High-dose vitamin D in pregnancy fails to prevent wheezing risk in children

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Sobering results

These are sobering findings. Even if we assume that prenatal vitamin D supplementation will prove more protective as the children in these studies grow older, vitamin D insufficiency still would explain only a small portion of the current asthma epidemic.

But neither study showed any unwanted effects from supplementation, so it seems reasonable for clinicians to prescribe vitamin D to mothers at high risk of having children with asthma by virtue of their own asthma, eczema, or allergic rhinitis – especially if those mothers are deficient in vitamin D. However, the data in these two clinical trials do not support the use of very high-dose vitamin D, since any beneficial effects achieved with 4,400 IU/day were identical to those achieved with approximately half as high a dose.

Dr. Erika von Mutius is at Ludwig Maximilians University, Munich. Dr. Fernando D. Martinez is at the asthma and airway disease research center and the department of pediatrics at the University of Arizona, Tucson. Both reported having no relevant financial disclosures. Their remarks are adapted from an editorial accompanying the two reports (JAMA 2016;315[4]:347-8.).




Among pregnant women at high risk for having a child with asthma, high doses of vitamin D administered during the third trimester failed to prevent persistent wheezing illness in their children at age 3, according to two separate reports published online Jan. 26 in JAMA.

Both studies were conducted because vitamin D insufficiency during pregnancy is commonplace and is thought to affect fetal immune programming and to contribute to asthma pathogenesis. In addition, observational studies have found an association between low levels of vitamin D in cord blood and later asthma in the child.

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The two randomized, double-blind placebo-controlled clinical trials found that neither 2,800 IU/day nor 4,400 IU/day of vitamin D significantly reduced the risk of persistent wheeze in the offspring through 3 years of age. However, both research groups noted that their studies may have been underpowered to detect a clinically important protective effect, and both recommended longer-term observation of their study participants, as well as further studies using larger sample sizes, higher doses of vitamin D, administration earlier in pregnancy, and postnatal supplementation to establish a definitive result.

In the first study – conducted as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort – 623 Danish women already taking the standard 400 IU of vitamin D3 during pregnancy were randomly assigned to receive an additional 2,400 IU (315 women) or a matching placebo (308 women) from 22 to 26 weeks’ gestation until delivery. After exclusions, researchers analyzed data on 581 children.

Maternal serum vitamin D levels increased markedly in the active-treatment group. “Correspondingly, the percentage of women with sufficient levels of vitamin D (greater than 30 ng/mL) after the intervention was 81% in the vitamin D group, compared with 44% in the control group,” wrote Dr. Bo L. Chawes of Copenhagen Prospective Studies on Asthma in Childhood, University of Copenhagen, and his associates.

Persistent wheeze developed in 104 (18%) of the 581 children: 47 (16%) in the vitamin D group and 57 (20%) in the control group, a nonsignificant difference. Similarly, asthma was diagnosed in 79 children: 32 (12%) in the vitamin D group and 47 (14%) in the control group, another nonsignificant difference.

Vitamin D supplementation also made no difference in infants’ levels of C-reactive protein, interleukin-6, tumor necrosis factor–alpha, or CXCL8, nor in the number of upper respiratory tract infections (5.2 per year vs 5.3 per year), the number of lower respiratory tract infections (32% vs 33%), the risk of allergic sensitization as measured by skin prick test or specific IgE level, or the development of eczema (23% vs 25%).

However, the risk of persistent wheeze was higher in children whose mothers’ vitamin D levels were lowest, compared with those whose mothers’ vitamin D levels were in the middle and upper tertiles. And high-dose vitamin D was protective with regard to some secondary endpoints, such as preventing more episodes of “troublesome lung symptoms” (5.9 vs. 7.2).

This finding, together with the study’s somewhat reduced statistical power, mean that a clinically important protective effect cannot be ruled out. In addition, the supplementation dose may have been too low or may have been given too late in the course of pregnancy to produce a significant effect, Dr. Chawes and his associates wrote (JAMA. 2016;315[4]:353-61. doi: 10.1001/jama.2015.18318).In the second study – the Vitamin D Antenatal Asthma Reduction Trial – 876 pregnant women in Boston, St. Louis, and San Diego who were already taking the standard 400 IU of vitamin D were randomly assigned to receive either an additional 4,000 IU/day (440 participants) or a matching placebo (436 participants). Maternal levels of vitamin D rose markedly in the active-treatment group (mean, 39.2 ng/mL), compared with the control group (mean, 26.8 ng/mL), and the proportion of women who achieved higher than “inadequate” levels was much greater (74.9% vs 34.0%), reported Dr. Augusto A. Litonjua of Brigham and Women’s Hospital, Boston, and his associates.

A total of 24.3% of the vitamin D group and 30.4% of the control group developed asthma or recurrent wheeze by age 3 years, a nonsignificant difference. However, the incidence of asthma was so much lower than anticipated in both study groups that the study may have lost statistical power to detect a clinically meaningful difference, according to the investigators (JAMA. 2016;315[4]:362-70. doi: 10.1001/jama.2015.18589).

It remains unclear whether vitamin D supplementation during pregnancy will reduce asthma and persistent wheezing in the offspring. “Larger studies and longer follow-up of the children in this study will be needed to answer the question,” the investigators wrote. “If additional studies identify a significant effect, given the high prevalence of low vitamin D levels in pregnant women, the effect of this inexpensive intervention on child health could be substantial.”

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