Objective Prenatal exposure to the antiepileptic drug (AED) valproic acid (VPA) is associated with an increased risk of impaired postnatal neurodevelopment, including autism spectrum disorder (ASD) and attention‐deficit/hyperactivity disorder (ADHD). We aimed to evaluate the influence of sex and drug dosage on the association between prenatal VPA exposure and postnatal behavioral outcomes. Methods The Australian Pregnancy Register of AEDs was interrogated to identify children aged 4–11 years prenatally exposed to AEDs. Parents reported on their child's behavior using the Autism Spectrum Quotient–Children's Version and the National Institute for Children's Health Quality Vanderbilt Assessment Scale for ADHD. General linear mixed‐effects models were used to investigate the relationship between clinicodemographic variables and psychometric scores. Results A total of 121 children were studied: 54 prenatally exposed to VPA (28 males, 26 females; mean dose ± SD: 644 ± 310 mg/day) and 67 exposed to other AEDs. There was a main effect of sex showing higher ASD scores in males compared to females (p = .006). An interaction between sex and VPA exposure revealed that males had higher ASD symptoms among children exposed to AEDs other than VPA (p = .01); however, this typical sex dynamic was not evident in VPA‐exposed children. There was no evidence of any dose–response relationship between VPA exposure and ASD symptoms. Males had higher ADHD scores compared to females, but there was no evidence for a link between ADHD symptoms and VPA exposure. Significance Prenatal VPA exposure seems to negate the usual male sex‐related predominance in the incidence of ASD. These initial findings deepen the concept of VPA as a "behavioral teratogen" by indicating that its effect might be influenced by sex, with females appearing particularly sensitive to the effects of VPA. No association between VPA doses and adverse postnatal behavioral outcomes was detected, possibly related to the low VPA doses used in this study.

IntroductionPrenatal exposure to certain antiseizure medications (ASMs) has been associated with increased risk of adverse neurodevelopmental outcomes in offspring. While the cognitive and intellectual outcomes of ASM-exposed offspring have been well-described, the long-term behavioural and functional sequalae in these children have received less attention. This systematic review aims to synthesise evidence on the relationship between prenatal ASM exposure and postnatal adverse neurodevelopmental outcomes, focusing on non-cognitive and intellectual domains of neurodevelopment including reduced social, emotional, behavioural, and adaptive functioning, as well as the frequency of neurodevelopmental and psychiatric disorders. This will have meaningful clinical implications for how we counsel women taking ASMs in pregnancy.Methods and analysisStudies reporting predefined neurodevelopmental outcomes will be identified by electronic searches of MEDLINE, PsychINFO, EMBASE, as well as additional manual and grey literature searches. Eligible studies will report outcomes of offspring exposed to ASMs in utero either prospectively or retrospectively from 1990 to present, with screening performed in duplicate. We will use the Newcastle-Ottawa Scale to conduct methodological quality assessments of included observational studies. A narrative synthesis will be used to report on the review findings. Meta-analysis is not anticipated.Ethics and disseminationEthics clearance is not required for the current study. The systematic review will be prepared as a journal article and published in a peer-reviewed journal upon completion.PROSPERO registration numberPROSPERO CRD42021281919Article SummaryStrengths and limitations of this studyThis protocol was developed and written according to the PRISMA-P guidelinesPublication of this protocol ensures transparency and reproducibility of the methods of the systematic review, as well as reduces the likelihood of review duplicationRestricting publications to English only may introduce bias whereby some relevant data is not includedMeta-analysis is not likely to be possible due to heterogeneity in study methodology, reducing the strength of the conclusions that can be drawnTargeting psychosocial and behavioural outcomes allows for a more nuanced understanding of the long-term clinical consequences of prenatal ASM-exposure