ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This prospective cohort study measured day 3 serum calcium and 25OH vitamin D (25OHD) in 1002 mother-newborn pairs to establish reference ranges in vitamin D replete babies.

Calcium declines in the first days of life and is frequently measured in the neonatal nursery, not only for symptomatic newborns but also for conditions such as prematurity, low birth weight or maternal diabetes mellitus. French guidelines recommend an oral bolus of Vit D3 (100,000) at the 7^th month of pregnancy, and those not receiving or taking the prescribed dose were noted. These investigators had previously published serum total calcium levels in 1000 healthy neonates delivered at term, and measured at the same age; they published a normal range of 2.06 to 2.73 mmol/L (2.5–97.5 percentiles) – a much wider range than that seen in adults. Day 3 neonatal calcium levels in this previous study were not correlated with maternal vitamin D3 supplementation (mean ± SD with Vit D3: 2.45±0.16; without Vit D3: 2.46±0.16), although cord blood 25OHD was associated with day 3 neonatal calcium levels¹.

Calcium levels in both studies were measured using a colorimetric assay with an automated chemistry system (Ortho Clinical Diagnostics), and 25OH vitamin D by RIA (Diasorin, Stillwater, MN, USA) specific for 25OHD2 and 25OHD3. This study took the added step of dividing the cohort into those neonates with a serum 25OHD ≥ 30 nmol/L and those neonates with a serum 25OHD ≥ 50 nmol/L, and they excluded extreme outliers at both ends of the distributions defined by concentrations below quartile 1–1.5 x the interquartile range and above quartile 3+1.5 x interquartile range. This is a robust method to avoid skewing of data by outliers. This entailed removing 39 subjects from the total cohort (6 high, 33 low).

Mean ± SD (interquartile range) day 3 serum calcium was 2.46±0.13 mmol/L (0.19) in the entire cohort (N=963), and 2.50±0.13 (0.18) in neonates with 25OHD ≥ 50 nmol/L (n=208), the latter by the which the authors considered as a normal 25OHD level (although others argue ideally it should be ≥ 75 nmol/L)². The normal range was 2.25–2.75 mmol/L (2.5–97.5 percentile), thus increasing the lower limit significantly.

This study reminds us that normal maternal vitamin D status is essential to maintain newborn calcium levels. Recent Endocrine Society guidelines³ suggest that empirical supplementation during pregnancy is desirable to ensure vitamin D sufficiency, and has potential to lower risks of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age (SGA) birth, neonatal hypocalcemic seizures and neonatal mortality. Supplement doses and timing vary widely worldwide. In previous trials, vitamin D doses ranged from 600-5000 IU equivalent (15-125 μg) daily, given daily or weekly, or sometimes as a single large bolus as in France. Well defined neonatal calcium ranges should also help identify neonates who need additional investigations to detect unusual disorders (such as ionised calcium, serum phosphate, magnesium, intact PTH, 25OHD and possibly 1,25OHD, with urine calcium and creatinine) particularly in newborns without predisposing factors, such as prematurity, SGA, neonatal asphyxia and the maternal factors above.

References: 1. Levaillant L, Linglart A, Letamendia E, Boithias C, Ouaras-Lounis S, Thérond P, Lambert AS, Levaillant M, Souberbielle JC, Benachi A, Gajdos V. Serum calcium normal range in 1,000 term newborns. Horm Res Paediatr. Published online March 12, 2024. doi: 10.1159/000534042.2. Roizen JD, Shah V, Levine MA, Carlow DC. Determination of reference intervals for serum total calcium in the vitamin D-replete pediatric population. J Clin Endocrinol Metab. 2013;98(12): E1946-E1950. doi: 10.1210/jc.2013-3105.3. Demay MB, Pittas AG, Bikle DD, Diab DL, Kiely ME, Lazaretti-Castro M, Lips P, Mitchell DM, Murad MH, Powers S, Rao SD, Scragg R, Tayek JA, Valent AM, Walsh JME, McCartney CR. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2024 Jul 12;109(8):1907-1947. doi: 10.1210/clinem/dgae290.