Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants.

PURPOSE: Miscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations. METHODS: We analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups. RESULTS: This study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1-10% of cases affected by biallelic lethal variants. CONCLUSION: This study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

Platelet-rich plasma infusion as an adjunct treatment for persistent thin lining in frozen embryo transfer cycles: first US experience report.

PURPOSE: To study effect of intrauterine infusion of platelet-rich plasma (PRP) on endometrial growth in the setting of thin endometrial lining in patients with prior cancelled or failed frozen embryo transfer (FET) cycles. MATERIALS AND METHODS: Single-arm cohort study of forty-six patients (51 cycles) with endometrial lining thickness (EMT) < 6 mm in prior cancelled or failed FET cycles requesting intrauterine PRP treatment in upcoming FET cycle. The primary outcomes were final EMT in FET cycle and change in EMT after PRP. The secondary outcomes were overall pregnancy rate, clinical pregnancy rate, miscarriage rate, ongoing pregnancy, and live birth rates. RESULTS: The mean pre-PRP EMT in all FET cycles was 4.0 ± 1.1 mm, and mean post-PRP EMT (final) was 7.1 ± 1.0 mm. Of 51 cycles, 33 (64.7%) reached ≥ 7 mm after PRP administration. There was a significant difference between pre-PRP EMT and post-PRP EMT in all FET cycles, with mean difference of 3.0 ± 1.5 mm. Three cycles were cancelled for failure to reach adequate lining. Total pregnancy rate was 72.9% in our cohort of 48 cycles that proceeded to transfer. Clinical pregnancy rate was 54.2% (26/48 FET cycles); clinical miscarriage rate was 14.3% (5/35 pregnancies). Twenty six women had live birth (18 with EMT ≥ 7 mm and 8 with EMT < 7 mm). Response to PRP was not correlated with any pre-cycle characteristics. CONCLUSION: We demonstrate a significant improvement in lining thickness and pregnancy rates in this challenging cohort of women after PRP infusion, with no adverse events. Cost-effectiveness of PRP with benefits and alternatives should be carefully considered.

Mosaic embryo transfer versus additional IVF with PGT-A Cycle: a decision model comparing live birth rate and cost.

PURPOSE: To evaluate the relative live birth rate and net cost difference between mosaic embryo transfer and an additional cycle of IVF with PGT-A for patients whose only remaining embryos are non-euploid. METHODS: A decision analytic model was designed with model parameters varying based on discrete age cutoffs (<35, 35-37, 38-39, 40-42, 43-44, >44). Model inputs included probabilities of successful IVF, clinical pregnancy, and live birth as well as costs of IVF with PGT-A, embryo transfer, live birth, amniocentesis, and dilation and curettage. All costs were modeled from the healthcare system perspective and adjusted for inflation to 2023 $USD. Model outcomes were sub-stratified by degree and type of mosaicism. RESULTS: For patients younger than 43, an additional cycle of IVF with PGT-A resulted in a higher relative live birth rate (<35, +20%; 35-37, +15%; 38-39, +17%; 40-42, +6%; average, +14.5%) compared to mosaic embryo transfer with an average additional cost of $16,633. For patients older than 42, mosaic embryo transfer resulted in a higher live birth rate (43-44, +5%; >44, +3%; average, +4%) while on average costing $9572 less than an additional cycle of IVF with PGT-A. CONCLUSION: Mosaic embryo transfers are a superior alternative to an additional cycle of IVF with PGT-A for patients older than 42 whose only remaining embryos are non-euploid. Mosaic embryo transfers also should be considered for patients younger than 42 who are unable to pursue additional autologous IVF cycles. Counseling and care should be personalized to individual patients and embryos.

Fertility issues in hypopituitarism.

Women with hypopituitarism have lower fertility rates and worse pregnancy outcomes than women with normal pituitary function. These disparities exist despite the use of assisted reproductive technologies and hormone replacement. In women with hypogonadotropic hypogonadism, administration of exogenous gonadotropins can be used to successfully induce ovulation. Growth hormone replacement in the setting of growth hormone deficiency has been suggested to potentiate reproductive function, but its routine use in hypopituitary women remains unclear and warrants further study. In this review, we will discuss the clinical approach to fertility in a woman with hypopituitarism.

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.

Pregnancy and neonatal outcomes of letrozole versus natural cycle frozen embryo transfer of autologous euploid blastocyst.

PURPOSE: To investigate the pregnancy and neonatal outcomes of letrozole-stimulated frozen embryo transfer (LTZ-FET) cycles compared with natural FET cycles (NC-FET). METHODS: Our retrospective cohort included all LTZ-FET (n = 161) and NC-FET (n = 575) cycles that transferred a single euploid autologous blastocyst from 2016 to 2020 at Stanford Fertility Center. The LTZ-FET protocol entailed 5 mg of daily letrozole for 5 days starting on cycle day 2 or 3. Outcomes were compared using absolute standardized differences (ASD), in which a larger ASD signifies a larger difference. Multivariable regression models adjusted for confounders: maternal age, BMI, nulliparity, embryo grade, race, infertility diagnosis, and endometrial thickness. RESULTS: The demographic and clinical characteristics were overall similar. A greater proportion of the letrozole cohort was multiparous, transferred high-graded embryos, and had ovulatory dysfunction. The cohorts had similar pregnancy rates (67.1% LTZ vs 62.1% NC; aOR 1.31, P = 0.21) and live birth rates (60.9% LTZ vs 58.6% NC; aOR 1.17, P = 0.46). LTZ-FET neonates on average were born 5.7 days earlier (P < 0.001) and had higher prevalence of prematurity (18.6% vs. 8.0%NC, ASD = 0.32) and low birth weight (10.4% vs. 5.0%, ASD = 0.20). Both cohorts' median gestational ages (38 weeks and 1 day for LTZ; 39 weeks and 0 day for NC) were full term. CONCLUSION: There were similar rates of pregnancy and live birth between LTZ-FET and NC-FET cycles. However, there was a higher prevalence of prematurity and low birth weight among LTZ-FET neonates. Reassuringly, the median gestational age in both cohorts was full term, and while the difference in gestational length of almost 6 days does not appear to be clinically significant, this warrants larger studies.

Association between preconception paternal health and pregnancy loss in the USA: an analysis of US claims data.

STUDY QUESTION: Is preconception paternal health associated with pregnancy loss? SUMMARY ANSWER: Poor preconception paternal health is associated with a higher risk of pregnancy loss as confirmed in sensitivity analyses accounting for maternal age and health. WHAT IS KNOWN ALREADY: Preconception paternal health can negatively impact perinatal outcomes. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of US insurance claims database from 2009 to 2016 covering 958 804 pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: US insurance claims database including women, men and pregnancies within the USA between 2007 and 2016. Paternal preconception health status (e.g. metabolic syndrome diagnoses (MetS), Charlson comorbidity index (CCI) and individual chronic disease diagnoses) was examined in relation to pregnancy loss (e.g. ectopic pregnancy, miscarriage and stillbirth). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 958 804 pregnancies were analyzed. The average paternal age was 35.3 years (SD 5.3) and maternal age was 33.1 years (SD 4.4). Twenty-two percent of all pregnancies ended in a loss. After adjusting for maternal factors, the risk of pregnancy loss increased with increasing paternal comorbidity. For example, compared to men with no components of MetS, the risk of pregnancy loss increased for men with one (relative risk (RR) 1.10, 95% CI 1.09-1.12), two (RR 1.15, 95% CI 1.13-1.17) or three or more (RR 1.19, 95% CI 1.14-1.24) components. Specifically, less healthy men had a higher risk of siring a pregnancy ending in spontaneous abortion, stillbirth and ectopic pregnancies. Similar patterns remained with other measures of paternal health (e.g. CCI, chronic diseases, etc.). When stratifying by maternal age as well as maternal health, a similar pattern of increasing pregnancy loss risk for men with 1, 2 or 3+ MetS was observed. A statistically significant but weak association between timing of pregnancy loss and paternal health was found. LIMITATIONS, REASONS FOR CAUTION: Retrospective study design covering only employer insured individuals may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: Optimization of a father's health may improve pregnancy outcomes. STUDY FUNDING/COMPETING INTERESTS: National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085). M.L.E. is an advisor for Sandstone Diagnostics, Dadi, Hannah and Underdog. No other competing interests were declared. TRIAL REGISTRATION NUMBER: N/A.

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.

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.

A Retrospective Study Examining Phentermine on Preconception Weight Loss and Pregnancy Outcomes.

OBJECTIVE: Obesity is a well-known risk factor for infertility. However, the use of weight loss medications prior to conception is underutilized. The objectives of our study are to describe weight loss, pregnancy rates, and live birth rates after short-term phentermine use in women with obesity and infertility. METHODS: This was a retrospective analysis of 55 women (18 to 45 years old) who were overweight or obese, diagnosed with infertility, and prescribed phentermine for weight loss in an ambulatory endocrinology clinic at a single, tertiary level academic medical center. Main outcome measures were mean percent weight change at 3 months after starting phentermine, and pregnancy, and live birth rates from start of phentermine to June 30, 2017. RESULTS: Median duration of phentermine use was 70 days (Q1, Q3 [33, 129]). Mean ± SD percent weight change at 3 months after starting phentermine was -5.3 ± 4.1% (P<.001). The pregnancy rate was 60% and the live birth rate was 49%. There was no significant difference in pregnancy rates (52% versus 68%; P = .23) or live birth rates (44% versus 54%; P = .50) in women who lost ≥5% versus <5% of their baseline weight. The number of metabolic comorbidities was negatively associated with the pregnancy rate. Phentermine was generally well-tolerated with no serious adverse events. CONCLUSION: Phentermine can produce clinically significant weight loss in women with obesity during the preconception period. Higher pregnancy or live birth rates were not observed with a greater degree of weight loss with phentermine.

Levonorgestrel IUD: is there a long-lasting effect on return to fertility?

Intrauterine devices (IUDs) are effective and safe long-acting reversible contraceptive methods for preventing unplanned pregnancies. While extensive studies were conducted to evaluate return to fertility after removal of IUDs, majority of them were focused on multiparous women using copper IUDs. Current trends indicate increased use of levonorgestrel (LNG) IUDs in nulliparous women for very long periods of time, with both nulliparity and long duration of LNG-IUD use being potentially associated with trends towards longer time to conception post removal. Understanding the effects that LNG-IUDs may have on endometrial morphology and gene expression has important implications to further understanding their mechanism of action. Studies examining endometrial gene expression show persistent changes in receptivity markers up to 1 year after removal of an inert IUD, and no similar studies have been performed after removal of LNG-IUDs. Given the current gap in the literature and trends in LNG-IUD use in nulliparous young women, studies are needed that specifically look at the interaction of nulliparity, long-term use of LNG-IUD, and return to normal fertility. Herein, we review the available literature on the mechanism of action of IUDs with a specific focus on the effect on endometrial gene expression profile changes associated with IUDs.

Preimplantation genetic testing for aneuploidy in poor ovarian responders with four or fewer oocytes retrieved.

PURPOSE: To assess whether preimplantation genetic testing for aneuploidies (PGT-A) at the blastocyst stage improves clinical outcomes compared with transfer of embryos without PGT-A in poor ovarian response (POR) patients. METHODS: Retrospective cohort study of IVF cycles from 2016 to 2019 at a single academic fertility center. IVF cycles with POR and four or fewer oocytes retrieved were stratified into PGT-A (n = 241) and non-PGT (n = 112) groups. In PGT-A cycles, trophectoderm biopsy, next-generation sequencing with 24-chromosome screening, and single euploid frozen embryo transfer were performed. In non-PGT cycles, fresh or frozen transfer of untested embryos on day 3 or 5 was performed. Main outcomes included live birth rate and miscarriage rate per retrieval. RESULT(S): Patients who underwent PGT-A cycles were significantly less likely to reach embryo transfer compared with those who underwent non-PGT cycles (13.7% vs 70.6%). The live birth rate per retrieval did not differ between the PGT-A and non-PGT groups (6.6% vs 5.4%). Overall, the miscarriage rate was low. The PGT-A group demonstrated a significantly lower miscarriage rate per retrieval (0.4% vs 3.6%) as well as per pregnancy (5.9% vs 40.0%) compared with the non-PGT group. The number needed to treat to avoid one clinical miscarriage was 31 PGT-A cycles. CONCLUSION(S): PGT-A did not improve live birth rate per retrieval in POR patients with four or fewer oocytes retrieved. PGT-A was associated with a lower miscarriage rate; however, a fairly large number of PGT-A cycles were needed to prevent one miscarriage.

The impact of culture conditions on blastocyst formation and aneuploidy rates: a comparison between single-step and sequential media in a large academic practice.

PURPOSE: To compare a single-step medium with a sequential medium on human blastocyst development rates, aneuploidy rates, and clinical outcomes. METHODS: Retrospective cohort study of IVF cycles that used Sage advantage sequential medium (n = 347) and uninterrupted Sage 1-step medium (n = 519) from July 1, 2016, to December 31, 2017, in an academic fertility center. Main outcome measures are blastocyst formation rates per two-pronuclear (2PN) oocyte and aneuploidy rates per biopsy. RESULTS: Of all IVF cycles, single-step medium yielded higher blastocyst formation rate (51.7% vs 43.4%) but higher aneuploidy rate (54.0% vs 45.8%) compared with sequential medium. When stratified by maternal age, women under age 38 had no difference in blastocyst formation (52.2% vs 50.2%) but a higher aneuploidy rate (44.5% vs 36.4%) resulting in a lower number of euploid blastocysts per cycle (2.6 vs 3.3) when using single-step medium compared to sequential medium. In cycles used single-step medium, patients ≥ age 38 had higher blastocyst rate (48.0% vs 33.6%), but no difference in aneuploidy rate (68.8% vs 66.0%) or number of euploid embryos (0.8 vs 1.1). For patients reaching euploid embryo transfer, there was no difference in clinical pregnancy rates, miscarriage rates, or live birth rates between two culture media systems. CONCLUSIONS: Our study demonstrates an increase in aneuploidy in young women whose embryos were cultured in a single-step medium compared to sequential medium. This study highlights the importance of culture conditions on embryo ploidy and the need to stratify by patient age when examining the impact of culture conditions on overall cycle potential.

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.

Are blastocyst aneuploidy rates different between fertile and infertile populations?

PURPOSE: This study aimed to determine if patients with infertility or recurrent pregnancy loss have higher rates of embryo aneuploidy than fertile controls. METHODS: This was a retrospective review of all pre-implantation genetic screening (PGS) cases processed by a single reference lab prior to March 2014 after a blastocyst biopsy. Cases were excluded if no indication for PGS was designated or patients were translocation carriers. The fertile control group consisted of patients undergoing IVF with PGS for sex selection only. The comparison cohorts included those with recurrent pregnancy loss, male factor infertility, unexplained infertility, prior failed IVF, or previous aneuploid conceptions. A quasi-binomial regression model was used to assess the relationship between the dependent variable, aneuploidy rate and the independent variables, maternal age and reason for PGS. A quasi-Poisson regression model was used to evaluate the relationship between similar independent variables and the number of blastocyst biopsies per case. RESULTS: The initial study population consisted of 3378 IVF-PGS cycles and 18,387 analyzed trophectoderm samples. Controlling for maternal age, we observed an increased rate of aneuploidy among patients with recurrent pregnancy loss (OR 1.330, p < 0.001), prior aneuploid pregnancy (OR 1.439, p < 0.001), or previous failed IVF cycles (OR 1.356, p = 0.0012) compared to fertile controls. Patients with unexplained and male factor infertility did not have a significantly different aneuploidy rate than controls (p > 0.05). The increase in aneuploidy in patients with RPL and prior IVF failure was driven by both an increase in meiotic (OR 1.488 and 1.508, p < 0.05) and mitotic errors (1.269 and 1.393, p < 0.05) relative to fertile controls, while patients with prior aneuploid pregnancies had only an increased risk of meiotic error aneuploidies (OR 1.650, p < 0.05). CONCLUSIONS: Patients with recurrent pregnancy loss, previous IVF failures, and prior aneuploid pregnancies have a significantly higher, age-independent, aneuploidy rate compared to patients without infertility.

Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss.

STUDY QUESTION: In an intent to treat analysis, are clinical outcomes improved in recurrent pregnancy loss (RPL) patients undergoing IVF and preimplantation genetic screening (PGS) compared with patients who are expectantly managed (EM)? SUMMARY ANSWER: Among all attempts at PGS or EM among RPL patients, clinical outcomes including pregnancy rate, live birth (LB) rate and clinical miscarriage (CM) rate were similar. WHAT IS KNOWN ALREADY: The standard of care for management of patients with RPL is EM. Due to the prevalence of aneuploidy in CM, PGS has been proposed as an alternate strategy for reducing CM rates and improving LB rates. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 300 RPL patients treated between 2009 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among two academic fertility centers, 112 RPL patients desired PGS and 188 patients chose EM. Main outcomes measured were pregnancy rate and LB per attempt and CM rate per pregnancy. One attempt was defined as an IVF cycle followed by a fresh embryo transfer or a frozen embryo transfer (PGS group) and 6 months trying to conceive (EM group). MAIN RESULTS AND THE ROLE OF CHANCE: In the IVF group, 168 retrievals were performed and 38 cycles canceled their planned PGS. Cycles in which PGS was intended but cancelled had a significantly lower LB rate (15 versus 36%, P = 0.01) and higher CM rate (50 versus 14%, P < 0.01) compared with cycles that completed PGS despite similar maternal ages. Of the 130 completed PGS cycles, 74% (n = 96) yielded at least one euploid embryo. Clinical pregnancy rate per euploid embryo transfer was 72% and LB rate per euploid embryo transfer was 57%. Among all attempts at PGS or EM, clinical outcomes were similar. Median time to pregnancy was 6.5 months in the PGS group and 3.0 months in the EM group. LIMITATIONS, REASONS FOR CAUTION: The largest limitation is the retrospective study design, in which patients who elected for IVF/PGS may have had different clinical prognoses than patients who elected for expectant management. In addition, the definition of one attempt at conception for PGS and EM groups was different between the groups and can introduce potential confounders. For example, it was not confirmed that patients in the EM group were trying to conceive for each month of the 6-month period. WIDER IMPLICATIONS OF THE FINDING: Success rates with PGS are limited by the high incidence of cycles that intend but cancel PGS or cycles that do not reach transfer. Counseling RPL patients on their treatment options should include not only success rates with PGS per euploid embryo transferred, but also LB rate per initiated PGS cycle. Furthermore, patients who express an urgency to conceive should be counseled that PGS may not accelerate time to conception. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A. TRIAL REGISTRATION DATE: N/A. DATE OF FIRST PATIENT'S ENROLLMENT: N/A.

Patient Experience with Karyotyping After First Trimester Miscarriage: A National Survey.

OBJECTIVE: To assess the frequency of chromosome testing after first trimester miscarriage as well as to investigate patient experiences. STUDY DESIGN: An anonymous online questionnaire was developed and made available. Inclusion criteria were female, age ≥ 18, first trimester miscarriage, occurrence of miscarriage within the past year, miscarriage care provided in the United States, and survey completion. RESULTS: Of the 980 women who started the survey, 448 met inclusion criteria. Of those, 37 participants had chromosome testing on the miscarriage specimen. Of those who did not have testing, 66% said they wished they had done so at the time of miscarriage, and 67% said they would still want testing if it were available today. There was no correlation between patient age and chromosome testing. Chromosome testing increased in frequency with higher number of miscarriages, although the low number of women with chromosome testing limits our ability to draw definitive conclusions. On average, providers needed to spend 15-20 minutes with patients for them to feel like it was "enough time." CONCLUSION: In this national survey we found that chromosome testing is performed in approximately 8% of first trimester miscarriages. Our data indicate that the majority of patients experiencing first trimester miscarriage desire chromosome testing.

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.

Increased body mass index negatively impacts blastocyst formation rate in normal responders undergoing in vitro fertilization.

PURPOSE: The aim of this study is to investigate the effect of female BMI and metabolic dysfunction on blastocyst formation rate. METHODS: This was a retrospective cohort study that was performed in an academic center for reproductive medicine. Patients who were normal weight, overweight with metabolic dysfunction, or obese who had ≥6 oocytes retrieved in a fresh IVF cycle were included in the study. The blastocyst formation rate was calculated from the number of ≥5 cell embryos on day 3 observed in culture until day 5 or day 6. Only good quality blastocysts were included in the calculation as defined by a morphologic grade of 3BB or better. RESULTS: The blastocyst formation rate was significantly better in the normal-weight controls versus overweight/obese patients (57.2 versus 43.6 %, p < 0.007). There was no difference in blastocyst formation between the patients with a BMI 25-29.9 kg/m(2) with metabolic dysfunction and those with a BMI ≥30 kg/m(2). CONCLUSION: The maternal metabolic environment has a significant impact on embryo quality as measured by blastocyst formation. A decreased blastocyst formation rate is likely a significant contributor to poorer reproductive outcomes in overweight and obese women with infertility.