Understanding the multifactorial causes of spina bifida

Spina bifida is among the most common and debilitating neural tube defects, affecting approximately 1 in every 2,875 newborns in the United States. This congenital malformation disrupts the normal closure of the neural tube, potentially leading to lifelong complications such as paralysis and hydrocephalus. Although the protective role of folic acid is well documented, many cases arise in mothers who receive adequate supplementation, suggesting a more complex etiology. A growing body of evidence points to multifactorial origins—where genetic predispositions and environmental triggers converge to disrupt fetal development. Due to these challenges, more in-depth research is needed to clarify the molecular and environmental factors contributing to spina bifida.

In a comprehensive review (DOI: 10.1002/pdi3.2517) published in Pediatric Discovery in January 2025, researchers from The University of Chicago and collaborators across China delved into the multifactorial causes of spina bifida. Drawing on a systematic review of literature from 2003 to 2023, the team identified significant genetic markers and environmental contributors that interact during embryonic development. The study emphasizes the limitations of current prevention strategies and advocates for a more nuanced understanding of gene-environment interactions to inform risk reduction and clinical intervention.

The review identifies inadequate folic acid supplementation as a well-established but incomplete protective factor. Despite public health fortification programs, cases of spina bifida—especially lipomyelomeningocele—remain unaffected, indicating additional contributors. Environmental exposures such as pesticides, solvents, arsenic, and methylmercury significantly elevate risk, especially when combined with genetic susceptibility. Medications like valproic acid and anticonvulsants, maternal obesity, diabetes, and infections also emerge as key risk enhancers. Genetic analysis reveals variants in the folate-homocysteine pathway, particularly in MTHFR, MTRR, and MTHFD1, as potent risk factors. Novel insights from genome-wide association studies and whole-exome sequencing have uncovered gene-environment interactions involving PON1 and NAT1, as well as mutations in oxidative stress (e.g., SOD1, SOD2) and Wnt signaling (e.g., CELSR1, PRICKLE2) pathways. Notably, high arsenic exposure appears to nullify the protective effect of folic acid. The authors suggest that combined genetic and environmental burdens may act synergistically to impair neurulation, the embryonic process of neural tube closure. These findings call for multi-layered prevention strategies that incorporate both environmental regulation and genetic risk screening.

Our review underscores the urgent need to move beyond a one-size-fits-all prevention model. We now know that spina bifida risk is influenced by a tangled network of genes and environmental exposures. This means personalized interventions—such as tailored folic acid dosages based on genetic profiles—could dramatically improve outcomes. It's time to integrate genomic insights into maternal care and public health policies."

Dr. Yi Zhu, corresponding author of the study

This comprehensive synthesis of spina bifida risk factors opens the door to targeted public health interventions and precision medicine. Incorporating routine genetic screening into prenatal care may help identify high-risk pregnancies, especially those involving known gene-environment interactions. Strengthening regulations on toxic exposures like pesticides and industrial solvents could mitigate environmental risk. Importantly, understanding individual genetic susceptibilities can refine folic acid supplementation strategies, potentially preventing cases that current policies miss. As sequencing technologies become more accessible, future research may further illuminate how genetic and environmental factors jointly shape embryonic development—paving the way for personalized, evidence-based prevention of spina bifida.