The first two blastomeres contribute unequally to the human embryo.

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.

The unbearable ignorance of the composition of IVF culture media.

Culture media play an essential role in the success of IVF. Their composition has undergone major modifications over the 45 years since the birth of Louise Brown. Most IVF programmes now rely on commercially produced media, which they buy in small vials, guaranteed to be sterile and non-embryotoxic. Unfortunately, information about the components of the culture media and their concentrations is no longer available. Arguing that culture media recipes are proprietary, relevant commercial interests have stopped labelling their products with this vital information. Given the critical role that is played by culture media in the success of IVF, as well as the subsequent health of the children who are born after IVF, this information should not remain a 'company secret'. Clinicians and scientists working in IVF must insist that the labelling of culture media includes all of the constituents and their concentrations. Only in this way can we monitor the influence of culture media on IVF outcomes, innovate and continue to advance the field of IVF.

Contraception and sterilization selection at delivery among pregnant patients with malignancy.

INTRODUCTION: Since malignancy during pregnancy is uncommon, information regarding contraception selection or sterilization at delivery is limited. The objective of this study was to examine the type of long-acting reversible contraception or surgical sterilization procedure chosen by pregnant patients with malignancy at delivery. MATERIAL AND METHODS: This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample in the USA. The study population was vaginal and cesarean deliveries in a hospital setting from January 2017 to December 2020. Pregnant patients with breast cancer (n = 1605), leukemia (n = 1190), lymphoma (n = 1120), thyroid cancer (n = 715), cervical cancer (n = 425) and melanoma (n = 400) were compared with 14 265 319 pregnant patients without malignancy. The main outcome measures were utilization of long-acting reversible contraception (subdermal implant or intrauterine device) and performance of permanent surgical sterilization (bilateral tubal ligation or bilateral salpingectomy) during the index hospital admission for delivery, assessed with a multinomial regression model controlling for clinical, pregnancy and delivery characteristics. RESULTS: When compared with pregnant patients without malignancy, pregnant patients with breast cancer were more likely to proceed with bilateral salpingectomy (adjusted odds ratio [aOR] 2.30) or intrauterine device (aOR 1.91); none received the subdermal implant. Pregnant patients with leukemia were more likely to choose a subdermal implant (aOR 2.22), whereas those with lymphoma were more likely to proceed with bilateral salpingectomy (aOR 1.93) and bilateral tubal ligation (aOR 1.76). Pregnant patients with thyroid cancer were more likely to proceed with bilateral tubal ligation (aOR 2.21) and none received the subdermal implant. No patients in the cervical cancer group selected long-acting reversible contraception, and they were more likely to proceed with bilateral salpingectomy (aOR 2.08). None in the melanoma group chose long-acting reversible contraception. Among pregnant patients aged <30, the odds of proceeding with bilateral salpingectomy were increased in patients with breast cancer (aOR 3.01), cervical cancer (aOR 2.26) or lymphoma (aOR 2.08). The odds of proceeding with bilateral tubal ligation in pregnant patients aged <30 with melanoma (aOR 5.36) was also increased. CONCLUSIONS: The results of this nationwide assessment in the United States suggest that among pregnant patients with malignancy, the preferred contraceptive option or method of sterilization at time of hospital delivery differs by malignancy type.

Pregnancy following assisted reproductive technology in morbidly obese patients: assessment of feto-maternal outcomes.

PURPOSE: To examine feto-maternal characteristics and outcomes of morbidly obese pregnant patients who conceived with assisted reproductive technology (ART). METHODS: This cross-sectional study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. Study population was 48,365 patients with ART pregnancy from January 2012 to September 2015, including non-obesity (n = 45,125, 93.3%), class I-II obesity (n = 2445, 5.1%), and class III obesity (n = 795, 1.6%). Severe maternal morbidity at delivery per the Centers for Disease and Control Prevention definition was assessed with multivariable binary logistic regression model. RESULTS: Patients in the class III obesity group were more likely to have a hypertensive disorder (adjusted-odds ratio (aOR) 3.03, 95% confidence interval (CI) 2.61-3.52), diabetes mellitus (aOR 3.08, 95%CI 2.64-3.60), large for gestational age neonate (aOR 3.57, 95%CI 2.77-4.60), and intrauterine fetal demise (aOR 2.03, 95%CI 1.05-3.94) compared to those in the non-obesity group. Increased risks of hypertensive disease (aOR 1.35, 95%CI 1.14-1.60) and diabetes mellitus (aOR 1.39, 95%CI 1.17-1.66) in the class III obesity group remained robust even compared to the class I-II obesity group. After controlling for priori selected clinical, pregnancy, and delivery factors, patients with class III obesity were 70% more likely to have severe maternal morbidity at delivery compared to non-obese patients (8.2% vs 4.4%, aOR 1.70, 95%CI 1.30-2.22) whereas those with class I-II obesity were not (4.1% vs 4.4%, aOR 0.87, 95%CI 0.70-1.08). CONCLUSIONS: The results of this national-level analysis in the United States suggested that morbidly obese pregnant patients conceived with ART have increased risks of adverse fetal and maternal outcomes.

The association between uterine adenomyosis and adverse obstetric outcomes: A propensity score-matched analysis.

INTRODUCTION: This study examined obstetric outcomes in patients diagnosed with uterine adenomyosis. MATERIAL AND METHODS: This historical cohort study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. The study population was all hospital deliveries in women aged 15-54 years between January 2016 and December 2019. The exposure was a diagnosis of uterine adenomyosis. The main outcome measures were obstetric characteristics, including placenta previa, placenta accreta spectrum, and placental abruption. Secondary outcomes were delivery complications including severe maternal morbidity. Analytic steps to assess these outcomes included (i) a 1-to-N propensity score matching to mitigate and balance prepregnancy confounders to assess obstetric characteristics, followed by (ii) an adjusting model with preselected pregnancy and delivery factors to assess maternal morbidity. Sensitivity analyses were also performed with restricted cohorts to account for prior uterine scar, uterine myoma, and extra-uterine endometriosis. RESULTS: After propensity score matching, 5430 patients with adenomyosis were compared to 21 720 patients without adenomyosis. Adenomyosis was associated with an increased odds of placenta accreta spectrum (adjusted-odds ratio [aOR] 3.07, 95% confidence interval [CI] 2.01-4.70), placenta abruption (aOR 3.21, 95% CI: 2.60-3.98), and placenta previa (aOR 5.08, 95% CI: 4.25-6.06). Delivery at <32 weeks of gestation (aOR 1.48, 95% CI: 1.24-1.77) and cesarean delivery (aOR 7.72, 95% CI: 7.04-8.47) were both increased in women with adenomyosis. Patients in the adenomyosis group were more likely to experience severe maternal morbidity at delivery compared to those in the nonadenomyosis group (aOR 1.86, 95% CI: 1.59-2.16). Results remained robust in the aforementioned several sensitivity analyses. CONCLUSIONS: This national-level analysis suggests that a diagnosis of uterine adenomyosis is associated with an increased risk of placental pathology (placenta accreta spectrum, placenta abruption, and placental previa) and adverse maternal outcomes at delivery.

Seasonal fluctuation of in vitro fertilization encounters in the United States.

PURPOSE: To examine patient and hospital characteristics related to seasonal fluctuation in in vitro fertilization (IVF). METHODS: This retrospective cohort study examined 33,077 oocyte retrievals identified in the National Ambulatory Surgery Sample. Exposure assignment was monthly IVF encounters: low-volume months (<25%ile), mid-volume months (≥25/<75%ile), and high-volume months (>75%ile). Main outcomes were patient and hospital characteristics related to the exposure groups, assessed with a multinomial regression model. RESULTS: The median IVF encounters were 977 per month, ranging from 657 to 1074 (absolute-difference 417). January, July, and December were the lowest-quartile volume months, ranging from 657 to 710 encounters per month (low-volume months). May, August, and November were the top-quartile volume months, ranging from 1049 to 1074 encounters per month (high-volume months). In a multivariable analysis, patients undergoing IVF in the low-volume months were younger and less likely to have infertility or comorbidities. Patients undergoing IVF in the high-volume months were more likely to have lower household income and receive IVF at urban teaching facilities. Northeastern residents were less likely to have IVF in the low-volume months but more likely to have IVF in the high-volume months. Sensitivity analyses showed that the lowest-to-highest variability in monthly IVF encounters was higher in Northeast region compared to other regions (320 vs 50-128); infertility patients compared to those without (317 vs 190); privately insured patients compared to self-pay (227 vs 156); and older patients compared to younger (234 vs 192). CONCLUSION: This study suggests substantial seasonal fluctuation in IVF oocyte retrieval in the USA based on patient and hospital factors.

The influence of obesity on incidence of complications in patients hospitalized with ovarian hyperstimulation syndrome.

OBJECTIVE: To study the impact of body habitus on risk of complications resulting from ovarian hyperstimulation syndrome (OHSS) in hospitalized patients. METHODS: This is a retrospective observational study examining the National Inpatient Sample between January 2012 and September 2015. Patients were women < 50 years of age diagnosed with OHSS, classified as non-obese, class I-II obesity, or class III obesity. Intervention included multinomial logistic regression to identify factors associated with obesity and binary logistic regression for independent risk factors for complications. Main outcome measures were incidence of (i) any or (ii) multiple complication(s). RESULTS: Of 2745 women hospitalized with OHSS, 2440 (88.9%) were non-obese, 155 (5.6%) had class I-II obesity, and 150 (5.5%) had class III obesity. Obese women (either class I-II or III) had a higher degree of comorbidity, had lower incomes, and were less likely to have private insurance than non-obese women (all P < 0.001). Obese women had lower rates of OHSS-related complications than non-obese women (any complication: non-obese 65.2%, class I-II 54.8%, and class III 46.7%, P < 0.001; and multiple complications: non-obese 38.5%, class I-II 32.3%, and class III 20.0%, P < 0.001). In the multivariable model, obesity remained independently associated with a decreased risk of complications (class I-II odds ratio 0.57, 95% confidence interval 0.39-0.83, P = 0.003; class III odds ratio 0.30, 95% confidence interval 0.20-0.44, P < 0.001). Obese women were also less likely to require paracentesis (non-obese 32.8%, class I-II 9.7%, and class III 13.3%, P < 0.001). CONCLUSION: Our study suggests that obesity is associated with decreased OHSS-related complication rates in hospitalized patients.

Effect of age and morphology on sustained implantation rate after euploid blastocyst transfer.

RESEARCH QUESTION: What impact does maternal age and embryo morphology have on sustained implantation rates of euploid blastocysts? DESIGN: This was a retrospective analysis of sustained implantation rates of euploid blastocysts stratified by maternal age and morphology. The primary analysis included 208 embryo transfers with a total of 229 embryos transferred from January 2017 through August 2020. RESULTS: For all ages the sustained implantation rates for day 5 good quality blastocysts were higher than for day 5 fair, day 5 poor and day 6 blastocysts. At a maternal age of 36 years the best-fit sustained implantation rates were 86% for day 5 good quality blastocysts, 64% for day 5 fair, 63% for day 5 poor, and 51% for all day 6 blastocysts analysed as one group. When controlling for morphology and day of biopsy, there were higher sustained implantation rates for euploid embryos of younger patients compared with older patients. The best-fit sustained implantation rates for age 33 compared to age 39 years were 86% versus 80% for day 5 good, 71% versus 62% for day 5 fair, 59% versus 55% for day 5 poor, and 81% versus 46% for all day 6. CONCLUSIONS: There was a clinically significant higher sustained implantation rate at all ages for euploid day 5 good quality embryos compared with day 5 fair, day 5 poor and day 6 embryos.

Paradigm shift from tubal ligation to opportunistic salpingectomy at cesarean delivery in the United States.

BACKGROUND: Opportunistic salpingectomy is now recommended at the time of routine gynecologic surgery to reduce the risk of future ovarian cancer, and performance of opportunistic salpingectomy has increased markedly at the time of benign hysterectomy. Salpingectomy has also been suggested to be feasible at the time of cesarean delivery in women desiring sterilization; however, uptake has not been previously studied on a national level. OBJECTIVE: This study aimed to examine recent population trends in the utilization and characteristics of salpingectomy at the time of cesarean delivery in the United States. STUDY DESIGN: This is a population-based retrospective observational study querying the National Inpatient Sample between October 2015 and December 2018. The primary outcome measure was the temporal trend of bilateral salpingectomy at cesarean delivery, assessed with linear segmented regression with log transformation utilizing 3-month time increments. The secondary outcome measures included patient characteristics associated with bilateral salpingectomy, assessed with a multinomial regression model, and surgical outcome (hemorrhage, blood transfusion, hysterectomy, and oophorectomy) at the time of bilateral salpingectomy vs bilateral tubal ligation, assessed with generalized estimating equation in a propensity score-matched model. RESULTS: There were 3,813,823 women at the age of 15 to 49 years who had cesarean deliveries included, of whom 397,260 (10.4%) had bilateral salpingectomy and 203,400 (5.3%) had bilateral tubal ligation overall. During the time period studied, performance of bilateral salpingectomy among women undergoing cesarean delivery significantly increased from 4.6% to 13.2% (odds ratio for the fourth quarter of 2018 vs the fourth quarter of 2015, 2.69; 95% confidence interval, 2.63-2.75; Figure panel). In contrast, performance of bilateral tubal ligation among women undergoing cesarean delivery significantly decreased from 11.3% to 2.4% (odds ratio, 0.20; 95% confidence interval, 0.19-0.21). By the third quarter of 2016, the number of women who had bilateral salpingectomy exceeded those who had bilateral tubal ligation at cesarean delivery (8.6% vs 7.3%). Increasing the utilization of bilateral salpingectomy did not vary across age groups; the salpingectomy rate increased from 7.5% to 21.1% among women at the age of ≥35 years and from 3.8% to 10.7% among women at the age of <35 years (both, P<.001). In a propensity score matched model, women in the bilateral salpingectomy group were more likely to have hemorrhage (3.8% vs 3.1%; odds ratio, 1.24; 95% confidence interval, 1.15-1.33), blood product transfusion (2.1% vs 1.8%; odds ratio, 1.16; 95% confidence interval, 1.04-1.30), hysterectomy (0.8% vs 0.4%; odds ratio, 2.28; 95% confidence interval, 1.84-2.82), and oophorectomy (0.3% vs 0.2%; odds ratio, 2.02; 95% confidence interval, 1.47-2.79) than those in the bilateral tubal ligation group. When restricted to the nonhysterectomy cases, the bilateral salpingectomy group had a higher rate of hemorrhage (3.4% vs 3.0%; odds ratio, 1.16; 95% confidence interval, 1.06-1.26) and oophorectomy (0.3% vs 0.1%; odds ratio, 1.75; 95% confidence interval, 1.22-2.50) than the bilateral tubal ligation group. CONCLUSION: In the United States, the utilization of bilateral salpingectomy at the time of cesarean delivery increased rapidly between 2015 and 2018, replacing tubal ligation as the most common type of sterilization performed with cesarean delivery. The higher surgical morbidity in the bilateral salpingectomy group than the bilateral tubal ligation group observed in this study warrants further investigation.

Examining pre-term birth and cesarean section rates in gestational carrier pregnancies.

PURPOSE: This study sought to report on the route and gestational age at delivery of gestational carrier (GC) pregnancies with respect to the GCs' prior obstetric history. METHODS: A retrospective analysis of all GC pregnancies from one of the largest surrogacy agencies in California between 2008 and 2018 was performed. Available demographic data and obstetric history, including a history of prior cesarean section (CS) and preterm birth (PTB), were collected for each GC and correlated to outcomes of the index GC pregnancy. Primary outcomes for the index GC pregnancies included delivery route and gestational age at delivery. RESULTS: Eight-hundred-thirty-six GCs were included in our analysis. 319 (38.2%) delivered via CS, and 517 (61.8%) delivered vaginally. 60 (18.8%) of the CS deliveries were due to multifetal gestation. Primary CS rate in singleton GC pregnancies was 38.5%. In women without a history of CS, neither age, BMI, interpregnancy interval, prior parity, nor year of delivery impacted the primary singleton CS rate (all, P > 0.05). Of GCs with a history of a prior CS (n = 350, 41.9%), 218 (62.3%) had a vaginal delivery after CS (VBAC) and 132 (37.7%) had a repeat CS. Women who had successful VBACs were significantly younger than those who had repeat CS (mean 33.7 vs. 35.2 years, P = .003). BMI was lower in patients who had a VBAC compared to those that had a repeat CS (mean BMI 24.6 vs. 25.5, P = 0.074), although this did not reach statistical significance. In GCs with a history of CS, interpregnancy interval, year of delivery, prior parity, and multiple gestation in the index GC pregnancy did not impact mode of delivery. VBAC rates did not change over the study period (P = 0.757). Overall PTB rate was 15.1%. Most PTB in GC pregnancies were in those with a history of PTB, and PTB was more likely in singletons rather than multifetal gestations (76.7% in singletons vs. 30% in multiples) in patients with history of PTB (P < 0.001). Those with no history of PTB and who carried multiples had a low rate of PTB; in fact, in this group, only 1 out of 35 patients had a PTB with multiples. CONCLUSIONS: Both primary CS and PTB rates in singleton GC pregnancies are higher than national averages. CS rates are independent of age, BMI, and interpregnancy interval. In GCs with a history of a CS, VBAC rates well exceed national averages and are higher in younger GCs with a lower BMI. PTB rates are impacted primarily by the GCs obstetric history. In those GCs without a history of PTB, rates of PTB are low, even in those with a multifetal gestation.

What is the optimal timing of intracytoplasmic sperm injection (ICSI) after EGG retrieval? A randomized controlled trial.

PURPOSE: To determine if oocyte denudation and ICSI at 36.5 versus 39 h post HCG and/or Lupron trigger (2.5 h versus 5 h post-oocyte retrieval) influences fertilization and blastulation rates in good prognosis couples METHODS: We performed a prospective, randomized controlled trial of 12 patients undergoing IVF with ICSI at an academic fertility center, resulting in 206 MII oocytes analyzed. At time of retrieval, patients with more than 10 oocytes retrieved had their oocytes randomized into two groups-one group for oocyte denudation and ICSI at 36.5 h post HCG and/or Lupron trigger and the other group for these procedures at 39 h post HCG and/or Lupron trigger (2.5 and 5 h after oocyte retrieval). Primary outcomes were fertilization and blastulation rates. RESULTS: No difference was observed in fertilization rate, total blastulation rate, or day of blastulation based on timing of denudation and ICSI (all p > 0.05). Multiple regression analyses for fertilization and blastulation controlling for age and BMI revealed no difference in fertilization based on time of ICSI (p = 0.38, 0.71, respectively). A conditional logistic regression to account for multiple oocytes derived from each patient also found no difference in fertilization or blastulation based on timing of ICSI, even when controlling for age and BMI (p = 0.47, 0.59, respectively). CONCLUSION(S): In good prognosis couples, we observed no difference in fertilization or blastulation rates based on timing of ICSI within the currently accepted 2- to 6-h window post-retrieval based on a 34-h trigger. The oocyte appears to have a physiological tolerance for fertilization during this window of time, and variability in the timing of ICSI during this window is unlikely to have an impact on cycle outcome.

Developmental potential of immature human oocytes aspirated after controlled ovarian stimulation.

PURPOSE: Intracytoplasmic sperm injection (ICSI) for initially immature oocytes that mature in vitro is controversial and practice varies widely. While it may increase the number of usable embryos, it may also be time-intensive and potentially low-yield. This study sought to elucidate which patients may benefit from ICSI of initially immature oocytes that matured in vitro. METHODS: A retrospective study comparing fertilization, cleavage, blastulation, and embryo usage rates between sibling initially immature and mature oocytes that underwent ICSI between 2015 and 2019 was performed. Outcomes of initially immature oocytes were stratified by initial maturation stage, timing of progression to metaphase II (MII) in vitro, percentage of mature oocytes in the cycle, and female age. RESULTS: Ten thousand eight hundred seventeen oocytes from 889 cycles were included. Of 3137 (29.0%) initially immature oocytes, 418 (13.3%) reached MII later on the day of retrieval (day 0) and 1493 (47.6%) on day 1. Overall, embryos originating from initially immature oocytes had lower cleavage and blastulation rates compared to those from initially mature oocytes (P<0.05, all groups). However, embryos from oocytes that matured later on day 0 comprised a unique subset that had clinically similar cleavage (75% vs 80%, RR 0.93, P=0.047) and blastulation rates (41% vs 50%, RR 0.81, P=0.024) compared to initially mature oocytes. Women with low percentages of mature oocytes in the cycle overall and women ≥40 in cleavage cycles derived the highest relative benefit from the use of immature oocytes. CONCLUSION: ICSI of immature oocytes, particularly those that mature later on the day of retrieval, may improve numbers of usable embryos. This study supports routine reassessment of immature oocytes for progression to MII and ICSI on day 0. An additional reassessment on day 1 may also be of use in older women or those with low percentage of mature oocytes.

Hidden in plain sight: the overstated benefits and underestimated losses of potential implantations associated with advertised PGT-A success rates.

The utilization of preimplantation genetic testing for aneuploidy (PGT-A) has understandable intuitive appeal in reassuring the clinician that 'everything possible' has been done to assure the birth of a healthy baby. Whereas the development of the PGT-A technology is still in a relatively early stage, great strides have nevertheless been made in the understanding of the genetics of the preimplantation human embryo. The problem lies not in the progress that has been achieved, but rather, in the reality that PGT-A is being actively marketed as a mature technology. Those that market the technology overstate its benefits and underestimate the losses of potential implantations that are the consequence of the practice of PGT-A. The implication is that the PGT-A technology is accurate, has minimal errors and is ready to be applied to every case of IVF. This approach is not evidence-based. Substantial losses of potential implantations are even evident in the analysis of the numbers presented by marketing materials themselves. In order to provide accurate, evidence-based counseling for patients undergoing IVF, we need to apply an appropriate level of scientific scrutiny to the data that are available and apply PGT-A selectively to those cases in which the benefits clearly outweigh the costs.

The rapid adoption of opportunistic salpingectomy at the time of hysterectomy for benign gynecologic disease in the United States.

BACKGROUND: Mounting evidence for the role of distal fallopian tubes in the pathogenesis of epithelial ovarian cancer has led to opportunistic salpingectomy being increasingly performed at the time of benign gynecologic surgery. Opportunistic salpingectomy has now been recommended as best practice in the United States to reduce future risk of ovarian cancer even in low-risk women. Preliminary analyses have suggested that performance of opportunistic salpingectomy is increasing. OBJECTIVE: To examine trends in opportunistic salpingectomy in women undergoing benign hysterectomy and to determine how the publication of the tubal hypothesis in 2010 may have contributed to these trends. STUDY DESIGN: This is a population-based, retrospective, observational study examining the National Inpatient Sample between January 2001 and September 2015. Women younger than 50 years who underwent inpatient hysterectomy for benign gynecologic disease were grouped as hysterectomy alone vs hysterectomy with opportunistic salpingectomy. All women had ovarian conservation, and those with adnexal pathology were excluded. Linear segmented regression with log transformation was used to assess temporal trends. An interrupted time-series analysis was then used to assess the impact of the 2010 publication of the tubal hypothesis on opportunistic salpingectomy trends. A regression-tree model was constructed to examine patterns in the use of opportunistic salpingectomy. A binary logistic regression model was then fitted to identify independent characteristics associated with opportunistic salpingectomy. Sensitivity analysis was performed in women aged 50-65 years to further assess surgical trends in a wider age group. RESULTS: There were 98,061 (9.0%) women who underwent hysterectomy with opportunistic salpingectomy and 997,237 (91.0%) women who underwent hysterectomy alone without opportunistic salpingectomy. The rate at which opportunistic salpingectomy was being performed gradually increased from 2.4% to 5.7% between 2001 and 2010 (2.4-fold increase; P<.001), predicting a 7.0% rate of opportunistic salpingectomy in 2015. However, in 2010, the rate of opportunistic salpingectomy began to increase substantially and reached 58.4% by 2015 (10.2-fold increase; P<.001). In multivariable analysis, the largest change in the performance of opportunistic salpingectomy occurred after 2010 (adjusted odds ratio, 5.42; 95% confidence interval, 5.34-5.51; P<.001). In a regression-tree model, women who had a hysterectomy at urban teaching hospitals in the Midwest after 2013 had the highest chance of undergoing opportunistic salpingectomy during benign hysterectomy (76.4%). In the sensitivity analysis of women aged 50-65 years, a similar exponential increase in opportunistic salpingectomy was observed from 5.8% in 2010 to 55.8% in 2015 (9.8-fold increase; P<.001). CONCLUSION: Our study suggests that clinicians in the United States rapidly adopted opportunistic salpingectomy at the time of benign hysterectomy following the publication of data implicating the distal fallopian tubes in ovarian cancer pathogenesis in 2010. By 2015, nearly 60% of women had undergone opportunistic salpingectomy at benign hysterectomy.

Progestin therapy for obese women with complex atypical hyperplasia: levonorgestrel-releasing intrauterine device vs systemic therapy.

BACKGROUND: Though hysterectomy remains the standard treatment for complex atypical hyperplasia, patients who desire fertility or who are poor surgical candidates may opt for progestin therapy. However, the effectiveness of the levonorgestrel-releasing intrauterine device compared to systemic therapy in the treatment of complex atypical hyperplasia has not been well studied. OBJECTIVE: We sought to examine differences in treatment response between local progestin therapy with the levonorgestrel-releasing intrauterine device and systemic progestin therapy in women with complex atypical hyperplasia. METHODS: This single-institution retrospective study examined women with complex atypical hyperplasia who received progestin therapy between 2003 and 2018. Treatment response was assessed by histopathology on subsequent biopsies. Time-dependent analyses of complete response and progression to cancer were performed comparing the levonorgestrel-releasing intrauterine device and systemic therapy. A propensity score inverse probability of treatment weighting model was used to create a weighted cohort that differed based on treatment type but was similar with respect to other characteristics. An interaction-term analysis was performed to examine the impact of body habitus on treatment response, and an interrupted time-series analysis was employed to assess if changes in treatment patterns correlated with outcomes over time. RESULTS: A total of 245 women with complex atypical hyperplasia received progestin therapy (levonorgestrel-releasing intrauterine device n = 69 and systemic therapy n = 176). The mean age and body mass index were 36.9 years and 40.0 kg/m2, respectively. In the patient-level analysis, women who received the levonorgestrel-releasing intrauterine device had higher rates of complete response (78.7% vs 46.7%; adjusted hazard ratio, 3.32; 95% confidence interval, 2.39-4.62) and a lower likelihood of progression to cancer (4.5% vs 15.7%; adjusted hazard ratio, 0.28; 95% confidence interval, 0.11-0.73) compared to those who received systemic therapy. In particular, women with class III obesity derived a higher relative benefit from levonorgestrel-releasing intrauterine device therapy in achieving complete response compared to systemic therapy: class III obesity, adjusted hazard ratio 4.72, 95% confidence interval 2.83-7.89; class I-II obesity, adjusted hazard ratio 1.83, 95% confidence interval 1.09-3.09; and nonobese, adjusted hazard ratio 1.26, 95% confidence interval 0.40-3.95. In the cohort-level analysis, the obesity rate increased during the study period (77.8% to 88.2%, 13.4% relative increase, P = .033) and levonorgestrel-releasing intrauterine device use significantly increased after 2007 (6.3% to 82.7%, 13.2-fold increase, P < .001), both concomitant with a higher proportion of women achieving complete response (32.9% to 81.4%, 2.5-fold increase, P = .005). CONCLUSION: Our study suggests that local therapy with the levonorgestrel-releasing intrauterine device may be more effective than systemic therapy for women with complex atypical hyperplasia who opt for nonsurgical treatment, particularly in morbidly obese women. Shifts in treatment paradigm during the study period toward increased levonorgestrel-releasing intrauterine device use also led to improved complete response rates despite increasing rates of obesity.

Route-specific association of progestin therapy and concurrent metformin use in obese women with complex atypical hyperplasia.

INTRODUCTION: Previous studies have suggested that metformin use may enhance the therapeutic effect of progestin therapy for endometrial hyperplasia or malignancy. However, it is not known how the impact of concurrent metformin may be altered by route of progestin therapy, either locally via an intrauterine device or systemically. This study examined the effectiveness of concurrent metformin use and progestin therapy for women with complex atypical hyperplasia stratified by progestin route (systemic vs local). METHODS: This single-institution retrospective study examined consecutive women with complex atypical hyperplasia who received progestin therapy from 2003 to 2018. Time-dependent analyses for complete response rate were performed comparing concurrent metformin users versus non-users in the oral progestin group and in the levonorgestrel-releasing intrauterine device group. RESULTS: Across the study cohort (n=245), there were 137 (55.9%) women who responded to progestin therapy. In the oral progestin group (n=176), the median age and body mass index were 36 years and 37.7 kg/m2, respectively. 36 (20.5%) of women on oral progestins also took metformin. After controlling for diabetes status, women taking both oral progestins and metformin had a complete response rate similar to those not taking metformin (6 month cumulative rates, 23.1% vs 27.8%, adjusted hazard ratio (aHR) 0.71, 95% confidence interval (95% CI) 0.36 to 1.41). In the levonorgestrel-releasing intrauterine device group (n=69), the median age and body mass index were 35 years and 39.9 kg/m2, respectively. There were 15 (21.7%) women who took metformin in addition to the levonorgestrel-releasing intrauterine device. After controlling for diabetes status, women who had the levonorgestrel-releasing intrauterine device and took metformin had a significantly higher complete response rate compared with those not taking metformin (6 month cumulative rates, 86.7% vs 58.9%, aHR 2.31, 95% CI 1.09 to 4.89). CONCLUSION: In a predominantly obese population, concurrent metformin may possibly offer treatment benefit when used with the levonorgestrel-releasing intrauterine device.

Fertility-sparing treatment for early-stage epithelial ovarian cancer: Contemporary oncologic, reproductive and endocrinologic perspectives.

AIM: Epithelial ovarian cancer (EOC) can be a devastating diagnosis in women of reproductive age who desire future fertility. However, in early-stage disease, fertility-sparing surgery (FSS) can be considered in appropriately selected patients. METHODS: This is a narrative descriptive review of the recent literature on FSS for EOC from oncologic, reproductive and endocrinologic perspectives. RESULTS: The recurrence rate following FSS performed for stage I EOC in published retrospective studies collectively is 13% but ranges from 5 to 29%, while mortality ranges from 0 to 18%. Five-year disease-free survival following FSS is over 90% but decreases with higher stage and grade. Recurrences following FSS are more likely to be localized with a more favorable prognosis compared to recurrences following radical surgery. Adjuvant chemotherapy is recommended in women with high-risk disease, and strategies to minimize gonadotoxicity during chemotherapy such as gonadotropin-releasing hormone (GnRH) agonists may be considered. Oocyte, embryo and/or ovarian cryopreservation can also be offered to patients desiring future biologic children. Reproductive outcomes following FSS, including pregnancy and miscarriage rates, resemble those of the general population, with a chance of successful pregnancy of nearly 80%. CONCLUSION: In retrospective data, FSS appears to be oncologically safe in stage IA and IC grade 1-2 non-clear cell EOC. In patients with grade 3 tumors or clear cell histology, treatment can be individualized, weighing a slightly higher risk of recurrence with fertility goals. A multidisciplinary approach with oncology and reproductive endocrinology may be of utility to help these patients achieve their fertility goals.

Long-term imatinib diminishes ovarian reserve and impacts embryo quality.

PURPOSE: Tyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model. METHODS: Adult female mice were treated with daily IP injections of imatinib for 4-6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts. RESULTS: Long-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells. CONCLUSION: This pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.

Patterns of utilization and outcome of ovarian conservation for young women with minimal-risk endometrial cancer.

OBJECTIVE: To profile patient characteristics associated with and outcomes of ovarian conservation at the time of hysterectomy in young women with minimal-risk endometrial cancer. METHODS: A population-based retrospective analysis of the Nationwide Inpatient Sample between 2007 and 2015 was performed. Women aged <50 with minimal-risk endometrial cancer who had ovarian conservation (n = 2314) were compared to those who had oophorectomy (n = 8191). A classification-tree model with recursive partitioning analysis was constructed to examine patterns of ovarian conservation. Propensity score matching was performed and length of stay and perioperative complications were compared. Two validation cohorts were also analyzed in a similar fashion (benign gynecologic disease and cervical cancer). RESULTS: There were nine distinct patterns of patient characteristics identified, and ovarian conservation rates ranged from 11.7% (women aged 40-49 who underwent abdominal hysterectomy at an urban teaching hospital) to 60.5% (non-obese women aged <40 with median household income ≥$63,000) (absolute difference, 48.8%, 95% confidence interval 39.9-57.7; P < 0.001). After propensity score matching, ovarian conservation was significantly associated with a decreased likelihood of hospitalization >2 days (relative risk reduction, 16.7%, P < 0.001). Rates of surgical complications were not different between the two groups (8.2% versus 8.3%, P = 0.91). In the benign gynecologic disease and cervical cancer cohorts, ovarian conservation was also associated with decreased length of hospitalization (all, P < 0.05). CONCLUSION: There is substantial variability in the utilization of ovarian conservation in young women with minimal-risk endometrial cancer based on patient, surgical, and hospital factors. Our study suggests that guidelines for ovarian conservation in this population would be helpful for improving patient selection and rates of ovarian conservation.

Characteristics and outcomes of reproductive-aged women with early-stage cervical cancer: trachelectomy vs hysterectomy.

BACKGROUND: Trachelectomy is the treatment of choice for reproductive-aged women with early-stage cervical cancer who desire future fertility. Comprehensive population-based statistics have been missing to date. OBJECTIVE: We sought to compare characteristics and survival of reproductive-aged women who underwent trachelectomy for early-stage cervical cancer to those who had hysterectomy. STUDY DESIGN: This is a retrospective observational study examining the Surveillance, Epidemiology, and End Results program from 1998 through 2014. Women <45 years of age with stage IA and IB1 (tumor size ≤2 cm) cervical cancer who underwent trachelectomy were compared to those who underwent hysterectomy. Multivariable models were used to identify clinicopathological factors associated with trachelectomy. Survival was compared between the 2 groups after propensity score matching. RESULTS: Among 6359 women, 190 (3.0%; 95% confidence interval, 2.6-3.4) underwent trachelectomy. The median age of the trachelectomy group was 31 years (interquartile range, 28-34). The proportion of women who underwent trachelectomy significantly increased during the study period (1.2% in 1998 through 2002, 3.0% in 2003 through 2008, and 4.5% in 2009 through 2014, P < .001). Younger age, nonblack race, single marital status, eastern registry area, recent disease diagnosis, nonsquamous histology, and higher stage were independent factors associated with trachelectomy use (all, adjusted P < .05). After propensity score matching, 5-year cause-specific survival (96.9% vs 96.6%; hazard ratio, 0.73; 95% confidence interval, 0.23-2.30; P = .59) and overall survival (96.1% vs 96.6%; hazard ratio, 0.76; 95% confidence interval, 0.26-2.20; P = .61) were similar between the trachelectomy group and the hysterectomy group. CONCLUSION: Our study found that there was a significant increase in the proportion of reproductive-aged women with stage IA or IB1 (≤2 cm) cervical cancer who underwent trachelectomy in recent years. Survival with trachelectomy was similar to those who had hysterectomy in this population.