There have long been concerns regarding the safety of the anticonvulsant valproic acid (Depakote) during pregnancy. Back in 2009, the American Academy of Neurology and American Epilepsy Society recommended against the use of valproic acid in women of childbearing age because of the various risks associated with prenatal exposure, citing significantly increased risk of congenital malformations (including neural tube defects) and a spectrum of neurodevelopmental deficits.
A recent study, which included women with epilepsy treated between January 1, 2009, and December 31, 2013, indicates, that despite these recommendations, valproic acid continues to be used in women of reproductive age. This retrospective cohort study examined a nationwide database which included Medicare and Medicaid insurance claims data and identified 46,767 women with epilepsy between the ages of 15 and 44 years.
The most commonly prescribed antiepileptic drugs (AEDs) for both focal and generalized epilepsy were levetiracetam, lamotrigine, and topiramate (about 10% to 15% of the women, depending on the type of seizure). Valproate was more often prescribed in women who had comorbid headache or migraine (892 or 9.6%), mood disorder (1175 or 15.0%), and anxiety or dissociative disorders (855 or 12.6%).
Half of all pregnancies are unplanned, and because the fetal neural tube develops so early on in the pregnancy, stopping the medication after documentation of the pregnancy is too late to avoid exposure during the vulnerable window of development. Therefore, the best way to reduce (and potentially eliminate) the risk of birth defects associated with prenatal exposure to valproic acid is to eliminate its use in women of childbearing age. This study suggests that, despite our efforts to make clinicians aware of the risks associated with valproic acid, clinicians continue to use this medication in women of reproductive age. There are, of course, some women in this population who are taking valproic acid because they have tried and failed other anticonvulsants with safer reproductive safety profiles; however, this study also observed that valproic acid was being used as a first line treatment for women with new onset of seizures.
The researchers also raised concerns regarding the frequent use of topiramate (Topamax) in this population. In this study, topiramate was the third most commonly used anticonvulsant, and it was used in about one-quarter of the women with comorbid headache or migraine (2657 or 28.6%). Clinically we do see a fair number of women with mood and anxiety disorders who are being treated with topiramate for chronic headache and migraines. While topiramate does not appear carry the extremely high risk of teratogenesis that valproic acid carries, there is a growing body of data which suggests that prenatal exposure to topiramate may be associated with increased risk of oral clefts.
This study highlights the importance of preconception planning. Many women come to see us in our clinic as they are planning pregnancy, and we discuss the reproductive safety of medications, review non-pharmacologic alternatives, and suggest changes to their treatment regimen when indicated. But in the real world, many women don’t have access to perinatal psychiatrists and, as stated earlier, half of all pregnancies are unplanned. Thus I think the best time for intervention occurs when any medication is first being prescribed to a woman of childbearing age. Even if that woman is not planning a pregnancy in the near future, we must consider the reproductive safety of the medications we prescribe and must inform women of the risks of becoming pregnant while taking a particular medication.
Ruta Nonacs, MD PhD
Kim H, Faught E, Thurman DJ, Fishman J, Kalilani L. JAMA Neurol. 2019 Apr 1.