin used as a

tocolytic agent. Am J Obstet Gynecol 1985;151:181–4.
[76] Niebyl JR, Witter FR. Neonatal outcome after indomethacin treatment of pre-

term labor. Am J Obstet Gynecol 1986;155:747–9.
[77] Savage AH, Anderson BL, Simhan HS. The safety of prolonged indomethacin

therapy. Am J Perinatol 2007;24(4):207–13.

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. [78]  Abou-Ghannam G, Usta IM, Nassar AH. Indomethacin in pregnancy: applica- tion and safety. Am J Perinatol 2012;29(3):175–86.

. [79]  Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal safety of indomethacin: a systematic review with meta-analysis. Obstet Gynecol 2005;106(1):173–9.

. [80]  Papatsonis D, Flenady V, Cole S, Liley H. Oxytocin receptor antagonists for inhibiting preterm labor. Cochrane Database Syst Rev 2005;3:CD004452.

. [81]  Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Vellie JC, Tabor B,
et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000;182:1173–83.

. [82]  www.fda.gov/ohrms/dockets/ac/98/transcpt/3407t1.rtf (accessed August 27, 2011).

20 Shannon M. Clark and Gary D.V. Hankins

Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

. 20.1  Thyroid function and physiology in pregnancy 331

. 20.2  Hyperthyroidism in pregnancy 333

. 20.3  Pharmacotherapy with thionamides in pregnancy 336

. 20.4  Hypothyroidism in pregnancy 339

. 20.5  Pharmacotherapy with levothyroxine in pregnancy 342

. 20.6  Summary 344

20.1 Thyroid function and physiology in pregnancy

In pregnancy, abnormalities of thyroid gland can be easily over- looked due to the normal physiologic changes of pregnancy often mimicking disturbances of thyroid gland function. As a result, basic knowledge of thyroid gland function and the changes the thyroid gland undergoes during the course of pregnancy are essential. Regulation of the thyroid gland and its hormones is controlled through an endocrine feedback loop that includes the hypothalamus and anterior pituitary [1]. The hypothalamus initi- ates this feedback loop with the release of thyrotropin-releasing hormone (TRH), which in turn regulates the release of thyroid- stimulating hormone (TSH) from thyrotrope cells in the anterior pituitary. TSH then prompts the release of thyroid hormones T4 and T3 from the thyroid gland. Abnormal production of T4 and T3 occurs with hyperthyroidism and hypothyroidism in the preg- nant patient, with various etiologies accounting for the observed abnormal levels.

332 20.1 Thyroid function and physiology in pregnancy
Table 20.1 Maternal thyroid function testing and associated physiologic alterations in normal

pregnancy

TBG TSH FT3

. TT3  Plasma iodide FT4

. TT4  Hepatic clearance

Thyroid gland size

hCG Albumin

The physiologic changes of pregnancy affect thyroid function in numerous ways. The thyroid gland itself increases in size and can be newly palpable on physical examination. This increase in size is due to an increase in thyroid volume, the formation of new thyroid nodules, and/or increased iodine turnover [2, 3]. These changes normally occur without any signi cant change in thyroid hormone levels. Although the formation of thyroid nodules can occur dur- ing pregnancy, any palpable nodule should be evaluated with an ultrasound of the thyroid gland [1]. The observed increase in iodine turnover and subsequent depletion of the maternal iodine pool is predominantly a result of a reduction in serum iodine due to fetal use of maternal iodine and increased maternal renal clearance of iodine, resulting in an increase in thyroid gland size in 15% of pregnant women [4–6]. As pregnancy progresses maternal renal clearance of iodine increases due to an increase in renal blood ow and glomeru- lar ltration rate, which further increases iodine clearance [7]. Physi- cal examination of the thyroid gland during pregnancy is important on entry to care, especially if the patient is exhibiting potential signs or symptoms of thyroid gland dysfunction. (See Table 20.1.)

The physiologic changes of thyroid gland function particularly dur- ing the rst trimester of pregnancy are well documented. TSH and human chorionic gonadotropin (hCG) are glycoproteins that share similar alpha subunits. This similarity between the alpha subunits results in negative feedback on the pituitary by hCG and decreased TSH production [5, 8]. As hCG levels continue to rise during the rst trimester, TSH levels decline by approximately 20–50% reach- ing a maximal decrease at 8–14 weeks’ gestation [5, 9, 10]. In fact, TSH levels may decrease below the lower limit of normal in up to 20% of women with little clinical consequence [8]. As a result of this decrease in TSH, FT4, and FT3 levels may slightly increase and even

Increased

Decreased

No change

  

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 333 Table 20.2 Maternal thyroid disease and relation to TSH and FT4

TSH

FT4

Subclinical hyperthyroidism (or GTT) Hyperthyroidism Subclinical hypothyroidism Hypothyroidism

Decreased Decreased Increased Increased

Normal to high-normal Increased Normal to low-normal Decreased

reach high-normal levels. The observed changes in TSH, FT4, and FT3 levels is referred to as transient subclinical hyperthyroidism or gestational transient thyrotoxicosis (GTT). It occurs in 10 to 20% of pregnant women and typically does not require treatment [1, 11]. In the second and third trimester TSH levels will start to rise due to the increased renal clearance of iodine and placental degradation of thyroid hormone, and FT4 and FT3 levels will then start to decrease back into normal range [1]. (See Tables 20.1 and 20.2.)

Although circulating T4 and T3 are predominantly bound (>99%) to the carrier proteins thyroid binding globulin (TBG) and albumin, it is the free hormone (<1%) that is biologically active. During pregnancy, serum TBG levels increase two- to three-fold due to increased TBG synthesis through the effects of increased estrogen and by decreased hepatic clearance [5, 8, 12]. Increased TBG leads to a rise in total T4 (TT4) and T3 (TT3) concentrations by approximately 50% starting at 6 weeks of gestation without sig- ni cantly altering free T4 (FT4) and T3 (FT3) concentrations [1, 6, 13, 14]. In addition, the thyrotrophic effect of hCG likely further contributes to the increase in TT4 and TT3 concentrations [15]. Since FT4 and FT3 are the biologically active hormones, unaltered levels of FT4 and FT3 ideally allow the pregnant patient to remain euthyroid. Although there can be a transient rise in FT4 during the rst trimester due to increasing levels of hCG and its interaction with TSH, TSH will start to increase in the latter trimesters result- ing in a fall in FT4 [16]. Overall, the FT4 levels should remain within normal range, and FT3 levels will parallel that of FT4 and remain in the normal reference range as well [16]. (See Table 20.1.)

20.2 Hyperthyroidism in pregnancy

Hyperthyroidism occurs in 0.2% of pregnant women, or 1 in every 1000–2000 pregnancies [13, 17, 18]. The causes of hyperthyroidism are multiple and include nodular goiter, solitary toxic adenoma,

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

334 20.2 Hyperthyroidism in pregnancy

gestational trophoblastic disease, subacute and lymphocytic thy- roiditis and tumors of the pituitary gland or ovary [8]. Graves’ dis- ease is the most common cause in pregnancy and occurs in 85–95% of all pregnant patients with hyperthyroidism [8, 19]. It is an auto- immune disease caused by autoantibodies, or stimulatory TSH- receptor antibodies (TRAb), that activate the TSH-receptor and stimulate the thyroid to produce an excessive amount of thyroid hormone [1]. These TRAb cause thyroid hyperfunction and thyroid gland hypertrophy, although there is no correlation between levels of antibody activity and disease severity [8]. The diagnosis may be particularly dif cult if the patient presents in the rst trimester, but the symptoms speci c to hyperthyroidism should help to con rm the diagnosis. Symptoms include tachycardia, nervousness, trem- ors, heat intolerance, weight loss, goiter, frequent stools, excessive sweating, insomnia, palpitations, hypertension, ophthalmopathy, and dermopathy [8, 20]. Any combination of these symptoms in concert with abnormal laboratory testing (TSH, FT4) and the pres- ence of TRAb should con rm the diagnosis.

As previously discussed, GTT can occur in the rst trimester of pregnancy due to the cross-reactivity of the alpha subunits of TSH and hCG. During this period of gestation, differentiating between GTT and true Graves’ disease is important as the former is expected to resolve spontaneously without intervention and the latter requires therapeutic intervention. If the TSH is sup- pressed and the FT4 is elevated, the diagnosis is overt hyper- thyroidism, and laboratory assays of TRAb, thyroid stimulatory immunoglobulins (TSI) or thyroid-stimulating hormone-binding immunoglobulins (TBII) will likely be abnormal. If the TSH is suppressed and the FT4 is normal to high-normal, laboratory assays of TRAb should be considered, especially if the diagnosis of hyperthyroidism versus GTT cannot be readily made [21]. If TRAb are normal, the diagnosis is GTT or subclinical thyrotoxi- cosis. If elevated levels of TRAb exist, the diagnosis is hyperthy- roidism. Furthermore, elevated TRAb levels carry a prognostic value for fetal and neonatal thyrotoxicosis as TRAb can cross the placenta resulting in neonatal thyrotoxicosis in 1–5% of neonates of mothers with Graves’ disease [10, 21]. If high titers persist in the third trimester, fetal or neonatal hyperthyroidism is more likely to develop [22]. Such a complication is more likely if maternal Graves’ disease has been dif cult to control or there has been a delay in diagnosis [6]. Once the diagnosis of hyperthyroid- ism is established, consideration for evaluation of TRAb levels in early pregnancy and again in the third trimester to assess for the potential of neonatal disease is recommended by some [21]. (See Tables 20.2 and 20.3.)

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 335 Table 20.3 Maternal thyroid disease, thyroid antibodies, and neonatal effects

TSH receptor antibodies (TRAb) Thyroglobulin antibodies (TgAb) – thyroid stimulatory immunoglobulins Thyroid peroxidase antibodies (TPOAb) (TSI): can cause neonatal thyrotoxicosis –neither affect fetal thyroid gland function – thyroid-stimulating hormone-binding

immunoglobulins (TBII): can cause hypothyroidism or transient neonatal hypothyroidism

GTT (suppressed TSH and normal-high normal FT4) is the diag- nosis if there are no TRAb, thyroid nodules, goiter, or orbitopathy present, and there is no maternal history of Graves’ disease [15, 21]. Once the diagnosis of GTT is con rmed, the patient can be reassured that symptoms and laboratory abnormalities will be resolved without intervention. Of note, the increase in hCG that is associated with GTT is also a contributor to the development of hyperemesis gravi- darum (HG). However, GTT more speci cally refers to the transient elevation of FT4 and FT3 associated with the decrease in TSH in the rst trimester, whereas HG is the more severe form of nausea and vomiting in pregnancy (NVP) seen in the rst trimester [21]. Abnormal thyroid function tests similar to that observed in GTT, consisting of elevated FT4 and suppressed or undetectable TSH, are found in about 60% of women with HG with levels typically nor- malizing after 16–20 weeks [23]. Finally, newly diagnosed cases of overt hyperthyroidism can present with HG or NVP, making thyroid function testing essential. In this scenario, once therapy is initiated, symptoms resolve with successful treatment of the disease [6].

Uncontrolled or poorly controlled hyperthyroidism in pregnancy has signi cant maternal and fetal/neonatal effects. Maternal com- plications include heart failure, preeclampsia, and thyroid storm, which can be precipitated by labor and delivery, infection, or pre- eclampsia. When considering the fetus, there is an increase in fetal loss, low birth weight, preterm labor, and congenital malformation [24, 25]. As stated earlier, the neonate can be affected by the trans- placental transfer of TRAb [26, 27]. Furthermore, the fetus may also develop tachycardia and goiter in utero due to the presence of these antibodies, and in severe cases cardiac failure and fetal hydrops can occur. There is not a general consensus on whether to routinely fol- low TRAb in a patient with Graves’ disease. However, if the patient is poorly controlled, continues to be symptomatic, or is noncompli- ant, evaluation of TRAb should be strongly considered.

Hyperthyroidism

Hypothyroidism

 

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

336 20.3 Pharmacotherapy with thionamides in pregnancy 20.3 Pharmacotherapy with thionamides in

pregnancy

Once the diagnosis of hyperthyroidism is made, prompt initiation of treatment with thionamides is recommended. Thionamides inhibit thyroid hormone synthesis by interfering with thyroid peroxidase-mediated iodination of tyrosine residues in thyroglob- ulin, an important step in the synthesis of T4 and T3 [28]. Pro- pylthiouracil (PTU) and methimazole (MMI) are the mainstays of treatment in pregnancy. PTU has historically been used more commonly in the US because it was believed that PTU crossed the placenta to a lesser degree than MMI due to the increased protein binding of PTU, therefore decreasing the chance of induc- ing fetal hypothyroidism and causing fetal anomalies. In addition, the association of MMI with aplasia cutis, a fetal scalp defect, and “MMI embryopathy”, characterized by facial abnormalities and choanal atresia, growth restriction, developmental abnormalities and esophageal atresia/tracheo-esophageal stula, has minimized its use in the US [29]. It has been suggested that PTU be used in the rst trimester and MMI thereafter, with continuation of MMI therapy postpartum [30].

Despite the fact that it has been proven that PTU and MMI cross the placenta equally and have equal chance of inducing fetal and/or neonatal hypothyroidism and goiter and fetal anomalies, there is still a continued preference of PTU over MMI use in preg- nancy [31–33]. In an analysis of 643 neonates from mothers with Graves’ disease, Momotani et al. were unable to demonstrate any signi cant teratogenic effects in those infants whose mothers took MMI [24]. In fact, signi cant teratogenicity was only observed in the neonates of mothers with untreated, uncontrolled hyperthy- roidism. Finally, Chen et al. did a matched case–control study of 2830 mothers with hyperthyroidism and 14,150 age-matched con- trols to compare the risk of adverse pregnancy outcomes among pregnant women with hyperthyroidism who were receiving PTU, MMI or no medical treatment [34]. They found that women tak- ing PTU had an increased risk of having a low birth weight infant when compared to women not receiving treatment. In contrast, women taking MMI during pregnancy did not have an increased risk of any adverse fetal outcomes when compared to women not receiving treatment.

The goal of treatment is to keep the patient euthyroid with maternal FT4 within the high-normal range, or in the upper one- third of each trimester-speci c reference interval, in order to avoid fetal hypothyroidism, goiter, and abnormal brain development

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 337

from transplacental passage of thionamides [8, 30]. As a result, the lowest possible dosage of PTU or MMI should be used while adequately controlling the signs and symptoms of hyperthyroid- ism. MMI can be given once daily because it has a longer duration of action than PTU. The oral dosing regimen of MMI is typically started at 10 to 15mg a day and adjusted accordingly, with the maximum dose being 40 mg a day. As symptoms improve, a main- tenance dose of 5–15 mg a day is usually suf cient. Because of its shorter half-life, less thyroidal tissue concentration, and decreased maximal concentration when compared to MMI, PTU requires twice daily to three times daily dosing in pregnancy. As a result, PTU is not ideal for the noncompliant patient, and appropriate dosing may be dif cult to both determine and achieve. PTU is started at 100–150mg every 8–12 hours up to a maximum dose of 600–800mg a day [18, 35]. A maintenance dose of 50–150mg a day is ideal. If a patient requires more than 300mg a day, dos- ing every 4–6 hours is recommended [36]. Monitoring of thyroid function tests (TSH, FT4, FT3) every 4 weeks is recommended after initiation of therapy in the mildly symptomatic patient. This can be decreased to every 6 weeks once the patient is euthyroid. Although information on the effectiveness of PTU versus MMI in the treatment of hyperthyroidism in pregnancy is limited, studies thus far have shown that they are equally effective. In a retrospec- tive cohort study by Wing et al. examining the maternal and fetal outcomes of 185 patients treated for hyperthyroidism with PTU or MMI, both drugs were found to be equally effective, with similar rates of normalization of thyroid hormone levels [37]. Finally, the pharmacokinetics of PTU and MMI do not appear to differ sig- ni cantly in the pregnant and non-pregnant patient in the limited number of studies addressing this issue.

Therapy with PTU and MMI can be started at moderate doses in order to bring the disease under control more quickly, i.e. in cases with a large goiter or signi cant symptoms. MMI can be started at 20–30 mg a day in divided doses and PTU can be started at 100 mg three times daily for a period of 2–3 days, with tapering once symptoms are under control. Treatment with PTU and MMI may take 6–8 weeks to see a change both clinically and in labo- ratory assessments. After initiation of therapy with higher doses, thyroid function tests (TSH, FT4, FT3) should be evaluated in 2 weeks followed by levels every 4–6 weeks depending on response to therapy. When monitoring response to therapy, normalization of FT4 precedes that of FT3 making FT4 a better indicator for the adjustment of medication dosage [38]. However, maternal TSH may remain suppressed for weeks to months following nor- malization of FT4 [21]. Monitoring of maternal thyroid function

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

338 20.3 Pharmacotherapy with thionamides in pregnancy

frequently during pregnancy is important in order to avoid over- treatment and the potential development of fetal hypothyroidism and goiter, especially when starting at a higher dose [21]. Approx- imately, 25% of cases of transient neonatal hypothyroidism can be attributed to treatment of maternal hyperthyroidism with thi- onamides, which can cause neuropsychological damage in severe cases when the fetus is overtreated [31].

Although maternal Graves’ disease is associated with the pas- sage of TRAb across the placenta to the fetus, whether or not to check antibody levels during pregnancy is debated. In those patients who enter pregnancy with a history of Graves’ disease, but who have no active disease and do not need treatment, neo- natal hyperthyroidism may still occur [16]. As a result, it is argued that TRAb should be monitored, and if the level is high, the fetus should be evaluated early in gestation and at 32–36 weeks. If there is a detectable level of TRAb at 32–36 weeks, evaluation of the neonate for hyperthyroidism is warranted [16]. If the patient enters pregnancy already on adequate treatment and is asymp- tomatic, there is usually no need to measure TRAb as clinical and laboratory maternal thyroid function gives a reliable estimate of fetal thyroid status and the risk of neonatal hyperthyroidism is very low in these cases [16]. In those patients where therapy can be stopped, discontinuation of PTU or MMI should occur no later than 36–37 weeks if maternal and fetal conditions are stable and allow for discontinuation of therapy [39]. Whether or not TRAb are followed, serial sonograms and fetal heart rate monitoring to assess the fetus for tachycardia, goiter, and growth are recom- mended during the course of the pregnancy [39]. (See Table 20.3.)

The occurrence of minor and major side effects with the use of thionamides does not appear to change in frequency in preg- nancy. Minor side effects occur in approximately 5% of patients and include the development of a papular urticarial rash, pruritus, joint pain, headache, nausea, and hair loss [36, 40, 41]. These side effects can often be managed conservatively with antihista- mines, by switching therapy, or stopping treatment [28]. How- ever, if arthralgias develop this may indicate the development of severe transient migratory polyarthritis, or “antithyroid arthritis syndrome”, and discontinuation of thionamide therapy is rec- ommended [28]. The more major side effects include drug fever, bronchospasm, agranulocytosis, hepatotoxicity, and vasculitis, which includes a lupus-like syndrome [8, 42, 43]. Agranulocyto- sis, believed to be autoimmune mediated, occurs in approximately 0.35% of patients taking thionamides and 0.1% of patients taking PTU [8, 44]. It has been associated with higher doses of MMI, but is not related to any particular dosage of PTU. Agranulocytosis is

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 339 Table 20.4 Maternal side effects with thionamides

Minor (5% of patients)

Major

Papular urticarial rash

Pruritus Joint pain Headache Nausea Hair loss

Arthralgias – severe transient migratory polyarthritis, or “antithyroid arthritis syndrome”

Drug fever

Bronchospasm

Agranulocytosis – 0.35% (more common with PTU)

Hepatotoxicity – 0.1–0.2% (more common with PTU)

Vasculitis – “lupus-like” syndrome (more common with PTU)

 

a contraindication to further thionamide therapy [8]. A baseline white blood cell count should be obtained prior to starting ther- apy, and if fever and sore throat develop, agranulocytosis should be suspected and therapy immediately stopped. Hepatotoxicity, in the form of allergic hepatitis followed by hepatocellular injury, is reported to occur in 0.1–0.2% of patients and is more common with PTU [40]. Vasculitis, which is considered to be autoimmune mediated as in agranulocytosis, is also a major side effect and is more common with PTU than MMI. (See Table 20.4.)

20.4 Hypothyroidism in pregnancy

Hypothyroidism occurs in 2.5% of pregnant women with approximately 1–2% of patients entering prenatal care already on thyroid replacement therapy for hypothyroidism [45, 46]. Most patients diagnosed in pregnancy are asymptomatic but are found to have an elevated TSH on antenatal screening [16]. The percentage of pregnant women with abnormal TSH that have autoimmune thyroiditis (AITD) is 40–60% compared to a prev- alence of 7–11% of antibody-positive non-pregnant women in the same age range [45]. In pregnant women TSH is the pri- mary screening test for thyroid disease and should especially be obtained in high-risk women, those with other autoimmune dis- eases (i.e. diabetes), thyroid nodules, or goiter, exposure to radia- tion, or personal or strong family history of thyroid disease [1]. Of note, women can have a rm painless goiter and be euthyroid initially during pregnancy, but then become hypothyroid as the pregnancy progresses [8].

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

340 20.4 Hypothyroidism in pregnancy

The most common cause of hypothyroidism in pregnancy is a primary thyroid abnormality known as Hashimoto’s thyroiditis, or chronic autoimmune thyroiditis (AITD), which is caused by the presence of thyroid antibodies [15]. In this disorder, titers of antithyroglobulin antibodies (TgAb) are elevated in 50–70% of patients and almost all patients have antithyroid peroxidase antibodies (TPOAb) present [47]. TPOAb are also found in 10% of euthyroid women in early pregnancy and are associated with the subsequent development of hypothyroidism during pregnancy [48]. In addition, the presence TPOAb at 32 weeks of gestation is associated with a signi cant decrease in the IQ of children even if the mothers were euthyroid [49]. Although TgAb and TPOAb are known to cross the placenta during the last trimester, they do not negatively affect fetal thyroid function [15]. Conversely, TRAb and TBII also cross the placenta, and if the patient has a high titer of one or both of these antibodies, the fetus is at risk for hypothy- roidism or transient neonatal hypothyroidism [50, 51]. TRAb are found in less than 1% of pregnancies and as previously discussed indicate the presence of Graves’ disease [19]. (See Table 20.3.)

The signs and symptoms of hypothyroidism are similar in the non-pregnant and pregnant patient, and some symptoms are con- sidered to be a normal response to the hypermetabolic state of pregnancy [45]. Symptoms include modest weight gain, lethargy, decrease in exercise capacity, intolerance to cold, constipation, hoarseness, hair loss, dry skin, goiter, or delayed relaxation of the deep tendon re exes [8]. A combination of these symptoms may be seen with overt hypothyroidism or symptoms may be subtle and thus attributed to the normal physiologic changes of preg- nancy. If hypothyroidism is suspected at any point during preg- nancy, serum TSH and FT4 should be measured. If the TSH is above normal and/or the FT4 is below normal, hypothyroidism should be suspected. Measurement of thyroid antibodies, TgAb and TPOAb, can be obtained to aid in the diagnosis especially when TSH and FT4 levels are not tting the typical pattern for hypothyroidism. If serum TSH is greater than 4 mU/L and/or FT4 is below normal, regardless of the presence of thyroid antibodies, the thyroid is likely underfunctioning and replacement is needed [45]. If the TSH is less than 2mU/L, regardless of thyroid anti- body status, treatment is not indicated, but monitoring of thyroid function tests throughout pregnancy is warranted. If the TSH is 2–4mU/L and thyroid antibodies are positive, treatment is usu- ally necessary. The decision to treat in this scenario can be based on FT4 levels. If FT4 is low to low-normal, treatment is bene cial [45]. Finally, as mentioned above, the presence of TPOAb and a normal to high-normal TSH level at the beginning of pregnancy

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 341

has been shown to correlate positively with the risk of develop- ing hypothyroidism in pregnancy [21]. As a result, if the decision is made not to initiate treatment, monitoring with TSH and FT4 during pregnancy is recommended.

Subclinical hypothyroidism (elevated TSH and normal to low- normal FT4) occurs in up to 2.5% of pregnancies, with a majority of patients being asymptomatic [10]. The decision as to whether or not to treat these patients has been controversial [46]. However, recent evidence suggests that treatment with thyroid hormone replacement in this setting is not harmful and in fact is likely advantageous for the patient and fetus [52–55]. It is well estab- lished that normal maternal thyroid function is essential for nor- mal fetal brain and neurologic development [39]. As a result, a diagnosis of subclinical hypothyroidism warrants thyroid replace- ment in order to keep maternal FT4 and FT3 levels in the normal to high-normal range and allow for normal fetal neurodevelop- ment [45, 55–60]. In addition, subclinical hypothyroidism has been associated with other adverse maternal–fetal outcomes. In a retrospective cohort study of nearly 26,000 pregnant women screened for TSH levels, those with subclinical hypothyroidism had three times the incidence of placental abruption and almost twice the incidence of preterm birth at less than 34 weeks [55, 61]. Finally, in the 62 pregnant women who had TSH levels at or above the 98% for pregnancy, IQ testing of their children at ages 7–9 showed that they performed slightly less well on all tests when compared to controls [55]. Although routine screening for subclinical hypothyroidism is not recommended by ACOG, other societies do recommend it [62]. The decision to screen at this time is based on provider preference.

Although the most common cause of hypothyroidism world- wide is iodine de ciency, it is typically not a cause in the US due to dietary iodine supplementation [8]. It is well established that the transplacental passage of maternal T4 is necessary for fetal brain development during the rst trimester as the fetal thyroid has yet to develop and start producing its own thyroid hormones. As a result, lack of maternal iodine during the rst trimester may lead to impaired fetal neurological development. Furthermore, if there is inadequate iodine substrate for the fetal thyroid gland to use once it has developed, the fetus is unable to synthesize its own thyroid hormones [8]. In fact during the second trimester, when there is development of the fetal brain, fetal thyroxine is derived almost exclusively from the mother [45, 63]. If a woman enters pregnancy with low iodine levels, the available iodine can decrease even further due to the increased renal clearance of iodine and the fetal–placental unit competing for available iodine [64, 65].

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

342 20.5 Pharmacotherapy with levothyroxine in pregnancy

Severe iodine de ciency during the rst trimester causes cretin- ism, with infants developing severe mental retardation, deafness, muteness, and pyramidal symptoms [8]. Other causes of maternal hypothyroidism include history of radioactive iodine treatment for Graves’ disease or thyroidectomy, subacute viral thyroiditis, suppurative thyroiditis, and hypothyroidism secondary to pitu- itary disease [8, 66]. Some drugs, i.e. ferrous sulfacrate, sucralfate, carbamazepine, phenytoin, and rifampin, can also depress thyroid function causing symptomatic hypothyroidism.

There are signi cant consequences of unrecognized or under- treated hypothyroidism in pregnancy. In general, there is an association between hypothyroidism and decreased fertility which is primarily due to ovulatory disturbances attributed to modi ed levels of gonadotropin, estradiol, testosterone, and sex hormone-binding globulin (SHBG) [45, 67]. When a hypothy- roid woman does become pregnant there is an increased rate of miscarriage, anemia, postpartum hemorrhage, preeclampsia, placental abruption, growth restriction, prematurity and still- birth, neonatal respiratory distress and impaired neurologic development of the fetus [8, 68]. Furthermore, the presence of thyroid antibodies in the maternal circulation is associated with a two- to three-fold increased risk for preterm delivery and lower birth weight [69]. In addition, the presence of circulating thy- roid antibodies in the maternal circulation is associated with an increased rate of early spontaneous abortions in both the overt hypothyroid patient and in the patient that is euthyroid [70, 71]. As a result, the presence of thyroid immunity represents an inde- pendent marker of an at-risk pregnancy [45]. Finally, because diabetes and thyroid disorders are both autoimmune conditions, monitoring the hypothyroid patient for the development of dia- betes is important.

20.5 Pharmacotherapy with levothyroxine in pregnancy

Treatment with thyroid hormone replacement should be initiated once the diagnosis of hypothyroidism is made so that potential adverse obstetrical outcomes, especially abnormal fetal neurode- velopment, can be minimized. Levothyroxine (LT4) is the drug of choice for thyroid hormone replacement therapy in pregnancy. Synthetic LT4 is a levo-isomer of thyroxine with identical activ- ity to the endogenous hormone [72]. It has a long half-life (6–7 days), thus allowing once daily dosing [73]. LT4 is converted to

20 Antenatal thyroid disease and pharmacotherapy in pregnancy 343

T3 supplying active hormone in the maternal circulation, with T3 concentrations rising much later than T4 concentrations due to the time needed for conversion of T4 to T3 [72, 73]. The initial dose is typically between 100 and 150mcg a day, with dosage adjustments every 4 weeks to keep the TSH at the lower end of normal and the FT4 and FT3 at the upper limit of normal [8]. The goal of therapy is to keep TSH between 0.5 and 2.5mIU/L and FT4 in the upper normal range. Monitoring of thyroid function is accomplished through routine measurement of maternal serum TSH and FT4.

If the patient is newly diagnosed in pregnancy and she is symp- tomatic and with signi cantly abnormal thyroid function testing, treatment with LT4 may be initiated at a dose that is 2–3 times the estimated maintenance dose for a period of 2–3 days [45]. This approach should allow for rapid normalization of the T4 pool and circulating T4 levels, and euthyroidism can be achieved more quickly [45]. In this scenario, TSH and FT4 should be evaluated 2 weeks after initiation of therapy rather than 4 weeks. As the pregnancy progresses, it is not uncommon for T4 requirements to increase due to increased maternal demand and the decreased maternal intestinal absorption that is associated with prenatal iron replacement therapy [8]. As a result, patients should be instructed to take their iron and thyroxine at least 4 hours apart to minimize the effect of the decreased intestinal absorption. (See Table 20.2.)

Women who enter pregnancy on LT4 will often require an increase in dosage as early as the fth week of gestation in order to stay euthyroid [21, 59, 60]. Ideally this should be accomplished before the onset of pregnancy, but the patient can immediately increase her pre-pregnancy maintenance dose once pregnancy is diagnosed. The dose of LT4 may need to be increased even further as the pregnancy progresses. This is a result of the estrogen-depen- dent increase in serum TBG concentration, increased placental production of Type II and III deiodinases that degrade T4 and increased tissue volume of distribution, which all contribute to the decrease in serum maternal T4 [5, 74, 75]. Typically a 40–50% increase in dosage (50–100mcg a day) is necessary in 75–85% of patients, and this increase should occur in the rst trimester in order to minimize the morbidities associated with undertreatment of maternal hypothyroidism [16, 21, 60, 76, 77]. Women with a history of radioiodine ablation for hyperthyroidism tend to need a more signi cant increase in LT4 dosage, whereas women with AITD typically need a smaller increase in dosage [45]. Women on a minimal dosage of LT4 for a diagnosis of subclinical hypothy- roidism may not require any change in dosage with the onset of pregnancy [45].

20 Antenatal Thyroid Disease and Pharmacotherapy in Pregnancy

344 References 20.6 Summary

To date, much is known about thyroid and maternal physiology and how they interplay during the course of the gestation; how- ever, the physiologic changes of pregnancy can not only make the diagnosis of maternal thyroid disease dif cult, but make appropri- ate pharmacotherapy more challenging as well. Adequate treat- ment of hyperthyroidism and hypothyroidism is necessary not only to treat the mother, but also to allow for normal fetal neurodevel- opment. Despite a wealth of evidence that MMI is equally as safe in pregnancy as PTU, there still remains a divide on whether MMI can be used in the rst trimester or throughout the gestation. A trial is desperately needed in order to quell these concerns. In addi- tion, pharmacokinetic and pharmacodynamic studies on each of these drugs throughout the different gestations of pregnancy are largely lacking, and more information in these areas would likely put to rest any concerns that remain on whether MMI is safe to use, especially in the rst trimester. When considering hypo- thyroidism, the data largely suggest that treatment of subclinical hypothyroidism is bene cial for the fetus. However, many preg- nant women are still not treated when subclinical hypothyroid- ism is diagnosed. More research into the bene ts of treatment is warranted in order to make treatment of subclinical hypothyroid- ism commonplace in obstetrics. Finally, as with the antithyroid drugs, pharmacokinetic and pharmacodynamic studies on thyroid replacement drugs are needed in order better to understand how pregnancy affects their pharmacotherapeutic pro les.

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21 Maria-Magdalena Roth and Caius Solovan

Dermatological Medications and Local Therapeutics

. 21.1  Introduction 349

. 21.2  Acne 350

. 21.3  Psoriasis 352

. 21.4  Bacterial infections 354

. 21.5  Viral infections 356

. 21.6  Fungal infections 356

. 21.7  Parasitic infections 357

. 21.8  Antipruritics 358

. 21.9  Glucocorticosteroids 360

. 21.10  Immunomodulators/immunosuppressive therapy 361

. 21.11  Analgesics 361

. 21.12  Antiseptics (disinfectants) 363

21.1 Introduction

With change as the only constant element during pregnancy or in the postpartum period the clinical practitioner may be confronted with a variety of clinical scenarios of different skin conditions. In this context, when facing pregnant or lacta- tion patients (or patients considering pregnancy), physicians’ portfolio of clinical options generally consists of:

1. the postponement of the treatment, especially for the common dermatoses which do not necessitate immediate therapy,

350 21.2 Acne

2. the preservation of the treatment, but under strict supervi- sion (if the used medication is considered safe in pregnancy or unlikely to cause fetal malformations),

3. the revision of the treatment and the search for safe alterna- tives, or

4. the temporary interruption of breastfeeding (with the patient pumping breast milk) and the resuming of breastfeeding at the end of the treatment.
However, the ethically induced absence of controlled studies or

clinical trials on medication safety during pregnancy and also the existence of multiple yet disuni ed Pregnancy Risk Assessment Systems (e.g. Australia, Switzerland, Denmark, or Sweden) are severely increasing the dif culty and the complexity of treatment.

This chapter provides a set of updated practical therapeutic options tailored to the particular clinical scenarios of frequent skin conditions like acne, psoriasis, and bacterial, viral, fungal, and parasitic skin infections, including the clinically recom- mended doses for all the drugs involved in the medication. The minimization of any possible fetal risk and of the increase of the maternal body weight during pregnancy act as critical therapeutic lters in all treatments. In addition, the chapter covers the use and administration of antipruritics, glucocorticosteroids, immu- nomodulators, analgesics, and antiseptics.

21.2 Acne
21.2.1 Systemic treatment for acne

Erythromycin (category B) is the antibiotic of choice when systemic therapy is needed for gestational acne [1], yet with some important safety-related speci cations. More speci cally the use of erythromycin esolate should be avoided in all stages of pregnancy since according to some studies [2] extended exposure to the drug (more than 3 weeks) might trigger mater- nal subclinical hepatotoxicity (cholestatic hepatitis) in up to 10–15% cases. Moreover, clinicians should refrain from using erythromycin in early pregnancy, due to possible risks of car- diovascular malformations after oral maternal ingestion of the substance [3–5].

The recommended oral dose is 400 mg every 8 hours (maximum 2g/day), administered 1 hour before meals [6], the drug being compatible with lactation (although 50% of the medication passes into the breast milk) [2].

21 Dermatological medications and local therapeutics 351

Of note, tetracycline (category D) – the rst-line treatment in the case of non-pregnant patients – is considered extremely unsafe for pregnant/lactating patients. According to multiple studies, administration of tetracycline after the rst trimester of pregnancy exhibits associations with decreased bony growth, deciduous den- tal staining in offspring, and fatty liver atrophy (a rare syndrome) in the mother [1, 3].

Other systemic drugs used in normal acne treatment, like isotretinoin or tazarotene, are contraindicated during pregnancy and lactation (they belong to category X). Isotretinoin manifests a teratogenic effect during gestation with the possible development of malformations such as central nervous system defects, craniofa- cial defects, cardiovascular defects, thymic defects etc. In particu- lar, since only one dose of isotretinoin can cause embriopathia, patients with childbearing potential should be allowed to conceive only after a period of a minimum of 1 month after administration. On the other hand, despite clinical evidence presenting six cases of women having healthy babies after taking tazarotene, its admin- istration has been proved to cause multiple retinoid-like mal- formations in animals studies [1, 2], thus maintaining the drug’s classi cation as extremely risky and absolutely contraindicated during pregnancy/lactation.

21.2.2 Local treatment for acne

Whenever the pregnant/lactating mother opts not to postpone the acne treatment until the postpartum/post-lactation period, topical therapy represents the method of choice. In this context, the prescribed medication consists of erythromycin (category B) 1–3% in petroleum jelly once daily; clindamycin (category B) 1% once daily; or benzoyl peroxide (category C) 2.5% once daily, all with a clinical history which quali es them as safe [2, 7]. Topical metronidazol (category B) 0.75% once daily is also considered to be a safe alternative in the treatment of acne, and also in the treat- ment of rosacea [1]. Azelaic acid (also in category B) represents another therapeutic option, with studies in animals revealing no mutagenic, teratogenic, or embryotoxic effects after its administra- tion [8] and also a systemic absorption of less than 4% after one application [2]. Yet, as in the case of any substance with a short market history, it is recommended rather as a marginal option, at least for a while.

In addition, there is no scienti c consensus regarding tretinoin (category C). Although generally classi ed as a safe alternative therapy during pregnancy [7], several published case reports link the intake of the medication during the rst trimester of pregnancy

21 Dermatological Medications and Local Therapeutics

352 21.3 Psoriasis

with subsequent fetal malformations, thus recommending its avoidance [9, 10]. A similar situation is recorded also in the case of another topical retinoid adapalene (category C), the use of which was causally linked with congenital ocular anomaly reports [11]. Tazarotene (category X) is absolutely contraindicated (see systemic treatment).

21.3 Psoriasis
21.3.1 Systemic treatment for psoriasis

Cyclosporine (category C) – an immunosuppressive agent which mostly inhibits the T helper lymphocytes – is considered an acceptable alternative in psoriatic patients during pregnancy (in doses of 3–5mg/kg/day) [12, 13], as its administration revealed no teratogenic effects in pregnant patients who had had an organ transplant [14]. Its introduction, however, should seriously take into consideration the extent to which the potential ben- e ts outweigh the potential risks. Of extreme importance is the fact that the drug is contraindicated during lactation due to its possible immunosuppressive dimension, to its unknown effects on fetal growth and carcinogenesis [15]. Other systemic thera- pies, based on acitretin (category X) or methotrexate (category X), rst-line treatments in non-pregnant psoriatic patients, are absolutely contraindicated in pregnancy. Acitretin, a systemic retinoid, is known to have a strong teratogenic effect and a long persistence in the adipose tissue, thus recommending the avoid- ance of pregnancy for up to 3 years in the case of the patients treated with the substance. Methotrexate, an antagonist of folic acid, is also known to have a teratogenic effect and to cause fetal malformations like anencephalus, cleft palate, abnormal ears or skeletal abnormalities [1]. Due to these aspects, all patients with childbearing potential should be advised to conceive only after a period of a minimum 1 month after the last administration of the substance.

On the other hand, the limited published data on the safety of biologic agents restricts their status to that of a relatively marginal alternative for the treatment of psoriasis during pregnancy.

However, when biologics are chosen, the portfolio of thera- peutic options consists of category B agents like alefacept, in ix- imab, adalimumab, and etanercept [1, 3]. In this context, clinical data from animal reproduction studies, and also evidence from

21 Dermatological medications and local therapeutics 353

women unaware of their pregnancy to whom alefacept (category B) – a mouse analog of efalizumab (category C) – was admin- istered in the incipient phase of gestation, reveal no proof of teratogenicity [16]. Similarly, etanercept (category B) is also considered safe in pregnancy, with no malformations reported in both animal studies and contextual human data from patients treated for rheumatoid arthritis [17]. Another clinical study on 65 pregnant patients treated with etanercept (B) or in iximab (B), revealed no evidence of teratogenicity for either substance [18]. Of interest is the study of Carter et al. [19], who reported adverse effects after anti-TNF therapy (etanercept or in iximab), consisting of 61 congenital abnormalities in 41 women. Fifty- nine percent of the newborns presented one or more congenital anomalies of what was de ned as the VACTERL syndrome – anomalies of the vertebrae (V), anal atresia (A), cardiovascular defects (C), tracheal (T), esophageal (E), renal system (R), and limb (L) abnormalities.

21.3.2 Local treatment for psoriasis

The use of keratolytics (salicylates with concentrations of 2–10% in petroleum jelly) administered once daily is consid- ered safe if performed only for short periods of time and only for small skin surfaces [20]. Likewise, the therapy based on mild to moderate topical corticosteroids (category C) and cal- cipotrione ointment (category C), considered the rst-line and most ef cacious topical therapy for patients with localized pso- riasis, is also considered safe for use in pregnancy [21, 22]. Of note, according to pharmacokinetic notes 3% of the topical application of the corticosteroid is absorbed after 8 hours of contact with normal skin, and approximately 6% of calcipotri- one ointment is absorbed systemically following contact with psoriatic plaques [1]. Special caution is, however, needed with the super-potent/potent topical corticosteroids, as their appli- cation on a big surface of the body is considered to have the same effects as systemic therapy with steroids [2]. Another safe option for the local treatment of psoriasis during pregnancy is tacrolimus (category C), a topical calcineurin inhibitor which has been reported to have no teratogenic or fetal loss effects, after being tested in animal reproduction studies [6, 22]. Other medications frequently administered in the case of non-preg- nant psoriatic patients, like anthralin (category C) – an anthra- cenic compound – or coal tar products (category C) must be avoided, due to their relatively high mutagenic and carcino- genic potential [23, 24].

21 Dermatological Medications and Local Therapeutics

354 21.4 Bacterial infections 21.3.3 Phototherapy

Narrowband ultraviolet B therapy is frequently conceptualized as a second-line treatment for localized psoriasis [25]. In particular, whenever the therapy based on topical corticosteroids and calci- potrione ointment proves inef cient and the lesions are becom- ing extensive, ultraviolet B phototherapy (either narrowband or broadband) is the treatment of choice [22, 25]. However, in this case, caution must be taken in order to avoid any overheating during treatment.

On the other hand, pregnant patients should avoid – whenever possible – the psoralen plus ultraviolet A (PUVA) therapy, due to its possible mutagenic effects [26–28] in spite of studies reporting no adverse reactions in more than 30 pregnant women exposed to PUVA therapy [27, 29]. One interesting side note, especially regarding patients with localized palmo-plantar psoriasis, is the absence of a rise in blood levels of 8-methoxypsoralen after topi- cal PUVA [28].

21.4 Bacterial infections
21.4.1 Systemic treatment of bacterial infections

The rst-line treatment with antibiotics during pregnancy consists of erythromycin (category B) and penicillins (category B). Over- all, erythromycin (with the exception of erythromycin esolate) is classi ed as safe in pregnancy and lactation, but its administration should be strictly avoided in the early pregnancy stages (for dos- age and explanations, see Section 21.2.1) [4, 5]. The long clini- cal history of penicillins quali es them also as a safe therapeutic alternative during pregnancy and lactation. Penicillin G is admin- istered in doses varying between 1,200,000 and 6,000,000UI/day IM (very painful) or IV every 4–6 hours for skin conditions like syphilis, ectimes, erysipelas, or impetigo. The excretion of the drug in breast milk reaches a concentration of 2–20% [3].

Safe alternatives in the systemic therapy of bacterial infections are cephalosporins (category B) and azythromicin (category B). The use of cephalosporins – cephalexin (category B) 500 mg every 6–12 hours, cefaclor (category B) 250–500mg every 8 hours, cephradine (category B) 250–500mg–1g every 6–12 hours, cef- triaxone (category B) 1–2g IV or IM – is generally considered to be non-teratogenic, with a myriad of studies reporting no adverse fetal effects after their administration, even when this occurred in the rst trimester of pregnancy. Nevertheless, one speci c study

21 Dermatological medications and local therapeutics 355

[6] indicates the presence of congenital malformations associated with the use of the above- mentioned cephalosporins in the rst trimester of pregnancy [6]. In conclusion, in order to avoid any risks which might outweigh the bene ts, the safest therapeutic approach would be to administer cephalosporins only after the rst trimester of pregnancy. Azithomycin (category B) therapy, consisting of daily doses of 250–500mg, is also considered a safe substitute for the rst-line treatment. Experimental studies on ges- tating animals exposed to high doses of the drug revealed no side effects [1].

As there are many safer alternatives, clarithromycin (category C) or dirithromycin (category C) should be avoided. Fluoroqui- nolones like cipro oxacin, nor oxacin, levo oxacin or nalidixic acid (all category C) should also remain on the list of excluded drugs, as their use can damage growing cartilage [1, 30].

Likewise, tetracycline (category D) and also minocycline (category D) should be avoided for the whole period of preg- nancy, and especially in the second and third trimester, as their administration could produce enamel hypoplasia – a dental staining and decreased bony growth to the offspring, and a fatty liver atrophy (a rare syndrome) for the mother [31].

Finally, the list of clinically invalidated drugs which should not be used in the systemic therapy of bacterial infections concludes with sulfonamides (category B normally, but involving category D near term). In this context, physicians should refrain from using sulfonamides, especially during the third trimester, near term, as their use has been associated with an increased risk of kernic- terus and hyperbilirubinemia, and also hemolytic anemia for the newborns (especially if the glucose-6-phosphate dehydrogenase [G6PD] is de cient) [32].

21.4.2 Local treatment of bacterial infections

Overall, topical antibacterial treatment follows the basic tenets of systemic treatment and especially the axiomatic rule stating that whatever antibiotics are safe in the systemic therapy are equally safe for topical use. For example, erythromycin (category B) – the rst-line treatment in systemic treatment – can be safely used in topical treatment, with the following dosage: 0.5–1–2g in petro- leum jelly (vaseline) 50–100 g once a day, but only for a short period of time. In addition, bacitracin (category C) or mupirocin (category C) could be considered as acceptable treatment options [2]. As a second axiomatic rule, the clinician has always to take into account the possible sensitization and bacterial resistance after topical use of antibiotics and thus stop the ongoing treatment [31].

21 Dermatological Medications and Local Therapeutics

356

21.6 Fungal infections

21.5 21.5.1

Viral infections
Systemic treatment of viral infections

Acyclovir (category B) in doses of 1g/day (200mg every 4 hours) is the rst-line treatment for herpes simplex virus infections which might occur during pregnancy and lactation. Its use – even from the rst trimester of pregnancy – has not been reported to cause any adverse effects [15]. Due to their newer clinical history, anti- viral agents such as famcyclovir (category B) or valacyclovir (cat- egory B) remain for the time being only secondary alternatives within the viral infections’ therapeutic portfolio. Of note, vaccina- tion of pregnant women for human papilloma virus is not recom- mended due to the limited clinical data available [20].

21.5.2 Local treatment of viral infections

Physical methods like cryotherapy, electrodesiccation, or CO2 laser are considered to be the safest treatment for human pap- illoma virus infections during pregnancy. Whenever the clinical manifestation occurs in the form of small warts, trichloracetic or dichloracetic acid in concentrations up to 85% in alcohol are also safe therapeutic options [1].

The newer antiviral agent, imiquimode (category B) 5% cream – with a standard application of three times/week – can be con- sidered as a secondary option, with the strong reservation that there are limited data on its safety when used in the treatment of viral infections during pregnancy. So far, several reports have indicated minimal systemic absorption after topical applications and the absence of any adverse fetal effects [34–36].

In addition, the list of absolutely contraindicated agents includes podophyllin/podophyllotoxin (category C), which has been asso- ciated with multiple fetal malformations – and even death – and also bleomycin (category D) [37–39].

21.6 Fungal infections
21.6.1 Systemic treatment for fungal infections

In use for a long time, amphotericin B (category B) – although an agent with high toxicity – has proven to be neither embryotoxic or teratogenic, thus gradually evolving into the agent of choice for extensive and severe fungal infections. The recommended dosage consists of 0.5–1.5 mg/day for 4–12 weeks [40]. There are no data

21 Dermatological medications and local therapeutics 357

available in lactation. The closest challenger, and a safe alterna- tive in pregnancy and lactation, would probably be terbina ne (category B) – administered in daily doses of 250mg – which was reported as non-embryotoxic in animal reproduction studies, yet lacking any clinical evidence from pregnant or lactating human patients [6, 26, 40].

The list of substances whose administration is contra indi- cated or forbidden during pregnancy includes griseofulvine (category C) – which has been reported to cause adverse effects in animal studies – and other antifungal agents such as keto- conazole (category C), uconazole (category C) or itraconazole (category C). Ketoconazole has been shown to be embryo- toxic and teratogenic and to cause sexual ambiguity in male fetus by inhibiting androgen synthesis [2]. The clinical reports on the use of uconazole and itraconzole reveal contrasting and sometimes ambiguous results. For instance, uconazole, a new imidazole, has been tested on 226 women in the rst trimester of pregnancy, who took it for vaginal candidosis in low doses (50–150mg) with no result of congenital malforma- tions or other adverse effects. Yet, when administered in high doses of 400 mg/day it has been proved to be teratogenic. Like- wise, itraconazole was shown to have teratogenic effects after the administration of high doses in animal studies [5], while a prospective cohort study reported the use of itraconazole to be safe in pregnancy [41].

21.6.2 Local treatment for fungal infections

Low percutaneous absorption makes topical antifungal therapy as the treatment of choice for mycotic infections, whenever treatment is really needed. Nystatin (category B) administered once/twice daily, clotrimazole (category B) once/twice daily, and miconazole (category C) once/twice daily, represent the rst-line treatment with no reported teratogenic or embryotoxic effects after their use in pregnant patients. Natamycin (category C), econazole (cat- egory C), and bifonazole (category C) are the second-line treat- ments for local antimycotic therapy [20].

21.7 Parasitic infections
21.7.1 Systemic and local treatment for parasitic infections

Permethrin (category B) 5% cream represents the rst-line topi- cal therapy for the treatment of scabies during pregnancy and

21 Dermatological Medications and Local Therapeutics

358 21.8 Antipruritics

lactation. The actual treatment consists of the application of the cream from head to toe, leaving it for 12 hours before wash- ing it off, then repeating the whole process after 1 week. Alter- natively, permethrin 1% lotion is indicated for the treatment of pediculosis; the recommended treatment involves an evening application of the lotion on dry clean hair, lasting for about 12 hours (thus it is left on the hair during the night under a shower cap), followed by another identical session after 1 week. Other antiscabies agents – although safe in pregnancy but which are less effective – are benzyl benzoate (category N) 25% or mala- thion (category B) 0.5%. Crotamiton (category N) cream and lotion 10% are not yet considered a therapeutic option, due to the absence of controlled clinical trials. With proven teratogenic effects when administered in high doses in animal reproduction studies, ivermectin (category C) is to be avoided [1, 42]. Further- more, mebendazole (category C), an antinematode agent (enter- obius, ascaris, trichuris, hookworms, ankylostoma, whipworms, roundworms), reported as not manifesting major teratogenic risk in human studies in the treatment of Enterobius vermicularis infestation [43], can be used in pregnancy, except during the rst trimester.

Albendazole (category C), an antiechinococcosis agent, is generally contraindicated in pregnancy, with clinical data from animal studies pointing out the existence of teratogenic effects [6], despite other studies revealing the absence of any fetal mal- formations after use of albendazole, and thus classifying it as tolerable in severe cases, during all trimesters of pregnancy [44, 45]. Finally, other antiparasitic medications like thiabendazole (category C) are not recommended in pregnancy, due to the absence of relevant clinical data which can establish its levels of safety in pregnant humans.

21.8 Antipruritics 21.8.1 Systemic antipruritics

With a clinical history going back decades, the rst-generation H1 antihistamines such as chlorpheniramine (category B), dex- chlorpheniramine dimetindene (category B), mebhydrolin (cat- egory C), and clemastine (category C) are considered relatively safe in pregnancy. However, with no available data regarding their use during lactation, physicians should focus on other means of treatment in this period. Overall, these agents are considered the rst-line therapy during early pregnancy for all

21 Dermatological medications and local therapeutics 359

allergic skin conditions [2, 33]. It is important that, whenever administered, the medical practitioner takes into account the possible side effects on the central nervous system (e.g. sedative effect) as an important causal factor which may trigger changes in the quality of a patient’s life [46]. In this context, the stan- dard prescription involves the intake of the substance, once a day, before sleeping. When selecting a drug of choice from the therapeutic portfolio of the rst-generation H1 antihista- mines, some authors propose (dex)chlorpheniramine (category B) [46], while others suggest diphenhydramine (category B) [47]; administration of the latter should be avoided in the last 2 weeks of pregnancy [6, 26] as it might trigger oxytocin-like effects with consecutive uterine contraction and fetal hypoxia if administered intravenously or in overdose [48]. In addition, a withdrawal syndrome has been reported after diphenhydr- amine administration [49]. On the other hand, other rst- generation H1 antihistamines, e.g. hydroxyzine (category C), associated with fetal malformations in 5.8% of cases if admin- istered in the rst trimester of pregnancy [6, 50, 51], should be avoided.

With the exception of loratadine (category B) and cetirizine (category B), there are limited clinical data regarding the admin- istration of second and third generation H1 antihistamines during pregnancy. Loratadine and cetirizine can be administered with no risks during late pregnancy and lactation for allergic skin condi- tions. In particular, neither animal reproduction studies [2], nor human clinical trials – e.g. Schaefer et al.’s study on 4000 preg- nancies [20] – revealed any teratogenic effects associated with the use of loratadine. A contrasting possible association with hypo- spadias reported by a Swedish study [52] was later classi ed as a random unrelated occurrence [53].

The list of antipruritics to be (partially) excluded from any ther- apy for pregnant and lactating women includes H2 inhibitors such as cimetidine (category C) whose administration in high doses has proven to have antiandrogenic effects, with the possible result of feminization of a male fetus, and doxepin (category C), a tricyclic antidepressant, whose use in the last part of pregnancy is associ- ated with multiple side effects such as cardiac dysrhythmias, respi- ratory distress, paralytic ileus, or irritability for the fetus/newborn [26].

21.8.2 Local antipruritics

Topical antipruritic medication like menthol (category N), poli- docanol (category C), camphor (category N) or emollients with

21 Dermatological Medications and Local Therapeutics

360 21.9 Glucocorticosteroids
urea (3–10%) are complementary therapies for the cessation of

pruritus, and are safe for use in pregnancy [33]. 21.9 Glucocorticosteroids

21.9.1 Systemic glucocorticosteroids

Despite the fact that during pregnancy the pharmacokinetics of the systemic corticosteroids are changing, clinical experi- ence indicates the absence of any fetal malformations following the administration of regular doses of prednisone (category C), prednisolone (category C), or methylprednisolone (category C) during the rst trimester of pregnancy [6]. Nevertheless, clinical trials in animal reproduction studies indicate that high doses of systemic corticosteroids may cause cleft palate. Furthermore, according to a series of clinical reports, both betamethasone (category C) and dexamethasone (category C) are known to cause intrauterine growth retardation or, rarely, lip/palate cleft if exposed in the rst trimester of pregnancy [54–56], mainly due to the fact that both drugs are crossing the placenta in higher amounts than, for instance, prednisone, prednisolone, and methylprednisolone. Due to this speci c clinical behavior, betamethasone and dexamethasone can be used to induce fetal lung maturation.

In conclusion, the rst-line treatment for cases of severe in ammatory skin diseases during pregnancy or lactation con- sists of prednisone, prednisolone, or methylprednisolone. A start-up prescription can be based on prednisolone – a metab- olite of prednisone – at an initial dose of 0.5–1mg/kg/day. In severe cases, in which these doses prove unsatisfactory for achieving the planned clinical objectives, physicians can opt for an increase in the dose to up to 2 mg/kg/day, yet only for a short period (weeks). The golden rules of prednisolone administra- tion involve avoiding a long exposure to high dosage (2mg/kg/ day) and monitoring the neonatal adrenal function and also fetal growth [33].

21.9.2 Local glucocorticosteroids

First-line topical treatment involves the daily/half-daily appli- cation of mild to moderate potent corticosteroids like hydro- cortisone acetate 1% (category C) or betamethasone valerate 0.1% (category C) for no more than several weeks [57]. On the other hand, there is no academic consensus regarding the

21 Dermatological medications and local therapeutics 361

overall safety of what is proposed to be the second-line topical treatment for maternal in ammatory skin diseases, namely the therapy focused on potent/more potent corticosteroids like clo- betasol propionate (category C), especially due to reports which associate it with infant lip/palate cleft after being used during the rst trimester of pregnancy [58], and also with possible low birth weight.

21.10 Immunomodulators/immunosuppressive therapy

Topical calcineurin inhibitors like tacrolimus (category C) or pimecrolimus (category C) can be used in pregnancy, once daily, for the treatment of atopic dermatitis, if no alternatives are avail- able and if the potential maternal bene ts outweigh the potential fetal risks. According to the existing clinical data tacrolimus is not associated with human teratogenicity [6] while pimecrolimus shares a similar classi cation, yet only in animal reproduction studies [59]. No data are, however, available regarding the safety of the products in lactation.

On the other hand, the safest procedure to be performed on pregnant patients is immunopheresis – a new variant of plas- mapheresis consisting of the removal of the circulating immu- noglobulins from the serum; this is especially helpful in severe autoimmune skin conditions [33].

21.11 Analgesics 21.11.1 Systemic analgesics

Acetaminophen (paracetamol) is a category B analgesic and anti- pyretic agent whose administration is generally considered to be safe during all trimesters of pregnancy and lactation. The stan- dard therapeutic plan consists of doses of 500mg ingested by the mother every 6–8 hours, but only for a short period of time. The peak plasmatic concentration occurs after 30–60 minutes and the diffusion is in all body tissues. Acetylsalicylic acid (aspirin), belonging to category C, represents the second-choice analge- sic and antipyretic agent. The prescribed medication involves the ingestion of 500mg of substance every 6 hours, with the pill crunched in the mouth after meals. The main negative effect of

21 Dermatological Medications and Local Therapeutics

362 21.11 Analgesics

aspirin therapy is its association – when used in the rst trimester of pregnancy – with an increased risk of gastroschisis [60].

Another possible therapeutic alternative, codeine (category C), commonly used for its analgesic or antitussive effects, is only partially safe when chosen for the treatment of pregnant patients. In particular, clinical reports associate it with respira- tory malformations in human fetuses – mainly occurring when the mother was exposed to the substance in the rst trimes- ter of pregnancy [1], with withdrawal symptoms after stopping the drug intake – especially during late pregnancy if ingested in high doses. However, when needed low doses of codeine (7.5–15mg) can be occasionally administered to pregnant patients [26].

The nonsteroidal anti-in ammatory agents NSAIDs (ketopro- fen, ibuprofen, diclofenac, naproxen, indomethacin) are classi- ed as belonging to category B during the rst two trimesters of pregnancy, but evolve to category D in the last trimester of gestation as – due to the inhibition of prostaglandin synthesis – side effects like oligohydramnios, prolonged labor or prema- ture closure/constriction of the ductus arteriosus might appear [2]. If anti-in ammatory therapy is needed the standard prescrip- tion consists of ibuprofen in doses of 200–400mg, 3 times a day, after meals, or diclofenac 50mg 2–3 times daily, after meals, but exclusively if the patient is in the rst and second trimester of pregnancy or in the lactation period. Starting with the 28th week of pregnancy, as they become category D agents, their use is con- traindicated [1].

Furthermore, the use of opioid narcotics during pregnancy has not been associated with teratogenicity, if administered in small occasional doses [26]. Nevertheless, morphine (cat- egory C) is contraindicated as it can cause infant withdrawal syndrome, if the mother becomes addicted [26, 61], neonatal respiratory depression [26], or inguinal hernias during child- hood [62].

21.11.2 Local analgesics (Anesthesia)

Local anesthesia for excisions or skin biopsies during pregnancy or lactation should raise no concerns, as lidocaine (category B) – used with or without adrenaline (epinephrine) (category B) – is classi ed as safe during pregnancy. Another local analgesic which can be considered is EMLA (lidocaine 2.5% and prilocaine 2.5%), also a category B agent. Mepivacaine or bupivacaine, classi ed within category C, are outclassed by the already mentioned safer alternatives [1].

21 Dermatological medications and local therapeutics 363 21.12 Antiseptics (disinfectants)

The rst-line therapeutic portfolio of disinfectants consists of alcohols such as ethanol (category C) or isopropanol (category N), topically applied to the skin, mucosa or wounds. Chlorhexi- dine (category B) is also considered equally safe, especially when used on intact skin or mucosa. Iodine-containing agents (category C), which can theoretically trigger functional disturbances of the fetal thyroid gland (transient hypothyroidism), should be avoided if the area on which the substance is to be applied involves body cavities [20].

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[21] Lebwohl M. Topical application of calcipotriene and corticosteroids: combi- nation regimens. J Am Acad Dermatol 1997;37:S55–8.

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[23] Ashton RE, Andre P, Lowe NJ, White eld M. Anthralin historical and current perspectives. J Am Acad Dermatol 1983;9:173–92.

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[27] Stern RS, Lange R. Outcome of pregnancies among women and partners of men with history of exposure to PUVA for the treatment of psoriasis. Arch Dermatol 1991;127:347–50.

[28] Pham CT, Kuo JY. Plasma levels of 8-methoxypsoralen after topical paint PUVA. J Am Acad Dermatol 1993;28:460–6.

[29] Gunnarskog JG, Kallen AJ, Lindelof BG, Sigurgeirsson B. Psoralen photoche- motherapy (PUVA) and pregnancy. Arch Dermatol 1993;129(3):320–3.
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[42] Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcomes after ivermectin treatment during community based distribution. Lancet 1990;336:1486–9.

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[45] Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic lariasis. Trop Med Intl Health 2003;8:1093–101.

[46] Chi CC, Kirtschig G. Clues to the safety of dermatological treatments in preg- nancy. US Dermatology 2008;1(3):14–7.

[47] Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–9.

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[49] Parkin DE. Probable Benadryl withdrawal manifestations in a newborn infant. J Pediatr 1974;85:580.

[50] Prenner BM. Neonatal withdrawal syndrome associated with hydroxyzine hydrochloride. Am J Dis Child 1977;131:529–30.

[51] Serreau R, Komiha M, Blanc F, Guillot F, Jacqz-Aigrain E. Neonatal seizures associated with maternal hydroxyzine hydrochloride in late pregnancy. Reprod Toxicol 2005;20:573–4.

[52] Kallen B, Olausson PO. Monitoring of maternal drug use and infant congeni- tal malformation. Does loratadine cause hypospadias? Int J Risk Safety Med 2001;14:115–9.

[53] Kallen B, Olausson PO. No increased risk of infant hypospadias after maternal use of loratadine in early pregnancy. Int J Med Sci 2006;3:106–7.

[54] Walker B. Induction of cleft palate in rats with anti-in ammatory drugs. Teratology 1971;4:39–42.

[55] Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999;86(3):242–4.

[56] Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts: a case–control study. Teratology 1998;58(1):2–5.

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22 Jean-Jacques Dugoua

Vitamins, Minerals, Trace Elements, and Dietary Supplements

22.1 Introduction 367

. 22.2  First trimester 369

. 22.3  Second trimester 376

. 22.4  Third trimester 378

22.1 Introduction

During pregnancy, a woman is in a unique physiological state in comparison to a non-pregnant woman. Drug exposure over the course of a pregnancy is a concern to women due to the potential risk of fetal malformations. A study on the pharmaceutical drug use of 295 pregnant women found that 37% of them reported non-compliance with their existing drug regimen due to hesita- tions on drug use during pregnancy [1]. In a similar study where women taking antidepressants during pregnancy were compared to controls, 15% of antidepressant users chose to discontinue their medication despite receiving evidence-based reassuring informa- tion of relative safety [2]. Another study found that a signi cant number of pregnant women had misperceptions and distorted information regarding the potential teratogenic risk of drugs and chemicals [3].

In cases where women hesitate with their existing drug regimen or choose to discontinue their drug use during pregnancy, they may seek natural health products (NHPs) as alternatives to phar- maceutical drugs. “NHP” is an “umbrella” term for supplements,

368 22.1 Introduction

dietary supplements, natural medicines or other such commonly used designations and includes: vitamins, minerals, herbal medi- cines, fatty acids, amino acids, probiotics, and nutraceuticals. The term NHP will be used throughout this chapter to refer to this group of compounds.

For many women, NHPs may seem a reasonable alternative to pharmaceutical drugs as they may equate the term “natural” with apparent safety. In many parts of the world, women still use herbal medicines for fertility and childbirth even when attended by Western medicine [4, 5]. In traditional Chinese medicine, there are approximately 20 herbal medicines used in pregnancy [6]. Research into native North Americans’ medicinal plants has found over 100 plants used as abortifacients and approximately 350 plants used as female gynecological aids [7]. The use of NHPs by pregnant women is somewhere between 7 and 55% [8]. A sur- vey in the United States (US) of 734 pregnant women found that 7.1% of women used herbal medicines during their pregnancy; most commonly Echinacea, St. John’s wort, and ephedra [9]. A US survey of 242 pregnant women found that 9.1% of women used herbal supplements during their pregnancy and 7.5% of women used these at least weekly; most commonly garlic, aloe, chamo- mile, peppermint, ginger, Echinacea, pumpkin seeds, and ginseng [10]. Another US survey of 150 pregnant women found that 13% of women used dietary supplements during their pregnancy; most commonly Echinacea, pregnancy tea, and ginger [11]. A survey in South Africa of 229 pregnant women found that 55% of women reported ingesting herbal medicines during pregnancy [12].

Although hesitant, some health care providers may recommend herbs during pregnancy. A survey of 242 medical and naturopathic doctors and students reported that only one physician actually recommended a herbal product to a pregnant patient whereas 49% of the naturopathic doctors felt comfortable doing so [13]. According to a survey of midwives in the US, between 45 and 93% of midwives will prescribe some form of NHP to women during their pregnancy [14]. Of the midwives who used herbal prepara- tions, 64% used blue cohosh, 45% used black cohosh, 63% used red raspberry, 93% used castor oil, and 60% used evening prim- rose oil [14].

Despite the prevalent use of NHPs by pregnant women, there is a large knowledge gap on NHP safety and ef cacy during preg- nancy. Many modern and classic texts warn against the use of herbal medicines during pregnancy for up to one-third of the products listed in their monographs [15–18]. However, most resources provide little information on the data used to evaluate reproductive toxicity apart from reports of historical use of herbs

22 Vitamins, minerals, trace elements, and dietary supplements 369

as abortifacients or uterine stimulants or animal data of genotox- icity or teratogenicity [15–18]. In some cases, pregnant women who inclined toward NHP treatments during their pregnancy and lactation will seek the advice of clinicians. In other cases, women may seek information on the internet. With knowledge that the evidence of NHP safety in pregnancy and lactation is perceived to be poor, clinical pharmacologists are faced with a dilemma on how to counsel these women.

With this in mind, the purpose of this chapter is to review the existing clinical and pharmacologic data on commonly administered NHPs during pregnancy. This chapter will present clinical studies of NHPs given throughout pregnancy according to trimester.

22.2 First trimester

The rst trimester of pregnancy is arguably the riskiest time in a women’s gestation. Organogenesis for the majority of the body systems occurs in this period, with some continuing onto the sec- ond trimester. Women are vulnerable to teratogens, potentially leading to birth defects in their offspring. Women are also at risk of miscarriages during this period. The NHPs discussed in this section are the most commonly administered for their preventive or therapeutic bene t, or most commonly reported as potential teratogens.

22.2.1 Vitamin B6 (pyridoxine)

Vitamin B6, also known as pyridoxine, is a water-soluble vitamin that is part of the B vitamin group. In the body, vitamin B6 is required for amino acid, carbohydrate, and lipid metabolism, for neurotransmitter synthesis (serotonin and norepinephrine), and for myelin formation. Through a number of metabolic reactions, pyridoxine is converted to coenzymes pyridoxal phosphate and pyridoxamine phosphate.

Clinically, pyridoxine is best known in pregnancy as a treatment for pregnancy-induced nausea and vomiting. A randomized con- trolled trial (RCT) was conducted on 59 pregnant women where 31 women received 25mg of pyridoxine hydrochloride tablets orally every 8 hours for 72 hours while 28 women received a placebo following the same regimen [19]. At study end, there was a signi cant difference in mean nausea scores favoring the pyridoxine group versus placebo (p<0.01) [19]. Only 8 of the 31

22 Vitamins, Minerals, Trace Elements, and Dietary Supplements

370 22.2 First trimester

women experienced vomiting in the pyridoxine group compared to 15 of the 28 women in the placebo group (p<0.05) [19]. In another RCT, 342 women were randomized to receive either oral pyridoxine hydrochloride 10mg every 8 hours or placebo [20]. Post-therapy, there was a signi cant decrease in the mean of nau- sea scores in the pyridoxine versus the placebo group (p<0.01) [20]. Although non-signi cant, there was a greater reduction in the mean number of vomiting episodes in the pyridoxine group versus the placebo group (p=0.0552) [20].

Pyridoxine has also been studied comparatively with ginger, another commonly used pregnancy antiemetic, for their ef cacy in the treatment of pregnancy-induced nausea and vomiting. One study showed no difference in ef cacy between the two while the other study favored ginger. An RCT was conducted on 138 pregnant women (GA ≤ 16 weeks) where they received either 500mg of ginger orally or 10mg of pyridoxine three times daily for 3 days [21]. At study end, both ginger and pyri- doxine signi cantly reduced nausea scores (p<0.001) and the number of vomiting episodes (p<0.01) [21]. When comparing the ef cacy, there was no signi cant difference between ginger and vitamin B6 for the treatment of nausea and vomiting dur- ing pregnancy [21]. An RCT was conducted on 126 pregnant women where they randomly received either 650mg of ginger or 25mg of pyridoxine three times daily for 4 days [22]. Both ginger and pyridoxine signi cantly reduced nausea and vomit- ing scores (p<0.05) where the mean score change after treat- ment with ginger was signi cantly greater than with pyridoxine (p < 0.05) [22].

Vitamin B6 may also have preventive bene ts to the newborn and mother. A case–control study showed that treatment with pyridoxine during pregnancy does not indicate a teratogenic risk to the fetus, but may provide some protective effect for cardio- vascular malformations [23]. Pyridoxine taken orally as capsules or lozenges was shown to decrease the risk of dental decay in pregnant women (capsules: relative risk (RR) 0.84 [0.71 to 0.98]; lozenges: RR 0.68 [0.56 to 0.83]) [24].

Vitamin B6 status appears to be important in pregnancy as a de ciency may increase the risk of certain conditions and symp- toms. A study found an association between oral lesions and vita- min B6 de ciency during pregnancy [25]. Another study observed lower Apgar scores in infants whose mothers were vitamin B6 de cient compared to those with adequate vitamin B6 status [26].

Pyridoxine appears to be generally well tolerated in pregnancy. Minor side effects, such as sedation, heartburn and arrhythmia, have been reported [22]. A small clinical trial reported a decrease

22 Vitamins, minerals, trace elements, and dietary supplements 371

in mean birth weight with pyridoxine supplementation during pregnancy [27]. Although there is con icting evidence and dis- agreement in the scienti c literature, there may be a risk that high dose maternal pyridoxine intake may cause neonatal seizures [28–31].

22.2.2 Vitamin B9 (folic acid)

Vitamin B9, most commonly referred to as folic acid or folate (general term for folic acid), is a water-soluble vitamin that is part of the B vitamin group. Folic acid plays a key role in intra- cellular metabolism where it plays a role in DNA synthesis. In pregnancy, folic acid is best known for preventing neural tube defects. In 2007, new recommendations were published for dosing folic acid for pre-conception, pregnancy, and lactation [24]. These recommendations are summarized in Figures 22.1 and 22.2.

In addition to preventing malformations, folic acid may play a role in the development of Down syndrome. A case–control study was conducted on 31 women who had pregnancies affected by Down syndrome where blood samples were collected from these women and compared to 60 age-matched controls from mothers who had not experienced miscarriages or abnormal pregnancies [32]. Plasma levels of homocysteine were signi – cantly increased in Down syndrome mothers (p=0.004) and serum levels of folic acid were signi cantly decreased in Down syndrome mothers (p=0.0001). No signi cant differences in vitamin B12 and B6 levels were observed between groups [32]. Based on these results, low levels of serum folic acid and elevated levels of plasma homocysteine may contribute to the occurrence of Down syndrome [32].

There is some con icting evidence that folic acid supplemen- tation during pregnancy may increase or decrease the risk of atopy and asthma in children. A prospective birth cohort study (n = 557) found that folic acid supplementation in late pregnancy was associated with an increased risk of childhood asthma at 3.5 years (relative risk (RR) =1.26 [1.08–1.43]) and with per- sistent asthma (RR=1.32 [1.03–1.69]) [33]. At 5.5 years of age, childhood asthma levels did not reach statistical signi cance (RR=1.17 [0.96–1.42]) [33]. The KOALA Birth Cohort Study (n=2834) found opposite results [34]. In this study, maternal folic acid supplementation during pregnancy was not associ- ated with an increased risk of wheeze, lung function, asthma or related atopic outcomes in the offspring [34]. Higher mater- nal intracellular folic acid in pregnancy tended toward a small

22 Vitamins, Minerals, Trace Elements, and Dietary Supplements

372 22.2 First trimester

Figure 22.1 Folic acid recommendations for pre-conception, pregnancy, and lactation [24].

22 Vitamins, minerals, trace elements, and dietary supplements 373

22 Vitamins, Minerals, Trace Elements, and Dietary Supplements

Figure 22.2 Recommended strategies (Options A, B or C) for folic acid supplementation during pre-conception, pregnancy, and lactation.

decreased risk for developing asthma, i.e. inverse association with asthma risk at age 6 to 7 years in a dose-dependent man- ner (P for trend=0.05) [34]. In the Avon Longitudinal Study of Parents and Children (ALSPAC), they found no association between the common polymorphism of the methylenetetra- hydrofolate reductase (MTHFR) gene associated with allergic sensitization and dietary folic acid intake [35].

374 22.2 First trimester 22.2.3 Vitamin A

Vitamin A is a fat-soluble vitamin involved in vision, gene tran- scription, skin health, and immune function. In pregnancy, vitamin A may be teratogenic in a dose-dependent manner. A clinical trial showed that daily intake of 6000IU of vitamin A during pregnancy did not increase the incidence of fetal malfor- mations [36]. In doses above 10,000IU daily, vitamin A intake may be teratogenic. A prospective cohort study of 22,748 preg- nant women found a higher prevalence of cranial neural crest defects in women consuming >15,000 IU and >10,000 IU of vitamin A daily than in women consuming only 5000 IU daily; approximately one infant in 57 had a malformation attributable to vitamin A supplementation [37]. The most marked frequency of malformations was observed in newborns born to women who had consumed high levels of vitamin A before the seventh week of gestation [37]. A case–control study of 1000 livebirths reported that a teratogenic effect might exist for exposures to high doses of vitamin A (>40,000IU daily), particularly during the rst 3 months of pregnancy [38]. On the other hand, another case– control study on 955 newborns found no association between vitamin A exposure at doses >8000IU or >10,000IU daily and malformations in general, cranial neural crest defects, or neural tube defects [39]. Based on the current research, women should not exceed 6000IU of vitamin A daily during their pregnancy. It should be noted that most prenatal multi-vitamin/mineral prod- ucts are set at 6000IU or lower as a daily dose; in some cases, the vitamin A component is removed entirely to be replaced by beta-carotene, a vitamin A precursor. Clinicians should be careful to ensure that women planning a pregnancy are taking a prenatal multi-vitamin/mineral and not a “general” multi-vitamin/min- eral, which typically contains higher doses of vitamin A.

Despite its teratogenic risk, vitamin A has many bene ts in pregnancy. A systematic review of ve trials involving 23,426 women found that weekly vitamin A supplementation resulted in a reduction in maternal mortality up to 12 weeks postpartum and a reduction in night blindness [40]. A study of women with habit- ual miscarriages showed that vitamin A levels were signi cantly lower in these women versus controls [41].

Special attention should be placed on pregnant women with an HIV infection or acquired immune de ciency syndrome (AIDS) and vitamin A supplementation. There is con icting evidence that vitamin A may either increase vertical transmission of HIV to the fetus or have no effect on vertical transmission [42–46]. A system- atic review and meta-analysis published in the Cochrane Data- base of Systematic Reviews concluded that based on the current

22 Vitamins, minerals, trace elements, and dietary supplements 375

best evidence, antenatal or postpartum vitamin A supplementa- tion probably has little or no effect on mother-to-child transmis- sion of HIV [47].

22.2.4 Vitamin E

Vitamin E is a fat-soluble vitamin that does not appear to have a speci c metabolic role. The major function of vitamin E is as a chain-breaking antioxidant that prevents the formation of free radicals; thereby, most of its action is due to its antioxidant prop- erties. In pregnancy, vitamin E may be of potential concern when taken in the rst trimester. A case–control study compared 276 mothers of children with congenital heart defects (CHD) to 324 control mothers with healthy children [48]. Vitamin E intake above 14.9mg/day in the rst 8 weeks of pregnancy was associ- ated with a 1.7- to 9-fold increased CHD risk [48].

A study of 50 spontaneously aborting women compared to preg- nant women whose pregnancies terminated uneventfully found a signi cantly higher percentage of aborting women had individual values of serum alpha-tocopherol above the 0.50mg/100mL nor- mal limit [49]. However, a study of 40 women with habitual abor- tion (HA) compared with controls showed that vitamin E levels were signi cantly lower in women with HA [41]. Based on the current published scienti c literature, it is unclear what the safe dose of vitamin E is in the rst trimester, excluding its use in a prenatal multi-vitamin/mineral.

22.2.5 Calcium

Calcium is a mineral found in the human body, particularly bones, teeth, blood, extracellular uid, muscle, and other tissues. Calcium is essential for nerve transmission, muscle contraction, vascular contraction, vasodilation, glandular secretion, cell membrane and capillary permeability, enzyme reactions, respiration, renal func- tion, and blood coagulation [50]. In pregnancy, calcium has been studied for its effect of improving bone mineralization.

A systematic review and meta-analysis were conducted on the effects of calcium supplementation during pregnancy focus- ing on hypertensive disorders of pregnancy and related maternal and child outcomes [51]. The meta-analysis included 13 RCTs, involving 15,730 pregnant women, comparing at least 1 g daily of calcium during pregnancy versus placebo [51]. In comparison to the placebo group, calcium supplementation led to a reduction in the following average risks for pregnant women: high blood pressure (RR = 0.65 [−0.53–0.81]), preeclampsia (RR = 0.45 [0.31–0.65]), preterm birth (RR = 0.76 [0.60–0.97]), preterm birth

22 Vitamins, Minerals, Trace Elements, and Dietary Supplements

376 22.3 Second trimester

among women at high risk of developing preeclampsia (RR = 0.45 [0.24–0.83]), and composite outcome maternal death or serious morbidity (RR = 0.80 [0.65–0.97]) [51]. The protective effect of calcium was greatest in women with high-risk hypertensive disorders (RR=0.22 [0.12–0.42]) and women with low baseline calcium intake (RR = 0.36 [0.20–0.65]) [51]. One death occurred in the calcium group and six in the placebo group, a difference which was not statistically signi cant (RR=0.17 [0.02–1.39]) [51]. In the offspring, calcium supplementation reduced systolic blood pressure where childhood systolic blood pressure greater than the 95th percentile was reduced (RR=0.59 [0.39–0.91]) [51]. In these RCTs, most of the women were of low hypertensive disorder risk and consumed a low calcium diet at baseline [51].

22.3 Second trimester

After the challenges of morning sickness, miscarriage, and birth defect prevention, the second trimester is usually a time of respite for the pregnant mother. Nonetheless, neonatal bone mineraliza- tion is an important concern as is the treatment of pregnant-asso- ciated disease, such as gestational diabetes. NHPs related to these topics will be discussed in this section.

22.3.1 Calcium

An RCT was conducted on 256 pregnant women who received 2000mg daily of elemental calcium or placebo from 22 weeks’ gestation till delivery [52]. Post-therapy, there were no signi – cant differences between treatment groups in gestational age, birth weight, or length of the infants, or in the total body or lumbar spine bone mineral content [52]. Total body bone min- eral content, however, was signi cantly greater in infants born to calcium-supplemented mothers in the lowest quintile of dietary calcium intake (less than 600mg/day) versus controls [52]. Thus, maternal calcium supplementation of 2000mg daily during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake [52]. In a prospective cohort study of 87 pregnant women belonging to poor socioeconomic groups, daily calcium supplementation of 300 and 600mg of elemental calcium from the 20th week of gestation onward until term brought a signi cant increase in the bone density of the offspring born to these mothers versus off- spring from unsupplemented mothers [53].

22 Vitamins, minerals, trace elements, and dietary supplements 377 22.3.2 Vitamins C, E, and zinc

A meta-analysis was conducted on seven studies involving the administration of vitamins C and E to 5969 pregnant women at risk of preeclampsia [54]. The meta-analysis found that combined vitamin C and E supplementation had no potential bene t in improvement of maternal and neonatal outcome but increased the risk of gestational hypertension in women at risk of pre- eclampsia (RR=1.3 [1.08–1.57]) and the risk of low birth weight in newborns (RR=1.13 [1.004–1.270]) [54].

Maternal intake of foods containing vitamin E and zinc during pregnancy was associated with a reduction in the risks of develop- ing childhood wheeze and asthma [55]. A longitudinal cohort study was conducted on 1861 children born to women recruited dur- ing pregnancy and followed up at 5 years [55]. Maternal nutrient status was assessed via food frequency questionnaire and plasma levels [55]. Maternal vitamin E intake during pregnancy was neg- atively associated with wheeze in the previous year (OR=0.82 [0.71–0.95]), asthma ever (OR=0.84 [0.72–0.98]), asthma and wheeze in the previous year (RR = 0.79 [0.65–0.95]), and persistent wheezing(OR=0.77[0.63–0.93])[55].Maternalzincintakeduring pregnancy was negatively associated with asthma ever (OR=0.83 [0.71–0.78]) and active asthma (OR=0.72 [0.59–0.89]) [55].

22.3.3 Chromium

Chromium is an essential trace element most commonly used in the management of type 2 diabetes. In pregnancy, a small study was conducted on eight women with gestational diabetes where they received 8mcg/kg of body weight daily of chromium pico- linate and reported improved blood glucose control [56].

22.3.4 Coenzyme Q10 (CoQ10)

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a vitamin- like fat-soluble substance found in the mitochondria of human cells. CoQ10 is involved in the electron transport chain and gen- eration of adenosine triphosphate (ATP). A study demonstrated that CoQ10 supplementation during pregnancy may prevent pre- eclampsia in at-risk women [57]. An RCT was conducted on 235 women at risk of preeclampsia where they received 200mg of CoQ10 or placebo daily from 20 weeks of pregnancy until deliv- ery [57]. There was a signi cant reduction (p=0.035) (RR=0.56 [0.33–0.96]) in preeclampsia where 30 women (25.6%) in the placebo group developed preeclampsia compared with 17 women (14.4%) in the CoQ10 group [57].

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378 References
22.4 Third trimester

The third trimester is another risky period for a pregnant woman as she may be at risk of preterm delivery and many complications with delivery. The NHPs discussed in this section are mostly herbal medi- cines or fatty acids that are typically administered for labor induction.

22.4.1 Castor oil (Ricinus communis)

Castor oil is produced by cold pressing ripe seeds from the cas- tor plant. Unlike the seeds, castor oil does not contain the deadly poison ricin [58]. Castor oil is mostly known for its strong laxative effect. In pregnancy, it is used to induce labor where 93% of US midwives reported using castor oil for labor induction [14].

A prospective cohort study was conducted on 103 pregnant women with intact membranes at 40 to 42 weeks’ gestational age [59]. Women were assigned to receive a single oral dose of castor oil (60mL) or no treatment [59]. Groups were compared for onset of labor in 24 hours, method of delivery, presence of meconium- stained amniotic uid, Apgar score, and birth weight. Following administration of castor oil, 30 of 52 women (57.7%) began active labor compared to 2 of 48 (4.2%) receiving no treatment [59]. When castor oil was successful at initiating delivery, 83.3% (25/30) of the women delivered vaginally [59]. Castor oil appears to work on the uterus by producing hyperemia in the intestinal tract, which causes re ex stimulation of the uterus [60]. Castor oil may also increase prostaglandin production, which stimulates uterine activity [59].

There have been some case reports of adverse effects associated with castor oil intake at delivery. One case reported precipitous and tumultuous labor, meconium-stained uid, and an amniotic uid embolism causing cardiorespiratory arrest [61]. A survey of midwives in Texas, US, reported that castor oil was more likely to cause adverse effects, including reports of an emergency c-section as a result of abruption, severe gastric cramping and diarrhea, and dehydration [62].

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[49] Vobecky JS, Vobecky J, Shapcott D, Cloutier D, Lafond R, Blanchard R. Vitamins C and E in spontaneous abortion. Int J Vitam Nutr Res 1976;46(3):291–6.

[50] Calcium Monograph. Therapeutic Research Faculty. 2011. Accessed August 2011.

[51] Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010(8); CD001059.

[52] Koo WW, Walters JC, Esterlitz J, Levine RJ, Bush AJ, Sibai B. Maternal calcium supplementation and fetal bone mineralization. Obstet Gynecol 1999;94(4):577–82.

[53] Raman L, Rajalakshmi K, Krishnamachari KA, Sastry JG. Effect of calcium supplementation to undernourished mothers during pregnancy on the bone density of the neonates. Am J Clin Nutr 1978;31(3):466–9.

[54] Rahimi R, Nikfar S, Rezaie A, Abdollahi M. A meta-analysis on the ef cacy and safety of combined vitamin C and E supplementation in preeclamptic women. Hypertens Pregnancy 2009;28(4):417–34.

[55] Devereux G, Turner SW, Craig LC, et al. Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Respir Crit Care Med 2006;174(5):499–507.

[56] Jovanovic-Peterson L, Gutierry M, Peterson CM. Chromium supplementation for gestational diabetic women (GDM) improves glucose tolerance and decreases hyperinsulinemia. Diabetes 1996;43(337a).

22 Vitamins, Minerals, Trace Elements, and Dietary Supplements

382 References

. [57]  Teran E, Hernandez I, Nieto B, Tavara R, Ocampo JE, Calle A. Coenzyme Q10 supplementation during pregnancy reduces the risk of pre-eclampsia. Int J Gynaecol Obstet 2009;105(1):43–5.

. [58]  Castor Monograph. Therapeutic Research Faculty. 2011. Accessed August 2011.

. [59]  Garry D, Figueroa R, Guillaume J, Cucco V. Use of castor oil in pregnancies at term. Altern Ther Health Med 2000;6(1):77–9.

. [60]  Gennaro A. Remington: The Science and Practice of Pharmacy. 19th ed. Philedelphia, PA: Lippincott: Williams & Wilkins; 1996.

. [61]  Steingrub JS, Lopez T, Teres D, Steingart R. Amniotic uid embolism associ- ated with castor oil ingestion. Crit Care Med 1988;16(6):642–3.

. [62]  Bayles BP. Herbal and other complementary medicine use by Texas midwives. J Midwifery Womens Health 2007;52(5):473–8.

Herbs and Alternative Remedies

Henry M. Hess

23

. 23.1  Herbal teas frequently used during pregnancy 384

. 23.2  Essential oils used as aromatherapy during pregnancy 385

. 23.3  Herbs used as capsules or dried extracts 386

. 23.4  Herbal topical preparations used in pregnancy 390

. 23.5  Non-herbal supplements used in pregnancy 390

. 23.6  Herbs used to induce labor 391

. 23.7  Acupuncture and acupressure therapy in pregnancy 392

. 23.8  Meditation and hypnosis in pregnancy 392

Pregnancy can be an ideal time to use herbal and alternative rem- edies. Herbs are often mild preparations of natural compounds that can be just perfect for some of the discomforts and illnesses during pregnancy. Several studies have shown that as many as 50% of women will choose herbs and alternative remedies as therapies during pregnancy [8, 13–15, 18].

Although herbal therapies have been used for centuries, herbs are complex mixtures of many compounds, and some have poten- tially signi cant negative effects for both the pregnant woman and the fetus. In the companion book Drugs during Pregnancy and Lactation, 2nd edition, edited by Schaefer, Peters, and Miller [13] we focused on the safety of herbs during pregnancy and counseled health care providers that the use of some herbs during pregnancy can have signi cant risks depending on the herb, the purity of the preparation, and the timing of use during pregnancy. In this

384 23.1 Herbal teas frequently used during pregnancy

chapter, we have focused on the herbs and alternative remedies that are safe and ef cacious for many conditions during preg- nancy. Using the best available up-to-date scienti c evidence, evidence based and traditional, we have listed and categorized herbs, supplements, and other alternative remedies that are safe and ef cacious for many of the common medical conditions and discomforts that occur during pregnancy.

For herbs and supplements, we have listed forms and dosage. It is important to recognize that herbs are extracts of plants or plant roots, and they therefore contain numerous compounds. This is very different to a pharmaceutical preparation, which is usually a single active ingredient. Different forms of herbal preparations will have different compounds and concentrations depending on how the plant or plant root is extracted. Herbal preparations are usually available in the following forms: teas or infusions (hot water extracts of dried herbs), capsules, dried extracts, and tinc- tures (alcohol extracts of dried herbs). The most common forms of herbs used in pregnancy are teas or infusions. These usually have the lowest concentration, contain the least amount of com- pounds, and therefore are the safest. Capsules and dried extracts are the next most commonly used. Tinctures should be avoided during pregnancy because of their higher concentrations as well as the use of alcohol as a carrier.

A very important difference between the use of herbs or supple- ments and a pharmaceutical preparation is the integrity and purity of the speci c herb or supplement preparation [13]. There is no Food and Drug Administration (FDA) oversight of these prod- ucts so patients as well as providers need to nd guidance on product selection from sources such as ConsumerLab.com [3]. We strongly recommend frequent evaluation of the integrity of the individual preparation.

We also have discussed the use of hypnosis and meditation as alternative remedies for many of the common discomforts and illnesses in pregnancy and delivery, where otherwise medications might be needed.

23.1 Herbal teas frequently used during pregnancy

The herbs most frequently used during pregnancy are teas or infu- sions. Some herbal teas have speci c indications; others are used by patients as general health tonics. Although there are minimal clinical trials available, and minimal evidence-based proof of safety and ef cacy in terms of Western medical standards, herbal

23 Herbs and alternative remedies 385

teas have been used for centuries and are regarded as safe and ef cacious during pregnancy. It is the general recommendation [13] that consumption of herbal teas be limited to two cups per day during pregnancy. This is similar to the safety data regarding coffee. The safety is unknown when used at higher levels. The following herbal teas are frequently and safely used during preg- nancy [1, 5, 13, 15]:

n Red raspberry leaf – Relief of nausea, increase in milk pro- duction, increase in uterine tone, and ease of labor pains. There is some controversy over the use of red raspberry leaf in the rst trimester, primarily because of concern of stimulating the uterine tone and potentially causing miscar- riage. Use in the second and third trimester is generally con- sidered safe.

n Peppermint – Nausea, atulence. Tea is the most common; enteric-coated tablets (187mg three times a day maximum) are also used. Peppermint may cause gastroesophageal re ux.

n Chamomile (German) – Gastrointestinal irritation, insomnia, and joint irritation.

n Dandelion – A mild diuretic, and to nourish the liver; known for high amounts of vitamins A and C, and the elements of iron, calcium, and potassium, as well as trace elements.

n Alfalfa – General pregnancy tonic; a source of high levels of vitamins A, D, B, and K, minerals and digestive enzymes; thought to reduce the risk of postpartum hemorrhage in late pregnancy.

n Oat and oat straw – Sources of calcium and magnesium; helps to relieve anxiety, restlessness, insomnia, and irritable skin.

n Nettle leaf – Traditional pregnancy tonic; source of high amounts of vitamins A, C, K, calcium, potassium, iron. NB: nettle root is different from nettle leaf; it is used for inducing abortions and is not safe in pregnancy.

n Slippery elm bark – Nausea, heartburn, and vaginal irritations. 23.2 Essential oils used as aromatherapy during

pregnancy

Some essential oils are frequently used as aromatherapy dur- ing pregnancy, and the ones described below are considered to be safe and ef cacious during pregnancy based on tradi- tional and historic use. They should always be used carefully, in

23 Herbs and Alternative Remedies

386 23.3 Herbs used as capsules or dried extracts

well-diluted form, and in an aromatherapy diffuser. They should not be ingested. Such essential oils and their uses are listed [1, 13, 15]:

n Chamomile – Respiratory tract disorders.
n Tangerine – Antispasmodic, decongestant, general relaxant.
n Grapefruit – Stimulant, antidepressant.
n Geranium – Dermatitis, hormone imbalances, mood dysfunc-

tion, viral infections.
n Rose – Astringent, used for mild in ammation of the oral and

pharyngeal mucosa.
n Jazmine – Stimulant, antidepressant, anxiety.
n Ylang-ylang – Antispasmodic, cardiac arrhythmias, anxiety,

antidepressant, hair loss, intestinal problems.
n Lavender – Loss of appetite, nervousness and insomnia.

23.3 Herbs used as capsules or dried extracts 23.3.1 Ginger

n Nausea and vomiting of pregnancy. Dose: 250mg 3 to 4 times per day.

n Ginger is the herb with the most evidence-based data showing ef cacy and safety in pregnancy. When used at 250mg 3 to 4 times a day, it is considered safe and effective for nausea and vomiting of pregnancy, as well as hyperemesis gravidarum [1, 6, 8, 13–15, 18]. Most of the antiemetic activity is believed to be due to the constituent 6-gingerol which acts directly in the gastrointestinal tract. The constituent galanolactone also acts on 5-HT3 receptors in the ileum, which are the same receptors affected by some prescription antiemetics. Ginger’s antiemetic activity may also involve the central nervous system, where the constituents 6-shogaol and galanolactone act on serotonin receptors [18].

23.3.2 Cranberry

n Prevention and treatment of urinary tract infection. Dose: 300 to 400mg 3 times a day. Can cause gastrointestinal upset.

n Cranberry is one of the most commonly used herbs during pregnancy, primarily for the prevention and treatment of uri- nary tract infections. Although there is a long history of the

23 Herbs and alternative remedies 387

safe and ef cacious use of cranberry during pregnancy, there are very little evidence-based data [1, 8, 13–15, 18, 24]. The literature does suggest that cranberry capsules may be more ef cacious than cranberry juice. Studies on the pharmacology of cranberry show that the proanthocyanidins in cranberry interfere with bacterial adherence to the urinary tract epithe- lial cells [18].

23.3.3 Echinacea

n Prevention and treatment of upper respiratory tract infections, vaginitis, herpes simplex virus. Dose: 900mg of dried root or equivalent 3 times a day.

n There is a long history of safe and ef cacious use of Echi- nacea in pregnancy [1, 7, 8, 13–15, 17, 18]. Two scienti c studies are frequently cited as evidence-based studies show- ing its safety in pregnancy [9, 18]. The ef cacy is based on tradition, not evidence based. Echinacea is known to inhibit the in uenza virus and the herpes simplex I and II viruses. It has been shown to increase the proliferation of phagocytes in the spleen and bone marrow, stimulate monocytes, increase the number of polymorphonuclear leukocytes and promote their adherence to the endothelial cells, and activate macro- phages [18].

23.3.4 St. John’s wort

n Treatment of mild to moderate depression, anxiety, and sea- sonal affective disorder. Dose: 300mg 3 times daily, of a stan- dardized extract.

n Although there is minimal evidence-based medicine of its safety or ef cacy in pregnancy, St. John’s wort is consid- ered safe in pregnancy by the German Commission E, the American Herbal Products Association, and much tradi- tional literature [1, 7, 8, 13–15, 17, 18]. It is very commonly used in pregnancy for mild to moderate depression. Studies have shown that St. John’s wort acts as an SSRI (selective serotonin reuptake inhibitor), and inhibits the reuptake of serotonin, norepinephrine, and dopamine. Also of signi – cance is that the hypericin in St. John’s wort induces some of the cytochrome P450 enzymes and may interfere with the metabolism of other drugs similarly metabolized [1, 18]. St. John’s wort can cause photo-sensitization, so caution must be exercised, and patients advised [1].

23 Herbs and Alternative Remedies

388 23.3 Herbs used as capsules or dried extracts 23.3.5 Valerian

n Treatment of anxiety and insomnia. Dose: 2 to 3 g of crude herb as a capsule or tea at bedtime.

n Valerian root is also very commonly used in pregnancy, but there is lack of any evidence-based medicine showing either its ef cacy or safety. Some scienti c publications as well as the World Health Organization [1] suggest caution in the use of valerian during pregnancy because its safety has not been clinically established. However, the German Commission E [1, 7, 13] and the Botanical Safety Handbook [17], as well as several articles and books, support the use of valerian dur- ing pregnancy and generally conclude that occasional use is safe and ef cacious when used in the dose described above. Valerian has sedative, anxiolytic, antidepressant, anticonvul- sant, hypotensive, and antispasmodic effects. The major con- stituents, valerenic acid and kessyl glycol, are known to cause sedation in animals. Valerenic acid may inhibit the enzyme system responsible for the catabolism of gamma-aminobutyric acid (GABA), thereby increasing GABA concentrations and decreasing central nervous activity [18].

23.3.6 Milk thistle/silymarin

n Treatment for intrahepatic cholestasis of pregnancy, alcoholic and non-alcoholic liver cirrhosis, chronic and acute viral hepa- titis, drug-induced liver toxicity, fatty degeneration of the liver. Dose: 400mg of standard silymarin extract in 2 to 3 divided doses per day. Recommended to be used in the second and third trimester of pregnancy only [11, 18, 20, 21].

n There are many references in the natural and herbal literature to the use of milk thistle in pregnancy for liver dysfunctions and for enhancement of milk production [18]. There are also concerns and warnings about possible signi cant side effects and insuf cient evidence-based studies to recommend milk thistle in pregnancy. However, the few evidence-based studies do support the safety and ef cacy for use of this herb for spe- ci c situations described above. In four studies, no evidence of adverse effects was reported in the mothers and offspring [18, 20, 21]. There are no reports of estrogenic effects on the fetus, a potential concern because the constituents of milk thistle are avonolignans [18]. There have been many suggestions as to the mechanism of action, but silybin has been shown to stimulate RNA polymerase A and DNA synthesis, increasing the regenerative capacity of the liver. Silymarin, the active con- stituent, is thought to competitively bind some toxins and act

23 Herbs and alternative remedies 389

as a free radical scavenger [18]. Clinically, regular consump- tion of milk thistle has been shown to reduce elevated liver enzymes [18].

23.3.7 Senna

n Treatment of constipation. Dose: 10 to 60mg at bedtime for a maximum of 10 days, in the second and third trimester [10, 13, 14, 18].

n The use of senna in pregnancy is very controversial because senna is a member of the anthraquinone laxatives group, thought to be contraindicated in pregnancy because overstimu- lation of the bowel or bladder has the potential to irritate/stim- ulate the uterus, potentially causing premature labor, or even miscarriage in the rst trimester [13]. The Compendium on Herbal Safety offered the opinion that senna should be avoided during pregnancy [13, 18]. However, there are no reports in the literature showing senna to be contraindicated during preg- nancy. A review article has reported that senna would appear to be the stimulant laxative of choice during pregnancy, probably because of the poor intestinal absorption of senna compared to the other anthraquinone laxatives [10, 18]. Traditional use has shown that with careful use, senna may be used in the sec- ond and third trimester with minimal risk. There are no studies showing a risk in the rst trimester either, but avoidance of use in the rst trimester is recommended based on the potential for senna to be an abortifacient [12]. The literature reports that sennosides irritate the lining of the large intestine, causing its contraction and evacuation. Sennosides A and B also induce uid secretion from the colon, softening the stool, and may also induce prostaglandins for more effective contractions of the colon. The laxative effect occurs 8 to 12 hours after administra- tion, although sometimes up to 24 hours can be required. It is important not to overuse senna in pregnancy. Diarrhea, uid loss, electrolyte imbalance, as well as habituation, have been reported [18].

23.3.8 Horse chestnut

n Chronic venous insuf ciency – 300mg twice daily of Venosta- sin (reg)retard (240 to 290mg of horse chestnut seed extract, standardized to 50mg escin). NB: Do not use unprocessed raw horse chestnut preparations. These can be very toxic and lethal when ingested in adults [18, 22].

n Oral horse chestnut has been shown in the literature to signi – cantly reduce leg edema and varicose veins and chronic venous

23 Herbs and Alternative Remedies

390 23.5 Non-herbal supplements used in pregnancy

insuf ciency when taken orally [1, 18, 22]. While oral horse chestnut has been found very useful, caution is advised when recommending this herb to a pregnant woman, as there is min- imal evidence-based study of ef cacy or safety in pregnancy. However, there is a randomized placebo-controlled trial of 52 women with symptomatic leg edema attributed to preg- nancy-induced venous insuf ciency where improvements were found with horse chestnut, and the authors did not observe any serious adverse effects after 2 weeks [18, 22].

23.4 Herbal topical preparations used in pregnancy 23.4.1 Aloe vera gel

n Treatment of skin burns. Topical use only [1, 7, 13, 15, 18].
n There is a long history of safe and ef cacious topical use of aloe

vera gel during pregnancy, but no evidence-based studies.

23.4.2 Horse chestnut

n Treatment of severe hemorrhoids in pregnancy. Topical 2% gel (Escin) 2–4 times a day [4, 18].

n The few studies done have shown safe and ef cacious use, par- ticularly with severe hemorrhoids in pregnancy.

23.5 Non-herbal supplements used in pregnancy 23.5.1 Fish oils

n Support for the development of a healthy mother and baby – including prevention of colds in infants of treated mothers, sup- port for the heart, immune system, in ammatory response, the development and maintenance of the brain, eyes, and central nervous system. Dose: 300–400mg DHA (docosahexaenoic acid) and 100–220mg of EPA (eicosapentaenoic acid) daily. The freshness of the oil is important because rancid sh oils have an extremely unpleasant odor and also may not be as effective [3, 18].

n Omega 3s have been found to be essential for both neurological and early visual development of the baby. Research has con- rmed that adding omega 3s to the diet of pregnant women has a positive effect on visual and cognitive development of

23 Herbs and alternative remedies 391

the child. Studies also have shown that higher consumption may reduce the risk of allergies in the fetus, may help to pre- vent preterm labor and delivery, lower the risk of preeclampsia, may increase birth weight, and may decrease the incidence of maternal and postpartum depression [3, 18]. Omega 3s are a family of long-chain polyunsaturated fatty acids that are essen- tial nutrients for health and development. They are not synthe- sized by the human body, and must be obtained through diet or supplementation. The typical American diet is greatly lacking in omega 3s. The two most bene cial omega 3s are EPA and DHA, and they work together in the body [3].

n Because of the potential for contamination of sh oils by mer- cury and other potential contaminants, the use of puri ed sh oils is essential [3]. Flaxseed is not a substitute for sh oils in pregnancy, as axseed constituents have potential estrogenic properties [13, 18].

23.5.2 Probiotics

n Prevention and treatment of vaginal infections (yeast vagini- tis and bacterial vaginosis). Dose: At least 4 billion organisms daily, with at least 1 billion each of Lactobacillus, Bi dobacte- rium, and Saccharomyces [3, 5, 18].

n May prevent preterm labor in the third trimester when caused by these infections. Maintains digestive systems in the face of pregnancy-related problems, eases diarrhea, constipation, hem- orrhoids, as well as boosting the immune system. Studies have also shown that babies and toddlers up to 2 years old were 40% less likely to suffer eczema/atopic dermatitis when mothers took probiotics. Limited studies have also shown that probiotics help limit excessive weight gain in pregnancy.

23.6 Herbs used to induce labor

In the traditional literature [16, 23], there are herbs and herbal mixtures reportedly used to induce labor. According to the recent literature [16, 18], many midwives in the US and elsewhere in the world use herbal mixtures to induce labor. There is no evidence- based literature establishing the safety or ef cacy of the herbs used, but there exists some literature expressing concern regarding signi cant risks and bad outcomes. Currently, there simply is not enough evidence of safety to recommend these treatments for this indication.

23 Herbs and Alternative Remedies

392 23.8 Meditation and hypnosis in pregnancy
23.7 Acupuncture and acupressure therapy

in pregnancy

There is a signi cant amount of evidence-based medicine in the literature regarding the use, ef cacy, and safety of acupuncture and acupressure therapy in pregnancy [2, 8].

The practice of acupuncture and acupressure dates back 5000 years. Acupuncture is based on a belief that a vital energy called “qi” (chee) ows through the body along pathways called meridians. Along these meridians there are some 2000 acupunc- ture points where the thin needles (or pressure) are inserted to relieve symptoms, cure the disease, and restore balance.

In pregnancy, both the mother and infant bene t. Acupuncture has been used successfully in pregnancy for maintenance of health, treatment for preexisting medical issues, and treatment of pregnancy related issues (including psychological issues, physical problems, fatigue, morning sickness, heartburn, constipation, hemorrhoids, back pain and sciatica, edema, carpal tunnel syndrome, and rhinitis of pregnancy). Acupressure is popular for relief of nausea and vom- iting in pregnancy. It has also been successfully used to assist with versions in breech presentations, and for pain analgesia in labor. Acupuncture has also been found ef cacious for many postpartum disorders such as fatigue, postpartum vaginal discharge, postpartum depression, mastitis, insuf cient or excessive lactation, and post- operative healing. A trained and experienced acupuncturist under- stands and knows the target points for the needle insertions during pregnancy, and for speci cally related pregnancy problems. Ef – cacy rates are signi cant, and there are no known risks. Acupunc- ture (and acupressure) may be very useful for pregnancy-related situations where otherwise a medication may be necessary.

23.8 Meditation and hypnosis in pregnancy

Meditation [19] and hypnotherapy [12] are excellent natural therapies for managing health during pregnancy, including the discomforts of pregnancy and labor and delivery as well as pre- vention of illnesses, and management of illnesses. Used for cen- turies, there are recent and long-term evidence-based studies showing their ef cacy and safety. These modalities, like other natural therapies, are becoming very popular with pregnant and postpartum women. The internet has several sites as well as CD products making it easier for patients to learn about and practice mindfulness meditation and self-hypnosis.

23 Herbs and alternative remedies 393

Mindful meditation and hypnosis have many similarities. Hypno- sis is a slightly deeper process where it is easier for suggestions to be incorporated by the subconscious. Hypnosis has been used for pregnancy-related symptoms including labor and delivery and has become particularly popular since the 1930s. Evidence-based data show that hypnosis in particular helps with an easier and less pain- ful labor. For mindful meditation during pregnancy, studies have shown that it decreases stress, and produces endorphins which reduce physical pain. It has also been shown to increase the pro- duction of dehydroepiandrosterone (DHEA), which stimulates the production of T and B lymphocytes, supporting the immune system. DHEA has also been linked to decreasing sadness and depression, both before and after birth. Studies have also shown that the medita- tion increases the level of melatonin, supporting the immune system and increasing the quality of sleep and improved mood. Endorphins are similarly increased, which have a strong pain relieving effect in preparation for childbirth. Studies also show that mindfulness med- itation can be very effective in lowering blood pressure and heart rate, potentially lowering the risk of preeclampsia.

References

[1] Blumenthal M, editor. The ABC Clinical Guide to Herbs. New York, NY: Thieme Medical Publishing; 2003.

[2] Carlsson CP. Manual acupuncture reduces hyperemesis gravidarum: a placebo controlled, randomized, single-blind, crossover study. Pain Symptom Manag 2000;41:273–9.

[3] https://www.consumerlab.com.
[4] Damianov L, Katsarova M. Our experience in using the preparation Proc-

tosedyl from the Roussel rm in pregnant women with hemorrhoids. Akush

Ginekol 1993;32:71.
[5] Dugoua JJ, Machado M, Xu Z, Chen X, Koren G, Einarson TR. Probiotic safety

in pregnancy: a systematic review and meta-analysis of randomized controlled trials of Lactobacillus, Bi dobacterium, and Saccharomyces spp. J Obstet Gynaecol Can 2009;31(6):542–52.

[6] Fischer-Rasmussen W, Kojer SK, Dahl C, Asping U. Ginger treatment of hyperemesis gravidarum. Eur J Obstet Gynecol Reprod Biol 1990;38: 19–24.

[7] Thomson H, editor. Physician’s Desk Reference for Herbal Medicines. 4th ed. Montvale, NJ: Thomson Reuters Publishing; 2007.

[8] Fugh-Berman A, Kronenberg F. Complementary and Alternative Medicine (CAM) in reproductive-age women: a review of randomized controlled trials. Reprod Toxicol 2003;17:137–52.

[9] Gallo M, Koren G. Can herbal remedies be used safely during pregnancy? Focus on Echinacea. Can Fam Physician 2001;47:1727–8.

23 Herbs and Alternative Remedies

394 References

. [10]  Gattuso JM, Kamm MA. Adverse effects of drugs used in the management of constipation and diarrhea. Drug Saf 1994;10:47–65.

. [11]  Giannola C, Buogo F, Forestiere G. A two-center study on the effects of silymarin in pregnant women and adult patients with so-called minor hepatic insuf ciency. Clin Ther 1998;114:129–35.

. [12]  Harms RW. Hypnobirthing: how does it work? Mayo Clinic, April 14, 2011. http://www./mayoclinic.com/health/hypnobirthing/AN02138.

. [13]  Hess HM, Miller RK. Herbs during pregnancy. In: Schaefer C, Peters P, Miller RK, editors. Drugs during Pregnancy and Lactation. 2nd ed. San Diego, CA: Academic Press; 2007. p. 485–501.

. [14]  Holst L, Wright D, Haavick S, Nordeng H. Safety and ef cacy of herbal rem- edies in obstetrics, review and clinical implications. Midwifery 2011;27:80–6.

. [15]  Low Dog T, Micozzi MS. Women’s Health in Complementary and Integrative
Medicine: Clinical Guide. Oxford: Elsevier; 2005.

. [16]  McFarlin BL, Gibson MH, O’Rear J, Harmon P. A national survey of herbal
preparation use by nurse-midwives for labor stimulation. J Nurse Midwifery
1999;44:205–16.

. [17]  McGuf n M, Hobb C, Upton R, Goldberg P. American Herbal Products As-
sociation’s Botanical Safety Handbook. Boca Raton, Fl: CRC Press; 1998.

. [18]  Mills E, Dugoua JJ, Perri D, Koren G. Herbal Medicines in Pregnancy & Lacta- tion. An Evidence-Based Approach. Boca Raton, Fl: Taylor and Francis; 2006.

. [19]  Murphy M, Donovan S. The Physical and Psychological Effects of Medita- tion: A Review of Contemporary Research with a Comprehensive Bibliog- raphy. 1931–1996, 2nd ed. San Francisco CA: Institute of Noetic Sciences
Press; 1997.

. [20]  Reys H. The spectrum of liver and gastrointestinal disease seen in cholestasis
of pregnancy. Gastrointestinal Clin North Am 1992;21:905–21.

. [21]  Reyes H, Simon FR. Intrahepatic cholestasis of pregnancy. An estrogen-related
disease. Semin. Liver Dis 1993;13:289–301.

. [22]  Steiner M. Untersuchungen Zur Odemvermindernden und Odemportektiven
Wirking von ro Kastanienoamenextrakt. Phlebol Prookto 1990;19:239–42.

. [23]  Weed S. Wise Women Herbal for the Childbearing Year. Woodstock, NY: Ash
Tree Publishing; 1986.

. [24]  Wing DA, Rumney PJ, Preslicka CW, Chung JH. Daily cranberry juice for the
prevention of asymptomatic bacteriuria in pregnancy: a randomized, con- trolled pilot study. J Urol 2008;180:367–1372.

24 Steffen A. Brown and William F. Rayburn

Envenomations and Antivenoms During Pregnancy

. 24.1  General principles about envenomation 395

. 24.2  Snake bites 398

. 24.3  Spider bites 400

. 24.4  Scorpion stings 402

. 24.5  Hymenoptera 404

. 24.6  Jelly sh 407

. 24.7  Antivenom use during pregnancy 409

Conclusions 410

24.1 General principles about envenomation

Envenomation is the exposure to a poison or toxin resulting from a bite or sting from an animal such as a snake, scorpion, spider, or insect, or from marine life. Information about a bite or sting is often obtained secondhand from patients or primary caregivers, and additional exposures may go unreported.

US poison centers assist in the assessment and management of envenomations and the national database is a source of demographic and clinical data regarding such cases, although the database is subject to a number of limitations. The database does not include all envenomations, as there is no mandatory reporting requirement, and the source of information on clinical effects and treatments is secondhand and often incomplete and

396 24.1 General principles about envenomation
Table 24.1 Cases of envenomation in pregnancy, 2000–2011. American Association

of Poison Control Centers Database

Scorpion Spider

Snake

TOTAL

2136 217 Black widow 214 Brown recluse 1 161 Unidenti ed 57 Copperhead 51 Rattlesnake 39 Constrictor 10 2514

Envenomation

Common name

Cases

variably documented [1]. Shown in Table 24.1 are the most com- mon envenomations during pregnancy reported to poison control centers.

Symptoms from an envenomation often produce a characteris- tic reaction, depending on the venomous animal involved, which may be the same as in the non-pregnant patient, or may be more pronounced during pregnancy due to physiologic circulatory changes. For example, black widow envenomation may produce hypertension, tachycardia, sweating, and other signs of adrenergic excess in both the pregnant and non-pregnant patient. The effect of stimulating muscle contraction, however, may result in uterine contractions, with other consequences in pregnancy [17].

Pharmacologic therapy of envenomations is directed at symp- tomatic and supportive care, as well as speci c therapy, if avail- able and appropriately indicated. In general, symptomatic and supportive drugs are used sparingly and at the lowest effective doses in order to avoid confounding clinical assessment [3]. The need for tetanus toxoid should be assessed and administered to people at risk of tetanus regardless of pregnancy status. Human studies have not suggested an increase in adverse outcome after maternal inoculation [3]. Routine use of antibiotics (e.g. dicloxa- cillin, cefazolin, metronidazole) after envenomation is question- able unless signs suggestive of infection are present [4], which is unlikely to be seen prior to 24–48 hours after an envenomation. There is no evidence in support of prophylactic antibiotics, even in snake envenomation, with its extensive tissue injury effects,

24 Envenomations and antivenoms during pregnancy 397

unless tissue necrosis occurs. Any short-term course of standard antibiotics is presumed to be safe during pregnancy.

Any decision to use a speci c antidotal therapy – antivenom – must take into account the potential for allergic reactions, either Type 1 (anaphylaxis or anaphylactoid) or Type 3 (serum sickness) and the risk–bene t assessment in pregnancy includes the potential for adverse effects on the fetus. Antivenoms are generally indicated when there is: [1] evidence of systemic envenomation (e.g. neurotoxicity, coagulopathy, rhabdomyoly- sis, persistent hypotension, or renal failure) or [2] severe local envenomation effects, for example extensive local tissue injury in snakebite [5, 6]. Although no antivenoms have been speci – cally evaluated in pregnant patients, long experience has not demonstrated any particular risks, and, in general, the manage- ment which is most bene cial to the mother will provide the best outcome for the pregnancy. Consultation with a poison cen- ter and its medical toxicologist or other clinician with expertise in managing envenomations is recommended when treating an envenomated pregnant patient. The poison center can also be helpful in locating and obtaining antivenom for unusual or non- native (exotic) envenomations, which may not be stocked at the hospital pharmacy.

Pregnancy tests are recommended for any woman of reproduc- tive age who is envenomated. Other laboratory studies are guided by the usual assessment of any particular envenomation. Addi- tional serum testing (electrolytes, coagulation tests, liver enzymes, etc.) may be needed depending upon the scenario and clinical course. As an example, it is standard to obtain a complete blood count, platelets, and coagulation studies with certain Crotalinae (rattlesnake, copperhead, cottonmouth) snakebites.

Concerns about pregnancy, or obvious pregnancy-related risks or effects, may prompt providers to observe envenomated patients longer in an emergency department, or to admit them to the hos- pital for monitoring or additional treatment. There are few data on pregnancy outcomes in most envenomations. Some studies and reports of high rates of fetal loss in other parts of the world may be secondary to venomous animals with higher degrees of maternal or fetal toxicity or may be secondary to a lack of appro- priate medical care in their native environments. In the US there are few reports of signi cant, adverse pregnancy outcomes with envenomations, other than when there is signi cant maternal tox- icity. Regardless, before discharge from a health facility, patients should be coherent, tolerate oral intake, have no progression of symptoms, and any pain should be adequately controlled with oral analgesics. Pregnant patients should have no pregnancy-related

24 Envenomations and Antivenoms During Pregnancy

398 24.2 Snake bites

risks and appropriate discharge instructions and follow-up care should be given. More long-term evaluations of individual cases are encouraged to better characterize the long-term results of speci c envenomations in pregnancy and to determine any addi- tional strategies other than standard therapies.

24.2 Snake bites

Snake bites account for approximately 125,000 annual deaths worldwide [7]. There are ve families of snakes: Atractaspididae, Colubridae, Elapidae, Hydrophiidae, and Viperidae. In the United States, viperids are represented by three genera and over 30 spe- cies of the subfamily Crotalinae (rattlesnakes, copperheads, and cottonmouths) and two genera and three species of one Elapid, the coral snake. Crotalinae generally produce a syndrome char- acterized by local tissue injury, which may include necrosis, and hematologic toxicity, including thrombocytopenia, hypo brino- genemia, and other coagulation abnormalities. There may be sys- temic effects, such as nausea and diaphoresis or hypotension and, rarely, neurotoxicity such as muscle fasciculations or weakness, that usually do not result in respiratory compromise. The coral snake, typical of elapids, generally does not produce signi cant local tissue effects and primarily produces neurotoxicity, which can include respiratory arrest. In other parts of the world, elapids may produce signi cant local tissue injury, rhabdomyolysis, renal injury or other effects [8]. Knowledge about the toxicity pro les of local snake species is vital, and expert advice should be sought when managing a snake envenomation in a pregnant patient, when the envenomation is unfamiliar to the clinician or severe or unusual effects occur.

Snakes vary widely in appearance, and identi cation is rarely possible by the clinician. A digital photo taken at a safe distance may be useful. Venom detection kits can be useful in determin- ing the appropriate monovalent antivenom [9]. If there is doubt about the snake’s identity, treatment should be administered for an unidenti ed snake bite.

24.2.1 Management during pregnancy

Initial rst aid is directed at reducing spread of the venom and expediting transfer to an appropriate medical center [10, 11]. The patient should be removed from the snake’s territory, kept warm and at rest, and be reassured. The injured part of the body

24 Envenomations and antivenoms during pregnancy 399

should be immobilized in a functional position below the level of the heart. As with non-pregnant adults, ongoing management is largely supportive but may be accompanied with signi cant aller- gic phenomena. Investigations into venom suctioning or removal devices do not show additional bene t and are therefore not rec- ommended [11].

Use of antivenom for systemic or severe local envenomation warrants consideration of corticosteroids, epinephrine, or antihis- tamines beforehand. Corticosteroids are often used with early and late allergic reactions. Prolonged corticosteroids are associated with fetal growth impairment in humans [12]. These medications increase oral clefting in experimental animals yet are less likely to do so in humans [13, 14]. Premedication, especially with epineph- rine, is appropriate in settings in which either antivenom is asso- ciated with high rates of allergic reactions, or the management of acute allergic reactions is problematic due to limited staf ng or facilities [9]. Injection of epinephrine in experimental animals interferes with embryo development, possibly through hemody- namic effects and decreased uterine perfusion [15]. Human stud- ies on inhaled beta-sympathomimetics during pregnancy have not suggested an increased risk of birth defects [16].

Snake envenomations during pregnancy may be accompanied by blood coagulation abnormalities, so prolonged monitoring in the hospital is understandable [16–19]. We recommend a minimum of 8 hours of fetal heart rate (FHR) monitoring if the pregnancy is at a viable stage (usually beginning at 24 weeks) [18]. Reports of decreased fetal movements and fetal death a few days after clini- cally signi cant envenomations suggest ongoing outpatient surveil- lance with daily FHR monitoring for up to 1 week may be helpful in identifying pregnancies at risk for adverse outcome [20, 21].

24.2.2 Reports during pregnancy

Several reports about snake bites during pregnancy have revealed normal outcomes, even when antivenom was necessary [16, 22, 23]. Adverse pregnancy affects may be due largely to maternal ill- ness. For example, there are case reports of placental abruptions associated with a maternal hypercoagulable state following snake bite [24, 25]. In another report, death of a gravid woman after a snake bite was believed to be associated with supine hypotension from aortocaval compression rather than entirely from the venom itself [9]. A third case involved a woman bitten by a pit viper at 10 weeks’ gestation [19]. Although the woman recovered from systemic symptoms, a fetal demise was con rmed 1 week later on ultrasound examination.

24 Envenomations and Antivenoms During Pregnancy

400 24.3 Spider bites

In a letter to the editor from Sri Lanka in 1985, indirect evidence of placental transfer was described with adverse fetal effects in the absence of maternal symptoms [26]. Four cases of maternal snake bites were reported in which fetal movements were perceived as being less or became absent before or in the absence of maternal illness. In three of those cases, where bites occurred at 32 to 36 weeks’ gestation, the fetuses survived and were delivered alive at term. In the fourth case, of unspeci ed gestational age, fatal mater- nal illness developed, although not until after fetal movement had slowed. The fetus was stillborn the day before the mother’s death, after the onset of maternal signs and symptoms of illness.

A 2010 report from Nepal described a 33 week pregnant woman who was bitten by a green tree viper [24]. She developed vaginal bleeding, anemia, and severe abnormalities in her coagulation pro le. Her fetus was dead when she presented for care. After correction of the coagulation pro le, labor was induced and she subsequently recovered.

A 1992 review of 50 cases of non-rattlesnake viper snake bites during pregnancy in the United States reported a 10% maternal mortality rate and a 43% fetal demise rate [17]. A 2002 series of 39 snake-envenomated pregnant women had a fetal loss rate of 30% [20]. Our report in 2010 with rattlesnake bites speci – cally, using the American Association of Poison Control Centers (AAPCC) database, suggested a lower short-term risk in preg- nancy than prior reports [18]. Sixty-one poison control centers reported a total of 8413 rattlesnake bites, with 767 (9.1%) involv- ing reproductive-age women. Of these, 11 (1.4%) were pregnant. There were no signi cant differences between pregnant and non- pregnant victims with regard to rates of hospital admission, anti- venom administration, or overall outcome codes. There were no adverse reactions to antivenom in pregnant women and no mater- nal deaths or fetal losses while in the hospital or during the period of poison control center follow-up.

24.3 Spider bites

Spider bites are rare medical events, since only a handful of spe- cies cause dif culties in humans [2]. Very few species have mus- cles powerful enough to penetrate human skin, and most of those spiders bite humans only in rare circumstances. Furthermore, the venom of most spiders has little or no effect [59]. The most likely to in ict signi cant bites in humans are widow and false black widow spiders and recluse spiders.

24 Envenomations and antivenoms during pregnancy 401

A spider bite usually presents acutely as a localized solitary pap- ule, pustule, or wheal. Systemic symptoms can accompany some envenomations [2]. Allergic reactions typically result from contact with spiders. Widow bites cause unremarkable local lesions but are sometimes accompanied by prominent, proximally-spreading pain and localized diaphoresis. Bites from recluse spiders are notorious for becoming necrotic.

Most patients’ reports of spider bites are unreliable. The diag- nosis of a spider bite is thus highly suspect, unless the patient actually observes a spider in icting the bite and can retrieve it for identi cation. Those who did not clearly witness the bite should be presumed to have some other disorder, and the nding of mul- tiple skin lesions essentially excludes the diagnosis of spider bite. Papules and pustules should be carefully unroofed and cultured to identify infectious causes. Common infections that could be mistaken for spider bites include staphylococcal and streptococ- cal infections, a skin lesion of early Lyme disease, and atypical presentations of herpes zoster or herpes simplex.

24.3.1 Management during pregnancy

Most patients who sustain a spider bite require only topical therapy (clean with mild soap and water; apply cold, not fro- zen, packs; elevate affected body part). Patients with moderate to severe envenomations, such as those from widow spiders as char- acterized by severe local symptoms or the presence of regional or systemic symptoms, require supportive care and monitoring for complications. Oral analgesia, parenteral benzodiazepines, and tetanus toxoid may be used safely during pregnancy in the short term [2].

Early surgical excision or debridement is not recommended for patients with recluse spider bites that have a dusky center or other signs of developing necrosis. There are reports of approximately 1000 pregnant women who have been treated with dapsone with- out adverse effect [60–63]. Those reviews and case reports were not speci cally designed to study possible reproductive effects of dapsone, however, and dosage and timing of dapsone use were not always clear. Some cases of hemolytic anemia have occurred in mothers and their offspring after exposure to dapsone, both during gestation and while breastfeeding [61, 64].

Mortality from widow bites is low, although envenomation can cause signi cant pain and require hospitalization [59]. Antivenom reduces the pain and the need for hospitalization, especially when other therapies are unsuccessful [65]. Several widow spider anti- venoms are commercially available, although there is suf cient

24 Envenomations and Antivenoms During Pregnancy

402 24.4 Scorpion stings

chemical similarity among widow venoms that all widow antive- noms provide some degree of relief. Representative symptoms in which antivenom therapy may be valuable include the following: severe and persistent local pain or muscle cramping, signi cant pain or diaphoresis extending beyond the immediate site of the bite, alterations in vital signs, dif culty breathing, and nausea and vomiting.

24.3.2 Reports during pregnancy

Black widow spider envenomation is a rare occurrence in preg- nant women, and short-term outcomes appear to be favorable [66]. There are four published case reports of widow spider bites in pregnant women, whose gestational ages ranged from 16 weeks to 38 weeks [67]. In addition, we reported a large observational study based on a review of the AAPCC database from 2003 to 2007 [68]. Of the 12,640 human black widow spider envenom- ations, 3194 (25.3%) involved women of reproductive age and 97 were pregnant. Comparing pregnant with non-pregnant women, there were no signi cant differences in recommended or admin- istered treatments. A signi cantly higher percentage of pregnant than non-pregnant patients were treated at a health care facility where they were either released (36.1% vs. 19.9%, p<0.001) or admitted (13.4% vs. 4.0%, p<0.001). There were no documented immediate pregnancy losses in that series.

There have been six reported cases of Loxosceles (recluse spider) bites in pregnant women. Although the victims were apparently in considerable discomfort, pregnancy outcomes were favorable in all instances [69, 70]. We have been unable to locate any reference about the use of Loxosceles antivenom during pregnancy.

24.4 Scorpion stings

Although scorpion envenomation is not usually a signi cant prob- lem, stings from Centruroides exilicauda (sculpturatus) can lead to major neurologic toxicity. C. exilicauda is found primarily in northern Mexico and the southwestern United States (e.g. Ari- zona, New Mexico, western Texas, southeastern California, and near Lake Mead, Nevada). The tubercle at the base of the stinger of its lobster-like body is helpful in differentiating this highly neu- rotoxic scorpion from other species [27, 28].

Envenomations involve injection of a scorpion toxin pro- tein which acts as a neurotoxin [29]. In neuronal membranes,

24 Envenomations and antivenoms during pregnancy 403

these toxins cause incomplete inactivation of sodium channels which lead to membrane hyperexcitability, and consequent repetitive uncontrolled ring of axons [30]. Enhanced release of neurotransmitters at synapses and the neuromuscular junc- tion leads to excessive neuromuscular activity and autonomic dysfunction [31].

After C. exilicauda envenomation, symptoms typically begin immediately, progress to maximum severity within 5 hours, and improve within 9 to 30 hours without antivenom therapy [32]. Local pain and paresthesias occur at the sting site. The punc- ture wound is usually too small to be observed initially, and local in ammation does not occur customarily. Symptoms often radiate proximally up the affected extremity but may present in remote sites as generalized paresthesias. Rarely, envenomations produce cranial nerve or somatic skeletal neuromuscular dysfunction.

24.4.1 Management during pregnancy

Most scorpion stings result in mild envenomations [32]. Manage- ment would be the same during pregnancy by cleansing of the sting site, using oral medications (e.g. ibuprofen 10mg/kg; maxi- mum single dose 800mg), and administering tetanus prophylaxis. An increased risk of miscarriage was reported with use of ibu- profen or naproxen particularly near the time of conception, but a reanalysis of the d