Vitamin D in Pregnancy, and Childhood Asthma and Wheezing
The results of two double-blind, randomized clinical trials were published today in one of the most influential medical journals. Both trials randomized pregnant women to a relatively high dose of vitamin D during the second trimester, and reported on outcomes related to childhood asthma and wheezing in their children at three years of age. Both studies found that children born to women supplemented with vitamin D had a lower incidence of wheezing or asthma, however the results were not statistically significant.
Both studies were similar, however there were a few differences in the studies’ designs.
The article written by Chawes et al. reported on the COPSAC2010 trial conducted in Copenhagen, Denmark. Women were supplemented with either 2800 IU or 400 IU vitamin D3 daily from 24 weeks of pregnancy. The main outcome was persistent wheezing during the first three years of life in the 581 children who were available for follow-up analyses. In total, 16% of the 2800 IU group and 20% in the 400 IU supplemented group were diagnosed with wheezing, which was not a statistically significant difference (p=0.16), however high dose supplemented children had a reduced prevalence of troublesome lung symptoms. There were no differences in safety outcomes between the two groups. The authors found the difference to be clinically meaningful, and felt that a larger study with a higher dose and a longer supplementation time may find a significant result.
The second study reported by Litonjua and associates supplemented a greater number of women earlier in pregnancy and with a larger dose (the VDAART study). It was a multi-center trial conducted in the US. Women at higher risk of having a child with asthma were randomized to either 4400 IU or 400 IU vitamin D3 from week 10 to week 18 of pregnancy. The primary outcome was a composite measure of recurrent wheezing or asthma by three years of age in 806 children for whom follow-up measurements were available. This study found that 24% of the children developed asthma or recurrent wheezing by three years of age in the higher dose group compared to 30% in the low dose group, a difference that was borderline significant (p=0.051). There were no differences in safety found between the two groups.
What is a significant difference? As nothing in science is certain, statisticians like to assign a measure of uncertainty to measurements. The p-value represents the likelihood that the differences found were due to chance. For example, the first study found that 2800 IU vitamin D3 reduced the incidence of wheezing and there was a 16% likelihood that the difference was a chance finding rather than an actual finding. In the second study, the reduction in asthma and wheezing in the group supplemented with 4400IU vitamin D was reduced, with a 5.1% likelihood that the results were a “false positive”. If the likelihood was less than 5.0%, then the results would have been considered to be significant. If one child less in the 4400 IU group, or one child more in the 400 IU group had been diagnosed with wheezing or asthma, or if the sample size was a little larger but still holding the same proportion of asthma and wheezing diagnoses, the results would have been considered significant.
In addition, even after months of supplementation in the high-dose groups, around 20% of the women in both studies still had low blood levels of vitamin D. Was this an issue with poor compliance, or perhaps linked to different uptake and metabolism of vitamin D due to polymorphisms?
Although the rather pessimistic editorial that discusses the studies reports that they were inconclusive, and suggests that enthusiasm for vitamin D supplementation in pregnancy should be restrained, I was more convinced. These results from two independently conducted studies with a similar design both showed that vitamin D doses of 2800-4400 IU per day reduced incidence of asthma and wheezing. There were also secondary analyses that explored the molecular mechanisms behind reduced asthma and wheezing that were supportive. The results from one child may have turned the results second study from “inconclusive” to widespread recommendations to supplement pregnant women with vitamin D3.
Chawes BL, Bønnelykke K, Stokholm J, et al. Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial. JAMA. 2016;315(4):353-361. doi:10.1001/jama.2015.18318. http://jama.jamanetwork.com/article.aspx?articleid=2484338
Litonjua AA, Carey VJ, Laranjo N, et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial. JAMA. 2016;315(4):362-370. doi:10.1001/jama.2015.18589. http://jama.jamanetwork.com/article.aspx?articleid=2484339
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