Pregnancy and the Risk of Teratogenicity

Summary: One in every 250 newborns is exposed to antiepileptic drugs (AEDs) in utero. Various studies have attributed a teratogenic effect to these AEDs, mainly consisting of major malformations, minor anomalies, intrauterine or postnatal growth failure, and psychomotor retardation. Prospective studies confirm the increased risk of major malformations. The absolute risk of 7–10% is about 3–5% higher than that in the general population. Barbiturates and phe-nytoin (PHT) are particularly associated with congenital heart malformations, facial clefts, and some other malformations. Valproate (VPA) and carbamazepine (CBZ) are associated predominantly with spina bifida aperta (1–2 and 0.5–1.0% risk, respectively) and hypospadias. Bilateral radial aplasia is a rare but specific effect of VPA. Several studies identified additional risk factors, i.e., high daily AED dosage, high maternal serum AED concentrations, low folate levels, or po-lytherapy [phenobarbital (PB) plus primidone (PRM) plus PHT or CBZ plus VPA plus PB with or without PHT]. The few prospective studies controlled for socioeconomic factors or that considered parental findings indicate that risk of specific cognitive defects rather than risk of overall mental retardation may be increased, that early growth retardation is followed by a catch-up growth to normal, and that ocular hypertelorism and nail hypoplasia are the only minor anomalies causally related to PHT exposure. However, no final conclusions can be made. Genetic predisposition to the teratogenic side effects of AEDs plays a role, codetermining the recurrence risk if the woman has previously given birth to a child with a major malformation. The molecular genetic basis of this predisposition is unclear. No tests are yet available for identifying parents or fetuses at particularly high risk. Prevention of teratogenic AED side effects is possible by critical evaluation, before pregnancy, of the woman's need for AED therapy. If AED therapy cannot be avoided, it should be monotherapy with the lowest possible dosage. High peak levels should be avoided by dividing the daily dosage into at least two or three doses. The efficacy of folate supplementation alone in reducing teratogenic risks is unclear. In cases of obvious folate deficiency, treatment is required, but concomitant vitamin B₁₂ deficiency should first be excluded or treated. Prenatal diagnosis should be offered. It may consist of fetal ultrasound examination during Week 18–20, and of afetoprotein analysis of amniotic fluid obtained during Week 16 if the mother is receiving VPA or CBZ. This should be discussed with the parents before the pregnancy. The choice of medication is made not only by balancing the therapeutic advantages and teratogenic risks of each AED or AED combination but also by considering the parental attitudes toward prenatal diagnosis and termination of pregnancy.     

Assessment of teratogenic risk.

Although the association between prenatal exposure to old generation antiepileptic drugs (AEDs) and major congenital malformations has been studied for many years, it is not clear whether any specific AED, or AED combination, is more harmful than others, or whether any pattern of malformations can be considered specific for any given drug. Relationships between dosage and plasma concentrations of AEDs and the risk of malformations also need to be clarified. The greatest limitation of all studies performed to date is the fact that none included a sufficiently large number of pregnancies. For newer generation AEDs the teratogenic risk, if any, is unknown. Large prospective studies are needed. The best approach is the establishment of registries through international collaboration. Inclusion of non-epileptic controls and untreated women is not strictly necessary to evaluate the comparative teratogenic risk of AEDs. The modalities of data collection should be pre-defined; common protocols, sufficiently exhaustive but at the same time easy to perform, should be shared from the beginning. Information on the presence or absence of major malformations or prenatal growth retardation, and on all major factors that may affect the teratogenic endpoints should be obtained. Study designs should ensure high quality data recording, and adequate quality assurance and auditing procedures. Further requisites are a clear definition of congenital malformation and prolonged follow-up to detect the occurrence of congenital malformations not detected at birth.     

Pregnancy in women who have epilepsy

Ideal, comprehensive care of women who have epilepsy during the reproductive years must include effective preconceptional counseling and preparation. The importance of planned pregnancies with effective birth control should be emphasized, with consideration of the effects of the enzyme-inducing AEDs on lowering efficacy of hormonal contraceptive medications and the need for back-up barrier methods. Before pregnancy occurs, the patient's diagnosis and treatment regimen should be reassessed. Once the diagnosis of epilepsy is confirmed, it is important to verify if the individual patient continues to need medications and if she is taking the most appropriate AED to balance control of her seizures with teratogenic risks. For most women who have epilepsy, withdrawal of all AEDs before pregnancy is not a realistic option. A decision to undergo a trial while not taking AEDs before a planned pregnancy should be based on the same principles used for AED withdrawal in any person who has epilepsy. The taper should be completed at least 6 months before planned conception to provide some reassurance that seizures are not going to recur. If a woman who has epilepsy is in the more prevalent category of needing AEDs for seizure control, then monotherapy at the lowest effective dosage should be used. If large daily doses are needed, then frequent smaller doses or extended-release formulations may be helpful to avoid high peak levels. Some of the newest information about differential risks between AEDs also should be considered. The woman's AED regimen should be optimized and folate supplementation should begin before pregnancy. Given that 50% of pregnancies are unplanned in the United States, folate supplementation should be encouraged in all women of childbearing age who are taking any AED for any indication. Dosing recommendations vary from 0.4 mg/d to 5 mg/d. It is not uncommon for a physician to consider changing AED regimens when the patient first reports that she is pregnant. In many cases, she already is in or past the critical period of organogenesis (Table 3). If a woman who has epilepsy presents after conception and is taking a single AED that is effective, her medication usually should not be changed. Exposing the fetus to a second agent during a crossover period of AEDs only increases the teratogenic risk, and seizures are more likely to occur with any abrupt medication changes. If a woman is on polytherapy, it may be possible to switch to monotherapy safely. Seizure control remains an important goal during pregnancy. In particular, convulsive seizures place the mother and fetus at risk. Nonconvulsive seizures also may be harmful, especially if they involve falling or other forms of trauma. Monitoring serum AED levels during pregnancy can be helpful in optimizing seizure control. Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given 10 mg/d orally during the last month of pregnancy followed by 1 mg intramuscularly or intravenously to the new-born. Although women who have epilepsy and women who are taking AEDs for other indications do have increased risks for maternal and fetal complications, these risks can be reduced considerably with effective preconceptional planning and careful management during pregnancy and the postpartum period.     

Epilepsy and Pregnancy

Summary:  Since 1963, the association between antiepileptic drugs (AEDs) and congenital malformations in the offspring of women with epilepsy has received attention. A number of articles reported affirmative as well as some negative findings regarding an increased risk of congenital malformations. Although a consensus has not been regarding the presence of the specific malformation syndromes in relation to individual AEDs, such as fetal hydantoin syndrome, it is evident that women taking AEDs carry a two- to sevenfold higher risk of congenital malformations than do the general population. In most recent studies, special attention has been placed on polytherapy, including the specific AED, or AED combinations, and high AED serum concentrations, responsible for the higher risk of congenital malformations. Based on these cumulative results, therapy guidelines for women of childbearing age with epilepsy have been established.     

Use of antiepileptic drugs in pregnancy

Babies born to mothers exposed to antiepileptic drugs (AEDs) are at increased risk for major congenital malformations, cognitive impairment and fetal death. For the millions of women with epilepsy, maintaining the safest drug that will successfully prevent seizures during pregnancy remains a primary consideration. The recent development of collaborative international registries to examine the differential and dose-dependent effects of the expanding number of old and new AEDs, have shed light upon potential differences during pregnancy. Valproic acid appears to be associated with the highest risk of overall, as well as AED-specific, birth defects, becoming more evident as doses exceed 1000 mg/day. Lamotrigine may be less teratogenic to humans than other AEDs, although orofacial clefts have recently been reported. The effects of polytherapy appear to carry greater risks compared with monotherapy. Limited data exist for many of the newer AEDs. Furthermore, AED effects may persist during postnatal development. Although no class 1 outcome data are available, prepregnancy counseling to optimize patient-specific treatment is recommended for women of childbearing potential with epilepsy.     

Neurodevelopmental effects of antiepileptic drugs

Although the vast majority of children born to women with epilepsy are normal, these children are at increased risk for both anatomic and cognitive impairments. Current evidence suggests that the defects are the result of in utero antiepileptic drug (AED) exposure combined with a genetic predispositon. However, the exact mechanisms underlying these effects remain to be delineated. AED polytherapy increases the risk, but it remains uncertain if specific AEDs pose an overall greater threat. Most women with epilepsy cannot avoid AEDs during pregnancy because of the greater risks posed by seizures to the mother and fetus. Therefore, current recommendations emphasize definitive diagnosis and the use of AED monotherapy at the lowest effective dose if treatment is indicated. Prenatal folate and multivitamins should also be given routinely to women of childbearing age who require AED therapy.     

Oxcarbazepine in pregnancy: clinical experience in Argentina

The potential teratogenicity of antiepileptic drugs (AEDs) is a major concern for women with epilepsy who are considering pregnancy. Traditional AEDs are associated with an at least twofold risk of fetal malformations compared with the general population. The risk of malformations with newer AEDs is unclear. This article reports the multicenter clinical experience in Argentina of pregnant women with epilepsy receiving AEDs. Of 114 pregnancies monitored, 16 newborns had anomalies: 3 cardiac, 3 skull, and 2 gastrointestinal malformations, and 8 facial dysmorphies. Most fetal anomalies were observed following exposure to phenobarbital, valproate, and carbamazepine. Of 55 babies exposed to the new-generation AED oxcarbazepine (20 as combination therapy and 35 as monotherapy), one malformation (cardiac) was reported (in a patient receiving oxcarbazepine and phenobarbital). Thus, newer AEDs may have a lower teratogenic risk than traditional AEDs. These data add to the growing experience with AED therapy in pregnant women with epilepsy.     

抗癫药物对妊娠癫癎患者子代的致畸风险

目的:旨在评估抗癫癎药物(AEDs)对妊娠癫癎患者子代出现先天畸形的风险。方法:对妊娠癫癎患者采用登记和随访研究,分析其孕期AEDs用药情况、癫癎发作、妊娠结局及子代出现畸形的风险。结果:入选105例妊娠癫癎患者。服用AEDs患者79/105例(75.2%),未服用AEDs患者26/105例(24.8%)。单药治疗60/79例(75.9%),其中1/60例(1.7%)流产;患者子代中2/60例(3.3%)先天性畸形(1例服用卡马西平,出现先天性心脏动脉导管未闭;1例服用拉莫三嗪,出现无胚心)。联合用药19/79例(24.1%),子代无先天畸形出现。未服用AEDs患者中有2/26例(7.7%)流产,其余患者子代未出现先天畸形。结论:妊娠癫癎孕妇多数于孕期仍服用AEDs,且以单药治疗居多;使用AEDs(分别为卡马西平和拉莫三嗪)患者子代出现2例先天性畸形;丙戊酸钠易致畸但仍在妊娠癫癎中经常使用,本研究中服用丙戊酸钠孕妇未出现子代先天性畸形。     

Antiepileptic drug use during pregnancy: Perinatal outcomes

Purpose

This study was undertaken to (1) measure the frequency of AED monotherapy or polytherapy during pregnancy and AED discontinuation prior to pregnancy in a cohort of women with treated epilepsy; and (2) describe the frequency of major congenital malformations according to maternal use of AED during pregnancy.

Methods

A cohort of epileptic pregnant women was identified within the Quebec Pregnancy Registry and was divided into three groups based on maternal AED use during pregnancy: AED monotherapy, AED polytherapy and no AED use.

Results

Of the 349 pregnancies meeting eligibility criteria, 79.6% were exposed to AED monotherapy and 5.8% to polytherapy during pregnancy; 14.6% discontinued AED prior to pregnancy. The most commonly used AEDs were carbamazepine (29.9%) and valproic acid (19.7%); the most common AED polytherapy combination was carbamazepine combined with clobazam (2.5%). Of 111 deliveries in the group of women on monotherapy during pregnancy, 9.9% (n = 11) were born with major congenital malformations; in the group of women treated with polytherapy, 19.0% (n = 8 over 42) of babies had major congenital malformations compared to 20.0% in women who discontinued AEDs prior to pregnancy.

Conclusion

This study demonstrates that the majority of women suffering from epilepsy were treated with monotherapy rather than polytherapy during pregnancy. While most used other agents, an important number of women continued to use valproate in pregnancy despite the long standing evidence of its teratogenicity and increasing evidence of its neuro-toxicity to the fetus.