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Study Question: Does follicular flushing during assisted reproductive technologies (ART) improve the number of oocytes retrieved?Summary Answer: Follicular flushing during ART does not result in a greater number of oocytes in normal responders.What Is Known Already: Despite limited evidence supporting the use of follicular flushing, it continues to be a common procedure in many ART clinics. Prior studies have provided conflicting results regarding the routine use of flushing during oocyte retrieval.Study Design, Size, Duration: Systematic review and meta-analysis of 518 patients who participated in 6 randomized trials over 20 years.Participants/materials, Setting, Methods: Literature searches were conducted to retrieve randomized controlled trials on follicle or ovarian flushing in ART. Databases searched included PubMed, EMBASE, Web of Science and the Cochrane Database of Clinical Trials (CENTRAL). Six trials that included 518 subjects matched the inclusion criteria. Studies included were limited to trials that were published, randomized trials comparing oocyte retrieval with a single-lumen pick-up needle versus follicle flushing after direct aspiration with a multi-channel oocyte pick-up needle in ART patients.Main Results and the Role Of Chance: In each of the trials, measures of the oocyte yield (oocytes retrieved divided by follicles aspirated), total oocytes retrieved, fertilization or pregnancy were not different when comparing direct aspiration with follicle flushing. Four trials reported a higher operative time with follicle flushing. Results of the meta-analysis indicated no significant differences in the oocytes retrieved [weighted mean difference: 0.07, 95% confidence interval (CI): -0.13 to 0.29] or the oocyte yield (odds ratio: 1.06, 95% CI: 0.95-1.18) between the non-flushing and flushing groups.Limitations, Reasons For Caution: All trials featured an open label design and the majority of patients in this meta-analysis were normal responders. The applications of these results to poor responders, patients undergoing natural cycle ART or minimal stimulation ART should be made with caution.Wider Implications Of the Findings: Follicle flushing does not improve ART outcomes in normal-responding patients and should not be performed. This meta-analysis should solidify this recommendation as it includes the largest trial published on the subject and is consistent with a recently published Cochrane review.Study Funding/competing Interest(s): This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD. The authors have no competing interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

An uncontrolled diabetic state during pregnancy results in serious medical complications to the fetus, occurring both in late gestation (ie hyaline membrane disease, hypoglycaemia) and in early gestation (ie abnormal organogenesis leading to malformations). Whether there are also deleterious effects of diabetes mellitus seen preconceptually, such as anovulation, or in early pregnancy, such as an increased rate of early fetal loss, is controversial. This report examines evidence that the diabetes may contribute to abnormalities in development beginning at these earlier stages of the developmental process. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the cost-effectiveness of in vitro fertilization with preimplantation genetic testing for monogenic disease (IVF + PGT-M) in the conception of a nonsickle cell disease (non-SCD) individual compared with standard of care treatment for a naturally conceived, sickle cell disease (SCD)-affected individual., Design: A Markov simulation model was constructed to evaluate a one-time IVF + PGT-M treatment compared with the lifetime standard of care costs of treatment for an individual potentially born with SCD. Using an annual discount rate of 3% for cost and outcome measures, quality-adjusted life years were constructed from utility weights and life expectancy values and then used as the effectiveness measurement. An incremental cost-effectiveness ratio was calculated for both treatment arms, and a willingness-to-pay threshold of $50,000 per quality-adjusted life year was assumed., Setting: Tertiary care or university medical center., Patients: A hypothetical cohort of 10,000 patients was analzyed over a lifetime horizon using yearly cycles., Interventions: In vitro fertilization with preimplantation genetic testing for monogenic disease use in conception of a non-SCD individual., Main Outcome Measures: The primary outcomes of interest were the incremental cost and effectiveness of an IVF+PGT-M conception compared with the SOC treatment of an SCD-affected individual., Results: In vitro fertilization with preimplantation genetic testing for monogenic disease was the optimal strategy in 93.17% of the iterations. An incremental savings of $137,594 was demonstrated with a gain of 1.96 QALYs and 3.69 life years over a lifetime. Sensitivity analysis demonstrated that SOC treatment never met equivalent cost-effectiveness., Conclusions: Our model demonstrates that IVF + PGT-M for selection against SCD, compared with lifetime SOC treatment for those affected, is the most cost-effective strategy within the United States healthcare sector.

Steroid-producing cells contain key cytochrome P450 enzymes, such as side-chain cleavage (P450-SCC) and 17α-hydroxylase (17α-OH). They are required for steroid hormone synthesis and considered antigens associated with Addison's disease and autoimmune primary ovarian insufficiency (POI). We studied an animal model for human autoimmune POI in mice with autoimmune oophoritis induced by neonatal thymectomy performed at day 3 (TX3). We previously identified an oocyte-specific protein as a major antigen inciting autoimmune oophoritis in mice. In this study, we characterized ovarian steroid-producing cell antigens. Using indirect immunofluorescence staining, we tested immune reactions in mouse ovarian and adrenal tissue sections with sera from TX3 female mice. More than half of the TX3 mice (8 of 15) produced antibodies reacting with both ovarian and adrenal steroid-producing cells, including some that reacted to oocytes as well. We produced recombinant proteins for the three key steroidogenic enzymes 17α-OH, P450-SSC, and 3β-hydroxysteroid dehydrogenase (3β-HSD) and tested their immune reactions with individual mouse sera. By immunoblotting, all mouse sera that reacted with the steroid-producing cells (n = 8) were shown to react with the P450-SCC, but not with the 17α-OH or 3β-HSD recombinant proteins. The sham-operated mouse sera and TX3 mouse sera negative for steroid-producing cells did not react with the P450-SCC recombinant protein. Our findings indicate that the P450-SCC is a specific and unique major antigen within the ovarian steroid-producing cells. Given their similarity of predicted antigenicity, we assume that P450-SCC acts in human autoimmune POI as it does in mouse autoimmune oophoritis., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: This study aimed to examine whether prenatal low-dose aspirin (LDA) therapy affects risk of cesarean versus vaginal delivery., Study Design: This study is a secondary analysis of the randomized clinical effects of aspirin in gestation and reproduction (EAGeR) trial. Women received 81-mg daily aspirin or placebo from preconception to 36 weeks of gestation. Mode of delivery and obstetric complications were abstracted from records. Log-binomial regression models estimated relative risk (RR) of cesarean versus vaginal delivery. Data were analyzed among the total preconception cohort, as well as restricted to women who had a live birth., Results: Among 1,228 women, 597 had a live birth. In the intent-to-treat analysis, preconception-initiated LDA was not associated with risk of cesarean (RR = 1.02; 95% confidence interval [CI]: 0.98-1.07) compared with placebo. Findings were similar in just women with a live birth and when accounting prior cesarean delivery and parity., Conclusion: Preconception-initiated daily LDA was not associated with mode of delivery among women with one to two prior losses., Key Points: · Aspirin was not associated with risk of cesarean section.. · Aspirin was not associated with mode of delivery.. · No increased risk of bleeding with use of aspirin.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2-3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases., Design: A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial., Setting: Four US academic medical centers., Patients: A total of 1,194 healthy women aged 18-40 years with a history of one or two pregnancy losses attempting spontaneous conception were observed for up to six cycles while attempting pregnancy and throughout pregnancy if they conceived., Interventions: Not applicable., Main Outcome Measures: Time to pregnancy, human chorionic gonadotropin pregnancy, clinical pregnancy, pregnancy loss, and live birth., Results: Although increasing preconception A1c level was associated with reduced fecundability (fecundability odds ratio [FOR] per unit increase in A1c 0.74; 95% confidence interval [CI] 0.57, 0.96) in unadjusted models and models adjusted for age, race, smoking and treatment arm (FOR 0.79; 95% CI 0.60, 1.04), results were attenuated after further adjustment for body mass index (FOR 0.91; 95% CI 0.68, 1.21). Preconception A1c levels among women without diagnosed diabetes were not associated with live birth or pregnancy loss., Conclusionss: Among healthy women without diagnosed diabetes, we observed no association of A1c with live birth or pregnancy loss. The association between A1c and fecundability was influenced by body mass index, a strong risk factor for both diabetes and infertility. These data support current recommendations that preconception A1c screening should be reserved for patients with risk factors for diabetes., Clinical Trial Registration Number: ClinicalTrials.gov: NCT00467363., (© 2022 Published by Elsevier Inc. on behalf of American Society for Reproductive Medicine.)

Objective: To examine the outcomes of in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) in couples in whom the male partner has a karyotypic abnormality or Y chromosome microdeletion (YCM)., Design: Retrospective cohort., Setting: Single infertility center., Patients: Couples treated with IVF-ICSI from January 2014 to April 2019 with male factor infertility, sperm concentration of <5 × 10 6 sperm/mL, and results for karyotype and/or YCM panel., Interventions: In vitro fertilization with intracytoplasmic sperm injection., Main Outcome Measures: In couples in whom the male partner had a karyotypic abnormality or YCM: live birth rate/ongoing pregnancy rate, lack of partner sperm for fertilization, complete fertilization failure, cycle cancellation, and no embryos for transfer. The prevalence of karyotypic abnormalities and YCMs in the IVF population was calculated., Results: The live birth rate/ongoing pregnancy rate for those using partner sperm was 51.4% per transfer. However, 8.5% of cycles that intended to use partner sperm and 22.2% of cycles that intended to use surgically extracted partner sperm had no sperm available. Of cycles that created embryos with partner sperm, 12.5% had no embryo to transfer. The prevalence of karyotypic abnormalities was similar to previous reports (6.0%), while that of YCMs was lower (4.4%). Azoospermia factor a and b mutations were not represented in this population., Conclusions: It is reasonable to attempt IVF-ICSI with partner sperm in patients with genetic causes of male infertility. Patients should be counseled regarding the possibility of no sperm being available from the male partner, poor/failed fertilization, and genetic implications for potential offspring. Contingency plans, including IVF with donor sperm backup or oocyte cryopreservation, need to be made for these scenarios.

We hypothesized that the creation of a 3-dimensional ovarian follicle, with embedded granulosa and theca cells, would better mimic the environment necessary to support early oocytes, both structurally and hormonally. Using a microfluidic system with controlled flow rates, 3-dimensional two-layer (core and shell) capsules were created. The core consists of murine granulosa cells in 0.8 mg/mL collagen + 0.05% alginate, while the shell is composed of murine theca cells suspended in 2% alginate. Somatic cell viability tests and hormonal assessments (estradiol, progesterone, and androstenedione) were performed on days 1, 6, 13, 20, and 27. Confocal microscopy confirmed appropriate compartmentalization of fluorescently-labeled murine granulosa cells to the inner capsule and theca cells to the outer shell. Greater than 78% of cells present in capsules were alive up to 27 days after collection. Artificially constructed ovarian follicles exhibited intact endocrine function as evidenced by the production of estradiol, progesterone, and androstenedione. Oocytes from primary and early secondary follicles were successfully encapsulated, which maintained size and cellular compartmentalization. This novel microfluidic system successfully encapsulated oocytes from primary and secondary follicles, recapitulating the two-compartment system necessary for the development of the mammalian oocyte. Importantly, this microfluidic system can be easily adapted for sterile, high throughput applications.

Polycystic ovarian syndrome and its associated endocrine abnormalities comprise one of the most common metabolic spectrum disorders within the human race. Because of the variance in phenotypic expression among individuals and within family lineages, attention has been turned to genetic and epigenetic changes in which the root cause of the disorder may lie. Further understanding of DNA/histone methylation and microRNA patterns may help to improve the accuracy of diagnosis and lead to future treatment options., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Polycystic ovary syndrome is a common endocrinopathy that has been associated with many medical conditions across nearly every specialty. This chapter reviews the current understanding of polycystic ovary syndrome and associated medical conditions., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare clinical and ongoing pregnancy after natural cycle (NC) intrauterine insemination (IUI) versus ovarian stimulation (OS) IUI in ovulatory women undergoing therapeutic donor insemination (TDI)., Design: Retrospective cohort., Setting: Single infertility center., Patient(s): A total of 76,643 IUI cycles in patients treated with intrauterine insemination were examined. Women undergoing TDI in the absence of diagnosed female factor infertility were included., Intervention(s): NC TDI or OS TDI with either clomiphene citrate or letrozole., Main Outcome Measure(s): Clinical and ongoing pregnancies were analyzed by generalized estimating equations adjusting for age, body mass index, total motile sperm at time of insemination and cycle number. Ongoing multiple gestations were examined as a secondary outcome., Result(s): Six thousand one hundred ninety-two TDI cycles from 2,343 patients (711 patients without repeated IUI cycles) met inclusion criteria and were available for analysis (3,837 NC and 2,355 OS). There was no difference in mean age between the two groups (NC, 34.2 years vs. OS, 34.3 years). Probability of clinical and ongoing pregnancy was higher in the OS cohort compared with the NC cohort (OS, 22.4% vs. NC, 18.7% and OS, 15.4% vs. NC, 14.9%, respectively). However, OS significantly increased ongoing multiple gestations (OS, 10.8% vs. NC, 2.4%)., Conclusion(s): Ovarian stimulation in TDI cycles resulted in a <4% increase in clinical and <1% increase in ongoing pregnancy, and more than fourfold increase in ongoing multiple gestations. Natural cycle IUI should be considered as a first-line treatment for ovulatory women who need donor insemination., (Published by Elsevier Inc.)

Menstrual irregularities due to anovulation or severe oligoovulation are a key feature of polycystic ovary syndrome for many women. First-line intervention should entail dietary and lifestyle modifications for overweight or obese polycystic ovary syndrome women. For women not seeking fertility, combination low-dose hormonal contraception are the most effective and first-line choice for regulating menstrual cycles. This option, as well as progestin-only options, have the important added benefit of reducing risks of endometrial hyperplasia and cancer. Metformin is an appropriate medical option to improve ovulation rates for women who cannot take combined hormone contraception or whom are attempting conception., (Copyright © 2021 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Lifestyle modification is widely considered to be the cornerstone of polycystic ovary syndrome (PCOS) treatment. However, 45% of women with PCOS have reported that they have never been provided information about lifestyle management. This highlights a significant gap in knowledge and is reflective of the lack of evidence-based guidance for lifestyle modification. While more detailed and comprehensive studies are being performed, it is necessary for health professionals to develop effective action plans utilizing the available evidence. This chapter aims to provide a comprehensive review of the current data regarding the impact of lifestyle modifications on the disease course of PCOS., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Polycystic ovarian syndrome (PCOS) is a common endocrinopathy with many clinical manifestations. The effects on women's lives start at puberty and can last throughout her lifetime. Women frequently experience anovulatory menstrual cycles, infertility, hirsutism, obesity and increased risk of diabetes mellitus, hypertension, lipid abnormalities, and metabolic syndrome. PCOS is a heterogenous disorder, and a diagnosis of exclusion. In general, women afflicted will have menstrual irregularities, ultrasound findings of abnormal ovarian size and morphology, and clinical or laboratory evidence of hyperandrogenism. This chapter reviews the current understanding of PCOS, associated metabolic abnormalities, and diagnosis in reproductive-aged women, as well as adolescents., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To determine whether subfertility in patients with endometriosis is due to impaired endometrial receptivity by comparing pregnancy and live-birth outcomes in women with endometriosis versus two control groups without suspected endometrial factors: noninfertile patients who underwent assisted reproduction to test embryos for a single-gene disorder and couples with isolated male factor infertility., Design: Retrospective cohort., Setting: Multicenter private practice., Patient(s): All patients aged 24 to 44 years undergoing euploid frozen blastocysts transfer from January 2016 through March 2018., Intervention(s): None., Main Outcome Measure(s): Live birth, clinical pregnancies, pregnancy losses, and aneuploid rates in preimplantation genetic testing for aneuploidy cycles., Result(s): The analysis included 459 euploid frozen embryo transfer cycles among 328 unique patients. There were no differences in clinical pregnancy, pregnancy loss, or live-birth rates in patients with endometriosis compared with both control groups. The aneuploidy rates were lowest in the preimplantation genetic testing for monogenic disorders cohort, and the endometriosis patients had aneuploidy rates similar to those of the male factor infertility patients., Conclusion(s): It is unclear whether endometriosis primarily affects in vitro fertilization outcomes via oocyte quality or the endometrium. By controlling for embryo quality using euploid frozen embryo transfer cycles, we found no difference in pregnancy outcomes in patients with endometriosis compared with patients undergoing treatment for male factor infertility and noninfertile patients., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To characterize variation in circulating vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase-1 (sFLT-1), across the menstrual cycle in normal ovulating women in relation to reproductive hormones to identify the utility of VEGF and sFLT-1 as peripheral biomarkers of endometrial remodeling., Methods: Ninety-six healthy, regularly menstruating ovulatory women, aged 18-44 years, enrolled in the BioCycle Study, a prospective cohort study at a U.S. academic research center. Vascular endothelial growth factor and sFLT-1 were measured in concurrently collected plasma, serum, and urine up to eight times across a single cycle. Reproductive hormones were measured in serum. Mean concentrations of VEGF and sFLT-1 were compared across phases of the cycle, and correlations between specimen types were calculated. Harmonic models estimated associations between VEGF and sFLT-1 and characteristics of hormonal patterns., Results: No variation in VEGF or sFLT-1 levels were detected over the menstrual cycle. Median (25th percentile, 75th percentile) concentrations of VEGF during the menstrual cycle were 31.2 pg/mL (24.1, 56.9) in plasma, 194.1 pg/mL (125.4, 350.2) in serum, and 101.7 pg/mL (64.2, 165.8) in urine. Plasma and serum measures were consistently correlated, whereas urinary measures were not. Vascular endothelial growth factor was not consistently associated with reproductive hormone concentrations, although sFLT-1 was associated with higher mean and amplitude of estradiol., Conclusion: Circulating VEGF and sFLT-1 did not vary across the menstrual cycle and therefore are unlikely to be useful peripheral biomarkers of endometrial changes across the menstrual cycle. For studies measuring circulating VEGF for other reasons, plasma may be the preferred medium and timing to menstrual cycle phase need not be considered for reproductive-age women., Competing Interests: Financial Disclosure Robert M. Silver reports that money was paid to his institution from the NIH and he received funds from Gestavision. Micah J. Hill reports a past role on the Research Advisory Board of Ohana Biosciences, unrelated to present research. The other authors did not report any potential conflicts of interest., (Copyright © 2020 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Anti-müllerian hormone (AMH) is an established marker of ovarian reserve that decreases with age. Though the pool of ovarian follicles is established during fetal development, impacts of in utero exposures on AMH are uncertain. Thus, we sought to evaluate associations of in utero exposures with AMH of adult daughters with a prospective cohort study of adult daughters at university medical centers. Women noted their mother's reported use of diethylstilbestrol (DES), vitamins, tobacco, alcohol, and caffeine during pregnancy, and their mother's occupation during pregnancy. All participants were reproductive age women (18-40 years) enrolled in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Serum AMH concentrations were measured at baseline prior to conception and categorized using clinical guidelines. Multinomial regression models estimated associations between each exposure and high (>3.5 ng/mL) and low (<1.0 ng/mL) versus normal AMH (1.0-3.5 ng/mL), adjusting for participant's age, mother's age, mother's history of fertility treatment, and mother's use of vitamins. In 1202 women with available data, maternal caffeine use was associated with an increased risk of low AMH, compared to normal (relative risk [RR] 1.90, 95 % confidence interval [CI] 1.09, 3.30). Vitamins were associated with an increased risk of high AMH compared to normal (RR 1.93, 95 % CI 1.24, 3.00). Other exposures were not associated with AMH concentrations in offspring. Maternal caffeine and vitamin use during pregnancy may be associated with ovarian reserve in adult offspring, highlighting the potential importance of pregnancy lifestyle on the reproductive health of daughters., (Published by Elsevier Inc.)

Objective: To estimate the effect of daily 81 mg low-dose aspirin (LDA) on menstrual cycle length and hormone profiles., Design: Secondary analysis of a trial evaluating the effect of daily LDA or placebo on live birth among women with one or two previous pregnancy losses., Setting: University medical centers., Patient(s): A total of 915 regularly menstruating women who had at least one menstrual cycle (3,190 total cycles) in which pregnancy did not occur., Intervention(s): Randomized allocation to LDA versus placebo., Main Outcome Measure(s): Menstrual cycle length and follicular and luteal phases were measured. Urinary pregnanediol glucuronide, follicle-stimulating hormone, luteinizing hormone, and estrone-3-glucuronide were assessed up to six times during the first two cycles. Generalized estimating equations estimated relative risk of short (<25th percentile: <27 days) and long (>75th percentile: ≥32 days) versus normal cycle length. Linear mixed models estimated mean hormone level differences with weights used to account for multiple cycles contributed per participant., Result(s): There were no significant differences in total menstrual cycle, follicular phase, or luteal phase length between LDA and placebo groups. LDA posed no greater risk of having a short versus normal-length or long versus normal-length follicular phase, or having a short versus normal-length or long versus normal-length luteal phase. There were no significant differences in hormone levels across the menstrual cycle between the LDA and placebo groups., Conclusion(s): Daily LDA use did not result in any changes to menstrual cycle, follicular phase, or luteal phase length or hormone levels across the menstrual cycle compared with placebo., Clinical Trial Registration Number: NCT00467363., (Published by Elsevier Inc.)

Science, propelled forward by noble aspirations and, at times, human hubris, has the capacity to affect lives and alter the world in unanticipated ways. Even seemingly minor discoveries have repeatedly proven to have far reaching implications that experts within their respective fields could not have predicted. Nuclear technology is both a source of energy and a potential means of annihilation. The internet has both seamlessly connected the world but has also opened society to the misuse and manipulation of information. Both exemplify how new technologies have the potential for positive and negative outcomes that often go beyond what was initially intended. This is not a fault of science and innovation but rather an inherent occupational hazard as new discoveries exist within a gray zone between ignorance and comprehension. These gaps in our knowledge can only be filled over time as our knowledge expands. Innovations that were once seen as fringe, over time, become mainstream and that which was once revolutionary becomes a part of everyday life. Occasionally, a scientific advancement comes along that challenges societal norms and causes us to question what is feasible, acceptable, and ethical. Nowhere in the twenty-first century has this been more evident than within the fields of genetics and genetic engineering. As we gain a deeper understanding of the source code of life, from individual base pairs to epigenetic influences, the implications of new discoveries will go far beyond curing genetic diseases, and the possibilities will be endless. Reproductive endocrinology and infertility (REI) specialists utilize many tools including expanded carrier screening, preimplantation genetic testing, and embryo selection and have become some of the experts at the forefront of the ongoing genetic revolution. Now more than ever, there is a need for REIs to be trained in the fundamentals of genetics, exposed to novel gene sequencing and editing techniques, and involved in the coming ethical discussions in order to be prepared for the genetically engineered future.

The use of assisted reproduction among women in relationships with other women has increased in the United States over the past decade as a result of increased legal access and social acceptance. Despite this shift, limited studies currently exist to guide optimal fertility care for this growing patient population of women seeking assisted reproduction. In this Commentary, assisted reproduction will be meant to include ovulation induction, intrauterine insemination (IUI), and in vitro fertilization (IVF). Conflicting studies suggest that self-identified lesbian women may demonstrate an increased prevalence of polycystic ovarian syndrome. Most available studies find that a woman's sexual orientation does not affect the outcome of fertility treatment. Self-identified lesbian women undergoing donor sperm IUI and IVF have similar pregnancy and live-birth rates as heterosexual women. Better evidence regarding patient demographics and comorbidities, underlying etiologies of subfertility, and assisted reproductive outcomes among women building families with other women is needed to optimize care.

Objective: To determine if transferring a lower-quality embryo with a good-quality blastocyst is detrimental, given that evidence suggests that embryos can signal the endometrium and that embryo quality may affect negatively endometrial receptivity., Design: Retrospective cohort study., Setting: In vitro fertilization center., Intervention(s): Single- versus double-embryo transfer., Patient(s): Patients with a double-embryo transfer of a good-quality blastocyst plus a lower-quality blastocyst, early blastocyst, or morula were compared with patients receiving a single good-quality blastocyst., Main Outcome Measure(s): Live birth, multiple gestation., Result(s): In this study, 4,640 in vitro fertilization cycles were analyzed. In none of the analyses did transferring a second lower-quality embryo negatively affect birth rate. In the primary analysis, transferring a second lower-quality embryo increased live birth by 10% and the multiple birth rate by 15%. The addition of a fair- or poor-quality blastocyst or early blastocyst markedly increased the twin birth rate by 22%-27% with an 8%-12% increase in live birth. The addition of a morula did not increase live birth but resulted in 12% more multiples. In women younger than 38 years, adding a lower-quality embryo increased the birth rate by 7% but resulted in 18% increase in multiples. In women 38 years or older, adding a lower-quality embryo increased the live birth rate by 9% with a 15% increase in multiples., Conclusion(s): Addition of a lower-quality embryo does not have a detrimental effect on a good-quality blastocyst and results in a small increase in live births. However, this is at the expense of a marked increase in the likelihood of multiple gestations., (Published by Elsevier Inc.)

Objective: To estimate the risk of a multiple gestation pregnancy in ovarian stimulation intrauterine insemination (IUI) cycles when stratified by patient age and mature follicle number., Methods: We conducted a retrospective cohort study at a single private practice fertility center of IUI cycles performed from 2004 to 2017. Intervention(s) were ovarian stimulation and IUI if postwash total motile sperm count was more than 8 million. Mature follicles were defined as 14 mm or more as measured on the day of ovulation trigger. Main outcomes and measures were rates of clinical pregnancy and multiple gestation., Results: We identified 24,649 women who underwent a total of 50,473 IUI cycles. Increasing the number of mature follicles from one to five at the time of IUI in women younger than age 38 years increased the clinical pregnancy rate from 14.6% to 21.9% (adjusted odds ratio [aOR] 1.6, 95% CI 1.4-1.9), almost entirely from a marked increase in multiple gestations per cycle from 0.6% to 6.5% (aOR 9.9, 95% CI 6.9-14.2). There was little increase in singleton pregnancies per IUI (14.1-16.4%) regardless of mature follicle number. The per-pregnancy twin and higher-order multiple gestation risk significantly increased (3.9-23.3%, P<.01 and 0.2-10.6%, P<.01, respectively) when comparing one with five mature follicles present at the time of IUI (P<.01). In women younger than age 38 years with more than three follicles present, more than one quarter of all pregnancies were multiples. Similar findings occurred in women aged 38-40 years. In women older than age 40 years, up to four follicles tripled the odds of pregnancy (aOR 3.1, 95% CI 2.1-4.5) while maintaining a less than 12% risk of multiple gestation per pregnancy and a 1.0% absolute risk of multiples., Conclusion: Caution should be used in proceeding with IUI after ovarian stimulation when there are more than two mature follicles in women younger than age 40 years owing to the substantially increased risk of multiple gestation without an improved chance of singleton clinical pregnancy.

With improvement in cancer therapies, there has been an increasing emphasis on survivorship, including options for fertility preservation. Fertility preservation is the process of either protecting or saving gametes or reproductive tissues for potential future procreation. Methods and outcomes of fertility preservation have similarly been rapidly advancing. Before initiation of gonadotoxic therapy, health care providers must consider future fertility of patients and provide options for fertility preservation. Nonetheless, the cost of fertility preservation can be prohibitory. Depending on a patient's state of residence, insurance may be mandated to cover, or offer to cover, the cost of fertility preservation. State legislation continues to change; however, legislation at the federal level has been proposed to make this coverage more cohesive. This commentary reviews current state legislation regarding mandates to cover the cost of fertility preservation for patients at risk for iatrogenic infertility and outlines the importance of developing federal legislation to improve patient access to care.

Objective: To compare live birth and multiple gestation in patients diagnosed with unexplained infertility undergoing intrauterine insemination after ovarian stimulation (OS-IUI) with oral medications versus gonadotropins., Design: Systemic review and meta-analysis., Setting: Not applicable., Patient(s): Patients undergoing OS-IUI for treatment of unexplained infertility., Intervention(s): Clomiphene, letrozole, or gonadotropins for OS-IUI., Main Outcome Measure(s): Live birth and multiple gestation., Result(s): Eight total trials were identified that met the inclusion criteria and comprised 2,989 patients undergoing 6,590 cycles. One study reported a significant increase in both live births and multiple gestations with the use of gonadotropins, two studies found an increased likelihood of live birth with the use of gonadotropins, and two studies found an increased risk of twins with gonadotropins. The relative risk of live birth in subjects receiving gonadotropins was 1.09. The relative risk of multiple gestation in subjects receiving gonadotropins was 1.06. Clinical pregnancy was higher in protocols with lax cancellation policies or higher gonadotropin doses, with subsequent increased relative risks of multiple gestations of 1.20 and 1.15, respectively. Singleton births per subject were similar between the two groups. The results did not change in per-protocol, per cycle, or fixed-effect model sensitivity analyses., Conclusion(s): For every birth gained with the use of gonadotropins, a similar increased risk of multiple gestation occurs. The randomized data do not support the use of gonadotropin for OS-IUI in women with unexplained infertility., Clinical Trial Registration Number: Prospero CRD4201911998., (Published by Elsevier Inc.)

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (T reg ) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4 + CD25 + FoxP3 + T regs from donors improves litter sizes in DEREG mice with depleted T regs . Our hypothesis is that DEREG mice treated with a single dose of DT will deplete T regs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase T regs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of T regs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of T regs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low T reg .

Research Question: How does oocyte cohort size affect IVF treatment outcomes?, Design: Retrospective cohort analysis of 10,193 fresh autologous oocyte retrievals among good-prognosis patients <35 years from 2009 to 2015. The primary outcome was live birth from a fresh transfer; secondary outcomes included cumulative live birth potential from the retrieved cohort and frequency of severe ovarian hyperstimulation syndrome (OHSS)., Results: Live birth per fresh transfer increased as the oocyte cohort increased up to 11-15 oocytes, then plateaued. Beyond 15 oocytes, live birth rates from fresh transfer did not decrease, even at the highest oocyte yields. When accounting for the availability of cryopreserved high-quality supernumerary blastocysts, the cumulative number of potential live births per retrieval continued to increase as oocyte yield increased. Rates of severe OHSS increased rapidly with increasing cohort size above 7-10 oocytes when final oocyte maturation was triggered with human chorionic gonadotrophin (HCG), up to nearly 7% of HCG-triggered retrievals of >25 oocytes, but when triggered with gonadotrophin-releasing hormone (GnRH) agonist the severe OHSS rate remained relatively low and stable at approximately 1% even among retrievals of the largest oocyte cohorts., Conclusions: Live birth rates per fresh embryo transfer are highest among cycles with retrieval of 11 or more oocytes. Larger cohorts are not associated with any decline in fresh transfer birth rates. Total potential births per retrieval continue to increase as the number of retrieved oocytes increases. Rates of OHSS remain relatively low after retrieval of large oocyte cohorts if final maturation is triggered with GnRH agonist rather than HCG., (Published by Elsevier Ltd.)

Research Question: Is ovulation suppression with progestins, requiring a freeze-all approach and subsequent frozen embryo transfer resulting from progestenic endometrial changes, cost-effective compared with gonadotropin releasing hormone analogues (GnRH) during assisted reproduction cycles., Design: Cost-effectiveness analysis derived from a PubMed literature search of average US costs of GnRH agonist and antagonist IVF cycles., Results: In all fresh IVF cycle models, progestin cycles were more expensive owing to the additional costs of increased gonadotropin use, embryo freezing and subsequent frozen embryo transfer (FET). The average cost per live birth with progestins ($32,466-$56,194) was higher than fresh IVF cycles with short (flare) GnRH agonist ($4,447-$12,797 higher) and GnRH antagonist ($1,542-$9,893 higher). When analyzing an initial embryo transfer plus additional FET in patients not initially pregnant, progestin cycles were still more expensive per live birth compared with conventional protocols. When planned freeze only cycles were analyzed, progestins became more cost-effective per live birth compared with antagonist cycles ($2,079 lower) but remained more expensive than short agonist cycles ($823 more expensive)., Conclusions: Ovulation inhibition in IVF using progestins requires a freeze-only approach of embryos, and thus progestin use was not cost-effective compared with fresh embryo transfer cycles. Progestins, however, may be cost-effective compared with GnRH antagonist in planned freeze only cycles such as in preimplantation genetic testing or fertility preservation., (Published by Elsevier Ltd.)

Objective: To evaluate methodologies to establish abnormal progesterone (P) levels on the day of trigger for recommending freeze only cycles., Design: Threshold analysis and cost analysis., Setting: Private ART practice., Patient(s): Fresh autologous ART., Interventions(s): None., Main Outcome Measure(s): Live birth., Result(s): Fourteen established statistical methodologies for generating clinical thresholds were evaluated. These methods were applied to 7,608 fresh ART transfer cycles to generate various P thresholds which ranged widely from 0.4 to 3.0 ng/mL. Lower thresholds ranged from 0.4 to 1 ng/mL and classified the majority of cycles as abnormal as well as required very large number needed to treat (NNT) to increase one live birth. Frozen embryo transfer was cost-effective when P was ≥1.5 ng/mL, with 12% of the population having an abnormal test result and an NNT of 13. Statistical and cost-effective thresholds clustered between 1.5 and 2.0 ng/mL., Conclusion(s): Statistically significant thresholds for P were demonstrated as low as 0.4 ng/mL but resulted in a very large NNT to increase one live birth. A clinical benefit to a freeze-only approach was demonstrated above P thresholds ranging from 1.5 to 2.0 ng/dL. At these thresholds, elevated P has a demonstrable and clinically significant negative effect and captures a smaller percentage of the patient population at higher risk for fresh transfer failure, thus making freeze-only a cost-effective option., (Copyright © 2018 American Society for Reproductive Medicine. All rights reserved.)