Vitamin B12 supplementation during pregnancy for maternal and child health outcomes.

2024-01-08
The Cochrane database of systematic reviews 2024(1)
- Julia L Finkelstein
- Amy Fothergill
- Sudha Venkatramanan
- Alexander J Layden
- Jennifer L Williams
- Krista S Crider
- Yan Ping Qi

PubMed: 38189492
DOI: 10.1002/14651858.cd013823.pub2

Study Design

Type: Systematic Review
Sample size: n = 412
Population: five trials with 984 pregnant women
Methods: Cochrane systematic review of RCTs, quasi-RCTs, or cluster-RCTs; four review authors independently assessed trial eligibility; two review authors independently extracted data; three review authors independently assessed risk of bias using RoB 1; GRADE used for certainty of evidence

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.

Research Insights

Vitamin B12→Improved Child Neurodevelopment
maternal vitamin B12 supplementation did not improve... neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Child Neurodevelopment (Adaptive Domain)
maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. ... 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)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Child Neurodevelopment (Motor Domain)
maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. ... motor (fine and gross)... domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Child Neurophysiological Outcome
or neurophysiological outcomes (72 months, event-related potential measures; 1 trial; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Delayed Memory
maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. cognitive... domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Expressive Language
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).
Effect
Beneficial
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Improved Language Development
maternal vitamin B12 supplementation did not improve neurodevelopment status (e.g. ... language (receptive and expressive)... domains) in children compared to placebo (9 months, Bayley Scales of Infant and Toddler Development Third Edition (BSID-III); 1 trial; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Increased Maternal Vitamin B12 Concentration
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)
Effect
Beneficial
Effect size
Moderate
Dose
5 μg/day to 250 μg/day
Vitamin B12→Increased Vitamin B12 Concentration
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)
Effect
Beneficial
Effect size
Moderate
Dose
5 μg/day to 250 μg/day
Vitamin B12→Reduced Low Birthweight
and low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Reduced Maternal Anemia
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% CI 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day
Vitamin B12→Reduced Maternal Vitamin B12 Deficiency
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)
Effect
Beneficial
Effect size
Large
Dose
5 μg/day to 250 μg/day
Vitamin B12→Reduced Preterm Births
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)
Effect
Neutral
Effect size
Small
Dose
5 μg/day to 250 μg/day

Adverse Events Reported

Vitamin B12→low birthweight
low birthweight (RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women; low-certainty evidence)
Finding
No significant difference
Magnitude
RR 1.50, 95% CI 0.93 to 2.43; 2 trials, 344 women
Significant
No
Vitamin B12→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% CI 0.93 to 1.26; 2 trials, 284 women; very low-certainty evidence).
Finding
No significant difference
Magnitude
RR 1.08, 95% CI 0.93 to 1.26
Significant
No
Vitamin B12→preterm birth
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)
Finding
No significant difference
Magnitude
RR 0.97, 95% CI 0.55 to 1.74; 2 trials, 340 women
Significant
No
Vitamin B12→spontaneous abortion
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.
Finding
Reported