Association between circulating neuregulin 4 levels and metabolic, aterogenic, and AMH profile of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic disorder associated with obesity and energy metabolic system disturbances in adipose tissue. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. In the present study, we aimed to evaluate the association between serum NRG4 levels in obese and normal weight PCOS patients. This cross-sectional study was conducted at a tertiary hospital in Turkey from April to August 2017. We included 148 women who were divided into four groups as follows: 40 normal weight and 39 obese PCOS women diagnosed according to the Rotterdam criteria as well as 38 normal weight and 31 obese, age-matched, non-hyperandrogenemic women with a regular menstrual cycle (controls). Levels of serum NRG4, anti-Müllerian hormone (AMH), fasting blood glucose (FBG), insulin, and high-sensitivity C-reactive protein (hs-CRP); lipid and hormone profiles; insulin resistance indices [homeostasis model assessment of insulin resistance (HOMA-IR)];and anthropometric parameters were evaluated. Serum NRG4 levels were elevated in the normal weight PCOS group than in the control group. Moreover, serum NRG4 levels were higher in the obese PCOS group than in the normal weight PCOS and obese control groups (p < .01). Serum NRG4 levels were positively correlated with body mass index (BMI); waist/hip ratio; HOMA-IR; and levels of triglycerides, hs-CRP, FBG, insulin, AMH, and dehydroepiandrosterone sulphate. Multiple regression analyses revealed that serum NRG4 levels were independently associated with BMI. Obesity appears to be the most influential factor for NRG4 secretion in PCOS patients. Management of obesity may be a key factor for resolving PCOS-related metabolic abnormalities and fertility problems. Impact Sstatement What is already known on this subject? PCOS is a dynamic syndrome with different clinical and metabolic features during the reproductive age. PCOS is associated with various metabolic abnormalities, such as insulin resistance (IR), glucose intolerance, dyslipidemia, and obesity (particularly visceral obesity) as well as long-term complications, such as type 2 diabetes and cardiovascular diseases. Neuregulin 4 (NRG4), which is secreted by adipose tissue, regulates energy metabolism. What do the results of this study add? To the best of our knowledge, this was the first study investigating NRG4 levels in PCOS patients with different BMIs. Obesity appears to be the most influential factor for NRG4 secretion in these patients. Managing obesity may be a key factor for resolving PCOS-related metabolic abnormalities. What are the implications of these findings for clinical practice and/or further research? Further research in PCOS is warranted to ameliorate obesity, and our study can provide basis for future studies investigating NRG4 levels in PCOS patients with different phenotypes as well as studies of gene polymorphisms, AMH, and infertility and can contribute to the elucidation of problems related to the pathophysiology of PCOS.

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

BACKGROUND: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth. METHODS: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134. FINDINGS: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 µmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 µmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 µmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001). INTERPRETATION: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 µmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery. FUNDING: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.

Modified abdominal packing method in "near miss" patients with postpartum hemorrhages.

OBJECTIVE: To describe a more effective abdominal packing method in patients with disseminated intravascular coagulation following peripartum hysterectomy due to postpartum hemorrhage (PPH). MATERIALS AND METHODS: The present retrospective and descriptive study was conducted to document six cases with refractory pelvic bleeding who underwent a second surgery for PPH between January 2016 and December 2017 at Istanbul Zeynep Kamil Woman and Children Diseases Training and Research Hospital. RESULTS: Karateke packing was performed to control intra-abdominal massive hemorrhages of five women who were referred to our clinic due to PPH who had undergone peripartum hysterectomy and hypogastric artery ligation but hemostasis could not be provided. In addition, a case of hypovolemic shock due to placenta percreta rupture in a woman who had also undergone an emergency hysterectomy and hypogastric artery ligation, which had failed. Hemostasis was provided in all patients. No method-related complication developed. CONCLUSION: Karateke packing is a very easy method to perform, it is more effective than the classic abdominal packing technique, with a low complication rate, and most importantly, life-saving in patients undergoing a peripartum hysterectomy due to PPH and thereafter experiencing diffuse hemorrhage.

Effect of vaginal washing before intravaginal dinoprostone insertion for labor induction: A randomized clinical trial.

AIM: Prostaglandins have a dual action of cervical ripening and induction of uterine contraction. This study was designed to compare the effectiveness of vaginal washing just before insertion of intravaginal dinoprostone. METHODS: A randomized controlled trial was conducted at the Zeynep Kamil Women and Children's Health Training and Research Hospital. One hundred and ninety-one women with singleton, term pregnancy who underwent labor induction were randomly assigned to two groups: Group 1 consisted of 95 pregnant women with vaginal washing before intravaginal dinoprostone (Propess system for slow release system of 10 mg of dinoprostone) insertion (study group), and 96 pregnant women constituted the control group who did not undergo vaginal washing before intravaginal dinoprostone insertion. A parallel randomized controlled trial was conducted with an allocation ratio of 1:1 to compare the effectiveness of vaginal washing before intravaginal dinoprostone insertion. RESULTS: The groups had similar mean age, body mass index, gestational age, gravidity, parity and Bishop score before agent insertion (P > 0.05). Duration of dinoprostone kept intravaginally, duration from the beginning of dinoprostone insert vaginally to the active phase of labor and duration from the time of intravaginal dinoprostone insertion to delivery were significantly longer in the control group (P < 0.05). Uterine hyperstimulation rate was significantly higher in study group compared to control group (P < 0.05). Meconium passage, fetal infection and neonatal intensive care unit admission were significantly higher in the control group (P < 0.05). CONCLUSION: Vaginal washing before intravaginal dinoprostone insertion may increase Prostaglandin E2 bioavailability as we found shorter duration and better outcome of labor induction in the present study.

Retrospective analysis of mature cystic teratomas in a single center and review of the literature.

OBJECTIVE: The aim af this study is to evaluate patients with mature cystic teratomas (MCT) with regard to the view of updated knowledge using our retrospective findings. MATERIALS AND METHODS: This was a retrospective study and included a total of 306 patients from 2013 through 2017 at the Istanbul Zeynep Kamil Women and Children's Diseases Training and Research Hospital. RESULTS: The mean age of the patients was 34.03±11.98 years. Thirty (9.8%) patients were postmenopausal. Torsion was detected in 17 (5.6%) patients. There was a statistically significant relationship between MCT and CA 19-9 levels in our series (p<0.01) but no statistically significant correlation was found with other markers. CONCLUSION: The possibility of malignancy at postmenopausal ages and in large MCT should not be forgotten. It should be kept in mind that MCT can be seen in unexpected places.

Prospective Randomized Trial Comparing Embryo Transfers of Cases with and without Catheter Rotation during Its Withdrawal.

OBJECTIVE: To compare embryo transfer (ET) technique based on catheter rotation during its withdrawal in cases with unexplained infertility in a prospective, randomized trial (NCT03097042). METHODS: Two hundred intracytoplasmic sperm injection (ICSI) patients undergoing ET with cleaving or blastocyst-stage fresh embryos were randomized into 2 groups: cases with (n = 100), and without (n = 100) catheter rotation during its withdrawal. Groups were matched for age and some clinical parameters. A soft catheter was used to transfer a single embryo with catheter rotation during its withdrawal in the study group and without rotation in the control. The use of a stiff catheter or tenaculum was not needed in any case. Groups were compared in terms of cycle characteristics and clinical pregnancy rates. RESULTS: Pregnancy rate was significantly higher in the study group (41 vs. 26%, p = 0.04). Clinical pregnancy rate was also significantly higher in the study group (39 vs. 25%, OR 1.9 [1.1-3.5], p = 0.05). On the other hand, the ongoing pregnancy rate was similar between the 2 groups (33 vs. 23%, p = 0.2). CONCLUSION: Catheter rotation during its withdrawal may be associated with increased pregnancy and clinical pregnancy rates; however, the difference in ongoing pregnancy rates did not reach statistical significance.

The impact of autoimmunity-related early ovarian aging on ICSI cycle outcome.

The aim of this study was to investigate the impact of anti-thyroid peroxidase antibodies (Anti-TPO) on the in vitro fertilization and embryo transfer (IVF-ET) outcome in women with poor ovarian reserve but normal thyrotropin levels. A total of 300 patients with poor ovarian reserve undergoing ICSI cycle from April 2015 to December 2017 were analyzed retrospectively. Subjects were divided into two groups: Group 1: Women with early ovarian aging, Group 2: Women with age related poor ovarian reserve. All subjects underwent anti-thyroid peroxidase antibody (anti-TPO) analysis. The impacts of age and anti-TPO positivity on cycle outcome were assessed. There were no significant differences in basal FSH, basal AMH levels, and antral follicle count between the two main groups. Groups were also comparable in terms of the duration of ovarian stimulation, peak estradiol level, starting gonadotropin dose, total gonadotropin dose, and number of oocytes retrieved. Clinical pregnancy and cycle cancelation rates were significantly higher in group with age-related poor ovarian reserve. While autoimmune thyroid disease rate was significantly higher in group with early ovarian aging. Anti-TPO positivity was a risk factor for poor cycle outcome [RR: 2.8 (95% CI: 1.2-6.3)]. Early ovarian aging may be associated with poorer cycle outcome compared to group with age-related poor ovarian reserve. This difference may be associated with high rate of autoimmunity which led to the impaired endometrial receptivity.

Evaluation of complete blood count parameters to predict endometrial cancer.

BACKGROUND: Complete blood count parameters have been introduced to be diagnostic biomarkers for many cancer-related diseases associated with inflammatory process. The aim of our study was to detect whether there is any relationship between benign or malignant endometrial pathologies and complete blood count parameters. METHODS: Four hundred and sixteen patients with a complaint of abnormal uterine bleeding who admitted to Zeynep Kamil Women and Children's Health Training and Research hospital between 2013 and 2016 and undergoing endometrial biopsy were included in the study. The patients were evaluated in three groups as follows: endometrial carcinoma (n: 97), endometrial hyperplasia (n: 135), and healthy control (n: 184) groups. All patients had a complete blood count on the day of biopsy or within the week of the biopsy, and the presence of a relationship between complete blood count parameters and benign or malignant endometrial disease was investigated. RESULTS: Mean corpuscular volume measurements were found to be significantly higher in endometrial carcinoma (P = .018) and endometrial hyperplasia (P = .001) groups compared to the control group. While red cell distribution width measurements were found to be significantly lower in patients with endometrial carcinoma group compared to other groups (P < .01); the area under curve obtained for MPV is 58.7% to determine endometrial carcinoma. CONCLUSION: Mean corpuscular volume and red cell distribution width are bio-markers that we can use as the predictive marker in patients with endometrial carcinoma and which are cheap, repeatable, and readily obtainable from complete blood count panels and promising.

Dual trigger with gonadotropin-releasing hormone and human chorionic gonadotropin for poor responders

OBJECTIVE: To compare metaphase II (MII) rate, fertilization rate, and embryo quality with dual trigger gonadotropin-releasing hormone agonist (GnRH) and normal dose human chorionic gonadotropin (hCG) versus a normal dose hCG trigger in antagonist intracytoplasmic sperm injection (ICSI) cycles of poor ovarian responders. MATERIAL AND METHODS: Patients defined as poor ovarian responders according to the Bologna criteria who underwent ICSI with GnRH antagonist protocol and triggered with dual trigger or hCG alone for oocyte maturation. Main outcome measures were MII rate, fertilization rate, and embryo quality. RESULTS: Total gonadotropin doses and E2 levels on trigger day were higher in the hCG trigger group. There were no significant differences with regard to implantation rate (p=0.304), biochemical pregnancy rate (p=0.815), clinical pregnancy rate (p=0.378), and ongoing pregnancy rate (p=0.635) between the groups. CONCLUSION: Dual trigger of oocyte maturation with GnRH agonist and normal dose hCG in poor responders does not demonstrate improved oocyte maturation, clinical pregnancy, and ongoing pregnancy rates.

Early amniotomy after dinoprostone insert used for the induction of labor: a randomized clinical trial.

PURPOSE: We assessed whether early amniotomy, after ripening with a dinoprostone insert, reduces the duration of labor or increases the rate of delivery within the following 24 h. METHODS: A prospective randomized controlled study was conducted on 200 consenting, term pregnant women at the Zeynep Kamil Maternity and Children's Training and Research Hospital. Each participant received vaginal inserts of 10 mg dinoprostone. The women were randomly assigned to one of two groups: early amniotomy (artificial rupture of membranes when cervical dilation was at 3 cm) or standard amniotomy (the membranes were left to rupture spontaneously). The primary outcome measures were the time from induction to delivery, and the proportion of women who delivered within 24 h. RESULTS: The median time interval from induction to delivery (13.72 h compared to 22.73 h) was significantly shorter for women who underwent early amniotomy (p < 0.05). The frequency of vaginal delivery within 24 h was higher in women with early amniotomy (89% compared with 45% in the standard amniotomy, p < 0.05). CONCLUSIONS: Early amniotomy, after ripening with a dinoprostone insert, is a safe and efficient method for speeding up delivery times without increasing caesarian rates during labor inductions.

Segmental resection of anterior uterine wall in cases with placenta percreta: a modified technique for fertility preserving approach.

AIM: The aim of this study was to introduce a modified form of fertility preserving approach in cases with placenta percreta. METHODS: Eleven pregnant women with anterior placenta previa and suspected to have placenta percreta underwent cesarean section between 2015 and 2016 in Zeynep Kamil Women and Children's Health Training and Research Hospital. In all cases, following confirmation of placenta percreta diagnosis, a modified minimal invasive form of uterine preserving surgery was performed. RESULTS: During the present study period, 11 pregnant women who were confirmed to have placenta previa and placenta percreta underwent modified form of segmental resection. In all cases, modified form of segmental resection was successful except for the two cases. There were significant statistical differences between pre-postoperative hemoglobin and hematocrit levels (p = .003). There was a significant correlation between the volume of resected segment and number of transfusions (r = .760, p = .047). Postoperative blood transfusion was not needed in 4 cases. No maternal mortality or other postoperative complication was observed in any case. CONCLUSION: A modified minimal invasive form of uterine preserving surgery seems to be safe and result in more cosmetic results with minimal blood loss.

Clinical significance of neuregulin 4 (NRG4) in gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is defined as glucose intolerance detected during pregnancy. GDM is increasing worldwide and is associated with adverse maternal and fetal outcomes. Neuregulin 4 (NGR4) is epidermal growth factor like signaling molecule. It plays an important role in cell to cell communication furthermore recent studies indicate that NRG4 may work as a novel adipokine with a possible role in maintaining energy and metabolic homeostasis. The aim of the present study was to assess serum NRG4 levels along with several metabolic parameters in patients diagnosed with gestational diabetic mellitus. MATERIALS AND METHODS: In this prospective cross-sectional study, the study group was composed of 63 women with GDM and 64 healthy pregnant women matched for age, body mass index (BMI) and gestational age. Blood samples were collected at the 24-28th gestational weeks. Serum NRG4, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides, glucose levels during 75-gr OGTT, fasting insulin, glycosylated hemoglobin A1c (HbA1c), alanine aminotransferase (ALT) and creatinine levels were measured. Homeostasis model assessment of insulin resistance (HOMA-IR) values were calculated. RESULTS: Serum NRG4 values were significantly elevated in the GDM group compared to the control group (p < .001). Multivariate linear regression analyzes revealed that BMI (ß = 0.910, p < .001), glucose 2-h OGTT (ß = 0.866, p < .001) and HOMA-IR (ß = 0.222, p < .001) independently and positively predicted NRG4 levels. CONCLUSIONS: Serum NRG4 levels were associated with metabolic parameters of GDM. The present study can be considered to be a guide for future studies to clarify the pathophysiology of NGR4 in GDM patients.

Can we predict severity of intrahepatic cholestasis of pregnancy using inflammatory markers?

OBJECTIVE: To investigate the association of inflammatory markers with severity of intrahepatic cholestasis of pregnancy (ICP). MATERIALS AND METHODS: This retrospective case-control study was conducted with 229 pregnant women, 84 with ICP, and 145 age-matched healthy pregnant women. Patients were categorized as mild ICP (<40 µmol/L) and severe ICP (≥40 µmol/L) with regard to serum bile acids. Inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), platelet-to- lymphocyte ratio (PLR) and mean platelet volume (MPV), and red blood cell distribution width (RDW) were compared between the groups. RESULTS: Patients with ICP had significantly decreased RDW and increased white blood cell counts (WBC), MPV and PLR, but no significant changes in NLR. The comparison of mild and severe cases with regard to NLR, PLR, WBC, and RDW was similar (p>0.05). MPV levels were significantly increased in severe group (p<0.05). CONCLUSION: WBC, MPV, and PLR were the inflammatory markers significantly increased, and RDW was signifantly reduced in ICP. MPV was the marker that significantly increased with the severity of disease. The use of inflammatory markers in the assessment of perinatal outcomes needs further studies.

Association between maternal circulating 25 hydroxyvitamin D concentration and placental volume in the first trimester.

OBJECTIVES: We aimed to assess placental volume and placental mean gray value in vitamin D deficiency and healthy placentas in the first trimester of pregnancy using three-dimensional (3D) ultrasonography (USG) and Virtual Organ Computer-aided Analysis (VOCAL). METHODS: This prospective cross sectional study comprised 274 patients, divided into two groups according to the presence or absence of vitamin D deficiency (<20 ng/ml deficient, n = 153, >20 ng/ml not deficient, n= 121) in the first trimester of pregnancy. Placental volume and placental volumetric mean gray values were evaluated. Placental volume (cm3) was analyzed using the VOCAL imaging program and a 3D histogram was used to calculate the volumetric mean gray value (%). RESULTS: Placental volume was significantly less in the vitamin D deficiency group (p = 0.017) Volumetric mean gray value of the placenta was significantly higher in the vitamin D deficiency group (p= 0.003). Maternal serum PAPP-A (MoM) and f-ß Hcg (MoM) were significantly lower in the vitamin D deficiency group (p= 0.008, p = 0.003, respectively). In linear regression analyses, serum vitamin D concentration was significantly associated with the plasental volume (ß = 0.16; p = 0.01). CONCLUSION: Placental configuration and development were associated with vitamin D even in the first trimester of pregnancy. To ensure healthy pregnancy outcomes, vitamin D screening applied in the early stages of pregnancy or even before pregnancy.