Breastfeeding history and adenomyosis risk using a novel case-control study design.

OBJECTIVE: To evaluate the association between breastfeeding history, including lifetime exclusive breastfeeding, and risk of adenomyosis. DESIGN: We used data from a case-control study designed with 2 control groups to address the challenge of selecting noncases for a valid epidemiologic study when cases are identified by hysterectomy. The case-control study was conducted among premenopausal and postmenopausal enrollees aged 18-59 years in a large, integrated health care system in western Washington state. PATIENT(S): Cases were enrollees with incident, pathology-confirmed adenomyosis diagnosed during 2001-2006 (n = 386). The 2 control groups were as follows: (1) randomly selected age-matched enrollees with intact uteri ("population controls," n = 323) and (2) hysterectomy controls (n = 233). INTERVENTION(S): Data on breastfeeding history were collected by in-person interviews. For each reported live birth, participants were asked whether they breastfed, along with infant age at supplemental feeding introduction and breastfeeding discontinuation. MAIN OUTCOME MEASURE(S): Among participants with at least 1 live birth (330 cases, 246 population controls, and 198 hysterectomy controls), we used unconditional logistic regression to estimate adjusted odds ratios and 95% confidence intervals (CIs) for the associations between the following: (1) ever breastfeeding, (2) ever breastfeeding for ≥8 weeks, (3) lifetime breastfeeding, and (4) lifetime exclusive breastfeeding and risk of adenomyosis. Analyses were adjusted for age, reference year, smoking, education, and parity. RESULT(S): In analyses comparing cases with population controls, we observed a 40% decreased odds of adenomyosis with a history of ever breastfeeding (adjusted odds ratio, 0.6; 95% CI, 0.3-1.0) and breastfeeding for ≥8 weeks (adjusted odds ratio, 0.6; 95% CI, 0.4-0.8). The strongest associations, 60%-70% decreased odds of adenomyosis, were observed with ≥12 months of lifetime breastfeeding (vs. <3 months) (adjusted odds ratio, 0.4; 95% CI, 0.2-0.6) and 9 to <12 months of lifetime exclusive breastfeeding (vs. <3 months) (adjusted odds ratio, 0.3; 95% CI, 0.2-0.6), comparing cases to population controls. In analyses using hysterectomy controls, we observed similar patterns of associations slightly attenuated in magnitude. CONCLUSION(S): Breastfeeding history was associated with a 40% decreased odds of adenomyosis, a condition that can confer substantial morbidity and requires hysterectomy for definitive treatment. The consistency of our findings with that of a previous study lends support that breastfeeding may modify risk of adenomyosis.

Maternal blood EBF1-based microRNA transcripts as biomarkers for detecting risk of spontaneous preterm birth: a nested case-control study.

OBJECTIVE: Both genetic variants and maternal blood mRNA levels of EBF1 gene have been linked to sPTB. Animal and human studies suggest that specific EBF1-based miRNAs are involved in various physiological and pathophysiological processes. However, to date, we did not find any reports of EBF1-based miRNAs or miRNA transcripts in relation to sPTB. We therefore aimed to examine whether maternal blood early B cell factor 1 (EBF1) gene-based microRNA (miRNA) transcripts can be used for detecting risk of spontaneous preterm birth (sPTB). METHODS: We conducted a nested case-control study within a Canadian cohort consisting of 1878 singleton pregnancies enrolled from May 2008 to December 2010 in Calgary, Alberta, Canada. We used a public gene expression dataset (GSE59491) derived from maternal blood in trimesters 2-3 that included women with sPTB (n = 51) and term births (n = 106) matched for maternal age, race/ethnicity, pre-pregnancy body mass index, smoking during pregnancy, and parity within the Canadian cohort. Two bioinformatics tools, miRWalk and STarMirDB, with different algorithms were applied to retrieve miRNA transcripts that putatively target the EBF1 gene (i.e. EBF1-based). Limma moderated t-tests were used to examine differentially expressed (DE) miRNA transcripts (sPTB vs term) within trimesters. Logistic regression models with miRNA transcript tertiles were applied to assess threshold associations between candidate miRNA transcripts' levels and sPTB. Receiver operating characteristic (ROC) analyses were used to identify the maximum Youden Index and its corresponding optimal sensitivity/specificity cut-point of EBF1-based miRNA transcripts for classifying sPTB, and to compare the classification performance of a linear combination (score) of miRNA transcripts with that of individual miRNA transcripts. A five-fold cross-validation was applied to examine the possible overfitting problem of the final ROC model. RESULTS: Four maternal blood EBF1-based miRNA transcripts (MIR4266, MIR1251, MIR601, MIR3612) in the 3rd trimester were significantly associated with sPTB. The odds ratios (95%CIs) for highest versus lowest tertile of the four miRNA transcripts were 3.01-5.25(1.21-13.14, p ≤ .018). The combined 4-miRNA transcripts' score significantly improved the classification of sPTB compared to individual miRNA transcripts (AUC increased from 0.65-0.69 to 0.82, p ≤ .0034) and showed a sensitivity for sPTB of 0.81 and a specificity of 0.72. The final ROC model of the EBF1-based 4 miRNA transcripts' score in cases and controls had no significant overfitting issue. CONCLUSIONS: Maternal blood EBF1-based miRNA transcripts may, along with other biomarkers, be useful in screening for sPTB risk in 3rd trimester. Our results also provide clues for further study of potential molecular mechanisms underlying the relationship between EBF1 gene and sPTB, e.g. connecting genetic variants, mRNA expression, and miRNA regulation.

EBF1 Gene mRNA Levels in Maternal Blood and Spontaneous Preterm Birth.

Genetic variants of six genes (EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C) have been linked recently to gestational duration and/or spontaneous preterm birth (sPTB). Our goal was to examine sPTB in relation to maternal blood mRNA levels of these genes. We used a public gene expression dataset (GSE59491) derived from maternal blood in trimesters 2 and 3 that included women with sPTB (n = 51) and term births (n = 106) matched for maternal age, race/ethnicity, pre-pregnancy body mass index, smoking during pregnancy, and parity. T tests were used to examine mRNA mean differences (sPTB vs term) within and across trimesters, and logistic regression models with mRNA quartiles were applied to assess associations between candidate gene mRNA levels and sPTB. Based on these analyses, one significant candidate gene was used in a Gene Set Enrichment Analysis (GSEA) to identify related gene sets. These gene sets were then compared with the ones previously linked to sPTB in the same samples. Our results indicated that among women in the lowest quartile of EBF1 mRNA in the 2nd or 3rd trimester, the odds ratio for sPTB was 2.86 (95%CI 1.08, 7.58) (p = 0.0349, false discovery rate (FDR) = 0.18) and 4.43 (95%CI 1.57, 12.50) (p = 0.0049, FDR = 0.06), respectively. No other candidate gene mRNAs were significantly associated with sPTB. In GSEA, 24 downregulated gene sets were correlated with 2nd trimester low EBF1 mRNA and part of previous sPTB-associated gene sets. In conclusion, mRNA levels of EBF1 in maternal blood may be useful in detecting increased risk of sPTB as early as 2nd trimester. The potential underlying mechanism might involve maternal-fetal immune and cell cycle/apoptosis pathways.

Lactation and Maternal Subclinical Atherosclerosis Among Women With and Without a History of Hypertensive Disorders of Pregnancy.

Background: We evaluated subclinical cardiovascular disease in relation to lactation history among women with normotensive pregnancies and women with hypertensive pregnancies, a distinction not previously examined. Materials and Methods: The POUCHmoms study included 678 women from a pregnancy cohort who were followed 7-15 years after delivery. We measured blood pressure, lipid levels, carotid intima-media thickness (CIMT), and lactation duration for each live birth (LB) at follow-up. We categorized lactation as never, <6 months/LB, or ≥6 months/LB. We analyzed associations between lactation and cardiometabolic risk factors and CIMT by using analysis of variance and multivariable linear regression (adjusted for age, race, socioeconomic status, smoking, time from last pregnancy, and total parity), which produced adjusted least square mean differences (LSMdiff) between groups. Results: In the normotensive pregnancies group with women who never lactated as the referent (n = 157): Women with some lactation but <6 months/LB (n = 284) had higher high density lipoprotein (HDL) (LSMdiff = +4.47 mg/dL, p = 0.013), lower triglycerides (LSMdiff = -38.1 mg/dL, p = 0.02), and thinner mean CIMT (LSMdiff = -0.03 mm, p = 0.005); women who lactated for ≥6 months/LB (n = 133) also had higher HDL (LSMdiff = +7.59 mg/dL, p < 0.001), lower triglycerides (LSMdiff = -41.6 mg/dL, p = 0.01), and thinner mean CIMT (LSMdiff = -0.03 mm, p = 0.003). After further adjustment for body mass index, associations between lactation and HDL, triglycerides, and mean CIMT persisted. These associations were not detected in women with prior hypertensive pregnancies. Conclusions: Women with a history of normotensive pregnancies and lactation for any duration had a more favorable cardiometabolic profile and were at decreased risk of subclinical atherosclerosis compared with those who never lactated.

Pregnancy as a Window to Racial Disparities in Hypertension.

BACKGROUND: The black-white disparity in hypertension (HTN) among U.S. women persists after accounting for known risk factors. Pregnancy complications may reveal increased risks for later HTN. We examined the contribution of HTN risk factors measured at both midlife and pregnancy to black-white disparities in midlife HTN. METHODS: Data came from a Michigan-based longitudinal study beginning in pregnancy. At 7-15 years postpregnancy (n = 615, mean age = 37), women were assessed for cardiovascular health, including blood pressure, and categorized as hypertensive (n = 126), prehypertensive (n = 149), and normotensive (n = 340). Midlife risk factors for HTN were assessed in four domains: socioeconomic status (SES), psychosocial, behavioral, and physiological. We used generalized logit models to assess the degree to which each domain attenuated the black (vs. white) odds ratio (OR) for HTN at midlife. We then added indicators of pregnancy health, that is, preterm delivery, prepregnancy body mass index (BMI), C-reactive protein (CRP) levels, depressive symptoms, smoking, hypertensive disorders, and lipid levels. RESULTS: Black women had 3.3 (95% CI: 2.0-5.5) times the odds of HTN compared to white women after adjusting for age. Following adjustment for midlife SES, and psychosocial, behavioral, and physiological factors, the OR was 2.1 (95% CI: 1.2-4.0). Adjustment for prepregnancy BMI, CRP, and depressive symptoms during pregnancy reduced the OR to 1.9 (95% CI: 1.0-3.7). CONCLUSIONS: Known risk factors measured at midlife explained some, but not all, of the race disparity in midlife HTN. Indicators of pregnancy health also contributed to the race disparity in HTN at midlife.

Women with Preterm Birth Have Evidence of Subclinical Atherosclerosis a Decade After Delivery.

Background: Women with preterm birth (PTB) have excess risk of cardiovascular disease (CVD) and metabolic dysregulation after delivery, but vascular mechanisms are poorly understood. We considered that women with PTB may have evidence of subclinical atherosclerosis after delivery, perhaps related to cardiometabolic risk factors. Materials and Methods: The Pregnancy Outcomes and Community Health Moms (POUCHmoms) study followed women from pregnancy through 7 to 15 years after delivery (n = 678). Women underwent B-mode ultrasound to measure the average intima-media thickness (IMT) across the common carotid, bulb, and internal carotid artery segments at follow-up (n = 605). Linear regression estimated the overall and segment-specific difference in IMT between women with preterm and term births. Results: Women were, on average, 38 years old (SD 5.7) at the follow-up visit. Those with a prior preterm versus term birth had thicker mean IMT (average of eight segments, 0.592 mm vs. 0.575, p = 0.04). Differences persisted after accounting for age, race, smoking, and body mass index (difference = +0.018 mm, p = 0.019) and were attenuated after adjustment for blood pressure, medication use, and total cholesterol (difference = +0.014, p = 0.052). Thicker mean bulb IMT in women with PTB was robust to cardiovascular risk factor adjustments (fully adjusted difference = +0.033, p = 0.029). Excluding cases of prepregnancy hypertension or preeclampsia did not change results. Conclusions: Mechanisms leading to subclinical atherosclerosis may link PTB with future CVD. PTB differences in maternal vessel remodeling in the carotid bulb, an arterial segment more prone to early development of atherosclerosis, were independent of traditional risk factors suggesting that novel processes may be involved.

Maternal serum uric acid levels and blood pressure during pregnancy: A community-based cohort study.

OBJECTIVE: Studies find both very low and high serum uric acid (UA) levels are related to oxidative stress and to conditions such as cardiovascular diseases and chronic kidney disease in the general population. Pregnancy studies have focused only on high maternal UA. In present study, we tested whether unusually high and low levels of maternal serum UA are associated with increases in blood pressure (BP) during pregnancy. STUDY DESIGN: The Pregnancy Outcomes and Community Health Study enrolled 3019 pregnant women between their 16th-27th week of pregnancy from 52 clinics in 5 Michigan communities (1998-2004). UA levels were measured in maternal blood collected at enrollment from a sub-cohort of 1223 participants. BP was abstracted from prenatal medical records; these analyses used highest recorded diastolic BP (DBP) and its companion systolic BP (SBP). Mean arterial pressure (MAP) was calculated using the formula of (2 × DBP + SBP)/3. Covariates, including maternal race/ethnicity, age at enrollment, education level, medical insurance status, body mass index before pregnancy, parity, smoking during pregnancy, alcohol use during pregnancy, and gestational week at blood collection, were considered as potential confounding variables. Associations between UA levels and BP were evaluated with linear spline or multiple linear regression models. Models' robustness was examined with bootstrap estimation of variance, sensitivity analysis, and 10-fold cross-validation. RESULTS: Both DBP and MAP had a J-shaped relationship with maternal UA; the breakpoints (nadirs) were 0.153 and 0.161 mmol/L UA, respectively. For DBP versus UA, adjusted regression coefficient (ß) = -95.67 (standard error (SE) = 37.67 and p = 0.01) for the left and adjusted ß = 48.95 (SE = 9.56 and p < 0.01) for the right; for MAP versus UA, adjusted ß = -58.48 (SE = 31.42 and p = 0.06) for the left and adjusted ß = 52.23 (SE = 11.39 and p < 0.01) for the right. Maternal SBP followed a positive linear trend with UA levels (adjusted ß = 37.75, SE = 12.93, and p < 0.01). All results were robust. CONCLUSION: Extreme high and low maternal serum UA levels may be informative in studying maternal blood pressure during pregnancy.

Maternal pre-pregnancy body mass index and circulating microRNAs in pregnancy.

BACKGROUND: Maternal pre-pregnancy overweight and obese status has been associated with a number of pregnancy complications and adverse offspring outcomes. Mechanisms for observed associations, however, are largely unknown. We investigated associations of pre-pregnancy body mass index with early-mid pregnancy epigenetic biomarkers, circulating microRNAs. METHODS: Peripheral blood was collected from participants (16-27 weeks gestation) of two multi-racial pregnancy cohorts, the Omega Study and the Pregnancy Outcomes and Community Health Study. Plasma miRNA expression was characterised using epigenome-wide (319 miRNAs) profiling among 20 pregnant women in each cohort. Cohort-specific linear regression models that included the predictor (pre-pregnancy body mass index), the outcome (microRNA expression), and adjustment factors (maternal age, gestational age at blood collection, and race) were fit. RESULTS: Expression of 27 miRNAs was positively associated with pre-pregnancy body mass index in both cohorts (p-values <0.05). A number of these differentially expressed miRNAs have previously been associated with adipogenesis (e.g. let-7d*, miR-103-2*, -130b, -146b-5-p, -29c, and -26b). Identified miRNAs as well as their experimentally validated targets participate in pathways that involve organismal injury, reproductive system disease, connective tissue disorders, cancer, cellular development, growth and proliferation. CONCLUSION: Pre-pregnancy body mass index is associated with circulating miRNAs in early-mid pregnancy.

Maternal Serum 25-Hydroxyvitamin D Concentrations during Pregnancy and Infant Birthweight for Gestational Age: a Three-Cohort Study.

BACKGROUND: In response to inconsistent findings, we investigated associations between maternal serum 25-hydroxyvitamin D [25(OH)D] concentrations and infant birthweight for gestational age (BW/GA), including potential effect modification by maternal race/ethnicity and infant sex. METHODS: Data from 2558 pregnant women were combined in a nested case-control study (preterm and term) sampled from three cohorts: the Omega study, the Pregnancy, Infection and Nutrition study, and the Pregnancy Outcomes and Community Health study. Maternal 25(OH)D concentrations were sampled at 4 to 29 weeks gestation (80% 14-26 weeks). BW/GA was modelled as sex and gestational age-specific birthweight z-scores. General linear regression models (adjusting for age, education, parity, pre-pregnancy body mass index, season at blood draw, and smoking) assessed 25(OH)D concentrations in relation to BW/GA. RESULTS: Among non-Hispanic Black women, the positive association between 25(OH)D concentrations and BW/GA was of similar magnitude in pregnancies with female or male infants [beta (ß) = 0.015, standard error (SE) = 0.007, P = 0.025; ß = 0.018, SE = 0.006, P = 0.003, respectively]. Among non-Hispanic White women, 25(OH)D-BW/GA association was observed only with male infants, and the effect size was lower (ß = 0.008, SE = 0.003, P = 0.02). CONCLUSIONS: Maternal serum concentrations of 25(OH)D in early and mid-pregnancy were positively associated with BW/GA among non-Hispanic Black male and female infants and non-Hispanic White male infants. Effect modification by race/ethnicity may be due, in part, to overall lower concentrations of 25(OH)D in non-Hispanic Blacks. Reasons for effect modification by infant sex remain unclear.

Association between pre-pregnancy depression/anxiety symptoms and hypertensive disorders of pregnancy.

BACKGROUND: Depression and anxiety symptoms have been linked with hypertensive disorders during pregnancy, but these associations have not been fully elucidated. Our objective was to consider hypertension in pregnancy and its subtypes (chronic hypertension, gestational hypertension, preeclampsia) and evaluate whether the proximity of psychological symptoms to pregnancy informs any associations observed. METHODS: Pregnancy Outcomes and Community Health Study participants who provided interview data at enrollment (16-27 weeks' gestation) and whose hypertensive disorder status was abstracted from medical records were eligible for inclusion (n=1371). Maternal history of depression/anxiety symptoms at four time points in the life course were ascertained via self-report at enrollment (i.e., lifetime history, 1 year prior to pregnancy, since last menstrual period, and past week). Weighted logistic regression models were used to examine depression/anxiety symptom measures in relation to hypertensive disorders (overall) and subtype. RESULTS: Following adjustment for maternal sociodemographic factors, smoking, and prepregnancy body mass index, prepregnancy depression or anxiety symptoms (i.e., lifetime history and 1 year prior to pregnancy) were associated with hypertensive disorders during pregnancy. Subtype analyses revealed that these associations were driven primarily by chronic hypertension (adjusted odds ratios=2.7-3.5). Preeclampsia accompanied by preterm delivery was also linked to women's lifetime history of depression symptoms (odds ratio=2.3, 95% confidence interval 1.0-5.2). CONCLUSION: Our results suggest that the link between maternal chronic hypertension and depression/anxiety symptoms precedes pregnancy. In addition, prepregnancy history of depression/anxiety symptoms may be considered part of a risk profile for preterm preeclampsia.

Inflammation biomarkers in vaginal fluid and preterm delivery.

STUDY QUESTION: Which inflammation biomarkers detected in the vaginal fluid are most informative for identifying preterm delivery (PTD) risk? SUMMARY ANSWER: Elevated interleukin (IL)-6 at mid-trimester was associated with increased odds of spontaneous PTD at <35 weeks and with PTD plus histologic chorioamnionitis (HCA), and had the greatest sensitivity for detecting these two PTD subtypes. WHAT IS KNOWN ALREADY: Maternal and/or fetal inflammation play a role in some preterm deliveries, therefore inflammation biomarkers might help to identify women at greater risk. STUDY DESIGN, SIZE, DURATION: We examined 1115 women from the Pregnancy Outcomes and Community Health Study, a cohort study conducted from September 1998 through June 2004, for whom data were available on mid-pregnancy inflammatory biomarkers. PARTICIPANTS/MATERIALS, SETTING, METHODS: At enrollment at 16-27 weeks gestation, vaginal fluid samples were collected from a swab and 15 eluted biomarkers were measured using the Meso Scale Discovery multiplex electrochemiluminescence platform. Associations of biomarkers with PTD were examined, according to clinical circumstance, week at delivery and presence/absence of HCA. Weighted logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) adjusted for race. Sensitivity and specificity were compared between individual and multiple biomarkers, identified by a bootstrapping method. MAIN RESULTS AND THE ROLE OF CHANCE: Elevated IL-6 (>75th percentile) displayed the strongest association with spontaneous PTD <35 weeks (OR 2.3; CI 1.3-4.0) and PTD with HCA (OR 2.8; CI 1.4-6.0). The sensitivity of IL-6 to detect spontaneous PTD <35 weeks or PTD with HCA was 0.43 and 0.51, respectively, while specificity was 0.74 and 0.75, respectively. IL-6 plus IL1ß, IL-6r, tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor increased specificity (range 0.84-0.88), but decreased sensitivity (range 0.28-0.34) to detect both PTD subtypes. Results were similar when a combination of IL-6 and bacterial vaginosis (BV) was explored. Thus, the use of multiple biomarkers did not detect PTD subtypes with a greater sensitivity than IL-6 alone, and IL-6 is a specific but non-sensitive marker for the detection of spontaneous PTD. LIMITATIONS, REASONS FOR CAUTION: Our ability to find small effect size associations between PTD and inflammation biomarkers (OR <2.0) might have been limited by the modest number of less common PTD subtypes in our population (e.g. spontaneous delivery <35 weeks, PTD accompanied by HCA) and by relatively higher variability for some cytokines, for example tumor necrosis factor-α, IL-12p70, IL-10 and granulocyte-macrophage colony-stimulating factor, that are less stable and commonly undetectable or detectable at low levels in human vaginal secretions. WIDER IMPLICATIONS OF THE FINDINGS: Larger studies are needed to further explore a role of inflammation biomarkers in combination with other risk factors, including specific BV-associated organisms, for the prediction of PTD subtypes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institute of Child Health and Human Development, National Institute of Nursing, March of Dimes Foundation, Thrasher Research Foundation and Centers for Disease Control and Prevention. The authors have no conflicts of interest.

Mid-pregnancy levels of angiogenic markers as indicators of pathways to preterm delivery.

OBJECTIVE: To determine whether mid-pregnancy levels of angiogenic markers were associated with increased risk of preterm delivery (PTD). METHODS: We studied a subcohort from the Pregnancy Outcomes and Community Health Study for whom mid-pregnancy angiogenic markers (soluble fms-like tyrosine kinase-1 [sFlt-1], soluble endoglin [sEng] and placental growth factor [PlGF]) and covariate data were available (N = 1301). Angiogenic marker levels were grouped as high/not high (sFlt-1 and sEng), low/not low (PlGF) and high/intermediate/low (sFlt-1). Associations between levels of angiogenic markers and PTD/PTD subtype were determined for women who were nonsmokers during pregnancy (N = 933). RESULTS: Low PlGF and high sEng were associated with medically-indicated PTD and PTD <35 weeks, largely due to preeclampsia (PE). Excluding PE and small-for-gestational-age infants, low sFlt-1 was positively associated with medically-indicated PTD. CONCLUSIONS: Among nonsmokers, mid-pregnancy levels of angiogenic markers may mark multiple pathways leading to PTD, only one attributable to PE.

Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery.

OBJECTIVE: There is little information about the combination of genetic variability in pregnant women and their children in relation to the risk of preterm delivery (PTD). In a sub-cohort of 487 non-Hispanic white and 288 African-American mother/child pairs, the Pregnancy Outcomes and Community Health Study assessed 10 functional polymorphisms in 9 genes involved in innate immune function. METHODS: Race-stratified weighted logistic regression models were used to calculate odds ratios for genotype and PTD/PTD subtypes. Polymorphisms significantly associated with PTD/PTD subtypes were tested for mother/child genotype interactions. RESULTS: Three maternal polymorphisms (IL-1 receptor antagonist intron two repeat (IL-1RN), matrix metalloproteinase- -C1562T, and TNF receptor two M196R (TNFR2)) and three child polymorphisms (IL1-RN, tumor necrosis factor-alpha -G308A, and TNFR2) were associated with PTD, but associations varied by PTD subtype and race. Two interactions were detected for maternal and child genotype. Among non-Hispanic white women, the odds of PTD was higher when both mother and child carried the IL-1RN allele two (additive interaction p < 0.05). Among African-American women, the odds of PTD were higher when both mother and child carried the TNFR2 R allele (multiplicative interaction p < 0.05). CONCLUSION: These results highlight the importance of assessing both maternal and child genotype in relation to PTD risk.

Midpregnancy levels of angiogenic markers in relation to maternal characteristics.

OBJECTIVE: The purpose of this study was to describe relations among maternal demographic and lifestyle characteristics and midpregnancy levels of angiogenic markers (soluble Fms-like tyrosine kinase-1, placental growth factor, soluble endoglin). STUDY DESIGN: In a large pregnancy cohort, linear models were used to evaluate relations among maternal characteristics and midpregnancy angiogenic markers with and without covariate adjustment. Associations were examined in a subcohort that included term and preterm deliveries (n = 1302) and among "normal" term pregnancies (n = 668). RESULTS: Concentrations of all factors declined with increasing maternal body mass index. Multiparous women had lower soluble Fms-like tyrosine kinase-1 levels than primiparous women. Higher placental growth factor and slightly lower soluble endoglin levels were observed among women who smoked at enrollment, but not among those women who quit before enrollment. African American women had higher levels of all markers. CONCLUSION: Understanding relations among maternal characteristics and levels of angiogenic factors may improve studies that use these markers to examine etiology and/or to predict adverse pregnancy outcome.

Interplay of cytokine polymorphisms and bacterial vaginosis in the etiology of preterm delivery.

Recent findings suggest that the association between inflammation-related genes and preterm delivery may be stronger in the presence of bacterial vaginosis (BV). Tumor necrosis factor-alpha (TNFα) and interleukin 1-beta (IL-1ß) are pro-inflammatory cytokines capable of inducing preterm labor in non-human primates. In this study the authors tested associations among two TNFα promoter polymorphisms (-G308A and -G238A), a single IL-1ß polymorphism (+C3954T), vaginal microbial findings, and risk of preterm delivery. Data were from the Pregnancy Outcomes and Community Health (POUCH) Study (n=777 term and n=230 preterm deliveries). Vaginal smears collected at mid-pregnancy (15-27 weeks gestation) were scored according to Nugent's criteria. A Nugent score of ≥ 4 was modeled as the cut-point for intermediate and positive BV. Logistic regression was used to estimate odds ratios for associations among independent covariates (vaginal flora, genotype) and preterm delivery. Results showed that women with a Nugent score of≥ 4 and the TNFα -238 A/G or A/A were at increased risk of delivering preterm (race/ethnicity adjusted OR 2.6, 95% CI 1.2, 5.8). The p-value for the genotype and Nugent score interaction=0.02. This study points to one more example of a potential gene-environment interaction in a preterm delivery pathway. Future tests of this finding will determine the robustness of these results.

Blood cadmium levels in women of childbearing age vary by race/ethnicity.

The heavy metal cadmium (Cd) is long-lived in the body and low-level cumulative exposure, even among non-smokers, has been associated with changes in renal function and bone metabolism. Women are more susceptible to the adverse effects of Cd and have higher body burdens. Due to increased dietary absorption of Cd in menstruating women and the long half-life of the metal, reproductive age exposures are likely important contributors to overall body burden and disease risk. We examined blood Cd levels in women of reproductive age in the US and assessed variation by race/ethnicity. Blood Cd concentrations were compared among female NHANES participants aged 20-44, who were neither pregnant nor breastfeeding. Sample size varied primarily based on inclusion/exclusion of smokers (n=1734-3121). Mean Cd concentrations, distributions and odds ratios were calculated using SUDAAN. For logistic regression Cd was modeled as high (the upper 10% of the distribution) vs. the remainder. Overall, Mexican Americans had lower Cd levels than other groups due to a lower smoking prevalence, smoking being an important source of exposure. Among never-smokers, Mexican Americans had 1.77 (95% CI: 1.06-2.96) times the odds of high Cd as compared to non-Hispanic Whites after controlling for age and low iron (ferritin). For non-Hispanic Blacks, the odds were 2.96 (CI: 1.96-4.47) times those of non-Hispanic Whites in adjusted models. Adjustment for relevant reproductive factors or exposure to environmental tobacco smoke had no effect. In this nationally representative sample, non-smoking Mexican American and non-Hispanic Black women were more likely to have high Cd than non-Hispanic White women. Additional research is required to determine the underlying causes of these differences.

Levels of maternal serum corticotropin-releasing hormone (CRH) at midpregnancy in relation to maternal characteristics.

BACKGROUND: Corticotropin-releasing hormone (CRH) in maternal blood originates primarily from gestational tissues and elevated levels in midpregnancy have been linked to adverse pregnancy outcomes. Investigators have hypothesized that high levels of maternal stress might lead to elevated CRH levels in pregnancy. Yet a few studies have measured maternal CRH levels among subgroups of women who experience disproportionate socioeconomic disadvantage, such as African-American and Hispanic women, and found that these groups have lower CRH levels in pregnancy. Our goal was to identify maternal characteristics related to CRH levels in midpregnancy and examine which if any of these factors help to explain race differences in CRH levels. METHODS: The Pregnancy Outcomes and Community Health (POUCH) Study prospectively enrolled women at 15-27 weeks' gestation from 52 clinics in five Michigan communities (1998-2004). Data from the POUCH Study were used to examine maternal demographics, anthropometrics, health behaviors, and psychosocial factors (independent variables) in relation to midpregnancy blood CRH levels modeled as logCRHpg/ml (dependent variable). Analyses were conducted within a sub-cohort from the POUCH Study (671 non-Hispanic Whites, 545 African-Americans) and repeated in the sub-cohort subset with uncomplicated pregnancies (n=746). Blood levels of CRH and independent variables were ascertained at the time of enrollment. All regression models included week of enrollment as a covariate. In addition, final multivariate regression models alternately incorporated different psychosocial measures along with maternal demographics and weight. Psychosocial variables included measures of current depressive symptoms, perceived stress, coping style, hostility, mastery, anomie, and a chronic stressor (history of abuse as a child and adult). RESULTS: In sub-cohort models, the adjusted mean log CRH level was significantly lower in African-Americans vs. non-Hispanic Whites; the difference was -0.48pg/ml (P<0.01). This difference was reduced by 21% (-0.38pg/ml, P<0.01) after inclusion of other relevant covariates. Adjusted mean log CRH levels were also lower among women with <12 years vs. >or=12 years of education (minimal difference=-0.19pg/ml, P<0.05), and among women with high levels of depressive symptoms who did not use antidepressants vs. women with lower levels of depressive symptoms and no antidepressant use (minimal difference=-0.13pg/ml, P<0.01). Log CRH levels were inversely associated with maternal weight (-0.03pg/ml per 10 pound increase, P<.05) but unrelated to smoking and all other psychosocial measures. Results were similar in the subset of women with uncomplicated pregnancies, except that lower CRH levels were also linked to higher perceived stress. CONCLUSION: African-American women have lower blood CRH levels at midpregnancy and the race difference in CRH levels is reduced modestly after adjustment for other maternal characteristics. CRH levels were not elevated among women with high levels of perceived stress or more chronic stressors. The inverse association between CRH levels and maternal weight is likely due to a hemodilution effect. Relations among maternal CRH levels and maternal race, educational level, and depressive symptoms are difficult to explain and invite further investigation. Our results highlight a group of covariates that merit consideration in studies that address CRH in the context of pregnancy and/or post-partum complications.

Maternal weathering and risk of preterm delivery.

OBJECTIVES: We compared the association between advancing maternal age and risk of preterm delivery across 4 groups (Black smokers, Black nonsmokers, White smokers, White nonsmokers) and within the context of neighborhood deprivation levels. METHODS: We obtained data from linked census and birth records for singletons (n = 182 938) delivered by women aged 20 to 39 years in Philadelphia, Pennsylvania; Baltimore, Maryland; 16 Michigan cities; 3 Maryland counties; and 2 North Carolina counties. Results from area-specific multilevel logistic regression models were combined to obtain pooled estimates of relations between maternal age and risk of preterm delivery. We repeated the models after categorizing women by neighborhood deprivation level (low, medium, and high). RESULTS: Among multiparous women, there was a significant age-related increase in preterm delivery in 3 of the 4 groups. The adjusted odds ratio per 5-year age increase was 1.31 in Black smokers, 1.11 in Black nonsmokers, and 1.16 in White smokers. In each group, the odds ratio increased as neighborhood deprivation increased. CONCLUSIONS: These results support the "weathering" hypothesis, suggesting that Black women, women with high-risk behaviors, and women living in high-deprivation neighborhoods may develop "accelerated aging" that increases preterm delivery risk.

Hostility and anomie: links to preterm delivery subtypes and ambulatory blood pressure at mid-pregnancy.

Underlying maternal vascular disease has been implicated as one of several pathways contributing to preterm delivery (PTD) and psychosocial factors such as hostility, anomie, effortful coping, and mastery may be associated with PTD by affecting maternal vascular health. Using data from the Pregnancy Outcomes and Community Health (POUCH) study, we included 2018 non-Hispanic White and 743 African American women from 52 clinics in five Michigan, USA communities. Women were interviewed at 15-27 weeks' gestation and followed to delivery. We found that relations between psychosocial factors and PTD subtypes (i.e. medically indicated, premature rupture of membranes, spontaneous labor) varied by race/ethnicity and socio-economic position (Medicaid insurance status). Among African American women not insured by Medicaid, anomie levels in mid-pregnancy were positively associated with medically indicated PTD after adjusting for maternal age and education. Among all women not insured by Medicaid, hostility levels were positively associated with spontaneous PTD after adjusting for maternal race/ethnicity, age, and education. Failure to detect links between psychosocial factors and PTD risk in poorer women may be due to their excess risk in multiple PTD pathways and/or a more complex web of contributing risk factors. In a subset of 395 women monitored for blood pressure, anomie scores were positively associated with systolic blood pressure and heart rate and hostility scores were positively associated with systolic and diastolic blood pressure, heart rate and mean arterial pressure in models that included time, awake/asleep, race/ethnicity, and age as covariates. Further adjustment for body mass index and smoking attenuated the anomie-vascular relations but had little effect on the hostility-vascular relations. Overall this study of pregnant women provides some physiologic evidence to support findings linking levels of anomie and hostility with risk of PTD.