Valproate for Epilepsy Poses Greater Risk for Major Congenital Malformations

fetal ultrasound pregnancy
fetal ultrasound pregnancy
Lamotrigine and carbamazepine may represent safer treatment alternatives for girls and women who are or who might become pregnant.

A new study from the United Kingdom reveals that valproate during pregnancy is associated with a nearly 3-fold increase in children born with major congenital malformations (MCMs), compared with children born to women not taking antiepileptic drugs (AEDs).1

The latest results support prior data from several population-based studies2-4 that showed a higher prevalence of MCMs in children exposed to valproate in utero, ranging from 6.7% to 9.7%. In a similar manner, a meta-analysis conducted by Kimford J. Meador, MD, professor of neurology at Stanford Neuroscience Health Center in Palo Alto, California and colleagues5 reported a prevalence of 10.7% with valproate monotherapy compared with 7.1% in children born to mothers with epilepsy who did not take valproate, but may have taken other AEDs.

A special report from the joint Task Force of the Commission on European Affairs of the International League Against Epilepsy (CEA-ILAE) and the European Academy of Neurology (EAN) in 2015 issued a set of guidelines for the use of valproate in girls and women of childbearing years in circumstances in which another therapy either failed or was not suitable.2

The current study was designed to examine the general risks of several common AEDs in pregnancy on a population basis, including valproate. In a cohort of 240,071 pregnant women from The Health Improvement Network (THIN) — a nationwide primary care database in the United Kingdom that captures 98% of clinical records — who gave birth between January 1, 1995 and December 31, 2014, a small subset were treated with AEDs for epilepsy or mental illness.

The vast majority — 239,151 — were not prescribed any AEDs. Among women who were, 229 took valproate, 357 took lamotrigine, and 334 took carbamazepine. The mean age of women given carbamazepine or no AED at all was 31 compared with 30 for valproate and lamotrigine. The most common types of MCMs were cardiovascular septal defects, hypospadias, and cleft palate.

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Neither lamotrigine nor carbamazepine significantly increased the prevalence of MCMs compared with no AEDs, while valproate increased the prevalence per 100 live births by 3-fold from 2.22 (range 2.16-2.28) to 6.55 (3.71-10.57) (95% CI). This included a prevalence range for valproate monotherapy of 5.68 (2.76-10.20) and polytherapy of 9.43 (3.13-20.66). The adjusted prevalence for valproate was 2 times higher when compared directly with lamotrigine/carbamazepine (6.55 [3.71-10.57] vs 3.04 [1.89-4.61], respectively).

The investigators concluded that lamotrigine and carbamazepine represent safer treatment alternatives in girls and women who are or who might become pregnant, “bearing in mind that for some women, switching to carbamazepine or lamotrigine may not be a suitable treatment option.” They noted that evidence of safety during pregnancy for many other available AEDs is very limited.


  1. Petersen I, Collings SL, McCrea RL, et al. Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies. Clin Epidemiol. 2017;9:95-103.
  2. Tomson T, Marson A, Boon P, et al. Valproate in the treatment of epilepsy in girls and women of childbearing potential. Epilepsia. 2015;56(7):1006-1019.
  3. Campbell E, Kennedy F, Russell A, et al. Malformation risks of antiepileptic drug monotherapies in pregnancy: updated results from the UK and Ireland Epilepsy and Pregnancy Registers. J Neurol Neurosurg Psychiatry. 2014;85:1029-1034.
  4. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12:244-252.
  5. Meador K, Reynolds MW, Crean S, et al. Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy Res. 2008;81:1-13.