Post-hoc analysis of vitamin D status and reduced risk of preterm birth in two vitamin D pregnancy cohorts compared with South Carolina March of Dimes 2009-2011 rates

Abstract

Background: Two vitamin D pregnancy supplementation trials were recently undertaken in South Carolina: The NICHD (n=346) and Thrasher Research Fund (TRF, n=163) studies. The findings suggest increased dosages of supplemental vitamin D were associated with improved health outcomes of both mother and newborn, including risk of preterm birth (<37 weeks gestation). How that risk was associated with 25(OH)D serum concentration, a better indicator of vitamin D status than dosage, by race/ethnic group and the potential impact in the community was not previously explored. While a recent IOM report suggested a concentration of 20 ng/mL should be targeted, more recent work suggests optimal conversion of 25(OH)D-1,25(OH)2D takes place at 40 ng/mL in pregnant women.

Objective: Post-hoc analysis of the relationship between 25(OH)D concentration and preterm birth rates in the NICHD and TRF studies with comparison to Charleston County, South Carolina March of Dimes (CC-MOD) published rates of preterm birth to assess potential risk reduction in the community.

Methods: Using the combined cohort datasets (n=509), preterm birth rates both for the overall population and for the subpopulations achieving 25(OH)D concentrations of ≤20 ng/mL, >20 to <40 ng/mL, and ≥40 ng/mL were calculated; subpopulations broken down by race/ethnicity were also examined. Log-binomial regression was used to test if an association between 25(OH)D serum concentration and preterm birth was present when adjusted for covariates; locally weighted regression (LOESS) was used to explore the relationship between 25(OH)D concentration and gestational age (weeks) at delivery in more detail. These rates were compared with 2009-2011 CC-MOD data to assess potential risk reductions in preterm birth.

Results: Women with serum 25(OH)D concentrations ≥40 ng/mL (n=233) had a 57% lower risk of preterm birth compared to those with concentrations ≤20 ng/mL [n=82; RR=0.43, 95% confidence interval (CI)=0.22,0.83]; this lower risk was essentially unchanged after adjusting for covariates (RR=0.41, 95% CI=0.20,0.86). The fitted LOESS curve shows gestation week at birth initially rising steadily with increasing 25(OH)D and then plateauing at ∼40 ng/mL. Broken down by race/ethnicity, there was a 79% lower risk of preterm birth among Hispanic women with 25(OH)D concentrations ≥40 ng/mL (n=92) compared to those with 25(OH)D concentrations ≤20 ng/mL (n=29; RR=0.21, 95% CI=0.06,0.69) and a 45% lower risk among Black women (n=52 and n=50; RR=0.55, 95% CI=0.17,1.76). There were too few white women with low 25(OH)D concentrations for assessment (n=3). Differences by race/ethnicity were not statistically significant with 25(OH)D included as a covariate. Compared to the CC-MOD reference group, women with serum concentrations ≥40 ng/mL in the combined cohort had a 46% lower rate of preterm birth overall (n=233, p=0.004) with a 66% lower rate among Hispanic women (n=92, p=0.01) and a 58% lower rate among black women (n=52, p=0.04).

Conclusions: In this post-hoc analysis, achieving a 25(OH)D serum concentration ≥40 ng/mL significantly decreased the risk of preterm birth compared to ≤20 ng/mL. These findings suggest the importance of raising 25(OH)D levels substantially above 20 ng/mL; reaching 40 ng/mL during pregnancy would reduce the risk of preterm birth and achieve the maximal production of the active hormone.

Keywords: Cholecalciferol; March of Dimes; Pregnancy health outcomes; Preterm birth; Vitamin D.

Figure 1. 25(OH)D concentration within 6 weeks of delivery by gestational age (weeks) at birth (NICHD & TRF, N=509)

Term birth is ≥37 weeks of gestation; late preterm birth is 34 to <37 weeks; moderately preterm is 32 to <34 weeks; and very preterm is <32 weeks. White circles represent women assigned to the control group (400 IU/day); gray triangles represent women assigned to the 2000 IU/day treatment group; and solid black squares represent women assigned to the 4000 IU/day treatment group. Black line represents fitted LOESS curve.

Figure 2. Zoom on the fitted LOESS curve of 25(OH)D concentration and gestational age (weeks) at birth to better show the change in average behavior with 1 and 2 SD windows superimposed (NICHD & TRF, N=509)

Black line represents fitted LOESS curve; dark gray area represents 1 standard deviation; and light gray area represents 2 standard deviations. Multivariable log-binomial regression found that 25(OH)D concentrations ≥40 ng/mL reduces the risk of preterm birth by 59% compared to ≤20 ng/mL, adjusted for covariates.

Figure 3. Comparison of preterm birth rates for Charleston County, South Carolina March of Dimes (CC-MOD) vs. NICHD & TRF combined cohort

CC-MOD rates are the published average percent of preterm births among live births for 2009-2011 in Charleston County, South Carolina; 25(OH)D concentrations unknown (15). Combined cohort includes participants from 2 studies conducted in South Carolina (10, 12). Percent lower risk and p-value between CC-MOD and combined cohort with 25(OH)D ≥40 ng/mL.