Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease. In endometriotic stromal cells, the levels of progesterone receptor (PR), particularly the PR-B isoform, are significantly decreased, leading to a loss of paracrine signaling. PR deficiency likely underlies the development of progesterone resistance in women with endometriosis who no longer respond to progestin therapy. Here we review the complex epigenetic and transcriptional mechanisms leading to PR deficiency. The initial event may involve deficient methylation of the estrogen receptor (ER)β promoter resulting in pathologic overexpression of ERβ in endometriotic stromal cells. We speculate that alterations in the relative levels of ERβ and ERα in endometrial tissue dictate E2-regulated PR expression, such that a decreased ERα--ERβ ratio may result in suppression of PR. In this review, we propose a molecular model that may be responsible for changes in ERβ and ERα leading to PR loss and progesterone resistance in endometriosis.

Objective To determine whether routine measurement of second-trimester transvaginal cervical length by ultrasound in low-risk singleton pregnancies is a costeffective strategy. Methods

OBJECTIVEThe International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recently recommended new criteria for diagnosing gestational diabetes mellitus (GDM). This study was undertaken to determine whether adopting the IADPSG criteria would be cost-effective, compared with the current standard of care.RESEARCH DESIGN AND METHODSWe developed a decision analysis model comparing the cost-utility of three strategies to identify GDM: 1) no screening, 2) current screening practice (1-h 50-g glucose challenge test between 24 and 28 weeks followed by 3-h 100-g glucose tolerance test when indicated), or 3) screening practice proposed by the IADPSG. Assumptions included that 1) women diagnosed with GDM received additional prenatal monitoring, mitigating the risks of preeclampsia, shoulder dystocia, and birth injury; and 2) GDM women had opportunity for intensive postdelivery counseling and behavior modification to reduce future diabetes risks. The primary outcome measure was the incremental cost-effectiveness ratio (ICER).RESULTSOur model demonstrates that the IADPSG recommendations are cost-effective only when postdelivery care reduces diabetes incidence. For every 100,000 women screened, 6,178 quality-adjusted life-years (QALYs) are gained, at a cost of $125,633,826. The ICER for the IADPSG strategy compared with the current standard was $20,336 per QALY gained. When postdelivery care was not accomplished, the IADPSG strategy was no longer cost-effective. These results were robust in sensitivity analyses.CONCLUSIONSThe IADPSG recommendation for glucose screening in pregnancy is cost-effective. The model is most sensitive to the likelihood of preventing future diabetes in patients identified with GDM using postdelivery counseling and intervention.

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BackgroundIntra-amniotic infection and/or inflammation (IAI) are important causes of preterm birth and early-onset neonatal sepsis (EONS). A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns.Methodology/Principal FindingsWe studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE) and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3) versus GA-matched controls (n = 3). Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1st-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP) in newborns with EONS (presumed and culture-confirmed) independent of GA at birth and birthweight (P<0.001). Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood (“switch-on pattern”) as opposed to non-EONS newborns who had near-absent “switch-off pattern” (P<0.001). Fetal Hp phenotype independently impacted Hp&HpRP. A Bayesian latent-class analysis (LCA) was further used for unbiased classification of all 180 cases based on probability of “antenatal IAI exposure” as latent variable. This was then subjected to 2nd-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input), interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20%) versus high (≥70%) probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses lowering the number needed to harm and increasing the odds ratios for several adverse outcomes including intra-ventricular hemorrhage.Conclusions/SignificanceAntenatal exposure to IAI results in precocious switch-on of Hp&HpRP expression. As EONS biomarker, cord blood Hp&HpRP has potential to improve the selection of newborns for prompt and targeted treatment at birth.