Beyond Folate: Non-Folate Risk Factors in Neural Tube Defect Pathogenesis

Globally, an estimated 214,000-322,000 infants are born each year with a neural tube defect (NTD), which represents a spectrum of disease severity. The landmark discovery of folic acid in the early 1990s reduced open NTD prevalence by nearly 30%, but closed NTD prevalence rates remain unchanged. This suggests an incompletely solved mechanism of action. Current prevention efforts target open NTDs while other forms of NTDs remain less understood. This review synthesizes evidence from 74 peer-reviewed English-language studies assessing factors associated with NTDs beyond folic acid. Results are organized across two domains: genetic pathways and environmental exposures with environmental exposures encompassing A) general exposures, B) iatrogenic exposures, and C) metabolic and dietary factors. NTDs are biologically heterogeneous, and it has become clear that folic acid supplementation and fortification alone is unlikely to eliminate their global incidence. Additional research, prevention efforts, and multidisciplinary strategies are necessary to reduce NTD burden.