Vitamin D3 During Pregnancy and Cognitive Performance at 10 Years

The Wayback Machine - http://web.archive.org/web/20260519165328/https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2849122 Close Original Investigation Pediatrics 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 Figure 1. Flow DiagramCOPSYCH indicates Copenhagen Prospective Study on Neuro-Psychiatric Development.Figure 2. Forest Plot of Association Between High-Dose vs Standard-Dose Vitamin D3 Supplementation During Pregnancy and Cognitive Functions at Age 10 Years Among Children Without an Attention-Deficit/Hyperactivity Disorder (ADHD) DiagnosisAnalyses were adjusted for child sex, age at assessment, n-3-long-chain polyunsaturated fatty acid supplementation, season of birth, and maternal 25(OH)D concentration at 24 weeks’ gestation. Higher z scores indicate better cognitive performance.aP ≥ .05.bP < .05. Table 1. Overview of Domains, Functions, Tests, and Outcome Metrics in the Neurocognitive Test BatteryDomain and functionTestOutcome metricIntelligence Estimated intelligenceVocabulary (WISC-IV)Total No. correctMatrices (WICV-IV)Total No. correctProcessing speed Speed of processingCoding (WISC-IV)Total No. correctSymbol search (WISC-IV)Sum of total No. correct, with errors subtractedReaction time Reaction timeReaction time (CANTAB)Simple- and 5-choice reaction timeAttention Sustained attentionRapid visual information processing (CANTAB)A-prime (unitless sensitivity score)Motor function Motor speedReaction time (CANTAB)Simple- and 5-choice movement timeMemory Verbal memoryWord selective reminding–immediate recall and object recall (TOMAL 2)Total No. of words recalled over 6 learning trials and total No. of objects recalled over 5 learning trials Visual memoryPaired associates learning (CANTAB)Total errors (adjusted)Working memory Verbal working memoryDigit span and letter-number sequencing (WISC-IV)Total No. of correct forward and backward sequences and total No.

of correct sequencesExecutive function Flexibility or set shiftIntra-extra dimensional set shift (CANTAB)Extra-dimensional stage errors Spatial working memorySpatial working memory (CANTAB)Total No. of errors PlanningStockings of Cambridge (CANTAB)Problems solved in minimum movesTable 2. Association of High-Dose vs Standard-Dose Vitamin D3 Supplementation During Pregnancy With Cognitive Functions at Age 10 YearsDomainFunctionUnadjustedAdjustedq ValuecNo. of childrenEstimate (95% CI)aP valueNo. of childrenEstimate (95% CI)bP valueEstimated intelligenceEstimated intelligence495−0.01 (−0.19 to 0.16).90491−0.01 (−0.19 to 0.16).89.89Processing speedSpeed of processing498−0.04 (−0.19 to 0.12).65494−0.02 (−0.17 to 0.13).81.81Reaction timeReaction time4960.12 (−0.05 to 0.28).174920.11 (−0.05 to 0.28).18.18AttentionSustained attention495−0.03 (−0.21 to 0.15).77491−0.03 (−0.21 to 0.16).79.79Motor functionMotor speed4960.10 (−0.07 to 0.27).254920.09 (−0.08 to 0.25).31.31MemoryVerbal memory4970.14 (−0.00 to 0.29).064930.17 (0.03 to 0.32).02.02Working memoryVerbal working memory498−0.11 (−0.25 to 0.04).16494−0.01

(−0.25 to 0.04).17.17MemoryVisual memory4970.25 (0.07 to 0.44).014930.24 (0.06 to 0.42).01.02Executive functionFlexibility or set shift4950.20 (0.02 to 0.38).034910.19 (0.01 to 0.37).04.10Executive functionSpatial working memory498−0.11 (−0.29 to 0.06).20494−0.12 (−0.30 to 0.06).18.27Executive functionPlanning4970 (−0.18 to 0.17).964930 (−0.17 to 0.17).98.98Table 3. Associations of Maternal 25(OH)D Levels at Week 24 With Offspring Cognitive Functions at Age 10 YearsDomainFunctionUnadjustedAdjustedq ValuecNo. of childrenEstimate (95% CI)aP valueNo. of childrenEstimate (95% CI)bP valueEstimated intelligenceEstimated intelligence5840 (−0.03 to 0.03).93483−0.02 (−0.06 to 0.02).36.35Processing speedSpeed of processing5870 (−0.03 to 0.03).834870 (−0.03 to 0.04).65.65Reaction timeReaction time585−0.01 (−0.04 to 0.02).544840.01 (−0.03 to 0.04).92.92AttentionSustained attention582−0.01 (−0.04 to 0.03).644810 (−0.04

to 0.04).86.86Motor functionMotor speed5850.01 (−0.02 to 0.04).554840.03 (−0.01 to 0.07).33.33MemoryVerbal memory5870.01 (−0.02 to 0.04).52486−0.01 (−0.04 to 0.03).94.94Working MemoryVerbal working memory5880.02 (−0.01 to 0.05).164870 (−0.03 to 0.04).70.70MemoryVisual memory5860.01 (−0.02 to 0.04).524850 (−0.04 to 0.04).67.94Executive functionFlexibility or set shift5840.03 (−0.01 to 0.06).114830.05 (0.01 to 0.09).03.08Executive functionSpatial working memory5870 (−0.03 to 0.03).964860 (−0.04 to 0.04).99.99Executive functionPlanning5860 (−0.03 to 0.04).79485−0.01 (−0.05 to 0.03).83.99 Key PointsQuestion Is high-dose vitamin D3 supplementation during pregnancy associated with improved cognition among offspring?Findings In this post hoc analysis of a randomized clinical trial including 498 children, high-dose vitamin D3 supplementation was associated with better verbal and visual memory and set shift at age 10 years compared with standard-dose vitamin D3, although the association with flexibility or set shift did not remain significant after false discovery rate correction.Meaning This study suggests that high-dose vitamin D3 supplementation during pregnancy may be associated with improved cognitive functioning at age 10 years.

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 Introduction Childhood cognition is a predictor of socioeconomic status, occupational achievement, and cognitive abilities later in life.1-4 Although heritability estimates for cognition are reported as high as 80%,5 meta-analyses show that several prenatal exposures can be associated with worse cognitive outcomes,6,7 illustrating how early environmental factors may shape cognitive development. Globally, vitamin D deficiency is a widespread problem among pregnant women.8 Vitamin D contributes to brain development during pregnancy,9 with in vitro and rodent models highlighting its involvement in essential neurodevelopmental processes, including neuronal differentiation, neurotransmitter synthesis, intracellular calcium signaling, and antioxidant activity.10,11 The distribution of vitamin D receptors and 1-α-hydroxylase in the human brain further supports its important role in neurodevelopment.12 Moreover, experimental rat models have demonstrated associations between vitamin D deficiency and cognitive functions, including learning and memory impairments.13,14 Prenatal vitamin D deficiency has been associated with

neuropsychiatric disorders such as autism spectrum disorder (ASD),15,16 attention-deficit/hyperactivity disorder (ADHD),17,18 and schizophrenia.19 These disorders are associated with impairments in several cognitive domains, including attention and executive functioning.20-22 Two previous studies have examined the association of prenatal vitamin D supplementation with neurodevelopment in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort; Sass et al23 found no effect on offspring neurodevelopment from birth to 6 years of age, and Aagaard et al24 reported no effect on neurodevelopmental disorders at age 10 years, but hitherto we have not investigated a potential effect on cognitive function at this age. Studies examining gestational vitamin D levels and cognitive functioning among offspring have reported inconsistent findings. Existing observational studies differ in exposure and outcome measurements. Exposure measurements have varied between first,25-30 second,25,30-35 and third trimester25,29-31,36-40 as well as cord blood25,30-32,34,36,41-44 levels of 25(OH)D. Outcome measurements varied in age at testing, cognitive function assessed, and types of tests used. Positive associations with vitamin D have been reported for language skills,25,33,40,45 gross motor skills,25,27,44,45 executive functioning,28 and intelligence.31,46 Two meta-analyses of observational studies found positive associations between maternal vitamin D during pregnancy and offspring cognitive abilities, as well as fewer ADHD and ASD traits.47,48 To date, only 1 other randomized clinical trial (RCT) has examined the role of vitamin D supplementation during pregnancy in offspring cognition. The study reported a positive effect of supplementation with 2000 IU/d of vitamin D from 12 to 16 weeks of pregnancy until delivery on receptive and expressive language at 3 to 5 years of age, although it was limited by a relatively small sample size (n = 156).49 To our knowledge, no RCT has investigated the effect of prenatal vitamin D supplementation on offspring cognition in middle childhood.