Vitamin D No Benefit in Pregnancy for Fetal or Infant Growth

Nancy A. Melville

August 13, 2018

Even in a population of women with vitamin D deficiency, supplementation of high-dose vitamin D from mid-pregnancy until birth and for 6 months postpartum shows no benefits on measures of fetal or infant growth compared with prenatal supplementation only, or placebo, according to a study of more than 1100 women and their infants.

"Vitamin D supplementation given to women during the latter half of pregnancy and in the postpartum period improved biochemical markers of vitamin D status and reduced the risk of vitamin D deficiency, as expected. However, even at higher than conventional doses, vitamin D supplementation did not have effects on infant growth up to 1 year of age," first author Daniel Roth, MD, PhD, an associate professor in the departments of pediatrics and nutritional sciences at the University of Toronto, Ontario, told Medscape Medical News.

Results from the Maternal Vitamin D for Infant Growth (MDIG) trial were published in the August 9 issue of the New England Journal of Medicine.

In the randomized, double-blind, placebo-controlled study, Roth and colleagues randomized pregnant women in Bangladesh, where a high proportion of women are vitamin D deficient, to one of five groups.

In evaluating 1164 infants from the study at 1 year of age, representing 89.5% of the 1300 pregnancies, the authors found no significant differences across the groups in terms of the primary outcome of infants' length-for-age z scores at 1 year, according to World Health Organization child growth standards.

In addition to finding no differences in fetal or infant growth with any of the vitamin D regimens compared with placebo, the results also showed no significant differences between groups in terms of birth outcomes or morbidity.

"Due to a lack of previous robust evidence, the World Health Organization has not recommended routine vitamin D supplementation during pregnancy," Roth explained.

"We conclude that the present findings support this position, even in communities where vitamin D deficiency and fetal–infant growth restriction are endemic."

With Deficiency, Some Benefits Were Expected

In Bangladesh, approximately a third of newborns are small for gestational age, and 36% of those younger than 5 years have stunted growth. Therefore, with as many as 64% of pregnant women in the trial population considered to be vitamin D deficient at baseline (defined as a serum 25-hydroxyvitamin D concentration < 30 nmol/L), there were expectations of benefits from bringing them up to sufficient levels.

"In general, with micronutrient interventions, we expect the benefits of supplementation to be most apparent in people who are deficient at the start of the trial or in communities where deficiency is common," Roth said.

One group of women received neither prenatal nor postpartum vitamin D (placebo group). Three groups received prenatal supplementation only in doses of 4200 IU (prenatal 4200 group), 16,800 IU (prenatal 16,800 group), and 28,000 IU (prenatal 28,000 group). The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation of 28,000 IU (prenatal and postpartum 28,000 group).

The specific mean length-for-age z scores among the infants were −0.93 in the placebo group; −1.11 in the prenatal 4200 group; −0.97 in the prenatal 16,800 group; −1.06 in the prenatal 28,000 group; and −0.94 in the prenatal and postpartum 28,000 group (P = 0.23 across the groups).

"Overall there was no effect of vitamin D on infant growth in this population," said Roth.

These results appear to confirm prior research on vitamin D supplementation in pregnancy and "do not support the hypothesis that prenatal vitamin D status in the second half of pregnancy is a determinant of newborn size," he and his coauthors state.

Furthermore, in secondary analyses, they did not see any benefit on infant growth in the large subgroup of participants who were very vitamin D deficient (maternal baseline 25-hydroxyvitamin D concentration < 30 nmol/L).

Vitamin D supplementation had expected effects on maternal and infant serum 25-hydroxyvitamin D and calcium concentrations, maternal urinary calcium excretion, and maternal parathyroid hormone concentrations. There were no significant differences in the frequencies of adverse events across groups, with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose.

"Effects on fetal or infant growth were absent despite the robust dose–response effects of vitamin D on serum concentrations of 25-hydroxyvitamin D, intact parathyroid hormone, and calcium, and on the urinary calcium-to-creatinine ratio," the authors conclude.

And as has been previously reported in a meta-analysis, no reductions in the incidence of preterm births were seen with the supplementation in the study.

Mechanisms of Vitamin D Thought to Affect Pregnancy

Vitamin D may potentially influence fetal and postnatal growth as a result of its effects on processes including calcium absorption, parathyroid hormone expression, phosphate metabolism, growth-plate function, and regulation of the insulin-like growth factor axis, the authors explain.

Previous meta-analyses have suggested potential benefits of vitamin D on fetal growth; however, the authors noted that those tended to have methodological limitations.

In a previous study (J Pediatr. 2013;163:1605-1611.e3), the authors of the current study found increases in early postnatal linear growth among infants born to women who received vitamin D supplementation of 35,000 IU/week in the third trimester of pregnancy compared with those who did not.

However, they note that that study, and another in the UK that had similar results, each were relatively small, involving fewer than 135 participants, in addition to other limitations.

Other recent research that has suggested benefits in other contexts of pregnancy includes a study suggesting that sufficient preconception levels of vitamin D improve the chances of conceiving and subsequent delivery of a live infant among women with a history of pregnancy loss, as reported by Medscape Medical News.

Although women in all groups of the current study were offered iron, folic acid, and calcium as routine co-supplements, Roth noted it is possible the women could have been lacking other micronutrients important for fetal and infant growth.

The study received support from the Bill and Melinda Gates Foundation. The authors have reported no relevant financial relationships.

N Engl J Med. 2018;379:535-546. Full text

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