Fetal Dilated Cardiomyopathy Associated With Variants of Uncertain Significance in MYH7 and DSG2 Genes: A Case Report and Review of the Literature.

BACKGROUND: Fetal dilated cardiomyopathy (DCM) is an uncommon prenatal diagnosis associated with significant morbidity and mortality. CASE: This report describes a patient with a diagnosis of fetal DCM at 310 weeks gestation, several weeks after a maternal flu-like illness. Spontaneous improvement was noted on serial echocardiograms. Maternal Coxsackievirus B titers were significantly elevated at 1:80, although post-natal cord blood test results were negative. Genetic panel testing for DCM demonstrated two heterozygous variants of uncertain significance in the MYH7 and DSG2 genes. Although an early post-natal echocardiogram demonstrated a normal left ventricular ejection fraction, right ventricular dysfunction was noted with subsequent cardiac decompensation requiring temporary inotropic support. An echocardiogram at the age of 2 years confirmed normal biventricular function. CONCLUSION: The finding of fetal DCM should trigger a broad evaluation. In the setting of limited fetal cardiac reserve, the significant hemodynamic changes that occur post-natally may trigger additional decompensation. Clinicians should be aware of the prognostic value of right ventricular function, as measured by fractional area change, in addition to the limitations of serologic and genetic testing.

Maternal High-Fat Diet Consumption and Chronic Hyperandrogenemia Are Associated With Placental Dysfunction in Female Rhesus Macaques.

The risk of adverse perinatal outcomes with maternal polycystic ovary syndrome may differ among hyperandrogenic and nonhyperandrogenic phenotypes and is likely modulated by maternal obesity and diet. The relative contribution of maternal hyperandrogenism and nutritional status to placental dysfunction is unknown. Female rhesus macaques (N = 39) were assigned at puberty to one of four treatment groups: subcutaneous cholesterol implants and a standard chow diet (controls); testosterone (T) implants and a normal diet; cholesterol implants and a high-fat, Western-style diet (WSD); and testosterone implants in combination with a high-fat diet. After 3.5 years of treatment, contrast-enhanced and Doppler ultrasound analyses of placental blood flow were performed for a representative subset of animals from each treatment group during pregnancy, and placental architecture assessed with stereological analysis. Placental growth factors, cellular nutrient sensors, and angiogenic markers were measured with ELISA and Western blotting. WSD consumption was associated with a 30% increase in placental flux rate relative to that in animals receiving a normal diet. T and WSD treatments were each independently associated with increased villous volume, and T also was associated with an ∼ 40% decrease fetal capillary volume on stereological analysis. T treatment was associated with significantly increased mTOR and SOCS3 expression. WSD consumption was associated with decreased GLUT1 expression and microvillous membrane localization. Hyperandrogenemic and nonhyperandrogenemic phenotypes are associated with altered placental angiogenesis, nutrient sensing, and glucose transport. WSD and T appear to have distinct effects on vascular impedance and capillary angiogenesis.

Optimal timing of delivery for women with breast cancer, according to cancer stage and hormone status: a decision-analytic model.

OBJECTIVE: To compare strategies for the timing of delivery in women with breast cancer and known cancer stage or hormone receptor subtype, and to determine the optimal gestational age for induction in regards to maternal-fetal outcomes. STUDY DESIGN: A decision-analytic model was designed comparing eight different strategies for scheduled delivery at 30, 31, 32, 33, 34, 35, 36, and 37 weeks gestation. Optimal breast cancer treatment was assumed to be delayed until after delivery. Baseline estimates of the stage- and subtype-specific mortality and the impact of delayed cancer treatment on 5-year survival rates were obtained from the literature. Outcomes factored into the model included the risk of intrauterine fetal demise, spontaneous delivery, respiratory distress syndrome, cerebral palsy, and neonatal demise at each gestational age. Univariate sensitivity analyses and Monte Carlo simulations were performed to test the robustness of our model. RESULTS: For women with stage I-II breast cancer, delivery at 36 weeks yielded the highest number of overall quality-adjusted life years (QALYs), while maternal QALYs were maximized with delivery at 34 weeks. For stage III and IV disease, maternal QALYs were maximized at 31 and 30 weeks, respectively. For women with estrogen or progesterone receptor-positive, human epidermal receptor-2 negative breast cancer, both maternal QALYs and overall QALYs were maximized with delivery at 36 weeks. More aggressive biological phenotypes were similarly associated with optimal delivery at decreasing gestational age. Our model was heavily driven by the baseline probability of maternal death within 5 years, in addition to the expected progression of disease and decreases in survival rates with each week of non-treatment, and remained robust across reasonable ranges for all variables of interest. CONCLUSIONS: For women with breast cancer diagnosed during pregnancy, decisions regarding timing of delivery should take into consideration both cancer stage and hormone receptor subtype.

Management Strategy for Breast Cancer in Pregnancy.

A 34-year-old primigravid woman presents for a routine prenatal visit at 18 weeks of gestation with a breast lump. On examination, she has a painless, firm breast mass measuring 3-4 cm in diameter with overlying skin dimpling. A diagnostic mammogram shows findings suspicious for malignancy (Breast Imaging Reporting and Data System [BI-RADS] 4), and core biopsy demonstrates an invasive ductal carcinoma with both estrogen and progesterone receptor-positive staining. The patient asks: "How will this affect my pregnancy, and what is the safest course of action?"

Maternal outcomes following the initiation of an institutional delayed cord clamping protocol: an observational case-control study.

OBJECTIVE: The objective of this study is to evaluate maternal outcomes before and after implementation of an institutional delayed cord clamping (DCC) protocol. STUDY DESIGN: We performed a secondary analysis of a retrospective cohort study of deliveries occurring at <34 weeks at a tertiary care center in 2013-2014. About 139 women who underwent early cord clamping were compared with 130 women delivered after DCC protocol implementation. Maternal estimated blood loss (EBL) was the primary outcome of interest. Operative times, post-Cesarean decrease in hemoglobin (Hgb), and rates of post-partum hemorrhage and transfusion were also examined in bivariate and multivariable analyses. RESULTS: About 75% of post-guideline deliveries had actual DCC. In regression analyses, only Cesarean delivery and multifetal gestation increased EBL. No trends were identified in EBL over time. In post-hoc analysis, the study had over 80% power to detect a difference in post-partum hemorrhage rates of 20%. CONCLUSION: An institutional DCC protocol for deliveries <34 weeks was not associated with an identifiable increase in adverse maternal outcomes.

Maternal, Fetal, and Neonatal Imatinib Levels With Treatment of Chronic Myeloid Leukemia in Pregnancy.

BACKGROUND: Pregnant women with chronic myeloid leukemia (CML) can be treated effectively with the tyrosine-kinase inhibitor imatinib, but data regarding fetal and neonatal exposure and safety are limited. CASE: We present a patient with newly diagnosed CML in early pregnancy. Leukapheresis and interferon-α were initiated in the second trimester with limited benefit. Imatinib was subsequently started at 28 weeks of gestation with complete hematologic response within 4 weeks. No significant maternal or neonatal adverse effects were noted, but imatinib and its primary active metabolite concentrated in maternal breast milk and neonatal urine. CONCLUSION: Imatinib is effective for CML in pregnancy, but caution is warranted in light of potentially unrecognized fetal and neonatal effects.

The Effect of Interprofessional Student-Led Reproductive Health Education on Youths in Juvenile Detention.

STUDY OBJECTIVE: To assess the effects of an interprofessional student-led comprehensive sexual education curriculum in improving the reproductive health literacy among at-risk youths in detention. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective cohort study involving 134 incarcerated youth and an interprofessional team of 23 medical, nursing, and social work students, who participated in a comprehensive reproductive health curriculum over the course of 3 days. INTERVENTIONS, AND MAIN OUTCOME MEASURES: Basic reproductive health knowledge, confidence in condom use with a new partner, and self-efficacy with regard to contraception use and sexual autonomy were assessed before and after completion of the curriculum. We also assessed the student teachers' level of comfort with teaching reproductive health to adolescents and their perception of interprofessionalism. RESULTS: Incarcerated youth showed a statistically significant increase in knowledge regarding sexually transmitted infections as well as self-reported confidence in condom use (P = .002). Self-efficacy in contraception use and sexual autonomy did not show significant improvement. Qualitative analysis of student teachers' surveys revealed theme categories regarding perception of youth, perception of self in teaching youth, perception of interacting with youth, and perception of working in interprofessional teams. CONCLUSIONS: Our program might represent a mutually beneficial community relationship to improve reproductive health literacy in this high-risk youth population.

Human Parturition Involves Phosphorylation of Progesterone Receptor-A at Serine-345 in Myometrial Cells.

The hypothesis that phosphorylation of progesterone receptor (PR) isoforms, PR-A and PR-B, in myometrial cells affects progesterone action in the context of human parturition was tested. Immunodetection of phosphoserine (pSer) PR forms in term myometrium revealed that the onset of labor is associated with increased phosphorylation of PR-A at serine-345 (pSer345-PRA) and that pSer345-PRA localized to the nucleus of myometrial cells. In explant cultures of term myometrium generation of pSer345-PRA was induced by interleukin-1ß and dependent on progesterone, suggesting that pSer345-PRA generation is induced by a proinflammatory stimulus. In the hTERT-HMA/B human myometrial cell line, abundance of pSer345-PRA was induced by progesterone in a dose- (EC50 ∼1 nM) and time-dependent manner. Prevention of pSer345 (by site-directed mutagenesis) abolished the capacity for PR-A to inhibit anti-inflammatory actions of progesterone mediated by PR-B but had no effect on the transrepressive activity of PR-A at a canonical progesterone response element. Taken together, the data show that human parturition involves the phosphorylation of PR-A at serine-345 in myometrial cells and that this process is ligand dependent and induced by a proinflammatory stimulus. We also found that in myometrial cells, pSer345 activates the capacity for PR-A to inhibit antiinflammatory actions of progesterone mediated by PR-B. Phosphorylation of PR-A at serine-345 may be an important functional link between tissue-level inflammation and PR-A-mediated functional progesterone withdrawal to trigger parturition.

Contemporary outcomes of sickle cell disease in pregnancy.

BACKGROUND: Data regarding pregnancy outcomes in sickle cell disease are conflicting. Previous studies are limited by small sample size, narrow geographic area, and a wide range of resource availability. OBJECTIVE: The purpose of this study was to examine the association between maternal sickle cell disease and adverse pregnancy outcomes in a contemporary North American cohort. STUDY DESIGN: We performed a retrospective cohort study of 2,027,323 women with singleton pregnancies delivered in California from 2005-2008. Deliveries at <24 or >42 6/7 weeks of gestation were excluded. Women with sickle cell disease were compared with control subjects. Maternal outcomes of interest included preeclampsia, preterm delivery, placental abruption, oligohydramnios, and cesarean delivery; neonatal outcomes included small for gestational age, anomalies, stillbirth, neonatal death, and infant death. RESULTS: The prevalence of sickle cell disease was 0.017%. Compared with control subjects, women with sickle cell disease were more likely to have limited prenatal care (7.4 vs 3.8%; P=.001), underlying chronic hypertension (2.3% vs 1.1%; P=.038), and fetal anomalies (14.0 vs 6.4%; P<.001). The increased odds of fetal anomalies persisted after adjustment for multiple confounders (odds ratio, 1.73; 95% confidence interval, 1.26-2.38). Women with sickle cell disease also had higher odds of severe preeclampsia (odds ratio, 3.75; 95% confidence interval, 2.21-6.38), preterm delivery (odds ratio, 2.50; 95% confidence interval, 1.93-3.21), small for gestational age (odds ratio, 1.96; 95% confidence interval, 1.18-3.25), and cesarean delivery (odds ratio, 1.93; 95% confidence interval, 1.40-2.67). CONCLUSION: Women with sickle cell disease are at high risk of maternal and neonatal morbidity. Low rates of fetal and neonatal death may reflect improved antenatal surveillance and management as compared with previous studies. The association between sickle cell disease and fetal anomalies warrants further investigation.

Determinants of the competing outcomes of intrauterine infection, abruption, or spontaneous preterm birth after preterm premature rupture of membranes.

OBJECTIVE: Patients with PPROM are at risk for a variety of outcomes, including chorioamnionitis (CA), placental abruption (PA), or preterm labor (PTL). Competing risk regression can analyze a cohort's risk of individual outcomes while accounting for ongoing deliveries secondary to competing events. METHODS: A secondary analysis of the subjects from MFMU BEAM study of neuroprotection after preterm birth (BEAM) with conservative PPROM management. Deliveries were categorized as: PA, CA, PTL, "elective" or "indicated". The association between outcomes of PA, CA or PTL and clinical predictors of twins, ethnicity, parity, gestational age at rupture, bleeding, contractions, cervical dilation, preterm birth history, weight, and genitourinary infections were evaluated via competing risk regression. RESULT: 1970 subjects were included. The significance and directionality of predictors varied according to specific outcomes. Patients with twins had an increased PTL hazard (1.85) though reductions in CA- (0.66) or PA-specific (0.56) hazards. Decreased latency in African-Americans was almost entirely due to an increased CA hazard (1.44) without a significant association with PTL. Increasing gestational age at membrane rupture was associated with a decreasing hazard of CA although increasing hazard of PTL. CONCLUSIONS: For patients with PPROM, the hazards associated with different clinical predictors vary according to exact outcomes.

Wandering Spleen. A Case of Spontaneous Hemoperitoneum in an HIV-positive Patient with Recurrent Tuboovarian Abscess.

BACKGROUND: Wandering spleen is a rare and potentially devastating condition that can present in a variety of ways. Here we present a case that led to acute abdomen and hemoperitoneum in a young woman. CASE: A 27-year-old woman with a history of human immunodeficiency virus (HIV), pelvic inflammatory disease, and tuboovarian abscess was readmitted to the hospital for intravenous antibiotic treatment. When her clinical picture did not improve, she underwent placement of a pelvic drain for abscess drainage. Overnight she developed an acute abdomen and hemorrhagic shock. She was taken to the operating room for an exploratory laparotomy, which revealed a ruptured spleen with a single, elongated vascular pedicle. CONCLUSION: Wandering spleen is a rare diagnosis, more common in reproductive-aged women, with potentially fatal complications. It is a necessary component of a differential diagnosis for acute abdomen in reproductive-aged women.

Evidence-based guidelines in labor management.

Evidence-based care of women in labor requires a thorough understanding of both "normal" and abnormal labor progress. In response to the growing cesarean delivery rate for dystocia at our institution, a multidisciplinary team of attending physicians, nurse-midwives, resident physicians, and nurses was established to review the literature and create evidence-based guidelines. This article describes the background literature and consensus guidelines reached for the diagnosis of active phase labor, active phase arrest, second-stage arrest, protraction of the active phase, and failed induction of labor. Our review illustrates that slower labor patterns than traditionally described often result in a vaginal delivery without unacceptable increases in maternal or neonatal morbidity.

Partnering with public schools: a resident-driven reproductive health education initiative.

STUDY OBJECTIVES: To assess the impact of a resident-driven sexual health educational initiative in an inner-city Cleveland middle school. DESIGN, SETTING, AND PARTICIPANTS: 10 resident physicians and 57 students in 7(th) and 8(th) grade participated in this prospective cohort study. INTERVENTIONS AND MAIN OUTCOME MEASURES: Residents taught 3 sessions on the topics of basic anatomy and physiology, pregnancy, sexually transmitted infections (STI), contraception, and safe relationships. Outcome measures included the percentages of students able to name at least 3 different STIs and contraceptive methods; to name potential complications of STIs; and to correctly identify condoms and abstinence as the only contraceptive methods also protective against STI transmission. RESULTS: Significant improvements were noted in students' baseline knowledge of human anatomy, contraception, and safe sex practices after completion of the curriculum. The percentage of students able to name at least 3 forms of birth control increased from 1.7% to 70.7% (P < .0001). The percentage able to name at least 3 different STIs increased from 5.3% to 72.4% (P < .0001). Follow-up testing 4 months after completion of the curriculum demonstrated significant knowledge retention. All residents and medical students surveyed described a perceived need for comprehensive-rather than abstinence-based-reproductive health education in schools. CONCLUSIONS: The socioeconomic burden of teen pregnancy justifies comprehensive efforts to improve reproductive health education.

Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents.

CONTEXT: Anorexia nervosa (AN) in adolescents is associated with low bone mineral density (BMD) and increases in ghrelin secretion, an orexigenic GH secretagogue that stimulates osteoblast proliferation in vitro. OBJECTIVE: We hypothesized that ghrelin may have independent effects on bone in AN adolescents. STUDY DESIGN, SUBJECTS, AND OUTCOME MEASURES: Frequent sampling was performed overnight every 30 min for 12 h in 23 adolescent AN girls aged 12-18 yr and 21 controls of comparable maturity. Ghrelin, leptin, cortisol, and GH secretion were examined using Cluster and deconvolution. We measured BMD and body composition (dual-energy x-ray absorptiometry) and carboxy-terminal peptide of type I procollagen and N-telopeptide levels. RESULTS: In healthy adolescents, ghrelin secretion strongly predicted BMD; secretory burst mass being the strongest predictor of lumbar spine (LS) bone mineral apparent density (BMAD) (r = 0.66, P = 0.003), LS BMAD z-scores (BMAD-z) (r = 0.59, P = 0.01), hip BMD (r = 0.55, P = 0.02), and hip BMD-z (r = 0.52, P = 0.03). When body composition measures (body mass index, lean and fat mass), and hormonal predictors (GH, IGF-I, cortisol, leptin, and estradiol) were entered into a regression model with ghrelin secretion to determine independent BMD predictors, ghrelin was the strongest predictor of LS BMAD, BMAD-z, hip BMD, and hip BMD-z, contributing to 43, 30, 26, and 19% of the variability, respectively, independent of GH or cortisol effects. Conversely, in AN, ghrelin secretion did not predict LS BMAD or hip-z and weakly predicted LS BMAD-z and hip BMD. Ghrelin did not predict carboxy-terminal peptide of type I procollagen or N-telopeptide/creatinine, which were predicted by GH and cortisol. CONCLUSION: Ghrelin secretion predicts bone density independent of body composition, the GH-IGF-I axis, cortisol, or estradiol in healthy girls but not in those with AN.

Resveratrol-induced apoptotic death in human U251 glioma cells.

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose- and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G0/G1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma.

Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents.

Leptin, an adipocytokine that suppresses appetite and may regulate neuroendocrine pathways, is low in undernourished states like anorexia nervosa (AN). Although leptin exhibits pulsatility, secretory characteristics have not been well described in adolescents and in AN, and the contribution of hypoleptinemia to increased growth hormone (GH) and cortisol in AN has not been explored. We hypothesized that hypoleptinemia in AN reflects decreased basal and pulsatile secretion and may predict increased GH and cortisol levels. Sampling for leptin, GH, cortisol, and ghrelin was performed every 30 min (from 2000 to 0800) in 23 AN and 21 controls 12-18 yr old, and data were analyzed using Cluster and deconvolution methods. Estradiol, thyroid hormones, and body composition were measured. AN girls had lower pulsatile and total leptin secretion than controls (P < 0.0001) subsequent to decreased burst mass (P < 0.0001) and basal secretion (P = 0.02). Nutritional markers predicted leptin characteristics. In a regression model including BMI, body fat, and ghrelin, leptin independently predicted GH burst interval and frequency. Valley leptin contributed to 56% of the variability in GH burst interval, and basal leptin and fasting ghrelin contributed to 42% of variability in burst frequency. Pulsatile leptin independently predicted urine free cortisol/creatinine (15% of variability). Valley leptin predicted cortisol half-life (22% of variability). Leptin predicted estradiol and thyroid hormone levels. In conclusion, hypoleptinemia in AN is subsequent to decreased basal and pulsatile secretion and nutritionally regulated. Leptin predicts GH and cortisol parameters and with ghrelin predicts GH burst frequency. Low leptin and high ghrelin may be dual stimuli for high GH concentrations in undernutrition.

Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents.

Ghrelin is an orexigenic peptide and a growth hormone (GH) secretagogue. Secretory dynamics of ghrelin have not been characterized in adolescents with anorexia nervosa (AN). We hypothesized that, compared with healthy adolescents, girls with AN would have increased ghrelin concentrations measured over 12 h of nocturnal sampling from increased basal and pulsatile secretion, and endogenous ghrelin would independently predict GH and cortisol. We examined ghrelin concentration and secretory dynamics in 22 girls with AN and 18 healthy adolescents 12-18 yr old. Associations between ghrelin, various hormones, and measures of insulin resistance were examined. On Cluster analysis, girls with AN had higher ghrelin concentrations than controls, including total area under the curve (AUC) (P = 0.002), nadir (P = 0.0006), and valley levels (P = 0.002). On deconvolution analysis, secretory burst amplitude (P = 0.03) and burst mass (P = 0.04) were higher in AN, resulting in higher pulsatile (P = 0.05) and total ghrelin secretion (P = 0.03). Fasting ghrelin independently predicted GH burst frequency (r = 0.44, P = 0.005). The nutritional markers body mass index and body fat predicted postglucose and valley ghrelin but not fasting levels. Ghrelin parameters were inversely associated with fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, and IGF-I. HOMA-IR was the most significant predictor of most ghrelin parameters. Valley ghrelin independently predicted cortisol burst frequency (52% of variability), and ghrelin parameters independently predicted total triiodothyronine and LH levels. Higher ghrelin concentrations in adolescents with AN are a consequence of increased secretory burst mass and amplitude. The most important predictor of ghrelin concentration is insulin resistance, and ghrelin in turn predicts GH and cortisol burst frequency.