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.

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.

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..

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.

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.

Large-Scale SARS-CoV-2 Testing Utilizing Saliva and Transposition Sample Pooling.

Identification and isolation of contagious individuals along with quarantine of close contacts, is critical for slowing the spread of COVID-19. Large-scale testing in a surveillance or screening capacity for asymptomatic carriers of COVID-19 provides both data on viral spread and the follow-up ability to rapidly test individuals during suspected outbreaks. The COVID-19 early detection program at Michigan State University has been utilizing large-scale testing in a surveillance or screening capacity since fall of 2020. The methods adapted here take advantage of the reliability, large sample volume, and self-collection benefits of saliva, paired with a cost-effective, reagent conserving two-dimensional pooling scheme. The process was designed to be adaptable to supply shortages, with many components of the kits and the assay easily substituted. The processes outlined for collecting and processing SARS-CoV-2 samples can be adapted to test for future viral pathogens reliably expressed in saliva. By providing this blueprint for universities or other organizations, preparedness plans for future viral outbreaks can be developed.

Differences in Psychosocial Protective Factors by Race/Ethnicity and Socioeconomic Status and Their Relationship to Preterm Delivery.

Background: Non-Hispanic Black ("Black") women in the United States deliver preterm at persistently higher rates than non-Hispanic White ("White") women, and disparities in preterm delivery (PTD) also exist by socioeconomic factors. Research is needed to identify and understand factors that are protective against PTD for Black women and low socioeconomic status (SES) women. Methods: We examined seven potential protective factors at the individual, interpersonal, and neighborhood levels during pregnancy to determine if they (1) differed in prevalence by race/ethnicity and SES and (2) were associated with risk of PTD overall or within specific race/ethnicity and SES groups. We used prospectively collected data from n = 2474 women who were enrolled in the Pregnancy Outcomes and Community Health Study conducted in Michigan (1998-2004). Results: White women reported higher levels of self-esteem, mastery, perceived social support, instrumental social support, and reciprocity compared to Black women (all p < 0.01), while Black women reported higher levels of religiosity compared to white women (p < 0.01). High SES women reported higher levels of all protective factors compared to middle and low SES women (all p < 0.01). While protective factors were not independently associated with PTD, religiosity was associated with lower odds of PTD among low SES women (OR 0.6, 95% CI 0.4-0.9) and among Black women (OR 0.6, 95% CI 0.4-1.0), respectively. Conclusions: Our findings highlight the importance of assessing how protective factors may operate differently across race/ethnicity and SES to promote healthy pregnancy outcomes. Future studies should examine mechanisms that elucidate potential causal pathways between religiosity and PTD for Black women and low SES women.

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.

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.

Maternal habitual snoring and blood pressure trajectories in pregnancy.

STUDY OBJECTIVES: Habitual snoring has been associated with hypertensive disorders of pregnancy. However, exactly when blood pressure (BP) trajectories diverge between pregnant women with and without habitual snoring is unknown. Moreover, the potentially differential impact of chronic vs pregnancy-onset habitual snoring on maternal BP trajectories during pregnancy has not been examined. This study compared patterns of BP across pregnancy in 3 groups of women: those with chronic habitual snoring, those with pregnancy-onset habitual snoring, and nonhabitual snoring "controls." METHODS: In a cohort study of 1,305 pregnant women from a large medical center, participants were asked about habitual snoring (≥ 3 nights/week) and whether their symptoms began prior to or during pregnancy. Demographic, health, and BP data throughout pregnancy were abstracted from medical charts. Linear mixed models were used to examine associations between habitual snoring-onset and pregnancy BP trajectories. RESULTS: A third of women reported snoring prior to pregnancy (chronic snoring) and an additional 23% reported pregnancy-onset snoring. Mean maternal age (SD) was 29.5 (5.6), 30 (6), and 30.5 (5.7) years in controls, chronic, and pregnancy-onset snoring, respectively. Overall, women with pregnancy-onset snoring had higher mean systolic BP and diastolic BP compared to those with chronic habitual snoring or nonhabitual snoring. In gestational week-specific comparisons with controls, systolic BP became significantly higher around 18 weeks' gestation among women with pregnancy-onset snoring and in the third trimester among women with chronic snoring. These differences became detectable at 1 mm Hg and increased thereafter, reaching 3 mm Hg-BP difference at 40 weeks' gestation in women with pregnancy-onset snoring relative to controls. Pairwise mean differences in diastolic BP were significant only among women with pregnancy-onset snoring relative to controls, after 15 weeks' gestation. CONCLUSIONS: Pregnancy-onset and chronic maternal snoring are associated with higher BPs beginning in the second and third trimester, respectively. Pregnancy BP trajectories could identify critical windows for enhanced BP surveillance; the divergent BP trajectories suggest that the 2 groups of women with habitual snoring in pregnancy may need to be considered separately when gestational time intervals are evaluated for increased BP monitoring. CITATION: Dunietz GL, Hao W, Shedden K, et al. Maternal habitual snoring and blood pressure trajectories in pregnancy. J Clin Sleep Med. 2022;18(1):31-38.

Association of Physical Activity and Sedentary Time with Cardio-Autonomic Regulation in Women.

Background: Low moderate-to-vigorous-intensity physical activity (MVPA) and high sedentary time (ST) may contribute to cardiovascular disease (CVD) risk in women, perhaps via cardiac autonomic dysregulation. We examined associations of total, leisure, and occupational MVPA and ST with cardiac autonomic regulation in women. Methods: Data were from 522 women (age = 37.7 ± 5.7 years; 59%white) who participated in the follow-up study of the Pregnancy Outcomes and Community Health Study (between 2011 and 2014). MVPA and ST (hours/day) were self-reported using the Modifiable Activity Questionnaire. Cardiac autonomic regulation was assessed by calculating heart rate variability (HRV) indices (resting heart rate, natural logarithm standard deviation of normal R-R intervals; lnSDNN [total variability], natural logarithm root mean square of the successive differences; lnRMSSD [cardiac parasympathetic activity]) with Kubios software from a 5-minute, seated electrocardiogram. Progressive generalized linear models evaluated associations of total, leisure, and occupational MVPA and ST with HRV indices while adjusting for confounders (demographics, health-related factors), and then potential mediators (clinical variables). A final model evaluated the relationship between ST and HRV stratified by MVPA level. Results: Adjusting for confounders, total and leisure MVPA were associated with favorable lnSDNN (B = 0.027 [p = 0.014] and B = 0.074 [p = 0.009], respectively) and lnRMSSD (B = 0.036 [p = 0.015] and B = 0.075 [p = 0.043], respectively). Adjustment for mediators tended to strengthen the observed significant associations. No associations were found between occupational MVPA or any ST measure with HRV indices (p > 0.05). Neither MVPA nor ST were associated with heart rate. When stratified by MVPA level, leisure ST was associated with unfavorable lnRMSSD (B = -0.041, [p = 0.042]) only among women who did not meet leisure MVPA recommendations. Conclusion: Cardiac autonomic dysregulation may be a mechanism through which low leisure MVPA and, among low-active women, high leisure ST contribute to CVD risk among women.

Placental circadian lincRNAs and spontaneous preterm birth.

Long non-coding RNAs (lncRNAs) have a much higher cell- and/or tissue-specificity compared to mRNAs in most cases, making them excellent candidates for therapeutic applications to reduce off-target effects. Placental long non-coding RNAs have been investigated in the pathogenesis of preeclampsia (often causing preterm birth (PTB)), but less is known about their role in preterm birth. Preterm birth occurs in 11% of pregnancies and is the most common cause of death among infants in the world. We recently identified that genes that drive circadian rhythms in cells, termed molecular clock genes, are deregulated in maternal blood of women with spontaneous PTB (sPTB) and in the placenta of women with preeclampsia. Next, we focused on circadian genes-correlated long intergenic non-coding RNAs (lincRNAs, making up most of the long non-coding RNAs), designated as circadian lincRNAs, associated with sPTB. We compared the co-altered circadian transcripts-correlated lincRNAs expressed in placentas of sPTB and term births using two published independent RNAseq datasets (GSE73712 and GSE174415). Nine core clock genes were up- or downregulated in sPTB versus term birth, where the RORA transcript was the only gene downregulated in sPTB across both independent datasets. We found that five circadian lincRNAs (LINC00893, LINC00265, LINC01089, LINC00482, and LINC00649) were decreased in sPTB vs term births across both datasets (p ≤ .0222, FDR≤.1973) and were negatively correlated with the dataset-specific clock genes-based risk scores (correlation coefficient r = -.65 ∼ -.43, p ≤ .0365, FDR≤.0601). Gene set variation analysis revealed that 65 pathways were significantly enriched by these same five differentially expressed lincRNAs, of which over 85% of the pathways could be linked to immune/inflammation/oxidative stress and cell cycle/apoptosis/autophagy/cellular senescence. These findings may improve our understanding of the pathogenesis of spontaneous preterm birth and provide novel insights into the development of potentially more effective and specific therapeutic targets against sPTB.

Associations Between Maternal Depression, Antidepressant Use During Pregnancy, and Adverse Pregnancy Outcomes: An Individual Participant Data Meta-analysis.

OBJECTIVE: To evaluate the associations of depressive symptoms and antidepressant use during pregnancy with the risks of preterm birth, low birth weight, small for gestational age (SGA), and low Apgar scores. DATA SOURCES: MEDLINE, EMBASE, ClinicalTrials.gov, and PsycINFO up to June 2016. METHODS OF STUDY SELECTION: Data were sought from studies examining associations of depression, depressive symptoms, or use of antidepressants during pregnancy with gestational age, birth weight, SGA, or Apgar scores. Authors shared the raw data of their studies for incorporation into this individual participant data meta-analysis. TABULATION, INTEGRATION, AND RESULTS: We performed one-stage random-effects meta-analyses to estimate odds ratios (ORs) with 95% CIs. The 215 eligible articles resulted in 402,375 women derived from 27 study databases. Increased risks were observed for preterm birth among women with a clinical diagnosis of depression during pregnancy irrespective of antidepressant use (OR 1.6, 95% CI 1.2-2.1) and among women with depression who did not use antidepressants (OR 2.2, 95% CI 1.7-3.0), as well as for low Apgar scores in the former (OR 1.5, 95% CI 1.3-1.7), but not the latter group. Selective serotonin reuptake inhibitor (SSRI) use was associated with preterm birth among women who used antidepressants with or without restriction to women with depressive symptoms or a diagnosis of depression (OR 1.6, 95% CI 1.0-2.5 and OR 1.9, 95% CI 1.2-2.8, respectively), as well as with low Apgar scores among women in the latter group (OR 1.7, 95% CI 1.1-2.8). CONCLUSION: Depressive symptoms or a clinical diagnosis of depression during pregnancy are associated with preterm birth and low Apgar scores, even without exposure to antidepressants. However, SSRIs may be independently associated with preterm birth and low Apgar scores. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42016035711.

Maternal Serum Antioxidants in Mid Pregnancy and Risk of Preterm Delivery and Small for Gestational Age Birth: Results from a Prospective Pregnancy Cohort.

Background: Preterm delivery (PTD) and poor fetal growth are major contributors to neonatal mortality and morbidity that can extend from birth onward. Although overt maternal nutrient deficiencies are associated with adverse pregnancy outcomes, such deficiencies are rare in developed countries. However, some evidence suggests that even within the normal range, higher levels of antioxidant nutrients are protective against adverse pregnancy outcomes. Materials and Methods: Using data from the prospective Pregnancy Outcomes and Community Health (POUCH) Study (n = 301 preterm; n = 246 term), we examined associations between maternal blood levels of selected antioxidants and pregnancy outcomes. Serum collected at 16-27 weeks' gestation was analyzed for carotenoids, retinol, and α- and γ-tocopherol. Using weighted polytomous regression, these nutrient concentrations were assessed in relation to (1) PTD (<37 weeks gestation) overall and grouped as spontaneous or medically indicated; and (2) small for gestational age (SGA) defined as birthweight-for-gestational age <10th percentile of a national reference population. Results: Women with total serum carotenoids in the upper quartile (Q4) had significantly lower odds of medically indicated PTD compared with women in the lower quartiles (Q1-Q3) even after adjustment for maternal characteristics (aOR = 0.4; 95% CI: 0.2-0.9). Odds ratios for SGA were consistently ≤0.5 among women with any of the serum nutrients in Q4 as compared with Q1-Q3, but final models did not reach statistical significance. Conclusion: Results support the possibility that high maternal serum antioxidants and/or the larger dietary or lifestyle pattern they represent may play a protective role in preventing adverse pregnancy outcomes.

EBF1-Correlated Long Non-coding RNA Transcript Levels in 3rd Trimester Maternal Blood and Risk of Spontaneous Preterm Birth.

Biomarkers associated with spontaneous preterm birth (sPTB) before labor onset could aid in prediction, triage, and stratification for testing interventions. In this study we examined maternal blood EBF1-correlated long non-coding RNAs (lncRNAs) in relation to sPTB. We retrieved all lncRNA transcripts from a public gene expression dataset (GSE59491) derived from maternal blood in trimesters 2 and 3 from a Canadian cohort with a matched set of sPTB (n = 51) and term births (n = 106). LncRNA transcripts differentially expressed (limma moderated t-tests) in sPTB vs. term were tested for correlations (Pearson) with EBF1 mRNA levels in the same blood samples. Using logistic regression, EBF1-correlated lncRNAs were divided into tertiles and assessed in relation to odds of sPTB. Two lncRNA transcripts in the 3rd trimester maternal blood were differentially expressed between sPTB and term births (all p < 0.001 and FDR < 0.250) and positively and negatively correlated with EBF1 mRNA levels. They were as follows: (1) LINC00094 r = 0.196 (95% CI: 0.039 to 0.344), p = 0.015, and BH adjusted p = 0.022 and (2) LINC00870 r = - 0.303 (95% CI: - 0.441 to - 0.152), p < 0.001, and BH adjusted p < 0.001. As compared with term births, sPTBs were more likely to be in the highest tertile of LINC00870 (odds ratio (OR) = 4.08 (95% CI 1.60, 10.40), p = 0.003) and the lowest tertile of LINC00094 (OR = 5.16 (95% CI 1.96, 13.61), p < 0.001). Two sPTB-associated EBF1-correlated lncRNAs (LINC00870 and LINC00094) had multiple potential enhancers containing EBF1 binding site(s). Our current findings, along with previous reports linking EBF1 and sPTB, motivate additional research on the EBF1 gene-related gene expression and regulation in relation to sPTB within other cohorts and within laboratory-based models.

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.

Placental pathology, corticotropin-releasing hormone, timing of parturition, and fetal growth in the pregnancy outcomes and community health study.

Background: Identification of vascular pathologies in delivered placentas and their associations with biomarkers measured during pregnancy may elucidate mechanisms of adverse pregnancy outcomes and inform early detection and intervention strategies.Objectives: To examine associations of placental vascular pathology with birth size and timing of parturition, and to evaluate maternal midpregnancy serum corticotropin-releasing hormone (CRH) levels as a marker of the above associations.Study design: The pregnancy outcomes and community health (POUCH) Study enrolled women at 16-27 weeks of pregnancy from five Michigan communities. Histological assessments of delivered placentas and assays of CRH in maternal blood sampled at enrollment were performed in a subcohort of 1152 participants. Five placental vascular pathology constructs were formulated: Maternal-Vascular-Obstructive (MVO), Fetal Vascular-Obstructive (FVO), Maternal Vascular-disturbance of Integrity (MVI), Fetal Vascular-disturbance of Integrity (FVI), and Maternal Vascular-Developmental (MVD). A four-level outcome variable combined small for gestational (SGA) yes/no and delivery timing preterm/term; the non-SGA/term served as the referent group. In multinomial logistic regression models, the five vascular pathology groups were evaluated in relation to the outcome variable and effect sizes were compared before versus after exclusion of participants with high CRH (top quartile).Results: Adjusted odds ratios (aOR) for MVO among SGA/term and SGA/preterm were 4.1 (95% CI: 2.2, 7.9) and 8.8 (95% CI: 3.3, 23.5) respectively. Among SGA/preterm births, the aOR was attenuated by ∼40%, i.e. 5.4 (95% CI: 1.1, 26.2) after removing high CRH pregnancies. MVI and FVO were each associated with SGA/preterm, aOR = 3.7 (95% CI: 1.3, 10.3) and 10.5 (95% CI: 3.6, 30.8) respectively. Removal of high CRH pregnancies reduced the OR estimates by nearly half, i.e. MVI aOR = 1.9 (95% CI: 0.34, 10.9), FVO aOR = 6.0 (95% CI: 1.3, 28.6). MVI, FVI and MVD were each associated with greater odds of non-SGA/preterm, but the aORs showed little change after removing high CRH pregnancies.Conclusions: Obstructive placental vascular pathologies in maternal or fetal vessels are associated with SGA. High CRH levels coincided with a portion of pregnancies that share these complications, particularly among pregnancies that also ended prematurely.

Maternal serum uric acid levels in pregnancy and fetal growth.

Objective: Studies of maternal serum uric acid (UA) in pregnancy focus primarily on high levels of UA, however, both low and high UA levels can be markers of oxidative stress, a biological state potentially linked to fetal growth. We therefore aimed to test whether low and high maternal serum UA levels during pregnancy are associated with atypical fetal growth (unusually small or large) measured as birthweight (BW) for gestational age.Methods: The Pregnancy Outcomes and Community Health Study enrolled 3019 pregnant women between their 16th-27th week of pregnancy from 52 clinics in five Michigan communities (1998-2004). Maternal UA levels were measured in blood collected at enrollment among a subcohort of 1291 participants. Infant BW and gestational age were used to calculate gestational age-specific BW Z-score. Infants were grouped as small (SGA = BW < 10th percentile), appropriate (AGA = BW 10th-90th percentile), or large (LGA) = BW > 90th percentile) for their gestational age. Analyses considered multiple potential confounders. Linear spline or multiple linear regression models were applied to evaluate the relationship between maternal UA levels and BW Z-score overall and within SGA, AGA, and LGA groups. Model robustness was tested through bootstrap, sensitivity analysis, and cross-validation techniques.Results: The relation between maternal UA levels and BW Z-score varied by infant group. Among SGA infants, the relation was nonlinear (J-shape): both extremes of UA had lower BW Z-score with a breakpoint of 0.267 mmol/L UA (adjusted regression coefficient ß = 2.32, p = .01 for lower UA; adjusted ß = -37.38, p < .01 for higher UA). Among AGA infants, there was no significant association, and among LGA infants, the relation was linear (adjusted ß = 2.86, p = .03).Conclusions: Future research on maternal UA levels in pregnancy may benefit from considering both very low and high levels, and identifying in utero conditions associated with the two extremes.

Pregnancy hypertension and its associations with pre-pregnancy depression, anxiety, antidepressants, and anxiolytics.

INTRODUCTION: Few studies have examined pre-pregnancy depression/anxiety and antidepressant/anxiolytic medication use in relation to hypertension disorders of pregnancy, i.e. chronic hypertension (CH), pre-eclampsia (PE), and gestational hypertension (GH). METHODS: This nested case-control study uses Blue Cross Blue Shield of Michigan (BCBSM) claims data of women with singleton live birth pregnancies (2010-2014) enrolled from 2 years prior to last menstrual period to ninety days after delivery. All women with ICD-9CM codes for CH, PE, GH, or unspecified hypertension were included as cases; women without hypertension were randomly sampled as controls. Linkage to Michigan birthfiles resulted in a sample of 12,647 women. Using weighted logistic regression, cases and controls were compared for depression and/or anxiety diagnoses (ICD-9CM codes) and anti-depressant and/or anxiolytic prescriptions throughout the study period. Depression and anxiety were defined as primary diagnosis in ≥1 inpatient or ≥2 outpatient visits. RESULTS: Among women with hypertension disorders of pregnancy, 59% had PE or GH, referred to here as pregnancy hypertension (PH). PH was associated with anti-depressant use prior to LMP only, (aOR = 1.2 95%CI 1.0, 1.5), continued use, (aOR = 1.4 95%CI 1.1, 1.7), and initiation of anxiolytic medication during pregnancy, (aOR = 2.5 95%CI 1.6, 4.2). In this latter group, 96% started medication before PH diagnosis. CH and PH were not associated with depression or anxiety in the absence of anti-depressants/anxiolytics. CONCLUSION: While anti-depressants/anxiolytics may be useful indicators in risk stratification for pregnancy hypertension, the same does not appear to be true for depression/anxiety without related medication use.