Alterations in the vitamin D endocrine system during pregnancy: A longitudinal study of 855 healthy Norwegian women

<div><p>To ensure optimal calcium accrual in the fetal skeleton, a substantial rise occurs in 1,25-dihydroxyvitamin D (1,25(OH)₂D), but is dependent on sufficient 25-hydroxyvitamin (25(OH)D). Large longitudinal studies addressing free 25(OH)D and 1,25(OH)₂D during pregnancy are scarce. We aimed to assess levels of and relationship between 25(OH)D, 1,25(OH)₂D, vitamin D-binding protein (DBP), parathyroid hormone (PTH), and free 25(OH)D during pregnancy; determinants of vitamin D status; and association between vitamin D indices or PTH and pregnancy outcomes (gestational diabetes mellitus and birthweight). Altogether 855 pregnant Norwegian Caucasian women from Trondheim and Stavanger (latitude 63°N and 58°N) were recruited; 94 were lost to follow-up. The study was originally a randomized controlled trial (2007–2009) with gestational diabetes as primary outcome. Data were collected in second and third trimester. In third trimester, 246 (34%) had vitamin D insufficiency and 52 (7%) deficiency (25(OH)D <50 and <30nmol/L, respectively). During wintertime in third trimester, 61 (47%) from Trondheim and 23 (51%) from Stavanger exhibited vitamin D insufficiency. PTH was elevated in 27 (3.7%). Estimate of change between trimesters was (95% CI): 25(OH)D -1.8 (-2.8 to -0.7) nmol/L, DBP 0.62 (0.57 to 0.66) μmol/L, calculated free 25(OH)D -1.7 (-2.0 to -1.4) pmol/L, PTH 0.81 (0.72 to 0.90) pmol/L, 1,25(OH)₂D (sub-analysis) 31.4 (CI 24.7 to 38.2) pmol/L. A decrease in 1,25(OH)₂D occurred in 45% of those with vitamin D deficiency, and they also exhibited lower levels than women with adequate vitamin D status. No association of vitamin D indices and PTH with pregnancy outcomes was observed. Women in Trondheim displayed lower 25(OH)D levels, despite minor latitudinal differences. Less than one-fifth adhered to the authorities’ vitamin D recommendations. These findings demonstrate that hypovitaminosis D is prevalent among pregnant women living in northern latitudes, especially during the dark season, and there is an unmet need to ensure adequate vitamin D intake.</p></div

Seasonal variation of serum measures in second trimester.

<p><b>(A)</b> Seasonal variation of serum total, free and bioavailable 25(OH)D, PTH and DBP in second trimester. <b>(B)</b> Seasonal variation of serum 1,25(OH)₂D in second trimester, in a sub-analysis including 250 women living in Trondheim, Norway. Solid squares represent women living in Trondheim, Norway (latitude 63°N) and grey dots represent women living in Stavanger, Norway (latitude 58°N). Vertical lines represent 95% confidence intervals. A multivariable linear regression analysis was used, and separate analyses were performed for second and third trimester. In analyses involving 1,25(OH)₂D, we used the pweight function in Stata to account for the sampling scheme (the inverse of the probability of an observation being selected into the sample). Abbreviations: PTH, parathyroid hormone; DBP, vitamin D-binding protein.</p

Adjusted serum values in second and third trimester, and estimates of change between trimesters.

<p>Adjusted serum values in second and third trimester, and estimates of change between trimesters.</p

Latitudinal differences between Trondheim, Norway (latitude 63°N) and Stavanger, Norway (latitude 58°N) in serum measures in second^* and third trimester^**.

<p>Latitudinal differences between Trondheim, Norway (latitude 63°N) and Stavanger, Norway (latitude 58°N) in serum measures in second^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195041#t005fn001" target="_blank">*</a>} and third trimester^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195041#t005fn002" target="_blank">**</a>}.</p

Baseline demographic and clinical characteristics of the study population^†.

<p>Baseline demographic and clinical characteristics of the study population<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195041#t001fn002" target="_blank">^†</a>.</p

Flow diagram of the study population.

<p>*Between 18 to 22 weeks of pregnancy. **Between 32 to 36 weeks of pregnancy. Abbreviations: DBP, Vitamin D-binding protein; PTH, parathyroid hormone.</p

Seasonal variation of serum measures in third trimester.

<p><b>(A)</b> Seasonal variation of serum total, free and bioavailable 25(OH)D, PTH and DBP in third trimester. <b>(B)</b> Seasonal variation of serum 1,25(OH)₂D in third trimester, in a sub-analysis including 250 women living in Trondheim, Norway. Solid squares represent women living in Trondheim, Norway (latitude 63°N) and grey dots represent women living in Stavanger, Norway (latitude 58°N). Vertical lines represent 95% confidence intervals. A multivariable linear regression analysis was used, and separate analyses were performed for second and third trimester. In analyses involving 1,25(OH)₂D, we used the pweight function in Stata to account for the sampling scheme (the inverse of the probability of an observation being selected into the sample). Abbreviations: PTH, parathyroid hormone, DBP, vitamin D-binding protein.</p

Vitamin D, calcium and fish intake in third trimester^*.

<p>Vitamin D, calcium and fish intake in third trimester^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0195041#t002fn002" target="_blank">*</a>}.</p

Additional file 1 of Serum and salivary inflammatory biomarkers in juvenile idiopathic arthritis—an explorative cross-sectional study

Additional file 1: Supplemental Table S1. Comorbidities and co-medication in the study groups. The table shows the number of individuals with co-existing health conditions and medication unrelated to juvenile idiopathic arthritis. It also shows the health conditions and medication of the control group