Blastocyst conversion rate and ploidy in patients with structural rearrangements.

OBJECTIVE: The primary objective of this study was to test the hypotheses that compared to IVF cycles undergoing preimplantation genetic testing for aneuploidy (PGT-A) with or without testing for monogenic disorders (PGT-M), IVF cycles undergoing PGT for structural rearrangements (PGT-SR) will have (1) a poorer blastocyst conversion rate and (2) fewer usable blastocysts available for transfer. Secondarily, the study aimed to compare pregnancy outcomes among PGT groups. PATIENTS: Retrospective cohort study including cycles started from January 1, 2012, to March 30, 2020, with the intent of pursuing PGT-A, PGT-A with PGT-M, and PGT-SR, with trophectoderm biopsy on days 5 or 6. RESULTS: A total of 658 women underwent 902 cycles, including 607 PGT-A, 216 PGT-A&M, and 79 PGT-SR cycles. When compared with the blastocyst conversion rate for the PGT-A group (59.4%), and after adjustment for patient age, total number of mature oocytes, BMI, and ICSI, there were no significant differences for either the PGT-A&M (69.7%, aRR 1.03, 95% CI 0.96-1.10) or PGT-SR (63.2%, aRR1.04, 95% CI 0.96-1.13) groups. Compared to the PGT-A group, the proportion of usable blastocysts was statistically significantly lower in the PGT-SR group: 35.1% versus 24.4% (aRR 0.57, 95% CI 0.46-0.71) and the PGT-A&M group: 35.1% versus 31.5% (aRR 0.68, 95% CI 0.58-0.81). Implantation, pregnancy, and miscarriage rates were equivalent for all groups. CONCLUSION: Patients with structural rearrangements have similar blastocyst development but significantly fewer usable blastocysts available for transfer compared to PGT-A testers. Nevertheless, with the transfer of a usable embryo, PGT-SR testers perform as well as those testing for PGT-A.

Quality of embryos on day 7 after medium refreshment on day 6: a prospective trial.

STUDY QUESTION: Are embryos that fail to meet biopsy or freezing criteria on day 6 (D6) more likely to meet these criteria on day 7 (D7) if cultured in fresh medium from D6 to D7? SUMMARY ANSWER: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7, with an adverse effect for women ≥40 years old. WHAT IS KNOWN ALREADY: Embryo development in continuous single-step medium, from fertilization to the blastocyst stage, is equivalent to that using a sequential media protocol. However, there remains a theoretical benefit of refreshing the culture environment by transitioning slowly developing D6 embryos to a fresh medium droplet of the same composition, with a renewed source of nutrients and a milieu free of metabolic toxins. STUDY DESIGN, SIZE, DURATION: This was a prospective trial of culture media exposure in which embryos were randomized on D6 to remain in the same culture medium from D3 to D7 (continuous, n = 620) or be moved to fresh medium (fresh, n = 603) on D6, with re-evaluation on D7. Data were collected from IVF cycles, with or without ICSI, between 29 March 2019 and 17 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos from 298 women, aged 18-44 years, from cycles with or without preimplantation genetic testing (PGT) that did not meet criteria for biopsy and/or freeze on D6 were included in the study. Embryos were only included if there was a minimum of two embryos meeting the inclusion criteria in any cohort. Only the first cycle undertaken by each woman in the study period from which embryos were randomized was included. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1254 embryos were randomized from 312 cycles (209 non-PGT and 103 PGT) including 200 women undergoing IVF without PGT and 98 women who underwent PGT. The proportion of usable blastocysts on D7 did not differ between groups: 10.1% (61/603) in fresh versus 9.7% (60/620) in continuous medium (relative risk (RR) 1.05, 95% CI 0.74-1.47)). Embryos from women ≥40 years old had a significantly decreased likelihood of achieving a usable blastocyst on D7 after culture in fresh versus continuous medium: 3.5% versus 12.2%; RR 0.29, 95% CI 0.08-0.98. In total, 9.9% of embryos otherwise discarded on D6 met the criteria for biopsy and/or freeze on D7. LIMITATIONS, REASONS FOR CAUTION: Future work investigating implantation, clinical pregnancy and miscarriage rates with D7 embryos is still needed. WIDER IMPLICATIONS OF THE FINDINGS: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7 overall. Younger women were more likely to develop D7 embryos after refreshment of medium on D6, while an adverse effect was seen in women ≥40 years old. However, by extending the culture of embryos to D7, additional blastocysts become available for clinical use. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided through the Department of Obstetrics and Gynecology at Brigham and Women's Hospital. I.G.I. works with Teladoc Health. A.L. has no disclosures. E.S.G. works as a consultant for Teladoc Health, and a writer and editor for UpToDate and BioMed Central. C.R. is a board member of the American Society for Reproductive Medicine and works with UpToDate. TRIAL REGISTRATION NUMBER: N/A.

Association of Fresh Embryo Transfers Compared With Cryopreserved-Thawed Embryo Transfers With Live Birth Rate Among Women Undergoing Assisted Reproduction Using Freshly Retrieved Donor Oocytes.

IMPORTANCE: In in vitro fertilization cycles using autologous oocytes, data have demonstrated higher live birth rates following cryopreserved-thawed embryo transfers compared with fresh embryo transfers. It remains unknown if this association exists in cycles using freshly retrieved donor oocytes. OBJECTIVE: To test the hypothesis that in freshly retrieved donor oocyte cycles, a fresh embryo transfer is more likely to result in a live birth compared with a cryopreserved-thawed embryo transfer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study using national data collected from the Society for Assisted Reproductive Technology for 33 863 recipients undergoing fresh donor oocyte cycles in the US between January 1, 2014 and December 31, 2017. EXPOSURES: Fresh embryo transfer and cryopreserved-thawed embryo transfer. MAIN OUTCOMES AND MEASURES: The primary outcome was live birth rate; secondary outcomes were clinical pregnancy rate and miscarriage rate. Analyses were adjusted for donor age, day of embryo transfer, use of a gestational carrier, and assisted hatching. RESULTS: Recipients of fresh and cryopreserved-thawed embryos had comparable median age (42.0 [interquartile range {IQR}, 37.0-44.0] years vs 42.0 [IQR, 36.0-45.0] years), gravidity (1 [IQR, 0-2] vs 1 [IQR, 0-3]), parity (0 [IQR, 0-1] vs 1 [IQR, 0-1]), and body mass index (24.5 [IQR, 21.9-28.7] vs 24.4 [IQR, 21.6-28.7]). Of a total of 33 863 recipients who underwent 51 942 fresh donor oocyte cycles, there were 15 308 (29.5%) fresh embryo transfer cycles and 36 634 (70.5%) cryopreserved-thawed embryo transfer cycles. Blastocysts were transferred in 92.4% of fresh embryo transfer cycles and 96.5% of cryopreserved-thawed embryo transfer cycles, with no significant difference in the mean number of embryos transferred. Live birth rate following fresh embryo transfer vs cryopreserved-thawed embryo transfer was 56.6% vs 44.0% (absolute difference, 12.6% [95% CI, 11.7%-13.5%]; adjusted relative risk [aRR], 1.42 [95% CI, 1.39-1.46]). Clinical pregnancy rates were 66.7% vs 54.2%, respectively (absolute difference, 12.5% [95% CI, 11.6%-13.4%]; aRR, 1.34; [95% CI, 1.31-1.37]). Miscarriage rates were 9.3% vs 9.4%, respectively (absolute difference, 0.2% [95% CI, -0.4% to 0.7%]); aRR, 0.98 [95% CI, 0.91-1.07]). CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of women undergoing assisted reproduction using freshly retrieved donor oocytes, the use of fresh embryo transfers compared with cryopreserved-thawed embryo transfers was associated with a higher live birth rate. However, interpretation of the findings is limited by the potential for selection and confounding bias.

Self-reported barriers to accessing infertility care: patient perspectives from urban gynecology clinics.

PURPOSE: (1) To test the hypothesis that under-represented minority women, including Hispanic/Latina and African American or Black women, will be more likely to report greater socioeconomic and cultural barriers to infertility care compared with white women. (2) To identify gaps in knowledge that can guide future educational interventions. METHODS: A cross-sectional survey was completed by 242 women, ages 18-44, at five gynecology clinics in the greater Boston, Massachusetts area from February 27, 2018, to February 25, 2019. RESULTS: Of the respondents, 61.4% identified as Hispanic/Latina, 24.5% as white, and 6.6% as Black or African American. Cost was the most commonly reported barrier to care (62.8%) regardless of race/ethnicity or insurance status. Only 8.9% of participants were aware of personal insurance coverage for infertility treatment. Compared with white patients, Hispanic/Latina patients were less likely to know if their own insurance covered infertility treatment: 14.3% vs 6.8%; aRR 0.36 (95% CI 0.17-0.74), after adjusting for a personal history of infertility. CONCLUSION: Cost was the most commonly reported barrier to care. Most women were unaware of their insurance coverage despite the state insurance mandate to cover infertility treatment in Massachusetts. Education and outreach will be instrumental in helping address disparities in access to care.

Fertility Preservation for Adolescent Transgender Male Patients: A Case Series.

This case series from a hospital-based academic in vitro fertilization clinic outlines the feasibility of oocyte cryopreservation for transgender male adolescents after varying degrees of exposure to pubertal blockers and/or testosterone. A description of each patient's oocyte cryopreservation cycle is reviewed, including prior exposure to pubertal blockers and/or testosterone, anti-Mullerian hormone level, stimulation medications, trigger injections, number of oocytes retrieved and cryopreserved, and complications. All patients tolerated stimulation and retrieval well and had mature oocytes cryopreserved in each cycle. There were no complications. Adolescent transgender males who choose to undergo oocyte cryopreservation tolerate the process well, reinforcing the importance of fertility preservation in providing comprehensive care for transgender patients.

Infertility, Inequality, and How Lack of Insurance Coverage Compromises Reproductive Autonomy.

Disparities in access to infertility care and insurance coverage of infertility treatment represent marked injustices in US health care. The World Health Organization defines infertility as a disease. Infertility has multiple associated billing codes in use, as determined by the International Statistical Classification of Diseases and Related Health Problems. However, the often-prohibitive costs associated with infertility treatment, coupled with the lack of universal insurance coverage mandates, contribute to health care inequity, particularly along racial and socioeconomic lines.

Neutral effect of body mass index on implantation rate after frozen-thawed blastocyst transfer.

OBJECTIVE: To examine the effects of body mass index (BMI) on implantation rate after uniform protocol frozen-thawed blastocyst transfer in women with a homogenous uterine environment. DESIGN: Retrospective cohort study. SETTING: Single IVF clinic at a large academic institution. PATIENT(S): Four hundred sixty-one infertile women treated at a large academic institution from January 2007 to January 2014. INTERVENTION(S): All women underwent standardized slow frozen-thawed blastocyst transfers with good-quality day 5-6 embryos, following an identical hormonal uterine preparation, with comparison groups divided according to BMI category: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥30.0 kg/m2). MAIN OUTCOME MEASURE(S): Implantation rate. RESULT(S): There were no statistically significant differences identified when comparing implantation rates among the four BMI cohorts. The implantation rate was 38.2% in normal weight patients, 41.7% in underweight patients, 45.1% in overweight patients, and 34.7% in obese patients. Adjusted odds ratios (OR) demonstrated no association between the main outcome, implantation rate, and BMI. Compared with the normal weight patients, the adjusted OR of implantation was 1.70 (95% confidence interval [CI], 0.40-7.72) for underweight patients, 1.61 (95% CI, 0.97-2.68) for overweight patients, and 0.92 (95% CI, 0.49-1.72) for obese patients. Secondary outcomes, including rates of miscarriage, clinical pregnancy, ongoing pregnancy, and live birth, were not significantly different between cohorts. While powered to detect a 16% difference between overweight and normal weight women, the study was underpowered to detect differences in the underweight and obese women, and no definitive conclusions can be drawn for these small cohorts. Patients with transfers that required the longest amount of time, greater than 200 seconds, had the highest average BMI of 27.5 kg/m2. CONCLUSION(S): Under highly controlled circumstances across 7 years of data from a single institution, using a uniform uterine preparation, following a precise transfer technique with high-quality day 5-6 slow frozen-thawed blastocysts, a BMI in the overweight range of 25-29.9 kg/m2 is not associated with a poorer implantation rate or live-birth rate, nor is it associated with an increased risk of miscarriage when compared with a normal BMI range. The increased length of time required during transfer for women with higher BMI suggests body habitus may contribute to difficult transfers, although this may not translate into poorer implantation rates. By using a standardized protocol for slow freezing and thawing of embryos, using identical hormonal preparation and a uniform ET protocol, a homogenous uterine environment was created in this carefully selected cohort of women, thereby minimizing confounders and uniquely highlighting the neutral effect of overweight BMI on implantation rate.

Outpatient endometrial aspiration: an alternative to methotrexate for pregnancy of unknown location.

BACKGROUND: Pregnancies of unknown location with abnormal beta-human chorionic gonadotropin trends are frequently treated as presumed ectopic pregnancies with methotrexate. Preliminary data suggest that outpatient endometrial aspiration may be an effective tool to diagnose pregnancy location, while also sparing women exposure to methotrexate. OBJECTIVE: The purpose of this study was to evaluate the utility of an endometrial sampling protocol for the diagnosis of pregnancies of unknown location after in vitro fertilization. STUDY DESIGN: A retrospective cohort study of 14,505 autologous fresh and frozen in vitro fertilization cycles from October 2007 to September 2015 was performed; 110 patients were diagnosed with pregnancy of unknown location, defined as a positive beta-human chorionic gonadotropin without ultrasound evidence of intrauterine or ectopic pregnancy and an abnormal beta-human chorionic gonadotropin trend (<53% rise or <15% fall in 2 days). These patients underwent outpatient endometrial sampling with Karman cannula aspiration. Patients with a beta-human chorionic gonadotropin decline ≥15% within 24 hours of sampling and/or villi detected on pathologic analysis were diagnosed with failing intrauterine pregnancy and had weekly beta-human chorionic gonadotropin measurements thereafter. Those patients with beta-human chorionic gonadotropin declines <15% and no villi identified were diagnosed with ectopic pregnancy and treated with intramuscular methotrexate (50 mg/m2) or laparoscopy. RESULTS: Across 8 years of follow up, among women with pregnancy of unknown location, failed intrauterine pregnancy was diagnosed in 46 patients (42%), and ectopic pregnancy was diagnosed in 64 patients (58%). Clinical variables that included fresh or frozen embryo transfer, day of embryo transfer, serum beta-human chorionic gonadotropin at the time of sampling, endometrial thickness, and presence of an adnexal mass were not significantly different between patients with failed intrauterine pregnancy or ectopic pregnancy. In patients with failed intrauterine pregnancy, 100% demonstrated adequate postsampling beta-human chorionic gonadotropin declines; villi were identified in just 46% (n=21 patients). Patients with failed intrauterine pregnancy had significantly shorter time to resolution (negative serum beta-human chorionic gonadotropin) after sampling compared with patients with ectopic pregnancy (12.6 vs 26.3 days; P<.001). CONCLUSION: With the use of this safe and effective protocol of endometrial aspiration with Karman cannula, a large proportion of women with pregnancy of unknown location are spared methotrexate, with a shorter time to pregnancy resolution than those who receive methotrexate.

Transferring embryos with indeterminate PGD results: the ethical implications.

BACKGROUND: In vitro fertilization (IVF) and pre-implantation genetic diagnosis (PGD) are becoming increasingly common techniques to select embryos that are unaffected by a known genetic disorder. Though IVF-PGD has high success rates, 7.5 % of blastocysts have inconclusive results after testing. A recent case involving a known BRCA-1 carrier was brought before our Assisted Reproductive Technology Ethics Committee in order to gain a better appreciation for the ethical implications surrounding the transfer of embryos with indeterminate testing. THE CASE PRESENTATION: Thirty-nine year old G0 BRCA-1 carrier requiring IVF for male factor infertility. The couple elected for PGD to select against BRCA-1 gene carrier embryos. However, several embryos were returned with inconclusive results. The couple wished to proceed with the transfer of embryos with an unknown carrier status. The case was presented before our Assisted Reproductive Technology Ethics Committee. CONCLUSION: Many considerations were explored, including the physician's duty to protect patient autonomy, the physician's duty to act in the best interest of the future child, and the physician's duty towards society. Transferring both embryos with unknown carrier status and known-carrier status was debated. Ultimately, the transfer of inconclusive embryos was felt to be ethically permissible in most cases if patients had been adequately counseled. However, the re-biopsy of embryos with inconclusive testing results was encouraged. The transfer of known-carrier embryos was felt to be unethical for certain disease-states, depending on the severity of illness and timing of disease onset. We strongly encourage physicians to create an action plan in advance with their patients, prior to testing, in the event that embryos are returned with inconclusive PGD results. The committee's decision, though helpful in guiding practice, should not overshadow the individual physician-patient relationship, and the need for thorough counseling.

Complementary and alternative therapy use in pediatric oncology patients with failure of frontline chemotherapy.

BACKGROUND: The use of CAM by the relapsed pediatric oncology population has largely gone unstudied. The main objective of this study was to describe the prevalence of and change in CAM use in oncology patients for whom frontline therapy had failed. Secondary objectives included describing patient/family objectives for using CAM, satisfaction with CAM, financial and time expenditures on CAM, and patient desire for physician involvement in CAM use. PROCEDURE: Fifty-four patients 0-25 years of age, for whom frontline therapy had failed, were enrolled. The subjects completed an anonymous one-time self-administered questionnaire. RESULTS: Eighty-two percent of respondents reported using CAM, 52% of which reported initiating or increasing CAM use after failure of frontline therapy. The most commonly used CAM categories were prayer/spiritual healing (83%) and oral/dietary supplements (31%). Prayer/spiritual healing was most commonly used to cure or slow the progression of cancer (59%). Oral/dietary supplements were used to improve overall health and well-being (65%). Estimates of money and time spent ranged from $0 to >$1,275 (median $225) and 1 to > 700 hr (median 10 hr). Sixty percent of CAM users reported their oncologist was unaware of their use. Most participants who used non-spiritual/prayer CAM continued use while hospitalized or while receiving chemotherapy. CONCLUSIONS: Understanding usage patterns may better help pediatric oncologists and palliative-care specialists address the needs of this population, and protect against potentially dangerous drug interactions or side effects from combined CAM and chemotherapy use.

Salvage therapy with nelarabine, etoposide, and cyclophosphamide in relapsed/refractory paediatric T-cell lymphoblastic leukaemia and lymphoma.

A combination of 5 d of nelarabine (AraG) with 5 d of etoposide (VP) and cyclophosphamide (CPM) and prophylactic intrathecal chemotherapy was used as salvage therapy in seven children with refractory or relapsed T-cell leukaemia or lymphoma. The most common side effects attributable to the AraG included Grade 2 and 3 sensory and motor neuropathy and musculoskeletal pain. Haematological toxicity was greater for the combination than AraG alone, although median time to neutrophil and platelet recovery was consistent with other salvage therapies. All patients had some response to the combined therapy and five of the seven went into complete remission after one or two courses of AraG/VP/CPM. Our experience supports the safety of giving AraG as salvage therapy in synchrony with etoposide and cyclophosphamide, although neurological toxicity must be closely monitored.