Rationale Vitamin-D-binding-protein transports vitamin-D metabolites and regulates vitamin-D levels in circulation. Additionally, maternal vitamin-D levels during pregnancy plays an important role in lung development and childhood asthma occurrence.

Objectives This study analyzes the joint effect of maternal 25-hydroxyvitamin-D and vitamin-D-binding-protein on offspring asthma.

Methods 806 mother-child pairs who participated in the Vitamin D Antenatal Asthma Reduction Trial were included in this analysis. The primary outcome was offspring asthma by age 3. Maternal plasma vitamin-D-binding-protein levels were measured for 515 participants at 10-18 and 32-38 weeks of gestation. Logistic regression models estimated the relationships between maternal vitamin-D-binding-protein, total 25-hydroxyvitamin-D, and offspring asthma. In addition, offspring asthma was modeled as a function of estimated free 25-hydroxyvitamin-D. A bootstrap approach was used for robust confidence interval estimation.

Measurements and Main Results Maternal vitamin-D-binding-protein levels generally increased as pregnancy progressed. A significant positive interaction effect between maternal vitamin-D-binding-protein and total 25-hydroxyvitamin-D on offspring asthma risk was observed for both the full cohort and the subset of mothers with asthma, suggesting that the protective effect of total 25-hydroxyvitamin-D increases with lower levels of vitamin-D-binding-protein. For mothers with asthma, estimated maternal free 25-hydroxyvitamin-D was found to have a significant protective effect against offspring asthma, surpassing the effects of vitamin-D-binding-protein or total 25-hydroxyvitamin-D individually.

Conclusions These results highlight the interplay between vitamin-D metabolites during pregnancy and their protective effects for offspring asthma. These results also provide evidence for the free hormone hypothesis, which suggests that free vitamin-D is more biologically relevant than total vitamin-D.

The authors have declared no competing interest.

NCT00920621

Research reported in this study was supported by the National Institutes of Health under award numbers K25HL150336 and R01HL171141 (AH); K24 HL171900 (DLD); NHLBI K01HL169756 (JH); and K01HL14697701(HM).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol was approved by the institutional review board at the Brigham and Womens Hospital. All women provided written informed consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data is available upon request.