Addressing Weight Bias in Reproductive Medicine: A Call to Revisit BMI Restrictions for In Vitro Fertilization.

The prevalence of obesity has doubled among reproductive age adults in the US over the past 40 years and is projected to impact half of the population by 2030. Obesity is associated with a two to threefold increase in infertility, largely due to anovulation, and is associated with a lower rate of pregnancy with ovulation induction among anovulatory women. As a result of these trends and associations, IVF care will need to be adapted to provide safe, effective and equitable access for patients with obesity. Research over the past 10 years has demonstrated safe sedation practices and effective procedure modifications for oocyte retrievals and embryos transfers in patients with obesity undergoing IVF. We encourage IVF medical directors to revisit BMI restrictions for IVF in favor of individualized patient risk assessments in order to minimize weight bias and provide timely access to safe and effective IVF care for patients with obesity and infertility.

Frozen embryo transfer outcomes decline with increasing female body mass index in female but not male factor infertility: analysis of 56,564 euploid blastocyst transfers.

OBJECTIVE: To evaluate the association of body mass index (BMI) with cycle outcomes after euploid frozen blastocyst transfer. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 56,564 first single autologous euploid frozen embryo transfers from the 2016-2019 Society for Assisted Reproductive Technology database were analyzed using BMI and using World Health Organization BMI cohorts. Subanalyses were performed on cycles among patients with a sole diagnosis of polycystic ovary syndrome (PCOS) (n = 4,626) and among patients with only a male factor (n = 10,854). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy, pregnancy loss, and live birth (LB). RESULT(S): Success rates and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for all outcomes were most favorable among those with normal BMI and progressively worsened with increasing BMI. These trends persisted among patients with PCOS for clinical pregnancy (aOR, 0.99; 95% CI, 0.98-0.997), pregnancy loss (aOR, 1.02; 95% CI, 1.01-1.04), and LB (aOR, 0.98; 95% CI, 0.97-0.99), but not among patients with a male factor only for clinical pregnancy (aOR, 1.00; 95% CI, 0.99-1.01), pregnancy loss (aOR, 1.01; 95% CI, 0.99-1.03), or LB (aOR, 0.99; 95% CI, 0.98-1.00). CONCLUSION(S): In the largest cohort to date, increasing BMI was associated with decreased pregnancy and LB and increased pregnancy loss after euploid frozen embryo transfers among the entire cohort and among patients with a sole diagnosis of PCOS; however, these results were attenuated among patients with a sole diagnosis of male factor infertility, suggesting that associated female infertility diagnoses and not BMI alone may underlie this trend.

Antimüllerian hormone level predicts ovulation in women with polycystic ovary syndrome treated with clomiphene and metformin.

OBJECTIVE: To describe the serum anti-Müllerian hormone (AMH) concentrations in a large, well-phenotyped cohort of women with polycystic ovary syndrome (PCOS) and evaluate whether AMH predicts successful ovulation induction in women treated with clomiphene and metformin. DESIGN: Secondary analysis of randomized controlled trial. SETTING: Not applicable. PATIENT(S): A total of 333 women with anovulatory infertility attributed to PCOS who participated in the double-blind randomized trial entitled the Pregnancy in Polycystic Ovary Syndrome I (PPCOS I) study (registration number, NCT00068861) who had serum samples from baseline laboratory testing available for further serum analysis were studied. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The association between the baseline AMH levels in each of the 3 treatment groups and ovulation, pregnancy, and live birth rates were assessed. RESULT(S): A total of 322 individuals had a baseline AMH concentration available, of which the mean AMH was 11.7 ± 8.3 ng/mL (range 0.1-43.0 ng/mL). With each unit (1 ng/mL) increase in baseline AMH, the odds of ovulation decreased by 10% (odds ratio, 0.90; 95% confidence interval, 0.86-0.93); this effect did not differ by treatment group. Women with a high baseline AMH concentration (>8 ng/mL) were significantly less likely to ovulate compared with those with a normal baseline AMH concentration (<4 ng/mL) (odds ratio, 0.23; 95% confidence interval, 0.05-0.68). This remained statistically significant when controlling for confounders, including age, body mass index, time in study, and Homeostatic Model Assessment for Insulin Resistance score. Ovulation occurred even at very high AMH concentrations; there was no maximum level noted at which no ovulation events occurred. Baseline AMH concentration was not associated with pregnancy or live birth rates when controlling for confounders. CONCLUSION(S): These AMH values in well-phenotyped individuals with PCOS add to the literature and will aid in identifying AMH criteria for the diagnosis of PCOS. In women with infertility and PCOS, a higher AMH concentration was associated with reduced odds of ovulation with ovulation induction with clomiphene, clomiphene + metformin, and metformin. CLINICAL TRIAL REGISTRATION NUMBER: The original trial from which this analysis is derived was entitled "Pregnancy in Polycystic Ovary Syndrome: A 30 Week Double-Blind Randomized Trial of Clomiphene Citrate, Metformin XR, and Combined Clomiphene Citrate/Metformin XR For the Treatment of Infertility in Women With Polycystic Ovary Syndrome" and was registered on ClinicalTrials.gov as number NCT00068861. The URL for the trial is https://clinicaltrials.gov/study/NCT00068861. The first subject was enrolled in November 2002.

Obesity and Miscarriage.

Obesity affects nearly 40% of reproductive-aged women and has serious implications for women's overall and reproductive health. Women with an elevated body mass index (BMI) have higher rates of anovulation and irregular menses, lower success with fertility treatment, and significantly higher rates of pregnancy complications, such as hypertension/preeclampsia, gestational diabetes, and preterm delivery. Many studies have also shown an association between obesity and early pregnancy loss. However, the causal association between BMI and miscarriage has not been elucidated, likely due to the multifactorial effects that BMI may have on early pregnancy development. In addition, BMI as an isolated variable fails to capture other relevant confounding health risk factors, such as nutrition, physical activity, and insulin resistance. In this review, we will summarize the current literature demonstrating the association between BMI and miscarriage, highlight the research that attempts to explain the association, and finally provide data on therapeutic interventions to improve reproductive outcomes in women suffering from obesity and early pregnancy loss.

Contemporary Management of the Patient with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex syndrome that affects menstrual regularity, causes hyperandrogenism, increases the risk of metabolic dysfunction and infertility, and is associated with higher rates of mental health disorders. The symptoms of PCOS are unique to each individual and will evolve throughout their reproductive lifespan and beyond. Thus, care should be personalized and provided by an appropriate team of multidisciplinary physicians and clinicians, such as dieticians and psychologists.

A new tissue-agnostic microfluidic device to model physiology and disease: the lattice platform.

To accurately phenocopy human biology in vitro, researchers have been reducing their dependence on standard, static two-dimensional (2D) cultures and instead are moving towards three-dimensional (3D) and/or multicellular culture techniques. While these culture innovations are becoming more commonplace, there is a growing body of research that illustrates the benefits and even necessity of recapitulating the dynamic flow of nutrients, gas, waste exchange and tissue interactions that occur in vivo. However, cost and engineering complexity are two main factors that hinder the adoption of these technologies and incorporation into standard laboratory workflows. We developed LATTICE, a plug-and-play microfluidic platform able to house up to eight large tissue or organ models that can be cultured individually or in an interconnected fashion. The functionality of the platform to model both healthy and diseased tissue states was demonstrated using 3D cultures of reproductive tissues including murine ovarian tissues and human fallopian tube explants (hFTE). When exogenously exposed to pathological doses of gonadotropins and androgens to mimic the endocrinology of polycystic ovarian syndrome (PCOS), subsequent ovarian follicle development, hormone production and ovulation copied key features of this endocrinopathy. Further, hFTE cilia beating decreased significantly only when experiencing continuous media exchanges. We were then able to endogenously recreate this phenotype on the platform by dynamically co-culturing the PCOS ovary and hFTE. LATTICE was designed to be customizable with flexibility in 3D culture formats and can serve as a powerful automated tool to enable the study of tissue and cellular dynamics in health and disease in all fields of research.

An Ovarian Steroid Metabolomic Pathway Analysis in Basal and Polycystic Ovary Syndrome (PCOS)-like Gonadotropin Conditions Reveals a Hyperandrogenic Phenotype Measured by Mass Spectrometry.

Prior work has demonstrated that murine ovarian explants and isolated ovarian follicles can recapitulate human-like 28-day cycles in vitro with normal patterns of estradiol and progesterone secretion in response to gonadotropin stimulation. The objective of this study was to manipulate the gonadotropin stimulation protocol to mimic polycystic ovary syndrome (PCOS) and assess the resulting changes in ovarian steroidogenesis. A secondary aim of the study was to develop a high-throughput, sensitive, and specific liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay to measure seven steroid hormones (estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone, and dihydrotestosterone) in conditioned culture media. Ovaries were harvested from 12-day-old CD-1 mice and cultured for 28 days, with ovulation induction on culture day 14. Media were supplemented human chorionic gonadotropin (hCG, a luteinizing hormone analog) and follicle stimulating hormone (FSH) at ratios of 1:0 (standard media), 1:1 (physiologic ratio), and 3:1 (PCOS-like ratio). Ovaries cultured in PCOS-like media displayed hyperandrogenism and impaired ovulation, two key features of a PCOS-like phenotype. Taken together, this first-of-its-kind presentation of hormone levels from single tissues creates a map of the enzymatic steps most acutely affected by gonadotropin dysregulation and may provide opportunities for assessing other potential insults in PCOS pathogenesis.

Maternal body mass index is not associated with increased rates of maternal embryonic aneuploidy.

OBJECTIVE: To evaluate the relationship between maternal body mass index (BMI) and embryonic aneuploidy of maternal origin. DESIGN: Retrospective cohort analysis. SETTING: University hospital-based reproductive center. PATIENTS: Maternal origin of aneuploidy was available for 453 cycles and 1,717 embryos. INTERVENTIONS: Data regarding BMI were collected before egg retrieval. Comparison groups included underweight (BMI, <18.5 kg/m2), normal weight (BMI, 18.5-24.9 kg/m2), overweight (BMI, 25-29.9 kg/m2), and obese (BMI, ≥30 kg/m2). Overall embryonic aneuploidy and maternal aneuploidy rates were compared. The aneuploidy rate was the number of embryos with either maternal or mixed (maternal and paternal) aneuploidy divided by the total number of embryos tested. MAIN OUTCOME MEASURES: Overall embryonic aneuploidy and maternal aneuploidy rates. RESULTS: Maternal aneuploidy rate was 51.5% for BMI of ≥30 kg/m2 and 39.3% for BMI of <30 kg/m2. Female age as well as several in vitro fertilization characteristics were significantly different across groups and were included in the adjusted model. Both the overall embryonic aneuploidy rate (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.11-1.59) and the maternal aneuploidy rate (OR, 1.64; 95% CI, 1.25-2.16) increased with increasing maternal BMI. However, after controlling for significant confounders, BMI did not significantly predict the rate of maternal aneuploidy (OR, 1.16; 95% CI, 0.85-1.59). CONCLUSIONS: Maternal BMI did not correlate with embryonic aneuploidy of maternal origin after adjusting for confounders.

Patients' views of delayed fertility care during the COVID-19 pandemic as a conception catastrophe: the experience of U.S. FertilityIQ users.

BACKGROUND: Assessment of psychological reactions to delays in fertility treatment have often utilized single clinic samples during the time that fertility treatments were paused. We, therefore, assessed emotional reactions to treatment cancelations due to COVID-19 in infertility patients across the United States after treatments had begun to resume. STUDY DESIGN: Cross-sectional survey emailed on 27 May 2020 and closed on 30 June 2020, to 53,600 FertilityIQ.com website users inquiring about their experience since the COVID-19 pandemic. A subset of FertilityIQ users (n = 13,490) opened the survey invitation and 1806 respondents participated in the survey (13.4% response rate). RESULTS: The majority of respondents (female, 67.4%; male, 61.7%) were 31-40 years old; most were planning to start treatment immediately (women, 42.6%; men, 44.7%) or were undergoing treatment (women, 34.9%; men, 29.8%) at the time of treatment cancelation. Patients (women, 21.1%; men 19.1%) or clinics (women, 57.7%; men, 40.4%) canceled treatment. Most clinics had resumed treatment at the time of the study (women, 90.0%; men, 73.7%). Cancelation resulted in sadness (women, 83.9%; men 86.7%) and anger (women, 45.4%; men, 36.7%); greater than half of the participants whose treatment was canceled (women: 66.8%, n = 630; men: 73.7%, n = 14) agreed with cancelations. Greater than 70% of respondents were at least somewhat concerned about reproductive chances (women, 84.7%; men, 72.4%) and exclusion of partners (women, 73.3%; men, 72.4%). Distress/concern was associated with clinic cancelation, disagreement with delays, age, diagnosis, and concern about delays and pregnancy chances (p <.05). CONCLUSIONS: Respondents were distressed/concerned about the effect of the pandemic on their fertility. Distress was highest in women with a poorer fertility prognosis, no control over treatment cancelation, and high concern about the effect of treatment delay on pregnancy chances. Emotional support, education regarding treatment delay and fertility, and efforts where possible, to include patients in decisions to delay treatment are warranted in future treatment delays.

The association of euploid miscarriage with obesity.

OBJECTIVE: To determine whether the frequency of euploid miscarriage is increased in obese women with early pregnancy loss. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: A total of 2,620 women with cytogenetic analysis results from products of conception after a pregnancy loss <20 weeks gestation from 2006-2018. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Frequency of euploid miscarriage was compared in obese (body mass index [BMI] ≥30 kg/m2) versus non-obese (BMI <30 kg/m2) patients. RESULTS: A total of 2,620 women with a mean (± standard deviation) age at time of loss of 34.9 years (± 4.9) and mean (± standard deviation) BMI of 25.3 kg/m2 (±5.5) were included in the final analysis. After adjusting for age and race, obese women were 56% more likely to have a euploid pregnancy loss compared with nonobese women (odds ratio 1.56; 95% confidence interval 1.32-1.92). Within the cohort, 63.8% of the losses were aneuploid, of which 41% were trisomies, 8% were monosomies, and 7% were polyploidies. Of the euploid losses, 50.1% were 46,XX and 49.9% were 46,XY, which suggests that the rate of maternal cell contamination was low. CONCLUSIONS: Obese women have an increased frequency of euploid miscarriage when compared with nonobese women.

Correction to: Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

The original version of this article unfortunately contained mistakes. The complete list of corrections is given below.

Effect of endometrial mechanical stimulation in an unselected population undergoing in vitro fertilization: futility analysis of a double-blind randomized controlled trial.

PURPOSE: Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population. METHODS: Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth. RESULTS: One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07). CONCLUSIONS: EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population.

Methotrexate does not affect ovarian reserve or subsequent assisted reproductive technology outcomes.

PURPOSE: The purpose of this research was to study whether methotrexate (MTX) as treatment for ectopic pregnancy (EP) impacts the future fertility of women undergoing assisted reproductive technology (ART) METHODS: In a systematic review and multi-center retrospective cohort from four academic and private fertility centers, 214 women underwent an ART cycle before and after receiving MTX as treatment for an EP. Measures of ovarian reserve and responsiveness and rates of clinical pregnancy (CP) and live birth (LB) were compared in the ART cycles prior and subsequent to MTX. RESULTS: Seven studies were identified in the systematic review, and primary data from four institutions was included in the final analysis. Women were significantly older in post-MTX cycles (35.3 vs 34.7 years). There were no differences in follicle stimulating hormone, antral follicle count, duration of stimulation, oocytes retrieved, or fertilization rate between pre- and post-MTX cycles. However, post-MTX cycles received a significantly higher total dose of gonadotropins (4206 vs 3961 IU). Overall, 42 % of women achieved a CP and 35 % achieved a LB in the post-MTX ART cycle, which is similar to national statistics. Although no factors were identified that were predictive of LB in young women, the number of oocytes retrieved in the previous ART cycle and current AFC were predictive of LB (AUC 0.76, 0.75) for the older women. CONCLUSIONS: MTX does not influence ovarian reserve, response to gonadotropin stimulation, and CP or LB rate after ART. MTX remains a safe and effective treatment option for women with asymptomatic EPs.

Inflammation and Human Ovarian Follicular Dynamics.

Inflammation is a biologic process that mediates tissue effects including vasodilation, hyperemia, edema, collagenolysis, and cell proliferation through complex immunologic pathways. In regard to the ovary, inflammation has key physiologic roles in ovarian folliculogenesis and ovulation. On the other hand, inflammatory processes are subject to underlying pathology and, if pushed, proinflammatory conditions may have a negative impact on ovarian follicular dynamics. Obesity and polycystic ovary syndrome (PCOS) serve as examples of conditions associated with chronic endogenous production of low-grade proinflammatory cytokines. Both conditions negatively impact ovarian folliculogenesis and ovulation. The pages that follow summarize the role of inflammation in normal ovarian follicular dynamics and evidence for its role in mediating the negative effects of obesity and PCOS on ovarian follicular dynamics. The review concludes with a summary supporting a role for lifestyle factors that favorably impact inflammatory process involved in obesity and PCOS to improve ovarian function.

Frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss.

OBJECTIVE: To determine whether the frequency of euploid miscarriage is increased in obese women with recurrent early pregnancy loss (REPL). DESIGN: Observational cohort study using prospectively collected data. SETTING: Academic RPL program. PATIENT(S): A total of 372 women with REPL, defined as ≥2 pregnancy losses<10 weeks, and at least one ultrasound-documented miscarriage with chromosome results. INTERVENTION(S): Body mass index (BMI) was measured at the initial consultation and at each subsequent pregnancy. Conventional cytogenetic analysis and, when indicated, microsatellite analysis and/or comparative genomic hybridization was performed. MAIN OUTCOME MEASURE(S): Frequency of euploid miscarriage in obese (BMI≥30 kg/m2) and nonobese (BMI<30 kg/m2) subjects, before and subsequent to REPL evaluation. RESULT(S): There were 578 miscarriages with chromosome results. Of the subjects, 18% were obese at the time of miscarriage. The mean maternal age at miscarriage was similar between the obese and nonobese groups. Due to the high rate of maternal cell contamination in the prior miscarriages, only subsequent miscarriages with chromosome results were included in the primary analysis. Of the 117 subsequent miscarriages, the frequency of an euploid miscarriage among obese women was 58% compared with 37% of nonobese women (relative risk=1.63; 95% confidence interval 1.08-2.47). CONCLUSION(S): Obese women with REPL have an increased frequency of euploid miscarriage, which is a known risk factor for subsequent miscarriage.