RNA profiles reveal signatures of future health and disease in pregnancy.

Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.

Diet Quality, Sedentary Time, and Blood Pressure in the POUCHmoms Study.

BACKGROUND: Elevated blood pressure (BP) is a major contributor to cardiovascular disease in womens; diet and sedentary time (ST) are modifiable lifestyle factors thought to influence BP. OBJECTIVES: The aim of this study was to examine 2 diet-quality measures and ST in relation to BP among parous womens. METHODS: This cross-sectional analysis uses data from 677 womens (age 25-55 y) enrolled in the Pregnancy Outcomes and Community Health (POUCH) Study and followed up in the POUCHmoms study 7-15 y after delivery (2011 and 2014). Follow-up measures included a food-frequency questionnaire (FFQ), self-report of ST (occupational and leisure), and systolic and diastolic blood pressure (SBP and DBP, respectively). The FFQ was used to calculate 2 diet-quality measures, Alternative Healthy Eating Index-2010 (AHEI) and Dietary Approaches to Stop Hypertension (DASH). Total ST h/wk was dichotomized at the median and labeled "low" or "high." In weighted unadjusted and adjusted regression models, BP was assessed in relation to diet scores (linear and threshold associations) and combinations of dichotomized diet-quality scores ("poor" = lowest quartile compared with "not poor" = upper 3 quartiles) and ST. RESULTS: Higher mean SBP and DBP occurred mainly in women with a '"poor" diet-quality score (AHEI and DASH). Among womens with a "poor"-quality diet (on the basis of the AHEI score) and "high" ST, (N = 93) adjusted mean SBP and DBP were 4.5 mmHg and 4.4 mmHg higher, respectively, than that of the counterparts who did not have a poor-quality diet and had "low" ST (N = 275). Results were similar in analyses using the DASH diet score. CONCLUSIONS: Women with poor-quality diets and more ST may need closer BP monitoring. Even modest improvements in womens' diet quality and reductions in ST might help lower their BP, but this observation needs testing in prospective studies..

Perinatal HIV exposure and infection and caregiver depressive symptoms.

Survival is possible for children perinatally exposed to or infected by HIV in the post-combined antiretroviral therapy era and identifying factors affecting children's ability to thrive has public health significance. Caregiver mental health is one such factor to consider given its impact on child development, but previous work has not included a full complement of HIV exposure/infection groups within HIV-endemic settings. We compared depressive symptoms among caregivers of 3 groups of 6-10-year-olds in Uganda: children with perinatally acquired HIV infection (CPHIV, n = 102), children with perinatal HIV exposure, but no infection (CPHEU, n = 101), and children without perinatal HIV exposure or infection (CHUU, n = 103). The Hopkins Symptom Checklist was used to assess caregiver depressive symptoms. Generalized linear models were used to estimate group mean differences. Adjusted models included caregiver demographics, social support, and lifetime trauma. Depression symptoms were higher among CPHEU compared to CPHIV caregivers (model coefficient [B] = -3.5, 95%CI -5.3, -1.8). This finding was minimally attenuated following adjustment for covariates (B = -2.2, 95%CI -4.1, -0.4) and among biological mothers. At lower levels of social support and wealth, CPHEU caregivers reported higher levels of depression symptoms than CPHIV caregivers. Our findings point to unmet mental health needs among CPHEU caregivers.

Isotemporal Associations of Device-Measured Sedentary Time and Physical Activity with Cardiac-Autonomic Regulation in Previously Pregnant Women.

BACKGROUND: High sedentary time (ST) and low physical activity may increase cardiovascular risk, potentially though cardiac-autonomic dysregulation. This study investigated associations of statistically exchanging device-measured ST and physical activity with measures of cardiac-autonomic regulation in previously pregnant women. METHOD: This cross-sectional, secondary analysis included 286 women (age = 32.6 ± 5.7 years; 68% white) measured 7-15 years after delivery. ST and light (LPA), moderate (MPA), vigorous (VPA), and moderate-to-vigorous (MVPA) intensity physical activity were measured by ActiGraph GT3X. ST was further partitioned into long (≥ 30 min) and short (< 30 min) bouts. MVPA was also partitioned into long (≥ 10 min) and short (< 10 min) bouts. Cardiac-autonomic regulation was assessed by heart rate variability (HRV) (resting heart rate, natural log transformed standard deviation of normal R-R intervals [lnSDNN], natural log-transformed root mean square of successive differences [lnRMSSD]) from a 5-min seated ECG. Progressive isotemporal substitution models adjusted for confounders. Sensitivity analyses removed women with related underlying medical conditions and who did not meet respiration rate criteria. RESULTS: Initial analyses found no significant associations with HRV when exchanging 30 min of ST and physical activity (p > 0.05). Yet, replacing long- and short-bout ST with 30 min of long-bout MVPA yielded significantly higher (healthier) lnRMSSD (B = 0.063 ± 0.030 and B = 0.056 ± 0.027, respectively; both p < 0.05). Sensitivity analyses strengthened these associations and yielded further associations of higher lnSDNN and lnRMSSD when replacing 30 min of short-bout MVPA with equivalent amounts of long-bout MVPA (B = 0.074 ± 0.037 and B = 0.091 ± 0.046, respectively). CONCLUSION: Replacing ST with long-bout MVPA is a potential strategy to improve cardiac-autonomic function in previously pregnant women.

Maternal Socioeconomic Mobility and Preterm Delivery: A Latent Class Analysis.

Objective Growing evidence suggests that maternal socioeconomic mobility (SM) is associated with pregnancy outcomes. Our study investigated the association between maternal SM from childhood to adulthood and the risk of preterm delivery (PTD), and examined heterogeneity of associations by race/ethnicity. Methods In this study, 3019 pregnant women enrolled from 5 Michigan communities at 16-27 weeks' gestation (1998-2004) provided their parents' socioeconomic position (SEP) indicators (education, occupation, receipt of public assistance) and their own and child's father's SEP indicators (education, occupation, Medicaid status, and household income) at the time of enrollment. Latent class analysis was used to identify latent classes of childhood SEP indicators, adulthood SEP indicators, and SM from childhood to adulthood, respectively. A model-based approach to latent class analysis with distal outcome assessed relations between latent class and PTD, overall and within race/ethnicity groups. Results Three latent classes (low, middle, high) were identified for childhood SEP indicators and adulthood SEP indicators, respectively; while four latent classes (static low, upward, downward, and static high) best described SM. Women with upward SM had decreased odds of PTD (Odds ratio = 0.60, 95% confidence interval: 0.42, 0.87), compared to those with static low SEP. This SM advantage was true for all women and most pronounced in white/others women. Conclusions Maternal experiences of upward SM may be important considerations when assessing PTD risk. Our results support the argument that policies and programs aimed at improving women's SEP could lower PTD rates.

Stressors Across the Life-Course and Preterm Delivery: Evidence From a Pregnancy Cohort.

Objectives Growing evidence suggests that pre-conception stressors are associated with increased risk of preterm delivery (PTD). Our study assesses stressors in multiple domains at multiple points in the life course (i.e., childhood, adulthood, within 6 months of pregnancy) and their relation to PTD. We also examine heterogeneity of associations by race/ethnicity, PTD timing, and PTD clinical circumstance. Methods We assessed stressors retrospectively via mid-pregnancy questionnaires in the Pregnancy Outcomes and Community Health Study (1998-2004), a Michigan pregnancy cohort (n = 2559). Stressor domains included abuse/witnessing violence (hereafter "abuse"), loss, economic stress, and substance use. We used logistic and multinomial regression for the following outcomes: PTD (<37 weeks' gestation), PTD by timing (≤34 weeks, 35-36 weeks) and PTD by clinical circumstance (medically indicated, spontaneous). Covariates included race/ethnicity, education, parity, and marital status. Results Stressors in the previous 6 months were not associated with PTD. Experiencing abuse during both childhood and adulthood increased adjusted odds of PTD among women of white or other race/ethnicity only (aOR 1.6, 95 % CI 1.1, 2.5). Among all women, abuse in childhood increased odds of late PTD (aOR 1.5, 95 % CI 1.0, 2.2) while abuse in both childhood and adulthood non-significantly increased odds of early PTD (aOR 1.6, 95 % CI 0.9, 2.7). Sexual, but not physical, abuse in both childhood and adulthood increased odds of PTD (aOR 1.9, 95 % CI 1.0, 3.5). Conclusions Experiences of abuse-particularly sexual abuse-across the life-course may be important considerations when assessing PTD risk. Our results motivate future studies of pathways linking abuse and PTD.

Assisted reproduction and risk of preterm birth in singletons by infertility diagnoses and treatment modalities: a population-based study.

PURPOSE: The purpose of this study is to examine the spectrum of infertility diagnoses and assisted reproductive technology (ART) treatments in relation to risk of preterm birth (PTB) in singletons. METHODS: Population-based assisted reproductive technology surveillance data for 2000-2010 were linked with birth certificates from three states: Florida, Massachusetts, and Michigan, resulting in a sample of 4,370,361 non-ART and 28,430 ART-related singletons. Logistic regression models with robust variance estimators were used to compare PTB risk among singletons conceived with and without ART, the former grouped by parental infertility diagnoses and treatment modalities. Demographic and pregnancy factors were included in adjusted analyses. RESULTS: ART was associated with increased PTB risk across all infertility diagnosis groups and treatment types: for conventional ART, adjusted relative risks ranged from 1.4 (95% CI 1.0, 1.9) for male infertility to 2.4 (95% CI 1.8, 3.3) for tubal ligation. Adding intra-cytoplasmic sperm injection and/or assisted hatching to conventional ART treatment did not alter associated PTB risks. Singletons conceived by mothers without infertility diagnosis and with donor semen had an increased PTB risk relative to non-ART singletons. CONCLUSIONS: PTB risk among ART singletons is increased within each treatment type and all underlying infertility diagnosis, including male infertility. Preterm birth in ART singletons may be attributed to parental infertility, ART treatments, or their combination.

Gestational Age at Term, Delivery Circumstance, and Their Association with Childhood Attention Deficit Hyperactivity Disorder Symptoms.

BACKGROUND: Perinatal characteristics may identify subgroups of term-born children at risk for academic and behavioural difficulties. Using follow-up data from the Pregnancy Outcomes and Community Health Study, we subdivided term births according to two potential markers of perinatal risk (gestational age, delivery circumstance) and evaluated their association with attention deficit hyperactivity disorder (ADHD) symptoms. METHODS: We included children born at term whose mothers completed the Conners' Parent Rating Scales-Revised-Short Form (CPRS-R-S) (n = 610; ages: 3-9 years). The CPRS-R-S yields age and sex-referenced T-scores for the two primary dimensions of ADHD (inattention, hyperactivity) and an ADHD Index that reflects both dimensions. Using general linear models, we evaluated whether: (1) term delivery defined by gestational week (reference: 39-40 weeks), or (2) term delivery circumstance defined by labour onset type and mode of delivery (reference: spontaneous labour, vaginal delivery) was associated with these problems. RESULTS: Following adjustment for parity, sociodemographics, and maternal mental health both during pregnancy and at the child follow-up survey, the induced labour plus caesarean group exhibited higher inattention and ADHD Index scores relative to the spontaneous labour, vaginal delivery group (inattention: mean difference = 5.1, 95% CI 0.6, 9.7; ADHD Index: mean difference = 4.1, 95% CI 0.5, 7.8). Findings were primarily driven by male children. CONCLUSIONS: Among term-born children, only those whose mothers experienced induction of labour that culminated in caesarean delivery exhibited higher levels of ADHD symptoms. Prenatal, antepartum, and/or postnatal factors associated with this delivery profile may reflect increased risk for such problems.

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.

Movin' on Up: Socioeconomic Mobility and the Risk of Delivering a Small-for-Gestational Age Infant.

OBJECTIVE: Poor fetal growth is associated with increased rates of adverse health outcomes in children and adults. The social determinants of poor fetal growth are not well understood. Using multiple socioeconomic indicators measured at the individual level, this study examined changes in maternal socioeconomic position (SEP) from childhood to adulthood (socioeconomic mobility) in relation to poor fetal growth in offspring. METHODS: Data were from the Pregnancy Outcomes and Community Health Study (September 1998-June 2004) that enrolled women in mid-pregnancy from 52 clinics in five Michigan communities (2463 women: 1824 non-Hispanic White, 639 non-Hispanic Black). Fetal growth was defined by birthweight-for-gestational age percentiles; infants with birthweight-for-gestational age <10th percentile were referred to as small-for-gestational age (SGA). In logistic regression models, mothers whose SEP changed from childhood to adulthood were compared to two reference groups, the socioeconomic group they left and the group they joined. RESULTS: Approximately, 8.2 % of women (non-Hispanic White: 6.3 %, non-Hispanic Black: 13.9 %) delivered an SGA infant. Upward mobility was associated with decreased risk of delivering an SGA infant. Overall, the SGA adjusted-odds ratio was 0.34 [95 % confidence interval (CI) 0.17-0.69] for women who moved from lower to middle/upper versus static lower class, and 0.44 (CI 0.28-1.04) for women who moved from middle to upper versus static middle class. There were no significant differences in SGA risk when women were compared to the SEP group they joined. CONCLUSIONS: Our findings support a link between mother's socioeconomic mobility and SGA offspring. Policies that allow for the redistribution or reinvestment of resources may reduce disparities in rates of SGA births.

Maternal mid-pregnancy lipids and birthweight.

OBJECTIVE: To describe associations between maternal lipids and birthweight and to determine whether pre-pregnancy body mass index (BMI) modifies these associations. DESIGN: Cohort study. SETTING: Multiple communities in Michigan, USA. POPULATION: Participants were a sub-cohort of women from the multi-community Pregnancy Outcomes and Community Health (POUCH) study (1998-2004). METHODS: Maternal total cholesterol, high-density lipoprotein (HDLc), and low-density lipoprotein (LDLc) cholesterol, and triglycerides were assessed at 16-27 weeks' gestation. Women were classified as having normal (< 25 kg/m(2) ) or overweight/obese (≥ 25 kg/m(2) ) pre-pregnancy BMI. MAIN OUTCOME MEASURES: Sex- and gestational-age-specific body weight z-score (BWz). RESULTS: Regression models examined associations among lipids (low: 1st quartile, referent: middle quartiles, high: 4th quartile) and BWz for the total sample and stratified by pre-pregnancy BMI. In adjusted analyses (n = 1207), low HDLc was associated with lower BWz (ß = -0.23, 95% CI -0.40 to -0.06), whereas high triglycerides were associated with higher BWz (ß = 0.23, 95% CI 0.06-0.41). Once stratified by pre-pregnancy BMI, low total cholesterol was associated with lower BWz in normal BMI women (ß = -0.25, 95% CI -0.47 to -0.03), whereas in overweight/obese BMI women, high HDLc was inversely (ß = -0.29, 95% CI -0.54 to -0.04) and high triglycerides were directly associated with BWz (ß = 0.32, 95% CI 0.07-0.54). Removing women with gestational diabetes/hypertensive disorders did not alter the results. CONCLUSIONS: The associations between maternal lipids and BWz vary by lipid measure and pre-pregnancy BMI. Future work should examine whether lipids and pre-pregnancy BMI make unique contributions to the fetal programming of disease.

Seasonal variation of 25-hydroxyvitamin D among non-Hispanic black and white pregnant women from three US pregnancy cohorts.

BACKGROUND: Vitamin D deficiency during pregnancy has been associated with increased risk of complications and adverse perinatal outcomes. We evaluated seasonal variation of 25-hydroxyvitamin D [25(OH)D] among pregnant women, focusing on patterns and determinants of variation. METHODS: Data came from three cohort studies in the US that included 2583 non-Hispanic Black and White women having prenatal 25(OH)D concentrations determined. Fourier time series and generalised linear models were used to estimate the magnitude of 25(OH)D seasonality. We modelled seasonal variability using a stationary cosinor model to estimate the phase shift, peak-trough difference, and annual mean of 25(OH)D. RESULTS: We observed a peak for 25(OH)D in summer, a nadir in winter, and a phase of 8 months, which resulted from fluctuations in 25(OH)D3 rather than 25(OH)D2. After adjustment for covariates, the annual mean concentrations and estimated peak-trough difference of 25(OH)D among Black women were 19.8 ng/mL [95% confidence interval (CI) 18.9, 20.5] and 5.8 ng/mL [95% CI 4.7, 6.7], and for non-Hispanic White women were 33.0 ng/mL [95% CI 32.6, 33.4] and 7.4 ng/mL [95% CI 6.0, 8.9]. CONCLUSIONS: Non-Hispanic Black women had lower average 25(OH)D concentrations throughout the year and smaller seasonal variation levels than non-Hispanic White women. This study's confirmation of 25(OH)D seasonality over a calendar year has the potential to enhance public health interventions targeted to improve maternal and perinatal outcomes.

The Affordable Care Act Dependent Coverage Provision and Unintended Pregnancy.

Background: Nearly half of all pregnancies in the United States are considered unintended (mistimed or unwanted), and this rate is even higher among younger and lower income women. The Affordable Care Act (ACA) dependent coverage provision may have influenced the frequency of unintended pregnancies by increasing accessibility to and affordability of family planning services among young adults. Furthermore, the impact of this provision may differ by young adult income level as those with lower income are less likely to be insured and thus more likely to benefit from this provision. Our objective was to estimate the association between the ACA dependent coverage provision and unintended pregnancy, overall, and by young adult income level. Methods: We applied a difference-in-differences approach to data from multiple cycles of the National Survey of Family Growth (n = 10,104) and compared trends in unintended pregnancy between those who were eligible to benefit (ages 18-25 years) and those who were ineligible to benefit (ages 26-33 years) from the provision, overall, and among income subgroups. Results: We found evidence that the dependent coverage provision was associated with a -7.4 percentage point reduction (95% CI: -13.5, -1.3) in the prevalence of unintended pregnancy among young adults with lower income (<100% of the federal poverty level). There was limited evidence, however, that the provision was associated with unintended pregnancy among young adults with higher income levels. Conclusions: These findings suggest the ACA dependent coverage provision may have reduced unintended pregnancy among a particularly high-risk group (i.e., young adults with lower income).

Subgroups of pelvic pain are differentially associated with endometriosis and inflammatory comorbidities: a latent class analysis.

ABSTRACT: Chronic pelvic pain is heterogeneous with potentially clinically informative subgroups. We aimed to identify subgroups of pelvic pain based on symptom patterns and investigate their associations with inflammatory and chronic pain-related comorbidities. Latent class analysis (LCA) identified subgroups of participants (n = 1255) from the Adolescence to Adulthood (A2A) cohort. Six participant characteristics were included in the LCA: severity, frequency, and impact on daily activities of both menstruation-associated (cyclic) and non-menstruation-associated (acyclic) pelvic pain. Three-step LCA quantified associations between LC subgroups, demographic and clinical variables, and 18 comorbidities (10 with prevalence ≥10%). Five subgroups were identified: none or minimal (23%), moderate cyclic only (28%), severe cyclic only (20%), moderate or severe acyclic plus moderate cyclic (9%), and severe acyclic plus severe cyclic (21%). Endometriosis prevalence within these 5 LCA-pelvic pain-defined subgroups ranged in size from 4% in "none or minimal pelvic pain" to 24%, 72%, 70%, and 94%, respectively, in the 4 pain subgroups, with statistically significant odds of membership only for the latter 3 subgroups. Migraines were associated with significant odds of membership in all 4 pelvic pain subgroups relative to those with no pelvic pain (adjusted odds ratios = 2.92-7.78), whereas back, joint, or leg pain each had significantly greater odds of membership in the latter 3 subgroups. Asthma or allergies had three times the odds of membership in the most severe pain group. Subgroups with elevated levels of cyclic or acyclic pain are associated with greater frequency of chronic overlapping pain conditions, suggesting an important role for central inflammatory and immunological mechanisms.

Mononuclear leukocyte infiltrate in extraplacental membranes and preterm delivery.

Large numbers of polymorphonuclear leukocytes in the amnion and chorion define histological chorioamnionitis (HCA), a condition linked to spontaneous preterm delivery (PTD). Less is known about placental patterns of mononuclear leukocyte (MNL) density and PTD. In this prospective study (1998-2004), women were sampled from 52 clinics in 5 Michigan communities and enrolled at 16-27 weeks' gestation. HCA and MNL distributions in delivered placentas were evaluated microscopically in a subcohort (290 preterm, 823 term). Midpregnancy biomarkers from maternal blood (i.e., C-reactive protein (CRP), corticotropin-releasing hormone, and cytokines) were compared among term and PTD subjects grouped by presence/absence of HCA and high MNL density. A density of more than 10 MNLs per high-power field in the chorion of the membrane roll, referred to as MNL-CMR, was associated with medically indicated PTD (odds ratio = 2.2, 95% confidence interval: 1.3, 3.6) and spontaneous PTD (odds ratio = 2.5, 95% confidence interval: 1.7, 3.7). Associations persisted after removal of women with HCA-positive placentas, abruption, hypertensive disorders, or obesity. HCA-associated PTD showed higher CRP and cytokine levels. MNL-CMR-associated PTD showed higher CRP and corticotropin-releasing hormone levels. These data suggest that an MNL infiltrate in the chorion of the membrane roll marks PTD pathways that are distinct from HCA and not entirely explained by pregnancy complications.

Mid-pregnancy maternal leptin levels, birthweight for gestational age and preterm delivery.

OBJECTIVE: Maternal blood leptin levels are positively associated with adiposity. Recent studies suggest that leptin is also abundantly produced by the placenta and may function as a regulator of foetal growth. Our goal was to examine mid-pregnancy levels of leptin in maternal blood in relation to birthweight for gestational age (BW/GA) and timing of delivery after accounting for maternal prepregnancy body mass index (prepreg-BMI) and pregnancy complications. PATIENTS: Data were from 1304 subcohort mother/infant pairs who participated in the Pregnancy Outcomes and Community Health (POUCH) Study (1998-2004). MEASUREMENTS: Leptin levels, measured at 16-27 weeks' gestation, were log-transformed. Geometric mean (GMean) leptin levels were estimated by weighted linear regression with gestational age at blood draw as a covariate. GMean was re-transformed to the original scale for reporting. RESULTS: Using the GMeans leptin in mothers of term appropriate-for-gestational age (AGA) neonates as the referent (25·2 µg/l), we observed lower levels in mothers of preterm-AGA (21·9 µg/l), term small-for-gestational age (SGA) (20·3 µg/l) and preterm-SGA neonates (21·7 µg/l). Results were largely unchanged after adjustment for prepreg-BMI. Leptin levels were higher in mothers who delivered large-for-gestational age (LGA) neonates, both preterm (33·6 µg/l) and term (29·1 µg/l), but the GMeans were markedly attenuated after adjustment for prepreg-BMI. CONCLUSION: The association between BW/GA and maternal leptin levels after adjustment for prepreg-BMI may represent: (i) a residual effect of maternal adiposity that is not fully captured by BMI; and/or (ii) variation in placental leptin levels entering the maternal circulation. In conclusion, mid-pregnancy maternal blood leptin levels may be an early indicator of foetal growth status.

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.

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 lipids at mid-pregnancy and the risk of preterm delivery.

OBJECTIVE: This study examined associations between maternal lipid levels at mid-pregnancy and preterm delivery, medically indicated or spontaneous. DESIGN: Prospective cohort study. SETTING: Women were recruited from 52 clinics in five Michigan, USA communities (1998-2004). POPULATION: Pregnant women were enrolled at 15-27 weeks' gestation and followed to delivery (n=3019). METHODS: A single blood sample was obtained at study enrollment. Blood lipids, i.e. total cholesterol (TC), high-density lipoprotein (HDLc), low-density lipoprotein (LDLc) cholesterol, and triglycerides (TG), were measured on a sub-cohort (n=1309). MAIN OUTCOME MEASURES: There were 221 spontaneous, 100 medically indicated preterm deliveries and 988 term deliveries. Polytomous logistic regression models examined relationships among cholesterol levels (Low: <10(th) percentile, Referent: 10(th) -<70(th) percentile, High: ≥70(th) percentile), quartiles of TG (Referent: first quartile) and delivery outcome (Referent: term). RESULTS: Odds of medically indicated preterm delivery were increased among women with low TC (adjusted odds ratio (aOR)=2.04, 95% confidence interval (CI): 1.12, 3.72), low HDLc (aOR=1.89, 95%CI: 1.04, 3.42) or low LDLc (aOR=1.96, 95%CI: 1.09, 3.54). Odds of spontaneous preterm delivery were increased among women with high TC (aOR=1.51, 95%CI: 1.06, 2.15), high LDLc (aOR=1.42, 95%CI: 0.99, 2.04) or high TG (aOR=1.90, 95%CI: 1.21, 2.97 and aOR=1.72, 95%CI: 1.06, 2.78 for third and fourth quartiles, respectively). CONCLUSIONS: Extremely low TC, HDLc, and LDLc were associated with a modest increase in risk of medically indicated preterm delivery, whereas high TC, LDLc and TG modestly increased the risk of spontaneous preterm delivery. Further research is needed to uncover explanations for these associations and to identify optimal ranges for maternal lipids.