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

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.

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.

Maternal vitamin D deficiency is linked to adverse pregnancy outcomes including spontaneous preterm birth (SPB). Placental corticotropin-releasing hormone (CRH) has been proposed to be part of a clock that governs the length of gestation in humans, with elevated maternal serum levels predicting early delivery. In this study, we test the hypothesis that vitamin D could contribute to the prevention of preterm labor by inhibiting CRH and other pro-labor mediators. The biological activity of vitamin D occurs via two pathways: non-genomic and genomic responses, both of which involve binding of 1,25-dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D binding to the vitamin D receptor (VDR). By using chromatin immunoprecipitation followed by sequencing (ChIP-seq), we found that 1,25(OH)2D stimulates association of VDR with a number of miRNA genes including MIR181B2 and MIR26B, and their mature products miR-181b-5p and miR-26b-5p are predicted to target CRH and cyclooxygenase-2 (COX-2) mRNA at 3′-untranslated region (UTR), respectively. We performed RT-qPCR analysis to validate that expression of mature miR-181b-5p and miR-26b-5p in term human syncytiotrophoblast increased in response to treatment with 1,25(OH)2D. miR-181b-5p- or miR-26b-5p-mediated inhibition of CRH or COX-2 was further assessed by the use of miRNA mimics/inhibitors and a luciferase reporter assay. Taken together, this study has identified novel mechanisms by which vitamin D downregulates pro-labor genes and could lower the risk of preterm delivery.

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: Premature cervical softening and shortening may be considered an early mechanical failure that predisposes to preterm birth. Preliminary clinical studies demonstrate that cervical elastography may be able to quantify this phenomenon and predict spontaneous preterm delivery. Objective: To explore a new approach for cervix elasticity and length measurements with tactile-ultrasound probe. Methods: Cervix probe has tactile array and ultrasound transducer designed to apply controllable load to cervix and acquire stress-strain data for calculation of cervical elasticity (Young’s modulus) and cervical length for four cervix sectors. Average values, standard deviations, intraclass correlation coefficients and the 95% limits of agreement (Bland-Altman plots) were estimated. Results: Ten non-pregnant and ten pregnant women were examined with the probe. The study with non-pregnant women demonstrated a reliable acquisition of the tactile signals. The ultrasound signals had a prolonged appearance; identification of the internal os of the cervix in these signals was not reliable. The study with pregnant women with the gestational age of 25.4 ± 2.3 weeks demonstrated reliable data acquisition with real-time visualization of the ultrasound signals. Average values for cervical elasticity and standard deviations of 19.7 ± 15.4 kPa and length of 30.7 ± 6.6 mm were calculated based on two measurements per 4 sectors. Measurement repeatability calculated as intraclass correlation coefficients between two measurements at the same cervix sector on pregnant women was found to be 0.97 for cervical elasticity and 0.93 for the cervical length. The 95% limits of agreement of 1) cervical elasticity were from ?22.4% to +14.9%, and 2) cervical length from ?13.3% to +16.5%. Conclusions: This study demonstrated clinically acceptable measurement performance and reproducibility. The availability of stress-strain data allowed the computation of cervical elasticity and length. This approach has the potential to provide cervical markers to predict spontaneous preterm delivery.

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.

Bardet-Biedl syndrome (BBS) is a rare pediatric ciliopathy characterized by marked clinical variability and extensive genetic heterogeneity. Typical diagnosis of BBS is secured at a median of 9 years of age, and sometimes well into adolescence. Here, we report a patient in whom prenatal detection of increased nuchal fold, enlarged echogenic kidneys, and polydactyly prompted us to screen the most commonly mutated genes in BBS and the phenotypically and genetically overlapping ciliopathy, Meckel-Gruber syndrome (MKS). We identified the common Met390Arg mutation in BBS1 in compound heterozygosity with a novel intronic variant of unknown significance (VUS). Testing of mRNA harvested from primary foreskin fibroblasts obtained shortly after birth revealed the VUS to induce a cryptic splice site, which in turn led to a premature termination and mRNA degradation. To our knowledge, this is the earliest diagnosis of BBS in the absence of other affected individuals in the family, and exemplifies how combining clinical assessment with genetic and timely assays of variant pathogenicity can inform clinical diagnosis and assist with patient management in the prenatal and neonatal setting.

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.

Circulating glucocorticoids are present in increasing quantities as human gestation progresses, peaking during labor whether it occurs before or at term. Although the precise role of glucocorticoids in pregnancy is not well defined, it is clear that glucocorticoids suppress inflammation in many cell types by antagonizing the acute stimulatory actions of members of the Rel/nuclear factor-kappaB (NF-kappaB) family on cytokine gene expression. In the present study we tested the hypothesis that during pregnancy, glucocorticoids chronically suppress inflammation in the human placenta. Cytotrophoblasts obtained from human term placentas were maintained for 48 h in culture medium supplemented with 10% charcoal-stripped calf serum with and without 100 nmol/L dexamethasone (DEX). Enzyme-linked immunosorbent assay studies revealed that cytotrophoblasts constitutively express interleukin-8 (IL-8), a known mediator of placental inflammation, between 24-96 h of culture. A 48-h treatment of cytotrophoblasts with 100 nmol/L DEX significantly reduced the production of IL-8 to 24+/-1% of control levels (P < 0.01). DEX and cortisol mediated a dose-dependent inhibition of IL-8 expression, with ED50 values of 5 and 50 nmol/L, respectively. DEX treatment also significantly reduced levels of IL-6 and tumor necrosis factor-alpha in culture medium, suggesting that glucocorticoids coordinately reduce cytokine levels in cytotrophoblasts. As cytokine expression is regulated by NF-kappaB and activator protein-1 (AP-1) transcription factors, electrophoretic mobility shift assays (n = 4) were used to determine whether DEX treatment altered the binding of nuclear proteins from cytotrophoblasts to labeled oligonucleotides corresponding to the kappaB and AP-1 response elements. We observed that a 48-h treatment of cytotrophoblasts with 100 nmol/L DEX markedly reduced binding of nuclear extracts from cytotrophoblasts to the kappaB response element. DEX treatment promoted a relatively smaller reduction of binding to the AP-1 response element. Northern blotting experiments revealed that DEX treatment did not alter the level of IkappaB, p50, or p65 messenger ribonucleic acid, suggesting that the antiinflammatory action of glucocorticoid in cytotrophoblasts did not directly involve alterations in the level of NF-kappaB proteins. Our results demonstrate a novel chronic suppressive action of glucocorticoid on cytokine production and nuclear binding of NF-kappaB and AP-1 proteins in cytotrophoblasts, providing a potential mechanism through which glucocorticoids may suppress inflammation at maternal-fetal interfaces across gestation.

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.