Teratogenic potential of antiepileptic drugs: need for research, patient education


A number of recent papers have re-focused attention on the teratogenic potential of antiepileptic drugs (AED) and the need to educate women with epilepsy about the need for effective contraception.

Over two decades ago, valproic acid exposure during pregnancy was associated with a risk of neural tube defects (Omtzigt et al. Eur J Clin Pharmacol 1992;43:381-388). Other risks include genitourinary and musculoskeletal abnormalities, cleft lip/palate, and congenital heart defects (Jackson et al. Arch Dis Child Fetal Neonatal Ed 2016;101:F207-11). A recent population-based cohort study for the period 1990-2013 reported an adjusted odds ratio for congenital anomalies with antiepileptic drug exposure of 1.82; the greatest risk was heart anomalies (OR 2.49) (Ban et al. PLoS One 2015;10:e0131130; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4492893/pdf/pone.0131130.pdf).

The estimated risk of congenital malformations with valproic acid is 2-7 times higher than with other antiepileptic drugs (Tanoshima et al. Clin Pharmacol Ther 2015;98:417-441). Other agents with teratogenic potential include lamotrigine, carbamazepine, ethosuximide, fosphenytoin, phenobarbital, phenytoin, primidone, and topiramate.

In addition, a prospective cohort study found that fetal exposure to high-dose valproate (>800 mg/day) was associated with impairments in cognitive development during childhood, including a lower intelligence quotient (mean IQ 9.7 points lower) and an 8-fold increased risk of educational intervention during childhood (Baker et al. Neurology 2015;84:382-390; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC4336006/pdf/NEUROLOGY2014590208.pdf).

Women with epilepsy may be unaware of these risks, or may use hormonal contraceptives, which can be less effective due to interactions with antiepileptic drugs. A retrospective observational study in Colorado surveyed 115 women with epilepsy (mean age 30.7 years) attending a neurology clinic (Bhakta et al. Epilepsy Behav 2015;52(Pt A):212-217). The most common antiepileptic drugs used were topiramate and carbamazepine. Only 26% of patients had a documented method of contraception. Among contraception users, 60% were taking a combined hormonal or progestin-only pill, a majority of which had a potential for drug-drug interactions. A total of 7% of patients received counselling about a contraception plan, and 18% received counselling on a pregnancy plan.

To address this issue, U.S. clinicians have recently made a number of recommendations, including a national reporting system for congenital malformations; government funding of the North American AED Pregnancy Registry; routine meta-analyses to detect teratogenic signals; monitoring of AED prescription practices for women; preclinical testing of all new AEDs for neurodevelopmental effects, more specific FDA requirements to establish AED effects on cognition in children; and improved research funding to investigate the underlying mechanisms for AED-induced teratogenic effects (Meador & Loring. Neurology 2016;86:297-306).

Recommend to a Colleague

Related Posts

Go back to home page