Methods

A nationwide population-based cohort study was conducted based on comprehensive data of the French National Health Data System (SNDS). Liveborn infants without brain malformation, born between January 2011 and December 2014, were followed from birth up to December 2016. NDs were identified based on diagnoses of mental or behavioural disorders and utilization of speech therapy, orthoptic or psychiatric services. The risk of NDs was compared between children exposed in utero to AED monotherapy and unexposed children, using Cox proportional hazard models adjusted for maternal and neonatal characteristics.

Results

The cohort included 1,721,990 children, 8,848 of whom were exposed in utero to AED monotherapy. During a mean follow-up of 3.6 years, 15,458 children had a diagnosis of mental or behavioural disorder. In utero exposure to VPA was associated with an increased risk of NDs overall (aHR: 3.7; 95%CI: 2.8-4.9) and among children born to a mother without mental illness (aHR 5.1; 95%CI: 3.6-7.3). A dose-response relationship was demonstrated and the risk of NDs was more particularly increased for an exposure to VPA during the second or third trimesters of pregnancy. Among the other AEDs, only pregabalin was consistently associated with an increased risk of NDs (aHR: 1.5; 95%CI: 1.0-2.1).

Conclusion

This study confirms a 4- to 5-fold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.