The importance of adequate vitamin B12 and folate during pregnancy for preventing birth defects is well-known, but a new study suggests fathers may also need to watch their levels of these key nutrients.

The research, published in Annals of Internal Medicine, found that low concentrations of vitamin B12 and folate in both mothers and fathers during conception and early pregnancy are associated with a higher risk for birth defects in their offspring.

The cohort study analyzed levels of B12 and folate in red blood cells in more than 23,000 parents in China (median age, 28-30 years) within 4 months of and after conception, comparing those results with 400 confirmed birth defects among the participants’ children.

Folate deficiency during pregnancy is associated with neural tube defects. However, as the paper suggests, how concentrations of B12 or folate during and following conception contribute to this risk is unclear.

Most defects develop during a fetus’ first 3 months — a period when a woman may not yet realize she is pregnant, said Weili Yan, PhD, epidemiologist at the Children’s Hospital of Fudan University in Shanghai, China, who helped conduct the new research.

“Waiting until pregnancy is confirmed may be too late,” Yan told Medscape Medical News.

Another unsettled area is how the father’s nutritional status may influence the likelihood of a fetal defect in his offspring, said Karen Puopolo, MD, PhD, neonatologist and chair of American Academy of Pediatrics’ Committee on Fetus and Newborn. “Generally, the data that we have, or we collect, is maternally derived because that is the patient in front of you in the obstetric setting,” Puopolo, who was not involved in the study, said.

After studying blood samples of 17,765 women pregnant for no longer than 4 months, a period that would likely reflect levels during organogenesis, lower concentrations of both vitamins had higher likelihoods of birth defects, the researchers concluded.

Red blood cells folate concentrations < 453 nmol/L — half of the World Health Organization’s threshold for preventing neural tube defects — were associated with the greatest risk, at 25.7 defects per 1000 births, they reported. Concentrations between 906 and 1131 nmol/L were associated with the fewest defects (16.5), with the predicted prevalence rising at levels beyond this range.

Concentrations of B12 < 148 pmol/L, considered in the US to be a deficiency, were associated with 16.8 defects per 1000 births. By comparison, the lowest predicted prevalence was observed among those with at least 590 pmol/L (11.8 defects).

Yan’s group also analyzed red blood cell turnover and spermatogenesis in a smaller sample of 3032 couples within 4 months of conception. Both nutrients were again associated with the risk for birth defects, with B12 having the strongest link.

Fathers and mothers with levels of B12 < 148 pmol/L had a predicted prevalence of 55.5 and 49.6 defects, respectively. This risk was more than halved in concentrations > 295 pmol/L. Folate levels in the red blood cells < 453 nmol/L in fathers and mothers were linked to the highest incidence of defects, at 26.4 and 28.3 per 1000 births, respectively.

While untested genetic and biological factors may have contributed to the results, the study supports the importance of both vitamins in preventing birth defects, Yan said. It also suggests the protective effects of B12 and folate extend beyond the prevention of neural tube defects. More than half of the 400 defects affected the heart, the study found.

“This has important implications for primary prevention strategies — shifting the focus from ‘preventing neural tube defects’ to a broader goal of ‘preventing major structural birth defects,’” Yan said.

In an editorial accompanying the journal article, Cuilin Zhang, MD, PhD, MPH, and Jing Zhu, MD, PhD, of the National University of Singapore, Singapore, wrote that alterations in sperm epigenomes, resulting from insufficient folate, are linked to increased birth defects in animal models. “Most previous studies have focused on associations between maternal folate status and offspring outcomes,” they wrote. “However, fathers contribute not only their haploid genomes but also their epigenomes to the offspring…. Chen and colleagues’ findings further indicate the importance of preconception paternal nutritional status in mitigating adverse offspring outcomes, particularly nutrients related to one-carbon metabolism,” including B12 and folate.

For Puopolo, a key takeaway is the place of a father’s nutrition in optimizing pregnancy outcomes. “That, again, is something we’ve traditionally looked [at] on the maternal side,” she said.

“Looking at the paternal side as well is something we should probably [study more] — and pay more attention to.”

The study was funded by the National Key Research and Development Program of China, National Natural Science Foundation of China, and Chinese Academy of Medical Sciences. 

Sam Nichols is an Australian science journalist, whose work often covers healthcare, drug policy, addiction, and medicine.