Changing the Perspective on Fertility Preservation for Women with Metastatic or Advanced Stage Cancer.

PURPOSE OF REVIEW: In this Perspective we share the personal story of a 33-year-old patient diagnosed with metastatic breast cancer and her journey through fertility preservation, surrogacy, and eventually motherhood, highlighting misconceptions about fertility preservation in this population. RECENT FINDINGS: There are nearly 1 million women under the age of 50 diagnosed and living with cancer in the USA. These patients are met with life-altering decisions, including those that may limit their reproductive ability. While there have been tremendous advances and advocacy in the field of oncofertility, there has been limited focus on patients with advanced stage or metastatic cancer. We describe five key misconceptions surrounding fertility preservation in patients with advanced stage cancer, offering a review of the literature and our approach to challenging topics like desiring fertility preservation in the face of Stage 4 disease, the safety and timing of ovarian stimulation during cancer treatment, and passing away following fertility preservation. We review the importance of assessing perceptions of fertility preservation in patients with metastatic cancer and highlight the lack of research in this area as a call to action.

Association between neighborhood poverty and ovarian reserve: the ovarian aging study.

OBJECTIVE: This study aimed to examine the association between neighborhood poverty and ovarian reserve. METHODS: Among 1,019 healthy premenopausal women in the Ovarian Aging Study, aggregate exposure to neighborhood poverty was examined in relation to biomarkers of ovarian reserve, antimüllerian hormone (AMH) and antral follicle count (AFC). Specifically, the interaction of age-x-neighborhood poverty was assessed cross-sectionally to determine whether AMH and AFC declines across women may be greater in women exposed to more neighborhood poverty. Neighborhood poverty was assessed by geocoding and linking women's residential addresses in adulthood to US Census data. RESULTS: Independent of covariates, a significant interaction term showed the association between age and AMH varied by degree of exposure to neighborhood poverty in adulthood ( b = -0.001, P < 0.05). AMH declines increased progressively across women exposed to low, medium, and high levels of neighborhood poverty. In addition, main effects showed that higher neighborhood poverty was related to higher AMH in the younger women only ( b = 0.022, P < 0.01). Results related to AFC were all nonsignificant ( P > 0.05). CONCLUSIONS: Across women, greater aggregate exposure to neighborhood poverty in adulthood was related to lower ovarian reserve, indexed by AMH. In addition, there was a positive association between neighborhood poverty and AMH in younger women that attenuated in the older women. Together, results suggest that neighborhood disadvantage may have detrimental impacts that manifest as initially higher AMH, resulting in greater ovarian follicle loss over time. However, it remains unclear whether these results examining differences across women may replicate when AMH declines by neighborhood poverty are examined longitudinally.

Vigorous vs. moderate exercise to improve glucose metabolism in inactive women with polycystic ovary syndrome and insulin resistance: a pilot randomized controlled trial of two home-based exercise routines.

Objective: To study the impact of vigorous vs. moderate exercise on metabolic parameters in polycystic ovary syndrome (PCOS). Design: Randomized controlled trial. Setting: Unsupervised home-based exercise program. Patients: Patients with PCOS on the basis of the Rotterdam criteria with insulin resistance. Interventions: Participants were block randomized to a home-based exercise program of 75 minutes of vigorous exercise or 150 minutes of moderate exercise per week, for 8 weeks total. Main Outcome Measures: Changes in glucose, insulin, and insulin resistance. Results: In total, 36 participants were randomized, of whom 20 completed the study. The percentage changes from baseline at 4 and 8 weeks for fasting glucose, insulin, and homeostatic model assessment for insulin resistance did not significantly differ between the groups, except for the change in the 8-week glucose level, which was more favorable in the moderate arm (8.06% [standard deviation, 6.44%] in the vigorous group compared with -0.32% [standard deviation, 4.91%] in the moderate group). The absolute values of the main outcomes (fasting glucose, insulin, and homeostatic model assessment for insulin resistance) at baseline and 4 and 8 weeks did not significantly differ between trial arms. When assessing the change from baseline at 4 and 8 weeks, overall and within each trial arm, only the 8-week fasting glucose level was significantly greater than the baseline value in the vigorous arm (93.5 [95% confidence interval, 88.7-98.3] vs. 86.8 [95% confidence interval, 81.1-92.4]). Conclusions: Unsupervised short-term exercise programs may not achieve significant metabolic improvements in patients with PCOS, regardless of vigorous vs. moderate intensity. Future studies should investigate this question in larger sample sizes and longer or structured exercise programs. Clinical Trial Registration Number: ClinicalTrials.gov identifier, NCT02303470.

In Utero Exposure to Maternal COVID-19 Vaccination and Offspring Neurodevelopment at 12 and 18 Months.

Importance: Uptake of COVID-19 vaccines among pregnant individuals was hampered by safety concerns around potential risks to unborn children. Data clarifying early neurodevelopmental outcomes of offspring exposed to COVID-19 vaccination in utero are lacking. Objective: To determine whether in utero exposure to maternal COVID-19 vaccination was associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at 12 and 18 months of age. Design, Setting, and Participants: This prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), enrolled pregnant participants from May 2020 to August 2021; follow-up of children from these pregnancies is ongoing. Participants, which included pregnant individuals and their offspring from all 50 states, self-enrolled online. Study activities were performed remotely. Exposure: In utero exposure of the fetus to maternal COVID-19 vaccination during pregnancy was compared with those unexposed. Main Outcomes and Measures: Neurodevelopmental scores on validated ASQ-3, completed by birth mothers at 12 and 18 months. A score below the established cutoff in any of 5 subdomains (communication, gross motor, fine motor, problem solving, social skills) constituted an abnormal screen for developmental delay. Results: A total of 2487 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled at less than 10 weeks' gestation and completed research activities, yielding a total of 2261 and 1940 infants aged 12 and 18 months, respectively, with neurodevelopmental assessments. In crude analyses, 471 of 1541 exposed infants (30.6%) screened abnormally for developmental delay at 12 months vs 203 of 720 unexposed infants (28.2%; χ2 = 1.32; P = .25); the corresponding prevalences at 18 months were 262 of 1301 (20.1%) vs 148 of 639 (23.2%), respectively (χ2 = 2.35; P = .13). In multivariable mixed-effects logistic regression models adjusting for maternal age, race, ethnicity, education, income, maternal depression, and anxiety, no difference in risk for abnormal ASQ-3 screens was observed at either time point (12 months: adjusted risk ratio [aRR], 1.14; 95% CI, 0.97-1.33; 18 months: aRR, 0.88; 95% CI, 0.72-1.07). Further adjustment for preterm birth and infant sex did not affect results (12 months: aRR, 1.16; 95% CI, 0.98-1.36; 18 months: aRR, 0.87; 95% CI, 0.71-1.07). Conclusions and Relevance: Results of this cohort study suggest that COVID-19 vaccination was safe during pregnancy from the perspective of infant neurodevelopment to 18 months of age. Additional longer-term research should be conducted to corroborate these findings and buttress clinical guidance with a strong evidence base.

Metabolic and endocrine status associate with obstructive sleep apnea risk among patients with polycystic ovary syndrome.

STUDY OBJECTIVES: Risk of obstructive sleep apnea appears to be increased among patients with polycystic ovary syndrome (PCOS), but the underlying physiology is unclear. We sought to identify predictors of OSA risk among patients with PCOS. METHODS: A cross-sectional analysis of patients evaluated for PCOS at a single tertiary center from 2017 to 2022 was completed. Inclusion criteria included: age 18-44, Rotterdam criteria for PCOS, and had completed a Berlin Questionnaire (BQ) for OSA risk assessment. All patients underwent standardized anthropometric, ultrasound, endocrine, and metabolic phenotyping. RESULTS: Of the 572 patients screened during the study period, 309 patients with PCOS met inclusion criteria, and 104 (33.7%) had a high risk BQ. Those with high-risk BQ, compared to those without, had significantly (p<0.05) higher waist:hip ratio, LDL-C, triglycerides, fasting insulin, 2-hour insulin, fasting glucose, 2-hour glucose, HOMA-IR, HbA1c, CRP, free testosterone, free androgen index, and lower HDL-C and SHBG. In multivariable modeling controlling for all significantly differing variables in univariate analyses, HbA1c (ß (S.E.) 1.05 (0.45), p=0.02), CRP (0.09 (0.04), p=0.01), and SHBG (-0.02 (0.01), p=0.02)) associated with high risk BQ. CONCLUSIONS: Dysglycemia, inflammation, and androgen status independently associate with predicted OSA risk by BQ. Future studies are needed to comprehensively assess the impact of treatment of OSA on these outcomes among patients with PCOS to better clarify the directionality and clinical implications of these associations.

Antimullerian Hormone, a Marker of Ovarian Reserve, Is Protective Against Presence and Severity of NASH in Premenopausal Women.

BACKGROUND & AIMS: Antimüllerian hormone (AMH) is a marker of ovarian reserve with emerging data linking lower levels to some metabolic and inflammatory diseases in women. Whether AMH levels influence nonalcoholic fatty liver disease (NAFLD) is unknown. METHODS: Leveraging the NASH Clinical Research Network we determined the association of AMH levels within 6 months of liver biopsy with presence and severity of histologic measures of NAFLD in premenopausal women. Outcomes included presence of nonalcoholic steatohepatitis (NASH), presence and severity of fibrosis, and NAFLD Activity Score and its components. Logistic and ordinal logistic regression models were adjusted for age, race/ethnicity, homeostatic model assessment for insulin resistance, body mass index, dyslipidemia, polycystic ovary syndrome, estrogen-progestin use, and menstrual cyclicity. RESULTS: Median cohort age was 35 years; 73% were white and 24% Hispanic. Thirty-three percent had diabetes, 81% had obesity, and 95% had dyslipidemia. On biopsy 71% had NASH, 68% had any fibrosis, and 15% had advanced fibrosis. On adjusted analysis (n = 205), higher AMH quartiles were inversely associated with NAFLD histology including prevalent NASH (adjusted odds ratio [AOR], 0.64; 95% confidence interval [CI], 0.41-1.00), NAFLD Activity Score ≥5 (AOR, 0.52; 95% CI, 0.35-0.77), Mallory hyaline (AOR, 0.54; 95% CI, 0.35-0.82), and higher fibrosis stage (AOR, 0.70; 95% CI, 0.51-0.98). The protective effects of AMH were more pronounced among women without polycystic ovary syndrome (n = 164), including lower odds of NASH (AOR, 0.53; 95% CI, 0.32-0.90) and any NASH fibrosis (AOR, 0.54; 95% CI, 0.32-0.93). CONCLUSIONS: AMH may reflect a unique biomarker of NASH in premenopausal women and findings suggest a novel link between reproductive aging and histologic severity of NAFLD in women.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

REI clinics and fellowship training-a national snapshot to improve access to reproductive care.

PURPOSE: To analyze the geographic distribution of REI fellowships and clinics across the USA and to strategize ways to improve patient access to care. METHODS: Cross-sectional study using population data obtained from publicly available United States Census Bureau, Society for Assisted Reproductive Technology (SART), and National Resident Matching Program websites. Outcomes include the number of REI clinics, REI fellowship-trained physicians, and REI fellowship programs. RESULTS: In 2020, there were 643 assisted reproductive technology (ART) clinics reporting to SART and 1351 fellowship-trained REI physicians. Most clinics are located in the south (n = 209); however, the northeast has the highest density of REI clinics. Out of 301,316 in vitro fertilization (IVF) cycles in the USA in 2020, northeastern states initiated the most cycles (n = 93,565), and Midwestern states initiated the fewest cycles (n = 50,000). The northeast has the most REI physicians per million women aged 20-44 years (42.4) while the Midwest has the lowest ratio (19.5). There are fewer REI physicians per million women aged 20-44 years in states with a lower proportion of patients with health insurance (r = 0.56, 95% confidence interval ([CI] 0.34-0.73) and in states with a lower average income per resident (r = 0.65, 95% CI 0.46-0.79). Most of the 49 accredited REI fellowship programs in the USA are in the northeast (n = 18), and there are fewest in the south (n = 10) and west (n = 10). CONCLUSION: Access to REI care has large geographic disparities from a clinic, physician, and training program perspective. Creative solutions are needed to remedy this problem.

Presence of Fibroids on Transvaginal Ultrasonography in a Community-Based, Diverse Cohort of 996 Reproductive-Age Female Participants.

Importance: Fibroids are benign uterine tumors that can cause significant morbidity. Knowledge on fibroid prevalence, especially in the asymptomatic population and in Asian and Hispanic or Latina individuals, is limited, and a better understanding of affected groups will improve timely diagnosis and motivate appropriate recruitment in clinical trials to reduce health disparities. Objective: To estimate the prevalence of fibroids in a diverse cohort of female individuals. Design, Setting, and Participants: This cross-sectional study included female individuals not seeking treatment for fertility or other conditions who were prospectively recruited in an academic medical center in San Francisco, California. Effort was made to recruit an equal proportion of participants from 4 large racial and ethnic groups in the United States (Asian-Chinese, Black or African American, Hispanic or Latina, and White) and across 4 equal age groups between 25 and 45 years. All participants reported regular menses (21-35 days), had not used estrogen- or progestin-containing medications in the 3 months prior to enrollment, and denied history of pelvic surgery. The assessment of ultrasonography results was part of an ongoing longitudinal cohort, with initial recruitment from October 2006 to September 2012. Data analysis was performed in April to September 2022. Main Outcomes and Measures: Fibroid presence and burden as assessed by transvaginal ultrasonography. Results: A total of 996 female participants were included in the analysis, including 229 (23.0%) Asian-Chinese, 249 (25.0%) Black or African American, 237 (23.8%) Hispanic or Latina, and 281 (28.2%) White individuals. Mean (SD) age was 34.8 (5.7) years in Asian-Chinese participants, 35.4 (6.1) years in Black or African American participants, 34.8 (5.3) years in Hispanic or Latina participants, and 35.3 (5.0) years in White participants. Fibroids were present in 21.8% (95% CI, 16.7%-27.8%) of Asian-Chinese participants, 35.7% (95% CI, 29.8%-42.0%) of Black or African American participants, 12.7% (95% CI, 8.7%-17.6%) of Hispanic or Latina participants, and 10.7% (95% CI, 7.3%-14.9%) of White participants. Black or African American and Asian-Chinese participants were more likely to have fibroids than White participants (Black or African American: adjusted odds ratio [OR], 4.72 [95% CI, 2.72-8.18]; P < .001; Asian-Chinese: adjusted OR, 3.35 [95% CI, 1.95-5.76]; P < .001). In those with fibroids, the proportion with multiple fibroids were 48.3% in Black or African American participants, 33.3% in White participants, 33.3% in Hispanic or Latina participants, and 26.0% in Asian-Chinese participants (P = .06). The largest mean (SD) fibroid diameter was 3.9 (1.9) cm in Black or African American participants, 3.2 (1.6) cm in Asian-Chinese participants, 3.2 (1.6) cm in White participants, and 3.0 (1.4) cm in Hispanic or Latina participants (P = .03). Conclusions and Relevance: In this study of female participants in a nonclinical setting, Black or African American and Asian-Chinese participants were disproportionately affected by uterine fibroids. Hispanic or Latina participants had similar fibroid burden to White participants.

Artificial intelligence in assisted reproductive technology: how best to optimize this tool of the future.

Artificial intelligence, at a simple level, involves the use of a computer that can perform "human" functions: learning from experience, adjusting to new inputs, and simulating human intelligence performing human tasks. This Views and Reviews brings together a diverse group of investigators to evaluate artificial intelligence and the roles it might play in the field of assisted reproductive technology.

Decision regret among women considering planned oocyte cryopreservation: a prospective cohort study.

PURPOSE: To (1) prospectively characterize the incidence of decision regret among women considering planned oocyte cryopreservation (planned OC), comparing those who pursued treatment vs those who did not freeze eggs, and (2) to identify baseline predictors for future decision regret. METHODS: A total of 173 women seen in consultation for planned OC were followed prospectively. Surveys were administered at (1) baseline (< 1 week after initial consultation) and (2) follow-up, 6 months after planned OC among participants who froze eggs or 6 months following consultation in the absence of further communication to pursue treatment. The primary outcome was the incidence of moderate-to-severe decision regret, indicated by a Decision Regret Scale score > 25. We also examined predictors of regret. RESULTS: The incidence of moderate-to-severe regret over the decision to freeze eggs was 9% compared to 51% over the decision not to pursue treatment. Among women who froze eggs, adequacy of information at baseline to decide about treatment (aOR 0.16, 95% CI 0.03, 0.87) and emphasis on future parenthood (aOR 0.80, 95% CI 0.66, 0.99) were associated with reduced odds of regret. Forty-six percent of women who froze eggs regretted not doing so earlier. Among women who did not freeze eggs, the primary reasons were financial and time constraints, correlating with increased odds of decision regret in an exploratory analysis. CONCLUSIONS: Among women undergoing planned OC, the incidence of decision regret is low compared to the regret confronting women seen in consultation for planned OC but who do not pursue treatment. Provider counseling is key to offset the regret risk.

B-cell lymphoma 6 expression significantly differs by the uterine preparation method used for frozen embryo transfer.

OBJECTIVE: To determine whether B-cell lymphoma 6 (BCL6), an endometriosis-associated marker postulated to predict poor pregnancy outcomes, is differentially expressed in the window of implantation with various uterine preparation regimens commonly used for frozen embryo transfers. DESIGN: A retrospective cohort study. SETTING: An academic center. PATIENT(S): Patients with infertility who underwent endometrial biopsy for BCL6 evaluation INTERVENTION(S): Exogenous estradiol and/or progesterone. MAIN OUTCOME MEASURE(S): Endometrial BCL6 histological score (HSCORE) and overexpression (HSCORE >1.4) RESULT(S): Two hundred and forty-four patients were included in the analysis: 76 patients were sampled in a natural menstrual cycle without exogenous hormone exposure (NC), 25 under a modified natural cycle embryo transfer protocol with choriogonadotropin alfa injection followed by luteal phase vaginal progesterone supplementation (mNC), and 143 under a programmed cycle embryo transfer protocol, with estradiol administration followed by addition of intramuscular progesterone-in-oil injections (PC). Median HSCORE (interquartile range) was the highest in NC (3.0 [1.8-3.6]). BCL6 expression was significantly lower in mNC (1.1 [0.4-2.1]) and PC groups (0.8 [0.3-1.3]) compared with NC. In addition, BCL6 overexpression (HSCORE >1.4) was observed in 80.3% of NC, 40.0 % of mNC, and 23.1 % of PC. After adjusting for covariates, the endometrium exposed to exogenous progesterone had significantly lower odds of BCL6 overexpression than that of a natural menstrual cycle (adjusted odds ratio, 0.12 [95% CI 0.04-0.35] for mNC; and odds ratio, 0.08 [95% CI 0.04-0.17] for PC). CONCLUSION(S): BCL6 expression differs by the type of uterine preparation method, with lower levels observed with exogenous progesterone exposure. The validity and utility of BCL6 testing under medicated endometrial state warrants further investigation.

Current Guidelines for Diagnosing PCOS.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women. Much of the confusion surrounding PCOS diagnosis stems from the broad heterogeneity of symptomology experienced by women with PCOS. The diverse features of the syndrome have led to a number of diagnostic criteria over the years. This manuscript describes each of the current composite criteria and individually breaks down each component. The importance of accurate diagnosis for both clinical care and research is emphasized.

Longitudinal trends in fertility in women of advanced maternal age in the United States and Sweden from 1935-2018 and comparison to maternal mortality ratios.

Advanced maternal age (AMA, >35 years at delivery) confers maternal and foetal risks, particularly with age >45 years and nulliparity, but longitudinal comparative data on age- and parity-specific AMA fertility is lacking. We used the Human Fertility Database (HFD), a publicly available, international database, to analyse fertility in US and Swedish women aged 35-54 from 1935 to 2018. Age-specific fertility rates (ASFR), total birth counts, and proportion of AMA births were evaluated across maternal age, parity, and time, and compared to maternal mortality rates during the same time. In the US, total AMA births nadired in the 1970s, and have risen since. Until 1980, most AMA births were to women completing parity 5 or higher; since then, most have been to low parity women. While ASFR in 35 to 39 year olds was highest in 2015, ASFR in women 40-44 and 45-49 were highest in 1935, though they have been rising recently, especially in low-parity women. While the same AMA fertility trends were seen in the US and Sweden from 1970-2018, maternal mortality rates have risen in the US despite remaining low in Sweden. Although AMA is known to contribute to maternal mortality, this discrepancy merits further consideration.