Genetic polymorphisms associated with adverse pregnancy outcomes in nulliparas.

Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Adverse Pregnancy Outcomes and Pharyngeal Flow Limitation during Sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

RATIONALE: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. OBJECTIVE: To determine whether a novel objective measure of flow limitation identifies an increased risk of preeclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be. METHODS: Flow limitation severity scores (0%=fully obstructed, 100%=open airway)- quantified from breath-by-breath airflow shape-were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and preeclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension, and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and infant birthweight. RESULTS: Of 1939 participants with flow limitation data at both time-points (age: 27.0±5.4 yr [mean±sd], BMI: 27.7±6.1 kg·m-2), 5.8% developed preeclampsia, 12.7% developed HDP, and 4.5% developed GDM. Greater flow limitation was associated with increased preeclampsia risk: adjusted Odds Ratio (OR) 2.49, 95% Confidence Interval [1.69, 3.69], per 2SD increase in severity. Findings persisted in women without sleep apnea (apnea-hypopnea index <5 events·hr-1). Flow limitation was associated with HDP (OR: 1.77 [1.33, 2.38]) and reduced infant birthweight (83.7 [31.8, 135.6] g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of preeclampsia, HDP, and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

Prediction of metabolic syndrome following a first pregnancy.

BACKGROUND: The prevalence of metabolic syndrome is rapidly increasing in the United States. We hypothesized that prediction models using data obtained during pregnancy can accurately predict the future development of metabolic syndrome. OBJECTIVE: This study aimed to develop machine learning models to predict the development of metabolic syndrome using factors ascertained in nulliparous pregnant individuals. STUDY DESIGN: This was a secondary analysis of a prospective cohort study (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be Heart Health Study [nuMoM2b-HHS]). Data were collected from October 2010 to October 2020, and analyzed from July 2023 to October 2023. Participants had in-person visits 2 to 7 years after their first delivery. The primary outcome was metabolic syndrome, defined by the National Cholesterol Education Program Adult Treatment Panel III criteria, which was measured within 2 to 7 years after delivery. A total of 127 variables that were obtained during pregnancy were evaluated. The data set was randomly split into a training set (70%) and a test set (30%). We developed a random forest model and a lasso regression model using variables obtained during pregnancy. We compared the area under the receiver operating characteristic curve for both models. Using the model with the better area under the receiver operating characteristic curve, we developed models that included fewer variables based on SHAP (SHapley Additive exPlanations) values and compared them with the original model. The final model chosen would have fewer variables and noninferior areas under the receiver operating characteristic curve. RESULTS: A total of 4225 individuals met the inclusion criteria; the mean (standard deviation) age was 27.0 (5.6) years. Of these, 754 (17.8%) developed metabolic syndrome. The area under the receiver operating characteristic curve of the random forest model was 0.878 (95% confidence interval, 0.846-0.909), which was higher than the 0.850 of the lasso model (95% confidence interval, 0.811-0.888; P<.001). Therefore, random forest models using fewer variables were developed. The random forest model with the top 3 variables (high-density lipoprotein, insulin, and high-sensitivity C-reactive protein) was chosen as the final model because it had the area under the receiver operating characteristic curve of 0.867 (95% confidence interval, 0.839-0.895), which was not inferior to the original model (P=.08). The area under the receiver operating characteristic curve of the final model in the test set was 0.847 (95% confidence interval, 0.821-0.873). An online application of the final model was developed (https://kawakita.shinyapps.io/metabolic/). CONCLUSION: We developed a model that can accurately predict the development of metabolic syndrome in 2 to 7 years after delivery.

The Role of cfDNA Biomarkers and Patient Data in the Early Prediction of Preeclampsia: Artificial Intelligence Model.

OBJECTIVE: Accurate individualized assessment of preeclampsia risk enables the identification of patients most likely to benefit from initiation of low-dose aspirin at 12-16 weeks' gestation when there is evidence for its effectiveness, as well as guiding appropriate pregnancy care pathways and surveillance. The primary objective of this study was to evaluate the performance of artificial neural network models for the prediction of preterm preeclampsia (<37 weeks' gestation) using patient characteristics available at the first antenatal visit and data from prenatal cell-free DNA (cfDNA) screening. Secondary outcomes were prediction of early onset preeclampsia (<34 weeks' gestation) and term preeclampsia (≥37 weeks' gestation). METHODS: This secondary analysis of a prospective, multicenter, observational prenatal cfDNA screening study (SMART) included singleton pregnancies with known pregnancy outcomes. Thirteen patient characteristics that are routinely collected at the first prenatal visit and two characteristics of cfDNA, total cfDNA and fetal fraction (FF), were used to develop predictive models for early-onset (<34 weeks), preterm (<37 weeks), and term (≥37 weeks) preeclampsia. For the models, the 'reference' classifier was a shallow logistic regression (LR) model. We also explored several feedforward (non-linear) neural network (NN) architectures with one or more hidden layers and compared their performance with the LR model. We selected a simple NN model built with one hidden layer and made up of 15 units. RESULTS: Of 17,520 participants included in the final analysis, 72 (0.4%) developed early onset, 251 (1.4%) preterm, and 420 (2.4%) term preeclampsia. Median gestational age at cfDNA measurement was 12.6 weeks and 2,155 (12.3%) had their cfDNA measurement at 16 weeks' gestation or greater. Preeclampsia was associated with higher total cfDNA (median 362.3 versus 339.0 copies/ml cfDNA; p<0.001) and lower FF (median 7.5% versus 9.4%; p<0.001). The expected, cross-validated area under the curve (AUC) scores for early onset, preterm, and term preeclampsia were 0.782, 0.801, and 0.712, respectively for the LR model, and 0.797, 0.800, and 0.713, respectively for the NN model. At a screen-positive rate of 15%, sensitivity for preterm preeclampsia was 58.4% (95% CI 0.569, 0.599) for the LR model and 59.3% (95% CI 0.578, 0.608) for the NN model.The contribution of both total cfDNA and FF to the prediction of term and preterm preeclampsia was negligible. For early-onset preeclampsia, removal of the total cfDNA and FF features from the NN model was associated with a 6.9% decrease in sensitivity at a 15% screen positive rate, from 54.9% (95% CI 52.9-56.9) to 48.0% (95% CI 45.0-51.0). CONCLUSION: Routinely available patient characteristics and cfDNA markers can be used to predict preeclampsia with performance comparable to other patient characteristic models for the prediction of preterm preeclampsia. Both LR and NN models showed similar performance.

Serum exosomal microRNA pathway activation in placenta accreta spectrum: pathophysiology and detection.

BACKGROUND: Placenta accreta spectrum disorders are a complex range of placental pathologies that are associated with significant maternal morbidity and mortality. A diagnosis of placenta accreta spectrum relies on ultrasonographic findings with modest positive predictive value. Exosomal microRNAs are small RNA molecules that reflect the cellular processes of the origin tissues. OBJECTIVE: We aimed to explore exosomal microRNA expression to understand placenta accreta spectrum pathology and clinical use for placenta accreta spectrum detection. STUDY DESIGN: This study was a biomarker analysis of prospectively collected samples at 2 academic institutions from 2011 to 2022. Plasma specimens were collected from patients with suspected placenta accreta spectrum, placenta previa, or repeat cesarean deliveries. Exosomes were quantified and characterized by nanoparticle tracking analysis and western blotting. MicroRNA were assessed by polymerase chain reaction array and targeted single quantification. MicroRNA pathway analysis was performed using the Ingenuity Pathway Analyses software. Placental biopsies were taken from all groups and analyzed by polymerase chain reaction and whole cell enzyme-linked immunosorbent assay. Receiver operating characteristic curve univariate analysis was performed for the use of microRNA in the prediction of placenta accreta spectrum. Clinically relevant outcomes were collected from abstracted medical records. RESULTS: Plasma specimens were analyzed from a total of 120 subjects (60 placenta accreta spectrum, 30 placenta previa, and 30 control). Isolated plasma exosomes had a mean size of 71.5 nm and were 10 times greater in placenta accreta spectrum specimens (20 vs 2 particles/frame). Protein expression of exosomes was positive for intracellular adhesion molecule 1, flotilin, annexin, and CD9. MicroRNA analysis showed increased detection of 3 microRNAs (mir-92, -103, and -192) in patients with placenta accreta spectrum. Pathway interaction assessment revealed differential regulation of p53 signaling in placenta accreta spectrum and of erythroblastic oncogene B2 or human epidermal growth factor 2 in control specimens. These findings were subsequently confirmed in placental protein analysis. Placental microRNA paralleled plasma exosomal microRNA expression. Biomarker assessment of placenta accreta spectrum signature microRNA had an area under the receiver operating characteristic curve of 0.81 (P<.001; 95% confidence interval, 0.73-0.89) with a sensitivity and specificity of 89.2% and 80%, respectively. CONCLUSION: In this large cohort, plasma exosomal microRNA assessment revealed differentially expressed pathways in placenta accreta spectrum, and these microRNAs are potential biomarkers for the detection of placenta accreta spectrum.

NuMoM2b Study Insights: Primary Exposures, Outcomes, and Directions for Future Research.

OBJECTIVE: To summarize the publications to date from a large obstetric cohort of nulliparous individuals. STUDY DESIGN: We summarized all of the publications from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b). We descriptively summarized the most common outcomes and exposures reported in current publications. RESULTS: Fifty-six publications to date are discussed. The most common primary exposures reported are participant baseline characteristics such as body mass index (24%), sociodemographic characteristics (22%), and sleep factors (16%). These exposures were most commonly measured in the first trimester (77%). The most commonly reported primary outcomes were related to adverse pregnancy outcomes (APOs, 51.6%), with 25% using a composite of multiple APOs as the primary outcome. At least 8,000 participants were used in the analyses of over half of the publications. CONCLUSION: The nuMoM2b study has generated a diverse array of publications and conclusions on factors associated with APOs. The publicly available data set from the nuMoM2b study continues to hold potential for considerable advances, new insights, and future research opportunities to optimize pregnancy and pregnancy-related health. KEY POINTS: · The nuMoM2b pregnancy cohort has generated 56 publications thus far.. · The main findings of these publications are summarized and categorized in this work.. · The data and specimens from this cohort are available and can answer many clinical questions..

Allostatic load in early pregnancy and sleep-disordered breathing.

OBJECTIVES: To assess the association between allostatic load in early pregnancy and sleep-disordered breathing (SDB) during pregnancy. METHODS: High allostatic load in the first trimester was defined as ≥ 4 of 12 biomarkers (systolic blood pressure, diastolic blood pressure, body mass index, cholesterol, low-density lipoprotein, high-density lipoprotein, high sensitivity C-reactive protein, triglycerides, insulin, glucose, creatinine, and albumin) in the unfavorable quartile. SDB was objectively measured using the Embletta-Gold device and operationalized as "SDB ever" in early (6-15 weeks) or mid-pregnancy (22-31 weeks); SDB at each time point was analyzed as secondary outcomes. Multivariable logistic regression was used to test the association between high allostatic load and SDB, adjusted for confounders. Moderation and sensitivity analyses were conducted to assess the role of allostatic load in racial disparities of SDB and obesity affected the relationship between allostatic load and SDB. RESULTS: High allostatic load was present in 35.0% of the nuMoM2b cohort. The prevalence of SDB ever occurred among 8.3% during pregnancy. After adjustment, allostatic load remained significantly associated with SDB ever (aOR= 5.3; 3.6-7.9), in early-pregnancy (aOR= 7.0; 3.8-12.8), and in mid-pregnancy (aOR= 5.8; 3.7-9.1). The association between allostatic load and SDB was not significantly different for people with and without obesity. After excluding BMI from the allostatic load score, the association decreased in magnitude (aOR= 2.6; 1.8-3.9). CONCLUSION: The association between allostatic load and SDB was independent of confounders including BMI. The complex and likely bidirectional relationship between chronic stress and SDB deserves further study in reducing SDB.

Community-level social determinants of health and pregestational and gestational diabetes.

BACKGROUND: Individual adverse social determinants of health are associated with increased risk of diabetes in pregnancy, but the relative influence of neighborhood or community-level social determinants of health is unknown. OBJECTIVE: This study aimed to determine whether living in neighborhoods with greater socioeconomic disadvantage, food deserts, or less walkability was associated with having pregestational diabetes and developing gestational diabetes. STUDY DESIGN: We conducted a secondary analysis of the prospective Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be. Home addresses in the first trimester were geocoded at the census tract level. The exposures (modeled separately) were the following 3 neighborhood-level measures of adverse social determinants of health: (1) socioeconomic disadvantage, defined by the Area Deprivation Index and measured in tertiles from the lowest tertile (ie, least disadvantage [T1]) to the highest (ie, most disadvantage [T3]); (2) food desert, defined by the United States Department of Agriculture Food Access Research Atlas (yes/no by low income and low access criteria); and (3) less walkability, defined by the Environmental Protection Agency National Walkability Index (most walkable score [15.26-20.0] vs less walkable score [<15.26]). Multinomial logistic regression was used to model the odds of gestational diabetes or pregestational diabetes relative to no diabetes as the reference, adjusted for age at delivery, chronic hypertension, Medicaid insurance status, and low household income (<130% of the US poverty level). RESULTS: Among the 9155 assessed individuals, the mean Area Deprivation Index score was 39.0 (interquartile range, 19.0-71.0), 37.0% lived in a food desert, and 41.0% lived in a less walkable neighborhood. The frequency of pregestational and gestational diabetes diagnosis was 1.5% and 4.2%, respectively. Individuals living in a community in the highest tertile of socioeconomic disadvantage had increased odds of entering pregnancy with pregestational diabetes compared with those in the lowest tertile (T3 vs T1: 2.6% vs 0.8%; adjusted odds ratio, 2.52; 95% confidence interval, 1.41-4.48). Individuals living in a food desert (4.8% vs 4.0%; adjusted odds ratio, 1.37; 95% confidence interval, 1.06-1.77) and in a less walkable neighborhood (4.4% vs 3.8%; adjusted odds ratio, 1.33; 95% confidence interval, 1.04-1.71) had increased odds of gestational diabetes. There was no significant association between living in a food desert or a less walkable neighborhood and pregestational diabetes, or between socioeconomic disadvantage and gestational diabetes. CONCLUSION: Nulliparous individuals living in a neighborhood with higher socioeconomic disadvantage were at increased odds of entering pregnancy with pregestational diabetes, and those living in a food desert or a less walkable neighborhood were at increased odds of developing gestational diabetes, after controlling for known covariates.

Placental Lesions Associated With Stillbirth by Gestational Age, as Related to Cause of Death: Follow-Up Results From the Stillbirth Collaborative Research Network.

BACKGROUND: We previously identified placental lesions associated with stillbirths of varying gestational ages (GA) using advanced feature analysis. We further investigated the relationships between placental lesions and cause of death in stillbirths within these GA ranges. METHODS: Using data from the Stillbirth Collaborative Research Network, we derived a sample of stillbirths who underwent placental examination and Initial Causes of Fetal Death (INCODE) evaluation for determining cause of death. We then compared the rates of causes of death within and among GA ranges (extreme preterm stillbirth [PTSB] [<28 weeks], early PTSB [28-336/7 weeks], late PTSB [34-366/7 weeks], term stillbirth [≥37 weeks]) according to the presence of these lesions. RESULTS: We evaluated 352 stillbirths. In extreme PTSB, obstetric complications and infections were associated with acute funisitis. In early PTSB, uteroplacental insufficiency was associated with parenchymal infarcts. In term stillbirth (vs early PTSB), increased syncytial knots were associated with umbilical cord causes and infection. CONCLUSIONS: Placental lesions of high importance in distinguishing stillbirths at different GAs are associated with specific causes of death. This information is important in relating the presence of placental lesions and fetal death and in helping to understand etiologies of stillbirths at different GAs.

Copy number variants and fetal structural abnormalities in stillborn fetuses: A secondary analysis of the Stillbirth Collaborative Research Network study.

OBJECTIVE: To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. SETTING: Multicenter, 59 hospitals in five geographic regions in the USA. POPULATION: 388 stillbirth cases of the SCRN study (2006-2008). METHODS: Fetal structural malformations were grouped by anatomic system and specific malformation type (e.g. central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500 kb. CNVs were classified into two groups: normal, defined as no CNVs >500 kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-square test. RESULTS: The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs than among those with normal CNVs (47.5 versus 19.1%; P-value <0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by hydrops, craniofacial defects and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g. CHD1L) and a duplication of 21q22.13 involving four genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. CONCLUSION: Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counselling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

Preconception Phthalate Exposure and Women's Reproductive Health: Pregnancy, Pregnancy Loss, and Underlying Mechanisms.

BACKGROUND: Phthalates are endocrine-disrupting chemicals linked to adverse pregnancy outcomes. Despite the sensitivity of female reproductive processes to oxidation-reduction reaction stress and endocrine disruption, evidence for the impact of women's phthalate exposure on the ability to establish and maintain pregnancy has been inconclusive. OBJECTIVES: We aimed to determine the relationship of preconception phthalate metabolite exposure with a) fecundability and pregnancy loss and b) markers of potential biological mechanisms, including reproductive hormones, inflammation, and oxidative stress. METHODS: Data were collected from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial, a preconception study following 1,228 women who were attempting pregnancy, for up to six menstrual cycles and throughout pregnancy if they became pregnant. Twenty phthalate metabolites were measured in a consecutive 3-d pooled urine sample at enrollment. Pregnancy was determined through urinary human chorionic gonadotropin (hCG) at the expected date of menses during each cycle and pregnancy loss as an observed loss following positive hCG. Highly sensitive C-reactive protein (hsCRP) and isoprostanes were measured at enrollment, and reproductive hormones were measured during the follicular phase, ovulation, and luteal phase. Discrete-time Cox proportional hazards models evaluated the relationship of phthalate metabolites with fecundability and weighted Poisson models with robust variance evaluated the risk of pregnancy loss. RESULTS: An interquartile range (IQR) higher mono-(2-ethylhexyl) phthalate [fecundability odds ratio (FOR)=0.88; 95% confidence interval (CI): 0.78, 1.00], mono-butyl phthalate (FOR=0.82; 95% CI: 0.70, 0.96), and mono-benzyl phthalate (FOR=0.85; 95% CI: 0.74, 0.98) was associated with lower fecundability. No consistent associations were observed with pregnancy loss. Preconception phthalates were consistently associated with higher hsCRP and isoprostanes, as well as lower estradiol and higher follicle-stimulating hormone across the menstrual cycle. DISCUSSION: Women's preconception exposure to phthalates was associated with lower fecundability, changes in reproductive hormones, and increased inflammation and oxidative stress. The pre- and periconception periods may represent sensitive windows for intervening to limit the reproductive toxicity of phthalate exposure. https://doi.org/10.1289/EHP12287.

Cannabis Exposure and Adverse Pregnancy Outcomes Related to Placental Function.

Importance: Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain. Objective: To evaluate the association between maternal cannabis use and adverse pregnancy outcomes known to be related to placental function. Design, Setting, and Participants: Ancillary analysis of nulliparous individuals treated at 8 US medical centers with stored urine samples and abstracted pregnancy outcome data available. Participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort were recruited from 2010 through 2013; the drug assays and analyses for this ancillary project were completed from June 2020 through April 2023. Exposure: Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol using frozen stored urine samples from study visits during the pregnancy gestational age windows of 6 weeks and 0 days to 13 weeks and 6 days (visit 1); 16 weeks and 0 days to 21 weeks and 6 days (visit 2); and 22 weeks and 0 days to 29 weeks and 6 days (visit 3). Positive results were confirmed with liquid chromatography tandem mass spectrometry. The timing of cannabis exposure was defined as only during the first trimester or ongoing exposure beyond the first trimester. Main Outcome and Measure: The dichotomous primary composite outcome included small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy ascertained by medical record abstraction by trained perinatal research staff with adjudication of outcomes by site investigators. Results: Of 10 038 participants, 9257 were eligible for this analysis. Of the 610 participants (6.6%) with cannabis use, 32.4% (n = 197) had cannabis exposure only during the first trimester and 67.6% (n = 413) had ongoing exposure beyond the first trimester. Cannabis exposure was associated with the primary composite outcome (25.9% in the cannabis exposure group vs 17.4% in the no exposure group; adjusted relative risk, 1.27 [95% CI, 1.07-1.49]) in the propensity score-weighted analyses after adjustment for sociodemographic characteristics, body mass index, medical comorbidities, and active nicotine use ascertained via urine cotinine assays. In a 3-category cannabis exposure model (no exposure, exposure only during the first trimester, or ongoing exposure), cannabis use during the first trimester only was not associated with the primary composite outcome; however, ongoing cannabis use was associated with the primary composite outcome (adjusted relative risk, 1.32 [95% CI, 1.09-1.60]). Conclusions and Relevance: In this multicenter cohort, maternal cannabis use ascertained by biological sampling was associated with adverse pregnancy outcomes related to placental dysfunction.

Thrombotic Markers in Pregnant Patients with and without SARS-CoV-2 Infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities and increased risk for venous and arterial thrombi. This study aimed to evaluate D-dimer levels and lupus anticoagulant (LAC) positivity in pregnant individuals with and without Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: This was a prospective cohort study of pregnant individuals delivering at a single academic institution from April 2020 to March 2022. Individuals with a positive SARS-CoV-2 result during pregnancy were compared with a convenience sample of those without a positive SARS-CoV-2 result. For individuals with SARS-CoV-2 infection, severity was assessed based on the National Institutes of Health classification system. The primary outcome was D-dimer level measured during delivery admission. The secondary outcomes were LAC positivity and thromboembolic events. Outcomes were compared between individuals with and without a positive SARS-CoV-2 result, and further by disease severity. RESULTS: Of 98 participants, 77 (78.6%) were SARS-CoV-2 positive during pregnancy. Among individuals with SARS-CoV-2 infection, severity was asymptomatic in 20 (26.0%), mild in 13 (16.9%), moderate in 4 (5.2%), severe in 38 (49.4%), and critical in 2 (2.6%). The D-dimer concentration at delivery did not significantly differ between those with a SARS-CoV-2 positive result compared with those without (mean 2.03 µg/mL [95% confidence interval {CI} 1.72-2.40] vs. 2.37 µg/mL [95% CI 1.65-3.40]; p = 0.43). Three individuals (4%) with SARS-CoV-2 infection and none (0%) without infection were LAC positive (p = 0.59). There were no clinically apparent thromboses in either group. D-dimer concentrations and LAC positive results did not differ by COVID-19 severity. CONCLUSION: Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection; however, high rates of LAC positivity were detected. KEY POINTS: · Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection.. · Higher than expected rates of LAC positivity were detected.. · There were no clinically apparent thromboses..

Examination of newborn DNA methylation among women with polycystic ovary syndrome/hirsutism.

Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium MethylationEPIC array. Multivariable robust linear regression was used to determine associations of maternal PCOS exposure or preconception testosterone with methylation ß-values at each CpG probe and corrected for multiple testing by false-discovery rate (FDR). In the birth cohort, 12% (102/849) had a PCOS diagnosis (8.1% PCOS without hirsutism; 3.9% PCOS with hirsutism). Infants exposed to maternal PCOS with hirsutism compared to no PCOS had differential DNAm at cg02372539 [ß(SE): -0.080 (0.010); FDR p = 0.009], cg08471713 [ß(SE):0.077 (0.014); FDR p = 0.016] and cg17897916 [ß(SE):0.050 (0.009); FDR p = 0.009] with adjustment for maternal characteristics including pre-pregnancy BMI. PCOS with hirsutism was also associated with 8 differentially methylated regions (DMRs). PCOS without hirsutism was not associated with individual CpGs. In an independent preconception cohort, total testosterone concentrations were associated with 3 DMRs but not with individual CpGs, though the top quartile of testosterone compared to the lowest was marginally associated with increased DNAm at cg21472377 near an uncharacterized locus (FDR p = 0.09). Examination of these probes and DMRs indicate they may be under foetal genetic control. Overall, we found several associations among newborns exposed to PCOS, specifically when hirsutism was reported, and among newborns of women with relatively higher testosterone around conception.

Labour agentry and subsequent adverse mental health outcomes: A follow-up study of the ARRIVE Trial.

OBJECTIVE: Labour can be traumatic for women who perceive they are not involved in decisions affecting their care during labour. Our objective was to assess the relation between labour agentry and subsequent mental health. DESIGN: Follow-up cohort study. SETTING: U.S. Tertiary care center. POPULATION: Participants from Utah who participated in the ARRIVE (A Randomized Trial of Induction Versus Expectant Management) trial. METHODS: During the ARRIVE trial, participants completed the Labor Agentry Scale twice, a validated questionnaire measuring perceived control of patients during childbirth. ARRIVE participants from Utah subsequently were asked to complete questions about mental health history and stressful events occurring since the trial, as well as surveys including the Primary Care Posttraumatic Stress Disorder (PC-PTSD) screen, Edinburgh Postnatal Depression Scale (EPDS) and Generalised Anxiety Disorder-7 (GAD-7) screen. The lower quartile of both agentry measurements defined a person's ordinal agentry category, used for assessing cohort characteristics by exposure category. Continuous minimum agentry was included in adjusted modelling. MAIN OUTCOME MEASURES: The primary outcome was a mental health composite including a positive screen for depression, anxiety, or PTSD or self-report of a diagnosis or exacerbation since their delivery. RESULTS: In all, 766 of 1042 (74%) people responded to the survey (median 4.4, range 2.5-6.4 years after delivery) and 753 had complete data for analysis. In unadjusted comparisons across ordinal agentry category, lower agentry was significantly associated with the primary composite endpoint, and depressive symptoms (test of trend p = 0.003 primary, p = 0.004 depression). Lower labour agentry scores were associated with incremental odds of the primary endpoint (1 SD [24 units], adjusted odds ratio [aOR] 1.21, 95% CI 1.41-1.03), driven by depressive symptoms or self-reported diagnosis (aOR 1.25, 95% CI 1.47-1.05). CONCLUSIONS: Lower labour agentry at the time of birth was associated with a greater risk for mental health conditions years after delivery, indicating a potential opportunity for primary prevention of subsequent depression.