Vitamin D supplementation for cardiometabolic risk markers in pregnant women based on the gestational diabetes mellitus or obesity status : a randomized clinical trial.

PURPOSE: Women with gestational diabetes mellitus (GDM) or obesity are vulnerable to impaired gestational cardiovascular health (CVH) and cardiovascular disease (CVD) in the future. It is unclear if prenatal vitamin D supplementation improves gestational CVH, especially in women at high risk for developing CVD. Our goal was to find out if vitamin D supplementation could protect against gestational CVH, including the women with GDM or obesity. DESIGN: We randomly assigned women with a serum 25(OH)D concentration < 75 nmol/L to receive 1600 IU/d (intervention group) or 400 IU/d (control group) of vitamin D3 for two months at 24-28 weeks' gestation. The primary outcome was gestational CVH marks (lipids, inflammatory cytokines, endothelial function). RESULTS: There were 1537 participants divided into the intervention (N = 766) and control groups (N = 771). No baseline differences existed among study groups in CVH markers. At the two-month visit, the intervention group's HDL-C levels (2.01 ± 0.39 VS 1.96 ± 0.39 mmol/L) were significantly higher than those of the control group, while the hs-CRP levels were significantly lower (3.28 ± 2.02 VS 3.64 ± 2.42 mg/L). Subgroup analysis found that HDL-C, TC, hs-CRP, E-Selectin, and SBP were improved in the intervention group among women with GDM or overweight/obesity, and the improvement was not found in women without GDM or overweight/obesity. Vitamin D supplementation significantly decreased the mean triglyceride-glucose index at the two-month visit in women with GDM. CONCLUSIONS: Vitamin D supplementation at mid-gestation might optimize the gestational CVH status for pregnant women, particularly the women with GDM or obesity, which is advantageous for later-life primary prevention of CVD. CLINICAL TRIAL REGISTRATION: The Chinese Clinical Trial Registry (ChiCTR2100051914, 10/9/2021, Prospective registered, https://www.chictr.org.cn/showproj.aspx?proj=134700 ).

The role of parathyroid hormone during pregnancy on the relationship between maternal vitamin D deficiency and fetal growth restriction: a prospective birth cohort study.

Previous studies have shown conflicting findings regarding the relationship between maternal vitamin D deficiency (VDD) and fetal growth restriction (FGR). We hypothesised that parathyroid hormone (PTH) may be an underlying factor relevant to this potential association. In a prospective birth cohort study, descriptive statistics were evaluated for the demographic characteristics of 3407 pregnancies in the second trimester from three antenatal clinics in Hefei, China. The association of the combined status of vitamin D and PTH with birth weight and the risk of small for gestational age (SGA) was assessed by a multivariate linear and binary logistic regression. We found that declined status of 25-hydroxyvitamin D is associated with lower birth weight (for moderate VDD: adjusted ß = -49·4 g, 95 % CI -91·1, -7·8, P < 0·05; for severe VDD: adjusted ß = -79·8 g, 95 % CI -127·2, -32·5, P < 0·01), as well as ascended levels of PTH (for elevated PTH: adjusted ß = -44·5 g, 95 % CI -82·6, -6·4, P < 0·05). Compared with the non-VDD group with non-elevated PTH, pregnancies with severe VDD and elevated PTH had the lowest neonatal birth weight (adjusted ß = -124·7 g, 95 % CI -194·6, -54·8, P < 0·001) and the highest risk of SGA (adjusted risk ratio (RR) = 3·36, 95 % CI 1·41, 8·03, P < 0·01). Notably, the highest risk of less Ca supplementation was founded in severe VDD group with elevated PTH (adjusted RR = 4·67, 95 % CI 2·78, 7·85, P < 0·001). In conclusion, elevated PTH induced by less Ca supplementation would further aggravate the risk of FGR in pregnancies with severe VDD through impaired maternal Ca metabolism homoeostasis.

Prenatal Exposure to Air Pollution and Pre-Labor Rupture of Membranes in a Prospective Cohort Study: The Role of Maternal Hemoglobin and Iron Supplementation.

BACKGROUND: Exposure to air pollution in prenatal period is associated with prelabor rupture of membranes (PROM). However, the sensitive exposure time windows and the possible biological mechanisms underlying this association remain unclear. OBJECTIVE: We aimed to identify the sensitive time windows of exposure to air pollution for PROM risk. Further, we examined whether maternal hemoglobin levels mediate the association between exposure to air pollution and PROM, as well as investigated the potential effect of iron supplementation on this association. METHOD: From 2015 to 2021, 6,824 mother-newborn pairs were enrolled in the study from three hospitals in Hefei, China. We obtained air pollutant data [particulate matter (PM) with aerodynamic diameter ≤2.5µm (PM2.5), PM with aerodynamic diameter ≤10µm (PM10), sulfur dioxide (SO2), and carbon monoxide (CO)] from the Hefei City Ecology and Environment Bureau. Information on maternal hemoglobin levels, gestational anemia, iron supplementation, and PROM was obtained from medical records. Logistic regression models with distributed lags were used to identify the sensitive time window for the effect of prenatal exposure to air pollutant on PROM. Mediation analysis estimated the mediated effect of maternal hemoglobin in the third trimester, linking prenatal air pollution with PROM. Stratified analysis was used to investigate the potential effect of iron supplementation on PROM risk. RESULTS: We found significant association between prenatal exposure to air pollution and increased PROM risk after adjusting for confounders, and the critical exposure windows of PM2.5, PM10, SO2 and CO were the 21th to 24th weeks of pregnancy. Every 10-µg/m3 increase in PM2.5 and PM10, 5-µg/m3 increase in SO2, and 0.1-mg/m3 increase in CO was associated with low maternal hemoglobin levels [-0.94g/L (95% confidence interval (CI): -1.15, -0.73), -1.31g/L (95% CI: -1.55, -1.07), -2.96g/L (95% CI: -3.32, -2.61), and -1.11g/L (95% CI: -1.31, -0.92), respectively] in the third trimester. The proportion of the association between air pollution and PROM risk mediated by hemoglobin levels was 20.61% [average mediation effect (95% CI): 0.02 (0.01, 0.05); average direct effect (95%): 0.08 (0.02, 0.14)]. The PROM risk associated with exposure to low-medium air pollution could be attenuated by maternal iron supplementation in women with gestational anemia. CONCLUSIONS: Prenatal exposure to air pollution, especially in the 21st to 24th weeks of pregnancy, is associated with PROM risk, which is partly mediated by maternal hemoglobin levels. Iron supplementation in anemia pregnancies may have protective effects against PROM risk associated with exposure to low-medium air pollution. https://doi.org/10.1289/EHP11134.

Maternal 25(OH)D attenuates the relationship between ambient air pollution during pregnancy and fetal hyperinsulinism.

Inflammatory responses have been demonstrated to link air pollution with insulin resistance and type 2 diabetes in adults. However, few studies have focused on the relationship between prenatal air pollution and fetal ß-cell function and the mediating effect of systematic inflammation remains elusive. Whether the anti-inflammatory effect of vitamin D could attenuate the ß-cell dysfunction in early life warrants further investigations. We aimed to determine whether maternal blood 25(OH)D attenuates the associations of ambient air pollution during pregnancy with fetal hyperinsulinism mediated by maternal inflammatory response. A total of 8250 mother-newborn pairs were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean air pollution exposure to fine particles (PM2.5 and PM10), SO2, and CO was estimated across pregnancy. Maternal serum samples in the third trimester were used to measure the high-sensitivity c-reactive protein (hs-CRP) and 25(OH)D. Cord blood samples at delivery were collected for the measurement of C-peptide. Fetal hyperinsulinism was based on cord C-peptide >90th centile. An increased fetal hyperinsulinism risk was associated with per 10 µg/m3 increase in PM2.5 [odds ratios (OR): 1.45 (95% confidence interval (CI):1.32, 1.59)], per 10 µg/m3 increase in PM10 [OR = 1.49 (95% CI:1.37, 1.63)], per 5 µg/m3 increase in SO2 [OR = 1.91 (95% CI: 1.70, 2.15)], and per 0.1 mg/m3 increase in CO [OR = 1.48 (95% CI:1.37, 1.61)] across pregnancy. Mediation analysis showed a 16.3% contribution of maternal hsCRP to the relationship between air pollution throughout pregnancy and fetal hyperinsulinism. Air pollution-associated higher levels of hsCRP and risk of fetal hyperinsulinism could be attenuated by higher maternal 25(OH)D levels. Prenatal ambient air pollution exposures were associated with an increased fetal hyperinsulinism risk mediated by maternal serum hsCRP. Higher antenatal 25(OH)D levels could attenuate air pollution-induced inflammatory responses and hyperinsulinism risk.

Previous pregnancy loss and gestational cardiovascular health: A prospective cohort of nulliparous women.

Objectives: To estimate the association of previous pregnancy loss with subsequent cardiovascular health during gestation and to examine the role of high-sensitivity C reactive protein (hs-CRP) in the association. Methods: A total of 2,778 nulliparous pregnant women were recruited between March 2015 and November 2020 in Hefei city, China. Their cardiovascular health (CVH) including prepregnancy body mass index (BMI), blood pressure, total cholesterol, fasting plasma glucose, and smoke status were recorded at 24-28 weeks' gestation, as well as their reproductive history. Multivariate linear and logistic regression were performed to examine the association of pregnancy loss with cardiovascular health. And the role of hs-CRP between pregnancy loss and CVH was assessed by the mediation analysis. Results: Compared with women who have no pregnancy loss, women with a history of spontaneous or induced abortions had higher BMI (ß, 0.72, 95% CI, 0.50 to 0.94) and fasting plasma glucose (ß, 0.04, 95% CI, 0.01 to 0.07), and had lower total CVH scores after adjusting for confounders (ß, -0.09, 95% CI, -0.18 to -0.01). CVH scores were most significantly decreased among women with 3 or more induced abortions (ß, -0.26, 95% CI, -0.49, -0.02). The contribution of pregnancy loss to poorer gestational CVH mediated by increased hs-CRP levels was 23.17%. Conclusion: Previous pregnancy loss was associated with poorer cardiovascular health during gestation, which may be mediated by their gestational inflammatory status. Exposure to miscarriage alone was not a significant predictor of poorer CVH.

Adequate 25(OH)D moderates the relationship between dietary inflammatory potential and cardiovascular health risk during the second trimester of pregnancy.

Background: Pro-inflammatory diets play an important role in developing cardiovascular disease (CVD). Vitamin D has been demonstrated to have an anti-inflammatory effect and promote cardiovascular health (CVH). However, it is unclear whether adequate vitamin D during pregnancy protects against poor CVH caused by pro-inflammatory diets. Objective: To investigate the association of pro-inflammatory diets with the cardiovascular risk (CVR) among pregnant women and whether such association was modified by vitamin D status. Methods: The study was based on a prospective birth cohort that included 3,713 pregnant women between 16 and 23 gestational weeks. In total, 25(OH)D concentrations and high-sensitivity C-reactive protein (hs-CRP) were measured from the collected blood. The dietary inflammatory potential was evaluated using the empirical dietary inflammatory pattern (EDIP) score based on a validated food frequency questionnaire. Gestational CVR was evaluated using the CVR score based on five "clinical" CVR metrics, including body mass index, blood pressure, total cholesterol, glucose levels, and smoking status. Results: The proportion of women with a CVR score >0 was 54.3%. We observed a positive association between the EDIP score and CVR score. Compared with the lowest quartile, the CVR score (ß = -0.114, 95% CI, -0.217, -0.011) and hs-CRP levels (ß = -0.280, 95% CI, -0.495, -0.065) were lower in the highest quartile (P for trend <0.05). Increased CVR connected with high EDIP score was observed only in women with 25(OH)D concentrations <50 nmol/L (RR = 1.85; 95% CI: 1.35, 2.54). Mediation analysis revealed that the proportion of association between the EDIP score and CVR score mediated by 25(OH)D was 28.7%, and the proportion of the association between 25(OH)D and the CVR score mediated by hs-CRP was 21.9%. Conclusion: The higher dietary inflammatory potential was associated with an increased CVR during pregnancy by promoting inflammation. Adequate vitamin D could exert anti-inflammatory effects and modify such association.

Sleep patterns modify the association of 25(OH)D with poor cardiovascular health in pregnant women.

Background: The relationship between vitamin D status and gestational cardiovascular health (CVH) is inconsistent in previous studies. Emerging evidence shows that sleep behaviors are related to vitamin D metabolism. However, no studies evaluate the interaction of vitamin D and sleep behaviors on gestational CVH. Objective: We aimed to estimate the relationship between 25-hydroxyvitamin D [25(OH)D] concentrations and gestational CVH, and whether the relationship was modified by sleep behaviors. Methods: The data of this study was from a multicenter birth cohort study. A total of 9,209 pregnant women at 16-23 weeks of gestation were included. 25(OH)D concentrations were measured from collected blood. Sleep patterns consisted of major sleep behaviors including duration, chronotype, insomnia, snoring, and excessive daytime sleepiness. Data on poor CVH was based on four "clinical" CVH metrics, including body mass index, blood pressure, total cholesterol, and glucose levels. Results: The proportion of women with poor CVH was 25.0%. The relative risk (RR) (95%CI) of poor CVH was 0.67 (0.58-0.76) in women with 25(OH)D ≥ 50 nmol/L after multivariate adjustments. Lower 25(OH)D concentrations were significantly associated with poor CVH. Such association was also evident in subgroups analysis. We found a significant interaction of 25(OH)D (P for interaction = 0.01) with sleep patterns on the risk of poor CVH. A negative dose-response relation was observed between 25(OH)D concentrations and poor CVH risk in healthy or intermediate sleep, not poor sleep. 25(OH)D concentrations were lower and the risk of poor CVH was higher in pregnant women with poor sleep patterns (P < 0.05). Conclusion: Our study suggests that sleep patterns modify the association of 25(OH)D concentrations with the CVH among pregnant women.

Associations of cord blood meta-inflammation and vitamin D with neurodevelopmental delay: A prospective birth cohort study in China.

Aim: To estimate the associations of cord meta-inflammatory markers with neurodevelopment, including the potential impact of cord blood vitamin D levels. Method: The prospective cohort study comprised 7198 participants based on the Maternal & Infants Health in Hefei study. Cord blood C-peptide, high-sensitive C-reactive protein (hsCRP), high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, total cholesterol, triglycerides and 25(OH)D levels were measured. The Gesell Developmental Schedules were used to assess neurodevelopmental outcomes in offspring. Results: After adjusting potential confounders, per quartile increase in cord blood 25(OH)D concentrations was associated with a decreased risk of neurodevelopmental delay [hazard ratios (HR) 0.65 (95% CI 0.57, 0.74)]. Conversely, significant positive associations with cord blood serum C-peptide levels above the 90th percentile [HR 2.38 (95% CI 1.81, 3.13)] and higher levels of cord hsCRP (per quartile increase) [HR 1.18 (95% CI 1.01, 1.37)] with neurodevelopmental delay were observed. These associations could vary by quartiles of cord blood 25(OH)D levels: the adjusted HRs in neurodevelopmental delay comparing children with vs without hyperinsulinemia were 1.28 (95% CI: 1.03, 1.59) for quartiles 1 (lowest), and 1.06 (95% CI: 0.78, 1.44) for quartile 4 (highest). Conclusions: Immune activation and metabolic abnormalities in fetal circulation were associated with neurodevelopmental delay in offspring, which could be attenuated by higher cord blood 25(OH)D levels in a dose-response manner.

The role of neonatal vitamin D in the association of prenatal depression with toddlers ADHD symptoms: A birth cohort study.

BACKGROUND: Vitamin D has been demonstrated a "neuroprotective" effect, but it is unclear whether early-life adequate vitamin D protect adverse neurodevelopment. We aimed to examine the role of neonatal vitamin D in the association of maternal depression (MD) symptoms with toddlers ADHD. METHODS: Participants included 1 125 mother-infant pairs from the China-Anhui Birth Cohort study. MD was assessed by the Center for Epidemiological Studies Depression Scale (CES-D) at 30-34 gestational weeks. Toddlers ADHD was reported by the Conners' Hyperactivity Index (CHI) at 48-54 months postpartum. Multiple logistic regression models were performed to evaluate the association of maternal depressive score and toddlers ADHD while cord blood 25(OH)D levels were stratified. RESULTS: Toddlers of mothers with higher depression score were at higher risk of ADHD (20.1% vs 11.1%, P = 0.003; adjusted RR=1.75, 95% CI: 1.10-2.81). Among toddlers with neonatal vitamin D deficiency (VDD), ADHD risk was significantly increased with maternal MD (adjusted RR=3.74, 95% CI: 1.49-9.41), but the association was not found in toddlers with neonatal vitamin D adequacy (VDA). Compared to toddlers without MD, toddlers with both MD and neonatal VDD had higher risk of ADHD (adjusted RR=3.10, 95% CI: 1.44-6.63). But the risk did not significantly increase in toddlers with MD and neonatal VDA (adjusted RR=1.53, 95% CI: 0.86-2.72). LIMITATIONS: Maternal depressive symptoms in early pregnancy and anxious symptoms were needed to include. CONCLUSION: This prospective study indicated that the detrimental effect of maternal prenatal depressive symptoms on offspring's ADHD symptoms strengthened in toddlers with neonatal VDD.

Maternal Glycemia During Pregnancy and Early Offspring Development: A Prospective Birth Cohort Study.

CONTEXT: The association of maternal gestational diabetes mellitus (GDM) with neurodevelopmental outcomes remains controversial and evidence that maternal increasing levels of glucose during pregnancy associated with the risk for impaired neurodevelopment were limited. OBJECTIVE: To identify the continuous association of increasing maternal glucose levels with neurodevelopmental disorders in offspring and explore the potential contribution of cord metabolites to this association. METHODS: The prospective birth cohort study included 1036 mother-child pairs. Primary predictors were maternal exposure GDM and maternal glucose values at a 75-g oral-glucose-tolerance test at 24 to 28 weeks during pregnancy. Primary neurodevelopmental outcomes at 12 months in offspring were assessed by the Ages and Stages Questionnaires, Third Edition (ASQ-3). RESULTS: Maternal GDM was associated with failing the communication domain in offspring in the adjusted models [relative risk (RR) with 95% CI: 1.97 (1.11, 3.52)]. Increasing levels of fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG) and 2-h plasma glucose (2-h PG) with 1 SD change were at higher risks in failing the personal social domain of ASQ-3 [RRs with 95% CI for FPG: 1.49 (1.09, 2.04); for 1-h PG: 1.70 (1.27, 2.29); for 2-h PG: 1.36 (1.01, 1.84)]. The linear association was also demonstrated. Compared with girls, boys exposed to higher maternal glucose levels were inclined to the failure of the personal social domain. Mediation analysis showed the contribution of maternal GDM to failure of communication domain mediated by C-peptide. CONCLUSIONS: Maternal glucose levels below those diagnostic of diabetes are continuously associated with impaired neurodevelopment in offspring at 12 months.

Vitamin D status affects the relationship between lipid profile and high-sensitivity C-reactive protein.

BACKGROUND: The biological pathways through which vitamin D is involved in the regulation of systemic inflammation remain largely unknown. OBJECTIVE: The objective of this study was to evaluate the role of vitamin D status on the relationship between lipid profile and high-sensitivity C-reactive protein (hs-CRP) in pregnant women. DESIGN: Serum 25-hydroxyvitamin D (25(OH)D), hs-CRP, and indicators of lipid profiles (total cholesterol, TC; triglyceride, TG; high-density lipoprotein cholesterol, HDL-C; low-density lipoprotein cholesterol, LDL-C), were measured in 2479 pregnant women during the second trimester. Potential confounding including maternal sociodemographic characteristics, perinatal health status, diet, and lifestyle was prospectively collected. Multiple regression models and cubic models were used to evaluate the associations. RESULTS: There was a significant non-linear relationship between lipid profile (TC, TG, HDL-C, LDL-C) and hs-CRP (P < 0.05). Increased serum 25(OH)D was significantly associated with decreasing TC, TG, HDL-C, LDL-C, and hs-CRP levels. Compared with medium levels of lipids group, pregnant women with higher levels of TC or TG have higher levels of hs-CRP, and pregnant women with lower levels of TC, HDL-C or LDL-C also have higher levels of hs-CRP in the vitamin D deficient group, and there was a significant correlation between low levels of TG and decreased hs-CRP (adjusted ß for TG: -0.063, 95%CI: - 0.120,-0.007) in the non-vitamin D deficient group. Mediators that had appreciable shares of the associations between 25(OH)D and hs-CRP was TG (10.2% of the association; ß = - 0.011; total indirect effect: 95% CI: - 0.019, - 0.002). The cubic model suggested that a steep increase in the adjusted regression coefficient of lipid with hs-CRP up to 50 nmol/L of 25(OH)D, and the highest adjusted regression coefficients were observed in pregnant women with 25(OH)D above 50 nmol/L. CONCLUSION: Our findings suggest that high levels of vitamin D during pregnancy may improve lipid profile levels and inhibit elevated hs-CRP induced by high lipid metabolism.

The association of vitamin D status and supplementation during pregnancy with gestational diabetes mellitus: a Chinese prospective birth cohort study.

BACKGROUND: Previous studies have shown conflicting findings regarding the relation of vitamin D status and supplementation during pregnancy with gestational diabetes mellitus (GDM). Most of these studies hypothesized that 25-hydroxyvitamin D [25(OH)D] concentrations were associated with GDM risk and glucose metabolism based on linear association models. OBJECTIVES: We aimed to estimate the associations of 25(OH)D concentrations and vitamin D supplementation with GDM risk and glucose metabolism and determine the threshold concentrations of 25(OH)D that could significantly affect glucose metabolism and GDM risk. METHODS: In a prospective birth cohort study, we collected information about sociodemographic characteristics, health status, and lifestyle from 4984 pregnant women. Vitamin D supplementation and 25(OH)D concentrations were assessed in the second trimester. Data from the 75-g oral-glucose-tolerance test were obtained at 24-28 weeks of gestation. RESULTS: A total of 922 (18.5%) women were diagnosed with GDM. Compared with women with 25(OH)D concentrations <25 nmol/L, the GDM risk was significantly lower in women with 25(OH)D concentrations ranging from 50 to 75 nmol/L (RR: 0.74; 95% CI: 0.58, 0.95) and >75 nmol/L (RR: 0.40; 95% CI: 0.22, 0.70). The curve-fitting models suggested a significant large reduction in GDM risk, fasting plasma glucose, and area under the curve of glucose with increasing 25(OH)D concentrations only for concentrations >50 nmol/L. Consistently, GDM risk was significantly reduced only in women who took 400-600 IU vitamin D/d (RR: 0.83; 95% CI: 0.70, 0.97) with a mean 25(OH)D concentration of 50 nmol/L but not in women taking vitamin D sometimes with a mean 25(OH)D concentration of 40 nmol/L. CONCLUSIONS: GDM risk was significantly reduced only in pregnant women with 25(OH)D concentrations >50 nmol/L. Pregnant women taking 400-600 IU vitamin D/d with mean 25(OH)D concentrations of 50 nmol/L had a lower risk of GDM.