As with the earlier versions of the review from 2012, 2016 and 2019, the researchers set out to examine whether supplementing with vitamin D might improve maternal and neonatal health outcomes and reduce the risk of adverse pregnancy events. But this time, they employed a new Cochrane Pregnancy and Childbirth Trustworthiness Screening Tool developed to appraise scientific integrity, risk of bias and certainty of evidence.
“This updated review using the trustworthy assessment tool removed 21 studies from the previous update and added one new study for a total of 10 included studies,” they reported. “This removal of the studies resulted in evidence that was downgraded to low-certainty or very low- certainty due to study design limitations, inconsistency between studies and imprecision.”
The review was led by Cristina Palacios, professor in the Department of Dietetics and Nutrition at Florida International University, working with researchers from the Daiichi Sankyo clinical safety program and the Cochrane Pregnancy and Childbirth Group at the University of Liverpool.
Studies considered and removed
For the updated review, the research team searched the Cochrane Pregnancy and Childbirth Trials Register (which includes results of comprehensive searches of CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and relevant conference proceedings) up until December 2022, as well as the reference lists of retrieved studies.
This generated 163 randomized trials on the effects of supplementation with vitamin D alone or in combination with other micronutrients for women during pregnancy compared to placebo or no intervention. Of these, 117 studies were excluded, primarily because the pregnant women in the studies received vitamin D either as part of different regimens or standard care.
“This excluded many trials that were conducted in the U.S., Canada and in certain countries in Europe, as there are published guidelines on the amounts of vitamin D recommended during pregnancy; therefore, trials conducted in those countries could not include a control group without any vitamin D supplementation,” Palacios et al. explained.
Using the trustworthiness tool’s criteria of governance, baseline data, feasibility and results, the reviewers also revisited the 30 studies included in the previous version. Only nine of these passed muster, one was excluded because it had been retracted, and 20 of the studies removed are now 'awaiting classification' following assessments.
“The main issues were over governance (for instance, no prospective clinical trial registration of trials submitted for publication in or after 2010) and feasibility (for instance, the trial dates overlapped with when the paper was sent for publication, or there was less than six months between the end of the trial and its publication, without reasonable explanation from the authors),” the reviewers wrote.
As noted in a 2023 research article published in Cochrane Evidence Synthesis and Methods, inclusion of untrustworthy and potentially fraudulent trials in meta-analyses and clinical guidelines may have serious implications for healthcare decisions that are informed by highly influential systematic reviews.
“Formal assessment of trustworthiness, and inclusion only of studies that satisfy prespecified criteria for trustworthiness, affect conclusions in a relatively large number of Cochrane reviews, with potentially important clinical implications for practice and research,” the paper stated.
Updated conclusions
As public health implication, the authors noted that vitamin D deficiency during pregnancy has been associated with health complications in mothers and their babies, suggesting that vitamin D supplementation might reduce the risk of these complications.
While the 2019 review of 30 trials (7,033 women) concluded that supplementing pregnant women with vitamin D alone likely reduces the risk of pre-eclampsia, gestational diabetes, low birth weight and possibly the risk of severe postpartum hemorrhage, the removal of the 20 studies led to the downgrading of evidence to low-certainty or very low- certainty due to study design limitations, inconsistency between studies and imprecision.
“Overall, we are not sure if supplementation with vitamin D alone compared to no intervention or a placebo (eight studies, 2,313 women) prevents pregnancy-associated hypertension, diabetes during pregnancy, babies born earlier than expected and kidney disease in this setting,” Palacios et al. reported. “It may prevent severe excessive bleeding at birth (although this was based on a single study), and it may reduce the risk of having a baby with a low birth weight, but an increase in this risk cannot be ruled out at this stage.”
Also unclear was whether supplementation with vitamin D and calcium combined prevents preterm birth and low birth weight or whether calcium with other vitamins and minerals (with and without vitamin D) prevents diabetes during pregnancy, maternal adverse events preterm births or low birth weight. Other outcomes were not reported.
Palacios et al. called for further rigorous, high-quality and larger randomized trials to evaluate the effects of vitamin D supplementation alone or in combination with other nutrients during pregnancy, particularly in relation to the risk of maternal adverse events.
“Information on the most effective and safe dosage, the optimal dosing regimen (daily, intermittent or single doses), the timing of initiation of vitamin D supplementation and the effect of vitamin D when combined with other vitamins and minerals is also needed to inform policy making,” they added.
Source: Cochrane Database of Systematic Reviews
doi: https://doi.org/10.1002/14651858.CD008873.pub5
“Vitamin D supplementation for women during pregnancy”
Authors: Cristina Palacios et al.
