25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: A population-based prospective cohort study

Background: 25-hydroxyvitamin D (25[OH]D) concentrations during fetal life might have long-lasting effects on skeletal development, but results from previous studies are inconsistent. We investigated the associations of maternal and fetal 25(OH)D concentrations with childhood bone health.

Methods: In a prospective multiethnic population-based cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), pregnant women living in the study area with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible for participation in the study at our research centre in the Erasmus MC-Sophia Children's Hospital. We measured maternal 25(OH)D concentrations during mid-pregnancy (at a median of 20·4 weeks gestation [IQR 19·9-21·1]) and fetal 25(OH)D concentrations at birth (at a median of 40·1 weeks gestation [39·3-41·0]). We measured total-body bone mineral density, bone mineral content (BMC), area-adjusted BMC, and bone area using dual-energy X-ray absorptiometry (DXA) in offspring at 6 years of age. We examined associations using multivariable linear regression models, adjusted for several sociodemographic and lifestyle variables, and for child's height.

Findings: We enrolled 9901 mother-and-child pairs and obtained both mid-pregnancy maternal 25(OH)D concentrations and offspring DXA scans at age 6 years in 4815 pairs. Severe maternal 25(OH)D deficiency (<25 nmol/L) during mid-pregnancy was associated with higher offspring BMC (4·71 g, 95% CI 1·09 to 8·33; p=0·011) and larger bone area (7·54 cm2, 2·99 to 12·11; p=0·001) at age 6 years, compared with maternal 25(OH)D sufficiency (≥50 nmol/L) during mid-pregnancy. However, in a subgroup of children with available data on 25(OH)D concentrations at 6 years (n=3034), such associations for BMC (4·67 g, -0·05 to 9·39; p=0·052) and bone area (5·25 cm2, -0·41 to 10·91; p=0·069) were no longer significant after adjustment for the child's own 25(OH)D concentrations. No associations were seen between maternal 25(OH)D concentrations in mid-pregnancy and offspring bone mineral density (1·07 mg/cm2, -1·84 to 3·99; p=0·47) or area-adjusted BMC (-1·58 g, -4·72 to 1·61; p=0·32), and the association with skeletal parameters at 6 years did not differ by maternal BMI, maternal calcium intake, child sex, or weight status. Similar associations were seen with fetal 25(OH)D concentrations at birth.

Interpretation: We found inverse associations between 25(OH)D concentrations during fetal life with BMC and bone area in childhood, but these associations were no longer significant after adjustment for childhood 25(OH)D status. Our data suggest that 25(OH)D concentrations during childhood might be more relevant for bone outcomes than than 25(OH)D concentrations during fetal life. Funding: Erasmus University Medical Center, Organization for Health Research and Development (ZonMw), Organization for Scientific Research (NWO), the Ministry of Health, Welfare and Sport.