Neonatal vitamin D status in relation to autism spectrum disorder and developmental delay in the CHARGE case–control study

Abstract

Vitamin D appears essential for normal neurodevelopment and cognitive and behavioral function. We examined neonatal vitamin D in relation to the child's later diagnosis of autism spectrum disorder (ASD) or developmental delay (DD). Children aged 24-60 months enrolled in the population-based CHARGE case-control study were evaluated clinically for ASD (n = 357), DD (n = 134), or typical development (TD, n = 234) at the MIND Institute (Sacramento, CA) using standardized assessments. Total 25-hydroxyvitamin D (25[OH]D) was measured using sensitive isotope dilution liquid chromatography-tandem mass spectrometry in archived dried blood spots collected for the California Department of Public Health's Newborn Screening Program. Multinomial logistic regression was used to calculate ORs as measures of the associations between 25 nmol/L change in 25(OH)D and ASD and DD. Associations between 25(OH)D and scores on Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales were assessed using robust linear regression. Effect modification was examined using stratified models and interaction product terms.Unadjusted mean (SD) 25(OH)D was lower for DD (73.2 [37.6]) than for TD (82.7 [39.3]) and ASD (80.1 [37.4]). After adjustment for maternal prepregnancy body mass index and education, a 25 nmol/L increase in total 25(OH)D was not associated with ASD (OR = 0.97; CI: 0.87-1.08) or DD (OR = 0.91; 95% CI: 0.78-1.06). Neonatal 25(OH)D was associated with significantly reduced ASD only in females (adjusted OR = 0.74; 95% CI: 0.55-0.99, P interaction = 0.03), and significantly reduced DD only in non-Hispanic white children (adjusted OR = 0.79; 95% CI: 0.63-0.98, P interaction = 0.11 for Hispanic, P interaction = 0.31 for other), driven by DD children with trisomy 21. This study provides evidence that neonatal vitamin D could be associated with ASD in females and with DD in non-Hispanic white children. Autism Res 2019, 12: 976-988.Lay Summary: Vitamin D appears essential for brain development and function. We examined neonatal total 25hydroxyvitamin D (25[OH]D) measured in dried blood spots in relation to later diagnoses of autism spectrum disorder (ASD) or developmental delay (DD) and related assessment scores. Higher neonatal 25(OH)D was associated with a 26% reduction in the odds for ASD only in females. After taking into account factors that could contribute to vitamin D status, a significant association with 21% reduced odds for DD was found only in non-Hispanic white children. Though results were nonsignificant overall, certain subgroups might benefit from higher neonatal vitamin D.

Vitamin D Status Is Not Associated with Cognitive or Motor Function in Pre-School Ugandan Children

“…Our findings of no association between vitamin D status and cognitive or motor function, agree with nine previous observational studies [34][35][36][37][38][39][40][41][42]. On the contrary, a small dose-response randomized controlled trial (n = 55) of vitamin D supplementation in Canadian infants reported that a lower dose of 400 international units (IU) of vitamin D was more beneficial for gross motor development than higher doses of 800 IU or 1200 IU [16].…”

The effect of vitamin D supplementation in treatment of children with autism spectrum disorder: a systematic review and meta-analysis of randomized controlled trials

“…The rising ASD rates are ascribed to complex interactions between multiple genes and environmental components 3,4 . Recent epidemiological studies indicate that concentrations of vitamin D are decreased in children with ASD compared to typically developing children [5][6][7] . Vitamin D acts as a neuroactive steroid and plays an important role in brain development and mature brain function, and vitamin D receptors have also been found in the human brain 8,9 .…”

Maternal Dietary Factors and the Risk of Autism Spectrum Disorders: A Systematic Review of Existing Evidence

“…Neonatal levels of Vitamin D level are dependent on maternal Vitamin D during pregnancy, reflecting 60-80% maternal Vitamin D level [Hollis, Johnson, Hulsey, Ebeling, & Wagner, 2011;Kiely, Hemmingway, & O'Callaghan, 2017;Marshall, Mehta, Ayers, Dhumal, & Petrova, 2016]; hence, studies examining neonatal levels were considered to meet our inclusion criteria of representing gestational exposures. We identified 11 studies evaluating maternal and/or neonatal biomarker-measured Vitamin D status in relation to ASD, including 4 prospective cohort studies (2 of these from the Generation R cohort) [Lopez-Vicente et al, 2019;Vinkhuyzen et al, 2017Vinkhuyzen et al, , 2018Whitehouse et al, 2013] and 7 case-control studies [Chen et al, 2016;Fernell et al, 2015;Lee et al, 2019;Schmidt, Niu, Eyles, Hansen, & Iosif, 2019;Windham et al, 2019;Wu et al, 2018].…”

“…Of these, 7 studies reported an inverse association between ASD-related outcomes in offspring and maternal (n = 4) and/or neonatal (n = 4) Vitamin D status according to continuous 25(OH)D or 25(OH)D3 levels (ranging from a 16 to 82% reduced risk [Chen et al, 2016;Lee et al, 2019;Schmidt, Niu, et al, 2019;Vinkhuyzen et al, 2017Vinkhuyzen et al, , 2018Whitehouse et al, 2013;Wu et al, 2018]. Of these studies reporting significant inverse associations, 3 defined Vitamin D deficiency as total 25(OH)D concentration <25 nmol/L, Vitamin D insufficiency as total 25(OH)D concentration 25 to <50 nmol/L, and Vitamin D sufficiency as total 25(OH)D concentration ≥50 nmol/L [Lee et al, 2019;Vinkhuyzen et al, 2017Vinkhuyzen et al, , 2018.…”

“…Only a handful of studies considered ASD outcomes according to both diagnosis and quantitative traits, as may help to inform strength of associations across the range of the autism spectrum [L. Gao, Cui, et al, 2016;Y. M. Li et al, 2018;Schmidt et al, 2011Schmidt et al, , 2012Schmidt et al, , 2014Schmidt, Niu, et al, 2019;Tan et al, 2020;Whitehouse et al, 2013]. Finally, while a number of studies considered certain other dietary factors that may influence associations in their analyses [Braun et al, 2014;Chen et al, 2016;House et al, 2018;Huang et al, 2020;Julvez et al, 2016;Y.…”