Research in context
Evidence before this study
Although the use of antiepileptic drugs during pregnancy has been known for more than 50 years to be associated with increased risks of major congenital malformations in the offspring, it is not until more recent years, with emerging data from prospective pregnancy registries, that the teratogenic potential of different antiepileptic drugs had begun to be delineated. We refer to two recently published systematic reviews and meta-analyses. One review focused on newer antiepileptic drugs and searched, on Nov 12, 2014, PubMed and Embase for all newer antiepileptic drugs, congenital anomalies, and pregnancy. The second systematic review searched MEDLINE, Embase, and the Cochrane Central Register of Controlled trials from inception to Dec 15, 2015. We did a separate PubMed search for articles published from Dec 16, 2015, to Dec 15, 2017, using the search terms “anticonvulsants”, “antiepileptic drugs”, “teratogenicity”, and “birth defects”. Our search was limited to studies in English and we did not set any criteria for assessment of quality.
Although meta-analyses increase the statistical power, they combine data from heterogeneous studies sometimes with different outcome criteria, and do not provide direct within-study comparisons between antiepileptic drug treatments. Such internal comparisons have been made in individual reports from independent prospective antiepileptic drug and pregnancy registries but so far only between the most frequently used antiepileptic drugs. Taken together, these studies have consistently reported increased risk of major congenital malformations associated with valproate and phenobarbital compared with pregnancies unexposed to antiepileptic drugs, as well as compared with pregnancies exposed to other antiepileptic drugs such as carbamazepine and lamotrigine. Findings also suggest increased risks associated with topiramate. Pregnancy registries have also reported that the risks associated with some drugs, in particular valproate, might be dose dependent.
Added value of this study
On the basis of the largest published prospective cohort of pregnancies in women with epilepsy so far, we provide the prevalence of major congenital malformations at 1 year after birth following exposure to the eight most frequently used antiepileptic drugs in monotherapy. Where a dose dependency relationship was apparent, risks are reported at different doses used at conception. In a multivariable analysis, we report 36 direct comparisons of risks between different treatment modalities.
Implications of all the available evidence
With epilepsy often managed by primary care physicians, and an increasing use of antiepileptic drugs for other indications, the risk of major congenital malformations is a concern for prescribers from many disciplines. Epilepsy, as well as some psychiatric conditions, might have serious consequences and require continuation of treatment during pregnancy. Treatment modalities should be reviewed regularly in all women of childbearing potential to assess risks and benefits of treatment alternatives and enable any appropriate modifications before pregnancy. Current evidence has made clear that, whenever possible, valproate should be avoided in the treatment of women of childbearing potential, but risks differ also between other treatments. Our comprehensive study, with comparisons of risks between a multitude of antiepileptic drug treatments and dosages, provides physicians with vital information when they consider alternatives for women of childbearing potential.