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

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          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        Design Systematic review and meta-analysis of randomised controlled trials; systematic review of registered but unpublished trials.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searches of reference lists of systematic reviews identified in the electronic search; and online trial registries for unpublished, ongoing, or planned trials.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

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          Most cited references24

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          Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial.

          Asthma and wheezing begin early in life, and prenatal vitamin D deficiency has been variably associated with these disorders in offspring.
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            Inclusion of zero total event trials in meta-analyses maintains analytic consistency and incorporates all available data

            Background Meta-analysis handles randomized trials with no outcome events in both treatment and control arms inconsistently, including them when risk difference (RD) is the effect measure but excluding them when relative risk (RR) or odds ratio (OR) are used. This study examined the influence of such trials on pooled treatment effects. Methods Analysis with and without zero total event trials of three illustrative published meta-analyses with a range of proportions of zero total event trials, treatment effects, and heterogeneity using inverse variance weighting and random effects that incorporates between-study heterogeneity. Results Including zero total event trials in meta-analyses moves the pooled estimate of treatment effect closer to nil, decreases its confidence interval and decreases between-study heterogeneity. For RR and OR, inclusion of such trials causes small changes, even when they comprise the large majority of included trials. For RD, the changes are more substantial, and in extreme cases can eliminate a statistically significant effect estimate. Conclusion To include all relevant data regardless of effect measure chosen, reviewers should also include zero total event trials when calculating pooled estimates using OR and RR.
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              Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis.

              Vitamin D has well-defined classical functions related to calcium metabolism and bone health but also has non-classical effects that may influence other aspects of health. There has been considerable recent interest in the role of vitamin D on outcomes related to pregnancy and young child health but few efforts have been made to systematically consolidate this evidence to inform the research and policy agenda for low-income countries. A systematic review was undertaken to identify intervention and observational studies of vitamin D supplementation, intake or status (25-hydroxy-vitamin D) during pregnancy on perinatal and infant health outcomes. Data from trials and observational studies isolating the effect of vitamin D supplementation and intake were extracted and study quality was evaluated. Meta-analysis was used to pool effect estimates. We identified five randomised trials with outcomes of relevance to our review. All had small sample size and dosage amount, duration and frequency varied as did the ability to correct deficiency. Pooled analysis of trials using fixed-effects models suggested protective effects of supplementation on low birthweight (three trials, risk ratio (RR) = 0.40 [95% confidence interval (CI) 0.23, 0.71]) and non-significant but suggestive effects of daily supplementation on small-for-gestational age (two trials, RR = 0.67 [0.40, 1.11]). No effect on preterm delivery (<37 weeks) was evident (two trials, RR = 0.77 [0.35, 1.66]). Little evidence from trials exists to evaluate the effect of vitamin D supplementation during pregnancy on maternal, perinatal or infant health outcomes. Based on both trials and observational studies, we recommend that future research explore small-for-gestational age, preterm delivery, pre-eclampsia, and maternal and childhood infections, as outcomes of interest. Trials should focus on populations with a high prevalence of vitamin D deficiency, explore the relevance of timing of supplementation, and the dosage used in such trials should be sufficient to correct deficiency. © 2012 Blackwell Publishing Ltd.
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                Author and article information

                Contributors
                Role: assistant professor of paediatrics and nutritional sciences
                Role: data analyst
                Role: research assistant
                Role: graduate student in nutritional sciences
                Role: graduate student in nutritional sciences
                Role: research project manager
                Journal
                BMJ
                BMJ
                bmj
                The BMJ
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2017
                30 November 2017
                : 359
                : j5237
                Affiliations
                [1 ]Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada
                [2 ]Centre for Global Child Health and SickKids Research Institute, Hospital for Sick Children, Toronto, ON, Canada
                [3 ]Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
                Author notes
                Correspondence to: D E Roth daniel.roth@ 123456sickkids.ca
                Article
                rotd039862
                10.1136/bmj.j5237
                5706533
                29187358
                ade83367-b706-4b29-adec-6dd059c4334a
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 22 October 2017
                Categories
                Research

                Medicine
                Medicine

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