High-Dose Vitamin D Supplementation in Pregnancy and Neurodevelopment in Childhood: A Prespecified Secondary Analysis of a Randomized Clinical Trial

IMPORTANCE: Observational studies have reported an association between high maternal vitamin D levels and improved neurodevelopment in offspring, but no randomized clinical trial (RCT) has investigated these observations. OBJECTIVE: To determine whether high-dose vitamin D supplementation during pregnancy improves offspring neurodevelopment from birth to age 6 years. DESIGN, SETTING, AND PARTICIPANTS: This prespecified secondary analysis of a double-blinded, placebo-controlled RCT of high-dose vitamin D(3) supplementation vs standard dose during the third trimester of pregnancy was conducted in the unselected prospective mother-child birth cohort at a single-center research unit in Denmark as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC-2010). Participants included pregnant women; women with vitamin D intake greater than 600 IU/d or an endocrine, heart, or kidney disorder, and those who did not speak Danish fluently were excluded. Neurodevelopmental assessments for offspring of these women were performed at ages 0 to 6 years. Children born prematurely (gestational week <37), with low birth weight (<2500 g), or with a neurological disease affecting neurodevelopment were excluded. Data were analyzed from August 2019 to February 2020. INTERVENTIONS: High-dose (ie, 2800 IU/d) vs standard dose (ie, 400 IU/d) vitamin D(3) supplementation from pregnancy week 24 until 1 week after birth. MAIN OUTCOMES AND MEASURES: The primary outcome of interest was cognitive development assessed at 2.5 years using the Bayley Scales of Infant and Toddler Development. Other neurodevelopmental outcomes included age of motor milestone achievement (Denver Developmental Index and World Health Organization milestone registration), language development (MacArthur-Bates Communicative Development Inventories), general neurodevelopment at age 3 years (Ages and Stages Questionnaire), and emotional and behavioral problems at age 6 years (Strengths and Difficulties Questionnaire). RESULTS: Among 623 women randomized, 315 were randomized to high-dose vitamin D(3) and 308 were randomized to standard dose placebo. A total of 551 children were evaluated from birth to age 6 years, (282 [51.2%] boys; 528 [95.8%] White), with 277 children in the high-dose vitamin D(3) group and 274 children in the standard dose group. There was no effect of the high-dose compared with standard dose of vitamin D(3) supplementation during pregnancy on offspring achievement of motor milestones (β = 0.08 [95% CI, −0.26 to 0.43]; P = .64), cognitive development (score difference: 0.34 [95% CI, −1.32 to 1.99]; P = .70), general neurodevelopment (median [IQR] communication score: 50 [50-55] vs 50 [50-55]; P = .62), or emotional and behavioral problems (odds ratio, 0.76 [95% CI, 0.53 to 1.09]; P = .14). There was no effect on language development expressed by the word production at 1 year (median [IQR], 2 [0-6] words vs 3 [1-6] words; P = .16), although a decreased word production was apparent at 2 years in children in the high-dose vitamin D(3) group (median [IQR], 232 [113-346] words vs 253 [149-382.5] words; P = .02). CONCLUSIONS AND RELEVANCE: In this prespecified secondary analysis of an RCT, maternal high-dose vitamin D(3) supplementation during the third trimester of pregnancy did not improve neurodevelopmental outcomes in the offspring during the first 6 years of life. These findings contribute essential information clarifying the effects of prenatal exposure to vitamin D on neurodevelopment in childhood. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00856947