Molecular Pathogenesis of Valproate-Induced Neural Tube Defects: A Systematic Review of Apoptosis, Folate Pathways, and Gene Expression Dysregulation

Abstract

Background: Significant morbidity and mortality are related to neural tube defects (NTDs), which are severe congenital malformations brought on by failure of neural tube closure during early development. Through several teratogenic processes, valproic acid (VPA), a commonly used antiepileptic treatment, is strongly correlated with a higher incidence of NTDs. 

Purpose of Study: This review attempts to synthesize current research and integrate molecular mechanisms associated with VPA-induced NTDs, which are often studied separately. 

Methods: Based on PRISMA 2020 guidelines, this study was conducted and the protocol was registered in PROSPERO (CRD420261384605). Literature from PubMed, ProQuest, Science Direct, and Wiley was screened independently by all the authors according to inclusion and exclusion criteria. A total of seven studies were included in this systematic review. A proper assessment of Risk of Bias was conducted using the Cochrane RoB 2.0 and Modified SYRCLE's RoB. 

Results: The results showed that valproic acid (VPA) causes neural tube defects (NTDs) via a variety of pathways, including oxidative stress, apoptosis, folate-pathway dysregulation, epigenetic modification, and retinoic acid signaling disruption. Genetic susceptibility affected teratogenic outcomes through differential regulation of folate-related and anti-apoptotic genes, whereas VPA exposure changed the expression of genes involved in neurulation and embryonic development. Additionally, new research indicated that by inhibiting apoptotic pathways and reducing the prevalence of NTDs, maternal immune activation can reduce the teratogenic impacts of VPA.

Conclusion: Developmental signaling dysregulation and host susceptibility variables interact complexly in VPA-associated teratogenicity. To support better preventive and therapeutic strategies for pregnant individuals in need of VPA treatment, further mechanistic research is required.