Vitamin D Measured in Maternal Serum and Offspring Neurodevelopmental Outcomes: A Prospective Study with Long-Term Follow-Up

Abstract

Background: Vitamin D is obtained from dietary sources and synthesized in the skin during exposure to ultraviolet B radiation in sunlight. During pregnancy, vitamin D is transported from mother to fetus through the placenta in the form of 25-hydroxyvitamin D [25(OH)D]. There is evidence that vitamin D influences neuronal differentiation, endocrine functions, and fetal brain growth. Animal studies indicate alterations in the offspring brain as a consequence of vitamin D deficiency during pregnancy. In humans, maternal vitamin D insufficiency has been linked to impaired child language development. Using data from a prebirth cohort with up to 22 years of follow-up, we examined the association of vitamin D status with proxies of offspring neurodevelopmental outcomes. During 1988-1989, pregnant women were recruited for the DaFO88 cohort (n = 965) in Aarhus, Denmark. Maternal concentrations of 25(OH)D were quantified in serum from week 30 of gestation via the LC-MS/MS method (n = 850). Offspring were followed up through national registries until the age of 22 years. We evaluated the association of the maternal concentration of 25(OH)D with offspring neurodevelopmental outcomes defined as first admission diagnosis or prescription of medication for (1) ADHD, (2) depression, and (3) scholastic achievement based on the mean grade on standardized written examinations in the 9th grade (final exams after 10 years of compulsory school in Denmark). Key Messages: Maternal concentrations of 25(OH)D were higher compared to current levels (median 76 nmol/l; 5th to 95th percentiles 23-152). There was a direct association between maternal vitamin D status and offspring depression (p_trend = 0.01); for ADHD there was no association. Scholastic achievement was slightly higher for offspring of mothers with a vitamin D status in the range of >50-125 nmol/l, but this nonlinear association was not statistically significant. Conclusions: Our analyses based on biomarker measurement of 25(OH)D from a cohort of 850 pregnant women combined with long-term follow-up showed no support for a beneficial fetal programming effect of vitamin D status with regard to behavioral and affective disorders and scholastic achievement.

Newborn vitamin D levels in relation to autism spectrum disorders and intellectual disability: A case–control study in california

“…Although the recent study from the ALSPAC cohort in the United Kingdom found detrimental effects of maternal 25(OH)D deficiency on early developmental assessments, there was no association at later assessments, nor with IQ at age 8 years [Darling et al, ], consistent with an earlier study from the United Kingdom that found no association with IQ at age 9 years [Gale et al, ]. A study of cognitive outcomes in Danish adolescents in Grade 9 also concluded that there was little evidence of beneficial effects of gestational 25(OH)D levels, with similar levels as our study, e.g., median of 76 nmol/L [Strom et al, ]. An Australian study found no effects of gestational 25(OH)D levels on behavior/emotional problems measured by the Child Behavior Checklist at any of several child follow‐ups up to age 17, despite some effects on language impairment at ages 5 and 10 [Whitehouse et al, ].…”

“…Other studies with measured perinatal 25(OH)D levels have examined related neurobehavioral metrics, with several finding adverse outcomes associated with lower vitamin D levels [Darling et al, ; Hanieh et al, ; Morales et al, ; Vinkhuyzen et al, ; Whitehouse et al, ]. However, not all studies, including the one U.S. study [Keim, Bodnar, & Klebanoff, ], observed associations of prenatal (maternal serum or cord blood) 25(OH)D levels with IQ or other neurodevelopmental outcomes, especially when assessments were done at older ages [Gale et al, ; Strom et al, ].…”

Association of cord blood vitamin D with early childhood growth and neurodevelopment

“…Only seven other observational studies have explored vitamin D during pregnancy and child neurodevelopment related outcomes, with varying results likely due to differences in sample populations, exclusion criteria, analysis of 25(OH)D, timing of 25(OH)D samples, cut‐offs for categorical comparisons, choice of confounder variables, as well as method and age of child at developmental assessments. Two studies reported a positive association of 25(OH)D concentration and scores on the Bayley; however, as with our study, others have reported no association between 25(OH)D concentration during pregnancy and Bayley‐III scores (with the exception of language), or with other cognitive, behavioural or scholastic outcomes. Interestingly, one of the only two other studies to use cord blood at delivery found the highest quintile had lower motor scores …”

“…Vitamin D receptors are widely distributed throughout the human brain in most neurons and some glia, providing biological plausibility for the link between vitamin D and brain development and function. We are aware of seven observational studies that assessed the relationship between vitamin D during early, mid and late pregnancy, and/or cord blood at birth, and child cognitive, language and behavioural development with mixed results, although most studies used suboptimal assessments of vitamin D …”

Maternal and Foetal Health Implications of Vitamin D Status during Pregnancy

“…In a population-based registry study of 850 women and their children born in 1988-1989, Strom et al [77] found no indication that maternal 25(OH)D concentrations <50 nmol/L (20 ng/mL) versus ≥50-75 nmol/L (20-30 ng/mL; or higher) at gestational week 30 were associated with higher risk of attention deficit hyperactivity disorder (ADHD) disorder, defined as prescription of psychostimulant medication, among offspring during 22 years of follow-up. On the contrary, by analysing data from 1,650 mother-child pairs embedded in the INMA birth cohort in Spain, Morales et al [78] found that the number of ADHD-like symptoms in preschoolers aged 4-5 decreased by 11% per 10 ng/mL increment of maternal 25(OH)D3 at 13 weeks of gestation.…”