Prognostic stratification of endometrial cancers with high microsatellite instability or no specific molecular profile.

Objective: To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP EC. Methods: We searched The Cancer Genome Atlas for DNA sequencing, RNA expression, and surveillance data regarding MSI-H/NSMP EC. We used a molecular classification system of E2F1 and CCNA2 expression and sequence variations in POLE, PPP2R1A, or FBXW7 (ECPPF) to prognostically stratify MSI-H/NSMP ECs. Clinical outcomes were annotated after integrating ECPPF and sequence variations in homologous recombination (HR) genes. Results: Data were available for 239 patients with EC, which included 58 MSI-H and 89 NSMP cases. ECPPF effectively stratified MSI-H/NSMP EC into distinct molecular groups with prognostic implications: molecular low risk (MLR), with low CCNA2 and E2F1 expression, and molecular high risk (MHR), with high CCNA2 and E2F1 expression and/or PPP2R1A and/or FBXW7 variants. The 3-year disease-free survival (DFS) rate was 43.8% in the MHR group with clinicopathologic low-risk indicators and 93.9% in the MLR group (P<.001). In the MHR group, wild-type HR genes were present in 28% of cases but in 81% of documented recurrences. The 3-year DFS rate in patients with MSI-H/NSMP EC with clinicopathologic high-risk indicators was significantly higher in the MLR (94.1%) and MHR/HR variant gene (88.9%) groups than in the MHR/HR wild-type gene group (50.3%, P<.001). Conclusion: ECPPF may resolve prognostic challenges for MSI-H/NSMP EC by identifying occult high-risk disease in EC with clinicopathologic low-risk indicators and therapeutic insensitivity in EC with clinicopathologic high-risk indicators.

Host immunity and KLF 11 deficiency together promote fibrosis in a mouse model of endometriosis.

BACKGROUND: Endometriosis is a debilitating disease typically characterized by prolific fibrotic scarring. Earlier we reported downregulation of two transcription factors belonging TGF-ßR signaling pathway Sp/Krüppel-like factor 11 (KLF11) and 10 (KLF10) in human endometriosis lesions. Here we investigated the role of these nuclear factors and immunity in the scaring fibrosis associated with endometriosis. METHODS: We used a well characterized experimental mouse model of endometriosis. WT, KLF10 or KLF11 deficient mice were compared. The lesions were evaluated histologically, fibrosis was quantified with Masons' Trichome staining, immune-infiltrates were quantified by immunohistochemistry, peritoneal adhesions were score, gene expression was evaluated by bulk RNA sequencing. RESULTS: Intense fibrotic reactions and large changes in gene expression were detected in KLF11 deficient implants associated with squamous metaplasia of the ectopic endometrium, as compared to KLF10 deficient or WT implants. Fibrosis was mitigated with pharmacologic agents that blocked histone acetylation or TGF-ßR signaling or with genetic deficiency for SMAD3. The lesions were richly infiltrated with T-cells, regulatory T-cells, and innate immune cells. Fibrosis was exacerbated when implants expressed ectopic genes implicating autoimmunity as a major factor contributing to the scaring fibrosis. CONCLUSIONS: Our findings identify KLF11 and TGF-ßR signaling as cell intrinsic mechanisms and autoimmune responses as cell extrinsic mechanisms of scaring fibrosis in ectopic endometrium lesions. GENERAL SIGNIFICANCE: Immunological factors associated with inflammation and tissue repair drive scaring fibrosis in experimental endometriosis, providing the rationale for immune therapy of endometriosis.

ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification: Profiling high-risk subtypes of histomorphologically low-risk and treatment-insensitive endometrioid endometrial cancer.

In endometrial cancer, occult high-risk subtypes (rooted in histomorphologically low-risk disease) with insensitivity to adjuvant therapies impede improvements in therapeutic efficacy. Therefore, we aimed to assess the ability of molecular high-risk (MHR) and low-risk (MLR) ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification to profile recurrence in early, low-risk endometrioid endometrial cancer (EEC) and insensitivity to platinum-based chemotherapy or radiotherapy (or both) in high-risk EEC. Using The Cancer Genome Atlas endometrial cancer database, we identified 192 EEC cases with available DNA sequencing and RNA expression data. Molecular parameters were integrated with clinicopathologic risk factors and adverse surveillance events. MHR was defined as high (-H) CCNA2 or E2F1 log2 expression (≥2.75), PPP2R1A mutations (-mu), or FBXW7mu; MLR was defined as low (-L) CCNA2 and E2F1 log2 expression (<2.75). We assessed 164 cases, plus another 28 with POLEmu for favorable-outcomes comparisons. MHR and MLR had significantly different progression-free survival (PFS) rates (P < .001), independent of traditional risk factors (eg, TP53mu), except for stage IV disease. PFS of CCNA2-L/E2F1-L paralleled that of POLEmu. ECPPF status stratified responses to adjuvant therapy in stage III-IV EEC (P < .01) and profiled stage I, grade 1-2 cases with risk of recurrence (P < .001). MHR was associated with CTNNB1mu-linked treatment failures (P < .001). Expression of homologous recombination repair (HR) and cell cycle genes was significantly elevated in CCNA2-H/E2F1-H compared with CCNA2-L/E2F1-L (P<1.0E-10), suggesting that HR deficiencies may underlie the favorable PFS in MLR. HRmu were detected in 20.7%. No treatment failures were observed in high-grade or advanced EEC with HRmu (P = .02). Favorable PFS in clinically high-risk EEC was associated with HRmu and MLR ECPPF (P < .001). In summary, MLR ECPPF and HRmu were associated with therapeutic efficacy in EEC. MHR ECPPF was associated with low-risk, early-stage recurrences and insensitivity to adjuvant therapies.

Impact of labor characteristics on maternal and neonatal outcomes of labor: A machine-learning model.

INTRODUCTION: Since Friedman's seminal publication on laboring women, numerous publications have sought to define normal labor progress. However, there is paucity of data on contemporary labor cervicometry incorporating both maternal and neonatal outcomes. The objective of this study is to establish intrapartum prediction models of unfavorable labor outcomes using machine-learning algorithms. MATERIALS AND METHODS: Consortium on Safe Labor is a large database consisting of pregnancy and labor characteristics from 12 medical centers in the United States. Outcomes, including maternal and neonatal outcomes, were retrospectively collected. We defined primary outcome as the composite of following unfavorable outcomes: cesarean delivery in active labor, postpartum hemorrhage, intra-amniotic infection, shoulder dystocia, neonatal morbidity, and mortality. Clinical and obstetric parameters at admission and during labor progression were used to build machine-learning risk-prediction models based on the gradient boosting algorithm. RESULTS: Of 228,438 delivery episodes, 66,586 were eligible for this study. Mean maternal age was 26.95 ± 6.48 years, mean parity was 0.92 ± 1.23, and mean gestational age was 39.35 ± 1.13 weeks. Unfavorable labor outcome was reported in 14,439 (21.68%) deliveries. Starting at a cervical dilation of 4 cm, the area under receiver operating characteristics curve (AUC) of prediction models increased from 0.75 (95% confidence interval, 0.75-0.75) to 0.89 (95% confidence interval, 0.89-0.90) at a dilation of 10 cm. Baseline labor risk score was above 35% in patients with unfavorable outcomes compared to women with favorable outcomes, whose score was below 25%. CONCLUSION: Labor risk score is a machine-learning-based score that provides individualized and dynamic alternatives to conventional labor charts. It predicts composite of adverse birth, maternal, and neonatal outcomes as labor progresses. Therefore, it can be deployed in clinical practice to monitor labor progress in real time and support clinical decisions.

Persistent Pelvic Pain in Patients With Endometriosis.

As our understanding of chronic pain conditions, including endometriosis-related pain and chronic pelvic pain evolves, the evaluation and management of patients should reflect our increasing appreciation of the role of central sensitization, comorbid conditions and biopsychosocial factors on the pain experience and treatment outcomes. This review provides a systematic approach to persistent pain in patients with endometriosis. Expanding the evaluation and treatment of endometriosis-related pain by all health care providers could limit unnecessary surgical interventions and best meet our patient's needs.

Introduction to Machine Learning in Obstetrics and Gynecology.

In the digital age of the 21st century, we have witnessed an explosion in data matched by remarkable progress in the field of computer science and engineering, with the development of powerful and portable artificial intelligence-powered technologies. At the same time, global connectivity powered by mobile technology has led to an increasing number of connected users and connected devices. In just the past 5 years, the convergence of these technologies in obstetrics and gynecology has resulted in the development of innovative artificial intelligence-powered digital health devices that allow easy and accurate patient risk stratification for an array of conditions spanning early pregnancy, labor and delivery, and care of the newborn. Yet, breakthroughs in artificial intelligence and other new and emerging technologies currently have a slow adoption rate in medicine, despite the availability of large data sets that include individual electronic health records spanning years of care, genomics, and the microbiome. As a result, patient interactions with health care remain burdened by antiquated processes that are inefficient and inconvenient. A few health care institutions have recognized these gaps and, with an influx of venture capital investments, are now making in-roads in medical practice with digital products driven by artificial intelligence algorithms. In this article, we trace the history, applications, and ethical challenges of the artificial intelligence that will be at the forefront of digitally transforming obstetrics and gynecology and medical practice in general.

Medicaid Cost and Reimbursement for Low-Risk Prenatal Care in the United States.

INTRODUCTION: We calculate the financial margins for delivery of routine antenatal care as reimbursed by Medicaid. Prenatal care cost varies with overhead, health care provider type, and number of office visits. Antenatal care is only one component of the global maternity bundle, which also includes intrapartum and postpartum care. METHODS: Time for provision of low-risk antenatal care was determined prospectively from a study of 133 low-risk pregnant patients. Health care provider time cost was estimated using mean wages for obstetricians and midwives. Margins were estimated by subtracting cost of provider services and overhead for the antenatal component of maternity care from total Medicaid reimbursement for the pregnancy global package (CPT 59400) using 2015 dollars. The maternity bundle elements of routine prenatal laboratory tests, ultrasounds, intrapartum care, and postpartum care were not included in our analysis of cost components. RESULTS: Patients received an average of 215 minutes of direct provider time per pregnancy. At the 50th percentile for physician payment and assuming overhead is 53.4% of revenue, practice margins varied by state from -$1067 to +$675, with a median of -$357. Median margins for midwifery care were +$15, with a range of -$579 to +$885. Margins were negative if overhead costs exceeded 33% of revenue for physician care and 55% of revenue for midwifery care. DISCUSSION: In many states, Medicaid reimbursement for the global maternity package is less than the actual cost of antenatal care alone. Improving reimbursement or decreasing costs is necessary to make maternity care more cost-effective.

PP2A and E3 ubiquitin ligase deficiencies: Seminal biological drivers in endometrial cancer.

OBJECTIVE: PI3K-AKT pathway mutations initiate a kinase cascade that characterizes endometrial cancer (EC). As kinases seldom cause oncogenic transformation without dysregulation of antagonistic phosphatases, pivotal interactions governing this pathway were explored and correlated with clinical outcomes. METHODS: After exclusion of patients with POLE mutations from The Cancer Genome Atlas EC cohort with endometrioid or serous EC, the study population was 209 patients with DNA sequencing, quantitative gene-specific RNA expression, copy number variation (CNV), and surveillance data available. Extracted data were annotated and integrated. RESULTS: A PIK3CA, PTEN, or PIK3R1 mutant (-mu) was present in 83% of patients; 57% harbored more than 1 mutation without adversely impacting progression-free survival (PFS) (P = .10). PIK3CA CNV of at least 1.1 (CNV high [-H]) was detected in 26% and linked to TP53-mu and CIP2A expression (P < .001) but was not associated with PFS (P = .24). PIK3CA expression was significantly different between those with CIP2A-H and CIP2A low (-L) expression (the endogenous inhibitor of protein phosphatase 2A [PP2A]), when stratified by PIK3CA mutational status or by PIK3CA CNV-H and CNV-L (all P < .01). CIP2A-H or PPP2R1A-mu mitigates PP2A kinase dephosphorylation, and FBXW7-mu nullifies E3 ubiquitin ligase (E3UL) oncoprotein degradation. CIP2A-H and PPP2R1A-mu (PP2A impairment) and FBXW7-mu (E3UL impairment) were associated with compromised PFS (P < .001) and were prognostically discriminatory for PIK3CA-mu and PIK3CA CNV-H tumors (P < .001). Among documented recurrences, 84% were associated with impaired PP2A (75%) and/or E3UL (20%). CONCLUSION: PP2A and E3UL deficiencies are seminal biological drivers in EC independent of PIK3CA-mu, PTEN-mu, and PIK3R1-mu and PIK3CA CNV.

OB Nest randomized controlled trial: a cost comparison of reduced visit compared to traditional prenatal care.

BACKGROUND: Traditional prenatal care includes up to 13 in person office visits, and the cost of this care is not well-described. Alternative models are being explored to better meet the needs of patients and providers. OB Nest is a telemedicine-enhanced program with a reduced frequency of in-person prenatal visits. The cost implications of connected care services added to prenatal care packages are unclear. METHODS: Using data from the OB Nest randomized, controlled trial we analyzed the provider and staff time associated with prenatal care in the traditional and OB Nest models. Fewer visits were required for OB Nest, but given the compensatory increase in connected care activity and supplies, the actual cost difference is not known. Nursing and provider staff time was prospectively recorded for all patients enrolled in the OB Nest clinical trial. Published 2015 national wages for healthcare workers were used to calculate the actual labor cost of providing either traditional or OB Nest prenatal care in 2015 US dollars. Overhead expenses and opportunity costs were not considered. RESULTS: Total provider cost was decreased caring for the OB Nest participants, but nursing cost was increased. OB Nest care required an average of 160.8 (+/- 45.0) minutes provider time and 237 (+/- 25.1) minutes nursing time, compared to 215.0 (+/- 71.6) and 99.6 (+/- 29.7) minutes for traditional prenatal care (P < 0.01). This translated into decreased provider cost and increased nursing cost (P < 0.01). Supply costs increased, travel costs declined, and overhead costs declined in the OB Nest model. CONCLUSIONS: In this trial, labor cost for OB Nest prenatal care was 34% higher than for traditional prenatal care. The increased cost is largely attributable to additional nursing connected care time, and in some practice settings may be offset by decreased overhead costs and increased provider billing opportunities. Future efforts will be focused on development of digital solutions for some routine nursing tasks to decrease the overall cost of the model. TRIAL REGISTRATIONS: ClinicalTrials.gov Identifier: NCT02082275 .

In Utero Restoration of Hindbrain Herniation in Fetal Myelomeningocele as Part of Prenatal Regenerative Therapy Program at Mayo Clinic.

OBJECTIVE: To assess our initial experience with prenatal restoration of hindbrain herniation following in utero repair of myelomeningocele (MMC). PATIENTS AND METHODS: Three consecutive patients with prenatally diagnosed MMC (between January 1, 2018 and September 30, 2018) were managed with open in utero surgery. As per institutional review board approval and following a protocol designed at the Mayo Clinic Maternal & Fetal Center, fetal intervention was offered between 19 0/7 and 25 6/7 weeks of gestation. Prenatal improvement of hindbrain herniation was the declared restorative end point. Obstetrical and perinatal outcomes were also assessed. RESULTS: Diagnosis of MMC was confirmed upon referral between 20 and 21 weeks' gestation by using fetal ultrasound and magnetic resonance imaging. In all cases reported here, the spinal defect was lumbosacral with evidence of hindbrain herniation. Open in utero MMC repair was performed between 24 and 25 weeks' gestation with no notable perioperative complications. Postprocedure fetal magnetic resonance imaging performed 6 weeks after in utero repair documented improvement of hindbrain herniation. Deliveries were at 37 weeks by cesarean section without complications. Most recent postnatal follow-ups were unremarkable at both 11 months (baby 1) and 3 months of age (baby 2), with mild ventriculomegaly. Antenatal and postnatal follow-up of baby 3 at 1 month of age was also unremarkable. CONCLUSION: Our study highlights the prenatal restoration of hindbrain herniation following in utero MMC repair in all cases presented here as an example of a prenatal regenerative therapy program in our institution.

Randomized comparison of a reduced-visit prenatal care model enhanced with remote monitoring.

BACKGROUND: Standard prenatal care, consisting of 12-14 visits per pregnancy, is expensive and resource intensive, with limited evidence supporting the structure, rhythm, or components of care. Some studies suggest a reduced-frequency prenatal care model is as safe as the standard model of care for low-risk pregnant women, but evidence is limited. We developed and evaluated an innovative, technology-enhanced, reduced prenatal visit model (OB Nest). OBJECTIVE: To evaluate the acceptability and effectiveness of OB Nest, a reduced-frequency prenatal care model enhanced with remote home monitoring devices and nursing support. STUDY DESIGN: A single-center randomized controlled trial, composed of pregnant women, aged 18-36 years, recruited from an outpatient obstetric tertiary academic center in the Midwest United States. OB Nest care consisted of 8 onsite appointments with an obstetric provider; 6 virtual visits consisting of phone or online communication with an assigned nurse, supplemented with fetal Doppler and sphygmomanometer home monitoring devices; and access to an online community of pregnant women. Usual care consisted of 12 prescheduled prenatal clinic appointments with obstetric providers. Acceptability of OB Nest was measured by validated surveys of patient satisfaction with care at 36 weeks; perception of stress at 14, 24, and 36 weeks; and perceived quality of care at 36 weeks of gestation. Effectiveness was analyzed by comparing adherence to the American College of Obstetricians and Gynecologists recommended routine prenatal and ancillary services, maternal and fetal safety outcomes, and healthcare utilization. RESULTS: Three hundred pregnant women at <13 weeks of gestation were recruited and randomized to OB Nest or usual care (150 in each arm) using a minimization algorithm. Demographic characteristics were similar between groups. Compared to usual care, patients in OB Nest had higher satisfaction on a 100-point validated modified Littlefield and Adams Satisfaction scale (OB Nest = 93.9% vs usual care = 78.9%, P < .01). Pregnancy-related stress, measured, on a 0-2 point PreNatal Maternal Stress validated scale, with higher scores indicating higher levels of stress, was lower among OB Nest participants at 14 weeks (OB Nest = 0.32 vs usual care = 0.41, P < .01) and at 36 weeks of gestation (OB Nest = 0.34 vs usual care = 0.40, P < .03). There was no statistical difference in perceived quality of care. Adherence to the provision of American College of Obstetricians and Gynecologists prenatal services was similar in both arms. Maternal and fetal clinical outcomes were similar between groups. Total reported nursing time was higher in OB Nest (OB Nest = 171.2 minutes vs usual care = 108.2 minutes, 95% confidence interval, 48.7-77.4). CONCLUSION: OB Nest is an innovative, acceptable, and effective reduced-frequency prenatal care model. Compared to routine prenatal care, OB Nest resulted in higher patient satisfaction and lower prenatal stress, while reducing the number of appointments with clinicians and maintaining care standards for pregnant women. This program is a step toward evidence-driven prenatal care that improves patient satisfaction.

What Is New in Hysterectomy for Benign Gynecologic Disorders?: Best Articles From the Past Year.

This month we focus on current research in hysterectomy for benign gynecologic disorders. Dr. Famuyide discusses four recent publications, which are concluded with a "bottom-line" that is the take-home message. A complete reference for each can be found on on this page along with direct links to abstracts.

Clinical Impact of a Restrictive Labor Induction Approval Process.

BACKGROUND/AIMS: The aim of this study was to evaluate the impact of a restrictive labor induction approval process on induction and primary cesarean delivery rates. METHODS: A retrospective cohort study was conducted at a tertiary care academic center from 2006 through 2012. The cohort of deliveries before (pre-intervention) and after (post-intervention) the process included term, singleton pregnancies with no contraindication to vaginal delivery. The primary outcome was induction of labor rates, subgrouped on the basis of whether it was medically or nonmedically indicated. Secondary outcomes included the primary cesarean rate and other maternal and neonatal outcomes. RESULTS: Of 13,753 deliveries, 6,746 met study inclusion criteria. There was a significant decrease in induction rates comparing the pre- and post-intervention periods (21.0 vs. 18.5%, p = 0.01). Nonmedically indicated induction rates also decreased significantly (2.9 vs. 0.6%, p < 0.001). No difference was observed in medically indicated induction (18.1 vs. 17.9%, p = 0.84), the primary cesarean rate (14.4 vs. 15.8%, p = 0.12), or any of the measured neonatal outcomes (p > 0.05). CONCLUSIONS: Implementation of a labor induction approval process was associated with a significant reduction in overall and non-indicated induction rates but did not affect the primary cesarean rate or neonatal outcomes.

Fetoscopic Therapy for Severe Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A First in Prenatal Regenerative Medicine at Mayo Clinic.

OBJECTIVE: To introduce the prenatal regenerative medicine service at Mayo Clinic for fetal endoscopic tracheal occlusion (FETO) care for severe congenital diaphragmatic hernia (CDH). PATIENTS AND METHODS: Two cases of prenatal management of severe CDH with FETO between January and August 2017 are reported. Per protocol, FETO was offered for life-threatening severe CDH at between 26 and 29 weeks' gestation. Regenerative outcome end point was fetal lung growth. Gestational age at procedure and maternal and perinatal outcomes were additional monitored parameters. RESULTS: Diagnosis by ultrasonography of severe CDH was based on extremely reduced lung size (observed-to-expected lung area to head circumference ratio [o/e-LHR], eg, o/e-LHR of 20.3% for fetus 1 and 23.0% for fetus 2) along with greater than one-third of the liver herniated into the chest in both fetuses. Both patients underwent successful FETO at 28 weeks. At the time of intervention, no maternal or fetal complications were observed. Postintervention, fetal lung growth was observed in both fetuses, reaching an o/e-LHR of 62.7% at 36 weeks in fetus 1 and 52.4% at 32 weeks in fetus 2. The balloons were removed successfully at 35 weeks and 4 days by ultrasound-guided puncture in the first patient and at 32 weeks and 3 days by ex utero intrapartum therapy-to-airway procedure in the second patient. Postnatal management followed standard of care with patch CDH therapy. At discharge, one patient was breathing normally, whereas the other required minimal nasal cannula oxygen support. CONCLUSION: The successful launch of the first fetoscopic therapy for CDH at Mayo Clinic reveals its feasibility and safety, with early signs of benefit documented by fetal lung growth and reversal of severe pulmonary hypoplasia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: G170062.

Endometrial Ablation.

The destruction of the endometrium in women with heavy menstrual bleeding has been used for well over a century, and the various techniques of delivering forms of thermal energy have been modified over the years to ensure a safe and effective treatment approach. Today, 6 nonresectoscopic devices are approved for use in the United States in addition to resectoscopic techniques that rely on the skillful use of the operative hysteroscope. Regardless of the technique used, endometrial ablation uniformly reduces menstrual blood loss, improves general and menstrual-related quality of life, and prevents hysterectomy in 4 of 5 women who undergo the procedure. When patients are appropriately selected, outcomes are optimized, and risks of serious complications are minimized. This article reviews the literature with singular reference to nonresectoscopic endometrial ablation procedures including historical background, appropriate patient selection, clinical outcomes data, complications, and special or unique considerations.

Intrapartum factors associated with neonatal hypoxic ischemic encephalopathy: a case-controlled study.

BACKGROUND: Neonatal encephalopathy (NE) affects 2-4/1000 live births with outcomes ranging from negligible neurological deficits to severe neuromuscular dysfunction, cerebral palsy and death. Hypoxic ischemic encephalopathy (HIE) is the sub cohort of NE that appears to be driven by intrapartum events. Our objective was to identify antepartum and intrapartum factors associated with the development of neonatal HIE. METHODS: Hospital databases were searched using relevant diagnosis codes to identify infants with neonatal encephalopathy. Cases were infants with encephalopathy and evidence of intrapartum hypoxia. For each hypoxic ischemic encephalopathy case, four controls were randomly selected from all deliveries that occurred within 6 months of the case. RESULTS: Twenty-six cases met criteria for hypoxic ischemic encephalopathy between 2002 and 2014. In multivariate analysis, meconium-stained amniotic fluid (aOR 12.4, 95% CI 2.1-144.8, p = 0.002), prolonged second stage of labor (aOR 9.5, 95% CI 1.0-135.3, p = 0.042), and the occurrence of a sentinel or acute event (aOR 74.9, 95% CI 11.9-infinity, p < 0.001) were significantly associated with hypoxic ischemic encephalopathy. The presence of a category 3 fetal heart rate tracing in any of the four 15-min segments during the hour prior to delivery (28.0% versus 4.0%, p = 0.002) was more common among hypoxic ischemic encephalopathy cases. CONCLUSION: Prolonged second stage of labor and the presence of meconium-stained amniotic fluid are risk factors for the development of HIE. Close scrutiny should be paid to labors that develop these features especially in the presence of an abnormal fetal heart tracing. Acute events also account for a substantial number of HIE cases and health systems should develop programs that can optimize the response to these emergencies.

Medical therapy versus radiofrequency endometrial ablation in the initial treatment of heavy menstrual bleeding (iTOM Trial): A clinical and economic analysis.

BACKGROUND: Radiofrequency endometrial ablation (REA) is currently a second line treatment in women with heavy menstrual bleeding (MHB) if medical therapy (MTP) is contraindicated or unsatisfactory. Our objective is to compare the effectiveness and cost burden of MTP and REA in the initial treatment of HMB. METHODS: We performed a randomized trial at Mayo Clinic Rochester, Minnesota. The planned sample size was 60 patients per arm. A total of 67 women with HMB were randomly allocated to receive oral contraceptive pills (Nordette ®) or Naproxen (Naprosyn®) (n = 33) or REA (n = 34). Primary 12-month outcome measures included menstrual blood loss using pictorial blood loss assessment chart (PBLAC), patients' satisfaction, and Menorrhagia Multi-Attribute Scale (MMAS). Secondary outcomes were total costs including direct medical and indirect costs associated with healthcare use, patient out-of-pocket costs, and lost work days and activity limitations over 12 months. RESULTS: Compared to MTP arm, women who received REA had a significantly lower PBLAC score (median [Interquartile range, IQR]: 0 [0-4] vs. 15 [0-131], p = 0.003), higher satisfaction rates (96.8%vs.63.2%, p = 0.003) and higher MMAS (median [IQR]: 100 [100-100] vs. 100 [87-100], p = 0.12) at 12 months. Direct medical costs were higher for REA ($5,331vs.$2,901, 95% confidence interval (CI) of mean difference:$727,$4,852), however, when indirect costs are included, the difference did not reach statistical significance ($5,469 vs. $3,869, 95% CI of mean difference:-$339, $4,089). CONCLUSION: For women with heavy menstrual bleeding, initial radiofrequency endometrial ablation compared to medical therapy offered superior reduction in menstrual blood loss and improvement in quality of life without significant differences in total costs of care. CLINICAL TRIAL REGISTRATION: NCT01165307.

Abnormal Uterine Bleeding Is Associated With Increased BMP7 Expression in Human Endometrium.

Abnormal uterine bleeding (AUB), a common health concern of women, is a heterogeneous clinical entity that is traditionally categorized into organic and nonorganic causes. Despite varied pharmacologic treatments, few offer sustained efficacy, as most are empiric, unfocused, and do not directly address underlying dysregulated molecular mechanisms. Characterization of such molecular derangements affords the opportunity to develop and use novel, more successful treatments for AUB. Given its implication in other organ systems, we hypothesized that bone morphogenetic protein (BMP) expression is altered in patients with AUB and hence comprehensively investigated dysregulation of BMP signaling pathways by systematically screening 489 samples from 365 patients for differences in the expression of BMP2, 4, 6, and 7 ligands, BMPR1A and B receptors, and downstream SMAD4, 6, and 7 proteins. Expression analysis was correlated clinically with data abstracted from medical records, including bleeding history, age at procedure, ethnicity, body mass index, hormone treatment, and histological diagnosis of fibroids, polyps, adenomyosis, hyperplasia, and cancer. Expression of BMP7 ligand was significantly increased in patients with AUB (H-score: 18.0 vs 26.7; P < .0001). Patients reporting heavy menstrual bleeding (menorrhagia) as their specific AUB pattern demonstrated significantly higher BMP7 expression. Significantly, no differences in the expression of any other BMP ligands, receptors, or SMAD proteins were observed in this large patient cohort. However, expression of BMPR1A, BMPR1B, and SMAD4 was significantly decreased in cancer compared to benign samples. Our study demonstrates that BMP7 is a promising target for future investigation and pharmacologic treatment of AUB.