Date Published: June 11, 2018
Publisher: Public Library of Science
Author(s): Mathilde Egelund Christensen, Signe Sparre Beck-Nielsen, Christine Dalgård, Søs Dragsbæk Larsen, Sine Lykkedegn, Henriette Boye Kyhl, Steffen Husby, Henrik Thybo Christesen, Marly Augusto Cardoso.
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.
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.
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:L-ratio (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. 8.0×10-05;0.01, linear trend, p = 0.01), compared to lowest quartile (<30.7 nmol/L). Similar associations with cord 25OHD were observed in 3-year-old boys. No consistent associations between 25OHD and anthropometrics were seen in girls at either age. No leg shortening was found with decreasing cord s-25OHD in a healthy population of infants. A small, yet significant inverse association between cord 25OHD and SLL in boys 1½-3 years warrants further investigations.
Vitamin D is well known for its calciotropic effects being pivotal to bone mineralization and linear bone growth in children. Severe vitamin D deficiency in children manifests clinically as rickets characterized by mineralization failure of the growth plates and of the newly formed osteoid at the bone matrix . Rickets exerts a broad palette of symptoms including disturbed apoptosis of the chondrocytes leading to cartilage hyperplasia of the growth plates in the metaphyseal bone with widening of the growth zones at wrists, ankles and knees . Furthermore, long bone growth impairment and bowing of weight-bearing long bones may lead to disproportional linear growth with shortening of the sub-ischial leg length (SLL) and thereby an increased ratio of sitting height to height (SH:H). Hypovitaminosis D may be defined as vitamin D deficiency or insufficiency (serum-25-hydroxyvitamin D (25OHD) < 25 nmol/L and 25–50 nmol/L, respectively) , although the most appropriate cut points are still under debate [4, 5]. The existing cut-off limits are generated in terms of adult bone-health and the applicability to children remains unknown [4–8]. In pregnancy, an increase in the active vitamin D calcitriol (1,25(OH)2D) ensures calcium and phosphate supply to the foetus. In foetal life, parathyroid-hormone-related protein (PTHrP) is the primary regulator of the mineral homeostasis and bone mineralization, which in the foetus is independent of maternal vitamin D and occurs uncomplicated as long as sufficient calcium and phosphorous is supplied from the maternal circulation across the placenta. This transport is independent of active vitamin D [9, 10]. Maternal 25OHD crosses the placenta and, as the foetus has no endogenous synthesis of 25OHD, maternal vitamin D insufficiency during pregnancy implies vitamin D insufficiency in the new born. This leaves the infant more susceptible to developing vitamin D deficiency rickets if not receiving adequate vitamin D supplementation, as the lower inborn vitamin D stores will decrease to severely insufficient levels sooner in accordance with the half-life of 25OHD. OCC is an on-going prospective birth cohort recruiting pregnant women residing in the Municipality of Odense, Denmark, between January 1st 2010 and December 31st 2012 as earlier described in details . The present analyses included 2080 women and their singletons with available cord 25OHD analyses and anthropometric measures of the child at three months, 18 months and three years of age. We excluded preterm infants (born before gestational week 37+0) and singletons with severe congenital malformations or severe chronic diseases affecting growth (Fig 1). Of the 2549 OCC participants, we included 2010 (79%) children who were born at term and had available cord 25OHD samples and anthropometrics. Of these, 504 (21%) children (231 girls, 273 boys) had their SLL measured at the second follow-up visit at a mean (SD) age of 19.1 (0.9) months. SLL was measured in 956 children (39%; 455 girls, 501 boys) at the third follow-up at a mean age of 36.3 (0.8) months. Post hoc power calculation indicated an 80% probability of detecting an association between cord 25OHD and SLL, if SLL changed a minimum of 0.09 cm with every 10 nmol/Lchange in cord 25OHD. In our prospective population-based Danish cohort of healthy children, leg shortening was not observed with lower values of pregnancy or cord 25OHD. In contrast, a novel, significant association was identified between higher late pregnancy and cord 25OHD values and shorter SLL and larger CCL:L ratios in 19-months- and 3-years-old boys, but not in girls. Source: http://doi.org/10.1371/journal.pone.0198724