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Association of High-Dose Vitamin D Supplementation During Pregnancy With the Risk of Enamel Defects in OffspringA 6-Year Follow-up of a Randomized Clinical Trial

Educational Objective
To assess the association of a high-dose vitamin D supplementation in pregnant women with enamel defects and caries in their offspring.
1 Credit CME
Key Points

Question  Is high-dose vitamin D supplementation during the third trimester of pregnancy associated with long-term dental health during childhood?

Findings  In a 6-year follow-up of a double-blind randomized clinical trial that included 623 pregnant women, high-dose vitamin D supplementation during third trimester was associated with reduced odds of enamel defects in the offspring by approximately 50%. No associations with caries were observed.

Meaning  Prenatal high-dose vitamin D supplementation may be a clinically relevant preventive intervention for enamel defects.


Importance  Enamel defects of developmental origin affect up to 38% of schoolchildren and is recognized as a global public health challenge. The impaired enamel formation results in pain owing to hypersensitivity, posteruptive breakdowns, rapid caries progression, and extractions in some cases. The etiology is unknown; therefore, prevention is currently not possible.

Objective  To assess the association of a high-dose vitamin D supplementation in pregnant women with enamel defects and caries in their offspring.

Design, Setting, and Participants  Post hoc analysis of a double-blind, single-center, randomized clinical trial, the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort (COPSAC2010). Enrollment began March 2009 and included 623 women recruited at 24 weeks of pregnancy and 588 of their children. A dental examination was completed at age 6 years in 496 of 588 children (84%). Data were analyzed in 2018.

Intervention  High-dose vitamin D3 (2400 IU/d; N = 315) or matching placebo tablets (N = 308) from pregnancy week 24 to 1 week post partum. In addition, all women received 400 IU/d of vitamin D3 as part of standard care.

Main Outcomes and Measures  Enamel defect was defined as having at least 1 molar affected by demarcated opacity, enamel breakdown, and/or atypical restoration. Caries was defined as decayed, missing, or filled surfaces in both the deciduous and permanent dentitions (World Health Organization standard).

Results  The risk of enamel defects in the permanent dentition was lower in the offspring of mothers who received high-dose vitamin D supplementation during pregnancy compared with standard dose (15.1% [n = 26 of 172] vs 27.5% [n = 44 of 160]; odds ratio, 0.47; 95% CI, 0.27-0.81). A similar association was observed for the deciduous dentition (8.6% [n = 21 of 244] vs 15.9% [n = 40 of 252]; odds ratio, 0.50; 95% CI, 0.28-0.87). There was no association between supplementation and caries.

Conclusions and Relevance  High-dose vitamin D supplementation during pregnancy was associated with approximately 50% reduced odds of enamel defects in the offspring. This suggests prenatal vitamin D supplementation as a preventive intervention for enamel defects, with a clinically important association with dental health.

Trial Registration identifier: NCT00856947

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Article Information

Corresponding Author: Hans Bisgaard, MD, DMSc, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Ledreborg Alle 34, DK-2820 Gentofte, Denmark (

Accepted for Publication: April 24, 2019.

Published Online: August 5, 2019. doi:10.1001/jamapediatrics.2019.2545

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. Dr Kühnisch scored the reliability of the dental registrations and the validation was performed at the Department of Conservative Dentistry and Periodontology, School of Dentistry, University of Munich. Drs Bisgaard and Bønnelykke contributed equally to the work.

Concept and design: Nørrisgaard, Kühnisch, Chawes, Stokholm, Bønnelykke, Bisgaard.

Acquisition, analysis, or interpretation of data: Nørrisgaard, Haubek, Chawes, Stokholm, Bønnelykke.

Drafting of the manuscript: Nørrisgaard, Kühnisch, Bønnelykke.

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

Statistical analysis: Nørrisgaard.

Obtained funding: Chawes, Bønnelykke.

Administrative, technical, or material support: Nørrisgaard, Haubek.

Supervision: Haubek, Kühnisch, Chawes, Stokholm, Bønnelykke, Bisgaard.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Copenhagen Prospective Study on Asthma in Childhood (COPSAC) is funded by private and public research funds that are all listed on The Lundbeck Foundation, Danish State Budget, Danish Council for Strategic Research, Danish Council for Independent Research, and the Capital Region Research Foundation have provided core support for COPSAC.

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.

Disclaimer: We are aware of and comply with recognized codes of good research practice, including the Danish Code of Conduct for Research Integrity. We comply with national and international rules on the safety and rights of patients and healthy individuals, including Good Clinical Practice as defined in the European Union's Directive on Good Clinical Practice, the International Conference on Harmonisation’s good clinical practice guidelines, and the Helsinki Declaration. We follow national and international rules on the processing of personal data, including the Danish Act on Processing of Personal Data and the practice of the Danish Data Inspectorate.

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

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