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Effect of High-Dose vs Standard-Dose Vitamin D Supplementation in Pregnancy on Bone Mineralization in Offspring Until Age 6 YearsA Prespecified Secondary Analysis of a Double-Blinded, Randomized Clinical Trial

Educational Objective
To investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring.
1 Credit CME
Key Points

Question  Is a 7-fold increased intake of vitamin D in pregnancy related to improved offspring bone health compared with standard dose?

Findings  In this prespecified analysis of a large-scale double-blinded randomized clinical trial, a high dose vs standard dose of vitamin D supplementation from pregnancy week 24 to 1 week post partum resulted in an overall higher bone mineralization status in the offspring during the first 6 years of life.

Meaning  This trial suggests that an increased vitamin D intake during pregnancy has the potential to promote greater bone health in the offspring, which could have a protective effect on risk of fractures.

Abstract

Importance  Studies suggest an association between maternal vitamin D status during pregnancy and offspring anthropometry and bone mineralization, but investigations are few and with mixed results.

Objective  To investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring.

Design, Setting, and Participants  A prespecified analysis of a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort that included 623 pregnant mothers and their 584 children. Data were analyzed between January 2019 and September 2019.

Interventions  Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth.

Main Outcomes and Measures  Longitudinal anthropometry assessments including length/height, weight, and body mass index until age 6 years and bone mineral content (BMC) and bone mineral density (BMD) at age 3 years and 6 years from dual-energy radiography absorptiometry scans.

Results  At age 6 years, 517 children (89%) completed the clinical follow-up. All participants were Danish and white; 261 were boys and 256 were girls. A mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that children in the vitamin D vs placebo group had higher whole-body BMC: mean difference adjusted (aMD) for age, sex, height, and weight was 11.5 g (95% CI, 2.3-20.7; P = .01); higher whole-body-less-head BMC aMD was 7.5 g (95% CI, 1.5-13.5; P = .01); and higher head BMD aMD was 0.023 g/cm2 (95% CI, 0.003-0.004; P = .03). The largest effect was in children from vitamin D–insufficient mothers (<30 ng/mL; to convert to nanomoles per liter, multiply by 2.496) and among winter births. In a post hoc analysis, we found borderline lower incidence of fractures in the vitamin D group (n = 23 vs n = 36; incidence rate ratio, 0.62 [95% CI, 0.37-1.05]; P = .08), but no differences in any anthropometric outcomes. Adjustment for a concomitant ω-3 polyunsaturated fatty acids intervention did not change the results.

Conclusions and Relevance  High-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose, suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. We found no supplementation effect on anthropometric outcomes.

Trial Registration  ClinicalTrials.gov Identifier: NCT00856947

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Article Information

Accepted for Publication: October 23, 2019.

Corresponding Author: Hans Bisgaard, MD, DMSc, Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, Gentofte 2820, Denmark (bisgaard@copsac.com).

Published Online: February 24, 2020. doi:10.1001/jamapediatrics.2019.6083

Author Contributions: Dr Bisgaard had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Brustad, Garland, Stokholm, Bisgaard, Chawes.

Acquisition, analysis, or interpretation of data: Brustad, Garland, Thorsen, Sevelsted, Krakauer, Vinding, Bønnelykke, Bisgaard, Chawes.

Drafting of the manuscript: Brustad, Garland, Bisgaard.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Brustad, Garland, Thorsen, Sevelsted, Vinding.

Obtained funding: Brustad, Bisgaard, Chawes.

Administrative, technical, or material support: Brustad, Krakauer, Bisgaard.

Supervision: Brustad, Sevelsted, Vinding, Stokholm, Bønnelykke, Bisgaard, Chawes.

Conflict of Interest Disclosures: None reported.

Funding/Support: All funding received by the Copenhagen Prospective Studies on Asthma in Childhood is listed on www.copsac.com. The Lundbeck Foundation (grant R16-A1694); the Ministry of Health (grant 903516); Danish Council for Strategic Research (grant 0603-00280B) and the Capital Region Research Foundation have provided core support to the COPSAC research center.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the children and families of the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort study for all their support and commitment. We acknowledge and appreciate the efforts of the COPSAC research team.

Additional Information: No honorarium, grant, or other form of payment was given to any of the authors to produce this article.

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