Vitamin D requirements in preterm infants
It is accepted that an infant’s vitamin D status at birth is completely dependent on maternal status. However, the definition of healthy vitamin D status during pregnancy, typically indicated by circulating concentrations of 25-hydroxyvitamin D (25(OH)D), has been challenged by a lack of data from well-powered, well-controlled trials in pregnant women. Despite the publication of many systematic reviews of the role of vitamin D supplementation during pregnancy, there is insufficient evidence that physiological requirements for 25(OH)D are higher during pregnancy than in non-pregnant adults. At the same time, there is evidence for a high prevalence of low vitamin D status during pregnancy, the burden of which is disproportionately borne by women of ethnic minority (Saraf et al., Matern Child Nutr 2015). Prevention of low vitamin D status (25(OH)D < 30 nmol/L at minimum) is required to prevent metabolic bone diseases such as nutritional rickets and osteomalacia, which have severe and lasting consequences for bone growth and skeletal integrity throughout life. The prevalence of low vitamin D status among newborn infants is common; in Ireland where there is no maternal vitamin D supplementation policy, 35% of >1,000 umbilical cord sera had 25(OH)D < 25 nmol/L (Kiely et al., J Ste- roid Biochem Mol Biol. 2017). (Fig. 1) Thus, prevention of infantile 25(OH)D (reflected in umbilical cord sera) <25 nmol/L has been proposed as a potential target for protection of the fetal/infant skeleton (Kiely et al., Ther Adv Musculoskelet Dis. 2017). O’Callaghan et al. (Am J Clin Nutr. 2018) reported the first dose-response study in pregnant women to address the question of how much vitamin D would prevent cord 25(OH)D < 25 nmol/L. When maternal 25(OH)D concentrations were > 50 nmol/L during the 3rd trimester, cord sera were > 25 nmol/L at delivery. The vitamin D3 intake required to maintain maternal 25(OH)D > 50 nmol/L among almost all mothers (97.5%) was 30 µg/day.
In an elegant dose-response randomised controlled trial (RCT) among infants from <1 month to 12 months, Gallo et al. (JAMA 2013) (Fig. 2) reported that 10 µg/day of vitamin D3 maintained 97% of infant 25(OH) D concentrations >50 nmol/L, with no advantages to vitamin D status or bone mineral density of higher doses (20, 30 and 40 µg/day). In fact, the 40 µg/day dose increased the risk of hypercalcemia and was discontinued during the trial. Following this study, there has been broad agreement between regulatory authorities around the world with respect to recommendations for vitamin D during infancy, which are typically set at around 10 µg/day (400 IU), a safe intake which maintains serum 25(OH)D > 30 nmol/L and is consistent with rickets prevention (Munns et al., J Clin Endocrinol Metab 2016). Recommendations for children >1 year and adults vary and are typically ~10-25 µg/day (400-1,000 IU).
Preterm infants have a higher vulnerability to very low vitamin D status
than term babies. Burris et al. (Paediatr Res 2014) compared 25(OH)D between term infants and preterms born < 32 weeks and between 32 and <37 weeks of gestation and found that the distribution of 25(OH) D was lower and the prevalence of 25(OH)D < 50 nmol/L was higher among babies born <32 weeks. The maternal transfer of 25(OH)D
across the placenta appears to be lower earlier in gestation (Kassai et al., BMC Pregnancy and Childbirth 2018), who reported a lower correlation between maternal and cord 25(OH)D among preterm than term dy- ads. Berry et al. (PLoS ONE 2017) compared international vitamin D re- commendations among healthy term and preterm infants and identified variability in recommendations between 5 g (200 IU) and 25 g (1,000 IU) per day to reach target 25(OH)D concentrations of 50-80 nmol/L for bone and non-skeletal effects. Several dose response studies of vita- min D among preterm infants have been described. Natarajan et al. (Pediatrics 2014) randomised 96 infants at 28 to 34 weeks of gestation to two different doses of vitamin D and reported a prevalence of 25(OH)D < 50 nmol/L of 67% in the 400 IU group vs 38% in those receiving 800 IU/day. Similarly, Fort et al. (J Pediatr 2016) conducted a dose-response study among 100 infants of 23 to 26 (+ 6 days) gestation equivalent to a daily dose of 200, 400 or 1,000 IU/day when routine feeding was accounted for. At birth, 67% of infants had 25(OH)D < 50 nmol/L; by postnatal day 28, 41% of those in the 200
IU group, 16% receiving 400 IU and 0% in the 800 IU group were < 50 nmol/L. No adverse outcomes in these studies were attributable to the supplementation regime (Fig. 3). In Nebraska, 32 infants born at 24–32 weeks’ gestation were randomized to receive 400 or 800 IU/day vitamin D3 in addition to their usual dietary supply (Berry et al., PLoS ONE 2017). Briefly, infants in the 800 IU group achieved higher 25(OH)D; only 4 babies between the two groups did not reach 50 nmol/L and there was no evidence of adverse effects, even among infants <1,200 g who responded similarly to their large counterparts.
While these studies were not powered to compare health outcomes, there is evidence between them that doses up to 1,000 IU/day are tolerated well. In Ankara, Bozkurt et al. (Early Human Development 2017) randomised 121 infants, gestational age of 24–32 weeks, to receive 400, 800 or 1,000 IU/d vitamin D. 25(OH)D increases were dose related in the 3 groups, and by 36 weeks post-menstrual age, 22.5, 10 and 2.5% were <
50 nmol/L of 25(OH)D in the 3 groups, respectively. Further, there was a significant decrease in PTH concentrations in the 1,000 IU group, with not additional health benefits. (Fig. 4)
Take home messages
For the prevention of very low vitamin D status at birth
(25(OH)D <25 nmol/L or 10 ng/mL), provide 1,200 IU/day (30 g/d) of vitamin D3 for pregnant women.
Vitamin D status is lower among preterm infants than term infants and the association between maternal and cord 25(OH)D is weaker in preterm infants.
Recommendations for vitamin D in preterm infants vary between 400IU & 1,000IU/day around the world but dose response studies conducted since recommendations were published show that 400 IU is effective at raising 25(OH)D > 50 nmol/L (20 ng/mL) in most infants but not all.
Some studies show that 800-1,000IU delivers very high
25(OH)D without evidence of toxicity. Recommendations are to conduct larger, well-controlled RCTs among preterm infants, with care to the study design, sample size and controls.
The use of heterogenous populations including stratification for GA as well as body size is encouraged. It is important to measure and include an estimate of the background vitamin D, calcium and phosphate availability and to use gold standard
LC-MS/MS analysis where possible, accounting for vitamin
D metabolites, which are variable in neonates and confound much of the analytical data available.