Infertility and risk of postmenopausal breast cancer in the women's health initiative.

PURPOSE: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up). METHODS: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy. RESULTS: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%). CONCLUSION: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

Reproduction as a window to future health in women.

Cultivating awareness for reproduction as a window to future health presents an opportunity for early identification and modification of risk factors that can affect both individual and population-level morbidity and mortality. Infertility could serve as both a window into future health as well as a pathway to future pathology. The underlying mechanisms of infertility may share common pathways with long-term risk for health and well-being. Making this identification early in the disease process may improve opportunities for intervention, and deepen our understanding of long-term risk. Additionally, fertility treatments may increase individual risk. Only by making these associations and designing studies to understand how disease and treatment risk impact health can we truly fulfill our goal of building healthy families. The aim of this review is to discuss the short-term impact of fertility challenges and treatment, long-term associations of infertility with morbidity and mortality, and the role of parity in modifying these risk associations.

Assessment of patients' perceptions towards embryo disposition after donation of embryos to a research biobank.

PURPOSE: To explore perceptions towards embryo disposition among patients donating excess embryos to a research biobank. METHODS: Cross-sectional study of survey responses collected as part of enrollment in a research biobank. Patients are asked questions regarding the difficulty of their disposition decision, their alternative disposition choice if donation to research was not available, quality of the counseling they received, and if additional counseling throughout their treatment would have been beneficial. Survey responses use 5-point Likert scales, with "1" being lowest/least and "5" being highest/most. RESULTS: A total of 157 men and 163 women enrolled in the biobank. Median scores for difficulty of disposition decision were 3 for females and 2 for males, and for quality of counseling, the median scores were 4 for females and 3 for males. Seventy percent of patients would have chosen to discard their excess embryos had donation to research not been an option. Statistical analyses showed no significant difference in responses based on variations in race, religion, sexual orientation, and infertility diagnoses. Concordance of responses within heterosexual couples was tested and found to be poor to moderate. CONCLUSIONS: Assessing patients' perceptions towards embryo disposition after donation of their excess embryos to a research biobank affords a unique perspective. The difficulty of the disposition decision, the tendency to discard embryos in the absence of a means for donation to research, and the poor agreement between heterosexual partners highlight the importance of donation to research as an accessible disposition option and the need for a personalized approach to counseling and consenting for embryo disposition.

Implementation of a comprehensive fertility biobanking initiative.

OBJECTIVE: To present the framework of Stanford Fertility and Reproductive Health's comprehensive reproductive biobanking initiatives and the results of the first year of recruitment. DESIGN: Technical description article. SETTING: Academic fertility center. PATIENT(S): Fertility patients >18 years of age. INTERVENTION(S): Enroll the patients interested in research in biobanking protocols. MAIN OUTCOME MEASURE(S): Patient recruitment and sample inventory from September 2020 to September 2021. RESULT(S): A total of 253 patients have enrolled in the Stanford Fertility and Reproductive Health biobanking initiatives since September 2020. The current inventory consists of 1,176 samples, including serums, plasmas, buffy coats, endometria, maternal deciduae, miscarriage chorionic villi, and human embryos (zygote, cleavage, and blastocyst stages). CONCLUSION(S): This biobanking initiative addresses a critical, unmet need in reproductive health research to make it possible for patients to donate excess embryos and gametes and preserves, for future research, valuable somatic and reproductive tissues that would otherwise be discarded. We present the framework of this biobanking initiative in order to support future efforts of establishing similar biorepositories.

Infertility and Risk of Heart Failure in the Women's Health Initiative.

BACKGROUND: There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known. OBJECTIVES: This study sought to examine the development of HF and HF subtypes in women with and without history of infertility. METHODS: We followed postmenopausal women from the Women's Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF]: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction [HFrEF]: left ventricular ejection fraction of <50%]). RESULTS: Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18). CONCLUSIONS: Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.

Association of infertility with atherosclerotic cardiovascular disease among postmenopausal participants in the Women's Health Initiative.

OBJECTIVE: To investigate the association of infertility with atherosclerotic cardiovascular disease (ASCVD) among postmenopausal participants in the Women's Health Initiative (WHI). We hypothesized that nulliparity and pregnancy loss may reveal more extreme phenotypes of infertility, enabling further understanding of the association of infertility with ASCVD. DESIGN: Prospective cohort study. SETTING: Forty clinical centers in the United States. PATIENT(S): A total of 158,787 postmenopausal participants in the Women's Health Initiative cohort. INTERVENTION(S): Infertility, parity, and pregnancy loss. MAIN OUTCOME MEASURE(S): The primary outcome was risk of ASCVD among women with and without a history of infertility, stratified by history of live birth and pregnancy loss. Cox proportional-hazards models were adjusted for demographics and risk factors for ASCVD. RESULT(S): Among 158,787 women, 25,933 (16.3%) reported a history of infertility; 20,427 (80%) had at least 1 live birth; and 9,062 (35%) had at least 1 pregnancy loss. There was a moderate overall association between infertility and ASCVD (adjusted hazard ratio, 1.02; 95% confidence interval [CI], 0.99-1.06) over 19 years of follow-up. Among nulliparous women, infertility was associated with a 13% higher risk of ASCVD (95% CI, 1.04-1.23). Among nulliparous women who had a pregnancy loss, infertility was associated with a 36% higher risk of ASCVD (95% CI, 1.09-1.71). CONCLUSION(S): Women with a history of infertility overall had a moderately higher risk of ASCVD compared with women without a history of infertility. Atherosclerotic cardiovascular disease risk was much higher among nulliparous infertile women and among nulliparous infertile women who also had a pregnancy loss, suggesting that in these more extreme phenotypes, infertility may be associated with ASCVD risk.

The impact of estradiol on pregnancy outcomes in letrozole-stimulated frozen embryo transfer cycles.

OBJECTIVE: To assess the impact of low estradiol (E2) levels in letrozole-stimulated frozen embryo transfer (FET) cycles on pregnancy and neonatal outcomes. DESIGN: Retrospective cohort. SETTING: University-affiliated fertility center. PATIENTS: All patients who underwent letrozole-stimulated FET cycles from January 2017 to April 2020 (n = 217). The "Low E2" group was defined as those with E2 serum levels on the day of trigger <10th percentile level (E2 <91.16 pg/mL, n = 22) and the "Normal E2" group was defined as those with E2 serum levels ≥10th percentile level (E2 ≥91.16 pg/mL, n = 195). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Pregnancy outcomes including rates of clinical pregnancy, clinical miscarriage, and live birth. Neonatal outcomes including gestational age at delivery, birth weight, and Apgar score. RESULTS: The mean ± SD estradiol level was 66.8 ± 14.8 pg/mL for the "Low E2" group compared with 366.3 ± 322.1 pg/mL for the "Normal E2" group. There were otherwise no substantial differences in cycle characteristics such as endometrial thickness on the day of ovulation trigger and progesterone levels in early pregnancy. The "Low E2" group had a significantly higher clinical miscarriage rate (36.4% vs. 8.8%, adjusted odds ratio 8.06) and lower live birth rate (31.8% vs. 57.9%, adjusted odds ratio 0.28). Neonatal outcomes such as gestational age at delivery, mean birth weight, Apgar scores, and incidence of newborn complications were not clinically different between the groups. CONCLUSION: Low E2 levels were associated with a significantly higher miscarriage rate and lower live birth rate, suggesting that E2 levels in the follicular phase may have an effect on cycle outcomes. Given the rise in use of FET, further studies are needed to confirm our findings and understand the mechanisms.

Development and validation of a risk prediction index for severe maternal morbidity based on preconception comorbidities among infertile patients.

OBJECTIVE: To develop and validate a preconception risk prediction index for severe maternal morbidity (SMM), defined by the Centers for Disease Control and Prevention as indicators of a life-threatening complication, among infertile patients. DESIGN: Retrospective analysis of live births and stillbirths from 2007 to 2017 among infertile women. SETTING: National commercial claims database. PATIENT(S): Infertile women identified on the basis of diagnosis, testing, or treatment codes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was SMM, identified as any indicator from the Centers for Disease Control and Prevention Index except blood transfusion alone, which was found to overestimate cases. Twenty preconception comorbidities associated with a risk of SMM were selected from prior literature. Targeted ensemble learning methods were used to rank the importance of comorbidities as potential risk factors for SMM. The independent strength of the association between each comorbidity and SMM was then used to define each comorbidity's risk score. RESULT(S): Among 94,097 infertile women with a delivery, 2.3% (n = 2,181) experienced an SMM event. The highest risk of SMM was conferred by pulmonary hypertension, hematologic disorders, renal disease, and cardiac disease. Associated significant risks were lowest for substance abuse disorders, prior cesarean section, age ≥40 years, gastrointestinal disease, anemia, mental health disorders, and asthma. The receiver operating characteristic area under the curve for the developed comorbidity score was 0.66. Calibration plots showed good concordance between the predicted and actual risk of SMM. CONCLUSION(S): We developed and validated an index to predict the probability of SMM on the basis of preconception comorbidities in patients with infertility. This tool may inform preconception counseling of infertile women and support maternal health research initiatives.

Karyotype of first clinical miscarriage and prognosis of subsequent pregnancy outcome.

RESEARCH QUESTION: Is the karyotype of the first clinical miscarriage in an infertile patient predictive of the outcome of the subsequent pregnancy? DESIGN: Retrospective cohort study of infertile patients undergoing manual vacuum aspiration with chromosome testing at the time of the first (index) clinical miscarriage with a genetic diagnosis and a subsequent pregnancy. Patients treated at two academic-affiliated fertility centres from 1999 to 2018 were included; those using preimplantation genetic testing for aneuploidy were excluded. Main outcome was live birth in the subsequent pregnancy. RESULTS: One hundred patients with euploid clinical miscarriage and 151 patients with aneuploid clinical miscarriage in the index pregnancy were included. Patients with euploid clinical miscarriage in the index pregnancy had a live birth rate of 63% in the subsequent pregnancy compared with 68% among patients with aneuploid clinical miscarriage (adjusted odds ratio [aOR] 0.75, 95% CI 0.47-1.39, P = 0.45, logistic regression model adjusting for age, parity, body mass index and mode of conception). In a multinomial logistic regression model with three outcomes (live birth, clinical miscarriage or biochemical miscarriage), euploid clinical miscarriage for the index pregnancy was associated with similar odds of clinical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage for the index pregnancy (32% versus 24%, respectively, aOR 1.49, 95% CI 0.83-2.70, P = 0.19). Euploid clinical miscarriage for the index pregnancy was not associated with likelihood of biochemical miscarriage in the subsequent pregnancy compared with aneuploid clinical miscarriage (5% versus 8%, respectively, aOR 0.46, 95% CI 0.14-1.55, P = 0.21). CONCLUSION: Prognosis after a first clinical miscarriage among infertile patients is equally favourable among patients with euploid and aneuploid karyotype, and independent of the karyotype of the pregnancy loss.

Association of preconception paternal health and adverse maternal outcomes among healthy mothers.

BACKGROUND: Maternal morbidity continues to be an issue of national and global concern. Paternal preconception health may play a significant role in pregnancy outcomes and has received less attention than maternal health. OBJECTIVE: This study aimed to examine the association between preconception paternal health and the risk for adverse maternal outcomes among healthy mothers. STUDY DESIGN: This was a retrospective analysis of live births from 2009 through 2016 to healthy women aged 20 to 45 years recorded in the IBM Marketscan research database. Infants were linked to paired mothers and fathers using family ID. Preconception paternal health was assessed using the number of metabolic syndrome component diagnoses and the most common individual chronic disease diagnoses (hypertension, diabetes mellitus, obesity, hyperlipidemia, chronic obstructive pulmonary disease, cancer, and depression). Women with metabolic syndrome components were excluded to avoid potential confounding of maternal and paternal factors. Adverse maternal outcomes that were assessed included (1) abnormal placentation including placenta accreta spectrum, placenta previa, and placental abruption; (2) preeclampsia with and without severe features including eclampsia; and (3) severe maternal morbidity, identified as any indicator from the Centers for Disease Control and Prevention Index of life-threatening complications at the time of delivery to 6 weeks postpartum. The trend between preconception paternal health and each maternal outcome was determined using the Cochran-Armitage Trend test. The independent association of paternal health with maternal outcomes was also determined using generalized estimating equations models, accounting for some mothers who contributed multiple births during the study period, and by adjusting for maternal age, paternal age, region of birth, year of birth, maternal smoking, and average number of outpatient visits per year. RESULTS: Among 669,256 births to healthy mothers, there was a significant trend between all adverse maternal outcomes and worsening preconception paternal health defined either as the number of metabolic syndrome diagnoses or number of chronic disease diagnoses (P<.001; Cochran-Armitage Trend test). In the generalized estimating equations model, the odds for preeclampsia without severe features increased in a dose-dependent fashion and were 21% higher (95% confidence interval, 1.17-1.26) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for preeclampsia with severe features and eclampsia increased in a dose-dependent fashion and were 19% higher (95% confidence interval, 1.09-1.30) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for severe maternal morbidity were 9% higher (95% confidence interval, 1.002-1.19) among women whose partners had ≥2 metabolic syndrome diagnoses than among women whose partners had no metabolic syndrome diagnosis. The odds for abnormal placentation were similar between the groups (adjusted odds ratio, 0.96; 95% confidence interval, 0.89-1.03). CONCLUSION: Among healthy mothers, we report that preconception paternal health is significantly associated with increased odds of preeclampsia with and without severe features and weakly associated with increased odds of severe maternal morbidity. These findings suggest that paternally derived factors may play significant roles in the development of adverse maternal outcomes in healthy women with a low a priori risk of obstetrical complications.

Association between infertility and all-cause mortality: analysis of US claims data.

BACKGROUND: The consequences of an infertility diagnosis extend beyond the pursuit of family building, because women with infertility also face increased risks for severe maternal morbidity, cancer, and chronic disease. OBJECTIVE: This study aimed to examine the association between female infertility and all-cause mortality. STUDY DESIGN: This retrospective analysis compared 72,786 women with infertility, identified in the Optum Clinformatics Datamart from 2003 to 2019 by infertility diagnosis, testing, and treatment codes, with 3,845,790 women without infertility seeking routine gynecologic care. The baseline comorbidities were assessed using the presence of ≥1 metabolic syndrome diagnoses and the Charlson Comorbidity Index. The primary outcome, which was all-cause mortality, was identified by linkage to the Social Security Administration Death Master File outcomes and medical claims. The association between infertility and mortality was examined using a Cox proportional hazard regression by adjusting for age, hypertension, hyperlipidemia, type II diabetes, year of evaluation, smoking, number of visits per year, nulliparity, obesity, region of the country, and race. RESULTS: Among 16,473,458 person-years of follow-ups, 13,934 women died. Women with infertility had a 32% higher relative risk for death from any cause (0.42% vs 0.35%, adjusted hazard ratio, 1.32; 95% confidence interval, 1.18-1.48) than women without infertility. The mean follow-up time per patient was 4.0±3.7 years vs 4.2±3.8 years for women with and without infertility, respectively. When stratified by age of <35 or ≥35 years or baseline medical comorbidity, the association between infertility and mortality remained. Women with infertility who delivered a child during the follow-up period faced a similar increased risk for mortality than the overall infertile group. Finally, receiving fertility treatment was not associated with a higher risk for death than receiving an infertility diagnosis or testing alone. CONCLUSION: Although the absolute risk for death was low in both groups, women with infertility faced a higher relative risk for mortality than women without infertility. The association remained across all age, race and ethnicity groups, morbidities, and delivery strata. Importantly, infertility treatment was not associated with an increased risk for death. These findings reinforce the disease burden associated with infertility and its potential for long-term sequelae.

Epigenetic clock measuring age acceleration via DNA methylation levels in blood is associated with decreased oocyte yield.

PURPOSE: To investigate how biologic age (phenotypic age at which your body functions) greater than chronologic age, (age acceleration (AgeAccel)), correlates with oocyte yield. METHODS: Thirty-nine women undergoing ovarian stimulation, inclusive of all infertility diagnoses, were included in this pilot study. Methylome analysis of peripheral blood was utilized to determine biologic age. AgeAccel was defined as biologic age > 2 years older than chronologic age. A negative binomial model was used to obtain the crude association of AgeAccel with number of oocytes. A parsimonious adjusted model for the number of oocytes was obtained using backwards selection (p < 0.05). RESULTS: Measures of age were negatively correlated with number of oocytes (chronological age Pearson ρ = - 0.45, biologic age Pearson ρ = - 0.46) and AMH was positively correlated with number of oocytes (Pearson ρ = 0.91). Patients with AgeAccel were noted to have lower AMH values (1.29 ng/mL vs. 2.29, respectively (p = 0.049)) and lower oocyte yield (5.50 oocytes vs. 14.50 oocytes, respectively (p = 0.0030)). A crude association of a 7-oocyte reduction in the age-accelerated group was found (- 6.9 oocytes (CI - 11.6, - 2.4)). In a model with AMH and antral follicle count, AgeAccel was associated with a statistically significant 3.3 reduction in the number of oocytes (- 3.1; 95% CI - 6.5, - 0.1; p = 0.036). CONCLUSIONS: In this small pilot study, AgeAccel is associated with a lower AMH and lower oocyte yield providing preliminary evidence that biologic age, specifically AgeAccel, may serve as an epigenetic biomarker to improve the ability of predictive models to assess ovarian reserve.

Increased risk of severe maternal morbidity among infertile women: analysis of US claims data.

BACKGROUND: Severe maternal morbidity continues to be an issue of national and global concern and is increasing in incidence. The incidence of infertility is also on the rise, and infertile women experience a higher risk of incident chronic medical disease and cancer, suggesting that fertility may serve as a window to a woman's overall health. OBJECTIVE: To investigate the risk of severe maternal morbidity by maternal fertility status. MATERIALS AND METHODS: This was a retrospective cohort analysis using Optum's de-identifed Clinformatics Data Mart Database between 2003 and 2015. Infertile women stratified by infertility diagnosis, testing, or treatment were compared to fertile women seeking routine gynecologic care. In both groups, only women who underwent pregnancy and delivery of a singleton during the follow-up period were included. Main outcomes were severe maternal morbidity indicators, defined by the Centers for Disease Control and Prevention and identified by International Classification of Diseases 10th Revision and Common Procedural Technology codes within 6 weeks of each delivery. Results were adjusted for maternal age, race, education, nulliparity, smoking, obesity, delivery mode, preterm birth, number of prenatal visits, and year of delivery. RESULTS: A total of 19,658 women comprised the infertile group and 525,695 women comprised the fertile group. The overall incidence of any severe maternal morbidity indicator was 7.0% among women receiving fertility treatment, 6.4% among women receiving a fertility diagnosis, 5.5% among women receiving fertility testing, and 4.3% among fertile women. Overall, infertile women had a significantly higher risk of developing any severe maternal morbidity indicator (adjusted odds ratio, 1.22; confidence interval, 1.14-1.31, P < .01) as well as a significantly higher risk of disseminated intravascular coagulation (adjusted odds ratio, 1.48; confidence interval, 1.26-1.73, P < .01), eclampsia (adjusted odds ratio, 1.37; confidence interval, 1.05-1.79, P < .01), heart failure during procedure or surgery (adjusted odds ratio, 1.54; confidence interval, 1.21-1.97, P < .01), internal injuries of the thorax, abdomen, or pelvis (adjusted odds ratio, 1.59; confidence interval, 1.12-2.26, P < .01), intracranial injuries (adjusted odds ratio, 1.77; confidence interval, 1.20-2.61, P < .01), pulmonary edema (adjusted odds ratio, 2.18; confidence interval, 1.54-3.10, P < .01), thrombotic embolism (adjusted odds ratio, 1.58; confidence interval, 1.14-2.17, P < .01), and blood transfusion (adjusted odds ratio, 1.50; confidence interval, 1.30-1.72, P < .01) compared to fertile women. Fertile women did not face a significantly higher risk of any maternal morbidity indicator compared to infertile women. In subgroup analysis by maternal race/ethnicity, the likelihood of severe morbidity was significantly higher among fertile black women compared to fertile white women. There was no difference between infertile black women and infertile white women after multivariable adjustment. CONCLUSION: Using an insurance claims database, we report that women diagnosed with infertility and women receiving fertility treatment experience a significantly higher risk of multiple indicators of severe maternal morbidity compared to fertile women. The increased risk of severe maternal morbidity noted among fertile black women compared to fertile white women is attenuated among infertile black women, who face risks similar to those of infertile white women.

PROGNOSTIC VALUE OF BLASTOCYST GRADE AFTER FROZEN EUPLOID EMBRYO TRANSFER IN PATIENTS WITH RECURRENT PREGNANCY LOSS.

OBJECTIVE: To determine if trophectoderm (TE) grade or inner cell mass (ICM) grade have predictive value after euploid frozen embryo transfer (euFET) among RPL patients. DESIGN: Retrospective cohort study. SETTING: Single fertility center, 2012-2018. PATIENTS: Patients with ≥ 2 prior pregnancy losses performing PGT-A with ≥1 euploid embryo for transfer. INTERVENTIONS: All patients underwent ICSI, trophectoderm biopsy, blastocyst grading and vitrification, and single euFET. Outcome of the first transfer was recorded. MAIN OUTCOME MEASURES: Live birth (LB) and clinical miscarriage (CM) rates. RESULTS: 660 euFET were included. In a binomial logistic regression analysis accounting for age, BMI, AMH and day of blastocyst biopsy, ICM grade C was not significantly associated with odds of live birth (aOR 0.50, 95% CI 0.24-1.02 p=0.057), miscarriage (aOR 1.67, 95% CI 0.56-5.00, p=0.36) or biochemical pregnancy loss (aOR 1.58, 95% CI 0.53-4.75, p=0.42). TE grade C was significantly associated with odds of live birth (aOR 0.49, 95% CI 0.28-0.86, p=0.01) and was not associated with odds of miscarriage (aOR 2.00, 95% CI 0.89-4.47, p=0.09) or biochemical pregnancy loss (aOR 1.85, 95% CI 0.77-4.44, p=0.17). Blastocyst grade CC had significantly lower LB rate compared to all other blastocyst grades (p<0.05, chi-square analysis). CONCLUSION: Embryo grade CC and TE grade C are associated with decrease in odds of LB after euFET in RPL patients. Embryo grade is not associated with odds of CM in this cohort of RPL patients, suggesting that additional embryonic or uterine factors may influence risk of pregnancy loss.

Hormone replacement versus natural frozen embryo transfer for euploid embryos.

PURPOSE: The goal of this study is to investigate hormone replacement (HR) versus natural frozen embryo transfer outcomes for euploid embryos. METHODS: This is a retrospective cohort study at an academic medical center of patients undergoing in vitro fertilization with 24-chromosome day 5/6 preimplantation genetic testing for aneuploidies (PGT-A), from 2014 to 2018 using euploid single embryo frozen transfer. Multivariable logistic regression was used to study the association between transfer outcomes (ongoing pregnancy and miscarriage) with type of frozen euploid embryo transfer (HR versus natural) while controlling for multiple patient and cycle confounders. RESULTS: From a total of 389 cycles, 45.0% utilized HR frozen embryo transfer and 55.0% were natural cycles. We found that when compared to HR frozen embryo transfer, natural cycle frozen embryo transfer had significantly higher ongoing pregnancy rates (aOR 2.05, 1.27-3.31, p = 0.003). There was no significant difference in miscarriage rates between the two groups (aOR for natural 0.69, 95% CI 0.37-1.32, p = 0.27). When limiting the analysis to only the first transfer at our institution, findings were similar of higher ongoing pregnancy rates and no difference in miscarriage rates. CONCLUSIONS: In our multivariate analysis, we found that natural cycle single euploid frozen embryo transfer was associated with significantly higher ongoing pregnancy rates than HR transfer, with no difference in miscarriage rates.

Antimullerian hormone is a predictor of live birth in patients with recurrent pregnancy loss.

BACKGROUND: Ovarian reserve testing is not routinely performed in the evaluation of recurrent pregnancy loss (RPL). The objective of this study was to determine if AMH levels are predictive of live birth rate in RPL patients pursuing expectant management (EM). METHODS: Retrospective cohort study of RPL patients. Patients tried to conceive spontaneously for 12 calendar months or until they achieved a live birth, whichever occurred first. All patients with the intent to conceive were included regardless of final outcome. RESULTS: One hundred fifty-five RPL patients treated from 2009 to 2017 were included. In a univariate logistic regression, AMH < 1 ng/mL was associated with decreased likelihood of live birth (OR 0.38; CI 0.16-0.87, p = 0.03) and increasing age (OR 0.91; CI 0.83-0.99, p = 0.04). Likelihood of live birth was not significantly associated with BMI (OR 1.21; CI 0.83-1.77, p = 0.31), three or four or more prior pregnancy losses (OR 0.93; CI 0.40-2.22, p = 0.87 and OR 0.52; CI 0.19-1.42, p = 0.20, respectively) and prior live births (OR 1.00; CI 0.48-2.08, p = 0.99). AMH < 1 ng/mL was shown to be a stronger predictor of live birth than age using a multivariate model adjusting for age, AMH, and time to conception. CONCLUSIONS: AMH < 1 ng/mL is associated with decreased likelihood of live birth among RPL patients pursuing EM, and may be a stronger predictor of live birth than age in this population.

Risk of cancer in infertile women: analysis of US claims data.

STUDY QUESTION: Is female infertility associated with higher risk of cancer? SUMMARY ANSWER: Although absolute risks are low, infertility is associated with higher risk of cancer compared to a group of non-infertile women. WHAT IS KNOWN ALREADY: Infertile women are at higher risk of hormone-sensitive cancers. Information on risk of non-gynecologic cancers is rare and conflicting, and the effect of pregnancy on these risk associations is known for only a minority of cancer types. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis between 2003 and 2016 using an insurance claims database. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 64 345 infertile women identified by infertility diagnosis, testing or treatment were compared to 3 128 345 non-infertile patients seeking routine gynecologic care. Women with prior diagnosis of cancer or within 6 months of index event were excluded. Main outcomes were development of any malignancy and individual cancers as identified by ICD-9/ICD-10 codes. Results were adjusted for age at index date, index year, nulliparity, race, smoking, obesity, number of visits per year and highest level of education. MAIN RESULTS AND THE ROLE OF CHANCE: Infertile women had an overall higher risk of developing cancer compared to non-infertile women (2.0 versus 1.7%, adjusted hazard ratio (aHR) = 1.18; CI: 1.12-1.24). In addition, the risk of uterine cancer (0.10 versus 0.06%, aHR = 1.78; CI: 1.39-2.28), ovarian cancer (0.14 versus 0.09%, aHR 1.64; CI: 1.33-2.01), lung cancer (0.21 versus 0.21%, aHR = 1.38; CI: 1.01-1.88), thyroid cancer (0.21 versus 0.16%, aHR = 1.29; CI: 1.09-1.53), leukemia (0.10 versus 0.06%, aHR = 1.55; CI: 1.21-1.98) and liver and gallbladder cancer (0.05 versus 0.03%, aHR = 1.59; CI: 1.11-2.30) were higher in infertile women compared to non-infertile women. In a subgroup analysis of women in each cohort who became pregnant and had a delivery during enrollment, the risk of uterine and ovarian cancer were similar between infertile and non-infertile women. In a subgroup analysis excluding women with PCOS and endometriosis from both cohorts, the risk of uterine cancer was similar between infertile and non-infertile women. LIMITATIONS, REASONS FOR CAUTION: Absolute risk of cancer was low, average follow up for each individual was limited, and average age at index date was limited. Insurance databases have known limitations. WIDER IMPLICATIONS OF THE FINDINGS: Using claims-based data, we report that infertile women may have a higher risk of certain cancers in the years after infertility evaluation; continued follow up should be considered after reproductive goals are achieved. STUDY FUNDING/COMPETING INTEREST(S): None.

Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data.

BACKGROUND: The risk of common chronic medical conditions among infertile women is not known. OBJECTIVE: The objective of the study was to study the association between female infertility and the risk of incident chronic disease. STUDY DESIGN: This was a retrospective cohort analysis using the Optum deidentified Clinformatics Datamart from 2003 through 2016. A total of 64,345 infertile women were identified by infertility diagnosis, testing, or treatment and compared with 3,128,345 noninfertile patients seeking routine gynecologic care. Women with a prior diagnosis of the relevant chronic disease or cancer or with either diagnosis within 6 months of the index event were excluded. The main outcome was a diagnosis of incident chronic disease as identified by International Classification of Diseases, ninth revision/International Classification of Diseases, 10th revision codes. Results were adjusted for age, index year, nulliparity, race, smoking, obesity, number of visits per year, and highest level of education. RESULTS: Infertile patients were more likely to develop diabetes (adjusted hazard risk, 1.44, confidence interval, 1.38-1.49), renal disease (adjusted hazard risk, 1.22, confidence interval, 1.12-1.32), liver disease (adjusted hazard risk, 1.25, confidence interval, 1.20-1.30), cerebrovascular disease (adjusted hazard risk, 1.26, confidence interval, 1.15-1.38), ischemic heart disease (adjusted hazard risk, 1.16, confidence interval, 1.09-1.24), other heart disease (adjusted hazard risk, 1.16, confidence interval, 1.12-1.20), and drug abuse (adjusted hazard risk, 1.24, confidence interval, 1.15-1.33) compared with noninfertile patients. Infertile patients were significantly less likely to develop alcohol abuse (adjusted hazard risk, 0.86, confidence interval, 0.79-0.95) compared with noninfertile patients. Risk associations were similar after excluding women with polycystic ovarian syndrome and premature ovarian insufficiency. In subgroup analyses of women who underwent pregnancy and childbirth during enrollment, several previously noted risk associations were attenuated compared with the overall cohort. CONCLUSION: While the absolute risk of chronic disease is low, infertility is associated with an increased risk of incident chronic disease compared with a group of noninfertile women.

Gestational carrier in assisted reproductive technology.

OBJECTIVE: To compare clinical outcomes of in vitro fertilization (IVF) cycles with the use of gestational carriers (GCs) with non-GC IVF cycles. DESIGN: Retrospective cohort study of assisted reproductive technology (ART) cycles performed with (24,269) and without (1,313,452) the use of a GC. SETTING: ART centers. PATIENT(S): Infertile patients seeking IVF with or without use of a GC. INTERVENTIONS(S): Autologous and donor oocyte cycles, fresh and cryopreserved embryo transfer cycles. MAIN OUTCOME MEASURE(S): Live birth rate (LBR), twin and high-order multiple birth rates. RESULT(S): Approximately 2% of embryo transfers used a GC. Per embryo transfer, GCs had greater pregnancy rate and LBR across all IVF types compared with non-GC cycles in crude models and models adjusted a priori for potential confounders. For women with uterine-factor infertility, embryo transfer with the use of a GC resulted in a higher odds of live birth for autologous fresh embryos and for cryopreserved embryos compared with patients with non-uterine-factor infertility diagnoses. CONCLUSION(S): GC benefits LBRs for some patients seeking ART. The highest LBRs occurred when the indication for GC was uterine-factor infertility.