Relative Safety of Seizure Medications During Pregnancy

ARTICLE HIGHLIGHTS

• The North American Antiepileptic Drug Pregnancy Registry recently reported its important new findings (Hernandez-Diaz, 2012).
• The report compares the frequency of major malformations in the developing fetus in women taking an antiepileptic drug (AED) during their pregnancy. New and older AEDs are analyzed. Major malformations are serious medical problems that the fetus can develop during early development in the womb.
• What is really important about this study: it describes the risks/safety of using the newer AEDs during pregnancy.
• The study provides information about the relative risk/safety during pregnancy of 11 of the most commonly used AEDs. It looks at older AEDs, such as Dilantin and Depakote, and newer AED, such as Lamictal and Keppra. Prior to this study, there was not enough information available to say, with hardly any degree of confidence, which of the newer AEDs are the safest. This study describes a relatively large number of women exposed to AEDs during their pregnancies in order to compare the rates of problems with the fetal development- for both old and the new AEDs.
• The study indicates that some of the newer AEDs may be safer during pregnancy than some of the older AEDs. Some of the relatively safer new AEDs:
  • Lamictal (generic = lamotrigine)
  • Keppra (generic = levetiracetam)
• Depakote (generic= valproate) was associated with a 9.3% prevalence of major malformations- significantly higher than the relatively safer AEDs.
• Take a look at the Table below—it lists the 11 AEDs and each AED’s prevalence of major malformations. A very valuable Table for clinicians and patients!
• The website for the pregnancy registry:www.aedpregnancyregistry.org

INTRODUCTION

In 1963, one of the earliest reports describing a problem with fetal development in a woman taking an antiepileptic drug (AED) was published. The report described that the woman was taking mephenytoin, a medication similar to Dilantin, throughout her pregnancy. The child was found to have a low IQ, cleft palate, speech problems and a small head. Since that early report, it is clear that AEDs can be associated with an increased risk of medical problems with the developing fetus.

While seizure medications can cause problems for the developing baby, not taking seizure medications may result in more problems- a real double edged sword! Remember, intense seizures, especially generalized tonic-clonic seizures (= grand mal seizures) can result in serious problems for developing fetus. For most women with epilepsy, the safest strategy for their developing baby is to take a seizure medication.

In the old days, women with epilepsy were discouraged by some clinicians from going through a pregnancy—because of concerns about having a medically handicapped child. The latest data suggests that it is quite safe for the overwhelming number of women with epilepsy to consider pregnancy. Although the risk of having a medical problem may be higher than the general population, the increased risk may not be all that high and the majority of women with epilepsy can deliver healthy children. See the Table below for more details.

So, which AED should a woman take during her pregnancy? This is an extremely important question. The North American Antiepileptic Drug Pregnancy Registry recently reported its important new findings. These findings will be of great help in this important decision making process. The report compares the frequency of major malformations in the developing fetus in women taking an antiepileptic drug (AED) during their pregnancy. New and older AEDs are analyzed. Major malformations are serious medical problems that the fetus can develop during early development in the womb. Examples of major fetal malformations include cleft palate, spina-bifida and heart valve defects.

What is really important about this study: it compares the risk/safety of taking older and the newer AEDs during pregnancy. The study provides information for clinicians about the relative safety during pregnancy of 11 of the most commonly used AEDs. Prior to this study, there was not enough information available to say, with hardly any confidence, which of the newer AEDs is the safest. Past studies had too few women exposed to the newer AEDs to make conclusions. I am sure it makes sense-you need a large number of women exposed to an AED during their pregnancy to see what the problems are. You also need to compare women taking AEDs to controls (women going through their pregnancy not taking AEDs). This way, you can study what the problems are. That is why the North American Pregnancy Registry report is so important. This study describes a relatively large number of women exposed to AEDs during their pregnancies in order to compare the rates of problems with the fetal development- for both old and the new AEDs.

The study evaluated women from 1997 through 2011. 7,370 women were enrolled in the study. 4,899 women were taking only one seizure medication. The women taking only one AED are an important group—because they are only on one AED, it is easier to determine what problems are the result of the seizure medication. In contrast, if a woman is on three AEDs (Depakote, Dilantin and Keppra, for example), then it is harder to determine which AED is causing an identified problem. The study describes the rates of fetal malformations in women taking only one AED. These women are compared to controls (women not taking AEDs).

The following table summarizes some of the key findings (based on Table from North American Antiepileptic Drug Pregnancy Registry Spring 2012 newsletter). This is a great Table!:

www.aedpregnancyregistry.org

Take-away points:

• Lamictal and Keppra appear to be safer, compared to some of the older AEDs (Depakote and Phenobarbital).
• Depakote has a relatively higher rate of major malformations (9.3%). This does not mean that women should never take Depakote during pregnancy. Rather, other AEDs should be considered first, and Depakote should only be used if it is clearly needed for seizure control.
• Topamax (a newer AED) was associated with a higher risk of cleft lip.
• You may have noticed that Zonegran had no reported malformations. It should be noted, only 90 women were on Zonegran – this is too few patients to make a determination on the safety of Zonegran. More study is needed!
• Please note- in the controls (women not taking AEDs) , 1.1% of patients had malformations.

CONCLUSIONS

The results of this study will be helpful as the clinician and patient consider going through a pregnancy on an AED. We encourage women with epilepsy who are considering pregnancy to have a detailed discussion with their healthcare provider—to optimally plan the pregnancy. The results from the North American Antiepileptic Drug Pregnancy Registry are a great addition to the literature (see their newsletter:www.aedpregnancyregistry.org for more information). The results of other pregnancy registries are going to be reported in the near future—and will further add to our understanding of this complicated and important topic!

REFERENCES

Hernandez-Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology 2012;78:1692-1699.

Mullers-Kupper vM. Embryopathy during pregnancy caused by taking anticonvulsants. Acta Paeddopsychiatr 1963;30:401-405.

The North American Antiepileptic Drug Pregnancy Registry Spring Newsletter: www.aedpregnancyregistry.org

Yerby MS, Battino D, Montouris GD. General principles: teratogenicity of antiepileptic drugs. In: Engel J, Pedley T, ed. Epilepsy: a comprehensive textbook. Philadelphia: LWW; p. 1213-1224.

LATEST UPDATE: 5/23/2012