Does maternal vitamin D status influence placental weight or vascular and inflammatory pathology? Secondary analysis from the Kellogg Pregnancy Study

Abstract

Introduction: Positive effects of vitamin D (vitD) supplementation on comorbidities of pregnancy (COP) have been explored; however, few studies have elucidated the pathophysiology behind the development of these COP and the potential relationship with derangements in placental development and morphology. Additionally, it is known that placentas weighing 10th-90th % for gestational age are associated with better outcomes. Therefore, the objective of this study was to assess the impact of resulting circulating serum 25(OH)D concentrations associated with intake of high or low doses of supplementary vitD on placental development and morphology in women who participated in a randomized double blind, placebo-controlled trial of vitD supplementation. We hypothesized that if maternal serum 25(OH)D concentration (vitD status marker) is insufficient/deficient, then placental weight and % for gestational age (GA) will be smaller and will correlate with increased vascular and inflammatory placental pathologic findings.

Methods: The findings of the present study are a secondary analysis of data generated from a previously reported randomized controlled trial (RCT), the Kellogg Vitamin D Pregnancy Study. Pregnant women (n = 297) in this RCT (January 2013 - April 2018) were randomly assigned to 400 IU vs. 4400 IU vitD/day (10-14 weeks' gestational age) and followed to delivery. 132 placentas were analyzed by pathologists blinded to treatment, and the 2016 Amsterdam Consensus Criteria were used to categorize grouping/grading of placental pathology and weight. Total [25(OH)D] was measured using radioimmunoassay (ng/mL). Chi-square and Student's t-test were used to show the difference in maternal characteristics by treatment group and by placental weight. Chi-square analysis was used to determine differences between the percent pathology findings by treatment group. Students t-test was used to determine the differences in vitD status and the frequency of placental lesions. Association between [25(OH)D] area under the curve (AUC) and placental morphology were determined in a regression model that included maternal BMI ≥ 30 kg/m², race/ethnicity, and vitD treatment group allocation. Data were analyzed using SAS v9.4 (Cary, NC) and statistical significance was indicated by p < 0.05.

Results: The percent pathology findings by treatment group were not significantly different for each of the placental pathology categories as defined by the 2016 Amsterdam Consensus Criteria including placental weight. However, when using 25(OH)D as a biomarker for vitD status, linear regression model showed maternal serum [25(OH)D] AUC was significantly associated with greater placental weight (p = 0.023). Logistic regression models showed mothers with BMI ≥ 30 kg/m² had larger placental weight (p = 0.046), and Hispanic and white/Caucasian mothers had greater placental weights than Black American mothers (p = 0.025). When placentas ≥ 90th % for GA, n = 7, were removed from the placental pool, Pearson correlation still showed a positive association between maternal serum 25(OH)D AUC and placental weight (p = 0.011). In a second linear regression model of placentas ≥ 90th % for GA (n = 7) vs. placentas < 90th % (n = 108), maternal serum 25(OH)D AUC was significantly greater in those placentas ≥ 90th % (p = 0.03); however, this was not associated with increased perinatal mortality. CONCLUSION FINDINGS: suggest increasing maternal serum [25(OH)D] via vitamin D supplementation during pregnancy did not adversely affect placental morphology; trends showed those in the treatment group had fewer placental lesions. Placental weight was found to be significantly associated with [25(OH)D] AUC, which represents maternal vitamin D status over the course of pregnancy; 7 placentas ≥ 90th % for GA were not associated with perinatal mortality.

Keywords: 25-hydroxyvitamin D; Inflammation; Placenta; Placental weight; Pregnancy; Vitamin D.

Figure 1.

CONSORT Flow Diagram

Figure 2.

Gross placental anatomy

Figure 3.

Chi-square analysis was used to determine the potential difference in percent placental pathology findings by treatment group. Trends did not reach statistical significance. MVM: maternal vascular malperfusion FVM: fetal vascular malperfusion Chorio: acute chorioamnionitis VUE: villitis of unknown etiology DVM: delayed villous maturation NS: nonspecific

Figure 4.

Pearson correlation was used to show that maternal serum [25(OH)D] AUC (representing mean [25(OH)D] over the course of pregnancy) was positively correlated with placental weight (r=0.30; p=0.0009).

Figure 5A.

Student’s t-test was used to show difference s in mean placental weight and maternal baseline BMI ≥30kg/m². No significance was found by t-test (p=0.61); however, in regression analysis, the difference is significant (see Table 2).

Figure 5B.

ANOVA was used to show difference in mean placental weight among the races. *Indicates that Black American mothers have significantly smaller placental weights than white/Caucasian mothers (p=0.03).