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.

Social media's impact on patient provider choice.

OBJECTIVE: This study aimed to investigate if social media (SM) impacts a patient's provider choice in the field of reproductive endocrinology and infertility (REI). METHODS: This was a survey-based study completed in July 2022. A survey link was distributed using Amazon Mechanical Turk, which directed participants to a Qualtrics-based survey. Participants were 18-50 years old. The primary outcome was to identify the preferred method for finding a REI provider based on time spent on SM (< 1 h, 1-3 h, 3 + h). RESULTS: A total of 336 responses were analyzed. Fifty-four percent of respondents used SM < 1 h, 33.33% used 1-3 h, and 12.80% used 3 + h. The majority (69.05%) of respondents stated that they would seek out a REI provider/clinic if they had difficulty conceiving. Most respondents identified asking their primary care physician (44.64%) as the primary means for finding an REI provider/clinic and did not prefer to use SM. Although Facebook (< 1 h: 30.94%, 1-3 h: 31.25%, 3 + h: 27.91%) was the most utilized SM platform among respondents, YouTube was the preferred SM platform if respondents were to follow a REI clinic with a preference for posts focusing on education (< 1 h: 55.68%, 1-3 h: 43.12%, 3 + h: 58.14%) or stress management (< 1 h: 17.61%, 1-3 h: 29.36%, 3 + h: 20.94%). CONCLUSION: Most respondents utilize traditional methods when choosing their REI provider or clinic and would not utilize SM. However, SM, primarily through YouTube, may be helpful for educating infertility patients and providing support and stress relief while they undergo treatment.

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.

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.

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 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.

Utility of Office Hysteroscopy in Diagnosing Retained Products of Conception Following Early Pregnancy Loss After In Vitro Fertilization.

OBJECTIVE: To evaluate the utility of office hysteroscopy in diagnosing and treating retained products of conception in patients with infertility who experience early pregnancy loss (EPL) after in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 597 pregnancies that ended in EPL in patients aged 18-45 years who conceived through fresh or frozen embryo transfer at an academic fertility practice between January 2016 and December 2021. All patients underwent office hysteroscopy after expectant, medical, or surgical management of the EPL. The primary outcome was presence of retained products of conception at the time of office hysteroscopy. Secondary outcomes included incidence of vaginal bleeding, presence of intrauterine adhesions, treatment for retained products of conception, and duration of time from EPL diagnosis to resolution. Log-binomial regression and Poisson regression were performed, adjusting for potential confounders including oocyte age, patient age, body mass index, prior EPL count, number of prior dilation and curettage procedures, leiomyomas, uterine anomalies, and vaginal bleeding. RESULTS: Of the 597 EPLs included, 129 patients (21.6%) had retained products of conception diagnosed at the time of office hysteroscopy. The majority of individuals with EPL were managed surgically (n=427, 71.5%), in lieu of expectant management (n=140, 23.5%) or medical management (n=30, 5.0%). The presence of retained products of conception was significantly associated with vaginal bleeding (relative risk [RR] 1.72, 95% CI 1.34-2.21). Of the 41 patients with normal pelvic ultrasonogram results before office hysteroscopy, 10 (24.4%) had retained products of conception detected at the time of office hysteroscopy. When stratified by EPL management method, retained products of conception were significantly more likely to be present in individuals with EPL who were managed medically (adjusted RR 2.66, 95% CI 1.90-3.73) when compared with those managed surgically. Intrauterine adhesions were significantly less likely to be detected in individuals with EPL who underwent expectant management when compared with those managed surgically (RR 0.14, 95% CI 0.04-0.44). Of the 127 individuals with EPL who were diagnosed with retained products of conception at the time of office hysteroscopy, 30 (23.6%) had retained products of conception dislodged during the office hysteroscopy, 34 (26.8%) chose expectant or medical management, and 63 (49.6%) chose surgical management. The mean number of days from EPL diagnosis to resolution of pregnancy was significantly higher in patients who elected for expectant management (31 days; RR 1.18, 95% CI 1.02-1.37) or medical management (41 days; RR 1.54, 95% CI 1.25-1.90) when compared with surgical management (27 days). CONCLUSION: In patients with EPL after IVF, office hysteroscopy detected retained products of conception in 24.4% of those with normal pelvic ultrasonogram results. Due to the efficacy of office hysteroscopy in diagnosing and treating retained products of conception, these data support considering office hysteroscopy as an adjunct to ultrasonography in patients with infertility who experience EPL after IVF.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

OBJECTIVES: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. METHODS: The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free ß and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. RESULTS: The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. CONCLUSION: The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

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.

Cumulus cell co-culture in media drops does not improve rescue in vitro maturation of vitrified-warmed immature oocytes.

OBJECTIVE: To assess whether co-culture with vitrified-warmed cumulus cells (CCs) in media drops improves rescue in vitro maturation (IVM) of previously vitrified immature oocytes. Previous studies have shown improved rescue IVM of fresh immature oocytes when cocultured with CCs in a three-dimensional matrix. However, the scheduling and workload of embryologists would benefit from a simpler IVM approach, particularly in the setting of time-sensitive oncofertility oocyte cryopreservation (OC) cases. Although the yield of developmentally competent mature metaphase II (MII) oocytes is increased when rescue IVM is performed before cryopreservation, it is unknown whether maturation of previously vitrified immature oocytes is improved after coculture with CCs in a simple system not involving a three-dimensional matrix. DESIGN: Randomized controlled trial. SETTING: Academic hospital. PATIENTS: A total of 320 (160 germinal vesicles [GVs] and 160 metaphase I [MI]) immature oocytes and autologous CC clumps were vitrified from patients who were undergoing planned OC or intracytoplasmic sperm injection from July 2020 until September 2021. INTERVENTIONS: On warming, the oocytes were randomized to culture in IVM media with CCs (+CC) or without CCs (-CC). Germinal vesicles and MI oocytes were cultured in 25 µL (SAGE IVM medium) for 32 hours and 20-22 hours, respectively. MAIN OUTCOME MEASURES: Oocytes with a polar body (MII) were randomized to confocal microscopy for analysis of spindle integrity and chromosomal alignment to assess nuclear maturity or to parthenogenetic activation to assess cytoplasmic maturity. Wilcoxon rank sum tests for continuous variables and the chi square or Fisher's exact test for categorical variables assessed statistical significance. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS: Patient demographic characteristics were similar for both the GV and MI groups after randomization to +CC vs. -CC. No statistically significant differences were observed between +CC vs. -CC groups regarding the percentage of MII from either GV (42.5% [34/80] vs. 52.5% [42/80]; RR 0.81; 95% CI: 0.57-1.15]) or MI (76.3% [61/80]; vs. 72.5% [58/80]; RR 1.05; 95% CI: 0.88-1.26]) oocytes. An increased percentage of GV-matured MIIs underwent parthenogenetic activation in the +CC group (92.3% [12/13] vs. 70.8% [17/24]), but the difference was not statistically significant (RR 1.30; 95% CI: 0.97-1.75), whereas the activation rate was identical for MI-matured oocytes (74.3% [26/35] vs. 75.0% [18/24], CC+ vs. CC-; RR 0.99; 95% CI: 0.74-1.32). No significant differences were observed between +CC vs. -CC groups for cleavage of parthenotes from GV-matured oocytes (91.7% [11/12] vs. 82.4% [14/17]) or blastulation (0 for both) or for MI-matured oocytes (cleavage: 80.8% [21/26] vs. 94.4% [17/18]; blastulation: 0 [0/26] vs. 16.7% [3/18]). Further, no significant differences were observed between +CC vs. -CC for GV-matured oocytes regarding incidence of bipolar spindles (38.9% [7/18] vs. 33.3% [5/15]) or aligned chromosomes (22.2% [4/18] vs. 0.0 [0/15]); or for MI-matured oocytes (bipolar spindle: 38.9% [7/18] vs. 42.9% [2/28]); aligned chromosomes (35.3% [6/17] vs. 24.1% [7/29]). CONCLUSIONS: Cumulus cell co-culture in this simple two-dimensional system does not improve rescue IVM of vitrified, warmed immature oocytes, at least by the markers assessed here. Further work is required to assess the efficacy of this system given its potential to provide flexibility in a busy, in vitro fertilization clinic.

Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates.

PURPOSE: Evaluate follicular phase progesterone elevation (≥ 1.5 ng/mL) prior to trigger during IVF stimulation and its effects on live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in fresh IVF cycles. METHODS: This was a retrospective cohort study within an academic clinic. A total of 6961 fresh IVF and IVF/ICSI cycles from October 1, 2015 to June 30, 2021 were included and grouped by progesterone (PR) prior to trigger: PR < 1.5 ng/mL (low PR group) and PR ≥ 1.5 ng/mL (high PR group). Main outcome measures included LBR, CPR, and IR. RESULTS: Among all cycle starts, 1568 (22.5%) were in the high PR group and 5393 (77.5%) were in the low PR group. Of the cycles which proceeded to an embryo transfer, 416 (11.1%) were in the high PR group and 3341 (88.9%) were in the low PR group. The high PR group had significantly lower IR (RR 0.75; 95% CI 0.64-0.88), CPR (aRR 0.74; 95% CI 0.64-0.87), and LBR (aRR 0.71; 95% CI 0.59-0.85) compared to the low PR group. When stratified by progesterone on the day of trigger (TPR), there was a clinically notable decrease in IR (16.8% vs 23.3%), CPR (28.1% vs 36.0%), and LBR (22.8% vs 28.9%) in the high PR group compared to the low PR group even when TPR < 1.5 ng/mL. CONCLUSIONS: In fresh IVF cycles in which TPR < 1.5 ng/mL, progesterone elevation ≥ 1.5 ng/mL at any point in time prior to trigger negatively impacts IR, CPR, and LBR. This data supports testing of serum progesterone in the follicular phase prior to trigger, as these patients may benefit from a freeze-all approach.

Perinatal and pediatric outcomes associated with the use of fertility treatment: a population-based retrospective cohort study in Ontario, Canada.

BACKGROUND: Around 2% of births in Ontario, Canada involve the use of assisted reproductive technology (ART), and it is rising due to the implementation of a publicly funded ART program in 2016. To better understand the impact of fertility treatments, we assessed perinatal and pediatric health outcomes associated with ART, hormonal treatments, and artificial insemination compared with spontaneously conceived births. METHODS: This population-based retrospective cohort study was conducted using provincial birth registry data linked with fertility registry and health administrative databases in Ontario, Canada. Live births and stillbirths from January 2013 to July 2016 were included and followed to age one. The risks of adverse pregnancy, birth and infant health outcomes were assessed by conception method (spontaneous conception, ART - in vitro fertilization and non-ART - ovulation induction, intra-uterine or vaginal insemination) using risk ratios and incidence rate ratios with 95% confidence intervals (CI). Propensity score weighting using a generalized boosted model was applied to adjust for confounding. RESULT(S): Of 177,901 births with a median gestation age of 39 weeks (IQR 38.0-40.0), 3,457 (1.9%) were conceived via ART, and 3,511 (2.0%) via non-ART treatments. There were increased risks (adjusted risk ratio [95% CI]) of cesarean delivery (ART: 1.44 [1.42-1.47]; non-ART: 1.09 [1.07-1.11]), preterm birth (ART: 2.06 [1.98-2.14]; non-ART: 1.85 [1.79-1.91]), very preterm birth (ART: 2.99 [2.75-3.25]; non-ART: 1.89 [1.67-2.13]), 5-min Apgar < 7 (ART: 1.28 [1.16-1.42]; non-ART: 1.62 [1.45-1.81]), and composite neonatal adverse outcome indicator (ART: 1.61 [1.55-1.68]; non-ART: 1.29 [1.25-1.34]). Infants born after fertility treatments had increased risk of admission to neonatal intensive care unit (ART: 1.98 [1.84-2.13]; non-ART: 1.59 [1.51-1.67]) and prolonged birth admission (≥ 3 days) (ART: 1.60 [1.54-1.65]; non-ART: 1.42 [1.39-1.45]). The rate of emergency and in-hospital health services use within the first year was significantly increased for both exposure groups and remained elevated when limiting analyses to term singletons. CONCLUSION(S): Fertility treatments were associated with increased risks of adverse outcomes; however, the overall magnitude of risks was lower for infants conceived via non-ART treatments.

Cytogenetic outcomes following a failed cell-free DNA screen: a population-based retrospective cohort study of 35,146 singleton pregnancies.

BACKGROUND: Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities. OBJECTIVE: This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies). STUDY DESIGN: This was a population-based retrospective cohort study using data from Ontario's prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies. RESULTS: Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7-262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6-8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9-7.9; relative difference, 1.2%; 95% confidence interval, -0.9 to 3.2). CONCLUSION: Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.

The effect of the Ontario Fertility Program on IVF utilization and outcomes in women of advanced reproductive age.

RESEARCH QUESTION: Are the demographics and clinical outcomes similar for patients aged ≥40 but <43 years seeking IVF in Ontario, Canada, before and after implementation of the Ontario Fertility Program (OFP), which supports public funding of IVF up to age 43? DESIGN: Retrospective database review using the Canadian Assisted Reproductive Technologies Registry Plus (CARTR Plus) and Better Outcomes Registry & Network (BORN) Ontario databases. Cycles from women who underwent autologous IVF and who were aged ≥40 and <43 years were analysed during a 2-year period prior to (2014-2015) and after (2016-2017) introduction of publicly funded IVF through the OFP. RESULTS: There was an almost doubling of treatment cycles in women aged 40-42 in Ontario after the OFP launch. Clinical pregnancy rate per cycle start (17.0% versus 13.3%, P < 0.001) and cumulative clinical pregnancy rate per stimulation cycle (20.5% versus 16.8%, P < 0.001) were statistically higher in women before OFP implementation. While cumulative live birth rate per cycle start was statistically lower after funding was introduced (12.5% versus 10.5%, P = 0.027), the clinical importance of this difference appears small. Outcomes were above the 10% live birth per cycle threshold recommended by the Advisory Process for Infertility Services panel, commissioned by the Ministry of Health, to determine access to publicly funded IVF. CONCLUSIONS: Use of IVF in women over age 40 doubled with access to OFP funding; however, eligibility criteria based on age still meet the target of achieving a cumulative live birth rate of at least 10%.

Optimizing pregnancy outcomes in intrauterine insemination cycles by stratifying pre-wash total motile count and patient-specific factors: a patient counseling tool.

PURPOSE: The purpose of this study is to clarify which pre-wash total motile count are associated with improved clinical pregnancy rate (CPR) and live birth rate (LBR) based on maternal age, AMH level, stimulation regimen, and infertility diagnosis. METHODS: This was a retrospective cohort study of first completed IUI cycles at two academic fertility centers from 5/2015 to 9/2019. Cycles were stratified by pre-wash TMC, maternal age, AMH level, stimulation regimen, and infertility diagnosis. The primary outcome was CPR and secondary outcomes were live birth and miscarriage. RESULTS: One thousand one hundred fifty-four cycles were analyzed. Of the 162 cycles that resulted in a CPR (14.0%), most had an insemination TMC > 20 million. Compared to TMC > 20 million, there was no difference in CPR or LBR for lower TMC categories, excluding the TMC < 2 million group, in which there were no pregnancies. When TMC was stratified by deciles, there was also no difference in CPR and LBR, including within the lowest decile (TMC 0.09-8.6 million). Younger age and higher ovarian reserve parameters were associated with higher pregnancy and LBR when stratified by TMC. There was no difference in pregnancy and LBR when considering different stimulation protocols. CONCLUSIONS: Our data suggest that pregnancy and LBR are equivalent above a TMC of 2 million. Data stratified by TMC and patient parameters can be used to counsel patients pursuing ART.

In vitro fertilization cycle and embryo transfer outcomes in oligoanovulatory patients with hypothalamic hypogonadism vs. polycystic ovary syndrome and compared with normo-ovulatory patients.

Objective: To study the difference in the live birth rates between anovulatory women with hypothalamic hypogonadism (HH) and those with polycystic ovary syndrome (PCOS) and normo-ovulatory women undergoing fresh embryo transfer or frozen embryo transfer (FET). Design: Retrospective cohort study. Setting: Academic medical center. Patients: Patients with oligoanovulation (HH, n = 47; PCOS, n = 533) and normo-ovulation (tubal factor infertility, n = 399) undergoing in vitro fertilization and intracytoplasmic sperm injection cycles from January 1, 2012, to June 30, 2019. Interventions: None. Main Outcome Measures: Live birth rate. Results: Patients with HH had longer stimulation durations than both patients with PCOS and tubal factor infertility. Patients with HH had fewer oocytes retrieved than patients with PCOS, but their numbers of blastocysts were similar. Patients with HH and tubal factor infertility had similar numbers of oocytes retrieved and blastocysts. In fresh embryo transfer cycles, the live birth rates were similar among patients with HH, PCOS, and tubal factor infertility (37.5% vs. 37.1% vs. 29.3%, respectively). When evaluating FET cycles, patients with HH had lower live birth rates than patients with PCOS (26.5% vs. 46.7%) and tubal factor infertility (42.6%). Conclusions: Live birth rates are similar among patients with HH, PCOS, and normo-ovulation undergoing fresh embryo transfer but are significantly lower in women with HH undergoing FET.

Day of trophectoderm biopsy and embryo quality are associated with outcomes following euploid embryo transfer.

PURPOSE: To compare clinical outcomes following transfer of euploid blastocysts of varying quality biopsied on day 5 versus day 6. METHODS: Retrospective cohort study to evaluate embryo transfer outcomes for women undergoing autologous cryopreserved next generation sequencing euploid single embryo transfer from 10/2015 to 2/2022 at an academic IVF program. The primary outcome was live birth rate (LBR). Secondary outcomes included ongoing pregnancy rate (OPR), implantation rate (IR), and miscarriage rate (SAB rate). RESULTS: Five hundred and fifty-five transfers from 418 patients were analyzed. Euploid embryos biopsied on day 5 resulted in higher LBR compared to those biopsied on day 6 (62.3% vs. 49.6%; aRR 0.81 95% CI 0.65-0.996). When stratified by biopsy day and blastocyst quality, there was no difference in IR, OPR, and SAB rate for good, fair, and poor quality blastocysts biopsied on day 5 versus day 6. However, day 5 good quality embryos were associated with a higher LBR compared to day 6 good quality embryos (74.3% vs. 51.3%; aRR 0.69; 95% CI 0.48-0.999). There were no significant differences in LBR for fair and poor quality embryos biopsied on day 5 versus day 6. CONCLUSION: Overall LBR are higher for euploid embryos biopsied on day 5 versus day 6. When stratified by embryo quality and day of biopsy, LBR are significantly higher for good quality day 5 versus day 6 embryos. When choosing between multiple euploid embryos, day 5 biopsied good quality embryos should be preferentially selected for transfer over day 6 embryos of the same quality.

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.