Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials

Abstract

Objectives To estimate the effects of vitamin D supplementation during pregnancy on 11 maternal and 27 neonatal/infant outcomes; to determine frequencies at which trial outcome data were missing, unreported, or inconsistently reported; and to project the potential contributions of registered ongoing or planned trials.Design Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials.Data sources Medline, Embase, PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to September 2017; manual searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials.Eligibility criteria for study selection Trials of prenatal vitamin D supplementation with randomised allocation and control groups administered placebo, no vitamin D, or vitamin D ≤600 IU/day (or its equivalent), and published in a peer reviewed journal.Results 43 trials (8406 participants) were eligible for meta-analyses. Median sample size was 133 participants. Vitamin D increased maternal/cord serum concentration of 25-hydroxyvitamin D, but the dose-response effect was weak. Maternal clinical outcomes were rarely ascertained or reported, but available data did not provide evidence of benefits. Overall, vitamin D increased mean birth weight of 58.33 g (95% confidence interval 18.88 g to 97.78 g; 37 comparisons) and reduced the risk of small for gestational age births (risk ratio 0.60, 95% confidence interval 0.40 to 0.90; seven comparisons), but findings were not robust in sensitivity and subgroup analyses. There was no effect on preterm birth (1.0, 0.77 to 1.30; 15 comparisons). There was strong evidence that prenatal vitamin D reduced the risk of offspring wheeze by age 3 years (0.81, 0.67 to 0.98; two comparisons). For most outcomes, meta-analyses included data from a minority of trials. Only eight of 43 trials (19%) had an overall low risk of bias. Thirty five planned/ongoing randomised controlled trials could contribute 12 530 additional participants to future reviews.Conclusions Most trials on prenatal vitamin D published by September 2017 were small and of low quality. The evidence to date seems insufficient to guide clinical or policy recommendations. Future trials should be designed and powered to examine clinical endpoints, including maternal conditions related to pregnancy (such as pre-eclampsia), infant growth, and respiratory outcomes.Systematic review registration PROSPERO CRD42016051292.

Fig 1 Screening and selection of studies for systematic review and meta-analysis of vitamin D supplementation during pregnancy

Fig 2 Accumulation of prenatal vitamin D supplementation trials 1980-2024. Bands represent number of trials in each geographical region. Hatched areas and solid line are based on completed and published trials up until September 2017. Non-hatched areas and broken line represent projections from September 2017 to 2024 for future/ongoing trials identified in clinical trial registries. No published trials were conducted in Africa, though one large trial in Tanzania (n=2300) is ongoing and projected to be completed and published before 2024

Fig 3 Effective equivalent daily vitamin D dose (IU/day) versus maternal baseline mean 25-hydroxyvitamin D (25(OH)D) concentration (nmol/L) in published prenatal vitamin D supplementation trials with regular dosing regimens (29 trials; 36 comparisons). “Effective” dose is dose administered in intervention group minus dose in control group (200-600 IU/day in active-control trials; 0 IU/day in placebo control trials). Each point represents intervention-control comparison from single trial. Linear trend line fitted with generalised estimating equations to account for correlations within trials for trials with more than one intervention arm. Estimated mean change in effective vitamin D dose for every 20 nmol/L increase in baseline mean 25(OH)D concentration was increase of 208 IU/day (P=0.54)

Fig 4 A: Weighted mean differences (WMDs) and B: cumulative WMDs for effect of prenatal vitamin D supplementation on mean birth weight (g), estimated with random effects meta-analysis, based on 37 intervention-control comparisons in 30 randomised controlled trials of regular or bolus regimen vitamin D at any dose in studies published by September 2017

Fig 5 Proportion of all participants (n=8406) enrolled in eligible trials for which maternal and neonatal/infant outcomes were reported and met criteria for case definition and method of ascertainment; reported but did not meet minimum criteria; reported, but in manner that prevented inclusion of data in meta-analysis; missing because of loss of follow-up in trials for which outcome was reported for some participants or because of apparent incomplete reporting of planned outcomes; or missing because outcome was not assessed or not mentioned in published reports