The importance of adequate vitamin B12 and folate during pregnancy for preventing birth defects is well-known, but a recent study suggests fathers may also need to watch their levels of these key nutrients, reports Medscape Medical News.
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 analysed levels of B12 and folate in red blood cells in more than 23 000 parents in China (median age, 28-30) within four 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 after conception contribute to this risk is unclear.
Most defects develop during a foetus’ first three months – a period when a woman may not yet realise 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 foetal defect in his offspring, said Karen Puopolo, MD, PhD, neonatologist and chair of American Academy of Paediatrics’ Committee on Foetus and Newborn, who was not involved with the study.
“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 four months, a period that was likely to 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 Organisation’s threshold for preventing neural tube defects – were associated with the greatest risk, at 25.7 defects per 1 000 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 1 000 births. By comparison, the lowest predicted prevalence was observed among those with at least 590 pmol/L (11.8 defects).
Yan’s group also analysed red blood cell turnover and spermatogenesis in a smaller sample of 3 032 couples within four 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 1 000 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 accompanying editorial, Cuilin Zhang, MD, PhD, MPH, and Jing Zhu, MD, PhD, of the National University of 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 optimising 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 to which we should pay more attention.”
Study details
Periconception parental red blood cell folate, vitamin b12, and birth defects in offspring: a prospective cohort study
Hongyan Chen, Xiaotian Chen, Yi Zhang et al.
Published in Annals of Internal Medicine in September 2026
Abstract
Background
Maternal folic acid prevents neural tube defects, but associations of parental folate and vitamin B12 with birth defects remain unclear.
Objective
To quantify associations of parental vitamin B12 and red blood cell (RBC) folate with offspring birth defects.
Design
Prospective cohort study.
Setting
Shanghai Preconception Cohort, China.
Participants
3032 couples (73 birth defect cases) with biomarkers sampled within 4 months before conception, and 17 765 women (327 birth defect cases) sampled at 4 months’ gestation or earlier.
Measurements
Standardised predicted prevalences of birth defects ascertained among live births, stillbirths, and abortions due to foetal abnormalities were estimated using weighted logistic regression.
Results
Higher preconception parental levels of vitamin B12 were associated with lower predicted prevalences of birth defects in dose–response analyses. For preconception maternal vitamin B12 from the lowest (<148 pmol/L) to highest (≥590 pmol/L) categories, predicted prevalence decreased from 49.6 to 16.2 cases per 1000 pregnancies; paternal vitamin B12 showed a similar but attenuated pattern (55.5 to 24.0 cases per 1000 pregnancies). Preconception parental RBC folate showed imprecise patterns of lower predicted prevalence. For postconception maternal RBC folate, predicted prevalence was lower at levels of 906 to 1131 nmol/L than at levels below 453 nmol/L (16.5 vs. 25.7 cases per 1000 pregnancies), with little further reduction at higher levels. For postconception maternal vitamin B12, predicted prevalence changed little across lower categories but was lower at higher levels (11.8 vs. 20.4 cases per 1000 pregnancies at ≥590 vs. 148 to 294 pmol/L, respectively).
Limitation
Residual confounding.
Conclusion
Periconception parental vitamin B12 and postconception maternal RBC folate were associated with lower predicted prevalences of birth defects.
Medscape article – Low B12, Folate in Fathers Linked to Birth Defects (Open access)
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