In their article, "Pregnancy Registries in Epilepsy: A ConsensusStatement on Health Outcomes," Dr. Meador and colleagues1 summarizeimportant information about the risks of taking seizure medicationswhile pregnant. On the surface, the question sounds simple:if pregnant, which seizure medications would be safe? Unfortunately,the answer is not so easily found. Only through an internationalcollaboration have doctors been able to at least come closerto answering this question.
The international Health Outcomes in Pregnancy and Epilepsy(HOPE) was established to learn more about the effects thatseizure medications (also called antiepileptic drugs or AEDs)might have on the developing baby. They have collected informationfrom around the world. Their information comes from pregnancyregistries. The registries collect and organize informationabout women with epilepsy and the babies who were exposed toAEDs during pregnancy. There are registries in North America,the United Kingdom, Australia, Sweden, Finland, and Europe.
Although each registry differs slightly, their goal is similar:to collect information about AEDs during pregnancy. Ideally,the women with epilepsy are enrolled when they learn of theirpregnancy. The pregnancy is then followed through its course.The baby is evaluated shortly after birth. The baby is thenfollowed for a period of time afterwards to determine whethereffects might have occurred that may not have been picked upright away.
In other words, the babies are evaluated for major malformationsand minor malformations. Major malformations include problemswith major organs such as the heart, skeleton, or brain. Theycan affect the way that the baby grows and develops. The significanceof minor malformations is more difficult to determine: minormalformations do not seem to cause medical problems during theperson’s life. Therefore, most attention to date has beenfocused on the major malformations.
When it comes to registries, more is better. A larger numberof people mean that there is much higher confidence in the results.So far, the North American registry has enrolled more than 5,500women. The United Kingdom registry has enrolled 5,400. Thereare almost 1,000 in Australia, and roughly 9,000 in the Europeanregistry. Already, this information has led to a better understandingof the effects of AEDs in pregnancy.
Despite the thousands of women in these registries around theworld, doctors do not yet have information on all of the AEDs.However, the registries have helped physicians understand therisks associated with certain AEDs. It is accepted that therisk of major malformations in women who are taking no medicationis 1.6% to 2.1%. In other words, about 2% is the lowest or usualrate of malformations. Therefore, 2% is the basis on which allstudies are compared.
The North American registry has given doctors information aboutphenobarbital, valproate, lamotrigine, and carbamazepine. Therate of major malformations is 6.5% with phenobarbital, 10.7%with valproate, 2.7% with lamotrigine, and 2.5% with carbamazepine.Unfortunately, there is still not enough information to calculatethe risks for other AEDs.
In the United Kingdom and Australia, information has emergedfor valproate, carbamazepine, and lamotrigine. In the UK, therisk of major malformations is 6.2% for valproate, 2.2% forcarbamazepine, and 3.2% for lamotrigine. In Australia, it is13.3% for valproate, 3.0% for carbamazepine, and 1.4% for lamotrigine.
In the Finnish and Swedish registries, information is availablefor valproate and carbamazepine only. In Finland, there is a9.7% risk of major malformation when the baby is exposed tovalproate and 4.0% with carbamazepine. In Sweden, it is 10.7%for valproate and 2.7% for carbamazepine.
The authors admit that there are problems with registry data.One key problem is that not all women with epilepsy who becomepregnant are enrolled in these registries. Therefore, the informationmay be biased. For example, what if the women who enrolled hada history of problems during previous pregnancies? They mayhave decided to enroll because of their concerns about havinganother baby with problems. In this instance, the registry datawould reflect the higher rate of birth defects. The end resultswould be that the registry would overestimate the risk of birthdefects.
Another issue is that women with all kinds of epilepsy wereenrolled. There are many kinds of epilepsy, and the type ofepilepsy may contribute to the overall risk. In addition, thecause of the mother’s epilepsy may not be known in theseregistries. Perhaps the cause of epilepsy also is importantin assessing the risk of problems in babies born to motherswith these problems.
Finally, information about confounding factors may not be knownthrough these registries. For instance, what was the mother’sdiet like during the pregnancy? Did she take vitamins? Did shesmoke? Did she use illicit drugs? What other medications (prescribedor over-the-counter) were used during the pregnancy? Obviously,any of these factors might influence the outcome of the pregnancy.Without studying these factors in detail, doctors may not knowthe exact risk of use of AEDs during pregnancy.
For a woman with epilepsy who is planning on becoming pregnant,the best time to see her neurologist occurs long before sheis planning to begin a family. Many issues need to be discussed.Often, the discussion focuses on two issues. The first is howseizures during pregnancy might affect the baby. The secondis how the medicines might affect the baby.
Of these concerns, the first is the concern for seizures duringpregnancy. Seizures that cause falls can not only injure thewoman, but can also injure the developing baby. Seizures cancause bleeding into the baby’s brain and changes in theunborn baby’s heart rate. Seizure control, therefore,must be maintained during the pregnancy. Available informationalso shows that the risk of seizures during pregnancy is greaterthan the risk of taking medications.
The second issue is teratogenicity, or the effect that AEDshave on the developing baby. The Food and Drug Administration(FDA) has developed a scheme that identifies the risk of teratogenicity.Using this scheme, many of the older seizure medications arepregnancy category D. There is a known risk during pregnancy;however, the benefits of their use may outweigh these risksduring pregnancy. The newer AEDs are pregnancy category C. Therisks of their use during pregnancy are unknown.
When confronted with these choices, most women are understandablyconcerned. They are required to make a decision regarding medicinesthat are known to cause problems vs ones for which the riskis unknown. Of all of the AEDs, valproate has consistently beenshown to cause congenital malformations, based on the informationfrom pregnancy registries around the world (North America, theUnited Kingdom, Europe, Sweden, and Finland).1,2 Many physiciansagree that this mediation should be avoided, if possible, duringpregnancy.
For doctors, the consultation is challenging. How should thedoctor best counsel a woman when she plans to start a family?In babies born to women taking no medications, birth defectsoccur at a rate of about 2%. Older studies suggest that whena woman is taking one AED, that risk is double (4%–6%).3With two AEDs, the risk is threefold (6%–9%). For womentaking several AEDs at the same time, the risk may be even higher.Some studies have shown up to 15% when a person is taking threeor more AEDs during pregnancy.
Doctors always try to "streamline" a person’s medicationsbefore pregnancy begins. This means two things. First, the doctorwill try to reduce the number of AEDs to the smallest possiblecombination. Second, the doctor will try to reduce the doseof the medications to the least that is needed to maintain seizurecontrol. Both measures help to reduce this risk of major malformations.
Doctors also counsel women to take folate (folic acid), a vitaminthat is important to the formation of the central nervous system.Ideally, folate should be started before pregnancy occurs. Itshould be continued throughout the pregnancy. Because so manypregnancies are unplanned, most physicians begin counselingpatients about the importance of taking multivitamins and folatelong before the woman is even thinking about starting a family.Though never proven with a randomized study, folate is thoughtto reduce the risk of congenital malformations. There are nostudies that tell physicians what is the best dose. The recommendedrange is anywhere from 400 µg (the amount contained ina usual multivitamin) to 4 mg of folate.
Doctors and patients want the same thing: good information.With good information, both the doctor and the patient can makebetter decisions about health care. Doctors and patients wantthis information now. No one wants to wait; it could take yearsfor the best information to be found. Most women with epilepsydo not want to wait all those years to be able to make a decisionabout what to do with their AEDs during pregnancy.
The pregnancy registries, even with their flaws, are a goodway to find out the answers to the majority of these questions.Although the information is still incomplete, it is startingto tell us more about the risks of taking AEDs during pregnancy.The registries are ongoing, and, as a result, the informationwill continue to emerge. Doctors will continue to analyze andsummarize this information so they may provide the best informationfor their patients.
Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology 2008;71:1109–1117.[Abstract/Free Full Text]
Kalviainen R, Tomson T. Optimizing treatment of epilepsy during pregnancy. Neurology 2006;67:S59–S63.[Abstract/Free Full Text]
Yerby MS, Collins SD. Pregnancy and the mother. In: Engel J, Pedley TA, editors. Epilepsy: A Comprehensive Textbook. Philadelphia: Lippincott-Raven; 1997.
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THE HOPE REGISTRY
