Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trialsBMJ 2017; 359 doi: https://doi.org/10.1136/bmj.j5237 (Published 29 November 2017) Cite this as: BMJ 2017;359:j5237
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I agree with Roth and colleagues (1) that there is insufficient evidence to assess the benefit-harm balance of vitamin D supplementation during pregnancy on the basis of their systematic review of randomised trials. Here it is important to note that the effects on maternal and offspring bone health have not yet been established. As described by the authors, for example, one trial (2) found that high-dose vitamin D supplementation during pregnancy was associated with lower whole-body bone mineral content (BMC) and areal bone mineral density (BMD) in offspring at 12-16 months of age. This seems to be an important finding that should be discussed.
Bone responds to physical activity through the resultant elastic deformation (strain) and its structure is under control of the mechanical strain-related stimuli; thus, the lower degree of mineralisation during growth is likely to support higher bone gain by increasing mechanical strain (3-5). This functional adaptation of bone to mechanical strain can reasonably explain the inverse association (2) because the vitamin D-related higher degree of mineralisation would cause lower bone gain by decreasing mechanical strain. Consequently, high-dose vitamin D supplementation during pregnancy might not be recommended for offspring bone health.
On the other hand, another trial published after the authors’ review (6) did not find a dose effect of vitamin D supplementation during pregnancy on maternal BMC or areal BMD in the lumbar spine and hip. Furthermore, a recent population-based cohort study showed no association between neonatal vitamin D status and fracture risk during childhood (7). Although it is clear that severe vitamin D deficiency causes rickets or osteomalacia, further randomised trials are expected to clarify this topic.
(1) Roth DE, Leung M, Mesfin E, Qamar H, Watterworth J, Papp E. Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials. BMJ 2017;359:j5237.
(2) Sahoo SK, Katam KK, Das V, Agarwal A, Bhatia V. Maternal vitamin D supplementation in pregnancy and offspring outcomes: a double-blind randomized placebo-controlled trial. J Bone Miner Metab 2017;35:464-71.
(3) Sugiyama T, Oda H. Vitamin D deficiency and fractures in children: a mechanistic point of view. J Clin Endocrinol Metab 2016;101:L95-6.
(4) Sugiyama T. Gestational vitamin D and childhood bone health. Lancet Diabetes Endocrinol 2017;5:417-8.
(5) Sugiyama T. Adaptation of bone to mechanical strain. JAMA Pediatr 2017; doi:10.1001/jamapediatrics.2017.4657
(6) Wei W, Shary JR, Garrett-Mayer E, Anderson B, Forestieri NE, Hollis BW, Wagner CL. Bone mineral density during pregnancy in women participating in a randomized controlled trial of vitamin D supplementation. Am J Clin Nutr 2017;106:1422-30.
(7) Händel MN, Frederiksen P, Cohen A, Cooper C, Heitmann BL, Abrahamsen B. Neonatal vitamin D status from archived dried blood spots and future risk of fractures in childhood: results from the D-tect study, a population-based case-cohort study. Am J Clin Nutr 2017;106:155-61.
Competing interests: No competing interests
Re: Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials
I am not surprised that only weak evidence was found by Roth (1) for benefits of a small dose of vitamin D in pregnancy. The studies in his systematic review, similarly to others, treat vitamin D like a drug. However, vitamin D is a nutrient and it is rather difficult to design a perfect randomized controlled trial with a nutrient. Especially when a very small dose is used. A person spending a day in summer sunshine easily gets 250 mcg (10,000 IU), whereas most trials only used 10 mcg (400 IU) daily. Being a nutrient, people of either group, treatment arm or placebo arm, could be just eating it in their diet. One portion of salmon contains 10 mcg, the same amount as the ‘active treatment’. Different genetic make-up as well as people’s various habits of time spent outdoors, contribute to an noisy overall picture. Not surprisingly the results are meager.
More interestingly two studies were publicized recently looking at pre-pregnancy vitamin D levels and higher doses throughout pregnancy. The outcomes were significant and encourage high vitamin D intake before and during pregnancy. They also demonstrate the need to redesign studies. (2,3) Roth’s systematic review, in the meantime, should not put off pregnant women from taking vitamin D.
1. Roth et al. Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials
2. Wolsk et al. Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial. J ALLERGY CLIN IMMUNOL NOVEMBER 2017
3. Wolsk et al. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials PLOS ONE | https://doi.org/10.1371/journal.pone.0186657 October 27, 2017
Competing interests: No competing interests
Re: Roth: Vitamin D supplementation during pregnancy: state of the evidence from a systematic review of randomised trials. BMJ November 29 2017
Dr. Roth accurately writes that randomized controlled trials (RCTs) of vitamin D in pregnancy have shown conflicting results. He also gives a number of reasons that may explain those negative trials. And, like a competent scientist, he opines that until RCTs show efficacy without toxicity, physiological doses of vitamin D should not be prescribed in pregnancy. Instead we should continue with the near homeopathic doses (10 – 15 mcg/day) that are now used in pregnancy. ( I can't think of any other nutrient used in such meaningless doses but I'm sure they exist.)
However, if his standard were followed, we would not treat scurvy with vitamin C, prevent beriberi with thiamine, pellagra with niacin, or help prevent neural tube defects with folic acid, none of which have RCTs supporting such use. Physicians of the past addressed the pathological consequences of the inadequate intake of nutrients, not with more RCTs, but by applying common sense.
Yesterday (11/29/17), yet another study (four to date) confirmed low levels of vitamin D during pregnancy are associated with a substantially increased risk of developing autism. (1) Almost ten years ago the vitamin D/autism link exposed in detail (2), ten years during which time 134 additional such papers appeared and during which time hundreds of thousands children were condemned to autism. Similar, but fewer, studies exist for the substantial risk of developing multiple sclerosis in later life as well as most of the diseases of pregnancy. As Dr. Roth points out, the results of most of those studies were mixed. What he did not dwell on is the fact that "the dose makes the medicine." and the doses in almost all the studies he reviewed used 10 or 15 mcg/day, a dose that often does not result in meaningful changes in vitamin D status levels nor in preventing disease, (It is instructional to stop using IUs to measure the mass of vitamin D and move to the metric system. For example, 250 mcg is considered a small dose by many, while 10,000 IU is a large one without knowing they are the same dose.)
Two crucial points are missed with Roth's opinion. The first is that vitamin D is safe. If you think it dangerous at physiological adult doses (125-250 mcg/day), you are ignorant about its toxicology. ( “Everything is toxic, nothing is without toxicity, the dose alone determines if something is toxic.) Since it is safe at these doses, one has to weigh the consequences of action vs. the inaction Dr. Roth advises. It seems to me, common sense dictates pregnant women should be supplemented now, not made the Guinea pigs of further RCTs.
Finally, there are stark differences between scientists and physicians. Scientists require definitive proof before a theorem is considered fact. In other words, beyond a reasonable doubt. But scientists do not treat patients, with few notable exceptions. Scientists do not take the Hippocratic Oath. The standard physicians used over history was to balance the known toxicity with the potential benefits and act accordingly. Physicians should ask their attorney if such a standard of treatment still exists and if they may the be held to it in a courtroom.
Physicians have never required endless RCT for proof until very recently with the onset and misunderstanding of Evidence Based Medicine. Instead physicians have always, until recently, weighed the potential consequences of treatment vs. inaction, that is potential harm vs. potential benefit. If you weigh on the potential harm call for inaction side, you are reading a different vitamin D literature (now at 61,323 publications) than I am reading.
Physicians are required by law and ethics to act on the evidence known today, not what may be discovered in the future. If inaction persists, what are we going to say to parents of the children with autism or the women who develop MS in the future? “Oh, I’m so sorry your child has autism but we decided to let scientists determine physician’s action instead medical tradition or common sense.”
1. Basheer S, et al. Vitamin D status of children with Autism Spectrum Disorder: Case-control study from India. Asian J Psychiatr. 2017 Dec;30:200-201.
2.Cannell J.J. Autism and vitamin D. Med Hypotheses. 2008;70(4):750-9.
Competing interests: No competing interests