Systematic Review and Meta-Analysis of Perioperative Administration of Acetazolamide for Management of Postoperative Pain after Laparoscopy.

Background and Objective: To perform a systematic review and meta-analysis to evaluate the efficacy of perioperative acetazolamide (ACTZ) administration with laparoscopy for reducing postoperative referred pain. Methods: The following databases were searched from inception to March 1, 2020: Cochrane, PubMed, PubMed Central, Ovid, and Embase. Electronic search used: Acetazolamide AND (laparoscopy OR laparoscopic OR Celioscopy OR Celioscopies OR Peritoneoscopy OR Peritoneoscopies). No limits or filters were used. We included only studies of patients who underwent abdominal laparoscopy (LSC), had a pain assessment at approximately 24 hours postoperatively, and included a treatment with ACTZ group and a no-treatment or minimal-treatment comparison group. Results: Five studies met inclusion criteria, with a combined total of 253 participants, 116 in the ACTZ group and 137 in the control group. A Bayesian hierarchical model was assumed for the study specific treatment effects. Posterior sampling was conducted via Markov Chain Monte Carlo methods, and posterior inference carried out on the hierarchical treatment effect. ACTZ significantly decreased average pain scores compared to control group by -0.726 points (95% confidence interval -1.175-0.264). The posterior probability that ACTZ decreases mean pain scores by ≥ 0.5 was 0.846. Conclusion: Current available evidence demonstrates that perioperative ACTZ may provide a modest improvement in postoperative referred pain following LSC.

Development of a dynamic machine learning algorithm to predict clinical pregnancy and live birth rate with embryo morphokinetics.

Objective: To evaluate the feasibility of generating a center-specific embryo morphokinetic algorithm by time-lapse microscopy to predict clinical pregnancy rates. Design: A retrospective cohort analysis. Setting: Academic fertility clinic in a tertiary hospital setting. Patients: Patients who underwent in vitro fertilization with embryos that underwent EmbryoScope time-lapse microscopy and subsequent transfer between 2014 and 2018. Interventions: None. Main Outcome Measures: Clinical pregnancy. Results: A supervised, random forest learning algorithm from 367 embryos successfully predicted clinical pregnancy from a training set with overall 65% sensitivity and 74% positive predictive value, with an area under the curve of 0.7 for the test set. Similar results were achieved for live birth outcomes. For the secondary analysis, embryo growth morphokinetics were grouped into five clusters using unsupervised clustering. The clusters that had the fastest morphokinetics (time to blastocyst = 97 hours) had pregnancy rates of 54%, whereas a cluster that had the slowest morphokinetics (time to blastocyst = 122 hours) had a pregnancy rate of 71%, although the differences were not statistically significant (P=.356). Other clusters had pregnancy rates of 51%-60%. Conclusions: This study shows the feasibility of a clinic-specific, noninvasive embryo morphokinetic simple machine learning model to predict clinical pregnancy rates.

Liraglutide 3 mg on weight, body composition, and hormonal and metabolic parameters in women with obesity and polycystic ovary syndrome: a randomized placebo-controlled-phase 3 study.

OBJECTIVE: To study the efficacy and safety of the GLP-1 analog liraglutide 3 mg (LIRA 3 mg) vs. placebo (PL) for reduction of body weight (BW) and hyperandrogenism in women with obesity and polycystic ovary syndrome (PCOS). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hospital-based outpatient endocrine and metabolic center. PATIENT(S): Women diagnosed with PCOS (NIH criteria) were randomly assigned to LIRA 3 mg (n = 55) or PL (n = 27) once daily for 32 weeks with lifestyle intervention. INTERVENTION(S): Study visits at baseline and 32 weeks included BW and body composition by dual-energy x-ray absorptiometry. Oral glucose tolerance tests were done with sex steroids, free androgen index (FAI), and lipids measured in the fasting sample. MAIN OUTCOME MEASURE(S): The primary end points were changes in BW and FAI. Safety was assessed in all patients who received at least one dose of the study drug. RESULT(S): Change in BW from baseline to week 32 was -5.7% (±0.75) with LIRA 3 mg vs. -1.4% (±1.09) with PL. At week 32, more participants on LIRA 3 mg than on PL achieved at least 5% weight reductions (25 of 44 vs. 5 of 23). Free androgen index significantly reduced with LIRA 3 mg compared with the PL where the mean FAI slightly increased. Gastrointestinal events, which were mostly mild to moderate, were reported in 58.2% of the LIRA 3 mg-subjects and 18.5% of PL subjects. CONCLUSION(S): LIRA 3 mg once daily appears superior to PL in reducing BW and androgenicity and improving cardiometabolic parameters in women with PCOS and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT03480022.

Pathology of hyperandrogenemia in the oocyte of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common ovulatory disorder in the world and is associated with multiple adverse outcomes. The phenotype is widely varied, with several pathologies contributing to the spectrum of the disease including insulin resistance, obesity and hyperandrogenemia. Of these, the role of hyperandrogenemia and the mechanism by which it causes dysfunction remains poorly understood. Early studies have shown that androgens may affect the metabolic pathways of a cell, and this may pose hazards at the level of the mitochondria. As mitochondria are strictly maternally inherited, this would provide an exciting explanation not only to the pathophysiology of PCOS as a disease, but also to the inheritance pattern. This review seeks to summarize what is known about PCOS and associated adverse outcomes with focus on the role of hyperandrogenemia and specific emphasis on the oocyte.

Hyperandrogenemia alters mitochondrial structure and function in the oocytes of obese mouse with polycystic ovary syndrome.

CAPSULE: Hyperandrogenemia in an obese PCOS mouse model results in altered glucose/insulin metabolism and mitochondrial structure and function in the oocytes, in part explaining adverse outcomes and inheritance patterns seen in PCOS. OBJECTIVE: To study the oocyte quality by means of mitochondrial structure and function in a well-established classic PCOS mouse model. DESIGN: Animal study using an obese PCOS mouse model compared with control. SETTING: Animal research facility in a tertiary care university hospital setting. ANIMALS: C57/B6J mice. INTERVENTION: Three week old mice had subdermal implants of DHT controlled release pellet or placebo for 90 days. MAIN OUTCOME MEASURES: The mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were subsequently isolated and were used to investigate mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance, histology and electron microscopy. RESULTS: Results showed glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of the oocytes demonstrated impaired inner mitochondrial membrane function, increased ATP production and mtDNA copy number, altered RNA transcript abundance and aberrant ovarian histology. Electron microscopy of the oocytes showed severely impaired mitochondrial ultrastructure. CONCLUSION: The obese PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial function.

Prenatal androgen induced lean PCOS impairs mitochondria and mRNA profiles in oocytes.

Polycystic ovary syndrome (PCOS) is the most common ovulatory defect in women. Although most PCOS patients are obese, a subset of PCOS women are lean but show similar risks for adverse fertility outcomes. A lean PCOS mouse model was created using prenatal androgen administration. This developmentally programmed mouse model was used for this study. Our objective was to investigate if mitochondrial structure and functions were compromised in oocytes obtained from lean PCOS mouse. The lean PCOS mouse model was validated by performing glucose tolerance test, HbA1c levels, body weight and estrous cycle analyses. Oocytes were isolated and were used to investigate inner mitochondrial membrane potential, oxidative stress, lipid peroxidation, ATP production, mtDNA copy number, transcript abundance, histology and electron microscopy. Our results demonstrate that lean PCOS mice has similar weight to that of the controls but exhibited glucose intolerance and hyperinsulinemia along with dysregulated estrus cycle. Analysis of their oocytes show impaired inner mitochondrial membrane function, elevated reactive oxygen species (ROS), increased RNA transcript abundance and aberrant ovarian histology. Electron microscopy of the oocytes showed impaired mitochondrial ultrastructure. In conclusion, the lean PCOS mouse model shows a decreased oocyte quality related to impaired mitochondrial ultrastructure and function.

Embryos from polycystic ovary syndrome patients with hyperandrogenemia reach morula stage faster than controls.

OBJECTIVE: To investigate if patients with polycystic ovary syndrome (PCOS) have altered embryo morphokinetics when compared with controls. DESIGN: Retrospective cohort analysis. SETTING: Single academic fertility clinic in a tertiary hospital setting. PATIENTS: Age- and body mass index-matched patients who underwent in vitro fertilization diagnosed with PCOS using the Rotterdam criteria. A subanalysis was performed on patients with PCOS with hyperandrogenemia. Sixty-four patients with PCOS were identified with 990 embryos that were matched with 64 control patients with 628 embryos. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Time to blastulation. RESULTS: Embryos from women with PCOS displayed faster growth rate at t7, t8, and t9; all other morphokinetic points were similar. Patients with PCOS also had a higher number of oocytes retrieved. No differences were seen in the fertilization rate or blastulation rate. Patients with PCOS had a higher miscarriage rate (38.1% in PCOS vs. 18.8% in controls). Patients with hyperandrogenic PCOS showed a faster growth rate at t5, t6, t7, t8, t9, and morula. CONCLUSIONS: Embryos from women with PCOS grew faster until 9-cell stage and women with hyperandrogenic PCOS until morula. Patients with PCOS also showed a higher miscarriage rate. The alterations in early embryo development are consistent with altered fertility and obstetric outcomes in the population with PCOS and may be due to the hyperandrogenic microenvironment in the ovarian follicle.

Pregnancy rates from intrauterine insemination are equivalent following 1- versus 5-day letrozole administration for ovulation induction: a retrospective study.

OBJECTIVE: To compare the efficacy of single-dose letrozole (25 mg) with a 5-day course (5 mg/day) for ovulation induction (OI). DESIGN: Retrospective cohort study. SETTING: Hospital. PATIENTS: Patients undergoing first round of OI and intrauterine insemination with letrozole from January 2015 through December 2017. INTERVENTIONS: Patients received letrozole as either a single 25 mg dose for 1 day (1D) versus 5 mg daily for 5 days (5D). A secondary analysis was performed on patients also receiving gonadotropins (GND). MAIN OUTCOME MEASURES: Pregnancy rate (PR) determined by positive human chorionic GND. RESULTS: There were 847 patients included in the study, 302 in the 1D group and 284 in the 5D group; 261 patients had concurrent GND administration, 162 1D+GND and 99 5D+GND. There was no difference in smoking status, primary versus secondary infertility, or total motile sperm concentration. Comparing 1D with 5D, there was a statistically significant, although not clinically relevant, difference in both age and body mass index (31 vs. 31.8 years; 26.2 vs. 27.4, respectively). Similarly, comparing 1D+GND with 5D+GND, there was statistically significant difference in body mass index (27.19 vs. 29.1). Secondary outcomes included live birth rate (LBR), multiple gestation rate (MG), and miscarriage rate (SAB). There were no differences between 1D and 5D in the primary outcome of PR (14.2% vs. 11.6%), LBR (9.6% vs. 7%), MG (16.2% vs. 13.8%), or SAB (16.22% vs. 13.8%). In looking at the GND groups alone, there was no difference in PR (18.3% vs. 23.8%), LBR (11.72% vs. 17.86%), MG (8.7% vs. 5.56%), or SAB (13.64% vs. 5.56%). There was a significant difference in cycle cancellation rate in the 1D versus 5D groups (3.9% vs. 9.6%); however, this was not seen in the 1D+GND versus 5D+GND groups. CONCLUSIONS: A single-dose protocol with letrozole in an OI/intrauterine insemination cycle may be considered an alternative to standard 5D dosing protocols with the potential for improved compliance and similar reproductive outcomes.

Neonatal outcomes among twins stratified by method of conception: secondary analysis of maternal fetal medicine (MFMU) network database.

PURPOSE: To investigate whether twin pregnancies conceived by different forms of fertility treatments are associated with adverse neonatal outcomes and to examine the difference in maternal and obstetrical characteristics between patients. METHODS: Our study was a retrospective analysis of twin pregnancies conceived by fertility treatments from a prospectively collected database. Treatments were stratified into two groups: group 1 (ART) consisted of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and group 2 (non-ART) included intrauterine insemination (IUI) and ovulation induction (OI). Composite neonatal morbidity included respiratory distress syndrome, intraventricular hemorrhage, leukomalacia, chronic lung disease, and death prior to discharge. RESULTS: There were 460 neonates in our study; among them, 67% (n = 310) were in group 1, and 33% (n = 150) in group 2. Group 1 patients were more likely to be older (p = 0.004), nulliparous (p = 0.01), delivered twins with lower birth weights (2278 g ± 605 vs. 2427 ± 519, p = 0.009), and had more deliveries < 32 weeks gestation (p = 0.001). In multivariable Poisson regression model, only neonatal intensive care unit admission rate was increased for group 1 twins (aRR = 1.27, 95% CI 1.003-1.60). CONCLUSIONS: After adjusting for confounders, twins conceived via ART compared to non-ART had similar neonatal outcomes. These data can help when counseling this patient population and assist in planning larger prospective cohorts.

The use of gonadotropin-releasing hormone antagonist post-ovulation trigger in ovarian hyperstimulation syndrome.

The purpose of this paper is to assimilate all data pertaining to the use of gonadotropin-releasing hormone (GnRH) antagonists in in vitro fertilization cycles after ovulation trigger to reduce the symptoms of ovarian hyperstimulation syndrome (OHSS). A systematic review of the literature was performed to identify all studies performed on the use of a GnRH antagonist in IVF cycle post-ovulation trigger with patients at high risk for OHSS. Ten studies were identified and reviewed. Descriptions of the studies and their individual results are presented in the following manuscript. Due to significant heterogeneity among the studies, it was not possible to perform a group analysis. The use of GnRH antagonists post-ovulation trigger for treatment of OHSS has been considered for almost 20 years, though research into its use is sparse. Definitive conclusions and recommendations cannot be made at this time, though preliminary data from these trials demonstrate the potential for GnRH antagonists to play a role in the treatment of OHSS in certain patient populations.