High-Dose Vitamin D3 Supplementation During Pregnancy and Test-Based Cognitive Performance at Age 10 Years: A Post Hoc Secondary Analysis of a Randomized Clinical Trial.

Olivia Frigast Frederiksen, Jens Richardt Møllegaard Jepsen, Nicklas Brustad, Rebecca Vinding, Julie Bøjstrup Rosenberg, Parisa Mohammadzadeh, María Hernández-Lorca, Ann-Marie Malby Schoos, Nilo Vahman, Birte Y Glenthøj, Birgitte Fagerlund, Niels Bilenberg, Klaus Bønnelykke, Bjørn H Ebdrup, Kristina Aagaard, Bo Chawes

Journal: JAMA network open 2026;9(5):e2611464

PMID: 42149595

View on PubMed

Abstract

IMPORTANCE

Observational studies have reported associations between pregnancy vitamin D levels and offspring cognition, but no randomized clinical trial (RCT) has investigated the effect of high-dose vitamin D3 supplementation in pregnancy on offspring cognition into middle childhood.

OBJECTIVE

To assess whether high-dose vitamin D3 supplementation during pregnancy is associated with improved offspring cognition at age 10 years.

DESIGN, SETTING, AND PARTICIPANTS

This is a post hoc secondary analysis of the blinded, placebo-controlled Copenhagen Prospective Studies on Asthma in Childhood 2010 RCT conducted from March 4, 2009, to November 17, 2010. The cohort included 700 mother-child pairs from Denmark, of whom 623 were randomized. Exclusion criteria were vitamin D intake above 600 IU/d; endocrine, kidney, or heart disease; and insufficient Danish language proficiency. Cognitive assessments were conducted for the offspring at age 10 years, excluding those born at less than 28 weeks' gestation and with birth weight less than 1500 g. Participants were unblinded at 3 years of age, while investigators remained unaware of group assignments. The 10-year visits were conducted from February 11, 2019, to December 13, 2021. Statistical analyses were conducted from February to June 2025.

INTERVENTION

High-dose (2800 IU/d) or standard-dose (400 IU/d) vitamin D3 from pregnancy week 24 to 1 week post partum.

MAIN OUTCOME AND MEASURES

The primary outcome was cognitive functioning across 11 functions assessed at age 10 years using a comprehensive neuropsychological test battery as part of the Copenhagen Prospective Study on Neuro-Psychiatric Development (COPSYCH).

RESULTS

The vitamin D3 RCT and the COPSYCH visit were completed by 498 children (mean [SD] age, 10.3 [0.4] years; 258 boys [51.8%]): 247 prenatally exposed to high-dose vitamin D3 and 251 prenatally exposed to standard-dose vitamin D3. Covariate-adjusted analyses of standardized scores (mean [SD], 0 [1]; higher values indicating better performance) showed positive associations of high-dose vitamin D3 with verbal memory (β = 0.17 SD; 95% CI, 0.03-0.32 SD; P = .02), visual memory (β = 0.24 SD; 95% CI, 0.06-0.42 SD; P = .01), and flexibility or set shift (β = 0.19 SD; 95% CI, 0.01-0.37 SD; P = .04); however, high-dose vitamin D3 was no longer associated with flexibility or set shift after multiple test correction.

CONCLUSION AND RELEVANCE

This post hoc analysis of an RCT suggests that high-dose vitamin D3 supplementation in pregnancy is positively associated with visual memory, verbal memory, and flexibility or set shift among offspring measured at age 10 years. These findings strengthen evidence on the association of prenatal vitamin D exposure with childhood cognition.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT00856947.

Address: Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Center for Neuropsychiatric Schizophrenia Research, Mental Health Center, Glostrup, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Child and Adolescent Mental Health Center, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Herlev and Gentofte, Herlev, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Center for Neuropsychiatric Schizophrenia Research, Mental Health Center, Glostrup, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Center for Neuropsychiatric Schizophrenia Research, Mental Health Center, Glostrup, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Pediatrics, Copenhagen University Hospital-Næstved, Slagelse and Ringsted, Slagelse, Denmark.; Department of Pediatrics, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark.; Center for Neuropsychiatric Schizophrenia Research, Mental Health Center, Glostrup, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Center for Neuropsychiatric Schizophrenia Research, Mental Health Center, Glostrup, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark.; Department of Psychology, University of Copenhagen, Copenhagen, Denmark.; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

DOI: 10.1001/jamanetworkopen.2026.11464

MeSH Terms: Humans, Female, Pregnancy, Cholecalciferol, Cognition, Child, Dietary Supplements, Male, Denmark, Prenatal Exposure Delayed Effects, Prospective Studies, Adult, Vitamins