Vitamin D Supplementation during Pregnancy and the Prevention of Childhood Asthma

[Swissallergy]

Asthma is a major cause of illness and health care costs: in 2016, almost 200,000 Americans were admitted to the hospital for an asthma attack, and 40% of them were children (https://www.cdc.gov/asthma/healthcare-use/healthcare-use-2016.htm. opens in new tab). It therefore makes sense to consider asthma prevention a major public health priority. In most cases of asthma, the first symptoms occur during the preschool years,1 and even in patients with bona fide adult-onset asthma, deficits in airway function and bronchial hyperresponsiveness could already be detected in early life.2 It is thus not surprising that many asthma-prevention strategies preferentially target the prenatal period or early postnatal life.

An important hurdle for asthma prevention is the marked heterogeneity of the disease at all ages. In the preschool years, for example, children who are having the first manifestations of persistent asthma (most often recurrent wheezing) are clinically indistinguishable from children who have transient wheeze — that is, children who wheeze only during or soon after viral respiratory infections and whose symptoms regress by the early school years.3 A large array of indexes based on clinical and molecular endotypes have been devised to distinguish transient from persistent wheezing among preschoolers, but the predictive capacity of these indexes is generally low. Therefore, if the goal is to prevent persistent asthma, it is very difficult — if not impossible — to know whether a given intervention works when outcomes are measured before the treated children reach school age (i.e., 5 to 6 years of age).

An illustrative case is the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized, placebo-controlled, double-blind supplementation trial in which either 4400 IU of vitamin D3 per day or 400 IU of vitamin D3 per day were administered to mothers starting at week 10 to 18 of pregnancy.4 The mother or the biologic father had to have asthma, allergic rhinitis, or eczema. In this issue of the Journal, Litonjua et al.5 report the results of VDAART after following the children in the trial up to the age of 6 years. In both an intention-to-treat analysis and an analysis with stratification according to maternal vitamin D level during pregnancy, there was no effect of maternal vitamin D supplementation on the primary outcome, which was asthma, recurrent wheeze, or both. Furthermore, there was no effect on most of the prespecified secondary clinical outcomes. The trial was appropriately powered and skillfully conducted, and thus the outcome should be considered quite definitive, especially in light of the similar results obtained in a study performed in Denmark6: vitamin D supplementation should not be used to prevent school-age asthma, which is most often associated with aeroallergen sensitization.

However, a previous report from the VDAART trial, limited to the first 3 years of life, showed some evidence that prenatal vitamin D supplementation provided protection against wheezing illnesses; this protection was strongest for the first year of life and tended to wane between the ages of 1 and 3 years.7 Findings reached significance when combined with those of the Danish study, which also involved children up to 3 years of age.8 Taken together, these results suggest that vitamin D supplementation may be effective in preventing the transient forms of wheezing that occur in preschoolers but not allergy-related asthma, the prevailing form of persistent disease during the school years. Unlike school-age asthma, transient wheezing is unrelated to allergies,3 and the most common cause of wheezing regardless of prognosis in this age group are viral lower respiratory tract illnesses.9 A previous report based on VDAART showed significant effects of vitamin D supplementation on the developing immune system,10 and it is thus plausible to surmise that during the first 3 years of life, vitamin D supplementation may decrease susceptibility to viral infection, as has been shown in a recent clinical trial involving older children.11

What practical conclusions can be derived from these results? Although supplementation in the VDAART trial was not effective in preventing school-age asthma, vitamin D supplementation during pregnancy may still play a role in averting less persistent forms of wheezing in infants with a parental history of asthma and allergies. In spite of its good prognosis, transient wheezing can be associated with severe asthmalike symptoms, especially during the virus season. If future studies confirm the preventive effect of high-dose vitamin D supplementation in pregnancy for preschool viral lower respiratory tract illnesses, then routine supplementation with higher doses than those currently recommended may be considered.

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