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BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure

Introduction The timing of parturition at end of human gestation may be controlled by fetal signals. The signaling molecules contributing to activation of human labor may be mediated by fetal exosomes. In this study, we focused on investigation of the role of microRNAs (miRNAs) derived from fetal exosomes in the regulation of human placental gene expression. Methods Using immunofluorescent labeling, array-based miRNA profiling assay, target prediction analysis, and conducting a variety of biochemical approaches including miRNA mimics, dual-luciferase, siRNA-mediated gene silencing, and immunohistochemical staining assay in primary trophoblast culture and formalin-fixed paraffin-embedded placental tissues, we examined whether fetal exosomal miRNAs can stimulate expression of proinflammatory mediators in human placenta. Results We showed placental uptake of exosomes derived from the umbilical artery, and found that 9 fetal exosomal miRNAs: let-7i-5p, miR-185-5p, miR-15b-5p, miR-376c-3p, miR-548d-5p, miR-92b-3p, miR-16-5p, and miR-1301-3p were significantly increased in placentas of women delivering following term labor compared to those delivering by Cesarean section in the late preterm period. Target prediction analysis identified miR-15b-5p of particular interest, because one of its predicted targets is Apelin, a potent inhibitor of proinflammatory mediators. We further found that miR-15b-5p repressed Apelin protein levels and activated pro-labor hormones and cytokines including IL-1, IL-6, IL-8, and TNF-α. Discussion These data suggest a potential fetal-to-placental signal that could play a role in the length of human gestation and onset of human labor.

Venous thromboembolism (VTE) remains a leading cause of maternal mortality. The American College of Obstetricians and Gynecologists (ACOG) and the Royal College of ObstetriciansGynecologists (RCOG) have proposed pregnancy-specific risk scoring guidelines for antepartum (AP) and postpartum (PP) thromboprophylaxis. We compared the impact of scoring thresholds and their potential preventative effect.We conducted a retrospective cohort study of hospitalized maternity patients over a 4-month period. Patients were assigned an AP and PP risk score using each guideline. Hospitalization-associated VTE was accessed over a 6-year period. Comparison was by Fischer's exact and Chi Square tests.638 women were included. Of AP patients, 20% met pharmacoprophylaxis criteria for baseline characteristics and 100% for length of stay using RCOG, and 12% met phrarmacoprophylaxis criteria using ACOG (In our population, using ACOG prophylaxis guidelines at an increased threshold would have potentially prevented all hospitalization related VTE without excessive anti-coagulation.

BACKGROUND Universal testing for COVID-19 on admission to the labor and delivery unit identifies asymptomatic patients. Whether or not these patients are at increased risk for adverse outcomes and go on to develop clinically significant disease is uncertain. OBJECTIVE This study aimed to assess the prevalence of asymptomatic COVID-19 presentation among pregnant patients admitted for delivery and to determine whether these patients become symptomatic or require hospital readmission after discharge. STUDY DESIGN We performed a multicenter, prospective cohort study of pregnant patients who delivered between 200/7 and 416/7 weeks’ gestation and who were found to have COVID-19 based on universal screening on admission for delivery at 1 of 4 medical centers in New Jersey (exposed group). The unexposed group, comprising patients who tested negative for COVID-19, were identified at the primary study site. The primary outcomes were the rates of asymptomatic COVID-19 presentation, the development of symptoms among the asymptomatic positive patients, and hospital readmission rates in the 2 weeks following discharge. We compared the frequency of the distribution of risk factors and outcomes in relation to the COVID-19 status among patients with COVID-19 across all centers and among those without COVID-19 at the primary site. Associations between categorical risk factors and COVID-19 status were expressed as relative risks with 95% confidence intervals. RESULTS Between April 10, 2020, and June 15, 2020, there were 218 patients with COVID-19 at the 4 sites and 413 patients without COVID-19 at the primary site. The majority (188 [83.2%]) of patients with COVID-19 were asymptomatic. Compared with the negative controls, these asymptomatic patients were not at increased risk for obstetrical complications that may increase the risk associated with COVID-19, including gestational diabetes (8.2% vs 11.4%; risk ratio, 0.72; 95% confidence interval, 0.24–2.01) and gestational hypertension (6.1% vs 7.0%; risk ratio, 0.88; 95% confidence interval, 0.29–2.67). Postpartum follow-ups via telephone surveys revealed that these patients remained asymptomatic and had low rates of family contacts acquiring the disease, but their adherence to social distancing guidelines waned during the 2-week postpartum period. Review of inpatient and emergency department records revealed low rates of hospital readmission. CONCLUSION Most of the pregnant patients who screened positive for COVID-19 are asymptomatic and do not go on to develop clinically significant infection after delivery. Routine surveillance of these patients after hospital discharge appears to be sufficient.

The Journal has had a profound influence in nearly 150 years of publishing. A bibliometric analysis, which uses citation analyses to evaluate the impact of articles, can be used to identify the most impactful papers in the Journal's history.The objective was to identify and characterize the top-cited articles published in the Journal since 1920.We used the Web of Science and Scopus databases to identify the most frequently cited articles of the Journal from 1920 through 2018. The top 100 articles from each database were included in our analysis. Articles were evaluated for several characteristics including year of publication, article type, topic, open access, and country of origin. Using the Scopus data, we performed an unadjusted categorical analysis to characterize the articles and a 2 time point analysis to compare articles before and after 1995, the median year of publication from each database list.The top 100 articles from each database were included in the analysis. This included 120 total articles: 80 articles listed in both and 20 unique in each database. More than half (52%) were observational studies, 9% were RCTs, and 75% were from US authors. When the post-1995 studies were compared with the articles published before 1995, articles were more frequently cited (median 27 vs 13 citations per year, P.001), more likely to be randomized (14.0% vs 4.8%, P = .009), and more likely to originate from international authors (33.3% vs 17.5%, P = .045).Slightly more than half of the top-cited papers in the Journal since 1920 were observational studies and three quarters of all papers were from US authors. Compared with top-cited papers before 1995, the Journal's top-cited papers after 1995 were more likely to be randomized and to originate from international authors.

Background Chromatin alterations are important mediators of gene expression changes. We have recently shown that activated non-canonical NF-κB signaling (RelB/p52) recruits histone acetyltransferase CBP and deacetylase HDAC1 to selectively acetylate H3K9 (H3K9ac) to induce expression of corticotropin-releasing hormone (CRH) and prostaglandin-endoperoxide synthase-2 (PTGS2) in the human placenta. Both of these genes play a role in initiating parturition in human pregnancy. Methods We performed chromatin immunoprecipitation followed by gene sequencing (ChIP-seq) in primary term human cytotrophoblast (CTB) with use of antibodies to RelB, CBP, HDAC1 and H3K9ac. We further associated these chromatin alterations with gene expression changes from mid-trimester to term in CTB by RNA sequencing (RNA-seq). Results We detected a genome-wide differential gene enrichment between mid-trimester and term human placenta. Pathway analysis identified that cytokine-cytokine receptor interaction, NF-κB, and TNF are the leading pathways enriched in term placenta and associated with these chromatin alterations. Discussions Our analysis has provided the first-time characterization of the key players of human placental origin with molecular changes resulting from chromatin modifications, which could drive human labor.

Advanced paternal age (APA) is associated with infertility and other reproductive risks. Studies looking at APA and outcomes have used different paternal age cut-offs, which has complicated systematic evaluations of reproductive risk associated with paternal aging. This review of the literature suggests that the impact of paternal aging on adverse reproductive outcomes is small, but significant. Studies suggest the incidence of paternal age effect disorders attributed to de novo autosomal dominant mutations is less than 0.5%. Other risks associated with APA include infertility, miscarriage, birth defects, poor neurodevelopmental outcomes, and childhood cancer. Although the increasing prevalence of APA has mirrored the rise in maternal age, this topic has not received similar attention. In this review, we summarize the available literature on the reproductive risks associated with APA to provide a framework for comprehensive genetic counseling and evidence-based management of APA pregnancies.

Intrauterine vacuum-induced hemorrhage control may provide an effective treatment option for postpartum hemorrhage that has the potential to prevent severe maternal morbidity and mortality., OBJECTIVE: To evaluate the effectiveness and safety of an intrauterine vacuum-induced hemorrhage-control device for postpartum hemorrhage treatment. METHODS: A multicenter, prospective, single-arm treatment study of a novel intrauterine device that uses low-level vacuum to induce uterine myometrial contraction to achieve control of abnormal postpartum uterine bleeding and postpartum hemorrhage was undertaken at 12 centers in the United States. The primary effectiveness endpoint was the proportion of participants in whom use of the intrauterine vacuum-induced hemorrhage-control device controlled abnormal bleeding without requiring escalating interventions. The primary safety endpoint was the incidence, severity, and seriousness of device-related adverse events. Secondary outcomes included time to bleeding control, rate of transfusion, and device usability scored by each investigator using the device. RESULTS: Of 107 participants enrolled with primary postpartum hemorrhage or abnormal postpartum uterine bleeding, 106 received any study treatment with the device connected to vacuum, and successful treatment was observed in 94% (100/106, 95% CI 88–98%) of these participants. In those 100 participants, definitive control of abnormal bleeding was reported in a median of 3 minutes (interquartile range 2.0–5.0) after connection to vacuum. Eight adverse events deemed possibly related to the device or procedure were reported, all of which were outlined as risks in the study and all of which resolved with treatment without serious clinical sequelae. Transfusion of 1–3 units of red blood cells was required in 35 participants, and five participants required 4 or more units of red blood cells. The majority of investigators reported the intrauterine vacuum-induced hemorrhage-control device as easy to use (98%) and would recommend it (97%). CONCLUSION: Intrauterine vacuum-induced hemorrhage control may provide a new rapid and effective treatment option for abnormal postpartum uterine bleeding or postpartum hemorrhage, with the potential to prevent severe maternal morbidity and mortality. FUNDING SOURCE: Alydia Health, Inc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02883673.

Background Retained placenta affects 2% to 3.3% of all vaginal deliveries and is one of the leading causes of postpartum hemorrhage worldwide. Despite the prevalence of this condition, there is limited guidance on its management. Objective A systematic review and meta-analysis were performed to evaluate the efficacy of pharmacologic interventions for the management of retained placenta. Study Design PubMed, ClinicalTrials.gov , Cochrane Library, Web of Science, and Scopus were searched for full-text publications in English. Search terms included “retained placenta” AND “treatment” OR “therapy” OR “disease management” OR “Pitocin” OR “misoprostol” OR “Cytotec” OR “dinoprostone” OR “nitroglycerin” OR “carbetocin” OR “ergotamine,” with no restriction on publication dates. Only randomized controlled trials were included. The primary outcome was the need for manual extraction of the placenta or dilation and curettage. Reviewers evaluated the quality of included articles using the Cochrane Collaboration’s tool for assessing the risk of bias. Pooled risk ratios were estimated based on random- and fixed-effects analyses. Interstudy heterogeneity was considered when I2≥50%. Results The literature search identified 29 randomized controlled trials that met the inclusion criteria (2682 subjects). The most commonly used agent across the studies was oxytocin administered via umbilical vein injection; there was high heterogeneity among these studies (I2=62%). Oxytocin was inferior to carbetocin (risk ratio, 1.61; 95% confidence interval, 1.03–2.52) and prostaglandins (risk ratio, 2.63; 95% confidence interval, 1.18–5.86) for the primary outcome. For oxytocin, prostaglandin agents, and nitroglycerin, there was a trend toward favoring the study drug for the primary outcome compared with control or placebo. Compared with placebo or control, estimated blood loss was lower if pharmacologic interventions were administered, with a mean difference of 121.5 mL (95% confidence interval, −185.7 to −52.3). There was no difference in postpartum hemorrhage or the need for blood transfusion between pharmacologic interventions and placebo or control. Conclusion Pooled estimates for oxytocin via umbilical vein injection, prostaglandin agents, and nitroglycerin performed favorably compared with placebo or control for the management of retained placenta. Carbetocin and prostaglandin agents were superior to oxytocin in reducing the need for manual extraction or dilation and curettage.

In most mammals, labor is heralded by the withdrawal of progesterone. In humans, circulating progesterone levels increase as gestation advances while placental expression of progesterone receptor A (PR-A) declines. As a result of PR-A downregulation, the non-canonical NF-κB pathway is activated, an event implicated in triggering labor. Here, we sought to identify fetal-derived mediator(s) that represses placental PR-A in human placenta leading to activation of pro-labor signaling. Lipidomic profiling demonstrated enrichment of platelet-activating factor (PAF) in exosomes originating from the human fetus. Exposure of primary cytotrophoblasts to fetal exosomes from term pregnancies reduced PR-A expression by > 50%, and PAF also reduced PR-A message levels in a dose-dependent manner. Notably, fetal exosomes from preterm pregnancies had lower PAF levels and no effect on PR-A expression. Synthetic PAF–induced DNA methylation increases by 20% at the PR-A promoter, leading to recruitment of corepressors and downregulation of PR-A in cytotrophoblast. Furthermore, suppression of PR-A by PAF-stimulated expression of the pro-labor genes, corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), which was reversed by disruption of the DNA methyltransferases 3B and 3L. Taken together, PAF represents a novel fetal–derived candidate for initiation of labor by stimulating methylation and repression of PR-A and activating pro-labor signaling in trophoblast.

OBJECTIVE As diagnostic methodologies evolve, we sought to determine whether invasive testing rates would decline, whether there would be a shift in indications for invasive testing, and whether the diagnostic yield would increase. METHODS We conducted a retrospective, observational study from 2006 through 2015. We quantified the number of invasive procedures per year and examined what percentage of these procedures yielded abnormal results. We also examined the indications for testing and determined the trend of these indications during the study period. RESULTS The number of amniocenteses showed a steady decline (P

The non-canonical NF-κB signaling may be a central integrator of a placental clock that governs the length of human pregnancy. We sought to identify fetal signals that could activate this NF-κB pathway in the placenta, and in turn, contribute to the onset of labor. Proteomics analysis of exosomes purified from fetal cord arterial blood revealed a total of 328 proteins, among which 48 were more significantly abundant (p

The BCRP/ABCG2 efflux transporter is expressed on the membrane of placental syncytiotrophoblasts and protects the fetus from toxicant exposure. Syncytiotrophoblasts arise from the fusion of cytotrophoblasts, a process negatively regulated by the endocannabinoid, anandamide (AEA). It is unknown whether AEA can influence fetal concentrations of xenobiotics by modulating the expression of transporters in syncytiotrophoblasts. Here, we sought to characterize and identify the mechanism(s) responsible for AEA-mediated down-regulation of the BCRP transporter in human placental explants and BeWo trophoblasts. Treatment of human placental explants with AEA (1 μM, 24 h) reduced hCGα, syncytin-1, and BCRP mRNAs by ˜30%. Similarly, treatment of BeWo trophoblasts with AEA (0–10 μM, 3-24 h) coordinately down-regulated mRNAs for hCGs, syncytin-2, and BCRP. In turn, AEA increased the sensitivity of trophoblasts to the cytotoxicity of mitoxantrone, a known BCRP substrate, and environmental and dietary contaminants including mycoestrogens and perfluorinated chemicals. AEA-treated trophoblasts also demonstrated reduced BCRP transport of the mycoestrogen zearalenone and the diabetes drug glyburide, labeled with BODIPY. The AEA-mediated reduction of BCRP mRNA was abrogated when placental cells were co-treated with AM630, a CB2 receptor inhibitor, or 8-Br-cAMP, a cAMP analog. AEA reduced intracellular cAMP levels in trophoblasts by 75% at 1 h, and completely inhibited forskolin-induced phosphorylation of the cAMP response element binding protein (CREB). AEA also decreased p-CREB binding to the BCRP promoter. Taken together, our data indicate that AEA down-regulates placental transporter expression and activity via CB2-cAMP signaling. This novel mechanism may explain the repression of placental BCRP expression observed during diseases of pregnancy.

Coronavirus disease 2019 may be associated with adverse maternal and neonatal outcomes in pregnancy, but there are few controlled data to quantify the magnitude of these risks or to characterize the epidemiology and risk factors.This study aimed to quantify the associations of coronavirus disease 2019 with adverse maternal and neonatal outcomes in pregnancy and to characterize the epidemiology and risk factors.We performed a matched case-control study of pregnant patients with confirmed coronavirus disease 2019 cases who delivered between 16 and 41 weeks' gestation from March 11 to June 11, 2020. Uninfected pregnant women (controls) were matched to coronavirus disease 2019 cases on a 2:1 ratio based on delivery date. Maternal demographic characteristics, coronavirus disease 2019 symptoms, laboratory evaluations, obstetrical and neonatal outcomes, and clinical management were chart abstracted. The primary outcomes included (1) a composite of adverse maternal outcome, defined as preeclampsia, venous thromboembolism, antepartum admission, maternal intensive care unit admission, need for mechanical ventilation, supplemental oxygen, or maternal death, and (2) a composite of adverse neonatal outcome, defined as respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, 5-minute Apgar score of5, persistent category 2 fetal heart rate tracing despite intrauterine resuscitation, or neonatal death. To quantify the associations between exposure to mild and severe or critical coronavirus disease 2019 and adverse maternal and neonatal outcomes, unadjusted and adjusted analyses were performed using conditional logistic regression (to account for matching), with matched-pair odds ratio and 95% confidence interval based on 1000 bias-corrected bootstrap resampling as the effect measure. Associations were adjusted for potential confounders.A total of 61 confirmed coronavirus disease 2019 cases were enrolled during the study period (mild disease, n=54 [88.5%]; severe disease, n=6 [9.8%]; critical disease, n=1 [1.6%]). The odds of adverse composite maternal outcome were 3.4 times higher among cases than controls (18.0% vs 8.2%; adjusted odds ratio, 3.4; 95% confidence interval, 1.2-13.4). The odds of adverse composite neonatal outcome were 1.7 times higher in the case group than to the control group (18.0% vs 13.9%; adjusted odds ratio, 1.7; 95% confidence interval, 0.8-4.8). Stratified analyses by disease severity indicated that the morbidity associated with coronavirus disease 2019 in pregnancy was largely driven by the severe or critical disease phenotype. Major risk factors for associated morbidity were black and Hispanic race, advanced maternal age, medical comorbidities, and antepartum admissions related to coronavirus disease 2019.Coronavirus disease 2019 during pregnancy is associated with an increased risk of adverse maternal and neonatal outcomes, an association that is primarily driven by morbidity associated with severe or critical coronavirus disease 2019. Black and Hispanic race, obesity, advanced maternal age, medical comorbidities, and antepartum admissions related to coronavirus disease 2019 are risk factors for associated morbidity.

The non-canonical NF-κB signaling (RelB/p52) pathway drives pro-labor genes in the human placenta, including corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2), making this a potential therapeutic target to delay onset of labor. Here we sought to identify small molecule compounds from a pre-existing chemical library of orally active drugs that can inhibit this NF-κB signaling, and in turn, human placental CRH and COX-2 production. We used a cell-based assay coupled with a dual-luciferase reporter system to perform an in vitro screening of a small molecule library of 1,120 compounds for inhibition of the non-canonical NF-κB pathway. Cell toxicity studies and drug efflux transport MRP1 assays were used to further characterize the lead compounds. We have found that 14 drugs have selective inhibitory activity against lymphotoxin beta complex-induced activation of RelB/p52 in HEK293T cells, several of which also inhibited expression of CRH and COX-2 in human term trophoblast. We identified sulfapyridine and propranolol with activity against CRH and COX-2 that deserve further study. These drugs could serve as the basis for development of orally active drugs to affect length of gestation, first in an animal model, and then in clinical trials to prevent preterm birth during human pregnancy.

Progesterone (P4)contributes to the maintenance of human pregnancy, in part by inhibiting activity of the human pro-labor genes CRH and cyclooxygenase-2 (COX-2). However, the molecular mechanisms underlying the action of P4 remain poorly defined. We have shown that in human placenta, the constitutively activated noncanonical nuclear factor (NF)-κB pathway positively regulates CRH and COX-2, which is further stimulated by glucocorticoid receptor signaling.We investigated the role of P4 receptor (PR) in the regulation of nuclear activity of v-rel avian reticuloendotheliosis viral oncogene homolog B (RelB)/NF-κB2 and, in turn, expression of placental CRH and COX-2.We used a variety of techniques including gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, quantitative RT-PCR, and immunohistochemical staining assays in human placental tissues and primary culture of human cytotrophoblast.We identified PR isoform-A (PR-A) as the only isoform of PR produced in human placenta. PR-A levels were lower in term placenta than in midterm placenta. Depletion of PR-A by short interfering RNA derepressed inhibition of CRH and COX-2 by P4 and the synthetic progestin 17α-hydroxyprogesterone caproate. Overexpression of PR-A inhibited transcription of CRH and COX-2, which was further downregulated by treatment with P4 or 17α-hydroxyprogesterone caproate. Such an inhibition was mediated by a negative functional interaction of PR-A with the activity of RelB/NF-κB2.P4 inhibits the pro-labor genes CRH and COX-2 via PR-A repression of the noncanonical NF-κB signaling in human placenta. Characterization of these pathways may identify potential drug targets for prevention of preterm birth.

Prior studies have reported an increased risk for preterm delivery following a term cesarean delivery. However, these studies did not adjust for high-risk conditions related to the first cesarean delivery and are known to recur.The objective of the study was to determine whether there is an association between term cesarean delivery in the first pregnancy and subsequent spontaneous or indicated preterm delivery.This was a retrospective cohort study of women with the first 2 consecutive singleton deliveries (2007-2014) identified through a linked pregnancy database at a single institution. Women with a first pregnancy that resulted in cesarean delivery at term were compared with women whose first pregnancy resulted in a vaginal delivery at term. Exclusion criteria were known to recur medical or obstetrical complications during the first pregnancy. A propensity score analysis was performed by matching women who underwent a cesarean delivery with those who underwent a vaginal delivery in the first pregnancy. The association between cesarean delivery in the first pregnancy and preterm delivery in the second pregnancy in this matched set was examined using conditional logistic regression. The primary outcome was overall preterm delivery37 weeks in the second pregnancy. Secondary outcomes included type of preterm delivery (spontaneous vs indicated), late preterm delivery (34-36 6/7 weeks), early preterm delivery (34 weeks), and small-for-gestational-age birth.Of a total of 6456 linked pregnancies, 2284 deliveries were matched; 1142 were preceded by cesarean delivery and 1142 were preceded by vaginal delivery. The main indications for cesarean delivery in the first pregnancy were dystocia in 703 (61.5%), nonreassuring fetal status in 222 (19.4%), breech presentation in 100 (8.8%), and other in 84 (7.4%). The mean (SD) gestational ages at delivery for the second pregnancy was 38.8 (1.8) and 38.9 (1.7) weeks, respectively, for prior cesarean delivery and vaginal delivery. The risks of preterm delivery in the second pregnancy among women with a previous cesarean and vaginal delivery were 6.0% and 5.2%, respectively (adjusted odds ratio, 1.46, 95% confidence interval, [CI] 0.77-2.76). In an analysis stratified by the type of preterm delivery in the second pregnancy, no associations were seen between cesarean delivery in the first pregnancy and spontaneous preterm delivery (4.6% vs 3.9%; adjusted odds ratio, 1.40, 95% confidence interval, 0.59-3.32) or indicated preterm delivery (1.6% vs 1.4%; adjusted odds ratio, 1.21, 95% confidence interval, 0.60-2.46). Similarly, no significant differences were found in late preterm delivery (4.6% vs 4.1%; adjusted odds ratio, 1.13, 95% confidence interval, 0.55-2.29), early preterm delivery (1.6% vs 1.2%; adjusted odds ratio, 1.25, 95% confidence interval, 0.59-2.67), or neonates with birthweight less than the fifth percentile for gestational age (3.6% vs 2.2%; adjusted odds ratio, 1.26, 95% confidence interval, 0.52-3.06).After robust adjustment for confounders through a propensity score analysis related to the indication for the first cesarean delivery at term, cesarean delivery is not associated with an increase in preterm delivery, spontaneous or indicated, in the subsequent pregnancy.

It has been widely documented that advanced maternal age constitutes a risk to both mother and child. The purpose of this review is to examine the risks posed to the pregnant mother over the age of 44 and determine if they are experienced in greater frequency than in their younger cohorts. A review of the recent literature demonstrates a significant increased incidence of cesarean section, pregnancy-induced hypertension, gestational diabetes, and perinatal mortality. There also appears to be different rates of maternal complications depending on mode of conception with assisted reproductive technology conferring a higher risk in this population. Further study is recommended in mode of conception and parity to examine the effects on maternal and fetal risks.

An unintended consequence of the rising cesarean section rate is abnormal placentation in subsequent pregnancies, leading to the clinical complications of placenta accreta and cesarean scar pregnancies. Both of these clinical entities are associated with high rates of maternal morbidity and mortality. This article reviews the potential mechanisms by which uterine scarring may lead to abnormal trophoblast invasion, the association of cesarean section with placenta accreta and scar pregnancies, current management, and suggestions for future research to reduce the incidence of these potentially devastating complications of pregnancy.

Corticotropin-releasing hormone (CRH) produced in the placenta may be part of a clock that regulates the length of human gestation. Maternal plasma CRH abundance exponentially increases as pregnancy advances. Glucocorticoid stimulates CRH expression in full-term human placenta by promoting noncanonical (RelB/p52 heterodimer-mediated) nuclear factor κB (NF-κB) pathway activity. Using dexamethasone to mimic glucocorticoid exposure, we found that an epigenetic switch mediated the glucocorticoid-induced expression of CRH as gestation advances. The amount of acetylated histone H3 lysine 9 (H3K9) associated with the CRH promoter was greater in cytotrophoblasts from full-term placenta than in those from midterm placenta. Knocking down the lysine acetyltransferase CBP reduced H3K9 histone acetylation and prevented dexamethasone-induced CRH expression. Unexpectedly, knocking down the histone deacetylase HDAC1 or pharmacologically inhibiting type I and II HDACs also decreased the expression of CRH yet increased the acetylation of H3K9 and other histone regions. Both CBP and HDAC1 bound at the CRH promoter in a complex with the RelB/p52 heterodimer in a mutually dependent manner; knocking down any one factor in the complex prevented binding of the others as well as the dexamethasone-induced CRH expression. Our results suggest that glucocorticoids induce a transcription complex consisting of RelB/p52, CBP, and HDAC1 that triggers a dynamic acetylation-mediated epigenetic change to induce CRH expression in full-term human placenta.

Multimodal prenatal screening for developmental pathology is increasingly common. In this case, definitive prenatal diagnosis of androgen insensitivity syndrome was diagnosed after discordant results from karyotypes determined by embryonic preimplantation genetic screening and antenatal ultrasound results.A 38-year-old woman, gravida 2 para 0010, undergoing in vitro fertilization with preimplantation genetic screening transferred one male and one female embryo. An anatomic ultrasonogram revealed two fetuses with female genitalia. Cell-free fetal DNA analyzed using noninvasive prenatal screening demonstrated Y chromosome material, and amniocentesis confirmed one 46,XX and one 46,XY fetus. Sequencing of the androgen receptor for the 46,XY fetus identified a mutation.With increased use, discordance among prenatal testing modalities such as preimplantation genetic screening, noninvasive prenatal screening, and ultrasonography will become more common requiring expert navigation to identify true pathology.

Recent advances in Down syndrome screening are providing women with additional options in how they are assessed for this condition. First trimester screening tests are at least as accurate as traditional second trimester testing and provide results earlier in a woman's pregnancy. Combining first and second trimester results increases the sensitivity and specificity of screening and reduce the number of women requiring invasive testing. This review summarizes and critiques the available data on Down syndrome screening and compares different testing algorithms. Meta-analyses of first trimester screening techniques are presented. Nuchal lucency measurements and other first trimester ultrasound markers, first trimester serum markers, and methods for combining these screens are addressed.

Objective To evaluate the effectiveness of low-level nerve stimulation therapy over the volar aspect of the wrist at the P6 point to treat nausea and vomiting in early pregnancy. Methods Pregnant volunteers (n = 230) with symptoms of mild to severe nausea and vomiting between 6 and 12 weeks’ gestation participated in a 21-day clinical trial. Participants were randomly assigned to receive a device for nerve stimulation therapy or an otherwise identical but nonstimulating placebo device. The primary outcome measure was self-recorded symptoms according to the Rhodes Index of Nausea, Vomiting, and Retching (Rhodes Index). Secondary outcome measures were medication use, weight gain, and presence of urinary ketones. Results Baseline characteristics were similar in both groups. A total of 187 women (81%) completed the trial. Pretreatment Rhodes Index scores for the entire population demonstrated no significant differences between study and control groups. The time-averaged change in Rhodes Index total experience of 6.48 for the study group was significantly better than the control value of 4.65 (P = .02). Study patients gained more weight than controls (2.9 versus 1.2 lb, P = .003). There were no statistically significant differences in medication use or urinary ketone measurements. Conclusion Nerve stimulation therapy is effective in reducing nausea and vomiting and promoting weight gain in symptomatic women in the first trimester of pregnancy.

Introduction Our recent studies have shown that constitutively activated non-canonical RelB/NF-κB2 (p52) in the human placenta positively regulates the pro-labor genes CRH and COX-2. STAT3 regulates NF-κB2 (p100) processing to active p52, and in turn, nuclear activation of RelB/p52, by directly binding to p100/p52 in a variety of cancer cells. In the current study, we tested the hypothesis that STAT3 is involved in regulation of pro-labor genes by associating with RelB/p52 heterodimers in the human placenta. Methods We used a variety of techniques including immunohistochemical staining, gene silencing, ectopic expression, chromatin immunoprecipitation, Western blot, RT-qPCR, and immunofluorescence assays in primary culture of cytotrophoblast and placental tissues. Results We found that knockdown of STAT3 led to down-regulation of both CRH and COX-2 in a dose-dependent manner. By using chromatin immunoprecipitation, we further showed that interaction of RelB with the CRH or COX-2 gene promoters decreased when STAT3 was depleted. Immunofluorescence demonstrated co-localization of STAT3 with RelB or p100/p52 in both the cytoplasm and nucleus of term cytotrophoblasts. Discussion Collectively, these results suggest that STAT3 constitutes part of the RelB/p52-containing activator complex that positively regulates pro-labor genes in the human placenta.

Apolipoprotein B is elevated in growth-retarded compared with normally grown fetuses, demonstrating a link between low birth weight and risk of subsequent atherosclerosis. Increased apolipoprotein B levels and an elevated apolipoprotein B to A-I ratio are predictors of atherogenesis. Elevated apolipoprotein B levels in young adults have been linked to atherosclerosis in later life, whereas impaired fetal growth has been linked to higher than normal apolipoprotein B levels in adulthood. We conducted this research to test the hypothesis that circulating apolipoprotein A-I and B concentrations differ in growth-retarded compared with normal fetuses. Fetal umbilical plasma samples were obtained at diagnostic cordocenteses in 18 growth-retarded and 23 normally grown fetuses. Levels of apolipoprotein A-I and B were measured by turbidimetric assay. There were no differences in median (range) plasma apolipoprotein A-I concentrations between growth-retarded and normal fetuses [0.61 (0.30-1.42) vs. 0.60 (0.30-1.63) g/L, respectively; P = 0.94]. In contrast, we found significantly higher plasma apolipoprotein B levels in growth-retarded vs. normal fetuses [0.62 (0.37-1.84) vs. 0.40 (0.16-1.47) g/L, respectively; P0.001]. Moreover, the ratio of apolipoprotein B to A-I was significantly higher in growth-retarded than in normal fetuses [1.00 (0.38-2.42) vs. 0.53 (0.31-1.80); P = 0.005]. Levels of apolipoprotein B are elevated in growth-retarded fetuses, suggesting a linkage between low birth weight and adult-onset atherosclerosis.

Our recent study demonstrated that constitutively activated RelB/NF-κB2 positively regulates the CRH in the human placenta. In the current study, we explored the role of the glucocorticoid receptor (GR) signaling in constitutive activation of the noncanonical NF-κB pathway. A glucocorticoid response element (GRE) motif search suggests that both NF-κB inducing kinase (NIK) and RelB genes, which are key regulators of the noncanonical NF-κB pathway, have a putative GRE within their promoter, approximately 1 kb upstream from the transcription start site. By using chromatin immunoprecipitation assay we identified that the GR and phosphorylated GR at Ser211 were associated with the GREs of both NIK and RelB. Dexamethasone stimulated expression of NIK, RelB, NF-κB2 as well as CRH and cyclooxygenase-2 (COX-2). Repression of GR by short interfering RNA resulted in inhibition of NIK, RelB, NF-κB2, CRH, and COX-2. In addition, depletion of GR attenuated glucocorticoid-mediated up-regulation of NIK, RelB, NF-κB2, CRH, and COX-2. Furthermore, siRNA specifically targeting NIK down-regulated CRH and COX-2. Taken together, these results suggest that constitutive activation of the noncanonical NF-κB pathway in term human placenta is driven by the GR signaling, which in turn up-regulates placental CRH and other NF-κB-responsive genes.

BACKGROUND: Cervical dilation in the second trimester is associated with a greater than 90% rate of spontaneous preterm birth and a poor perinatal prognosis. OBJECTIVE: To compare the perinatal outcomes of twin pregnancies with dilated cervix in women who underwent either cerclage or expectant management. STUDY DESIGN: Retrospective cohort study of asymptomatic twin pregnancies identified with cervical dilation of ≥1 cm at 16-24 weeks (1997-2014) at 7 institutions. Exclusion criteria were genetic or major fetal anomaly, multifetal reduction at >14 weeks, prior cerclage placement, monochorionic-monoamniotic placentation, active vaginal bleeding, labor, chorioamnionitis, elective termination of pregnancy, or medically indicated preterm birth. The primary outcome was incidence of spontaneous preterm birth at

Women exposed to phthalates during pregnancy are at increased risk for delivering preterm, but the mechanism behind this relationship is unknown. Placental corticotropin-releasing hormone (CRH) and cyclooxygenase-2 (COX-2) are key mediators of parturition and are regulated by the non-canonical NF-kB (RelB/p52) signaling pathway. In this study, we demonstrate that one of the major phthalate metabolites, mono-(2-ethylhexyl)-phthalate (MEHP), increased CRH and COX-2 mRNA and protein abundance in a dose-dependent manner in primary cultures of cytotrophoblast. This was coupled with an increase in nuclear import of RelB/p52 and its association with the CRH and COX-2 promoters. Silencing of NF-kB inducing kinase, a central signaling component of the non-canonical NF-kB pathway, blocked MEHP-induced upregulation of CRH and COX-2. These results suggest a potential mechanism mediated by RelB/p52 by which phthalates could prematurely induce pro-labor gene activity and lead to preterm birth.

Placental CRH may be part of a clock that governs the length of human gestation. The mechanism underlying differential regulation of CRH in the human placenta is poorly understood. We report here that constitutively activated RelB/nuclear factor-κB2 (NF-κB)-2 (p100/p52) acts as an endogenous stimulatory signal to regulate CRH by binding to an NF-κB enhancer of CRH gene promoter in the human placenta. Nuclear staining of NF-κB2 and RelB in villous syncytiotrophoblasts and cytotrophoblasts was coupled with cytoplasmic CRH in syncytial knots of cytotrophoblasts. Chromatin immunoprecipitation identified that CRH gene associated with both RelB and NF-κB2 (p52). Dexamethasone increased synthesis and nuclear translocation of RelB and NF-κB2 (p52) and their association with the CRH gene. In contrast, progesterone, a down-regulator of placental CRH, repressed NF-κB2 (p100) processing, nuclear translocation of RelB and NF-κB2 (p52), and their association with the CRH gene. Luciferase reporter assay determined that the NF-κB enhancer of CRH was sufficient to regulate transcriptional activity of a heterologous promoter in primary cytotrophoblasts. RNA interference-mediated repression of RelB or NF-κB2 resulted in significant inhibition of CRH at both transcriptional and translational levels and prevented the dexamethasone-mediated up-regulation of CRH transcription and translation. These results suggest that the noncanonical NF-κB pathway regulates CRH production in the human placenta and is responsible for the positive regulation of CRH by glucocorticoids.

The objective of this article was to review the literature to identify the most promising markers of preeclampsia (PE) and the relationship to cardiovascular disease to gain a better understanding of the mechanism of PE to identify women at risk for cardiovascular disease to improve their outcomes.Forty case-control studies were assessed for relationships between different serum markers to identify PE and to identify markers that may predict women who may be at greater risk for cardiovascular sequela in later life.Angiogenic, proteomic, and tumor necrosis markers were the most promising and important in the development of PE. The interplay among various growth factors, hormones, proteins, and other molecular compounds appears to be critical in the development of PE. Specific angiogenic (sVEGF, PLGF) and antiangiogenic (sFlt-1, sENG) markers and proteomic markers (fibrinogen and a-1-antichymotrypsin, SERPINA1, albumin, 1-antichymotryps) are the most promising markers of PE. Evidence of metabolic abnormalities associated with PE and common markers with cardiovascular disease include free leptin concentration which increases in normal pregnancy and is further increased in PE.Markers are important to help understand disease, potentially identify women at risk to improve their outcomes, design therapies to ameliorate symptoms so that pregnancy can be prolonged and neonatal outcomes improved, and provide a better understanding the link between PE and increased risk for disease later in life.

Objective: To determine changes in length of incompetent cervices after cerclage, using transvaginal ultrasound. Methods: Patients were enrolled in a prospective, observational study under an Institutional Review Board–approved protocol. McDonald or Shirodkar sutures were placed according to physician preference. Pre- and postcerclage cervical lengths were measured within 72 hours of the procedure. At each examination, the first measurement was discarded, and a mean of the subsequent three measurements was calculated. Results: Twenty-one Shirodkar and ten McDonald operations were done. The mean (± standard deviation) precerclage cervical length was 2.7 ± 0.9 cm and the postcerclage cervical length was 3.6 ± 0.9 cm (P < .001, paired t test). Conclusion: Prophylactic cerclage results in measurable increases in cervical length, which might contribute to the success of the procedure. Further study is needed to determine whether the degree of cervical lengthening after cerclage predicts term delivery.

Given the strong clinical association between the decidual hemorrhage of placental abruption and subsequent preterm premature rupture of the membranes, we assessed the effects of thrombin on the expression of the potent interstitial collagenase, matrix metalloproteinase-1 (MMP-1), in cultured endometrial stromal and decidual cells.Stromal cells derived from predecidualized cycling endometrium and decidual cells from term decidua were cultured in a defined medium containing estradiol, to mimic the hormonal milieu of the non-pregnant proliferative phase, or estradiol plus medroxyprogesterone acetate (MPA), to mimic the hormonal milieu of pregnancy, in the presence and absence of thrombin. Culture media were examined for MMP-1 protein levels and cell lysates were examined for steady-state MMP-1 mRNA levels.MPA strongly inhibited MMP-1 levels in endometrial stromal and term decidual cells. However, thrombin overcame this suppression, producing MMP-1 levels that were several-fold higher than control levels.Extrapolation of thrombin-enhanced MMP-1 expression in cultured endometrial stromal and decidual cells to the in vivo pregnant state provides an explanation for the strong association between placental abruption and preterm membrane rupture.

AIMS The purpose of this study was to assess the effect, if any, of color Doppler on the measurement of the amniotic fluid index in term pregnancies. It is hypothesized that color Doppler may enhance the detection of oligohydramnios. METHODS The amniotic fluid index was performed with and without color Doppler on pregnancies greater than or equal to 36 weeks gestational age. Differences in the mean amniotic fluid index measurements were assessed. The incidence of oligohydramnios was examined using both techniques. Differences in continuous variables were assessed with the paired t test, differences in categorical variables were assessed using the Fisher Exact Test. RESULTS There were 155 pregnancies examined, the amniotic fluid index was significantly decreased when color Doppler was added to the standard technique. (P < .0001) The incidence of oligohydramnios was higher with the application of color Doppler to the standard amniotic fluid index. (P < .05). CONCLUSIONS Color Doppler results in a significantly lower amniotic fluid volume measurement and may enhance the detection of oligohydramnios.

Study objectives: To describe the spectrum of illness that presents to shipboard hospitals and thereby recommend optimal qualifications for the ship's medical personnel. Design: Retrospective review of medical logs from two cruise ships' hospitals. Settings: Two passenger cruise ships, with seven-to-ten day cruises in the Caribbean. Participants: All patients presenting to the ships' hospitals from January 4, 1989, to June 10, 1989, on one ship and from October 13, 1990, to November 10, 1990, on another ship. Methods: Analysis of ship medical logs with regard to patient complaint, diagnosis, and treatment. Results: Of 1,547 new patient visits, 12% were related to injuries and 88% to medical problems; 97% of visits were noncritical, and 3% required immediate emergency intervention. Among these were four cardiac arrests, two stab wounds, two serious ocular injuries, one closed-head injury, and one near-drowning. Five patients required endotracheal intubation. Conclusion: There is a sizeable number of visits to ships' hospitals by patients with acute and serious problems of a wide variety. Physicians and nurses with significant emergency training or experience are best qualified to deal with this broad spectrum of patient problems in this isolated environment.