*Is lamotrigine safe for use in pregnancy? Part one*

The use of psychotropic medications during pregnancy. For women with bipolar disorder, one of the medications that is very frequently used is lamotrigine.

For many psychotropic medications, we just don’t have enough data on their use in pregnancy. But we do have a fair amount of data on lamotrigine use in pregnancy from both retrospective and prospective studies. Many lamotrigine “registries” had been set up and these have been helpful in increasing the amount of data available. In these registries, data were gradually accumulated on pregnancy outcomes in individual women who had been on lamotrigine during the pregnancy. Several systematic reviews and meta-analyses of the data on lamotrigine in pregnancy have recently been published (Kong et al., 2017; Pariente et al., 2017; Veroniki et al., 2017).

*We have a problem*

There is one big problem in trying to find out whether the use of a particular medication leads to an increase in major congenital malformations in the newborn. Women who are not taking any medication also give birth to babies with major congenital malformations. So, the risk of major congenital malformations with a medication has to be compared with the “baseline” risk.

*Overall risk of major congenital malformations*

The lamotrigine registry data suggest that when lamotrigine is used in pregnancy, there is a 2 to 5% risk of major congenital malformations. This is not more than the baseline risk in newborns whose mothers were not taking any medications.

A review of 21 studies on this topic (Pariente et al., 2017) did not find lamotrigine to be associated with more congenital defects compared to disease-matched controls or healthy controls.

A review comparing different antiepileptic medications (Veroniki et al., 2017) found that many antiepileptic medications (ethosuximide, valproate, topiramate, phenobarbital, phenytoin, carbamazepine) were associated with a statistically significantly increased risk of major congenital malformations. But lamotrigine and levetiracetam were not.

Well, that’s good news.

But what about a possible increased risk of a specific malformation or of neurodevelopmental delays?

*Is lamotrigine safe for use in pregnancy? Part two*

Lamotrigine use during pregnancy has not been found to be associated with an increased risk of major congenital malformations in the newborn.

But, we should look not only at the overall risk of “major malformations,” but also at the risk of specific malformations.

In the past, there were some data that suggested that lamotrigine use during pregnancy may be associated with an increased risk of oral clefts. But subsequent and larger studies have not found a statistically significant association (e.g., Dolk et al., 2016). The FDA-approved Prescribing Information does not mention oral clefts (cleft lip or cleft palate) as a potential risk of being exposed to lamotrigine in utero.

Note: Let’s say that we compare 1000 babies born to women who took medication X to 1000 babies born to women who did not take any medication. And let’s say that two babies exposed to medication X were born with an oral cleft and one baby not exposed to any medication was born with an oral cleft.

What would you conclude?

Did medication X increase the risk of oral cleft or could the difference have been simply due to chance? I guess either is possible. It is hard to be sure when some bad outcome occurs rarely.

Now, what if ten out of 1000 babies exposed to medication X were born with an oral cleft compared to only one out of 1000 babies not exposed to any medication. In this case, we might say that it is unlikely that such a big difference was simply due to chance. Not impossible, but unlikely. This is what we mean when we say there was a “statistically significant difference”. It simply means that the findings are unlikely to be due to chance alone.

So, when we say that there was no statistically significant increase in the risk of oral clefts in newborns who had been exposed in utero to lamotrigine, what we mean is that there was not an increased risk so big that it is unlikely that it was simply due to chance. It does not mean that it has been conclusively shown that lamotrigine is not associated with any increased risk of oral cleft.

Researchers have calculated that what they can say is that if an increased risk of oral cleft is present in newborns exposed in utero to lamotrigine, it is unlikely to be more than one in 550 (Dolk et al., 2016). If the risk had been more than that, the study had the ability to identify that with statistical confidence.

*Is lamotrigine safe for use in pregnancy? Part three*

Lamotrigine use during pregnancy has not been associated with an increased risk of major congenital malformations in the newborn, and that

– the increased risk of oral clefts (cleft lip or cleft palate) that was initially suspected was not confirmed in subsequent, larger studies.

But, the risks of medication use during pregnancy are not limited to congenital malformations. Medications can also affect the brain as the fetus develops inside the uterus. This can lead to neurodevelopmental problems after birth.

So, is there any risk of developmental problems in children whose mothers took lamotrigine during pregnancy?

A 2017 review of the literature (Kellogg and Meador, 2017) found that, based on the limited data available, lamotrigine does not have any significant neurodevelopmental adverse effects. Other reviews have reached the same conclusions.

But, let’s look at what “limited data” means. The most important study on this topic, as of July 2017, was the NEAD study (Meador et al., 2013). It followed children exposed in utero to antiepileptic drugs for up to the age of six years and did not find any neurodevelopmental delay in children whose mothers took lamotrigine during pregnancy (compared to the control group). But, if we look more closely, this study included only 99 mothers who took lamotrigine during pregnancy. Also, the children of only 73 of these mothers could be followed at the six-year mark. Studies of this kind cannot identify, with statistical confidence, problems that occur in a small percentage of children.

Also, it is a generally good principle of interpreting research that while being unable to follow up on all participants is unavoidable, not being able to follow up is not random. Those who do not complete the study are likely to be different from the ones who do. Is it possible that not completing the study was sometimes related to having had problems with child?

Let’s think it is certain that lamotrigine is safer in pregnancy than valproate. I also think that it is probable that it is safer in pregnancy than carbamazepine. But I pointed out the limitations of small sample size and incomplete follow up only to warn us that we should not say to the patient with confidence that there is no risk without saying “as far as is known based on the limited data so far” or something like that.

*Is lamotrigine safe for use in pregnancy? Part four*

This is the fourth and last in this series about the potential risks of lamotrigine during pregnancy.

The data so far are reassuring about the use of lamotrigine during pregnancy, both in terms of major congenital malformations and regarding neurodevelopmental delays. This makes lamotrigine one of the first-line options when a woman with bipolar disorder needs to take medication during pregnancy.

Few last words:

1. As discussed, while the available data have not shown any statistically significantly increased risks, this does not mean that there is zero risk. It only means that no risk has been identified so far. And that if there is a risk, it is small. So, we should carefully consider the options before prescribing any medication during pregnancy.

2. For most medications, risks during pregnancy tend to be related to the dose. So, if lamotrigine is used, the lowest possible dose should be used.

3. These four emails were written in July 2017. The most recent data should be consulted before making decisions regarding prescribing any medication during pregnancy. As for all pages, we will continue to update the relevant page (http://simpleandpractical.com/lamotrigine-pregnancy/) when important new data become available to us. For the most updated information, please refer to the web page rather than emails received in the past.

4. Patient registries are very important for increasing the amount of data available on the outcome of pregnancies in which the mother was on a particular type of medication.

We, as prescribing mental health clinicians, should encourage all women who become pregnant while taking a mood stabilizer that is an antiepileptic to participate in registries for such patients. These registries also include pregnant women who take an antiepileptic medication for epilepsy or for pain.