Prevention and Management of Gestational Diabetes Using Vitamin D Supplementation: An Overview and Appraisal of Clinical Trials

Round 1

Reviewer 1 Report

The author has prepared an important and well thought-out summary of the issues that arise when interpreting the current literature as it pertains to the potential for adequate vitamin D to help prevent gestational diabetes.

I feel there is one large area that is missing from the discussion - serum 25(OH)D concentrations. One of the major contentions is that dose is not adequate to raise 25(OH)D concentrations into a target range, but while there are a couple of brief comments eluding to this, it is not adequately addressed.

The second topic that was not explored is the implications of improving glycemic control in the trials whether there is also an effect on GD incidence or not. Could better control have longer term implications, perhaps T2DM or future pregnancies?

Comments by line:

80-81: "Vitamin D is a secosteroid hormone with pleiotropic functions including anti-proliferative, pro-differentiative and potent immunomodulatory actions" - this is not entirely correct. Vitamin D, specifically 1,25(OH)2D, is a hormone when it is in the blood stream and thus mediating calcium levels. It is not a hormone when used locally as is the case for its anti-proliferative, pro-differentiative and immunomodulatory actions.

135 - Is there an estimate for deficiency rates in Australia?

162-7 - A comment on the recommendations for vitamin D during pregnancy in Australia?

195 - GDM and T2DM are related - a comment that vitamin D has similarly been implicated in the prevention of T2DM is warranted.

210 - "Participants were vitamin D-deficient at baseline (25(OH)D < 50 nmol/L; Table 1) in 13 of the 18 trials" - Are you referring to mean 25(OH)D concentrations? I.e. not all participants were deficient.

212 - "Twelve trials" - references required.

224 - "Three studies" in the statement but 4 references provided.

218-222 - It would be beneficial to supply an overall average daily dose range (e.g. for the biweekly and monthly doses convert to ave. daily dose).

252 - Other limitations that are particularly important include timing of supplementation and duration of supplementation.

351 - The discussion of inflection point - where is this? Is it the same as for bone health (i.e. IOM recommendation target?) Is there a range that is suggested based on the evidence to date? This should be part of the 25(OH)D levels discussion.

362 - Heaney's paper is very on point here, however, you could elaborate further, particularly with respect to "a sufficiently large dose of vitamin D to shift their status into the range where disease risk 362 decreases (or benefit increases)" - again this is part of the 25(OH)D levels discussion.

382 - contamination of control groups - again this is part of the 25(OH)D levels discussion.

419 - "Co-supplementation was often used, making it impossible to isolate the effects of vitamin D alone." This is an important point, especially if considering co-supplementation with magnesium that is integral to the enzymatic conversion of vitamin D3 to 25(OH)D and to 1,25(OH)2D.

424 - What is meant by "pre-supplementation"??? Is this similar to large bolus doses that significantly increase 24-OHase activity?

 

 

 

 

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

The presented article entitled "Prevention and management of gestational diabetes using vitamin D supplementation: an overview and appraisal of clinical trials" by Aya Mousa deal with the still unquenchable topic of vitamin D and the effect of its deficiency on various diseases.

Vitamin D is a promising molecule for intervention studies, based on in vitro studies. Unfortunately, the use of this molecule in practice is contradictory in almost all diseases with which vitamin D deficiency is associated. As the author correctly describes, there are many factors (external and internal) that can affect vitamin D levels in specific individuals. There is also a disagreement on vitamin D deficiency/deficiency levels. And, of course, there is the problem of vitamin D determination itself, as many of the methods available for determining this parameter can vary widely in their results, complicating comparative studies.

The author of the article is aware of the limits of his work. However, the work is clearly processed and provides insight into the issue of gestational diabetes in connection with vitamin D, or with the possibilities of its use in supplementation. The methodology of these studies is very well documented and the scope of the cited literature is quite sufficient, based on recent work (but with a predominant ethnic origin). The conclusions do not exceed the fields defined by the mentioned results.

Author Response

We thank the reviewer for their time and detailed review and for their positive and insightful feedback on the manuscript. Indeed, we intended to offer a useful overview of the topic and the current challenges faced in this field and we hope that the manuscript will be received positively by the general readership of the journal.