Risk of Major Congenital Anomalies in Children Born to Women Prescribed Anti-epileptic Drugs with and without Periconceptional Folic Acid Supplementation: A United Kingdom Population-based Cohort Study

INTRODUCTION: Clinical guidelines recommend women exposed to anti-epileptic drugs(AED) take high-dose(5mg) folic acid(FA) daily before pregnancy until the end of first trimester to reduce the risk of neural tube defects and other congenital anomalies. We assessed whether such FA supplementation modified the risk of major congenital anomaly(MCA) in children of mothers prescribed AEDs during pregnancy.

METHODS: We identified 258,523 singletons born to women aged 15-44 years between 1990-2013 from The Health Improvement Network, a United Kingdom primary care database. We classified MCAs into system-specific groups according to the European Surveillance of Congenital Anomalies classification. We identified whether women had prescriptions of AED in the first trimester and 5mg FA supplementation in the three months before pregnancy up to the first trimester. We used logistic regression with a generalised estimating equation to assess the association of MCA with antenatal exposure to AED and with periconceptional FA supplementation, with adjustment for maternal socio-demographic factors.

RESULTS: The MCA risk was 2.7% in the 257,126 children unexposed to AED and 5.0% in 1,184 exposed. Compared to unexposed children, there was a 2-fold increase of MCA in children exposed to any AED (adjusted odds ratio[AOR]=1.90, 95% confidence interval 1.35-2.68). In children of mothers with antenatal exposure to AED, the MCA risk was 5.9% in 649 children whose mothers were prescribed 5mg FA and 4.0% in those with no or low-dose FA only (AOR=1.79, 0.82-3.91). MCA risk was highest in children of mothers with more than one AED (7.3%) than those with monotherapy and 5mg FA did not decrease this risk.

CONCLUSIONS: Only half of women prescribed AEDs in early pregnancy by their general practitioner were also prescribed periconceptional high-dose FA. There is no evidence that this reduced the MCA risk associated with AEDs, although this may reflect selective prescribing to those with more severe morbidity.