An update and review of nontubal ectopic pregnancy management.

PURPOSE OF REVIEW: Nontubal ectopic pregnancies appear to be increasing in prevalence. Increasingly, minimally invasive methods for management are being utilized. A current literature review and recommendations for management of nontubal ectopic pregnancy is presented in this review. RECENT FINDINGS: Nontubal ectopic pregnancies are less common than tubal ectopic pregnancies but present a unique and significant threat to patient's health and are optimally managed by specialists familiar with the condition. Early diagnosis, prompt treatment and close follow-up to resolution are critical. Recent publications focus on fertility-sparing and conservative management through the use of medications both systemic and local; as well as minimally invasive surgical techniques. The Society of Maternal Fetal Medicine recommends against expectant management of cesarean scar pregnancies; however, optimal treatment is unknown and this holds true for management of other nontubal ectopic pregnancies. SUMMARY: Minimally invasive and fertility sparing management should be the mainstay in treatment of stable patients with nontubal ectopic pregnancy.

Apoptotic qPCR gene expression array analysis demonstrates proof-of-concept for rapid blastocoel fluid-conditioned media molecular prediction.

PURPOSE: Successful identification of transcriptomic biomarkers within human IVF embryos may enhance implantation prediction and provide insights not available through conventional embryo biopsy genomic analysis. We demonstrate proof-of-concept for a methodology to assess overall embryo gene expression using qPCR with blastocoel fluid-conditioned media by examining the comparative presence of apoptotic genes. METHODS: Blastocoel fluid-conditioned media were collected from 19 embryos (11 euploid) following trophectoderm biopsy of day-5 ICSI-IVF blastocysts. Media were assessed for apoptotic gene expression via qPCR. Statistical analysis of gene expression was conducted via Wilcoxon Signed-Ranks test (overall expression), multivariate ANOVA (functional gene groups), and chi-square test of independence (gene level). RESULTS: A significantly higher overall apoptotic gene expression within euploid versus aneuploid embryos (p = 0.001) was observed. There was significantly (p = 0.045) higher expression of pro-apoptotic genes between implanted and not implanted embryos. Pro- vs. anti-apoptotic gene expression from all euploid embryos approached significance (p = 0.053). The ploidy status-based claim is further substantiated at the gene level with significantly higher expression of BBC3 (p = 0.012) and BCL2L13 (p = 0.003) in euploid embryos compared to aneuploid embryos. CONCLUSIONS: In this preliminary study, we demonstrate that (1) qualitative analysis of blastocoel fluid-conditioned media gene expression is possible, (2) global trends of expression are potentially related to clinical outcomes, and (3) gene-level expression trends exist and may be another viable metric for comparative expression between samples. The presence of statistical significance within analyses conducted with this sample size warrants a larger investigation of blastocoel fluid-conditioned media as an additional beneficial predictive tool for future IVF cases.

Intrauterine insemination performance characteristics and post-processing total motile sperm count in relation to live birth for couples with unexplained infertility in a randomised, multicentre clinical trial.

STUDY QUESTION: Are intrauterine insemination (IUI) performance characteristics and post-processing total motile sperm count (TMC) related to live birth rate in couples with unexplained infertility? SUMMARY ANSWER: Patient discomfort with IUI and lower inseminate TMC were associated with a reduced live birth rate, while time from hCG injection to IUI, sperm preparation method and ultrasound guidance for IUI were not associated with live birth success. WHAT IS ALREADY KNOWN: We previously determined that some baseline characteristics of couples with unexplained infertility, including female age, duration of infertility, history of prior loss and income, were related to live birth rate across a course of ovarian stimulation and IUI treatment. However, the relationship between treatment outcomes and per-cycle characteristics, including ultrasound guidance for IUI, timing of IUI relative to hCG injection, difficult or painful IUI and inseminate TMC, are controversial, and most prior investigations have not evaluated live birth outcome. STUDY DESIGN, SIZE, DURATION: This was a secondary analyses of 2462 cycles from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial. This prospective, randomised, multicentre clinical trial determined live birth rates following IUI after ovarian stimulation with clomiphene citrate, letrozole or gonadotropins in 854 couples with unexplained infertility. It was conducted between 2011 and 2014, and couples could undergo up to four consecutive treatment cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: AMIGOS was an NIH-sponsored Reproductive Medicine Network trial conducted at 12 clinical sites. Participants were women with unexplained infertility who were between 18 and 40 years of age. Cluster-weighted generalised estimating equations (GEE), which account for informative clustering of multiple IUI treatment cycles within the same patient, were used to determine associations between IUI performance characteristics, including inseminate TMC, and live birth rate. Efficiency curves were also generated to examine the relationship between inseminate TMC and live birth rate. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for treatment group and baseline factors previously associated with live birth across a course of OS-IUI treatment, patient discomfort during the IUI procedure was associated with a reduction in live birth rate (aRR 0.40 (0.16-0.96)). Time from hCG trigger injection to IUI was not significantly associated with outcome. Higher TMC was associated with greater live birth rate (TMC 15.1-20.0 million (14.8%) compared to ≤5 million (5.5%)) (aRR 2.09 (1.31-3.33)). However, live births did occur with TMC ≤ 1 million (5.1%). LIMITATIONS, REASONS FOR CAUTION: This investigation is a secondary analysis, and AMIGOS was not designed to address the present question. Since timed intercourse was allowed as part of the AMIGOS trial, we cannot rule out the possibility that any given pregnancy resulted from intercourse rather than IUI. WIDER IMPLICATIONS OF THE FINDINGS: Most factors associated with the performance of IUI were not significantly related to obtaining live birth. Our findings suggest that higher TMC inseminated leads to an increase in live birth rate up to TMC ~20 million. However, there may be no reasonable threshold below which live birth is not possible with IUI. STUDY FUNDING/COMPETING INTEREST(S): Funding was received through grants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): U10 HD077680, U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10 HD055925. This research was made possible by funding by the American Recovery and Reinvestment Act. Dr Hansen reports grants from NIH/NICHD and Yale University during the conduct of the study, grants from Roche Diagnostics and grants from Ferring International Pharmascience Center US outside the submitted work. Dr Peck reports support from Ferring Pharmaceuticals outside the submitted work. Dr Coward has nothing to disclose. Dr Wild reports grants from NICHD during the conduct of the study. Dr Trussell has nothing to disclose. Dr Krawetz reports grants from NICHD during the conduct of the study, grants from Merck and support from Taylor and Frances and from Springer, outside the submitted work. Dr Diamond reports grants from NIH/NICHD, Yale University, during the conduct of the study and support from Advanced Reproductive Care AbbVie, Bayer and ObsEva, outside the submitted work. Dr Legro reports support from Bayer, Kindex, Odega, Millendo and AbbVie and grants and support from Ferring, outside the submitted work. Dr Coutifaris reports grants from NICHD/NIH and personal fees from American Society for Reproductive Medicine, outside the submitted work. Dr Alvero has nothing to disclose. Dr Robinson reports grants from NIH during the conduct of the study. Dr Casson has nothing to disclose. Dr Christman reports grants from NICHD during the conduct of the study. Dr Santoro reports grants from NIH during the conduct of the study. Dr Zhang reports grants from NIH during the conduct of the study and support from Shangdong University outside the submitted work. TRIAL REGISTRATION NUMBER: n/a.

Fertility Related Quality of Life, Gonadal Function and Erectile Dysfunction in Male Partners of Couples with Unexplained Infertility.

PURPOSE: We sought to determine whether lower fertility related quality of life or depression in men of couples with unexplained infertility is associated with low total testosterone levels, abnormal semen quality or erectile dysfunction. MATERIALS AND METHODS: This study is a secondary analysis of a large, multicenter, randomized controlled trial in couples with unexplained infertility. Male partners underwent baseline semen analysis with measurement of fasting total testosterone and gonadotropin. They also completed surveys, including the FertiQOL (Fertility Quality of Life), the PHQ-9 (Patient Health Questionnaire-9) and the IIEF (International Index of Erectile Function). The primary study outcomes were total testosterone with low total testosterone defined as less than 264 ng/dl, semen parameters and the IIEF score. We performed multivariable logistic regression analyses adjusted for patient age, race, body mass index, education, smoking, alcohol use, infertility duration and comorbidity. RESULTS: A total of 708 men with a mean ± SD age of 34.2 ± 5.6 were included in study. Of the men 59 (8.3%) had a PHQ-9 score of 5 or greater, which was consistent with depression, 99 (14.0%) had low total testosterone and 63 (9.0%) had mild or worse erectile dysfunction. Neither the FertiQOL score nor depression was associated with total testosterone or any semen parameter. The FertiQOL score was inversely associated with erectile dysfunction (for every 5-point score decline AOR 1.30, 95% CI 1.16-1.46). Depressed men were significantly more likely to have erectile dysfunction than nondepressed men (AOR 6.31, 95% CI 3.12-12.77). CONCLUSIONS: In men in couples with unexplained infertility lower fertility related quality of life and depression are strongly associated with erectile dysfunction. However, neither is associated with spermatogenesis or testosterone levels. Erectile dysfunction in infertile men merits longitudinal investigation in future studies.

Does assisted hatching affect live birth in fresh, first cycle in vitro fertilization in good and poor prognosis patients?

PURPOSE: To assess the effect of assisted hatching (AH) on live birth rate (LBR) in first cycle, fresh in vitro fertilization (IVF) in good and poor prognosis patients. METHODS: Retrospective cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Live birth rate was compared in women who underwent first cycle, autologous, fresh IVF cycles with (n = 48,858) and without (n = 103,413) AH from 2007 to 2015. RESULTS: The propensity-weighted LBR was 39.2% with AH versus 43.9% without AH in all patients. The rate difference (RD) with AH was - 4.7% ([CI - 0.053, - 0.040], P < 0.001) with the calculated number needed to harm being 22. AH affected live birth in both good prognosis and poor prognosis patients. The propensity-weighted monozygotic twinning (MZT) rate was 2.3% in patients treated with AH as compared to 1.2% patients that did not receive AH. The RD with AH on MZT in fresh, first IVF cycles was 1.1% ([0.008, 0.014], P < 0.001). CONCLUSION: AH may affect LBR across all patients and in poor prognosis patients in fresh IVF cycles. Caution should be exercised when applying this technology. More prospective research is needed.

Letrozole, Gonadotropin, or Clomiphene for Unexplained Infertility.

BACKGROUND: The standard therapy for women with unexplained infertility is gonadotropin or clomiphene citrate. Ovarian stimulation with letrozole has been proposed to reduce multiple gestations while maintaining live birth rates. METHODS: We enrolled couples with unexplained infertility in a multicenter, randomized trial. Ovulatory women 18 to 40 years of age with at least one patent fallopian tube were randomly assigned to ovarian stimulation (up to four cycles) with gonadotropin (301 women), clomiphene (300), or letrozole (299). The primary outcome was the rate of multiple gestations among women with clinical pregnancies. RESULTS: After treatment with gonadotropin, clomiphene, or letrozole, clinical pregnancies occurred in 35.5%, 28.3%, and 22.4% of cycles, and live birth in 32.2%, 23.3%, and 18.7%, respectively; pregnancy rates with letrozole were significantly lower than the rates with standard therapy (gonadotropin or clomiphene) (P=0.003) or gonadotropin alone (P<0.001) but not with clomiphene alone (P=0.10). Among ongoing pregnancies with fetal heart activity, the multiple gestation rate with letrozole (9 of 67 pregnancies, 13%) did not differ significantly from the rate with gonadotropin or clomiphene (42 of 192, 22%; P=0.15) or clomiphene alone (8 of 85, 9%; P=0.44) but was lower than the rate with gonadotropin alone (34 of 107, 32%; P=0.006). All multiple gestations in the clomiphene and letrozole groups were twins, whereas gonadotropin treatment resulted in 24 twin and 10 triplet gestations. There were no significant differences among groups in the frequencies of congenital anomalies or major fetal and neonatal complications. CONCLUSIONS: In women with unexplained infertility, ovarian stimulation with letrozole resulted in a significantly lower frequency of multiple gestation but also a lower frequency of live birth, as compared with gonadotropin but not as compared with clomiphene. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01044862.).

Allostatic load, a measure of chronic physiological stress, is associated with pregnancy outcomes, but not fertility, among women with unexplained infertility.

STUDY QUESTION: Among infertile women undergoing ovarian stimulation, is allostatic load (AL), a measure of chronic physiological stress, associated with subsequent fertility and pregnancy outcomes? SUMMARY ANSWER: AL at baseline was not associated with conception, spontaneous abortion or live birth, however, it was significantly associated with increased odds of pre-eclampsia and preterm birth among women who had a live birth in the study. WHAT IS KNOWN ALREADY: Several studies have linked AL during pregnancy to adverse outcomes including preterm birth and pre-eclampsia, hypothesizing that it may contribute to well-documented disparities in pregnancy and birth outcomes. However, AL biomarkers change over the course of pregnancy, raising questions as to whether gestational AL assessment is a valid measure of cumulative physiologic stress starting long before pregnancy. To better understand how AL may impact reproductive outcomes, AL measurement in the non-pregnant state (i.e. prior to conception) is needed. STUDY DESIGN, SIZE, DURATION: A secondary data analysis based on data from 836 women who participated in Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS), a multi-center, randomized clinical trial of ovarian stimulation conducted from 2011 to 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovulatory women with unexplained infertility (ages 18-40) were enrolled and at baseline, biological and anthropometric measures were collected. AL scores were calculated as a composite of the following baseline variables determined a priori: BMI, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, dehydroepiandrosterone sulfate, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, C-reactive protein and HOMA score. Participants received ovarian stimulation for up to four cycles and if they conceived, were followed throughout pregnancy. We fit multi-variable logistic regression models examining AL (one-tailed and two-tailed) in relation to the following reproductive outcomes: conception, spontaneous abortion, live birth, pre-eclampsia, preterm birth and low birthweight. MAIN RESULTS AND THE ROLE OF CHANCE: Adjusting for covariates, a unit increase in two-tailed AL score was associated with 62% increased odds of pre-eclampsia (OR: 1.62, 95% CI: 1.14, 2.38) 44% increased odds of preterm birth (OR: 1.44, 95% CI: 1.02, 2.08), and 39% increased odds of low birthweight (OR: 1.39, 95% CI: 0.99, 1.97). The relationship between AL and preterm birth was mediated by pre-eclampsia (P = 0.0003). In one-tailed AL analyses, associations were similar, but slightly attenuated. AL was not associated with fertility outcomes (conception, spontaneous abortion, live birth). LIMITATIONS, REASONS FOR CAUTION: Results may not be generalizable to fertile women who conceive naturally or women with other types of infertility. Comparisons to previous, related work are difficult because variables included in AL composite measures vary across studies. AL may be indicative of overall poor health, rather than being specific to chronic physiological stress. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that chronic physiological stress may not impact success of ovarian stimulation, however, they confirm and extend previous work suggesting that AL is associated with adverse pregnancy outcomes. Physiological dysregulation due to chronic stress has been proposed as a possible mechanism underlying disparities in birth outcomes, which are currently poorly understood. Assessing biomarkers of physiological dysregulation pre-conception or in early pregnancy, may help to identify women at risk of adverse pregnancy outcomes, particularly pre-eclampsia. STUDY FUNDING/COMPETING INTEREST(S): Support for AMIGOS was provided by: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936 and U10HD055925. Support for the current analysis was provided by T32ES007271, R25HD075737, P30ES001247 and P30ES005022. This research was made possible by funding by American Recovery and Reinvestment Act. The content is solely the responsibility of the authors and does not necessarily represent the official views of NICHD, NIEHS or NIH. E.B., W.V., O.M., R.A., M.R., V.B., G.W.B., C.C., E.E., S.K., R.U., P.C, H.Z., N.S. and S.T. have nothing to disclose. R.L. reported serving as a consultant to Abbvie, Bayer, Kindex, Odega, Millendo and Fractyl and serving as a site investigator and receiving grants from Ferring. K.H. reported receiving grants from Roche Diagnostics and Ferring. R.R. reported a grant from AbbVie. M.D. reported being on the Board of Directors of and a stockholder in Advanced Reproductive Care. TRIAL REGISTRATION NUMBER: Clinical Trials.gov number: NCT01044862.

Sexual function in infertile women with polycystic ovary syndrome and unexplained infertility.

BACKGROUND: While female sexual dysfunction is a frequent occurrence, characteristics in infertile women are not well delineated. Furthermore, the impact of infertility etiology on the characteristics in women with differing androgen levels observed in women with polycystic ovary syndrome and unexplained infertility has not been assessed. OBJECTIVE: The objective of the study was to determine the characteristics of sexual dysfunction in women with polycystic ovary syndrome and unexplained infertility. STUDY DESIGN: A secondary data analysis was performed on 2 of Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Networks clinical trials: Pregnancy in Polycystic Ovary Syndrome Study II and Assessment of Multiple Intrauterine Gestations From Ovarian Stimulation. Both protocols assessed female sexual function using the Female Sexual Function Inventory and the Female Sexual Distress Scale. RESULTS: Women with polycystic ovary syndrome had higher weight and body mass index than women with unexplained infertility (each P < .001), greater phenotypic (Ferriman-Gallwey hirsutism score, sebum score, and acne score; each P < .001), and hormonal (testosterone, free testosterone, and dehydroepiandrosterone; each P < .001) evidence of androgen excess. Sexual function scores, as assessed by the Female Sexual Function Inventory, were nearly identical. The Female Sexual Distress Scale total score was higher in women with polycystic ovary syndrome. The mean Female Sexual Function Inventory total score increased slightly as the free androgen index increased, mainly as a result of the desire subscore. This association was more pronounced in the women with unexplained infertility. CONCLUSION: Reproductive-age women with infertility associated with polycystic ovary syndrome and unexplained infertility, despite phenotypic and biochemical differences in androgenic manifestations, do not manifest clinically significant differences in sexual function.

Fertility-related quality of life from two RCT cohorts with infertility: unexplained infertility and polycystic ovary syndrome.

STUDY QUESTION: Does fertility-related quality of life (FertiQOL) differ by infertility diagnosis between women with polycystic ovary syndrome (PCOS) and their partners, compared with couples with unexplained infertility (UI)? SUMMARY ANSWER: Women with PCOS report lower QOL than those with UI, whereas males with UI report lower QOL than males with PCOS partners. WHAT IS KNOWN ALREADY: The fertility-specific QOL survey, FertiQOL, has been used to examine fertility-related QOL in a number of worldwide cohorts. Few data have addressed fertility-related QOL as a function of infertility diagnosis. Overall, men report better QOL than women with infertility, and there is variation in FertiQOL scores across different samples from different countries. STUDY DESIGN, SIZE, DURATION: This was a prospective, cohort study derived from two concurrent, randomized clinical trials, and designed to examine QOL in infertile females with PCOS and UI at the time of enrollment compared with each other and their male partners; to compare concordance FertiQOL scores in this study across other worldwide cohorts; and to determine if baseline FertiQOL was associated with pregnancy outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS and their partners (n = 733 and n = 641, respectively), and couples with UI (n = 865 women and 849 men) completed a validated fertility-specific QOL survey (FertiQOL) at the time of the study screening visit. PCOS women were randomized to either clomiphene citrate or letrozole treatment; couples with UI were randomized to clomiphene citrate, letrozole or gonadotrophin plus IUI. FertiQOL results were compiled by diagnosis (PCOS or UI) and compared by diagnosis and sex using Wilcoxon Rank-Sum testing. Relationships between baseline FertiQOL and pregnancy outcomes were examined using logistic regression. Multivariable models were performed to assess the association between FertiQOL scores and key participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS had lower total FertiQOL scores (72.3 ± 14.8) than those with UI (77.1 ± 12.8; P < 0.001); this was true for each domain (except Relational). These differences were largely explained by variation in BMI, hirsutism, household income and age. Women had lower overall FertiQOL scores than their male partners. Males with PCOS partners had higher scores than males with UI (84.9 ± 10.2 versus 83.3 ± 10.8; P = 0.003). Scores were not consistently associated with conception or pregnancy outcome. LIMITATIONS, REASONS FOR CAUTION: The use of multiple tests of association may have resulted in spurious statistically significant findings. Inherent sociodemographic differences between women with PCOS and those with UI largely account for the lower QOL in women with PCOS. Our study was unable to assess if changes in QOL affected pregnancy outcome as FertiQOL data were collected prior to treatment. Finally, the participants for both studies represent their local communities, but are not a population-based sample and thus firm conclusions about how representative these couples are to the general population must be made with caution. WIDER IMPLICATIONS OF THE FINDINGS: Women with PCOS with elevated BMI and hirsutism scores and with lower socioeconomic status may require more, targeted psychosocial support than those with other diagnoses. Possible attribution of infertility to the male partner appears to result in a lower QOL. There appears to be substantial national variation in FertiQOL scores, with US-based cohorts reporting overall higher QOL. STUDY FUNDING/COMPETING INTERESTS: This work was supported by National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD39005 (to M.D.), U10 HD38992 (to R.S.L.), (to C.C.), U10 HD38998 (to R.A.), U10 HD055942 (to R.D.R.), HD055944 (to P.C.), U10 HD055936 (to G.C.), U10HD055925 (to H.Z.); and U10 U54-HD29834 (to the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core of the Specialized Cooperative Centers Program in Reproduction and Infertility Research). Most importantly, this research was made possible by the funding by American Recovery and Reinvestment Act. N.S., E.E., J.C.T., C.G., H.H., R.A., P.C., G.C., C.C., M.D., S.J., W.D.S. and H.Z. report no conflicts of interests/disclosures. L.B.C. reports research support from Ferring Pharmaceuticals and Roche Diagnostics; R.S.L. reports receipt of consulting fees from AstraZeneca, Euroscreen, Sprout Pharmaceuticals, Taken, Kindex, Clarus and Bayer, Inc., and research support from AstraZeneca and Ferring Pharmaceuticals. R.D.R. reports research support from AbbVie. TRIAL REGISTRATION NUMBER: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II), NCT00719186; Assessment of Multiple Intrauterine Gestations in Ovulation Stimulation (AMIGOS) NCT01044862, clinicaltrials.gov. TRIAL REGISTRATION DATE: PPCOS II 17 July 2008; AMIGOS 7 January 2010. DATE OF FIRST PATIENT'S ENROLMENT: PPCOS II 19 February 2009; AMIGOS 2 August 2010.

Applying to subspecialty fellowship: clarifying the confusion and conflicts!

Of graduating obstetrics and gynecology residents, 40% apply for fellowship training and this percentage is likely to increase. The fellowship interview process creates a substantial financial burden on candidates as well as significant challenges in scheduling the multiple interviews for residents, residency programs, and fellowship programs. Coverage with relatively short lead time is needed for some resident rotations, multiple residents may request time off during overlapping time periods, and applicants may not be able to interview based on conflicting interview dates or the inability to find coverage from other residents for their clinical responsibilities. To address these issues, we propose that each subspecialty fellowship within obstetrics and gynecology be allocated a specified and limited time period to schedule their interviews with minimal overlap between subspecialties. Furthermore, programs in close geographic areas should attempt to coordinate their interview dates. This will allow residents to plan their residency rotation schedules far in advance to minimize the impact on rotations that are less amenable to time away from their associated clinical duties, and decrease the numbers of residents needing time off for interviews during any one time period. In addition, a series of formal discussions should take place between subspecialties related to these issues as well as within subspecialties to facilitate coordination.

Tubal Ligation and Risk of Endometrial Cancer: Findings From the Women's Health Initiative.

OBJECTIVE: Bilateral tubal ligation (BTL) is a common form of birth control in the United States. There are limited, contradictory data examining BTL and the risk of endometrial cancer and none examining type I and type II cancers separately. We investigated the association between BTL and endometrial cancer risk using the Women's Health Initiative (WHI) Observational and Dietary Modification Studies. METHODS: Demographic information and history of BTL were obtained from the baseline questionnaires from 76,483 WHI participants in the Observational and Dietary Modification Studies. Univariable and multivariable models were used to examine the association of BTL with type I and type II endometrial cancers. RESULTS: A total of 1137 women were diagnosed with incident endometrial cancer (972 type I and 128 type II) during a mean follow-up of 11.3 years. Overall, 14,499 (19%) women had undergone BTL. There were no statistically significant associations noted between BTL and age at BTL for type I or type II cancers. CONCLUSIONS: We examined the largest patient cohort to date in an effort to determine the impact of BTL on endometrial cancer risk. In the WHI trial, we observed no overall effect of BTL on the risk of type I or type II endometrial cancer, suggesting that patients undergoing this popular birth control method likely do not have an associated change in their baseline risk for endometrial cancer.

Identifying post-menopausal women at elevated risk for epithelial ovarian cancer.

OBJECTIVE: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma. METHODS: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data. RESULTS: Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001). CONCLUSION: CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.

Fertility preservation in patients receiving chemotherapy or radiotherapy.

The preservation and restoration of fertility are key aspects for enhancing quality of life in cancer survivors. Cytotoxic agents and radiation can produce gonadal dysfunction in both men and women. Survival rates for cancers that occur before or during reproductive age have improved dramatically. Current fertility preservation options are available but limited in males and females. Referral to a reproductive endocrinologist around the time of diagnosis is important to optimize treatment options.

Standardized Reproductive Endocrinology and Infertility Consultation for Pediatric and Adolescent Oncology Patients.

Purpose: To investigate the role of formal reproductive endocrinology and infertility (REI) consultation in fertility preservation counseling in a pediatric/adolescent oncology patient population. Methods: Retrospective chart review was performed at an academic adult hospital from 2021 to 2022. Pre- and postpubertal patients admitted to the pediatric/adolescent oncology service with cancer diagnoses and imminent gonadotoxic chemotherapy plans were included. Baseline characteristics were collected, including patient age, sex, race, language, insurance, and cancer diagnosis. Primary outcomes were formal REI consultation and fertility preservation election. Results: Nineteen of 58 eligible patients received a formal REI consultation. Patients were more likely to elect fertility preservation if they received a consult. Females were more likely to receive a consult than males and more likely to elect fertility preservation. Patients of age ≥16 years were more likely to receive consultation than younger patients. However, all patients of age <16 years who received a consult elected fertility preservation. There was no difference in consultation based on race, language, or insurance. Thirteen of 19 patients who received an REI consultation elected fertility preservation. Ten of 11 female elections were ovarian suppression, an unproven method of fertility preservation. The two male elections were semen cryopreservation. Conclusion: Underutilization of formal REI consults and a relative lack of proven fertility preservation elections may shed light on a need for increased fertility preservation awareness among young oncology patients and the providers who care for them. A streamlined process that automates formal REI consultation for all eligible patients may maximize the potential for comprehensive counseling and improve patient participation in fertility preservation.

A seed or soil problem in early endometriosis: stromal cell origin drives cellular invasion and coupling over mesothelial cell origin.

OBJECTIVE: To study the role of the mesothelial cells in early endometriosis lesion formation by assessing in vitro cell-to-cell communication and invasion of endometrial cells across a mesothelial cell monolayer, with both cell types derived from both patients with endometriosis and control patients. DESIGN: Laboratory-based experimental study. SETTING: University hospital and laboratory. PATIENT(S): Consenting reproductive-age women who underwent laparoscopy for gynecologic reasons and were confirmed to have either endometriosis with pathology tissue diagnosis (n = 8) or no endometriosis n = 8) at the time of surgery. INTERVENTION(S): Primary stromal cells cultured from endometrial pipelle biopsies and primary mesothelial cells cultured from peritoneal explants were used in transmesothelial invasion assays and gap junction coupling assays. MAIN OUTCOME MEASURE(S): Comparison of potential for lesion formation, using in vitro models, of both primary endometrial and mesothelial cells from patients with endometriosis and control patients, establishing the former as the primary disease driver. RESULT(S): When comparing mesothelial cells from control patients with those from patients with endometriosis, there was no significant difference in the amount of stromal cell invasion across either barrier. In contrast, when comparing stromal cell origin, the amount of invasion by endometriosis stromal cells was greater than control stromal cells regardless of whether the mesothelial cell monolayer was derived from patients with the disease or control patients. Additionally, primary mesothelial cells induced more gap junction coupling, a requirement for invasion, in stromal cells from patients with endometriosis than control patients, again independent of mesothelial origin. The notable exception was mesothelial cells derived from endometriotic lesion-affected areas that showed depressed ability to support invasion. CONCLUSION(S): Although both endometrial and mesothelial cells need to function for establishment of endometriosis lesions, the endometrium seems to be the key player, serving as an ideal target for diagnostic strategies and therapeutic intervention. While this notion is consistent with previous studies, to our knowledge, we are the first to directly test both primary mesothelial and endometrial cells from patients with endometriosis and control patients to compare propensities for mesothelial invasion.

Perinatal Outcomes of Women with Recurrent Pregnancy Loss Undergoing Frozen Embryo Transfer from the Society of Assisted Reproductive Technology Database.

OBJECTIVE: To assess whether infants born to women with a history of recurrent pregnancy loss (RPL) have an increased risk of adverse perinatal outcomes following frozen embryo transfer (FET) compared to women without a history of infertility or RPL. DESIGN: Retrospective cohort study utilizing the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART CORS) database between 2014 and 2020. SUBJECTS: Patients in the SART CORS database who underwent their first FET resulting in live birth either with a diagnosis of RPL (cases n=3,299) or without a history of RPL or infertility, the comparison population being tubal ligation (TL) only (n=1408). EXPOSURE: Recurrent pregnancy loss MAIN OUTCOME: Low birthweight (<2500g), additional outcomes included gestational age (continuous), birthweight (continuous), preterm delivery (< 37 weeks), mode of delivery, and neonatal death, defined as death prior to the completion of the 28th day of life. RESULTS: We observed no statistically significant difference in low birthweight, birthweight overall, mode of delivery or risk of neonatal death between patients with RPL compared to women with tubal ligation who underwent their first FET resulting in live birth. Patients with history of RPL compared to TL utilizing FET were more likely to have a later gestational age at delivery (p<0.001). Patients with RPL were also less likely to have a preterm delivery (imputed AOR 0.75 [0.64, 0.89]) than the TL patients. Furthermore, performing preimplantation genetic testing for aneuploidy (PGTA) in both patients with recurrent pregnancy loss or tubal ligation did not impact perinatal outcomes compared to patients who did not undergo PGTA. CONCLUSIONS: Patients with history of recurrent pregnancy loss do not have an increased risk of adverse perinatal outcomes when they undergo FET compared to patients without infertility or recurrent pregnancy loss. In addition, performing IVF/PGTA in patients with RPL does not adversely impact birth outcomes of their infants.

Impact of updated international diagnostic criteria for the diagnosis of polycystic ovary syndrome.

Objective: To study whether application of the new 2018 guidelines for the diagnosis of polycystic ovary syndrome (PCOS) would decrease the diagnosis of PCOS. Second, to compare the metabolic profiles of women included and excluded in this new definition. Design: Retrospective cross-sectional chart review. Setting: University-affiliated hospital system. Patients: Women, ages 12-50, with the International Classification of Diseases code "Polycystic Ovary Syndrome" in 2017. Interventions: Application of the new 2018 guidelines for the diagnosis of PCOS. Main Outcome Measures: The primary outcome was the retention of PCOS diagnosis after applying the new 2018 guidelines. Secondary outcomes included the comparison of metabolic risk factors. Analysis was performed using chi-square tests for categorical variables and unpaired t tests for continuous variables, with a P value of <.05 determined to be significant. Results: Of 258 women with PCOS based on Rotterdam criteria, only 195 (76%) met the criteria based on the new 2018 guidelines. Those women who only met Rotterdam criteria (n = 63) had significantly lower body mass index (32.7 vs. 35.8), lower total cholesterol levels (151 vs. 176 mg/dL), lower triglyceride levels (96 vs. 124 mg/dL), lower total (33.2 vs. 52.3 ng/dL) and free testosterone levels (4.7 vs. 8.3), lower antimüllerian hormone levels (3.1 vs. 7.7 ng/mL), and were more likely to be multiparous (50% vs. 29%) than women who met 2018 criteria. Conclusions: Increasing the minimum antral follicle count to ≥20 antral follicles significantly decreases the number of women with the diagnosis of PCOS. Furthermore, the women that meet the new criteria have more health risks for metabolic syndrome than those who only meet the Rotterdam criteria.

Robotic surgery applications in the management of gynecologic malignancies.

This review evaluates the use of robotic-assisted laparoscopic surgery in the treatment of gynecologic malignancies and objectively evaluates the use of these systems in performing radical hysterectomies and surgical staging of gynecologic malignancies. The review focuses on surgical length, blood loss, complications, recovery time, and adequacy of surgical staging of robotic-assisted surgery compared to abdominal and non-robotically assisted laparoscopic surgery for malignancies.

Effect of length of controlled ovarian hyperstimulation using a gonadotropin-releasing hormone antagonist on in vitro fertilization pregnancy rates.

OBJECTIVE: To compare pregnancy outcomes between shorter and longer in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles using GnRH antagonist protocol. STUDY DESIGN: Retrospective cohort analysis at a large military academic hospital. A total of 351 patients underwent 412 IVF/ICSI cycles using a GnRH antagonist protocol from September 2002 through May 2008. Clinical pregnancy and live birth rates for all IVF/ICSI cycles were compared independently for both total length of ovarian stimulation with gonadotropins (< 10 days vs. > or = 10 days) and GnRH antagonist use (< 4 days vs. > or = 4 days), respectively. RESULTS: Clinical pregnancy rates were 54.6% among cycles with total gonadotropin use <10 days vs. 48.6% for those cycles > or = 10 days, odds ratio 0.82 (0.53-1.27); live birth rates were 50.0% vs. 47.7%, odds ratio 0.91 (0.59-1.42). Clinical pregnancy rates were 54.0% among cycles with GnRH antagonist use < 4 days vs. 52.8% with GnRH antagonist use > or = 4 days, odds ratio 0.95 (0.62-1.45); live birth rates were 46.8% vs. 50.4%, odds ratio 1.15 (0.76-1.76). CONCLUSION: Clinical pregnancy and live birth rates are not adversely affected by longer IVF/ICSI cycles using GnRH antagonists.

Common practices among consistently high-performing in vitro fertilization programs in the United States: 10-year update.

OBJECTIVE: To evaluate similarities and differences in clinical and laboratory practices among high-performing fertility clinics. DESIGN: Cross-sectional questionnaire study of selected programs. SETTING: Academic and private fertility practices performing in vitro fertilization (IVF). PATIENT(S): Not applicable. INTERVENTION(S): A comprehensive survey was conducted of 13 IVF programs performing at least 100 cycles a year and having high cumulative singleton delivery rates for 2 years. MAIN OUTCOME MEASURE(S): Clinical and laboratory IVF practices. RESULT(S): Although many areas of clinical practice varied among top programs, some commonalities were observed. All programs used a combination of follicle-stimulating hormone and luteinizing hormone for IVF stimulation, intramuscular progesterone in frozen embryo transfer cycles, ultrasound-guided embryo transfers, and a required semen analysis before starting the IVF cycle. Common laboratory practices included vitrification of embryos at the blastocyst stage, air quality control with positive air pressure and high-efficiency particulate air filtration, use of incubator gas filters, working on heated microscope stages, and incubating embryos in a low-oxygen environment, most often in benchtop incubators. CONCLUSION(S): Some areas of consistency in clinical and laboratory practices were noted among high-performing IVF programs that are likely contributing to their success. High-performing programs focused on singleton deliveries. As the field of IVF is rapidly evolving, it is imperative that we share best practices in an effort to improve outcomes from all clinics for the good of our patients.