Pregnancies helped by Vitamin D – recommendations and trials underway – review Dec 2017

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

the bmj | BM/2017;359:j5237 | doi: 10.1136/bmj.j5237
Daniel E Roth,1,2,3 Michael Leung,2 Elnathan Mesfin,2 Huma Qamar,2,3 Jessica Watterworth,2,3 Eszter Papp2
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 Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Correspondence to: D E Roth daniel.roth at sickkids.ca

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Numerous randomised trials and systematic reviews of vitamin D supplementation during pregnancy have been published, with conflicting results and conclusions
• Recommendations regarding vitamin D supplementation vary widely among medical and professional organisations, and WHO currently recommends against routine prenatal vitamin D supplementation

WHAT THIS STUDY ADDS

• Systematic review and meta-analyses of 43 trials including 8406 participants showed that prenatal vitamin D supplementation was associated with increased maternal and cord serum 25-hydroxyvitamin D concentrations, increased mean birth weight, reduced the risk of small for gestational age, reduced the risk of wheeze in offspring, and increased infant length at one year of age There was a lack of evidence of benefits of prenatal vitamin D supplementation for maternal health conditions related to pregnancy, no effect on other birth outcomes of public health importance such as preterm birth, and scant evidence on safety outcomes
• Few of the trials were designed to test the effect of vitamin D on clinical or functional outcomes, and most trials were small and at overall high or uncertain risk of bias
• Thirty five planned or ongoing prenatal vitamin D trials could contribute an additional 12 530 participants to future systematic reviews

Increasing number of studies and participating mothers

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

 Download the main PDF from VitaminDWiki

Vitamin D recommendations for pregnancies

Canadian Paediatric Society	2000 IU
Indian – govt	400 IU – if have little access to sunlight
Canada – Health	Drink milk, and 600 IU (IoM)
US Institute of Medicine	600 IU
US American College of Obstetricians and Gynecologists	1,000-2,000 IU
US Endocrine Society	1500 IU only if at risk for Vitamin D deficiency
Australia	200 IU if have minimal access to sunlight
European Food Safety Authority	600 IU
UK Scientific Advisory Committee on Nutrition (SCAN)	400 IU
World Health Organization	0 – is not recommended

Condensed from Data Supplement     Recommendations

Data supplements

1: Selected recent recommendations for vitamin D intake or supplementation in pregnancy
    Download the PDF from VitaminDWiki
2: Search strategies for electronic databases
3: Outcome variable case definitions and methods of ascertainment criteria
4: Search strategy for clinical trial registries
5: Studies included in systematic review and eligible for inclusion in meta-analyses
6: Contributions of prenatal vitamin D trials to meta-analyses
    Download the PDF from VitaminDWiki
7: Unpublished outcome data and clarifications of published findings
8: Prenatal prospective controlled vitamin D supplementation trials ineligible for inclusion in meta-analyses
    Download the PDF from VitaminDWiki
9: Risk of bias for trials eligible for inclusion

Birth weight increased in RCT using any amount of vitamin D

Suspect that only 2 trials which found a weight loss were those (1986) which used vitamin D2

4,000 IU placebo?