Risk of early neurodevelopmental disorders associated with in utero exposure to valproate and other antiepileptic drugs: a nationwide cohort study in France

Abstract

Information available on the risks of neurodevelopmental disorders (NDs) associated with in utero exposure to valproate (VPA) and to other antiepileptic drugs (AEDs) is limited. 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. The cohort included 1,721,990 children, 8848 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). This study confirms a four to fivefold increased risk of early NDs associated with exposure to VPA during pregnancy. The risk associated with other AEDs appears much lower.

Neurodevelopmental outcomes in children exposed to newer antiseizure medications: A systematic review

“…Our limited findings regarding dose, in addition to existing literature investigating dose associations between newer ASMs and congenital malformations, 2 suggest that larger samples, utilizing ASM blood levels, will be needed to detect dose‐dependent effects in newer ASMs. Studies will need to consider exposure throughout the entire duration of gestation, while noting the importance of the late second and third trimester for fetal brain development 56 . Outcomes will also vary by maternal and fetal genotypes, 57 which alter susceptibility to the ASM exposure; large populations of ASM‐exposed children are necessary to address this and will likely require international collaboration.…”

Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders

“…Moreover, these effects were stronger when exposures occurred during the second and third trimesters of pregnancy. However, these findings were not affected by the mother’s mental health 213 .…”

“…In the case of VPA, human evidence supports only a poor interaction between the effects of prenatal exposure to VPA and maternal mental health. Thus, a very recent nationwide population-based analysis has shown that in utero exposure to VPA is associated with an increased risk of neurodevelopmental mental and behavioral disorders in exposed children 213 . Moreover, these effects were stronger when exposures occurred during the second and third trimesters of pregnancy.…”

Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010–2018

“…Observational studies are therefore essential to study the efficacy and safety drugs in pregnant women and their offspring. For instance, a French nationwide study on recent data confirmed that valproic acid, a treatment for epilepsy, cause birth defects and delayed cognitive development [ 2 , 3 ].…”