In a new review, researchers found several factors that contributed to the risk of spina bifida development—from solvent, pesticide, and heavy metal exposure, to medications, health conditions and genetic pathways.
Environmental Toxicities
According to their research, maternal solvent and pesticide exposure increased spina bifida risk more than tenfold compared with modest increases from paternal exposure. Nonetheless, paternal exposures to organic solvents, arsenic, welding fumes, and Agent Orange from the Vietnam War were significant: Agent Orange exposure specifically doubled the risk of spina bifida in offspring.
Heavy metals also contributed to the development of spina bifida. Arsenic and selenium exposure increased risk, while higher maternal zinc levels were linked to lower odds of spina bifida. Methylmercury exposure, often through contaminated food sources, increased risk as well.
Medications
Valproic acid, an older-generation anticonvulsant, carried a particularly high risk for spina bifida, even when women took folic acid supplements, because valproic acid does not reduce serum folate levels. "Anticonvulsants may operate under a different mechanism than other folic acid antagonists or may have a second mechanism that further augments the risk of spina bifida: free radical-mediated cellular damage during neurodevelopment," wrote Ethan S. Wong, BS, of the Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine at The University of Chicago Medical Center, in Illinois, with colleagues. High-dose folic acid supplementation (5 mg daily) lowered risk for other medications, such as carbamazepine and trimethoprim, but remained ineffective for valproic acid.
Other medications that were associated with increased risk included antimalarials, which deprive parasites of folate but may also interfere with fetal folate metabolism; nitrosatable drugs, which can form carcinogenic and teratogenic compounds; and guaifenesin, which showed a small but measurable association.
Health and Lifestyle Conditions
Maternal diabetes increased spina bifida risk two- to sixfold. Pregestational diabetes posed higher risk than gestational diabetes because it is present during early fetal development, the authors noted, and women with overweight showed elevated odds compared with those of normal weight. Inadequate weight gain during pregnancy was an additional factor. Maternal fever, cytomegalovirus infection, common cold, and asthma were associated with increased risk, as was low maternal vitamin B12 levels. Smoking nearly doubled risk, and caffeine intake showed possible effects, though results were inconsistent.
Genetics
Variants in folate–homocysteine pathway genes, including MTHFR, MTHFD1, MTR, and MTRR, were strongly implicated. Interactions between genetic variants and environmental exposures amplified risk, such as pesticide exposure in mothers with PON1 variants or arsenic exposure, which negated folic acid’s protective effect.
“Understanding these intricate interactions is crucial for developing effective prevention and intervention strategies,” the authors summarized.
Methods
The researchers reported that spina bifida is a neural tube defect that affects about 1 in 2,875 births in the United States. The most severe form, myelomeningocele, accounts for most cases and is associated with significantly diminished quality of life. Folic acid supplementation before and during early pregnancy lowers neural tube defect risk by about 70%, they noted. Following mandatory fortification, US prevalence fell by 19% to 34%, yet subtypes such as lipomyelomeningocele have shown little to no decline, indicating that other factors, such as the ones the authors described in their review, remain important.
The researchers conducted a systematic search of PubMed, Embase, and Cochrane Library for studies from 2003 through 2023, and analyzed those that were focused specifically on spina bifida risk factors and genetics. Limitations of their review included differences in study design, geographic variation, and small sample sizes in some analyses. Data on newer medications and emerging pollutants remain sparse, and gene–environment interactions are not fully understood.
"Spina bifida represents a multifactorial birth defect influenced by a complex interplay of genetic and environmental factors," the authors concluded. They suggested areas of future multidisciplinary research, including whole-genome and whole-exome sequencing to better understand the interactions between genes and environmental factors and to develop precision medicine that is personalized to each patient's genetic profile. They added that adjusting folic acid supplementation based on genetic variants could optimize prevention for patients who are at higher risk, and understanding the mechanistic pathways through which endocrine disruptors and neurotoxins contribute to the development of spina bifida would be important to mitigate risks during fetal development. They also explained the benefits of strengthening regulations on pollutants and developing other public health policies to reduce the incidence and impact of spina bifida.
Full disclosures can be found in the published study.
Source: Pediatric Discovery