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RESEARCH ARTICLE

A novel inverse association between cord 25hydroxyvitamin D and leg length in boys up to three years. An Odense Child Cohort study Mathilde Egelund Christensen1,2, Signe Sparre Beck-Nielsen3,4, Christine Dalgård4,5, Søs Dragsbæk Larsen1,2, Sine Lykkedegn2, Henriette Boye Kyhl6,7, Steffen Husby2,6, Henrik Thybo Christesen1,2,6*

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1 Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, 2 Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark, 3 Department of Pediatrics, Kolding Hospital a part of Lillebaelt Hospital, Kolding, Denmark, 4 Department of Regional Health Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark, 5 Department of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark, 6 Odense Child Cohort, Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark, 7 Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Odense, Denmark * [email protected]

Abstract OPEN ACCESS Citation: Christensen ME, Beck-Nielsen SS, Dalgård C, Larsen SD, Lykkedegn S, Kyhl HB, et al. (2018) A novel inverse association between cord 25-hydroxyvitamin D and leg length in boys up to three years. An Odense Child Cohort study. PLoS ONE 13(6): e0198724. https://doi.org/10.1371/ journal.pone.0198724 Editor: Marly Augusto Cardoso, Universidade de Sao Paulo, BRAZIL Received: August 6, 2017 Accepted: May 24, 2018 Published: June 11, 2018 Copyright: © 2018 Christensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist.

Background and aim Long standing vitamin D deficiency in children causes rickets with growth impairment. We investigated whether sub-ischial leg length (SLL) is shorter, and cephalo-caudal length: length (CCL:L) ratio and sitting height:height (SH:H) ratio larger, with lower cord s-25-hydroxyvitamin D (25OHD) in the population-based prospective Odense Child Cohort, Denmark.

Methods We included healthy singletons born to term with available measures of cord 25OHD and anthropometrics up to three years’ age. Linear regression was stratified by sex a priori and adjusted for maternal ethnicity, pre-pregnancy body mass index and smoking during pregnancy, season of blood sampling and child age.

Results Median (IQR) cord 25OHD was 48.0 (34.0–62.4) nmol/L. At mean age 19.1 months, n = 504, mean (SD) SLL was 31.7 (1.7) cm; CCL:L-ratio 0.62 (0.01). At 36.3 months, n = 956, mean SLL was 42.9 (2.0) cm; SH:H-ratio 0.56 (0.01). No participants had rickets. In adjusted analyses, 19-months-old boys had 0.1 cm shorter SLL (p = 0.009) and 0.1% higher CCL:Lratio (p = 0.04) with every 10 nmol/L increase in cord 25OHD. Similar findings were seen for late pregnancy 25OHD. In the highest cord 25OHD quartile (>60.7 nmol/L), SLL was 0.8 cm shorter (95% C.I.: 1.36;-0.29, linear trend, p = 0.004), and CCL:L-ratio 0.8% higher (95% C. I. 8.0x10-05;0.01, linear trend, p = 0.01), compared to lowest quartile (