**6.2 Birth anthropometry, small-for-gestational-age (SGA), and childhood growth**

There is controversy regarding the relationship between maternal vitamin D status and neonatal birth weight, with some studies reporting an association between reduced maternal vitamin D levels and lower neonatal birth weight [169–174], and others showing no association [175–178]. While some studies found no association between maternal vitamin D levels and other anthropometric birth outcomes such as length and head circumference [176–179], others suggested a nonlinear relation between 25(OH)D levels and head circumference [171, 174].

Inconsistencies in the literature have led several researchers to conduct meta-analyses to further clarify the association between maternal vitamin D concentrations and anthropometric outcomes in offspring. Four meta-analyses of observational studies have been published in recent years [45, 52, 180, 181]. In

*Vitamin D Deficiency*

like pregnancy [126]. Pregnant women who live in southern Europe have more pigmented skin, probably with less efficient vitamin D synthesis [145]. In Italy, vitamin D deficiency of pregnant women (with different ethnic groups) was examined based on their skin color (fair, black, light brown). It was found that 22% had severe vitamin D deficiency (<25 nmol/L) in total and fair-skinned mothers had higher 25(OH)D concentrations [146]. Another study in Netherland observed several ethnic backgrounds who reside in The Hague in the Netherlands (52°N), that vitamin D deficiency is more common among most non-Western participants (dark-skinned) (59–84%) compare to western women (fair-skinned) (8%) [147]. In southwestern Sweden, vitamin D deficiency was examined among pregnant women from different backgrounds with various skin colors. The prevalence of vitamin D deficiency was 10% overall, and 2% among mothers born in north Europe, while vitamin D deficiency among women born in Africa was 50% (<30 nmol/L) and deficiency was common among Asian mothers as well [148]. A recent US study reported in the multi-ethnic population of pregnant women in the southeastern USA, non-Hispanic black pregnant women are most at risk for vitamin D insufficiency (91%) compare to non-Hispanic white women (47%) and Hispanic women (75%) [149]. The concentration of melanin in the skin determines vitamin D production. Melanin, which absorbs UV-B in the 290–320 nm range, functions as a light filter and therefore regulates the proportion of the vitamin D production [150]. Thus, skin pigmentation is a dominant variable controlling the production of vitamin D under circumstances of low levels of sun exposures because melanin absorbs UV photons in competition with 7-dehydrocholesterol [151, 152]. Overall, darker-skinned pregnant women need a greater duration of sun exposure (4–5 times) (they are more at risk in higher latitudes) in comparison to light-skinned

ones to provide a comparable amount of vitamin D [153].

of fetal and postnatal outcomes.

**6.1 Fetal skeletal development**

bone mineral accrual.

**6. Maternal vitamin D status and fetal and postnatal outcomes**

A growing body of evidence suggests that maternal vitamin D deficiency is associated with not only pregnancy outcomes, but also later physical and mental health of the offspring. In this section, we aim to review the existing literature investigating the impact of maternal vitamin D status during pregnancy on a range

During pregnancy, the fetus relies on maternal supply and placental delivery of vitamin D and calcium for optimal development and function, particularly of the skeletal system [154]. Maternal vitamin D deficiency during pregnancy predisposes breast-fed infants to neonatal hypocalcemia and infantile rickets [155, 156]. It has been reported that maternal UV-B exposure in pregnancy is related to bone mineral content (BMC) and bone mineral density (BMD) at age 9.9 years independently of height and lean mass [157]. Further, winter newborns in Korea were found to have 6% lower total body BMC, lower cord serum 25(OH)D and 1,25-dihydroxyvitamin D than summer newborns [158]. These results suggest that low maternal vitamin D concentrations due to limited UV-B exposure may exert direct effects on offspring

The influence of maternal vitamin D status on bone outcomes has been investigated in several observational studies at fetal [159–161], postnatal [162–164], and adult stages [115, 165–167]. Using data from a prospective longitudinal study, Mahon et al. observed that lower maternal 25(OH)D concentration was associated with the

**44**

the first study, Wei et al. carried out a meta-analysis on six studies and found that pregnant women with circulating 25(OH)D levels less than 50 nmol/L experienced an about 1.5-fold increased risk of SGA [45]. These results were confirmed in another meta-analysis of 13 prospective cohort studies, in which a significant positive association was found between maternal vitamin D deficiency and risk of SGA infants (pooled odds ratio 1.58; 95% CI 1.14–2.22) in the random effects model [180]. Similar results were obtained in subgroup analyses by study quality (high vs. low), gestational week for blood sampling (first trimester vs. second trimester vs. mixed), cut-off vitamin D levels (<10 ng/mL vs. <15 ng/mL vs. <20 ng/mL), sample size (N > 1000 vs. N < 1000), adjustment for critical confounders (Yes vs. No), and method for measuring vitamin D (liquid chromatography with tandem mass spectrometry vs. others) [180]. There results suggest that maternal vitamin D deficiency may be associated with an increased risk of SGA infants.

A meta-analysis conducted in 2013 showed that insufficient serum levels of 25(OH)D in pregnant women was associated with increased risk of having SGA infants (pooled odds ratio 1.85; 95% CI 1.52–2.26) [52]. In terms of birth weight, the authors used data from four observational studies and found infants of mothers with low 25(OH)D concentrations during pregnancy (<37.5 nmol/L) had lower birth weight (random weighted mean difference −130.9 g). However, no significant difference was observed between maternal vitamin D status and other anthropometric outcomes such as birth length and head circumference [52]. The most recent meta-analysis conducted by Tous et al. included 54 eligible studies and reported that vitamin D-deficient mothers (<30 nmol/L) had offspring with lower birth-weight (mean difference −87.82 g), head circumference (mean difference −0.19 cm), and a higher risk of SGA infants (odds ratio 1.59; 95% CI 1.24–2.03) compared to mothers with concentrations ≥30 nmol/L. However, no difference was observed in terms of infants' length [181]. The results also revealed a significant association between vitamin D insufficiency (<50 nmol/L) and increased risk of SGA (odds ratio 1.43; 95% CI 1.08–1.91). The authors found no significant differences in birth-weight and SGA between offspring born to mothers with 25(OH)D concentrations <75 nmol/L and those born to mothers with 25(OH)D concentrations ≥75 nmol/L [181]. Further, a meta-analysis of 13 interventional studies revealed that vitamin D supplementation during pregnancy was associated with significantly higher circulating 25(OH)D levels (mean difference: 66.5 nmol/L), birth weight (mean difference: 107.6 g), and birth length (mean difference: 0.3 cm), when compared to the control group [182]. Neonates exposed to low levels of vitamin D *in utero* (<30 nmol/L) showed accelerated growth in length and weight during the first year of life to compensate for their small initial size [183, 184]. There results suggest that maternal vitamin D deficiency is associated not only with increased risk of SGA infants but also with lower birth-weight. However, more studies are required to draw a firm conclusion on the relationship between maternal vitamin D status and other anthropometric outcomes.
