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Pregnancy and the risk of teratogenicity
1Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
Insights
Antiepileptic drugs (AEDs) exposure in utero increases major malformation risks by 3-5% in newborns. Specific AEDs like valproate and carbamazepine are linked to birth defects such as spina bifida, while genetic predisposition may influence recurrence risks.
Area of Science:
- Obstetrics and Gynecology
- Pediatrics
- Pharmacology
Background:
- One in 250 newborns are exposed to antiepileptic drugs (AEDs) during pregnancy.
- AEDs are associated with teratogenic effects including major malformations, growth failure, and psychomotor retardation.
Purpose of the Study:
- To review and synthesize existing evidence on the teratogenic effects of antiepileptic drugs.
- To identify specific AEDs associated with particular birth defects and risk factors.
Main Methods:
- Review of prospective studies and existing literature on AEDs and congenital anomalies.
- Analysis of associations between specific AEDs (phenytoin, valproate, carbamazepine) and malformations.
- Identification of risk factors such as dosage, maternal serum concentrations, folate levels, and polytherapy.
Main Results:
- Increased risk of major malformations (7-10%) compared to the general population.
- Specific associations: barbiturates/phenytoin with heart malformations and facial clefts; valproate/carbamazepine with spina bifida and hypospadias.
- Valproate is specifically linked to bilateral radial aplasia; PHT to ocular hypertelorism and nail hypoplasia.
Conclusions:
- AEDs pose a significant teratogenic risk, with specific drugs linked to distinct malformations.
- High dosage, maternal serum levels, low folate, and polytherapy are identified risk factors.
- Genetic predisposition likely plays a role in teratogenic susceptibility and recurrence risk.
Abstract:
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 phenytoin (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 polytherapy [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.(ABSTRACT TRUNCATED AT 250 WORDS)