Placental differences between severe fetal growth restriction and hypertensive disorders of pregnancy requiring early preterm delivery: morphometric analysis of the villous tree supported by artificial intelligence.

BACKGROUND: The great obstetrical syndromes of fetal growth restriction and hypertensive disorders of pregnancy can occur individually or be interrelated. Placental pathologic findings often overlap between these conditions, regardless of whether 1 or both diagnoses are present. Quantification of placental villous structures in each of these settings may identify distinct differences in developmental pathways. OBJECTIVE: This study aimed to determine how the quantity and surface area of placental villi and vessels differ between severe, early-onset fetal growth restriction with absent or reversed umbilical artery Doppler indices and hypertensive disorders of pregnancy or the 2 conditions combined among subjects with disease severity that warrant early preterm delivery. We hypothesized that the trajectories of placental morphogenesis diverge after a common initiating insult of deep defective placentation. Specifically, we postulated that only villi are affected in pregnancy-related hypertension, whereas both villous and vascular structures are proportionally diminished in severe fetal growth restriction with no additional effect when hypertension is concomitantly present. STUDY DESIGN: In this retrospective cohort study, paraffin-embedded placental tissue was obtained from 4 groups, namely (1) patients with severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities and hypertensive disorders of pregnancy, (2) patients with severe fetal growth restriction with absent or reversed umbilical artery Doppler indices and no hypertension, (3) gestational age-matched, appropriately grown pregnancies with hypertensive disease, and (4) gestational age-matched, appropriately grown pregnancies without hypertension. Dual immunohistochemistry for cytokeratin-7 (trophoblast) and CD34 (endothelial cells) was performed, followed by artificial intelligence-driven morphometric analyses. The number of villi, total villous area, number of fetoplacental vessels, and total vascular area across villi within a uniform region of interest were quantified. Quantitative analyses of placental structures were modeled using linear regression. RESULTS: Placentas from pregnancies complicated by hypertensive disorders of pregnancy exhibited significantly fewer stem villi (-282 stem villi; 95% confidence interval, -467 to -98; P<.01), a smaller stem villous area (-4.3 mm2; 95% confidence interval, -7.3 to -1.2; P<.01), and fewer stem villous vessels (-4967 stem villous vessels; 95% confidence interval, -8501 to -1433; P<.01) with no difference in the total vascular area. In contrast, placental abnormalities in cases with severe growth restriction were limited to terminal villi with global decreases in the number of villi (-873 terminal villi; 95% confidence interval, -1501 to -246; P<.01), the villous area (-1.5 mm2; 95% confidence interval, -2.7 to -0.4; P<.01), the number of blood vessels (-5165 terminal villous vessels; 95% confidence interval, -8201 to -2128; P<.01), and the vascular area (-0.6 mm2; 95% confidence interval, -1.1 to -0.1; P=.02). The combination of hypertension and growth restriction had no additional effect beyond the individual impact of each state. CONCLUSION: Pregnancies complicated by hypertensive disorders of pregnancy exhibited defects in the stem villi only, whereas placental abnormalities in severely growth restricted pregnancies with absent or reversed umbilical artery end-diastolic velocities were limited to the terminal villi. There were no significant statistical interactions in the combination of growth restriction and hypertension, suggesting that distinct pathophysiological pathways downstream of the initial insult of defective placentation are involved in each entity and do not synergize to lead to more severe pathologic consequences. Delineating mechanisms that underly the divergence in placental development after a common inciting event of defective deep placentation may shed light on new targets for prevention or treatment.

High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Identification and verification of plasma protein biomarkers that accurately identify an ectopic pregnancy.

BACKGROUND: Differentiating between a normal intrauterine pregnancy (IUP) and abnormal conditions including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge in early pregnancy. Currently, serial ß-human chorionic gonadotropin (ß-hCG) and progesterone are the most commonly used plasma biomarkers for evaluating pregnancy prognosis when ultrasound is inconclusive. However, neither biomarker can predict an EP with sufficient and reproducible accuracy. Hence, identification of new plasma biomarkers that can accurately diagnose EP would have great clinical value. METHODS: Plasma was collected from a discovery cohort of 48 consenting women having an IUP, EPL, or EP. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) followed by a label-free proteomics analysis to identify significant changes between pregnancy outcomes. A panel of 14 candidate biomarkers were then verified in an independent cohort of 74 women using absolute quantitation by targeted parallel reaction monitoring mass spectrometry (PRM-MS) which provided the capacity to distinguish between closely related protein isoforms. Logistic regression and Lasso feature selection were used to evaluate the performance of individual biomarkers and panels of multiple biomarkers to predict EP. RESULTS: A total of 1391 proteins were identified in an unbiased plasma proteome discovery. A number of significant changes (FDR ≤ 5%) were identified when comparing EP vs. non-EP (IUP + EPL). Next, 14 candidate biomarkers (ADAM12, CGA, CGB, ISM2, NOTUM, PAEP, PAPPA, PSG1, PSG2, PSG3, PSG9, PSG11, PSG6/9, and PSG8/1) were verified as being significantly different between EP and non-EP in an independent cohort (FDR ≤ 5%). Using logistic regression models, a risk score for EP was calculated for each subject, and four multiple biomarker logistic models were identified that performed similarly and had higher AUCs than models with single predictors. CONCLUSIONS: Overall, four multivariable logistic models were identified that had significantly better prediction of having EP than those logistic models with single biomarkers. Model 4 (NOTUM, PAEP, PAPPA, ADAM12) had the highest AUC (0.987) and accuracy (96%). However, because the models are statistically similar, all markers in the four models and other highly correlated markers should be considered in further validation studies.

Abnormal uterine bleeding in anticoagulated patients by drug class: outcomes and management.

BACKGROUND: Although abnormal uterine bleeding is a known adverse effect of anticoagulant drugs, true rates have not been widely studied. Society-backed recommendations and guidelines do not yet exist for prevention and management of abnormal uterine bleeding among anticoagulated patients. OBJECTIVE: This study aimed to describe the incidence of new-onset abnormal uterine bleeding among patients receiving therapeutic anticoagulation by anticoagulant class, and to evaluate gynecologic treatment patterns. STUDY DESIGN: We conducted an institutional review board-waived retrospective chart review of female patients aged 18 to 55 years and prescribed therapeutic anticoagulants, including vitamin-K antagonists, low-molecular-weight heparins, and direct oral anticoagulants, in an urban hospital network from January 2015 through January 2020. We excluded patients with antecedent abnormal uterine bleeding and menopause. Associations between abnormal uterine bleeding, anticoagulant class, and other covariates were evaluated with Pearson chi-square and analysis-of-variance tests. The primary outcome, abnormal uterine bleeding odds by anticoagulant class, was modeled with logistic regression. Age, antiplatelet therapy, body mass index, and race were included in our multivariable model. Secondary outcomes included emergency department visits and treatment patterns. RESULTS: Of the 2479 patients who met the inclusion criteria, 645 were diagnosed with abnormal uterine bleeding after initiating therapeutic anticoagulation. After adjusting for age, race, body mass index, and concurrent use of antiplatelet therapy, those receiving all 3 classes of anticoagulants had higher odds of experiencing abnormal uterine bleeding (adjusted odds ratio, 2.63; confidence interval, 1.70-4.08; P<.001), whereas those taking only direct oral anticoagulants had the lowest odds (adjusted odds ratio, 0.70; confidence interval, 0.51-0.97; P=.032), with vitamin-K antagonists as the reference group. Race other than White was associated with higher odds of abnormal uterine bleeding, as was lower age. The most common hormone therapies used among patients with abnormal uterine bleeding were levonorgestrel intrauterine devices (7.6%; 49/645) and oral progestins (7.6%; 49/645). Sixty-eight patients (10.5%; 68/645) had an emergency department visit for abnormal uterine bleeding; 29.5% (190/645) of patients received a blood transfusion; 12.2% (79/645) began any pharmacologic therapy for bleeding; and 18.8% (121/645) underwent any gynecologic procedure. CONCLUSION: Abnormal uterine bleeding occurs frequently among patients on therapeutic anticoagulation. Incidence in this sample varied considerably by anticoagulant class and race; use of single-agent direct oral anticoagulation carried the lowest risk. Important sequelae such as bleeding-related emergency department visits, blood transfusions, and gynecologic procedures were common. Balancing bleeding and clotting risk in patients on therapeutic anticoagulation requires a nuanced approach and should involve collaborative management between hematologists and gynecologists.

Validation of a multiple marker test for early pregnancy outcome prediction.

PURPOSE: To validate the use of a multiple biomarker test panel for predicting first trimester pregnancy outcome in a multi-center cohort. METHODS: A case-control study of women presenting with pain and bleeding in early pregnancy at 5-10 weeks gestational age was performed at three academic centers. Sera from women with ectopic pregnancy (EP), viable intrauterine pregnancy (IUP), and miscarriage (SAB) were analyzed via immunoassay for Activin A (AA), Progesterone (P4), A Disintegrin And Metalloprotease-12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), glycodelin (Glyc), and human chorionic gonadotropin (hCG). Biomarkers were assessed for reproducibility using medians, ranges, standard deviations, and area under receiver-operating characteristic curve (AUC) and accuracy in early pregnancy outcome classification compared to a previous derivation population. RESULTS: In 192 pregnancies, the biomarkers demonstrated good reproducibility with similar medians, ranges, and AUCs when compared to the derivation population except glycodelin. Pregnancy location was conclusively classified in 53% (n = 94) of the whole study sample with 78% accuracy. Pregnancy viability was conclusively classified in 58% (n = 112) of the new sample with 89% accuracy. Results were similar with subsequent model revisions where glycodelin was excluded and in the subgroups of subjects with a hCG below 2000 mIU/mL and a gestational age less than 6 weeks. CONCLUSION: The use of a panel of biomarkers to maximize test accuracy of a prediction of pregnancy location and prediction of pregnancy viability was reproducible and validated in an external population from which it was derived, but clinical utility is limited based on the test characteristics obtained.

Proteome-defined changes in cellular pathways for decidua and trophoblast tissues associated with location and viability of early-stage pregnancy.

BACKGROUND: In early pregnancy, differentiating between a normal intrauterine pregnancy (IUP) and abnormal gestations including early pregnancy loss (EPL) or ectopic pregnancy (EP) is a major clinical challenge when ultrasound is not yet diagnostic. Clinical treatments for these outcomes are drastically different making early, accurate diagnosis imperative. Hence, a greater understanding of the biological mechanisms involved in these early pregnancy complications could lead to new molecular diagnostics. METHODS: Trophoblast and endometrial tissue was collected from consenting women having an IUP (n = 4), EPL (n = 4), or EP (n = 2). Samples were analyzed by LC-MS/MS followed by a label-free proteomics analysis in an exploratory study. For each tissue type, pairwise comparisons of different pregnancy outcomes (EPL vs. IUP and EP vs. IUP) were performed, and protein changes having a fold change ≥ 3 and a Student's t-test p-value ≤ 0.05 were defined as significant. Pathway and network classification tools were used to group significantly changing proteins based on their functional similarities. RESULTS: A total of 4792 and 4757 proteins were identified in decidua and trophoblast proteomes. For decidua, 125 protein levels (2.6% of the proteome) were significantly different between EP and IUP, whereas EPL and IUP decidua were more similar with only 68 (1.4%) differences. For trophoblasts, there were 66 (1.4%) differences between EPL and IUP. However, the largest group of 344 differences (7.2%) was observed between EP and IUP trophoblasts. In both tissues, proteins associated with ECM remodeling, cell adhesion and metabolic pathways showed decreases in EP specimens compared with IUP and EPL. In trophoblasts, EP showed elevation of inflammatory and immune response pathways. CONCLUSIONS: Overall, differences between an EP and IUP are greater than the changes observed when comparing ongoing IUP and nonviable intrauterine pregnancies (EPL) in both decidua and trophoblast proteomes. Furthermore, differences between EP and IUP were much higher in the trophoblast than in the decidua. This observation is true for the total number of protein changes as well as the extent of changes in upstream regulators and related pathways. This suggests that biomarkers and mechanisms of trophoblast function may be the best predictors of early pregnancy location and viability.

Progesterone Increases Nicotine Withdrawal and Anxiety in Male but Not Female Smokers During Brief Abstinence.

INTRODUCTION: Although exogenous progesterone may hold promise as a treatment for nicotine use disorders, it is unclear whether it is similarly effective in males and females. This study examined the effects of progesterone on nicotine use disorder comprehensively using behavioral, psychological, and neural measures in male and female smokers exposed to brief abstinence. AIMS AND METHODS: Thirty-three male and 33 female non-treatment-seeking smokers participated in a double-blind, randomized, placebo-controlled crossover study of 200 mg of progesterone or placebo daily over a four-day abstinence period. Smoking behavior and subjective effects of nicotine were assessed at baseline and after final drug administration. Nicotine withdrawal, smoking urges, mood states, and neural response to smoking cues were measured at baseline, after the first drug administration, and after the final drug administration. RESULTS: No main effect of drug (progesterone vs. placebo) emerged for any outcome. Significant sex by drug interactions emerged for nicotine withdrawal (p = .020), perceived strength of nicotine (p = .040), and perceived bad effects of nicotine (p = .029). Males receiving progesterone reported worse nicotine withdrawal (p = .046) and a trend towards decreased bad effects of nicotine (p = .070). Males on progesterone also reported greater tension and anxiety relative to placebo (p = .021). Females on progesterone perceived nicotine's effects as being stronger relative to placebo (p = .046). CONCLUSIONS: Progesterone causes sex-dependent effects on smoking-related outcomes during brief abstinence. Specifically, progesterone in males may increase rather than decrease nicotine withdrawal and negative affect during abstinence, potentially hindering efforts to quit smoking. IMPLICATIONS: In male and female smokers undergoing a brief period of abstinence, we examined the effects of progesterone on smoking outcomes. While progesterone had limited effects in female smokers, in males, it worsened nicotine withdrawal and negative affect. Our findings emphasize the importance of analyzing sex differences in future studies examining progesterone as a potential treatment and suggest that progesterone in males could potentially exacerbate aspects of nicotine dependence. CLINICALTRIALS.GOV REGISTRATION: NCT01954966. https://clinicaltrials.gov/ct2/show/NCT01954966.

Course of Illness and Treatment Updates for Bipolar Disorder in the Perinatal Period.

PURPOSE OF REVIEW: The perinatal period is a time of increased vulnerability for people with bipolar disorder (BD). The purpose of this review is to provide an update of the literature from the last 3 years regarding course of illness and treatments for BD in the perinatal period to guide clinical care. RECENT FINDINGS: Postpartum manic and depressive episodes are emerging as having a unique presentation that may differentiate them from non-perinatal mood episodes. Many important updates regarding medication treatment in the perinatal period have been published recently that have considered the risks of untreated illness versus treatment risks in this population.' Despite significant research, there are still gaps in knowledge regarding safety and efficacy of medications for the mother and child. Crucial future areas of study include improved screening guidelines, randomized controlled trials examining medication safety in pregnancy and lactation, and efficacy of nonpharmacologic treatments.

Pregnant and bleeding: A model to assess factors associated with the need for emergency care in early pregnancy.

OBJECTIVE: To assess the prevalence of Critical or Emergent patient classification among pregnant patients presenting to the Emergency Department (ED) and to identify characteristics that discriminate between patients requiring Emergency care from those who can be safely triaged to the ambulatory setting. STUDY DESIGN: In this cross-sectional study conducted in 3 urban EDs, patients under 16 weeks gestation who presented with bleeding and/or cramping completed a 7-item questionnaire. We compared baseline clinical variables and survey responses among patients classified as Critical or Emergent per the American Board of Emergency Medicine's patient acuity definitions with those classified as Lower Acuity to identify independent risk factors for outcomes. RESULTS: Of 484 participants, 21 (4.3%) were classified as Critical or Emergent and required interventions. While no demographic characteristics differentiated Critical patients from Lower Acuity patients, survey questions associated with a higher likelihood of emergency intervention included history of prior ectopic pregnancy (OR 8.7, 95% CI 3.2-23.5) heavy bleeding in the past two hours (OR 11.8, 95% CI 3.8-36.1), as well as having made a prior ED visit in the current pregnancy (OR 1.9, 95% CI 0.7-5.1). Joint consideration of these risk factors in a multivariable model performed well at discriminating between Critical and Lower Acuity patients with an area under the ROC curve of 0.82 (95% CI 0.71-0.93). CONCLUSION: Patients with a history of ectopic pregnancy, heavy bleeding in the past two hours, and/or prior presentation to the ED in the current pregnancy had the highest risk of needing emergency-level care. The vast majority of patients presenting to the ED with early pregnancy complaints were discharged without intervention.

Discontinuation of hormonal contraception due to changes in mood and decreases in sexual desire: the role of adverse childhood experiences.

PURPOSE: To evaluate if adverse childhood experiences are associated with hormonal contraception discontinuation due to mood and sexual side effects. MATERIALS AND METHODS: Women, ages 18-40 (N = 826), with current and/or previous hormonal contraceptive use completed surveys on demographics, contraceptive history, and the Adverse Childhood Experiences Questionnaire. We characterised women into high (≥2 adverse experiences) and low (0 or 1) adverse childhood experience groups. We calculated risk ratios for associations between adverse childhood experiences and outcomes of interest using log binomial generalised linear models, and adjusted for relevant demographic variables. RESULTS: Women in the high adverse childhood experiences group (n = 355) were more likely to report having discontinued hormonal contraception due to decreases in sexual desire (adjusted risk ratio 1.44, 1.03-2.00, p = .030). Covariates included age, current hormonal contraception use, and various demographic variables associated with discontinuation. Adverse childhood experiences were not associated with mood or sexual side effects among current (n = 541) hormonal contraceptive users. CONCLUSIONS: Self-reported adverse childhood experiences were associated with greater likelihood of discontinuing hormonal contraception due to behavioural side effects, particularly decreases in sexual desire. Identification of risk factors for behavioural side effects can assist patients and clinicians in making informed choices on contraception that minimise risk of early discontinuation.

Postpartum complications increased in women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome are at a higher risk of cardiometabolic and psychiatric comorbidities and preconception and antepartum complications, but the impact of polycystic ovary syndrome during the postpartum period is unknown. OBJECTIVE: This study aimed to investigate the risk of postpartum cardiovascular disease complications and perinatal and postpartum depression. STUDY DESIGN: This was a retrospective cohort study conducted using a United States insurance claims database. Women with and without polycystic ovary syndrome aged 18 to 50 years enrolled continuously in a single health plan during the preconception, antepartum, and postpartum periods between 2000 and 2016 were included. The primary outcome was postpartum cardiovascular disease and depression (perinatal and postpartum). Multivariable logistic regression was used to adjust for covariates including age, geographic location, preterm delivery, assisted reproductive technology use, multiple births, prepregnancy depression, prepregnancy diabetes, prepregnancy hypertension, gestational diabetes, gestational hypertension, obesity, history of hyperlipidemia, smoking, and race. RESULTS: We identified 42,391 unique women with polycystic ovary syndrome and 795,480 women without polycystic ovary syndrome. In multivariable models, women with polycystic ovary syndrome had significantly higher odds of cardiovascular disease complications, including postpartum preeclampsia (adjusted odds ratio, 1.30; 95% confidence interval, 1.17-1.45), eclampsia (adjusted odds ratio, 1.45; 95% confidence interval, 1.14-1.86) cardiomyopathy (adjusted odds ratio, 1.26; 95% confidence interval, 1.03-1.54), hypertensive heart disease (adjusted odds ratio, 1.32: 95% confidence interval, 1.07-1.64), thrombotic disease (adjusted odds ratio, 1.50; 95% confidence interval, 1.20-1.87), congestive heart failure (adjusted odds ratio, 1.35; 95% confidence interval, 1.13-1.61), and cerebrovascular accidents (adjusted odds ratio, 1.21; 95% confidence interval, 1.14-1.29), than those without polycystic ovary syndrome, as well as both perinatal (adjusted odds ratio, 1.27; 95% confidence interval, 1.22-1.33) and postpartum depression (adjusted odds ratio, 1.46; 95% confidence interval, 1.36-1.57). Nonobese women with polycystic ovary syndrome had higher odds of postpartum eclampsia (adjusted odds ratio 1.72; 95% confidence interval, 1.31-2.26), peripartum cardiomyopathy (adjusted odds ratio, 1.43; 95% confidence interval, 1.14-1.79), and cerebrovascular accidents (adjusted odds ratio, 1.28; 95% confidence interval, 1.19-1.38) than nonobese women without polycystic ovary syndrome. In the group of women without prepregnancy depression, the odds of perinatal depression (adjusted odds ratio, 1.32; 95% confidence interval, 1.26-1.39) and postpartum depression (adjusted odds ratio, 1.50; 95% confidence interval, 1.39-1.62) were higher in women with polycystic ovary syndrome than those without polycystic ovary syndrome. CONCLUSION: In a large United States cohort, our study found that women with polycystic ovary syndrome are at increased risk of both cardiovascular and psychiatric complications during the postpartum period. Polycystic ovary syndrome should be recognized as an at-risk condition; our findings underscore the need for routine screening and early interventions for these major comorbidities.

Impact of Surgical Wait Time to Hysterectomy for Benign Gynecologic Disease.

STUDY OBJECTIVE: To determine the impact of surgical wait time on healthcare use and surgical outcomes for patients undergoing hysterectomy for benign gynecologic indications. DESIGN: Retrospective cohort study. SETTING: Urban, academic tertiary care center. PATIENTS: Patients who underwent hysterectomy for benign disease between 2012 and 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized into 2 groups, dichotomized by surgical wait times >30 days or ≤30 days. Healthcare use was measured by the number of discrete patient interactions with the healthcare system through phone calls, secure electronic messaging, and office and emergency room visits. Univariate and multivariable logistic regression models were performed to assess the association between surgical wait time and healthcare use and perioperative outcomes while controlling for confounders. A total of 277 patients were included in our analysis: 106 (38.3%) had surgical wait times >30 days (median 47 days, range 24-68 days), and 171 (67.1%) had surgical wait times ≤30 days (median 19 days; range 12-26 days). The groups did not differ by age, insurance status, substance use, or comorbid conditions. Patients in the group with surgical wait times >30 days were more likely to have increased healthcare use (69 of 106, 65% vs 43 of 171, 25%; odds ratio 5.55; 95% confidence interval, 3.27-9.41). There were no differences in intraoperative complications (9 of 106, 8% vs 19 of 171, 11%; p = .482) or postoperative complications (28 of 106, 26% vs 32 of 171, 19%; p = .13) between the groups; however, after controlling for potential confounders, patients with surgical wait times >30 days were 3.22 times more likely to be readmitted than patients with surgical wait times ≤30 days (95% confidence interval, 1.27-8.19). CONCLUSION: A surgical wait time >30 days in patients undergoing a hysterectomy for benign disease is associated with increased healthcare use in the interim. Although patients who experience longer surgical wait times do not experience worse surgical outcomes, they may be at higher risk for readmission after surgery. Targeted interventions to optimize perioperative coordination of care for patients undergoing a hysterectomy for benign disease, especially those within vulnerable populations, are needed to improve quality of care, decrease any redundant or inefficient healthcare use, and reduce any unnecessary delays.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.

Infertility and mortality.

BACKGROUND: Infertility affects 1 in 10 American reproductive-age women. The impact of this disease beyond the reproductive years is largely unknown. OBJECTIVE: The objective of the study was to determine the association of infertility history with all-cause and cause-specific mortality. STUDY DESIGN: This secondary analysis of a multicenter randomized clinical trial included 75,784 women (aged 55-74 years) prospectively enrolled in the Prostate, Lung, Colorectal, and Ovarian cancer-screening trial from 1992 through 2001 and followed up a minimum of 10 years for health-related outcomes and death (856,935 person-years). We examined the association of infertility history (inability to conceive for 1 year or greater) of all-cause and cause-specific mortality using disease risk score-adjusted Cox-proportional hazard regression models. RESULTS: Infertile women had a 10% increased risk of death (from any cause) during the study period compared with the unexposed (adjusted hazard risk, 1.10, 95% confidence interval, 1.02-1.18, P = .010). This effect was predominantly noted in women at an otherwise low risk of mortality who had a 26% increased risk of death (adjusted hazard risk, 1.26, 95% confidence interval, 1.12-1.42, P < .001). No differences in cardiovascular or diabetic mortality were noted. The risk of cancer death at any time over the study period was increased by 23% in infertile women compared with the unexposed (adjusted hazard risk, 1.23, 95% confidence interval, 1.10-1.37, P < .001). This effect was predominantly noted in women at an otherwise low risk of cancer mortality who had a 47% increased risk of cancer death (adjusted hazard risk, 1.47, 95% confidence interval, 1.25-1.73, P < .001). While no differences are seen in the risk of death from endometrial or ovarian cancer, the risk of death from breast cancer was more than doubled in infertile women at an otherwise low risk of breast cancer death compared with the unexposed (adjusted hazard risk, 2.64, 95% confidence interval, 1.71-4.08, P < .001). CONCLUSION: Infertility is a harbinger of future morbidity and mortality. Infertile women are at an increased risk of all-cause and cancer-related mortality. Consideration of infertility history in health care maintenance presents an opportunity for screening and early intervention for long-term health outcomes.

Cervicovaginal microbial communities deficient in Lactobacillus species are associated with second trimester short cervix.

BACKGROUND: The cervix functions as a barrier to ascending pathogens in pregnancy. Short cervical length and lack of cervicovaginal Lactobacillus species are risk factors for spontaneous preterm birth; however, whether they interact to increase risk remains unknown. OBJECTIVE: We sought to examine the relationship between cervicovaginal microbiota and short cervix as well as their combined impact on spontaneous preterm birth risk. STUDY DESIGN: This was a secondary analysis of a prospective nested, case-control pregnancy study. Cervical swabs were collected between 16 and 20 weeks of gestation. Cervical length was measured per standard clinical care during a clinically indicated ultrasound at approximately 20 weeks of gestation. Cervicovaginal microbiota were analyzed with 16S ribosomal RNA gene sequencing and classified into community state types among 67 cases of spontaneous preterm birth, 47 cases of medically indicated preterm birth, and 358 cases of term births. Logistic regression was used to model associations of community state type IV, a community characterized by a paucity of Lactobacillus species and a wide array of anaerobic bacteria, and short cervix (<25 mm) as well as to model the association of a combination of short cervix and community state type IV with the odds of spontaneous preterm birth. RESULTS: Among the 472 women in the data set, there were 38 with short cervix (8.1%) and 177 with community state type IV (37.5%). Short cervix was associated with spontaneous preterm birth (adjusted odds ratio, 15.59; 95% confidence interval, 6.77-35.92). Women with community state type IV had higher odds of short cervix (adjusted odds ratio, 2.17; 95% confidence interval, 1.04-4.53) as well as spontaneous preterm birth (adjusted odds ratio, 1.97; 95% confidence interval, 1.06-3.65). While the interaction of community state type IV and short cervix was not significant (P = .771), women with both short cervix and community state type IV (n = 20) had higher odds of spontaneous preterm birth compared with women with both normal cervical length and community state types I, II, III, or V (n = 277) (adjusted odds ratio, 21.8; 95% confidence interval, 6.78-70.2). CONCLUSION: Community state type IV, characterized by a diverse set of strict and facultative anaerobes and a paucity of Lactobacillus species, is associated with increased odds of short cervix. Women with both community state type IV and short cervix have higher odds of spontaneous preterm birth than women with either factor alone. Determining the cascade of events leading to premature cervical shortening, including dysbiosis, may be critical in preventing spontaneous preterm birth.

Management of early pregnancy loss with mifepristone and misoprostol: clinical predictors of treatment success from a randomized trial.

BACKGROUND: Early pregnancy loss is a common event in the first trimester, occurring in 15%-20% of confirmed pregnancies. A common evidence-based medical regimen for early pregnancy loss uses misoprostol, a prostaglandin E1 analog, with a dosage of 800 µg, self-administered vaginally. The clinical utility of this regimen is limited by suboptimal effectiveness in patients with a closed cervical os, with 29% of patients experiencing early pregnancy loss requiring a second dose after 3 days and 16% of patients eventually requiring a uterine aspiration procedure. OBJECTIVE: This study aimed to evaluate clinical predictors associated with treatment success in patients receiving medical management with mifepristone-misoprostol or misoprostol alone for early pregnancy loss. STUDY DESIGN: We performed a planned secondary analysis of a randomized trial comparing mifepristone-misoprostol with misoprostol alone for management of early pregnancy loss. The published prediction model for treatment success of single-dose misoprostol administered vaginally included the following variables: active bleeding, type of early pregnancy loss (anembryonic pregnancy or embryonic and/or fetal demise), parity, gestational age, and treatment site; previous significant predictors were vaginal bleeding within the past 24 hours and parity of 0 or 1 vs >1. To determine if these characteristics predicted differential proportions of patients with treatment success or failure, we performed bivariate analyses; given the small proportion of treatment failures in the combined treatment arm, both arms were combined for analysis. Thereafter, we performed a logistic regression analysis to assess the effect of these predictors collectively in each of the 2 treatment groups separately as well as in the full cohort as a proxy for the combined treatment arm. Finally, by using receiver operating characteristic curves, we tested the ability of these predictors in association with misoprostol treatment success to discriminate between treatment success and treatment failure. To quantify the ability of the score to discriminate between treatment success and treatment failure in each treatment arm as well as in the entire cohort, we calculated the area under the curve. Using multivariable logistic regression, we then assessed our study population for other predictors of treatment success in both treatment groups, with and without mifepristone pretreatment. RESULTS: Overall, 297 evaluable participants were included in the primary study, with 148 in the mifepristone-misoprostol combined treatment group and 149 in the misoprostol-alone treatment group. Among patients who had vaginal bleeding at the time of treatment, 15 of 17 (88%) in the mifepristone-misoprostol combined treatment group and 12 of 17 (71%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. Among patients with a parity of 0 or 1, 94 of 108 (87%) in the mifepristone-misoprostol treatment group and 66 of 95 (69%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. These clinical characteristics did not predict treatment success in the combined cohort alone (area under the curve=0.56; 95% confidence interval, 0.48-0.64). No other baseline clinical factors predicted treatment success in the misoprostol-alone treatment arm or mifepristone pretreatment arm. In the full cohort, the significant predictors of treatment success were pretreatment with mifepristone (adjusted odds ratio=2.51; 95% confidence interval, 1.43-4.43) and smoking (adjusted odds ratio=2.15; 95% confidence interval, 1.03-4.49). CONCLUSION: No baseline clinical factors predicted treatment success in women receiving medical management with misoprostol for early pregnancy loss. Adding mifepristone to the medical management regimen of early pregnancy loss improved treatment success; thus, mifepristone treatment should be considered for management of early pregnancy loss regardless of baseline clinical factors.

Enduring impact of childhood adversity on lower urinary tract symptoms in adult women.

AIMS: To determine whether childhood adversity is associated with self-reported lower urinary tract symptoms (LUTS) among older adult women. METHODS: A convenience sample of women (≥55 years old) who presented to an academic urology practice or who had participated in a previous bladder health prevention study completed questionnaires including the LUTS Tool (on frequency and bother of LUTS), the Adverse Childhood Experiences (ACEs) Questionnaire, the Spielberger State-Trait Anxiety Inventory, and the Center for Epidemiologic Studies Depression Scale. RESULTS: The average age (SD) of participants (N = 151) was 64.7 (6.9) years. The total number of ACEs predicted the total number of LUTS, ß = .39 (95% confidence interval [CI] = 0.14, 0.64), P = .003, as well as LUTS frequency, ß = .09 (95% CI = 0.04, 0.13), P < .001. ACEs predicted bother for nocturia, ß = 0.12 (95% CI = 0.03, 0.22), P = .008. Negative affect symptoms did not mediate the relationship between the total number of ACEs and the total number of LUTS. Rather, ACEs predicted LUTS and negative affect symptoms through (at least partially) independent pathways. Analyses controlled for tobacco use, number of vaginal deliveries, hypertension, overactive bladder medication use, body mass index, income, and race because these variables were significantly associated with the total number of ACEs or total number of LUTS. CONCLUSIONS: Childhood adversity has an enduring impact on risk for LUTS in adulthood even when controlling for potential confounds and this relationship cannot be explained by negative affect symptoms.

Association between cell-free DNA fetal fraction and gestational diabetes.

OBJECTIVE: To determine the association between cell-free DNA (cfDNA) fetal fraction and gestational diabetes (GDM) in a cohort of women presenting for cfDNA screening for fetal aneuploidy. METHODS: A retrospective cohort study of women with singleton pregnancies who had cfDNA screening at a single institution at 10 to 20 weeks gestation between October 2011 and October 2017. Fetal fractions were adjusted for gestational age (GA) using multiples of the median (MoM). Multivariable logistic regression was used to estimate the odds ratio (OR) of GDM controlling for potential confounders. RESULTS: Two thousand six hundred twenty-three pregnancies met criteria. Women with GDM had a lower fetal fraction (0.93 MoM vs. 1.05 MoM, P = .002). However, the association between fetal fraction and GDM was not significant after adjusting for body mass index (BMI) [OR 0.84, 95% confidence interval (CI) 0.52-1.36; P = .48]. Since insulin resistance increases at later GAs, separate analysis on women with GA 14 to 20 weeks was performed. Again, the association between fetal fraction and GDM was not significant after adjusting for BMI, (OR 0.81, 95% CI 0.31-2.12; P = .67). CONCLUSION: Low or high fetal fraction of cfDNA was not associated with GDM. Although fetal fraction was lower among women diagnosed with GDM, this relationship was no longer statistically significant once maternal BMI was taken into account.

Effects of maternal investment, temperament, and cognition on guide dog success.

A continuing debate in studies of social development in both humans and other animals is the extent to which early life experiences affect adult behavior. Also unclear are the relative contributions of cognitive skills ("intelligence") and temperament for successful outcomes. Guide dogs are particularly suited to research on these questions. To succeed as a guide dog, individuals must accomplish complex navigation and decision making without succumbing to distractions and unforeseen obstacles. Faced with these rigorous demands, only ∼70% of dogs that enter training ultimately achieve success. What predicts success as a guide dog? To address these questions, we followed 98 puppies from birth to adulthood. We found that high levels of overall maternal behavior were linked with a higher likelihood of program failure. Furthermore, mothers whose nursing style required greater effort by puppies were more likely to produce successful offspring, whereas mothers whose nursing style required less effort were more likely to produce offspring that failed. In young adults, an inability to solve a multistep task quickly, compounded with high levels of perseveration during the task, was associated with failure. Young adults that were released from the program also appeared more anxious, as indicated by a short latency to vocalize when faced with a novel object task. Our results suggest that both maternal nursing behavior and individual traits of cognition and temperament are associated with guide dog success.

Childhood adversity impact on gut microbiota and inflammatory response to stress during pregnancy.

BACKGROUND: Adverse childhood experiences (ACEs), such as abuse or chronic stress, program an exaggerated adult inflammatory response to stress. Emerging rodent research suggests that the gut microbiome may be a key mediator in the association between early life stress and dysregulated glucocorticoid-immune response. However, ACE impact on inflammatory response to stress, or on the gut microbiome, have not been studied in human pregnancy, when inflammation increases risk of poor outcomes. The aim of this study was to assess the relationships among ACE, the gut microbiome, and cytokine response to stress in pregnant women. METHODS: Physically and psychiatrically healthy adult pregnant women completed the Adverse Childhood Experiences Questionnaire (ACE-Q) and gave a single stool sample between 20 and 26 weeks gestation. Stool DNA was isolated and 16S sequencing was performed. Three 24-hour food recalls were administered to assess dietary nutrient intake. A subset of women completed the Trier Social Stress Test (TSST) at 22-34 weeks gestation; plasma interleukin-6 (IL-6), interleukin-1ß (IL-1ß), high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), and cortisol were measured at four timepoints pre and post stressor, and area under the curve (AUC) was calculated. RESULTS: Forty-eight women completed the ACE-Q and provided stool; 19 women completed the TSST. Women reporting 2 or more ACEs (high ACE) had greater differential abundance of gut Prevotella than low ACE participants (q = 5.7 × 10^-13). Abundance of several gut taxa were significantly associated with cortisol, IL-6, TNF-α and CRP AUCs regardless of ACE status. IL-6 response to stress was buffered among high ACE women with high intake of docosahexaenoic acid (DHA) (p = 0.03) and eicosapentaenoic acid (EPA) (p = 0.05). DISCUSSION: Our findings suggest that multiple childhood adversities are associated with changes in gut microbiota composition during pregnancy, and such changes may contribute to altered inflammatory and glucocorticoid response to stress. While preliminary, this is the first study to demonstrate an association between gut microbiota and acute glucocorticoid-immune response to stress in a clinical sample. Finally, exploratory analyses suggested that high ACE women with high dietary intake of ω-3 polyunsaturated fatty acids (PUFAs) had a dampened inflammatory response to acute stress, suggesting potentially protective effects of ω-3s in this high-risk population. Given the adverse effects of inflammation on pregnancy and the developing fetus, mechanisms by which childhood adversity influence the gut-brain axis and potential protective factors such as diet should be further explored.