High-Dose Vitamin D Supplementation in Pregnancy and Neurodevelopment in Childhood

Laerke Sass,Jonathan Thorsen,Rikke Bjersand Sunde,Hans Bisgaard,Elín Bjarnadóttir,Rebecca Kofod Vinding,Bo Chawes,Klaus Bønnelykke,John Mcgrath,Jakob Stokholm,Sarah Noergaard

doi:10.1001/jamanetworkopen.2020.26018

Abstract

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. To determine whether high-dose vitamin D supplementation during pregnancy improves offspring neurodevelopment from birth to age 6 years. This prespecified secondary analysis of a double-blinded, placebo-controlled RCT of high-dose vitamin D3 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. High-dose (ie, 2800 IU/d) vs standard dose (ie, 400 IU/d) vitamin D3 supplementation from pregnancy week 24 until 1 week after birth. 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). Among 623 women randomized, 315 were randomized to high-dose vitamin D3 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 D3 group and 274 children in the standard dose group. There was no effect of the high-dose compared with standard dose of vitamin D3 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 D3 group (median [IQR], 232 [113-346] words vs 253 [149-382.5] words; P = .02). In this prespecified secondary analysis of an RCT, maternal high-dose vitamin D3 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. ClinicalTrials.gov Identifier: NCT00856947.

Highlights

There was no effect of the high-dose compared with standard dose of vitamin D3 supplementation during pregnancy on offspring achievement of motor milestones (β = 0.08 [95% CI, −0.26 to 0.43]; P = .64), cognitive development, general neurodevelopment
Study Design This study is a prespecified secondary analysis of a double-blinded, placebo-controlled randomized clinical trial (RCT) of highdose vs standard dose vitamin D3 supplementation given to pregnant Danish women enrolled in the COPSAC-2010 cohort, which consists of 738 pregnant women and their 700 children followed prospectively with deep clinical phenotyping through childhood
The intervention resulted in increased maternal serum vitamin D levels 1 week after birth

Summary

Introduction

Vitamin D deficiency is a major global health problem affecting people at all ages and in all racial/ ethnic groups.[1,2,3,4,5] Vitamin D deficiency is prevalent among pregnant women,[2,6,7,8,9] and since fetal and newborn vitamin D status is almost completely dependent on vitamin D from the mother, an adequate maternal level is pivotal.[10,11,12,13] Vitamin D is an essential micronutrient and a neuroactive steroid that plays an important role in the development of the brain.[14,15,16] Animal models of developmental vitamin D deficiency have found altered brain structure and behavior, which are thought to be mediated by various mechanisms affecting neurotransmission, neuronal differentiation, gene transcription, and immunological modulation.[16,17,18]Several observational studies have found associations of prenatal vitamin D deficiency with a series of neurodevelopmental and psychiatric diseases, such as attention deficit/hyperactivity disorder, autism spectrum disorder, and schizophrenia.[19,20,21,22,23,24,25] adequate prenatal vitamin D levels may be important to assure proper brain development and for the maintenance of mental functions later in life.[18,26].

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