Vitamin B12 Deficiency Raises South Asian Pregnancy Concerns

A narrative review of 59 studies finds that vitamin B12 deficiency is common among pregnant women in South Asia and is associated with an array of maternal, fetal and offspring outcomes, although most of the evidence is observational. The synthesis, published in Frontiers in Nutrition, reports pooled global prevalence estimates of approximately 17% to 25%, while estimates for pregnant women in India and neighboring countries commonly reach 40% to 70%. The reviewers say the figures are difficult to compare directly because studies use different assays and thresholds, including vitamin B12 concentrations ranging from about 148 to 350 picograms per milliliter, and pregnancy-specific diagnostic cutoffs remain unsettled.

The regional burden appears closely tied to diet and socioeconomic conditions. Vitamin B12 is found almost exclusively in animal-source foods and is largely absent from unfortified plant foods, placing women who follow vegetarian or vegan diets at increased risk when animal-source foods are unaffordable. Limited dietary diversity, recurrent gastrointestinal infections that may impair absorption, and low awareness among patients and health workers may compound the problem. Population surveys reinforce the possibility that deficiency begins before pregnancy: among non-pregnant women of reproductive age, 57.7% in rural Haryana and 48.3% in southern India were deficient, while further substantial proportions had marginal concentrations.

Pregnancy itself raises the challenge. Maternal blood concentrations can fall by approximately 10% to 30% as plasma volume expands, while fetal growth, placental transfer and increased maternal red-cell production increase requirements. Reference intervals derived from non-pregnant adults may therefore underestimate depletion. Diagnosis also depends on the marker used. Total serum vitamin B12 is widely available but measures circulating rather than tissue vitamin B12 and can miss functional deficiency. Holotranscobalamin, the fraction bound to transport proteins, can decline earlier, while methylmalonic acid can indicate impaired intracellular function; however, none has a universally validated pregnancy-specific threshold, and methylmalonic acid may also rise with renal impairment.

The clinical associations are broad. Low maternal vitamin B12 and elevated homocysteine have been linked to anemia, pregnancy loss, preeclampsia, gestational diabetes, fetal growth restriction, low birth weight and preterm birth. In a meta-analysis of 10 observational studies involving 10,595 pregnant women, vitamin B12 deficiency was associated with gestational diabetes with an odds ratio of 1.46 and a 95% confidence interval of 1.21 to 1.79. A separate synthesis found that deficiency in the second or third trimester was associated with a higher risk, with an odds ratio of 1.59, and that the association was stronger in Asian populations, with an odds ratio of 2.08. The same analysis linked a high folate-to-vitamin B12 ratio to gestational diabetes, with an odds ratio of 1.87.

Not every outcome or population shows the same relationship, however. Individual-participant data from 18 longitudinal studies found a modest association between maternal deficiency and low birth weight, with an adjusted risk ratio of 1.15 and a 95% confidence interval of 1.01 to 1.31, as well as a consistent association between higher vitamin B12 concentrations and lower preterm-birth risk. Yet the urban MAASTHI cohort in Bengaluru associated low birth weight with vitamin B6 deficiency and impaired folate status rather than vitamin B12 deficiency, and an Irish cohort found no relationship between dietary vitamin B12 and fetal growth, placental weight or birth weight. These discordant results show that circulating vitamin B12 may sometimes mark broader dietary, socioeconomic or metabolic conditions rather than act as an independent cause.

The review also links low maternal status to congenital anomalies and later development. A meta-analysis of 38 case-control studies found lower maternal vitamin B12 in pregnancies affected by neural tube defects, with a standardized mean difference of -0.23 and a 95% confidence interval of -0.32 to -0.14; the association persisted in analyses where folate levels did not differ. Small studies have also associated low maternal vitamin B12 with orofacial clefts and, in Bangladeshi pregnant women, with oligohydramnios, fetal hydrocephalus and neural tube defects. Offspring neurodevelopment is more difficult to assess. Observational cohorts and small interventions suggest possible differences in language, cognition and motor development, but a scoping review of 19 studies involving 23,825 mothers and children judged the overall evidence inconclusive.

Randomized trials provide the clearest answer about treatment, and their main consistent effect is biochemical rather than clinical. A Cochrane review of five trials involving 984 pregnant women found that supplementation increased maternal vitamin B12 concentrations by 60.89 picomoles per liter on average, with a 95% confidence interval of 40.86 to 80.92, and reduced the risk of maternal deficiency, with a risk ratio of 0.38. The certainty of this evidence was rated very low, and clinical benefits for mothers and children remained uncertain. Trials in Bangladesh also reported improvements in breast-milk and infant vitamin B12 status, lower methylmalonic acid and changes in immune or oxidative-stress markers, but these findings do not establish prevention of pregnancy complications.

The multicentre MATCOBIND trial illustrates both the promise and the limits of intervention research. It randomized 708 predominantly vegetarian women in India and Nepal, of whom 531 completed follow-up. Participants received either 250 micrograms of methylcobalamin daily or 50 micrograms as an active comparator from the first trimester until six months after delivery. The higher dose produced larger improvements in maternal and infant vitamin B12 status and was associated with a roughly two-point improvement in infant mental developmental quotient at nine to 12 months, but not in motor development. A large Nepalese trial likewise improved maternal status without detecting differences in infant length or cognitive development at 12 months. These results are preliminary because MATCOBIND was a single trial with short follow-up and an active comparator rather than a placebo, and its neurodevelopmental findings have not yet been independently replicated.

Mechanistic evidence offers a possible explanation for the associations while reinforcing the need for caution. Vitamin B12 is required for remethylation of homocysteine to methionine, linking it to folate-dependent one-carbon metabolism and the production of methyl donors. Deficiency can create a functional folate trap, potentially limiting nucleotide synthesis in rapidly dividing blood, placental and embryonic tissues. Accumulated homocysteine may also contribute to oxidative stress, reduced nitric oxide availability and endothelial dysfunction, while changes in DNA and histone methylation could affect fetal development. These pathways are biologically plausible, but the direction, persistence and clinical importance of epigenetic changes remain uncertain, and homocysteine may be a marker of disrupted metabolism rather than its sole mediator.

The low-vitamin B12, high-folate imbalance is especially relevant because India’s national antenatal programme supplies iron and folic acid but not vitamin B12. Observational studies associate this pattern with gestational diabetes, small-for-gestational-age infants and childhood insulin resistance, including in the Pune Maternal Nutrition Study, but the evidence does not justify withdrawing folic acid. Indeed, some analyses attribute elevated gestational-diabetes risk to high red-blood-cell folate independently of vitamin B12, and lower folate concentrations have predicted progression from pregnancy-induced hypertension to preeclampsia in one large cohort. The review therefore concludes that current evidence supports identifying and treating confirmed deficiency, particularly among women with vegetarian or vegan diets, low dietary diversity, socioeconomic disadvantage, suggestive clinical features or relevant pregnancy histories, while maintaining folic acid provision. It finds that the evidence remains insufficient for universal vitamin B12 supplementation across all pregnancies. Priorities are pregnancy-specific diagnostic thresholds, independently replicated trials beginning around conception and continuing into childhood, and cost-effectiveness studies of risk-based screening in South Asian antenatal care.

Subject of Research: Maternal vitamin B12 deficiency, pregnancy outcomes and antenatal care in South Asia

Article Title: Maternal vitamin B12 deficiency in pregnancy: burden, associated outcomes, and implications for antenatal care in South Asia—a narrative review

Article References: Yadav, A., Gandhi, K. Y., & Puri, M. (2026). Maternal vitamin B12 deficiency in pregnancy: burden, associated outcomes, and implications for antenatal care in South Asia—a narrative review. Frontiers in Nutrition, 13, 1896162. https://doi.org/10.3389/fnut.2026.1896162

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1896162

Keywords: vitamin B12 deficiency, pregnancy, South Asia, antenatal care, folic acid, one-carbon metabolism, gestational diabetes, neural tube defects, offspring neurodevelopment, supplementation, Maternal, vitamin