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. 2024 Jan 8;1(1):CD013823.
doi: 10.1002/14651858.CD013823.pub2.

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes

Julia L Finkelstein  1 , Amy Fothergill  1   2 , Sudha Venkatramanan  1 , Alexander J Layden  3 , Jennifer L Williams  2 , Krista S Crider  2 , Yan Ping Qi  2
Affiliations

Vitamin B12 supplementation during pregnancy for maternal and child health outcomes

Julia L Finkelstein et al. Cochrane Database Syst Rev. .

Abstract

Background: Vitamin B12 deficiency is a major public health problem worldwide, with the highest burden in elderly people, pregnant women, and young children. Due to its role in DNA synthesis and methylation, folate metabolism, and erythropoiesis, vitamin B12 supplementation during pregnancy may confer longer-term benefits to maternal and child health outcomes.

Objectives: To evaluate the benefits and harms of oral vitamin B12 supplementation during pregnancy on maternal and child health outcomes.

Search methods: We searched the Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) on 2 June 2023, and reference lists of retrieved studies.

Selection criteria: Randomised controlled trials (RCTs), quasi-RCTs, or cluster-RCTs evaluating the effects of oral vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation during pregnancy.

Data collection and analysis: We used standard Cochrane methods. Four review authors independently assessed trial eligibility. Two review authors independently extracted data from included studies and conducted checks for accuracy. Three review authors independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool. We used GRADE to evaluate the certainty of evidence for primary outcomes.

Main results: The review included five trials with 984 pregnant women. All trials were conducted in low- and middle-income countries, including India, Bangladesh, South Africa, and Croatia. At enrolment, 26% to 51% of pregnant women had vitamin B12 deficiency (less than 150 pmol/L), and the prevalence of anaemia (haemoglobin less than 11.0 g/dL) ranged from 30% to 46%. The dosage of vitamin B12 supplementation varied from 5 μg/day to 250 μg/day, with administration beginning at 8 to 28 weeks' gestation through to delivery or three months' postpartum, and the duration of supplementation ranged from 8 to 16 weeks to 32 to 38 weeks. Three trials, involving 609 pregnant women, contributed data for meta-analyses of the effects of vitamin B12 supplementation compared to placebo or no vitamin B12 supplementation. Maternal anaemia: there may be little to no difference for maternal anaemia by intervention group, but the evidence is very uncertain (70.9% versus 65.0%; risk ratio (RR) 1.08, 95% confidence interval (CI) 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence). Maternal vitamin B12 status: vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain (25.9% versus 67.9%; RR 0.38, 95% CI 0.28 to 0.51; 2 trials, 272 women; very low-certainty evidence). Women who received vitamin B12 supplements during pregnancy may have higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (mean difference (MD) 60.89 pmol/L, 95% CI 40.86 to 80.92; 3 trials, 412 women). However, there was substantial heterogeneity (I2 = 85%). Adverse pregnancy outcomes: the evidence is uncertain about the effect on adverse pregnancy outcomes, including preterm birth (RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women; low-certainty evidence), and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence). Two trials reported data on spontaneous abortion (or miscarriage); however, the trials did not report quantitative data for meta-analysis and there was no clear definition of spontaneous abortion in the study reports. No trials evaluated the effects of vitamin B12 supplementation during pregnancy on neural tube defects. Infant vitamin B12 status: children born to women who received vitamin B12 supplementation had higher total vitamin B12 concentrations compared to placebo or no vitamin B12 supplementation (MD 71.89 pmol/L, 95% CI 20.23 to 123.54; 2 trials, 144 children). Child cognitive outcomes: three ancillary analyses of one trial reported child cognitive outcomes; however, data were not reported in a format that could be included in quantitative meta-analyses. In one study, maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive, language (receptive and expressive), motor (fine and gross), social-emotional, or adaptive (conceptual, social, practical) domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence) or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence), though children born to women who received vitamin B12 supplementation had improved expressive language domain compared to placebo (30 months, BSID-III; 1 trial; low-certainty evidence).

Authors' conclusions: Oral vitamin B12 supplementation during pregnancy may reduce the risk of maternal vitamin B12 deficiency and may improve maternal vitamin B12 concentrations during pregnancy or postpartum compared to placebo or no vitamin B12 supplementation, but the evidence is very uncertain. The effects of vitamin B12 supplementation on other primary outcomes assessed in this review were not reported, or were not reported in a format for inclusion in quantitative analyses. Vitamin B12 supplementation during pregnancy may improve maternal and infant vitamin B12 status, but the potential impact on longer-term clinical and functional maternal and child health outcomes has not yet been established.

Trial registration: ClinicalTrials.gov NCT00641862 NCT03258385.

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Conflict of interest statement

The protocol for this review was initially developed during the World Health Organization (WHO)/Cochrane/Cornell University Summer Institute for Systematic Reviews in Nutrition for Global Policy Making, held annually at the Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA (Finkelstein 2020). The WHO has partially supported this programme beginning in 2014. The protocol was not directly supported by the WHO.

JLF is a principal investigator on research grants to examine the burden and aetiology of anaemia in women of reproductive age (US Centers for Disease Control and Prevention), biomarkers of anaemia and nutritional status in women of reproductive age (National Institutes of Health), and to conduct randomised trials with micronutrient interventions to improve the health of women of reproductive age (US Centers for Disease Control and Prevention). JLF has no known conflicts of interest to declare.

AF is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

SV has no known conflicts of interest to declare.

YPQ is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

AJL has no known conflicts of interest to declare.

JLW is an employee of the US Government at the Centers for Disease Control and Prevention working as a PhD nurse epidemiologist and family nurse practitioner for the US Public Health Service and has no known conflicts of interest to declare.

KSC is an employee of the US Government at the Centers for Disease Control and Prevention and has no known conflicts of interest to declare.

None of the authors are investigators on any trials included in this review.

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  • doi: 10.1002/14651858.CD013823

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