Vitamin D, pre-eclampsia, and preterm birth among pregnancies at high risk for pre-eclampsia: an analysis of data from a low-dose aspirin trial.

OBJECTIVE: To examine the relation between maternal vitamin D status and risk of pre-eclampsia and preterm birth in women at high risk for pre-eclampsia. DESIGN: Analysis of prospectively collected data and blood samples from a trial of prenatal low-dose aspirin. SETTING: Thirteen sites across the USA. POPULATION: Women at high risk for pre-eclampsia. METHODS: We measured 25-hydroxyvitamin D [25(OH)D] concentrations in stored maternal serum samples drawn at 12-26 weeks' gestation (n = 822). We used mixed effects models to examine the association between 25(OH)D and risk of pre-eclampsia and preterm birth, controlling for confounders including prepregnancy BMI and race. MAIN OUTCOME MEASURES: Pre-eclampsia and preterm birth. RESULTS: Twelve percent of women were vitamin D deficient [25(OH)D <30 nmol/l]. Women with 25(OH)D <30 versus ≥75 nmol/l had a 2.4-fold (95% CI 1.0-5.6) higher risk of early-onset pre-eclampsia (<35 weeks' gestation) after confounder adjustment. Women with 25(OH)D <50 nmol/l had a 1.8-fold (95% CI 1.0-3.2) increased risk of preterm birth at <35 weeks compared with women who had 25(OH)D ≥75 nmol/l, which was driven by indicated preterm births at <35 weeks' gestation [25(OH)D <50 versus ≥75 nmol/l adjusted RR 2.5 (95% CI 1.1-5.8)]. There was no association between vitamin D status and pre-eclampsia or preterm birth at <37 weeks. CONCLUSION: Maternal vitamin D status in the second trimester was inversely associated with risk of early-onset pre-eclampsia and preterm birth at <35 weeks in women at high risk for pre-eclampsia. TWEETABLE ABSTRACT: Vitamin D is inversely related to risk of pre-eclampsia and preterm birth at <35 weeks in high-risk pregnancies.

Association of ultrasound-based measures of fetal body composition with newborn adiposity.

BACKGROUND: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. OBJECTIVE: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. METHODS: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. RESULTS: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized ß = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. CONCLUSIONS: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

Maternal vitamin D status, prolonged labor, cesarean delivery and instrumental delivery in an era with a low cesarean rate.

OBJECTIVE: To examine the association between maternal 25-hydroxyvitamin D (25(OH)D) and adverse labor and delivery outcomes. STUDY DESIGN: We measured serum 25(OH)D at ⩽ 26 weeks gestation in a random subsample of vertex, singleton pregnancies in women who labored (n=2798) from the 12-site Collaborative Perinatal Project (1959 to 1966). We used labor and delivery data to classify cases of adverse outcomes. RESULT: Twenty-four percent of women were vitamin D deficient (25(OH)D <30 nmol l(-1)), and 4.5, 3.3, 1.9 and 7.5% of women had prolonged stage 1 labor, prolonged stage 2 labor, primary cesarean delivery or indicated instrumental delivery, respectively. After adjustment for prepregnancy body mass index, race and study site, 25(OH)D concentrations were not associated with risk of prolonged stage 1 or 2, cesarean delivery or instrumental delivery. CONCLUSION: Maternal vitamin D status at ⩽ 26 weeks was not associated with risk of prolonged labor or operative delivery in an era with a low cesarean rate.

Early-pregnancy maternal vitamin D status and maternal hyperglycaemia.

AIMS: To estimate the association between serum 25-hydroxyvitamin D concentrations and maternal hyperglycaemia (post-load glucose concentration ≥ 7.5 mmol/l). METHODS: Pregnant women (n = 429; 61% black, 36% obese, 45% smokers) enrolled in a cohort study at <16 weeks gestation. Non-fasting blood samples were assayed for serum 25-hydroxyvitamin D at enrolment. At 24-28 weeks gestation, maternal hyperglycaemia was determined using a 50-g 1-h oral glucose challenge test. RESULTS: A total of 67% of women had 25-hydroxyvitamin D concentrations < 50 nmol/l and 11% had maternal hyperglycaemia. Among smokers, each 23-nmol/l increase in serum 25-hydroxyvitamin D was associated with a reduction in the odds of maternal hyperglycaemia [odds ratio: 0.30 (95% CI: 0.13, 0.68)] after adjustment for parity, race/ethnicity, age, pre-pregnancy BMI, marital status, income, family history of diabetes, and gestational age of gestational diabetes mellitus screening. Among non-smokers, we found no association between early pregnancy vitamin D status and maternal hyperglycaemia. CONCLUSIONS: Smoking status may modify the relationship between poor maternal vitamin D status and maternal hyperglycaemia.

Genetic association of Toll-like receptor 4 with cervical cytokine concentrations during pregnancy.

Toll-like receptors (TLRs) are critical components of innate immunity, recognizing bacterial microorganisms and initiating local inflammatory responses. In this study, we assessed the impact of genetic variation in TLR genes on cervical concentrations of pro- and anti-inflammatory cytokines, and determined whether this relationship is influenced by bacterial vaginosis (BV). A total of 4 single nucleotide polymorphisms (SNPs) in TLR2 and 12 in TLR4 were examined for associations with 10 cervical pro- and anti-inflammatory cytokine concentrations in 91 African-American (AA) and 97 European-American (EA) women in the first trimester of pregnancy. In EAs, individuals with the TT genotype at rs1554973 (TLR4) had higher cervical concentrations of interleukin-1 beta (IL-1b) compared with those with the CT or TT genotypes (P=1.5 x 10(-5)), which remains significant after correction for multiple testing. This association was more significant in women with BV (P=5 x 10(-3)) than those without BV (P=0.02). This SNP was also associated with cervical concentrations of IL-1a, IL-6, IL-8 and IP10 (interferon-gamma-inducible protein 10) (P=6 x 10(-3), 0.03, 0.05, 6 x 10(-3), respectively). Our study demonstrates that TLR4 is an important mediator of pro-inflammatory cervical immune responses, particularly in EA women and especially in those with microbial disorders such as BV.

Predicting risk of bacterial vaginosis: the role of race, smoking and corticotropin-releasing hormone-related genes.

Bacterial vaginosis (BV) is one of the most prevalent vaginal disorders in adult women and is associated with adverse pregnancy outcomes such as pre-term birth. Genetic factors, particularly in genes involved in inflammation and infection, are associated with this condition. Additionally, environmental risk factors including stress and smoking are associated with BV. The purpose of this study was to identify genetic variants in stress-related genes such as corticotropin-releasing hormone (CRH), receptor 1, receptor 2 and binding protein (CRH-BP) that associate with BV. Also gene-environment effects with smoking are determined. BV was quantified using the Nugent score in 82 white and 65 black women in the first trimester of pregnancy. Associations between Nugent score, genotype and smoking were analyzed using Kruskal-Wallis and Wilcoxon rank sum non-parametric tests. In white women, non-smokers with the CT genotype at CRH-BP + 17487 have lower Nugent scores (median: 0, range: 0-0) than non-smokers with the TT genotype (median: 2, range: 0-8) (P = 0.002); whereas smokers with the CT genotype have higher Nugent scores (median: 6, range: 0-10) than smokers with the TT genotype (median: 1, range: 0-10) (P = 0.021). In black women, the AG genotype at CRH + 3362 or CRH - 1667 is associated with lower Nugent scores (median for both: 3, range: 0-10) compared with the homozygous genotypes (median for each homozygous genotype: 8, range: 0-10). Also, in black women, models remain significant after adjusting for smoking (P = 0.04 for both). These data indicate that susceptibility to BV is affected by patterns of genetic variation in stress-related genes and smoking plays an important role.

Activation of the fibrinolytic cascade early in pregnancy among women with spontaneous preterm birth.

OBJECTIVE: To evaluate the association of early pregnancy concentrations of thrombin-antithrombin III complex with subsequent spontaneous preterm birth. METHODS: In a nested case-control study, thrombin-antithrombin III complex was measured in plasma before 20 weeks of gestation (mean 9.9 weeks) among women without chronic conditions, preeclampsia, or growth restriction. C-reactive protein and non-high-density lipoprotein cholesterol were also measured. Women with spontaneous preterm birth before 34 weeks of gestation (n=29) and 34 weeks to 36 weeks of gestation (n=72) were compared with women with term births occurring at or after 37 weeks (n=219). Polychotomous logistic regression was used to relate elevated thrombin-antithrombin III complex (greater than 5.5 ng/mL), dyslipidemia (non-high-density lipoprotein cholesterol greater than the 90th percentile), and inflammation (C-reactive protein at or above 8 micrograms/mL) to risk of spontaneous preterm birth subtypes. RESULTS: Women with spontaneous preterm birth compared with term births had elevated thrombin-antithrombin III complex (P=.02), and they were more likely to have a thrombin-antithrombin III complex greater than 5.5 ng/mL (P<.01). Women with thrombin-antithrombin III complex in the highest compared with lowest quartile had a 4.6-fold (95% confidence interval 1.3-15.8) increased risk for spontaneous preterm birth before 34 weeks of gestation, adjusted for body mass index, race, inflammation, dyslipidemia, and gestational age at sampling. There was a dose-response trend between thrombin-antithrombin III complex and spontaneous preterm birth before 34 weeks (P<.01) and 34 to 36 weeks (P=.03). CONCLUSION: There is evidence of early pregnancy systemic fibrinolysis among women with spontaneous preterm birth before 34 weeks of gestation independent of inflammation and dyslipidemia, perhaps secondary to microvascular injury. LEVEL OF EVIDENCE: II.

Maternal and fetal variation in genes of cholesterol metabolism is associated with preterm delivery.

OBJECTIVE: To examine the contribution of variants in fetal and maternal cholesterol metabolism genes in preterm delivery (PTD). STUDY DESIGN: A total of 40 single-nucleotide polymorphisms (SNPs) in 16 genes related to cholesterol metabolism were examined for 414 preterm infants (gestational ages 22 to 36 weeks; comprising 305 singletons and 109 twins) and at least 1 parent. Fetal effects were assessed using the transmission disequilibrium test (TDT) for each SNP, followed by a log linear model-based approach to utilize families with missing parental genotypes for those SNPs showing significance under TDT. Genetic variant effects were examined for a role in PTD, gestational age and birth weight. Maternal effects were estimated using a log linear model-based approach. RESULT: Among singleton gestations, suggestive association (P<0.01 without adjusting for multiple comparisons) was found between birth weight and fetal DHCR7 gene/SNP combinations (rs1630498, P=0.002 and rs2002064, P=0.003). Among all gestations, suggestive associations were found between PTD and fetal HMGCR (rs2303152, P=0.002) and APOA1 (rs 5070, P=0.004). The result for HMGCR was further supported by the log linear model-based test in the single births (P=0.007) and in all births (P=0.006). New associations (APOE and ABCA1) were observed when birth weight was normalized for gestational age suggesting independent effects of variants on birth weight separate from effects on PTD. Testing for maternally mediated genetic effects has identified suggestive association between ABCA1 (rs4149313, P=0.004) and decreased gestational age. CONCLUSION: Variants in maternal and fetal genes for cholesterol metabolism were associated with PTD and decreased birth weight or gestational age in this study. Genetic markers may serve as one mechanism to identify high-risk mothers and fetuses for targeted nutritional treatment and/or prevention of low birth weight or PTD.