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.

Resolution of Hyperandrogenism, Insulin Resistance and Acanthosis Nigricans (HAIR-AN) Syndrome After Sleeve Gastrectomy.

Hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) is a severe subphenotype of polycystic ovary syndrome (PCOS). A 32-year-old woman with HAIR-AN and class 3 obesity presented to an endocrinology clinic after she failed sequential trials of treatment with metformin, estrogen-progestin OCP, spironolactone, leuprolide, and a levonorgestrel intrauterine device. She complained of hirsutism and acanthosis nigricans severely affecting her quality of life and had secondary amenorrhea. Laboratory evaluation showed extremely elevated testosterone and insulin levels and elevated glycated hemoglobin A1c (HbA1c). She underwent laparoscopic sleeve gastrectomy. One year after the surgery, she lost 32% of her body weight and reported normalization of menses, dramatic improvement in hirsutism, and near-resolution of acanthosis nigricans. Her testosterone, insulin, and HbA1c normalized. This case demonstrates the central role of hyperinsulinemia in HAIR-AN and suggests that aggressive measures to normalize insulin resistance and reduce excess weight can effectively treat the reproductive abnormalities in this syndrome. We suggest that bariatric surgery can be an effective cure for HAIR-AN syndrome and that PCOS, including HAIR-AN, should be considered a comorbidity of obesity during evaluation of bariatric surgery candidates.

Weight Bias in Reproductive Medicine: A Curiously Unexplored Frontier.

Obesity has been associated with a multitude of medical comorbidities, infertility, and adverse obstetric outcomes. Weight stigma and weight bias pervade not only the medical field but also education, employment, and activities of daily living. The experience of weight stigma has been shown to adversely impact not only the mental health of individuals with overweight or obesity but also worsen obesogenic behaviors, and medical comorbidities. This review frames the rise of weight stigma and weight bias within the context of the "obesity epidemic" and explores its associations with infertility and decreased access to health care and its subsequent impact on the lives of individuals. Furthermore, it explores the concepts of intrinsic and extrinsic weight stigma/bias and highlights the need for further examination and research into the impact of these factors on access to reproductive medicine and subsequent outcomes.

Moderate and increased physical activity is not detrimental to live birth rates among women with unexplained infertility and obesity.

Objective: To determine if moderate physical activity is associated with live birth rates in women with unexplained infertility and obesity. Design: Secondary analysis of the Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial. Setting: US fertility centers, 2015-2019. Patients: A total of 379 women participated in Improving Reproductive Fitness through Pretreatment with Lifestyle Modification in Obese Women with Unexplained Infertility trial, a lifestyle modification program with increased physical activity (phase I, 16 weeks) and up to three cycles of clomiphene citrate treatment and intrauterine insemination (phase II). Interventions: Participants were instructed to add 500 steps/day weekly until a maximum of 10,000 steps/day was reached and maintained. Participants were stratified as active (top third, N = 125) and less active (lower third, N = 125) on the basis of the average number of steps per day recorded using a FitBit activity tracker. Main Outcome Measures: Live birth rate. Results: Active participants were more physically active at the time of enrollment than less active participants (average baseline steps per day, 8,708 [7,079-10,000] vs. 4,695 [3,844-5,811]; P ≤ 0.001) and were more likely to reach 10,000 steps/day than less active participants (average steps per day, 10,526 [9,481-11,810] vs. 6,442 [4,644-7,747]; P ≤ 0.001), although both groups increased their average steps per day by a similar amount (1,818 vs.1,747; P = 0.57). There was no difference in live birth rates (24/125 [19.2%] vs. 25/125 [20%]; P = 0.87) between active and less active participants nor were there differences in clinical pregnancy rates (P = 0.45) or miscarriage rates (P = 0.49) between the two groups. Conclusions: Active participants were more likely to achieve the physical activity goal, although this was not associated with benefit or harm with respect to live birth. Clinical Trial Registration Number: ClinicalTrials.gov (NCT02432209), first posted: May 4, 2015.

Recurrence risk and risk factors for monozygotic twin and triplet birth in over 65,000 single-embryo transfers.

PURPOSE: To determine the recurrence risk and risk factors for monozygotic splitting after elective single-embryo transfers (eSET). METHODS: A retrospective cohort study was performed investigating 65,664 eSET cycles that resulted in a clinical pregnancy as reported in the Society for Assisted Reproductive Technology (SART) Clinical Outcomes Reporting System (CORS) between 2004 and 2017. Monozygosity was defined as more than one fetal heart tone by the first-trimester ultrasound and concordant sex at live birth. The primary outcome was recurrence risk, with recurrence defined as one patient having two or more cycles of eSET resulting in monozygotic multiples. The secondary objective was to identify factors associated with smonozygotic splitting, using a multivariable logistic regression model and a stepwise purposeful model selection. RESULTS: There were 1355 (2.05%) pregnancies that resulted in two or more fetal heart tones after SET, including 840 monozygotic twins and triplets at birth. Recurrence occurred in two cases-0.0001% of patients with multiple eSET cycles. One case resulted from embryos created from a single cohort with intracytoplasmic sperm injection (ICSI), assisted hatching (AH), and blastocyst transfers. The second case resulted from donor egg embryos with ICSI and blastocyst transfers. Risk factors associated with monozygotic live birth were blastocyst transfer (OR 1.23, 95% CI 1.04-1.47, P = 0.0176) and AH (OR 1.23, 95% CI 1.05-1.44, P = 0.0081). CONCLUSION: Recurrence of monozygotic live births in eSET was very rare. Blastocyst transfer and AH were confirmed to be risk factors for monozygotic live births, while ICSI, PGT, and FET do not appear to be associated.

Order from chaos: a case report of a healthy live birth from a genetically "chaotic" embryo.

Objective: To report a case of a healthy, live birth resulting from a "chaotic" embryo (at least 6 chromosomal aneuploidies) after preimplantation genetic testing for aneuploidy (PGT-A). Design: Case report. Setting: University-affiliated fertility clinic. Patients: A same-sex couple with infertility due to failed donor intrauterine insemination and past implantation failure with in vitro fertilization (IVF)/intracytoplasmic sperm injection using donor sperm. Interventions: Frozen single embryo transfer of a "chaotic" embryo after genetic counseling and informed consent. Main Outcome Measures: Live birth of a healthy infant. Results: Controlled ovarian hyperstimulation and transvaginal oocyte retrieval in a 35-year-old female yielded 10 mature oocytes that underwent intracytoplasmic sperm injection with anonymous donor sperm and in vitro culture for 6 days. A single embryo underwent trophectoderm (TE) biopsy at the blastocyst stage and was cryopreserved. PGT-A revealed a "chaotic" test result. After genetic counseling and proper informed consent, a frozen single embryo transfer of this "chaotic" embryo resulted in a successful pregnancy and live birth of a healthy male infant. Conclusions: The reproductive potential of embryos with a "chaotic" TE biopsy result is unknown, but herein, we report a healthy, live birth from a "chaotic" embryo. We recommend that patients and providers faced with disposition decisions regarding "chaotic" embryos seek genetic counseling, consider rebiopsy, or consider transfer with informed consent.

Preconception health optimization in women with polycystic ovary syndrome - how to find the time?

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among reproductive-age women, the most common cause of infertility among women and a major contributor to pregnancy complications. RECENT FINDINGS: Diagnostic and associated features of PCOS, including hyperandrogenism, insulin resistance, and obesity, contribute to the 2-4-fold increased risk of pregnancy-induced hypertension and preeclampsia, gestational diabetes and preterm birth observed among pregnant women with PCOS. PCOS should be diagnosed according to the 2018 International Guideline. Screening for and optimizing management of hypertension, impaired glucose tolerance and obesity in the preconception window in women with PCOS provides an opportunity to increase the odds of a spontaneous pregnancy, live birth with fertility treatment and possibly reduce the risk of pregnancy complications. SUMMARY: Providers should prioritize individualizing recommendations for preconception health optimization in women with PCOS in order to maximize the chance of conception, a healthy pregnancy and the health of future generations.

Worth the wait? Preconception weight reduction in women and men with obesity and infertility: a narrative review.

Short and long-term weight reduction interventions are considered in the preconception period for women and men with obesity and infertility as obesity is associated with poorer reproductive outcomes. Short-term weight loss achieved with diet, exercise, and medications does not improve per cycle conception or live birth rates in women undergoing ovulation induction, intrauterine insemination, or in vitro fertilization (IVF), but may increase the rate of natural conception. Long-term weight loss achieved through surgical interventions may increase spontaneous conceptions, particularly among women with polycystic ovary syndrome, and may increase the live birth rate from IVF, though these findings are limited by recent evidence. There is a clear need for additional treatment options and well-designed weight loss intervention trials that address the heterogeneous causes of obesity among women and men with infertility and include fertility outcomes and perinatal morbidity as outcome measures.

Virtual Compared With In-Clinic Transvaginal Ultrasonography for Ovarian Reserve Assessment.

OBJECTIVE: To evaluate noninferiority of virtual transvaginal ultrasonography compared with in-clinic ultrasonography for ovarian reserve assessment. METHODS: We conducted a single-site, head-to-head crossover trial. Participants performed self-administered virtual transvaginal ultrasonography at home, guided by a remote-certified ultrasound technologist, then underwent transvaginal ultrasonography in-clinic with another ultrasound technologist. Participants were women in the greater Boston area interested in evaluating ovarian reserve and recruited through social media, health care referrals, and professional networks. The uterus and ovaries were captured in sagittal and transverse views. These randomized recordings were reviewed by two or three independent, blinded reproductive endocrinologists. The primary outcome was noninferiority of the rate of clinical quality imaging produced at home compared with in clinic. Sample size was selected for greater than 90% power, given the 18% noninferiority margin. Secondary outcomes included antral follicle count equivalency and net promoter score superiority. RESULTS: Fifty-six women were enrolled from December 2020 to May 2021. Participants varied in age (19-35 years), BMI (19.5-33.9), and occupation. Ninety-six percent of virtual and 98% of in-clinic images met "clinical quality." The difference of -2.4% (97.5% CI lower bound -5.5%) was within the noninferiority margin (18%). Antral follicle counts were equivalent across settings, with a difference in follicles (0.23, 95% CI -0.36 to 0.82) within the equivalence margin (2.65). Virtual examinations had superior net promoter scores (58.1 points, 97.5% CI of difference 37.3-79.0, P<.01), indicating greater satisfaction with the virtual experience. CONCLUSION: Virtual transvaginal ultrasonography remotely guided by an ultrasonography technologist is noninferior to in-clinic transvaginal ultrasonography for producing clinical quality images and is equivalent for estimating antral follicle count. Virtual transvaginal ultrasonography had superior patient satisfaction and has potential to significantly expand patient access to fertility care. FUNDING SOURCE: This study was sponsored by Turtle Health. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04687189.

Preconception ovarian reserve and placenta-mediated pregnancy complications among infertile women.

RESEARCH QUESTION: Are preconception ovarian reserve markers, such as Anti-Mullerian hormone and antral follicle count, associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation? DESIGN: This is a secondary analysis of women with unexplained infertility who had a singleton live birth after enrollment in the Analysis of Multiple Intrauterine Gestations after Ovarian Stimulation (AMIGOS) trial that randomized couples to superovulation with letrozole, clomiphene, or gonadotropins with insemination for up to 4 cycles. RESULTS: Compared to controls (N = 156), women who developed preeclampsia (N = 17) had lower Anti-Mullerian hormone levels (2.24 ± 1.20 vs. 2.89 ± 2.32, p = 0.07) and lower antral follicle count (18 ± 7.67 vs. 21 ± 11.43, p = 0.16); though these differences were not statistically significant. There was no relationship between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.76-1.25) or antral follicle count (OR: 0.98, 95% CI 0.93-1.04) with preeclampsia and between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.83-1.17) and antral follicle count (OR: 1.00, 95% CI: 0.97-1.04) with placenta medicated pregnancy complications after adjusting for age, BMI and race. CONCLUSIONS: Preconception ovarian reserve markers are not associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation with insemination.

Adolescent Fertility Preservation: Where Do We Stand Now.

Adolescence is a period of flux for many body systems. While fertility potential typically increases after menarche, there are diseases where the opposite occurs and fertility preservation options need to be considered early. In cases of cancer, options vary by pubertal status and can include ovarian tissue cryopreservation, oocyte cryopreservation, sperm cryopreservation, and testicular tissue cryopreservation. Much remains to be learned about fertility and preservation options in those with differences in sexual development (DSDs); however, depending on the form of DSD, fertility preservation may not be necessary. Similarly, traditional fertility counseling in children with galactosemia may need to be changed, as data suggest that fertility rates attributed to other causes of premature ovarian insufficiency may not be as applicable to this disease. Adolescents with Turner's syndrome are at high risk for premature ovarian failure; therefore, it is important to consider options as early as possible since ovarian reserves are depleted quickly. On the other hand, transgender and gender diverse adolescents may even be able to undergo fertility preservation after starting hormone therapy. In all cases, there are additional ethical components including technical/surgical risks in childhood, offering experimental therapies without creating false hope and evaluating children's consent and assent capabilities that must be considered.

Weight Cycling in Women: Adaptation or Risk?

Obesity, dieting, and weight cycling are common among reproductive-age women. Weight cycling refers to intentional weight loss followed by unintentional weight regain. Weight loss is accompanied by changes in gut peptides, adipose hormones, and energy expenditure that promote weight regain to a tightly regulated set point. While weight loss can improve body composition and surrogate markers of cardiometabolic health, it is hypothesized that the weight regain can result in an overshoot effect, resulting in excess weight gain, altered body composition, and negative effects on surrogate markers of cardiometabolic health. Numerous observational studies have examined the association of weight cycling and health outcomes. There appears to be modest association between weight cycling with type 2 diabetes mellitus and dyslipidemia in women, but no association with hypertension, cardiovascular events, and overall cancer risk. Interestingly, mild weight cycling may be associated with a decreased risk of overall and cardiovascular mortality. Little is known about the effects of weight cycling in the preconception period. Although obesity and weight gain are associated with pregnancy complications, preconception weight loss does not appear to mitigate the risk of most pregnancy complications related to obesity. Research on preconception weight cycling may provide insight into this paradox.

Natural vs. programmed cycles for frozen embryo transfer: study protocol for an investigator-initiated, randomized, controlled, multicenter clinical trial.

BACKGROUND: Randomized trials of assisted reproductive technology (ART) have been designed for outcomes of clinical pregnancy or live birth and have not been powered for obstetric outcomes such as preeclampsia, critical for maternal and fetal health. ART increasingly involves frozen embryo transfer (FET). Although there are advantages of FET, multiple studies have shown that risk of preeclampsia is increased with FET compared with fresh embryo transfer, and the reason for this difference is not clear. NatPro will compare the proportion of preeclampsia between two commonly used protocols for FET,modified natural and programmed cycle. METHODS: In this two-arm, parallel-group, multi-center randomized trial, NatPro will randomize 788 women to either modified natural or programmed FET and follow them for up to three FET cycles. Primary outcome will be the proportion of preeclampsia in women with a viable pregnancy assigned to a modified natural cycle FET (corpus luteum present) protocol compared to the proportion of preeclampsia in pregnant women assigned to a programmed FET (corpus luteum absent) protocol. Secondary outcomes will compare the proportion of live births and the proportion of preeclampsia with severe features between the protocols. CONCLUSION: This study has a potential significant impact on millions of women who pursue ART to build their families. NatPro is designed to provide clinically relevant guidance to inform patients and clinicians regarding maternal risk with programmed and modified natural cycle FET protocols. This study will also provide accurate point estimates regarding the likelihood of live birth with programmed and modified natural cycle FET. TRIAL REGISTRATION: ClinicalTrials.gov NCT04551807 . Registered on September 16, 2020.

Short-term weight change and live birth among women with unexplained infertility and polycystic ovary syndrome undergoing ovulation induction.

OBJECTIVE: To determine if short-term weight change among women with unexplained infertility (UI) and polycystic ovary syndrome (PCOS) undergoing ovulation induction is associated with live birth. DESIGN: Secondary analysis of randomized trials. SETTING: Multicenter fertility trial sites. PATIENT(S): A total of 900 women with UI and 750 women with PCOS. MAIN OUTCOME MEASURE(S): Live birth. INTERVENTION(S): Weight assessment at enrollment and start of up to 4-5 cycles of clomiphene, letrozole, or gonadotropins and intrauterine insemination for women with UI and clomiphene or letrozole with regular intercourse for women with PCOS. RESULT(S): Weight data were available for 856 women with UI and 697 women with PCOS. Mean weight change was -0.2 ± 0.3 kg among women with UI and +2.2 ± 0.2 kg among women with PCOS and did not differ based on treatment allocation. There were 115 women with PCOS (16.4%) who gained ≥3 kg. Increased body mass index and three or more cycles were associated with weight gain in women with PCOS. There was no difference in live birth rate among women with PCOS and ≥3 kg weight gain and women with PCOS who did not gain weight. CONCLUSION(S): Women with PCOS gained an average of 2.2 kg regardless of the medication received, whereas women with UI experienced no short-term weight change during ovulation induction. Weight gain in women with PCOS was not associated with live birth rate.

Embryo cryopreservation and utilization in the United States from 2004-2013.

OBJECTIVE: To evaluate the quantity and use of embryos cryopreserved at assisted reproductive technology (ART) clinics in the United States from 2004 through 2013 and to characterize trends in ART cycles in which all embryos were cryopreserved. DESIGN: Retrospective analysis. SETTING: Not applicable. PATIENTS: Registry data from the Society for Assisted Reproductive Technology. INTERVENTIONS: Historical cohort of U.S. ART cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System between 2004 and 2013. MAIN OUTCOME MEASURES: Number of embryos cryopreserved and factors associated with having cryopreserved embryos. RESULTS: The percentage of fresh cycles in which all embryos were frozen increased dramatically each year after 2010: 15.6% (2010), 19.9% (2011), 30.7% (2012), and 40.7% (2013). During 10 years, 1,954,548 embryos were cryopreserved and 717,345 embryos were transferred. In freeze-only cycles from 2004 to 2013, there was a significant increase in the percentage of women with diminished ovarian reserve (19.9% to 34.1%) and in those who used preimplantation genetic testing (3.2% to 6.9%). During the 10-year period, there were 294,575 fresh cycles with embryo transfer and at least one embryo cryopreserved. Overall, 52.5% (n = 154,543) did not undergo a subsequent frozen embryo transfer, 29.5% (n = 40,462) were left with no frozen embryos, 50.4% (n = 68,875) had one-five embryos, and 20.0% (n = 27,396) had ≥six. Factors associated with having excess embryos included donor oocyte cycles and increased antimüllerian hormone levels. CONCLUSIONS: There has been a sharp increase in U.S. ART cycles in which all embryos are frozen and this may result in more embryos in storage.

Lower antimüllerian hormone is associated with lower oocyte yield but not live-birth rate among women with obesity.

BACKGROUND: Antimüllerian hormone is produced by small antral follicles and reflects ovarian reserve. Obesity is associated with lower serum antimüllerian hormone, but it is unclear whether lower levels of antimüllerian hormone in women with obesity reflect lower ovarian reserve. OBJECTIVE: To determine whether lower antimüllerian hormone in women with obesity undergoing in vitro fertilization is associated with oocyte yield and live-birth rate. MATERIALS AND METHODS: Retrospective cohort from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database of 13,316 women with obesity and 16,579 women with normal body mass index undergoing their first autologous in vitro fertilization with fresh transfers between 2012 and 2014. Normal body mass index was defined as body mass index 18.5-24.9 kg/m2, and obesity was defined as body mass index ≥30 kg/m2. Subjects with obesity were stratified as those with class 1 obesity (body mass index, 30.0-34.9 kg/m2), class 2 obesity (body mass index, 35.0-39.9 kg/m2), and class 3 obesity (body mass index, ≥40 kg/m2) based on the World Health Organization body mass index guidelines. Antimüllerian hormone levels were stratified as normal (>1.1 ng/mL), low (0.16-1-1 ng/mL), and undetectable (≤0.16 ng/mL). Multivariable modeling was used to assess oocyte yield using linear regression with a logarithmic transformation and odds of live birth using logistic regression. RESULTS: Women with obesity were older (36.0 ± 4.8 vs 35.5 ± 4.8, P < .001), had lower antimüllerian hormone (1.8 ± 2.0 ng/mL vs 2.1 ± 2.0 ng/mL, P < .001), and had fewer oocytes retrieved (11.9 ± 7.3 vs 12.8 ± 7.7, P < .001) than women with normal body mass index. Lower oocyte yield was observed among women with obesity and normal antimüllerian hormone levels compared to women with normal body mass index and normal antimüllerian hormone levels (13.6 ± 7.3 vs 15.8 ± 8.1, P < .001). No difference in oocyte yield was observed among women with obesity and low antimüllerian hormone levels (P = .58) and undetectabl antimüllerian hormone (P = .11) compared to women with normal BMI and similar antimüllerian hormone levels. Among women with a body mass index ≥30 kg/m2, antimüllerian hormone levels were associated with the number of oocytes retrieved (ß = 0.069; standard error, 0.005; P < .001) but not live-birth rate (odds ratio, 0.98; 95% confidence interval, 0.93-1.04, P = .57). CONCLUSION: Lower antimüllerian hormone in infertile women with obesity appears to reflect lower ovarian reserve, as antimüllerian hormone is associated with lower oocyte yield. Despite lower oocyte yield, lower antimüllerian hormone was not associated with lower live-birth rate among women with obesity.