Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Multiple embryo manipulations in PGT-A cycles may result in inferior clinical outcomes.

RESEARCH QUESTION: Do embryos that undergo a thaw, biopsy and re-vitrification (TBR) for pre-implantation genetic testing for aneuploidy (PGT-A) have different ploidy and transfer outcomes compared with fresh biopsied embryos? DESIGN: Retrospective cohort study of all embryos that underwent the following procedures: fresh biopsy for PGT-A (fresh biopsy); embryos that were warmed, biopsied for PGT-A and re-vitrified (single biopsy TBR); embryos with a no signal result after initial biopsy that were subsequently warmed, biopsied and re-vitrified (double biopsy TBR). The patients who underwent transfers of those embryos at a single academic institution between March 2013 and December 2021 were also studied. RESULTS: About 30% of embryos planned for TBR underwent attrition. Euploidy rates were similar after biopsy: fresh biopsy (42.7%); single biopsy TBR (47.5%) (adjusted RR: 0.99, 0.88 to 1.12); and double biopsy TBR 50.3% (adjusted RR: 0.99, 0.80 to 1.21). Ongoing pregnancy over 8 weeks was not statistically significant (double biopsy TBR: 6/19 [31.6%] versus fresh biopsy: 650/1062 [61.2%]) (adjusted RR 0.52, 95% CI 0.26 to 1.03). The miscarriage rate increased (double biopsy TBR: 4/19 [21.1%] versus fresh biopsy: 66/1062 [6.2%])(RR 3.39, 95% CI 1.38 to 8.31). Live birth rate was also lower per transfer for the double biopsy TBR group (double biopsy TBR [18.75%] versus fresh biopsy [53.75%]) (RR 0.35, 95% CI 0.12 to 0.98), though not after adjustment (adjusted RR 0.37, 95% CI 0.13 to 1.09). These differences were not seen when single biopsy TBR embryos were transferred. CONCLUSIONS: Embryos that undergo TBR have an equivalent euploidy rate to fresh biopsied embryos. Despite that, double biopsy TBR embryos may have impaired transfer outcomes.

The impact of increasing body mass index on in vitro fertilization treatment, obstetrical, and neonatal outcomes.

BACKGROUND: Citing the risks of administering anesthesia to patients with obesity, few fertility centers offer in vitro fertilization as a treatment modality for patients with body mass indexes ≥40 kg/m2. Although previous studies have assessed clinical pregnancy and cumulative live birth rates in patients who spontaneously conceive with body mass indexes ≥50 kg/m2, there is a paucity of in vitro fertilization, obstetrical, and neonatal outcome data in patients with severe obesity who conceive after in vitro fertilization. OBJECTIVE: This study aimed to evaluate the impact of increasing body mass index on in vitro fertilization, obstetrical, and neonatal outcomes in patients with obesity undergoing in vitro fertilization. STUDY DESIGN: This was a retrospective cohort study within an academic fertility center including 2069 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycles from January 1, 2012 to April 30, 2020; this cohort was used to determine in vitro fertilization treatment outcomes. A second embedded cohort of 867 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycles that resulted in ongoing clinical pregnancies and deliveries within a single tertiary hospital system was used to determine pregnancy, maternal, and neonatal outcomes. All patients with a body mass index ≥40 kg/m2 underwent consultation with a maternal-fetal medicine specialist before starting treatment and a preoperative evaluation with an anesthesiologist before oocyte retrieval. Cycles were grouped by body mass index at cycle start (30-34.9, 35-39.9, 40-44.9, 45-49.9, and ≥50 kg/m2). Log-binomial regression and Poisson regression with an offset were fitted with body mass index of 30 to 34.9 kg/m2 as the reference group, adjusting for potential confounders including oocyte age, patient age, embryo quality, transfer type, and coexisting comorbidities. The primary outcome was live birth rate. Secondary outcomes included fertilization rate, blastulation rate, miscarriage rate, incidence of preeclampsia with severe features, gestational diabetes, labor induction, cesarean delivery, preterm delivery, and birthweight. RESULTS: There were 2069 fresh in vitro fertilization/intracytoplasmic sperm injection and frozen embryo transfer cycle starts from January 1, 2012 to April 30, 2020. Of these, 1008 cycles were in the 30 to 34.9 kg/m2 group, 547 in the 35 to 39.9 kg/m2 group, 277 in the 40 to 44.9 kg/m2 group, 161 in the 45 to 49.9 kg/m2 group, and 76 in the ≥50 kg/m2 body mass index group. Live birth rate was not significantly different between groups. The body mass index ≥50 kg/m2 group was significantly more likely to experience preeclampsia with severe features when compared with the 30 to 34.9 kg/m2 body mass index group (absolute risk reduction, 2.75; 95% confidence interval, 1.13-6.67). Fertilization rate, blastulation rate, miscarriage rate, incidence of gestational diabetes, labor induction, cesarean delivery, preterm delivery, and neonatal birthweights were not significantly different between groups. CONCLUSION: Among patients with body mass indexes from 30 to 60 kg/m2 who conceived via in vitro fertilization and received comprehensive prenatal care at a tertiary care hospital, in vitro fertilization, obstetrical, and neonatal outcomes were largely comparable. These data support a collaborative care approach with maternal-fetal medicine specialists and skilled anesthesiologists, reinforcing the notion that in vitro fertilization should not be withheld as a treatment modality from patients with obesity.

Treatment of intrauterine adhesions and subsequent pregnancy outcomes in an in vitro fertilization population.

BACKGROUND: Asherman syndrome refers to the presence of intrauterine adhesions, which have clinical implications, including infertility. There are few studies assessing the effect of serial hysteroscopies for adhesiolysis on reproductive and pregnancy outcomes among women who subsequently undergo in vitro fertilization, and none have looked at maternal, neonatal, or placental pregnancy complications. OBJECTIVE: This study aimed to explore the effect of hysteroscopic adhesiolysis among a cohort of patients who subsequently undergo in vitro fertilization. STUDY DESIGN: This was a retrospective cohort study of all patients who underwent hysteroscopic adhesiolysis for intrauterine adhesions at our center between 2005-2020 and subsequently attempted conception by in vitro fertilization. A control group of patients who underwent in vitro fertilization for nonuterine factor infertility and had no history of intrauterine adhesions was chosen for comparison. RESULTS: There were 691 patients included in this study, of whom 168 were intrauterine adhesion cases. The implantation rate (41.3% in both groups) and live birth rate (adjusted relative risk, 0.93 [95% confidence interval, 0.76-1.14]) were not statistically different between cases and controls. When grouped by number of previous adhesiolysis surgeries, patients who underwent ≥2 adhesiolysis surgeries had a lower live birth rate than controls (adjusted relative risk, 0.53 [95% confidence interval, 0.28-0.99]). Endometrial thickness before the transfer was significantly reduced in cases vs controls (8.23 vs 10.25 mm; adjusted relative risk, 0.84 [95% confidence interval, 0.78-0.90]). Adverse placental outcomes, including placenta accreta spectrum, placenta previa, or vasa previa, were significantly more likely to occur in cases than controls (adjusted relative risk, 2.08 [95% confidence interval, 1.25-3.46]). When grouped by the number of adhesiolysis surgeries, the risk appeared to increase as the number of prior surgeries increased. This is likely because of the increased severity of these adhesions. CONCLUSION: Overall, patients with a history of treated intrauterine adhesions have the same live birth rate as patients undergoing in vitro fertilization for nonuterine factor indications. However, the subgroup of patients who require multiple surgeries for correction of intrauterine adhesions had a lower live birth rate after in vitro fertilization than controls. Patients with a history of treated intrauterine adhesions are at significantly greater risk of placenta accreta syndrome disorder than control patients who underwent in vitro fertilization for nonuterine factor indications.

Predictors of gamete donation: a cross sectional survey study.

PURPOSE: In 2015, assisted reproductive technology (ART) accounted for 1.7% of all U.S. births, donor eggs accounted for over 17,000 started cycles in 2015, and donor sperm accounting for 6.2% of all cycles started in 2014. With increasing utilization of donor gametes as a method of assisting patients with infertility, the number of babies born each year utilizing gamete donation will also continue to increase. This study aimed to elucidate factors impacting decision to donate, amongst a representative national population. METHODS: A survey was distributed via the internet utilizing SurveyMonkey Enterprise with HIPAA compliance. Univariate regressions and frequencies were conducted between each demographic and personal characteristic and the willingness to donate. Log Binomial and linear regression was used categorical and continuous variables, and Risk ratios were calculated. RESULTS: In this large survey study, 64% of men and 50% of women reported they would be willing to donate gametes, with the majority desiring monetary compensation. Men with a high Consumer Financial Protection Bureau score were less likely to report that they would consider donating sperm compared to a medium high CFPB score. No other financial indicators were associated with considering donating sperm. There were no associations between CFPB score and egg donation outcomes. Black or African American women were less likely to consider donating their eggs compared to other groups, and more likely to desire > $5000 in compensation. CONCLUSIONS: In this large survey study, a small minority of participants reported they would be willing to donate to an unknown infertility patient for reproductive purposes. High and very high CFPB scores were associated with willingness to donate games, but not with desire for monetary compensation or amount.

The effects of male anxiety and depression on IVF outcomes.

STUDY QUESTION: What are the effects of male anxiety and depression on IVF outcomes? SUMMARY ANSWER: Men with anxiety had lower final total motile sperm counts (fTMSC) during IVF compared to men without anxiety; however, there were no differences in live birth rates (LBRs). WHAT IS KNOWN ALREADY: Studies have shown that male anxiety causes low sperm motility, worse sperm morphology, and increased DNA fragmentation, which are known to be influential factors on fertilization rates and embryo quality during IVF. However, data are lacking on whether there is a direct association between male anxiety and/or depression and IVF outcomes. STUDY DESIGN, SIZE, DURATION: This was a survey-based, retrospective cohort study completed at a single, large hospital-affiliated fertility center with 222 respondents who underwent IVF with or without ICSI. The study was conducted between 6 September 2018 and 27 December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners of couples who underwent IVF or IVF/ICSI completed a Hospital Anxiety and Depression Scale (HADS) questionnaire. They were separated into two groups for both anxiety (HADS-A ≥ 8 or HADS-A < 8) and depression (HADS-D ≥ 8 or HADS-D < 8). Men with an elevated HADS-A or HADS-D score ≥8 were considered to have anxiety or depression, respectively. The primary outcome was LBR. Secondary outcomes included semen parameters at the time of IVF, cycle outcomes, pregnancy outcomes, and prevalence of erectile dysfunction and low libido. MAIN RESULTS AND THE ROLE OF CHANCE: There were a total of 222 respondents, of whom 22.5% had a HADS-A ≥ 8 and 6.5% had a HADS-D ≥ 8. The average age of respondents was 37.38 ± 4.90 years old. Antidepressant use was higher in the respondents with a HADS-A or HADS-D ≥ 8 (P < 0.05). Smoking use was similar between groups for both HADS-A and HADS-D (P > 0.05). When adjusted for male BMI, antidepressant use and smoking, men with a HADS-A or HADS-D ≥ 8 had similar rates of erectile dysfunction (adjusted relative risk (aRR) = 1.12 (95% CI 0.60, 2.06)) and low libido (aRR = 1.70 (95% CI 0.91, 3.15)) compared to those with a HADS-A or HADS-D ≤ 8. Men with a HADS-A ≥ 8 were more likely to have a lower fTMSC on the day of oocyte retrieval (11.8 ≥ 8 vs 20.1 < 8, adjusted ß = -0.66 (95% CI -1.22, -0.10)). However, the LBR per embryo transfer (ET) was similar between the HADS-A groups (43.2% ≥8 vs 45.1% <8, adjusted relative risk = 0.90 (95% CI 0.65, 1.06)). Although depression was uncommon in the entire cohort, the HADS-D groups were clinically similar for fTMSC (18.7 ≥ 8 vs 16.0 < 8) and LBR per ET (46.7% ≥8 vs 45.4% <8). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are the survey-based design, the lack of sperm morphology assessment at the time of IVF, our inability to fully assess the HADS-D ≥ 8 cohort due to the small sample size and the large Caucasian demographic. WIDER IMPLICATIONS OF THE FINDINGS: Couples undergoing IVF have an increased likelihood of suffering from anxiety and/or depression. There is currently a debate on whether or not men should be treated with antidepressants while attempting to conceive due to potential detrimental effects on sperm quality. Our study shows that, regardless of antidepressant use, couples with men who did or did not report anxiety and/or depression have similar LBRs when undergoing IVF. Therefore, it is important to assess both partners for mental health and to not withhold treatment due to a concern about a potential impact of antidepressants or anxiety/depression on sperm quality. STUDY FUNDING/COMPETING INTEREST(S): There was no funding to report for this study. Z.W. is a contributing author for UptoDate. S.S.S. is on the advisory board for Ferring Pharmaceuticals. E.G. was a medical consultant for Hall-Matson Esq, Teladoc, and CRICO and is a contributing author for UptoDate. The remaining authors have nothing to report. TRIAL REGISTRATION NUMBER: N/A.

What to do with one good quality blastocyst and where do we place the emphasis?

The use of preimplantation genetic testing for aneuploidy (PGT-A) in poor responders undergoing assisted reproductive technology has been a topic of debate with controversial results. It is critical to note the denominators used in data presented. Herein, we comment on the results found in the study by Kahraman et al. on the utility of PGT-A in poor responders with a single, good-quality blastocyst.

Ultra-low-dose and very-low-dose Lupron downregulation protocols for poor responders based on POSEIDON group 3 and 4 classifications.

PURPOSE: The objective of this study was to assess if very-low-dose Lupron (VLDL) and ultra-low-dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other "poor responder" stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). METHODS: A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). RESULTS: The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. CONCLUSION: Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

Oocyte cryopreservation review: outcomes of medical oocyte cryopreservation and planned oocyte cryopreservation.

BACKGROUND: The utilization of oocyte cryopreservation (OC) has become popularized with increasing numbers of reproductive-aged patients desiring to maintain fertility for future family building. OC was initially used for fertility preservation in postmenarchal patients prior to gonadotoxic therapies; however, it is now available to patients to circumvent age-related infertility and other diagnoses associated with early loss of ovarian reserve. The primary aim of this paper is to provide a narrative review of the most recent and robust data on the utilization and outcomes of OC in both patient populations. OC results in similar oocyte yield in patients facing gonadotoxic therapies and patients undergoing planned OC. Available data are insufficient to predict the live birth rates or the number of oocytes needed to result in live birth. However, oocyte yield and live birth rates are best among patients < 37.5 years old or with anti-mullerian hormone levels > 1.995 ng/dL, at the time of oocyte retrieval. There is a high 'no use' rate (58.9%) in patients using planned OC with 62.5% returning to use frozen oocytes with a spouse. The utilization rate in medical OC patients is < 10%. There is currently no data on the effects of BMI, smoking, or ethnicity on planned OC outcomes. CONCLUSION: It is too early to draw any final conclusions on outcomes of OC in medical OC and planned OC; however, preliminary data supports that utilization of OC in both groups result in preservation of fertility and subsequent live births in patients who return to use their cryopreserved eggs. Higher oocyte yield, with fewer ovarian stimulation cycles, and higher live birth rates are seen in patients who seek OC at younger ages, reinforcing the importance of age on fertility preservation. More studies are needed in medical OC and planned OC to help guide counseling and decision-making in patients seeking these services.

The impact of insurance mandates on donor oocyte utilization: an analysis of 39,338 donor oocyte cycles from the Society for Assisted Reproductive Technology registry.

BACKGROUND: A total of 19 states passed legislation mandating insurance coverage of assisted reproductive technology, and out-of-pocket costs associated with in vitro fertilization vary significantly depending on the region. Consequently, it has been observed that assisted reproductive technology utilization differs regionally and is associated with the presence of an insurance mandate. However, it is unknown whether regional differences exist among patients using donor oocytes. OBJECTIVE: This study aimed to determine the patient and cycle-specific parameters associated with the use of donor oocytes according to the insurance mandate status of the Society for Assisted Reproductive Technology clinic in which the assisted reproductive technology cycle was performed. STUDY DESIGN: This study was a retrospective cohort study using national data collected from the Society for Assisted Reproductive Technology registry for 39,338 donor oocyte cycles and 242,555 autologous oocyte cycles performed in the United States from January 1, 2014, to December 31, 2016. Cycles were stratified by insurance mandate of the state in which the assisted reproductive technology cycle was performed: comprehensive (coverage for at least 4 cycles of assisted reproductive technology), limited (coverage limited to 1-3 assisted reproductive technology cycles), offer (insurance mandates exist but exclude assisted reproductive technology treatment), and no mandate. The primary outcome was the number of previous autologous assisted reproductive technology cycles of the recipient. The secondary outcomes included age, serum follicle stimulating hormone level, frozen donor oocyte utilization, day of embryo transfer, number of embryos transferred, clinical pregnancy rate, and live birth rate. Analyses were adjusted for day of transfer, number of embryos transferred, and age of the recipient. RESULTS: Patients in no mandate states underwent fewer autologous assisted reproductive technology cycles (mean, 1.1; standard deviation, 1.6) before using donor oocytes than patients in offer (mean, 1.7; standard deviation, 2.5; P<.01), limited (mean, 1.5; standard deviation, 2.5; P<.01), and comprehensive (mean, 1.7; standard deviation, 2.0; P<.01) states. Patients in no mandate states were more likely to use frozen oocytes than patients in offer (relative risk, 0.54; 95% confidence interval, 0.52-0.57), limited (relative risk, 0.50; 95% confidence interval, 0.46-0.54), and comprehensive (relative risk, 0.94; 95% confidence interval, 0.89-0.99) states. Clinical pregnancy and live birth rates were similar among recipients of donor oocytes, regardless of insurance mandate. CONCLUSION: Despite similar ages and ovarian reserve parameters, patients without state-mandated insurance coverage of assisted reproductive technology were more likely to use frozen donor oocytes and undergo fewer autologous in vitro fertilization cycles than their counterparts in partial or comprehensive insurance coverage states. These differences in donor oocyte utilization highlight the financial barriers associated with pursuing assisted reproductive technology in uninsured states.

Use of preimplantation genetic testing for monogenic disorders and subsequent prenatal care and diagnostic testing.

OBJECTIVE: The goal of preimplantation genetic testing for monogenic or single gene defects (PGT-M) is to identify inherited pathogenic variants in the embryo prior to embryo transfer, increasing the likelihood of an unaffected child. Prenatal diagnostic testing is recommended to confirm the results of PGT-M. The purpose of this study was to characterize the population undergoing PGT-M over time. METHODS: This retrospective study examined patients who had a positive pregnancy test after PGT-M from 2012 to 2019. A query of the internal assisted reproductive technology database and chart review were used. RESULTS: One hundred and 42 patients completed IVF cycles for PGT-M during this time period and progressed past 10 weeks gestation. There were more PGT-M cycles over time with 46 cycles between 2012 and 2015 and 96 cycles between 2016 and 2019. Patients varied on the decision to pursue prenatal diagnostic testing after PGT-M. For those with known follow-up (130/142), 16 patients underwent diagnostic testing (12%) and 114 did not. CONCLUSION: As PGT-M is increasingly utilized prior to pregnancy, it is important for genetic counselors and OB/GYNs to understand the characteristics and outcomes of the population of patients undergoing PGT-M, including how to counsel about the residual risk of an affected pregnancy after PGT-M.

The impact of fertility preservation on the timing of breast cancer treatment, recurrence, and survival.

BACKGROUND: Many young women with breast cancer undergo fertility preservation (FP) before cancer treatment. This study examined the impact of FP on breast cancer outcomes. METHODS: The authors performed a retrospective cohort study of 272 women aged 20 to 45 years with newly diagnosed stage 0 to III breast cancer who underwent an FP consultation between 2005 and 2017. Among these women, 123 (45.2%) underwent FP (fertility preservation-positive [FP+]). The remaining 149 women did not undergo FP (fertility preservation-negative [FP-]). RESULTS: The characteristics at enrollment were similar with the exception of ethnicity (FP+, 87.8% White; FP-, 67.8% White; P = .002) and BRCA status (FP+, 27.7% BRCA+; FP-, 15.5% BRCA+; P = .021). The median follow-up was approximately 4 years. Women who underwent FP had longer times to first treatment (FP+, 37 days; FP-, 31 days; adjusted hazard ratio [aHR], 0.74; confidence interval [CI], 0.56-0.99) and neoadjuvant chemotherapy (FP+, 36 days; FP-, 26 days; aHR, 0.41; CI, 0.24-0.68) and from surgery to adjuvant chemotherapy (FP+, 41 days; FP-, 33 days; aHR, 0.58; CI, 0.38-0.90). Adjusted 3- and 5-year invasive disease-free survival (IDFS) rates were comparable between the 2 groups (3-year IDFS: FP+, 85.4%; FP-, 79.4%; P = .411; 5-year IDFS: FP+, 73.7%; FP-, 67.1%; P = .288). Similarly, no difference in overall survival (OS) was observed between the 2 groups (3-year OS: FP+, 95.5%; FP-, 93.5%; P = .854; 5-year OS: FP+, 84.2%; FP-, 81.4%; P = .700). CONCLUSIONS: FP after a breast cancer diagnosis delays the time to treatment by a small amount, but this delay does not lead to inferior IDFS or OS.

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.

The cost-effectiveness of preimplantation genetic testing for aneuploidy in the United States: an analysis of cost and birth outcomes from 158,665 in vitro fertilization cycles.

BACKGROUND: A controversial and unresolved question in reproductive medicine is the utility of preimplantation genetic testing for aneuploidy as an adjunct to in vitro fertilization. Infertility is prevalent, but its treatment is notoriously expensive and typically not covered by insurance. Therefore, cost-effectiveness is critical to consider in this context. OBJECTIVE: This study aimed to analyze the cost-effectiveness of preimplantation genetic testing for aneuploidy for the treatment of infertility in the United States. STUDY DESIGN: As reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System, a national data registry, in vitro fertilization cycles occurring between 2014 and 2016 in the United States were analyzed. A probabilistic decision tree was developed using empirical outputs to simulate the events and outcomes associated with in vitro fertilization with and without preimplantation genetic testing for aneuploidy. The treatment strategies were (1) in vitro fertilization with intended preimplantation genetic testing for aneuploidy and (2) in vitro fertilization with transfers of untested embryos. Patients progressed through the treatment model until they achieved a live birth or 12 months after ovarian stimulation. Clinical costs related to both treatment strategies were extracted from the literature and considered from both the patient and payer perspectives. Outcome metrics included incremental cost (measured in 2018 US dollars), live birth outcomes, incremental cost-effectiveness ratio, and incremental cost per live birth between treatment strategies. RESULTS: The study population included 114,157 first fresh in vitro fertilization stimulations and 44,508 linked frozen embryo transfer cycles. Of the fresh stimulations, 16.2% intended preimplantation genetic testing for aneuploidy and 83.8% did not. In patients younger than 35 years old, preimplantation genetic testing for aneuploidy was associated with worse clinical outcomes and higher costs. At age 35 years and older, preimplantation genetic testing for aneuploidy led to more cumulative births but was associated with higher costs from both perspectives. From a patient perspective, the incremental cost per live birth favored the no preimplantation genetic testing for aneuploidy strategy from the <35 years age group to the 38 years age group and beginning at age 39 years favored preimplantation genetic testing for aneuploidy. From a payer perspective, the incremental cost per live birth favored preimplantation genetic testing for aneuploidy regardless of patient age. CONCLUSION: The cost-effectiveness of preimplantation genetic testing for aneuploidy is dependent on patient age and perspective. From an economic perspective, routine preimplantation genetic testing for aneuploidy should not be universally adopted; however, it may be cost-effective in certain scenarios.

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.

Confounding and effect measure modification in reproductive medicine research.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.

Hyperglycosylated human chorionic gonadotropin as a predictor of ongoing pregnancy.

BACKGROUND: Hyperglycosylated human chorionic gonadotropin, the predominant human chorionic gonadotropin variant secreted following implantation, is associated with trophoblast invasion. OBJECTIVE: To determine whether the initial serum hyperglycosylated human chorionic gonadotropin differs between ongoing and failed pregnancies, and to compare it to total serum human chorionic gonadotropin as a predictor of ongoing pregnancy. MATERIALS AND METHODS: Women undergoing fresh/frozen in vitro fertilization cycles at a university-based infertility clinic with an autologous day 5 single embryo transfer resulting in serum human chorionic gonadotropin >3 mIU/mL (n = 115) were included. Human chorionic gonadotropin was measured 11 days after embryo transfer in a single laboratory (coefficient of variation <6%). Surplus frozen serum (-80oC) was shipped to Quest Laboratories for measurement of hyperglycosylated human chorionic gonadotropin (coefficient of variation <9.1%). Linear regression analyses adjusted for oocyte age a priori were used to compare human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin in ongoing pregnancies (>8 weeks of gestation) and failed pregnancies (clinical pregnancy loss, biochemical and ectopic pregnancies). RESULTS: A total of 85 pregnancies (73.9%) were ongoing. Hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated (Pearson correlation coefficient 92.14, P < .0001), and mean values of both were positively correlated with blastocyst expansion score (P value test for trend < .0004). Mean human chorionic gonadotropin and hyperglycosylated human chorionic gonadotropin were significantly higher in ongoing vs failed pregnancies. Among ongoing pregnancies vs clinical losses, mean hyperglycosylated human chorionic gonadotropin, but not human chorionic gonadotropin, was significantly higher (19.0 vs 12.2 ng/mL, ß -8.1, 95% confidence interval -13.0 to -3.2), and hyperglycosylated human chorionic gonadotropin comprised a higher proportion of total human chorionic gonadotropin (4.6% vs 4.1%; risk ratio, 0.79; 95% confidence interval, 0.66-0.94). CONCLUSION: Measured 11 days after single blastocyst transfer, hyperglycosylated human chorionic gonadotropin and human chorionic gonadotropin values were highly correlated, but only mean hyperglycosylated human chorionic gonadotropin and its ratio to total human chorionic gonadotropin were significantly higher in ongoing pregnancies vs clinical pregnancy losses. Further evaluation of hyperglycosylated human chorionic gonadotropin, including in multiple embryo transfers and multiple pregnancy, and using serial measurements, is required.

Fertility preservation outcomes in women with gliomas: a retrospective case-control study.

PURPOSE: With advances in cancer therapy, reproductive-aged women can look forward to a life post-malignancy. Fortunately, fertility preservation (FP) may provide relief from potential infertility caused by cancer or associated caustic treatments. Outcomes of FP in pre-treatment reproductive-aged women with gliomas have not been previously characterized. METHODS: Between 2007 and 2018, 10 patients undergoing FP prior to chemotherapy and/or radiation treatment for gliomas were identified at Brigham and Women's Hospital. They were matched 3:1 to male-factor infertility patients by age ± 1 year. RESULTS: Patients with gliomas had significantly lower baseline anti-Müllerian hormone levels than male-factor infertility controls (2.37 vs 5.16 ng/mL, p = 0.002, log transformed). Despite higher starting (350 vs. 240 IU, p = 0.004) and total gonadotropin doses (4270 vs. 2270 IU, p < 0.001) over a similar stimulation duration (12.1 vs. 11.1 days, p = 0.219), cancer patients had lower peak estradiol levels (1420 vs. 2245 pg/mL, p = 0.003). The total number of follicles on the day of trigger (14.1 vs. 15.6, p = 0.284), the number of oocytes retrieved (18.4 vs. 20.5, p = 0.618), and the percentage of mature oocytes (69.9 vs. 73.8%, p = 0.076) were similar between cases and controls. One patient returned for a cryopreserved embryo transfer and delivered a healthy child. CONCLUSIONS: Patients undergoing FP prior to chemotherapy and/or radiation for a glioma achieve satisfactory FP outcomes and should be appropriately counseled regarding the opportunity to family-build after treatment.

Delta-9 THC can be detected and quantified in the semen of men who are chronic users of inhaled cannabis.

PURPOSE: The purpose of this proof-of-concept study was to determine whether delta-9-tetrahydrocannabinol (THC) and THC metabolites (11-OH THC and THC-COOH) can be detected in semen. METHODS: Twelve healthy men aged 18-45 years who identified as chronic and heavy users of inhaled cannabis were recruited. THC and THC metabolite levels were measured in serum, urine, and semen of the participants. Semen analyses were performed. Serum reproductive hormones were measured. RESULTS: The median age and BMI of participants were 27.0 years and 24.7 kg/m2, respectively. Over half the participants were daily users of cannabis for over 5 years. Serum reproductive hormones were generally within normal ranges, except prolactin, which was elevated in 6 of 12 participants (mean 13.9 ng/mL). The median sperm concentration, motility, and morphology were 75.5 million/mL, 69.5%, and 5.5%, respectively. Urinary THC-COOH was detected in all 12 participants, and at least one serum THC metabolite was present in 10 of 12 participants. Two semen samples had insufficient volume to be analyzed. THC was above the reporting level of 0.50 ng/mL in the semen of two of the remaining participants. Seminal THC was moderately correlated with serum levels of THC (r = 0.66), serum 11-OH THC (r = 0.57), and serum THC-COOH (r = 0.67). Seminal delta-9 THC was not correlated with urinary cannabinoid levels or semen analysis parameters. CONCLUSION: This is the first study to identify and quantify THC in human semen, demonstrating that THC can cross the blood-testis barrier in certain individuals. Seminal THC was found to be moderately correlated with serum THC and THC metabolites.

The impact of polycystic ovary syndrome and body mass index on the absorption of recombinant human follicle stimulating hormone.

PURPOSE: Women with polycystic ovary syndrome (PCOS) have an increased ovarian responsiveness to exogenous recombinant follicle stimulating hormone (rFSH) but also have high rates of obesity, which is known to affect serum FSH concentrations following exogenous injection. The purpose of this study was to compare rFSH absorption and ovarian response between lean and overweight/obese PCOS subjects and normo-ovulatory controls. METHODS: Fourteen women with PCOS aged 18-42 years old with a BMI of 18.5-24.9 kg/m2 (normal) or 25.0-40.0 kg/m2 (overweight/obese) and eleven normo-ovulatory controls matched by age and BMI were included. After downregulation with oral contraceptives, participants were administered a single subcutaneous injection of 225 IU rFSH and underwent serial blood draws over 72 h. RESULTS: Lean PCOS subjects exhibited a significantly higher area under the curve (AUC) of baseline-corrected serum FSH over 72 h when compared with overweight/obese PCOS subjects (183.3 vs 139.8 IU*h/L, p = 0.0002), and lean, normo-ovulatory women had a significantly higher AUC FSH when compared with overweight/obese, normo-ovulatory women (193.3 vs 93.8 IU*h/L, p < 0.0001). Within overweight/obese subjects, those with PCOS had a significantly higher AUC FSH compared with normo-ovulatory controls (p = 0.0002). Lean PCOS subjects similarly had the highest AUC of baseline-corrected estradiol (6095 pg h/mL), compared with lean normo-ovulatory subjects (1931 pg h/mL, p < 0.0001) and overweight/obese PCOS subjects (2337 pg h/mL, p < 0.0001). CONCLUSION: Lean PCOS subjects exhibited significantly higher baseline-corrected FSH and estradiol levels following rFSH injection compared with overweight/obese PCOS subjects with similar ovarian reserve markers. Amongst overweight/obese subjects, those with PCOS had significantly higher FSH and E2 levels when compared with normo-ovulatory controls.