Teratogênese associada ao ácido valproico: padrões de malformações congênitas, relação dose-dependente e estratégias de prevenção primária

This study aimed to determine the incidence, dose-dependent relationship, and structural, somatic, and neurocognitive consequences of gestational exposure to valproic acid, while examining primary prevention and pharmacological switching strategies. A systematic review of exposure and incidence or prevalence with a quantitative approach and qualitative synthesis without meta-analysis was conducted following PRISMA 2020 guidelines and PROSPERO principles across PubMed/MEDLINE, VHL/LILACS, and SciELO databases, assessing the methodological quality of the twenty-one included studies using the Newcastle-Ottawa Scale. The results showed that the overall prevalence of major congenital malformations with valproic acid monotherapy ranged between 7.8% and 9.9%, reaching 25.2% at doses exceeding 1450 milligrams per day, with each 100 milligram daily increase during the first trimester raising the malformation risk by 15%. Specific anatomical tropism was identified for hypospadias, spina bifida, orofacial clefts, congenital heart defects, and severe microcephaly, alongside lower birth weight centiles and higher rates of small-for-gestational-age infants. Neurodevelopmental assessments revealed a reduction of up to 19.5 points in full-scale intelligence quotient with disproportionate verbal impairment, autism spectrum disorder rates reaching 62.9%, and sensory processing dysfunction in 80.6% of patients with the clinical phenotype. Preconception switching to lamotrigine and levetiracetam combination therapy decreased major malformation risk by 59%, whereas folic acid failed to prevent structural anatomical damage. In conclusion, valproic acid induces a dose-dependent triaxial teratogenic spectrum, requiring multidisciplinary preconception planning and timely switching to safer therapeutic alternatives in women of childbearing potential.