The association between uterine adenomyosis and adverse obstetric outcomes: A propensity score-matched analysis.

INTRODUCTION: This study examined obstetric outcomes in patients diagnosed with uterine adenomyosis. MATERIAL AND METHODS: This historical cohort study queried the Healthcare Cost and Utilization Project's National Inpatient Sample. The study population was all hospital deliveries in women aged 15-54 years between January 2016 and December 2019. The exposure was a diagnosis of uterine adenomyosis. The main outcome measures were obstetric characteristics, including placenta previa, placenta accreta spectrum, and placental abruption. Secondary outcomes were delivery complications including severe maternal morbidity. Analytic steps to assess these outcomes included (i) a 1-to-N propensity score matching to mitigate and balance prepregnancy confounders to assess obstetric characteristics, followed by (ii) an adjusting model with preselected pregnancy and delivery factors to assess maternal morbidity. Sensitivity analyses were also performed with restricted cohorts to account for prior uterine scar, uterine myoma, and extra-uterine endometriosis. RESULTS: After propensity score matching, 5430 patients with adenomyosis were compared to 21 720 patients without adenomyosis. Adenomyosis was associated with an increased odds of placenta accreta spectrum (adjusted-odds ratio [aOR] 3.07, 95% confidence interval [CI] 2.01-4.70), placenta abruption (aOR 3.21, 95% CI: 2.60-3.98), and placenta previa (aOR 5.08, 95% CI: 4.25-6.06). Delivery at <32 weeks of gestation (aOR 1.48, 95% CI: 1.24-1.77) and cesarean delivery (aOR 7.72, 95% CI: 7.04-8.47) were both increased in women with adenomyosis. Patients in the adenomyosis group were more likely to experience severe maternal morbidity at delivery compared to those in the nonadenomyosis group (aOR 1.86, 95% CI: 1.59-2.16). Results remained robust in the aforementioned several sensitivity analyses. CONCLUSIONS: This national-level analysis suggests that a diagnosis of uterine adenomyosis is associated with an increased risk of placental pathology (placenta accreta spectrum, placenta abruption, and placental previa) and adverse maternal outcomes at delivery.

Aneuploidy rates and morphokinetic parameters of embryos cultured in distinct culture media: a sibling oocyte study.

STUDY QUESTION: Do embryos from sibling oocytes assigned to distinct single-step media culture systems demonstrate differences in early embryo development, morphokinectics or aneuploidy rates? SUMMARY ANSWER: Embryo quality, morphokinetic parameters and aneuploidy rates from trophectoderm biopsy were similar between sibling embryos cultured in distinct media systems from the time of gamete isolation. WHAT IS KNOWN ALREADY: Studies on the effect of commercially available embryo culture media systems have demonstrated inconsistent impact on human embryonic development, morphokinetics, aneuploidy rates and clinical outcomes. In addition, these studies have been primarily randomized at the level of the embryo or the patient to culture media. STUDY DESIGN, SIZE, DURATION: Prospective sibling oocyte cohort derived from 200 subjects undergoing IVF at a tertiary academic medical center between February 2018 and November 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sibling oocytes were allocated to Global® or SAGE® media system based upon laterality of ovary from which they were retrieved. All embryos were cultured in a time-lapse incubator. Blastocysts underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy using next-generation sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: One hundred twenty-seven subjects (n = 127) had paired blastocysts for biopsy in each culture media system. There was no difference in top quality blastocyst formation (47.1 ± 31.0 vs 48.1 ± 27.2%; P = 0.87) nor aneuploidy rate (62.3 ± 34.0 vs 56.1 ± 34.4%; P = 0.07) for sibling embryos cultured in Global versus SAGE media system. Embryo morphokinetic parameters including time to each cell division from two cells (t2) to eight cells (t8), time to morula stage (tM), time to blastocele formation (tSB), time to fully formed blastocyst (tB) and time to expansion of the blastocyst (tEB) were similar between paired blastocysts from each culture media system. LIMITATIONS, REASONS FOR CAUTION: Pregnancy outcomes and offspring health data were not available for analysis. WIDER IMPLICATIONS OF THE FINDINGS: Commercially available culture media may not have a differential impact on embryo development and blastocyst aneuploidy rate when patient and stimulation-related factors are held constant. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. C.H. is owner of a consultancy company, IVF Professionals, Chief Scientific Officer at Apricity, Executive Director at TMRW and co-owner and shareholder of Aria Fertility. She has received speaker fees, consulting fees and travel support from Cooper Surgical and Vitrolife. J.B. is an employee and shareholder of vitrolife. TRIAL REGISTRATION NUMBER: N/A.

Microfluidic preparation of spermatozoa for ICSI produces similar embryo quality to density-gradient centrifugation: a pragmatic, randomized controlled trial.

STUDY QUESTION: Does processing of spermatozoa for IVF with ICSI by a microfluidic sperm separation device improve embryo quality compared with density-gradient centrifugation? SUMMARY ANSWER: Patients randomized to microfluidic sperm preparation had similar cleavage- and blastocyst-stage embryo quality and clinical and ongoing pregnancy rates to those who underwent standard sperm processing for IVF with ICSI. WHAT IS KNOWN ALREADY: Microfluidic sperm preparation can isolate spermatozoa for clinical use with minimal DNA fragmentation but with unclear impact on clinical outcomes. STUDY DESIGN, SIZE, DURATION: A prospective randomized controlled trial of 386 patients planning IVF from June 2017 through September 2021 was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and ninety-two patients were allocated to sperm processing with a microfluidic sperm separation device for ICSI, while 194 patients were allocated to clinical standard density-gradient centrifugation (control) at an academic medical centre. MAIN RESULTS AND THE ROLE OF CHANCE: In an intention to treat analysis, there were no differences in high-quality cleavage-stage embryo fraction [66.0 (25.8)% control versus 68.0 (30.3) microfluidic sperm preparation, P = 0.541, absolute difference -2.0, 95% CI (-8.5, 4.5)], or high-quality blastocyst fraction [37.4 (25.4) control versus 37.4 (26.2) microfluidic sperm preparation, P = 0.985, absolute difference -0.6 95% CI (-6, 5.9)] between groups. There were no differences in the clinical pregnancy or ongoing pregnancy rates between groups. LIMITATIONS, REASONS FOR CAUTION: The population studied was inclusive and did not attempt to isolate male factor infertility cases or patients with a history of elevated sperm DNA fragmentation. WIDER IMPLICATIONS OF THE FINDINGS: Microfluidic sperm separation performs similarly to density-gradient centrifugation in sperm preparation for IVF in an unselected population. STUDY FUNDING/COMPETING INTEREST(S): No external funding to declare. M.P.R. is a member of the Clinical Advisory Board for ZyMot® Fertility, Inc. TRIAL REGISTRATION NUMBER: NCT03085433. TRIAL REGISTRATION DATE: 21 March 2017. DATE OF FIRST PATIENT'S ENROLLMENT: 16 June 2017.

Expanded carrier screening for recessively inherited disorders: economic burden and factors in decision-making when one individual in a couple is identified as a carrier.

PURPOSE: When undergoing expanded carrier screening (ECS), couples are often screened sequentially to reduce need for a second individual's test. It is unknown how often partners of individuals found to be carriers complete the recommended testing with a sequential approach and what factors contribute to decision-making regarding partner testing. Additionally, the economic burden placed on individuals by ECS testing and its effect on partner testing has not been evaluated. METHODS: In part 1, all individuals at a university-affiliated reproductive endocrinology and infertility practice identified to be carriers of a recessively inherited mutation using the Counsyl/Foresight ECS were included. Conditions were categorized by severity according to a previously described classification system. In part 2, all individuals who underwent ECS with a single test provider between September 1, 2013 and February 1, 2020 were contacted via email to complete a confidential and anonymized online survey. RESULTS: In part 1, a total of 2061 patients were screened. 36.9% were carriers of one or more recessively inherited disorders. Twenty-seven percent of positively screened individuals did not have their partner screened. Carriers of a moderate condition had a trend towards a reduced odds for having their partner screened compared to a profound condition (OR 0.36, 95% CI 0.12-1.05, p = 0.06). Number of conditions was not predictive of subsequent partner screening (OR 0.95, 95% CI 0.72-1.25, p = 0.72). In part 2, the cost of ECS was not covered by insurance for 54.5% (103/189) and most paid over $300 out-of-pocket for testing (47.6%). The most common reason for not completing partner testing was that the results would not alter their course when seeking conception (33.3%). 73.5% of patients knew that the largest benefit of ECS comes from knowing a partner's results as well as their own. CONCLUSIONS: Not all carriers of recessively inherited disorders choose to undergo partner screening. Patients found to be carrier of more debilitating genetic disorders may be more likely to screen their reproductive partners. For many, ECS testing is not covered by insurance, and this test may impose a significant economic burden. For some patients, the results of ECS would not change what they would do when seeking conception. Providers should evaluate whether a patient's ECS result would change their treatment course prior to testing.

Sonographic abnormalities in pregnancies conceived following IVF with and without preimplantation genetic testing for aneuploidy (PGT-A).

PURPOSE: To report the rate of fetal anomalies detected on anatomy ultrasound in pregnant patients who underwent IVF with preimplantation genetic testing for aneuploidy (PGT-A) compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. METHODS: Retrospective cohort study at a single maternal-fetal medicine practice. Patients with singleton pregnancies who had a mid-trimester anatomy ultrasound between January 2017 and December 2018 were screened for inclusion. A total of 712 patients who conceived after IVF with or without PGT-A were age-matched with natural conception controls. The primary outcome was the rate of fetal and placental anomalies detected on mid-trimester anatomical survey. Secondary outcomes included the rates of abnormal nuchal translucency (NT), second trimester serum analytes, non-invasive prenatal testing (NIPT), and invasive diagnostic testing. RESULT(S): There were no differences in the rate of fetal anomalies in patients who underwent IVF with PGT-A compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. Rate of abnormal NT, high-risk NIPT, and abnormal invasive diagnostic testing were also similar. Patients who conceived after IVF with or without PGT-A had higher rates of abnormal placental ultrasound findings and abnormal second trimester serum analytes compared to natural conception controls. CONCLUSION: The use of PGT-A was not associated with a difference in risk of fetal anomaly detection on a mid-trimester anatomical survey. The results of this study highlight the importance of improved patient counseling regarding the limitations of PGT-A, and of providing standard prenatal care for pregnancies conceived through ART, regardless of whether PGT-A was performed.

We are here for you: infertility clinic communication during the first wave of the COVID-19 pandemic.

PURPOSE: To study how SART-member fertility clinics communicated via clinic websites during the first wave of the COVID-19 pandemic following publication of ASRM COVID-19 Task Force recommendations. METHODS: SART-member fertility clinic websites were systematically surveyed for the presence of an REI-specific COVID-19 message (REI-CM) and analyzed for their adherence to ASRM guidance. RESULTS: Of the 381 active clinic websites, 249 (65.3%) had REI-specific COVID messaging. The presence of REI-CM was more common in private than in academic practices (73% vs 38%, p < 0.001) and with increasing practice volume: 38% of clinics with < 200 annual cycles vs 91% of clinics with > 1000 cycles (p < 0.001). Adherence to ASRM guidance was more common in academic than in private practices (54% vs 31%, p = 0.02). Additionally, 9% of REI-CM (n = 23) announced continued treatment regardless of a patient's clinical urgency. This messaging was more common in groups doing > 1000 cycles a year (18%, p = 0.009). Clinics treating all-comers were less likely to cite ASRM than other clinics (41% vs 62%, p = 0.045). However, 75% (n = 14) cited COVID-19 guidance from WHO, CDC, and state and local governments. CONCLUSIONS: Clinic response to ASRM recommendations during the first wave of COVID-19 pandemic was heterogeneous. Although academic practices were more likely to follow ASRM guidance, there was a lower extent of patient-facing messaging among academic practices than private clinics. In event of further escalations of this and future pandemics, clinics can learn from experiences to provide clear messaging to patients.

Perceptions, motivations and decision regret surrounding preimplantation genetic testing for aneuploidy.

STUDY QUESTION: Is there a difference in level of decision regret following IVF treatment between those who choose to complete or not complete preimplantation genetic testing for aneuploidy [PGT-A]? SUMMARY ANSWER: Approximately one-third of the participants expressed moderate to severe regret (MSR) following their decision to either complete or not complete PGT-A; notably, decision regret was higher in those who chose not to complete PGT-A, primarily driven by significantly higher regret scores in those that experienced a miscarriage after not testing. WHAT IS KNOWN ALREADY: Previous research has found that 39% of participants who completed PGT-A expressed some degree of decision regret and that negative clinical outcomes, such as lack of euploid embryos, negative pregnancy test or miscarriage, were associated with a higher level of decision regret. To date, there are no published studies assessing the possible disparity in decision regret surrounding PGT-A in a population of IVF patients that either chose to pursue PGT-A or not. STUDY DESIGN, SIZE, DURATION: An anonymous online survey was distributed to 1583 patients who underwent IVF with or without PGT-A at a single university institution between January 2016 and December 2017. In total, 335 women accessed the survey, 220 met eligibility criteria and 130 completed the full study survey. Six participants were excluded due to refusal of medical record review, and nine participants were excluded after record review due to not meeting eligibility based on cycle start date or completing only embryo banking without attempting transfer. One hundred and fifteen participants were included in the final analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 115 participants included, 55 (48%) completed PGT-A and 60 (52%) did not complete PGT-A. The online survey included four sections: Demographics; Perceptions about PGT-A risks and benefits [scale from 0 (absolutely not true) to 100 (absolutely true)]; Decision-making factors [scale from 0 (not important) to 100 (very important)]; and Brehaut Decision Regret Scale [DRS] [range 0-100, with >25 indicating MSR]. A retrospective chart review was conducted to confirm study eligibility and collect cumulative clinical outcomes of consenting participants who completed the survey. MAIN RESULTS AND THE ROLE OF CHANCE: Demographics of the PGT-A and no PGT-A cohorts were similar, with the majority of respondents being Caucasian or Asian, unaffiliated with any religion and with a graduate or professional degree. The two groups differed significantly in mean age, with the PGT-A group being slightly older (mean ± SD: 37 ± 3.7 versus 36 ± 3.4; P = 0.048), and in rate of miscarriages, with fewer participants in the PGT-A cohort experiencing a miscarriage (5% versus 22%; P = 0.012). The majority of participants in both PGT-A and no PGT-A cohorts strongly believed in the purported benefits of PGT-A, including that it decreases the risk of birth defects (median 82 versus 77; P = 0.046), improves the chances of having a healthy baby (median 89 versus 74; P = 0.002) and selects the best embryo for transfer (median 85 versus 80; P = 0.049). When asked to report their motivating factors for decision-making, both groups cited physician counseling as important (median 70 versus 71; P = 0.671); however, the PGT-A cohort was more strongly motivated by a desire to not transfer abnormal embryos (median 84 versus 53; P = 0.0001). Comparison of DRS score between those who did or did not undergo PGT-A showed significantly higher median DRS score after not completing PGT-A (median 15 versus 0; P = 0.013). There was a significantly higher proportion of participants who did not complete PGT-A that expressed mild (36% versus 16%) and MSR (32% versus 24%) compared to those who completed PGT-A (χ2 = 9.03, df = 2; P = 0.011). Sub-group analyses of DRS scores by outcomes of clinical pregnancy, miscarriage and live birth revealed that the higher DRS score in those not completing PGT-A was driven by a large increase in regret noted by those with history of a miscarriage (median 45 versus 0; P = 0.018). Multivariate logistic regression modeling found no evidence that any specific demographic factor, clinical outcome or perception/motivation surrounding PGT-A was independently predictive of increased risk for MSR. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of data collection incurs the possibility of sampling and recall bias. As only 59% of eligible respondents completed the full survey, it is possible that mainly those with very positive or negative sentiments following treatment felt compelled to complete their response. This bias, however, would apply to the whole of the population, and not simply to those who did or did not complete PGT-A. WIDER IMPLICATIONS OF THE FINDINGS: The proportion of participants expressing any degree of decision regret in this PGT-A cohort was 40%, which is comparable to that shown in prior research. This study adds to prior data by also assessing decision regret experienced by those who went through IVF without PGT-A, and showed that 68% expressed some level of regret with their decision-making. These results should not be interpreted to mean that all patients should opt for PGT-A to pre-emptively mitigate their risk of regret. Instead, it suggests that drivers of decision regret are likely multifactorial and unique to the experience of one's personal expectations regarding PGT-A, motivations for pursuing or not pursuing it and resultant clinical outcome. Highlighting the complex nature of regret, these data should encourage physicians to more carefully consider individual patient values toward risk-taking or risk-averse behavior, as well as their own positions regarding PGT-A. Until there are clear recommendations regarding utilization of PGT-A, a strong collaboration between physicians and genetic counselors is recommended to educate patients on the risks and potential benefits of PGT-A in a balanced and individualized manner. STUDY FUNDING/COMPETING INTEREST(S): No funding was utilized for study completion and the authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Microfluidic sorting selects sperm for clinical use with reduced DNA damage compared to density gradient centrifugation with swim-up in split semen samples.

STUDY QUESTION: Does microfluidic sorting improve the selection of sperm with lower DNA fragmentation over standard density-gradient centrifugation? SUMMARY ANSWER: Microfluidic sorting of unprocessed semen allows for the selection of clinically usable, highly motile sperm with nearly undetectable levels of DNA fragmentation. WHAT IS KNOWN ALREADY: Microfluidic devices have been explored to sort motile and morphologically normal sperm from a raw sample without centrifugation; however, it is uncertain whether DNA damage is reduced in this process. STUDY DESIGN, SIZE, DURATION: This is a blinded, controlled laboratory study of differences in standard semen analysis parameters and the DNA fragmentation index (DFI) in split samples from infertile men (n = 70) that were discarded after routine semen analysis at an academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm concentration, progressive motility and forward progression were assessed by microscopic examination. For each sample, the unprocessed semen was tested for DNA fragmentation and split for processing by density-gradient centrifugation with swim-up or sorting by a microfluidic chip. DNA fragmentation was assessed in unprocessed and processed samples by sperm chromatin dispersion assay. The DFI was calculated, from up to 300 cells per slide, as the number of cells with fragmented DNA divided by the number of cells counted per slide. MAIN RESULTS AND THE ROLE OF CHANCE: The median DFI in unprocessed samples was 21% (interquartile range (IQR): 14-30). In paired analyses of all samples, those processed by the microfluidic chip demonstrated significantly decreased DFI compared to those processed by density-gradient centrifugation (P = 0.0029) and unprocessed samples (P < 0.0001). The median DFI for chip specimens was 0% (IQR: 0-2.4) while those processed by density-gradient centrifugation had a median DFI of 6% (IQR: 2-11). Unprocessed samples in the highest DFI quartile (DFI range: 31-40%) had a median DFI of 15% (IQR: 11-19%) after density-gradient centrifugation and DFI of 0% (IQR: 0-1.9%) after processing with the microfluidic chip (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: While a high DFI has been associated with poor outcomes with IVF/ICSI, there are limited data illustrating improvements in clinical outcomes with a reduction in DFI. As this study utilized discarded, non-clinical samples, clinical outcomes data are not available. WIDER IMPLICATIONS OF THE FINDINGS: While microfluidic sorting of unprocessed semen allowed for the selection of clinically usable, highly motile sperm with nearly undetectable levels of DNA fragmentation, standard processing by density-gradient centrifugation with swim-up did not increase DNA fragmentation in an infertile population. The proposed microfluidic technology offers a flow-free approach to sort sperm, requiring no peripheral equipment or filtration step, while minimizing hands-on time. STUDY FUNDING/COMPETING INTEREST(S): No external funding to declare. Utkan Demirci, PhD is the Co-founder and Scientific Advisor for DxNow Inc., LevitasBio Inc. and Koek Biotech. Mitchell Rosen, MD is a member of the Clinical Advisory Board for DxNow Inc.

Decreased clinical pregnancy and live birth rates after short interval from delivery to subsequent assisted reproductive treatment cycle.

STUDY QUESTION: Does the interval from delivery to initiation of a subsequent ART treatment cycle impact clinical pregnancy or live birth rates? SUMMARY ANSWER: An interval from delivery to treatment start of <6 months or ≥24 months is associated with decreased likelihood of clinical pregnancy and live birth. WHAT IS KNOWN ALREADY: Short interpregnancy intervals are associated with poor obstetric outcomes in the naturally conceiving population prompting birth spacing recommendations of 18-24 months from international organizations. Deferring a subsequent pregnancy attempt means a woman will age in the interval with an attendant decline in her fertility. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of the Society for Assisted Reproductive Technology Clinical Outcome Reporting System (SARTCORS) cohort containing 61 686 ART cycles from 2004 to 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The delivery-to-cycle interval (DCI) was calculated for patients from SARTCORS with a history of live birth from ART who returned to the same clinic for a first subsequent treatment cycle. Generalized linear models were fit to determine the risk of clinical pregnancy and live birth by DCI with subsequent adjustment for factors associated with outcomes of interest. Predicted probabilities of clinical pregnancy and live birth were generated from each model. MAIN RESULTS AND THE ROLE OF CHANCE: A DCI of <6 months was associated with a 5.6% reduction in probability of clinical pregnancy (40.1 ± 1.9 versus 45.7 ± 0.6%, P = 0.009) and 6.8% reduction in live birth (31.6 ± 1.7 versus 38.4 ± 0.6%, P = 0.001) per cycle start compared to a DCI of 12 to <18 months. A DCI of ≥24 months was associated with a 5.1% reduction in probability of clinical pregnancy (40.6 ± 0.5 versus 45.7 ± 0.6%, P < 0.001) and 5.7% reduction in live birth (32.7 ± 0.5 versus 38.4 ± 0.6%, P < 0.001) compared to 12 to <18 months. LIMITATIONS, REASONS FOR CAUTION: The SART database is reliant upon self-report of many variables of interest including live birth. It remains unclear whether poorer outcomes are a result of residual confounding from factors inherent to the population with a very short or long DCI or the interval itself. WIDER IMPLICATIONS OF THE FINDINGS: Birth spacing recommendations for naturally conceiving populations may not be generally applicable to patients with a history of infertility. Patients planning ART treatment should wait a minimum of 6 months, but not more than 24 months, from a live birth for optimization of clinical pregnancy and live birth rates. STUDY FUNDING/COMPETING INTEREST(S): National Center for Advancing Translational Sciences, National Institutes of Health, UCSF-CTSI Grant number UL1TR001872. The authors have no competing interests.

Decision-making surrounding the use of preimplantation genetic testing for aneuploidy reveals misunderstanding regarding its benefit.

PURPOSE: We aimed to explore how patients make decisions regarding use of preimplantation genetic testing for aneuploidy (PGT-A) for in vitro fertilization (IVF). METHODS: This is a cross-sectional survey at an academic medical center. Three hundred subjects initiating an IVF cycle over 8 weeks were asked to complete a validated survey to determine how they decided whether or not to pursue PGT-A. All patients were previously counseled that the primary goal of PGT-A is to maximize pregnancy rates per embryo transfer. Survey responses were compared between those who elected PGT-A and those who did not with a chi-squared or t test. RESULTS: Of 191 subjects who completed the survey, 117 (61%) planned PGT-A, while 74 (39%) did not. Among those who decided to undergo PGT-A, 56% stated their primary reason was to have a healthy baby, while 18% chose PGT-A to reduce the incidence of birth defects, and 16% aimed to decrease the risk of miscarriage. Patients who decided not to pursue PGT-A stated they prioritized avoiding the scenario in which they might have no embryos to transfer (36%) or reducing cost (31%). Both groups rated physicians as the single most important source of information in their decision-making (56% vs 68%, p = NS). CONCLUSIONS: Patients who chose to undergo PGT-A have different priorities from those who do not. Many patients planning PGT-A do so for reasons that are not evidence-based. While patients cite physicians as their primary source of information in the decision-making process, rationales for selecting PGT-A are inconsistent with physician counseling.

Women with polycystic ovary syndrome demonstrate worsening markers of cardiovascular risk over the short-term despite declining hyperandrogenaemia: Results of a longitudinal study with community controls.

OBJECTIVE: To compare age-associated changes in cardiovascular risk markers in lean and obese reproductive-aged women with polycystic ovary syndrome (PCOS) with community controls. DESIGN: Longitudinal study at an academic medical centre PATIENTS: Patients diagnosed with PCOS by 2004 Rotterdam criteria in a multidisciplinary clinic were systematically enrolled from 2006-2014 in a PCOS cohort study and subsequently agreed to participate in a longitudinal study. The comparison controls were from the prospective, longitudinal Ovarian Aging (OVA) study, which consists of healthy women with regular menstrual cycles recruited from 2006 to 2011. MEASUREMENTS: Cardiovascular risk markers and hormone parameters at baseline and follow-up. RESULTS: Obese and lean PCOS (n = 38) and control women (n = 296) completed two study visits. The follow-up time (3.5 ± 1.5 vs 4.0 ± 0.8 years, P = .06) and magnitude of BMI gain (+0.1 kg/m2 /y [-0.11, 0.36] vs +0.26 [-0.18, 0.87] P = .19) did not differ between obese and lean PCOS and controls. In PCOS subjects, total testosterone decreased in both obese and lean, but the decrease was greater in obese subjects (-0.09 nmol/L per year; 95% CI: -0.16, -0.02 vs -0.04 nmol/L per year; 95%CI: -0.11, 0.03). Compared to their respective controls, obese and lean PCOS saw worsening triglyceride (TG) levels (P < .05) and HOMA-IR (P < .05) over time, but there was no difference in change in LDL, HDL, fasting glucose, C-reactive protein or ALT. CONCLUSIONS: In a longitudinal study, reproductive-aged women with PCOS demonstrated declines in biochemical hyperandrogenaemia over time. Despite this, PCOS subjects experienced steeper increases in cardiovascular risk factors associated with insulin resistance, including triglycerides and HOMA-IR.

Age-stratified thresholds of anti-Müllerian hormone improve prediction of polycystic ovary syndrome over a population-based threshold.

OBJECTIVE: Due to its consistent elevation in polycystic ovary syndrome (PCOS) and correlation with polycystic ovarian morphology (PCOM), anti-Mullerian hormone (AMH) has been proposed as a marker of the syndrome. However, prior studies reporting thresholds of AMH for a PCOS diagnosis have been limited by small sample size, inappropriate controls, and heterogeneous AMH assays. We sought to evaluate the suitability of a standardized AMH assay as a biomarker of PCOS. DESIGN: Cross-sectional study at academic medical centres across the United States. PATIENTS: Women with PCOS were diagnosed by Rotterdam criteria and included 282 subjects from the multisite PPCOS II trial and 109 patients from a tertiary academic centre's multidisciplinary PCOS clinic. Controls included 245 participants in the ovarian ageing (OVA) study, a community-based cohort of ovulatory women not seeking treatment for fertility. MEASUREMENTS: Determination of AMH by a central laboratory. Receiver-operating characteristic (ROC) analyses were used to investigate the accuracy of AMH thresholds for prediction of PCOS diagnosis with stratification by age. RESULTS: The optimal threshold of AMH to distinguish PCOS from controls was 55.36 pmol/L (sensitivity: 0.82, specificity: 0.78, J: 0.60). When examining the population by age groups, the optimal AMH threshold decreased with increasing age. CONCLUSIONS: AMH is an effective biomarker of PCOS. Age-stratified thresholds more accurately predicted PCOS than an overall population-based threshold.

Response to ovarian stimulation is not impacted by a breast cancer diagnosis.

STUDY QUESTION: Does a breast cancer diagnosis impact ovarian function in the setting of fertility preservation? SUMMARY ANSWER: Ovarian reserve and ovarian stimulation outcomes are similar in patients with a new diagnosis of breast cancer and patients undergoing elective fertility preservation. WHAT IS KNOWN ALREADY: Prior studies, with small study populations, lack of controlling for individual differences in ovarian reserve and infertile controls, have reported conflicting outcomes for cancer patients undergoing ovarian stimulation for fertility preservation. STUDY DESIGN, SIZE, DURATION: This retrospective cohort analysis included 589 patients undergoing ovarian stimulation for fertility preservation between 2009 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a recent breast cancer diagnosis (n = 191) and women desiring elective fertility preservation (n = 398) underwent ovarian stimulation with an antagonist protocol at an academic medical center. The aromatase inhibitor letrozole was administered to breast cancer patients with estrogen-sensitive disease. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline antral follicle count (AFC) was not different between the breast cancer patients and controls (15.4 ± 10.4 [mean ± SD] vs 15.4 ± 10.0, P = NS), even after categorization by age. Total (19.4 ± 0.9 [mean ± SEM] vs 17.0 ± 0.5, P = NS) and mature (MII) oocytes retrieved (13.7 ± 0.7 vs 13.2 ± 0.4, P = NS), adjusted for age, BMI and total gonadotropin dose, were also similar between the two groups. Letrozole use was associated with a decreased maturity rate (MII/total oocytes retrieved) compared to elective cryopreservation (0.71 ± 0.01 vs 0.77 ± 0.01, P < 0.001), although the mature oocyte yield [MII/AFC] was comparable (1.01 ± 0.06 vs 0.93 ± 0.03, P = NS). LIMITATIONS, REASONS FOR CAUTION: The single center design may impact generalizability. Additionally, the lack of subsequent embryo and pregnancy data is an inherent weakness. WIDER IMPLICATIONS OF THE FINDINGS: In females, a breast cancer diagnosis does not impact gonadal function as measured by AFC or ovarian stimulation outcomes. Breast cancer patients should be counseled that their response to ovarian stimulation for fertility preservation is similar to that of patients undergoing elective oocyte cryopreservation. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Obstetric outcomes of women with congenital uterine anomalies in the United States.

BACKGROUND: Due to the rarity, congenital uterine anomaly type-specific evaluation of pregnant women has been relatively understudied. OBJECTIVE: To describe national-level obstetric outcomes in women with congenital uterine anomalies. STUDY DESIGN: This cross-sectional study queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Pregnant women with diagnosis of congenital uterine anomalies who had hospital delivery between 2016 and 2019 were examined. The World Health Organization's International Classification of Disease, 10th revision coding was used to delineate type of congenital uterine anomaly, diagnoses, and procedures performed during the index admission. Primary outcomes included pregnancy outcome, which was classified as full-term live birth, preterm live birth, abortion/stillbirth, or ectopic pregnancy. Secondary outcomes included obstetric comorbidities and severe maternal mortality, which were compared between different subtypes of congenital uterine anomalies with multivariable logistic regression model. RESULTS: A total of 50,180 pregnant women with congenital uterine anomalies were identified. Bicornuate was the most common subtype (73.5%), followed by arcuate (13.5%) and unicornuate (10.0%). 70.6% of women with congenital uterine anomalies had a full-term live birth, 26.8% had a preterm live birth, 2.1% had an abortion or stillbirth, and 0.4% had an ectopic pregnancy. 61.8% of preterm births occurred between 33 and 36 weeks, 16.9% between 30 and 32 weeks, and 21.3% at <30 weeks. There were 1,440 (2.9%) periviable births. The preterm (34.5%) and periviable (6.9%) birth rates were highest in the uterine didelphys group. Overall, two-thirds (65.7%) of patients with congenital uterine anomalies were delivered via cesarean section. When compared to arcuate uterus, risk of severe maternal morbidity in septate uterus (4.8% vs 2.6%, adjusted-odds ratio [aOR] 2.60, 95% confidence interval [CI] 1.49-4.52) was increased, including hemorrhage (14.5% vs 7.7%, aOR 2.16, 95% CI 1.51-3.07). This was followed by uterine didelphys (4.2% vs 2.6%, aOR 1.75, 95% CI 1.24-2.47), unicornuate uterus (3.8% vs 2.6%, aOR 1.61, 95% CI 1.29-2.01), and bicornuate uterus (3.0% vs 2.6%, aOR 1.23, 95% CI 1.04-1.47). CONCLUSION: While the majority of patients with congenital uterine anomalies result in full-term viable deliveries, each subtype of congenital uterine anomalies confers different obstetric risks. Uterine didelphys was associated with the highest risk of preterm birth, while septate uterus was associated with the highest risk of severe maternal morbidity. While this hospital delivery dataset likely overrepresents bicornuate uteri, this populational data may help inform patients with congenital anomalies considering pregnancy.

More follicle-stimulating hormone may not improve outcomes, but can it be counterproductive?

Many studies have sought to explore the impact of high-dose gonadotropin on stimulation outcomes based on a hypothesis that higher doses of follicle-stimulating hormone may harm the quantity or quality of oocytes and, therefore, be counterproductive. Herein, we describe the results of a narrative review aimed at elucidating any harm associated with "excess" follicle-stimulating hormone dosing in poor-to-moderate responders. Additionally, we sought to describe the outcomes associated with mild ovarian stimulation, with an eye toward determining whether this approach is superior. We concluded that there is no apparent harm to higher-dose gonadotropin stimulation for poor-to-moderate responders. Simultaneously, we did not find compelling data to suggest that mild stimulation is superior. Finally, we close by presenting data that suggest that more gonadotropin may be beneficial in specific clinical scenarios.

Planned Oocyte Cryopreservation: A Review of Current Evidence on Outcomes, Safety and Risks.

Although oocyte cryopreservation was initially used as a fertility preservation strategy for medical indications, it is now is increasingly used to circumvent age-related infertility. Outcomes following planned oocyte vitrification, also known as elective egg freezing, are limited. Current studies show higher success rates for individuals undergoing fertility preservation treatment under age 35. Additionally, while freezing 20 oocytes is optimal to achieve pregnancy, freezing at least 8-10 oocytes is recommended. While fertility is not guaranteed, current evidence demonstrates that planned oocyte vitrification is an overall safe, low risk method of fertility preservation to reduce the risk for age-related infertility.

A deep dive into the morphokinetics and ploidy of low-quality blastocysts.

Objective: To describe morphokinetic parameters and ploidy among low-quality blastocysts not meeting the criteria for clinical use. Design: Prospective cohort study. Setting: Academic medical center. Patients: Two hundred patients undergoing in vitro fertilization between February 2018 and November 2019. Interventions: All embryos were cultured in a time-lapse incubator. All expanded blastocysts underwent preimplantation genetic testing for aneuploidy using next-generation sequencing. Main Outcome Measures: Static blastocyst morphology grading; morphokinetic parameters, including time to each cell division (2-cell formation to 8-cell formation); time to morula formation; time to the start of blastulation; time to blastocyst formation; and preimplantation genetic testing for aneuploidy results. Results: A total of 1,306 embryos progressed to the expanded blastocyst stage; of these, 935 embryos met the criteria for clinical use and were designated as high quality, whereas 371 embryos were graded as low quality and did not meet the criteria for use. In morphokinetic evaluation, low-quality embryos developed more quickly to 5-cell formation (t5) 48.4 [42.4-48.7) vs 50.2 [46.3-50.1] hours, but progressed more slowly thereafter with tM 91.5 [85.9-92.3] vs 88.3 [82.1-88.3] and tB 114.0 [106.4-113.9] vs 106.9 [101.3-107.4] hours. Among the low-quality embryos, 75.5% were aneuploid, 22.4% were euploid, and 2.2% had undetermined chromosome copy number results. Morphokinetic parameters did not differ between the euploid and aneuploid low-quality embryos. Conclusions: Morphokinetic analysis did not distinguish between euploid and aneuploid low-quality embryos.

Provision of infertility care for the underserved in reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency training programs in the United States.

Objective: To survey practice patterns designed to increase access to infertility care and evaluate the exposure of obstetrics and gynecology residents to infertility care for the underserved. Design: Cross-sectional. Setting: Reproductive endocrinology and infertility (REI) practices associated with Accreditation Council for Graduate Medical Education-accredited obstetrics and gynecology residency training programs. Patients: None. Interventions: Questionnaire survey. Main Outcome Measures: Presence of clinical programs designed to improve access to REI care, resident involvement in such programs, and perceived barriers to expanding access to care. Results: Clinical initiatives to expand access included discounted infertility services (38%, n = 30), utilization of a low-cost in vitro fertilization (IVF) program (28%, n = 22), and utilization of a resident- and/or fellow-staffed clinic to provide infertility care (39%, n = 31). The most commonly discounted infertility services were IVF (73%, n = 22), clinical consultation (70%, n = 21), and intrauterine insemination (53%, n = 16). The provision of discounted prices was correlated with the increasing practice size (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.23-4.24) and number of assisted reproductive technology cycles performed annually (OR, 3.65; 95% CI, 1.48-9.02). Academic REI practices (OR, 3.6; 95% CI, 0.98-13.25) were more likely to have a low-cost IVF program. Less than half of obstetrics and gynecology residency programs (39%, n = 31) had an associated REI clinic in which obstetrics and gynecology residents provide direct infertility care to the medically underserved. Frequency and services offered in trainee clinics varied. Multiple barriers to expanding access to care were reported. Conclusions: Reproductive endocrinology and infertility practices associated with obstetrics and gynecology residency programs utilize a diverse range of approaches to provide infertility care to the underserved in the backdrop of considerable challenges and barriers, but significant gaps persist.

Access, barriers, and decisional regret in pursuit of fertility preservation among transgender and gender-diverse individuals.

OBJECTIVE: To query transgender and gender-diverse individuals on their desire for fertility preservation, perceived barriers to access care, and decisional regret. DESIGN: Cross-sectional. SETTING: Not applicable. PATIENT(S): A total of 397 gender-diverse individuals undergoing intake to the University of California Los Angeles Gender Health Program from January 2018 to March 2019. Seventy participated in a follow-up survey from September to October 2019 clarifying reproductive desires or intentions. INTERVENTION: Multiple-choice questionnaire. MAIN OUTCOME MEASURE(S): Perceived barriers to access fertility preservation and decisional regret surrounding choice to pursue fertility preservation as measured with the use of the validated Decision Regret Scale (scored 0 to 100). RESULT(S): Barriers to accessing care were primarily cost of treatment (36%), discontinuation/delay of hormonal therapy (19%), or worsening of gender dysphoria with treatment/pregnancy (11%). Respondents indicated that their family planning goals were addressed by primary care providers and/or medical endocrinologists (multiple responses allowed), but 37% stated that their family planning goals were not adequately addressed. Those who had made a firm decision to pursue or not pursue fertility treatment had mild decisional regret. Moderate-to-severe decisional regret was noted in those who were undecided regarding the pursuit of fertility perseveration before transition and in those who were interested in referral to reproductive endocrinology. CONCLUSION(S): Consultation with a reproductive endocrinologist may reduce decisional regret as well as clarify perceived barriers to fertility preservation in transgender and gender-diverse individuals interested in fertility preservation.