The association of obesity with euploidy rates in women undergoing in vitro fertilization with preimplantation genetic testing.

PURPOSE: The purpose of this study was to determine the impact of body mass index (BMI) on euploidy rates for in vitro fertilization (IVF) cycles with preimplantation genetic testing (PGT) utilizing primarily next-generation sequencing (NGS). METHODS: This retrospective cohort study included women aged ≤ 45 years who underwent IVF/PGT between September 2013 and September 2020 at a single university-affiliated fertility center. The primary outcome was euploidy rate. Secondary outcomes included peak serum estradiol (E2), number of oocytes retrieved, oocyte maturation rate, high-quality blastulation rate, clinical loss rate (CLR), clinical pregnancy rate (CPR), and ongoing pregnancy/live birth rate (OPR/LBR). RESULTS: The study included 1335 IVF cycles that were stratified according to BMI (normal, n = 648; overweight, n = 377; obese, n = 310). The obese group was significantly older with significantly lower baseline FSH, peak E2, high-quality blastulation rate, and number of embryos biopsied than the normal group. Overall euploidy rates were not significantly different between BMI groups (normal 36.4% ± 1.3; overweight 37.3% ± 1.8; obese 32.3% ± 1.8; p = 0.11), which persisted after controlling for covariates (p = 0.82) and after stratification of euploidy rate by age group and by number of oocytes retrieved per age group. There were no significant differences in CLR, CPR, and OPR/LBR across BMI groups. CONCLUSIONS: Despite a lower high quality blastulation rate with obesity, there is not a significant difference in euploidy rates across BMI groups in women undergoing IVF/PGT.

Embryologic outcomes among patients using a microfluidics chip compared to density gradient centrifugation to process sperm: a paired analysis.

PURPOSE: To evaluate embryologic outcomes among paired IVF cycles in which a microfluidics chip was utilized compared to density gradient centrifugation for sperm processing. METHODS: This was a retrospective cohort study of 88 paired IVF cycles from patients aged 18-44 years at a university-affiliated IVF center. Fresh cycles from patients undergoing ICSI with sperm processed by a microfluidics chamber (microfluidics cycles) were compared to the same patients' previous ICSI cycles in which sperm was processed via density gradient centrifugation (control cycles). The primary outcome was the high-quality blastulation rate. RESULTS: High-quality blastulation rate per oocyte retrieved was significantly higher in the microfluidics group compared to the control group (21.1% versus 14.5%, p < 0.01) as was the blastulation rate per 2PN (42.7% versus 30.8%, p < 0.01). Fertilization rates were significantly higher in the microfluidics group. The euploidy rate per oocyte retrieved was significantly higher in the microfluidics group compared with the control group (8.5% versus 4.3%, p = 0.04), while the euploidy rate per embryo biopsied was comparable (32.6% versus 21.8%, p = 0.09). In patients with male factor infertility, the high-quality blastulation rate was similar between the control and microfluidics cycles. There was a significantly higher blastulation rate among microfluidics cycles in patients without a diagnosis of male factor infertility (p < 0.01). CONCLUSION: In this study, several embryologic outcomes, including fertilization rate, high-quality blastulation rate, and euploidy rate, were significantly higher in the microfluidics group compared to the control group. Microfluidics sperm processing may be a way to improve embryologic outcomes.

Impact of trophectoderm biopsy on obstetric and perinatal outcomes following frozen-thawed embryo transfer cycles.

STUDY QUESTION: Does trophectoderm biopsy for preimplantation genetic testing (PGT) increase the risk of obstetric or perinatal complications in frozen-thawed embryo transfer (FET) cycles? SUMMARY ANSWER: Trophectoderm biopsy may increase the risk of hypertensive disorders of pregnancy (HDP) in pregnancies following FET cycles. WHAT IS KNOWN ALREADY: Trophectoderm biopsy has replaced blastomere biopsy as the standard of care to procure cells for PGT analysis. Recently, there has been concern that trophectoderm biopsy may adversely impact obstetric and perinatal outcomes. Previous studies examining this question are limited by use of inappropriate control groups, small sample size or reporting on data that no longer reflects current IVF practice. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study conducted at a single university-affiliated fertility center. A total of 756 patients who underwent FET with transfer of previously vitrified blastocysts that had either trophectoderm biopsy or were unbiopsied and resulted in a singleton live birth between 2013 and 2019 were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Obstetric and perinatal outcomes for patients aged 20-44 years who underwent FET with transfer of previously vitrified blastocysts that were either biopsied (n = 241) or unbiopsied (n = 515) were analyzed. Primary outcome was odds of placentation disorders including HDP and rate of fetal growth restriction (FGR). Binary logistic regression was performed to control for potential covariates. MAIN RESULTS AND THE ROLE OF CHANCE: The biopsy group was significantly older, had fewer anovulatory patients, was more often nulliparous and had fewer embryos transferred compared to the unbiopsied group. After controlling for potential covariates, the probability of developing HDP was significantly higher in the biopsy group compared with unbiopsied group (adjusted odds ratio (aOR) 1.943, 95% CI 1.072-3.521; P = 0.029).There was no significant difference between groups in the probability of placenta previa or placenta accreta. There was also no significant difference in the rate of FGR (aOR 1.397; 95% CI, 0.815-2.395; P = 0.224) or the proportion of low (aOR 0.603; 95% CI, 0.336-1.084; P = 0.091) or very low (aOR 2.948; 95% CI, 0.613-14.177; P = 0.177) birthweight infants comparing biopsied to unbiopsied groups. LIMITATIONS, REASON FOR CAUTION: This was a retrospective study performed at a single fertility center, which may limit the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: Trophectoderm biopsy may increase the risk of HDP in FET cycles, however, a prospective multicenter randomized trial should be performed to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: NA.

Reduction in multiple pregnancy rate in donor oocyte-recipient gestational carrier (GC) in vitro fertilization (IVF) cycles in the USA with single-embryo transfer and preimplantation genetic testing.

PURPOSE: To evaluate the utilization of single-embryo transfer (SET) and preimplantation genetic testing (PGT) in gestational carrier IVF cycles in the USA with donor oocyte and examine the impact on live birth and multiple gestation. METHODS: Retrospective cohort study using the Society of Assisted Reproductive Technology (SART) clinic database of 4776 donor oocyte-recipient IVF cycles in which a GC was used. The cycles were separated into 4 groups by use of PGT and number of embryos transferred as follows: (1) PGT and single-embryo transfer (PGT-SET); (2) PGT and multiple embryo transfer (PGT-MET); (3) no PGT and SET (NoPGT-SET); (4) no PGT and MET (NoPGT-MET). Primary outcomes were live birth rate (LBR) and multiple pregnancy rate (MPR). RESULTS: More than one blastocyst was transferred in 48.7% (2323/4774) of the cycles. When ≥1 blastocyst was transferred, with or without the use of PGT, the MPR was 45.5% and 42.0%, respectively. In comparison, in the PGT-SET and NoPGT-SET groups, the MPR was 1.4% (8/579) and 3.3% (29/883), respectively. Live birth rates increased with the use of PGT-A and with MET. CONCLUSION: This study shows that SET, with or without PGT, is associated with a significantly reduced MPR in donor oocyte-recipient GC IVF cycles while maintaining high LBR. It also demonstrates that many infertility centers in the USA are not adhering to ASRM embryo transfer guidelines. Our findings highlight an opportunity to increase GC safety, which ultimately may lead to widened access to this increasingly restricted service outside the USA.

Factors associated with study protocol adherence and bio banking participation in reproductive medicine clinical trials and their relationship to live birth.

STUDY QUESTION: What demographic and baseline characteristics are predictive of adherence to reproductive medicine clinical trial protocols, live birth or participation in genetic studies? SUMMARY ANSWER: Race, BMI and lower income are associated with likelihood of non-adherent to reproductive medicine clinical trial protocols, while race influences collection of biological samples and non-adherent to study protocols is associated with lower probability of live birth. WHAT IS KNOWN ALREADY: Although aspects of adherence to study protocol have previously been evaluated as individual factors in infertile women, the factors that affect overall non-adherent to study protocol have not been previously evaluated. STUDY DESIGN, SIZE, DURATION: A secondary data analysis of 1650 participants from two prospective multicenter, double-blind controlled studies was carried out: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were women aged 18-40 years old with either polycystic ovary syndrome (PCOS) with ovulatory dysfunction in combination with either hyperandrogenemia and/or polycystic ovarian morphology (PPCOS II), or regular ovulatory cycles with unexplained infertility (AMIGOS). The study was carried out in 14 clinical sites in the USA. Non-adherence to clinical trial protocol was chosen as the primary outcome for this analysis. To evaluate whether demographic and baseline characteristics were predictive of adherence to study protocols, live birth or participation in blood sampling for DNA and repository, and pregnancy registry, these putative factors were compared between the outcome measures. Logistic regression was used to establish a prediction model using the putative predictors introduced above. MAIN RESULTS AND THE ROLE OF CHANCE: Women who self-identified as African American or Asian and those with higher BMI and lower household income were less likely to adhere to protocol. Non-adherence to the study protocol was associated with a lower probability of live birth (odds ratio: 0.180, 95% CI: 0.120, 0.272, P < 0.001). African Americans or Asians were less likely to participate in optional study DNA collection compared to Whites. Participants who were African American or with high annual income or from the Southwest sites or had PCOS were less likely to participate in the blood repository studies. LIMITATIONS, REASONS FOR CAUTION: Race and ethnicity were self-reported and such self-classification to strict race and ethnicity may not always be representative of a whole racial or ethnic group. This study included two US multicenter trials and therefore the findings may not be extrapolated to international trials. WIDER IMPLICATIONS OF THE FINDINGS: Identification of populations with low participation is an important initial step, as further investigation can develop specific measures to improve adherence to study protocols and participation in biospecimen banking and thereby extend the representativeness of reproductive medicine clinical trial findings. STUDY FUNDING/COMPETING INTEREST(S): Supported by NIH Eunice Kennedy Shriver NICHD Grants: U10 HD39005, U10 HD38992, U10 HD27049, U10 HD38998, U10 HD055942, HD055944, U10 HD055936, U10HD055925, PPCOSII: U10 HD27049, U10 HD38992, U10 HD055925, U10 HD39005, U10 HD38998, U10 HD055936, U10 HD055942, U10 HD055944; Clinical Reproductive Endocrine Scientist Training Program (CREST): R25HD075737. Outside this study, M.P.D. received NIH/NIHCD research grant and R.S.L. received research grant from Ferring and was consultant for Bayer, Kindex, Odega, Millendo and AbbVie. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT00719186; NCT01044862.

Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles.

RESEARCH QUESTION: Do maternal and perinatal outcomes differ between natural and programmed frozen embryo transfer (FET) cycles? DESIGN: Retrospective cohort study at a university-affiliated fertility centre including 775 patients who underwent programmed or natural FET cycles resulting in a singleton live birth using blastocysts vitrified between 2013 and 2018. RESULTS: A total of 384 natural and 391 programmed FET singleton pregnancies were analysed. Programmed FET resulted in higher overall maternal complications (32.2% [126/391] versus 18.8% [72/384]; P < 0.01), including higher probability of hypertensive disorders of pregnancy (HDP) (15.3% [60/391] versus 6.3% [24/384]; P < 0.01), preterm premature rupture of membranes (2.6% [10/391] versus 0.3% [1/384]; P = 0.02) and caesarean delivery (53.2% [206/387] versus 42.8% [163/381]; P = 0.03) compared with natural FET. After controlling for potential confounders, including age, body mass index, parity, smoking status, history of diabetes or chronic hypertension, infertility diagnosis, number of embryos transferred and use of preimplantation genetic testing, the adjusted odds ratio for HDP was 2.39 (95% CI 1.37 to 4.17) and for overall maternal complications was 2.21 (95% CI 1.51 to 3.22) comparing programmed with natural FET groups. The groups did not significantly differ for any perinatal outcomes analysed, including birth weight (3357.9 ± 671.6 g versus 3318.4 ± 616.2 g; P = 0.40) or rate of birth defects (1.5% [6/391] versus 2.1% [8/384]; P = 0.57), respectively. CONCLUSION: Vitrified-warmed blastocyst transfer in a programmed cycle resulted in a twofold higher probability of HDP compared with transfer in a natural cycle. Natural FET cycle should, therefore, be recommended as first line for all eligible patients undergoing FET to reduce the risk of HDP.

Pregnancy outcomes after frozen-thawed single euploid blastocyst transfer following IVF cycles using GNRH agonist or HCG trigger for final oocyte maturation.

PURPOSE: To assess whether GnRH agonist trigger impacts the implantation potential of euploid embryos. METHODS: Retrospective cohort study done at an academic IVF center evaluating frozen-thawed embryo transfer (FET) cycles in which single-euploid blastocysts were transferred between 2014 and 2019. All embryos were generated in an IVF cycle which used GnRHa or hCG trigger and then were transferred in a programmed or natural FET cycle. Only the first FET cycle was included for each patient. Primary outcome was ongoing pregnancy rate or live birth rate (OPR/LBR). Secondary outcomes were implantation rate (IR), clinical pregnancy rate (CPR), clinical loss rate (CLR), and multiple pregnancy rate (MPR). Logistic regression was performed to control for confounding variables. A p value of < 0.05 was considered statistically significant. RESULTS: Two hundred sixty-three FET cycles were included for analysis (GnRHa = 145; hCG = 118). The GnRHa group was significantly younger (35.2 vs. 37.5 years) and had higher AMH values (4.50 ng/ml vs. 2.03 ng/ml) than the hCG group, respectively (p < 0.05). There was no significant difference in OPR/LBR (64.1% (93/145) vs. 65.3% (77/118); p = 0.90) between the GnRHa and hCG groups, respectively. There was also no significant difference in IR, CPR, CLR, or MPR between groups. After controlling for confounding variables, the adjusted odds ratio for OPR/LBR was 0.941 (95% CI, 0.534-1.658); p = 0.83) comparing GnRHa to hCG. Pregnancy outcomes did not significantly differ when groups were stratified by age (< 35 vs. > 35 years old). CONCLUSIONS: Our findings confirm that euploid embryos created after hCG or GnRHa trigger have the same potential for pregnancy.

The window is wide: flexible timing for vitrified-warmed embryo transfer in natural cycles.

RESEARCH QUESTION: What is the optimal timing for transfer in natural cycle vitrified-warmed embryo transfers (NC-VET)? DESIGN: This retrospective cohort study uses data from a large university-affiliated IVF clinic. The study included 341 NC-VET cycles with autologous oocytes and non-preimplantation genetic testing, vitrified embryos from January 2013 to September 2017. Each cycle was classified by timing of embryo transfer in relation to LH surge ≥20 IU/l. Group 1: LH ≥20 IU/l one day and blastocyst was transferred 6 days later; Group 2: LH ≥20 IU/l two consecutive days and blastocyst was transferred 6 days after the initial surge; Group 3: LH ≥20 IU/l two consecutive days and blastocyst was transferred 7 days after the initial surge. The primary outcome was ongoing pregnancy rate (OPR). The secondary objective was to compare OPR in relation to serum oestradiol dynamics and progesterone concentration (according to threshold 1.0 ng/ml) 6 days prior to embryo transfer. RESULTS: OPR were similar for all three groups (66.8%, 65.0%, 62.9% for Groups 1, 2 and 3, respectively). When stratified according to oestradiol and progesterone, no significant differences were noted in OPR. CONCLUSIONS: The results suggest that the timing of blastocyst transfer in a natural cycle after LH surge is flexible within 24 h. Outcomes are equally good with day of embryo transfer 6 or 7 days after LH surge date. Oestradiol dynamics and progesterone concentration 6 days prior to NC-VET did not have a significant impact on OPR.

Frozen blastocyst transfer outcomes in immediate versus delayed subsequent cycles following GnRH agonist or hCG triggers.

PURPOSE: The aim of this study is to analyze clinical pregnancy rates (CPR) and ongoing pregnancy rates (OPR) for frozen embryo transfers (FET) performed with blastocysts in the cycle immediately after GnRH agonist (GnRHa) versus human chorionic gonadotropin (hCG) triggers, with outcomes of delayed FET for comparison. METHODS: Retrospective cohort study at a university-affiliated in vitro fertilization (IVF) clinic, including patients undergoing IVF between 2013-16 with a blastocyst FET performed within two menstrual cycles of a previous stimulation cycle and vaginal oocyte retrieval (VOR). FETs included programmed and natural endometrial preparation. Outcome measures were clinical and ongoing pregnancy rates. RESULTS: CPR and OPR for 344 FET cycles were similar when comparing immediate and delayed transfer overall (crude CPR 67.5 versus 76.5%, p = 0.11; OPR 57.5 versus 66.7%, p = 0.13), and after stratifying by cycles following hCG trigger (OPR 62.5 versus 66.3%, p = 0.61) and GnRHa trigger (OPR 55.6 versus 64.5%, p = 0.17). When considering a number of predictors for OPR, an adjusted odds ratio (OR) of 1.74 [95% CI 1.00-3.03] approached significance in favor of delayed FET. CONCLUSIONS: Regardless of trigger modality, patients can be reassured that pregnancy rates with FET are high in immediate and delayed cycles. However, our study suggests a potential benefit in delaying a cycle before proceeding with FET.

Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype.

BACKGROUND: Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent. OBJECTIVE: We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome. STUDY DESIGN: We conducted secondary data analysis of a prospective multicenter, double-blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non-Hispanic whites, non-Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups. RESULTS: Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m2) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic white, non-Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic whites. Non-Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups. CONCLUSION: Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non-Hispanic white women.

Pregnancy rates for single embryo transfer (SET) of day 5 and day 6 blastocysts after cryopreservation by vitrification and slow freeze.

PURPOSE: The purpose of this study was to compare clinical and ongoing pregnancy rates in cycles with single embryo transfer (SET) of blastocysts cryopreserved on day 5 or day 6. Our aim was to determine whether day 6 blastocysts perform adequately to recommend SET. METHODS: Retrospective cohort study including 468 transfer cycles for 392 women younger than age 38 undergoing SET at a university-affiliated IVF clinic in the USA. A total of 261 day 5 blastocysts and 207 day 6 blastocysts for frozen-thawed SET between 2010 and 2016 were analyzed. Data included cryopreservation by both a slow freeze method and vitrification. RESULTS: In total, 59.0% of day 5 SET cycles resulted in a clinical pregnancy compared to 54.1% of day 6 blastocysts (p = 0.54). Ongoing pregnancy rates from day 5 frozen-thawed blastocysts (51.7%) were comparable to day 6 (44.9%, p = 0.14). When looking at vitrified blastocysts only, there were no significant differences between day 5 and day 6 blastocysts, with a clinical pregnancy rate of 69.2% for day 5 and 72.5% for day 6 (p = 0.68). CONCLUSIONS: SETs of day 6 cryopreserved blastocysts resulted in similar clinical and ongoing pregnancy rates compared to day 5, particularly after vitrification.

GnRH agonist trigger for the induction of oocyte maturation in GnRH antagonist IVF cycles: a SWOT analysis.

Gonadotrophin releasing hormone agonist (GnRHa) trigger is effective in the induction of oocyte maturation and prevention of ovarian hyperstimulation syndrome during IVF treatment. This trigger concept, however, results in early corpora lutea demise and consequently luteal phase dysfunction and impaired endometrial receptivity. The aim of this strenghths, weaknesses, opportunities and threats analysis was to summarize the progress made over the past 15 years to optimize ongoing pregnancy rates after GnRHa trigger. The advantages and potential drawbacks of this type of triggering are reviewed. The current approach to the management of GnRHa trigger in autologous cycles is based on the peak serum oestradiol level or follicle number and aims at a fresh embryo transfer or a segmentation approach with elective cryopreservation policy. We recommend intensive luteal support with transdermal oestradiol and intramuscular progesterone alone if peak serum oestradiol is 4000 or more pg/ml after GnRHa trigger or dual trigger with GnRHa and HCG 1000 IU if peak serum oestradiol is less than 4000 pg/mL. On the contrary, we recommend HCG 1500 IU 35 h after GnRHa trigger if there are less than 25 follicles, or freeze all oocytes or embryos if there are over 25 follicles.

Correlation of normal-range FMR1 repeat length or genotypes and reproductive parameters.

PURPOSE: This study aims to ascertain whether the length of normal-ranged CGG repeats on the FMR1 gene correlates with abnormal reproductive parameters. METHODS: We performed a retrospective, cross-sectional study of all FMR1 carrier screening performed as part of routine care at a large university-based fertility center from January 2011 to March 2014. Correlations were performed between normal-range FMR1 length and baseline serum anti-Müllerian hormone (AMH), cycle day 3 follicle stimulating hormone (FSH), ovarian volumes (OV), antral follicle counts (AFC), and incidence of diminished ovarian reserve (DOR), while controlling for the effect of age. RESULTS: Six hundred three FMR1 screening results were collected. One subject was found to be a pre-mutation carrier and was excluded from the study. Baseline serum AMH, cycle day 3 FSH, OV, and AFC data were collected for the 602 subjects with normal-ranged CGG repeats. No significant difference in median age was noted amongst any of the FMR1 repeat genotypes. No significant correlation or association was found between any allele length or genotype, with any of the reproductive parameters or with incidence of DOR at any age (p > 0.05). However, subjects who were less than 35 years old with low/low genotype were significantly more likely to have below average AMH levels compared to those with normal/normal genotype (RR 3.82; 95 % CI 1.38-10.56). CONCLUSIONS: This large study did not demonstrate any substantial association between normal-range FMR1 repeat lengths and reproductive parameters.

The updated Cochrane review 2014 on GnRH agonist trigger: repeating the same errors.

Cochrane reviews are powerful tools, internationally recognized as the highest standard in evidence-based health care. A Cochrane analysis makes use of precise, reproducible criteria in the selection of studies for review. In the context of a previous Cochrane review (2010) on the subject of gonadotrophin-releasing hormone agonist (GnRHa) trigger, we questioned whether a review should be conducted during the research phase when new concepts are being developed. Recently, an updated Cochrane review was published, reaching the same general conclusion as the first one, i.e., GnRHa triggers lower the chance of pregnancy in fresh autologous IVF and intracytoplasmic injection treatment cycles. We argue that the new review repeats previous errors by compiling data from studies that were not comparable as different luteal phase protocols were used. From the clinical point of view, the luteal support used is the variable which affects the pregnancy rate and not the use of the GnRHa trigger for final oocyte maturation. Therefore, a meaningful comparison between GnRHa and HCG trigger must be confined to outcome measures that are not affected by the luteal support used. We conclude that the updated review falls short of addressing meaningful clinical and fundamental questions in the context of GnRHa trigger.

Estradiol and Antagonist Pretreatment Prior to Microdose Leuprolide in in Vitro Fertilization. Does It Improve IVF Outcomes in Poor Responders as Compared to Oral Contraceptive Pill?

OBJECTIVE: To compare in vitro fertilization (IVF) outcomes in low responders stimulated with microdose leuprolide protocol (ML) following pretreatment with either oral contraceptive pill (OCP) or luteal estradiol (E2) + GnRH antagonist (E2 + antag) for follicular synchronization prior to controlled ovarian hyperstimulation (COH). STUDY DESIGN: This was a retrospective study of 130 women, who were poor responders, undergoing IVF with either OCP/ML or E2+ antag/ML protocols. The main outcome measures were ongoing pregnancy rates, number of oocytes retrieved, and cancellation rate. RESULTS: Both groups were similar in baseline characteristics. There were no significant differences in gonadotropin requirement, cancellation rate, and number of embryos transferred. Ongoing pregnancy rates (40% vs. 15%) were significantly higher in the OCP/ML group. Trends toward greater number of oocytes retrieved (7.7 ± 3.4 vs. 5.9 ± 4.2) and improved implantation rates (20% vs. 12%) were also noted, but these did not reach statistical significance. CONCLUSION: E2+antag pretreatment does not appear to improve IVF outcomes in ML protocol when compared to the standard OCP in poor responders. Randomized trials with adequate power to study the optimal method of steroid pretreatments appear justified.

The impact of microfluidics sperm processing on blastocyst euploidy rates compared with density gradient centrifugation: a sibling oocyte double-blinded prospective randomized clinical trial.

OBJECTIVE: To compare the euploidy rates among blastocysts created from sibling oocytes injected with sperm and processed using microfluidics or density gradient centrifugation. DESIGN: Sibling oocyte randomized controlled trial. SETTING: Single university-affiliated infertility practice. PATIENTS: A total of 106 patients aged 18-42 years undergoing fresh in vitro fertilization treatment cycles with preimplantation genetic testing between January 2021 and April 2022 contributed 1,442 mature oocytes, which were injected with sperm and processed using microfluidics or density gradient centrifugation. INTERVENTION(S): The sperm sample is divided and processed using a microfluidics device and density gradient centrifugation for injection into sibling oocytes. MAIN OUTCOME MEASURE(S): The primary outcome was the embryo euploidy rate. Secondary outcomes included fertilization, high-quality blastulation, and ongoing pregnancy rates. RESULT(S): The blastocyst euploidy rate per mature oocyte was not significantly different in the study group compared with the control group (22.9% vs. 20.5%). The blastocyst euploidy rate per biopsied embryo was also similar between the 2 groups (53.0% vs. 45.7%). However, the fertilization rate per mature oocyte injected was found to be significantly higher in the study group compared with the control group (76.0% vs. 69.9%). The high-quality blastulation rate per mature oocyte injected was similar between the 2 groups, as was the total number of embryos frozen. There were no differences in the number of participants with no blastocysts for biopsy or the number of participants with no euploid embryos between the 2 groups. Among the male factor infertility and recurrent pregnancy loss subgroups, there were no differences in euploidy rates, fertilization rates, blastulation rates, or total numbers of blastocysts frozen, although the study was underpowered to detect these differences. Seventy-seven patients underwent frozen embryo transfer; there were no significant differences in pregnancy outcomes between the 2 groups. CONCLUSION(S): Microfluidics processing did not improve embryo euploidy rates compared with density gradient centrifugation in this sibling oocyte study, although fertilization rates were significantly higher. CLINICAL TRIAL REGISTRATION NUMBER: NCT04744025.

A prospective pilot study comparing fertilization and embryo development between fresh and vitrified sibling oocytes.

OBJECTIVE: To evaluate the outcome of a newly established oocyte vitrification program in women undergoing in vitro fertilization (IVF) within a short timeframe by simultaneously evaluating embryos derived from vitrified and fresh oocytes from the same stimulated cycle. DESIGN: Cohort prospective controlled trial and case-control study. SETTING: University-based tertiary fertility center. PATIENT(S): Fourteen women who fulfilled the inclusion criteria underwent controlled ovarian hyperstimulation and Intracytoplasmic sperm injection (ICSI) treatment. INTERVENTION(S): Oocyte vitrification. MAIN OUTCOME MEASURE(S): The primary outcome measures were oocyte survival, fertilization and cleavage rate, and subsequent embryo development, compared between vitrified and fresh oocytes. Secondary outcomes were implantation, clinical pregnancy, miscarriage and live birth rates using embryos derived from the vitrified oocytes for transfer. This was compared with age-matched controls who met similar inclusion criteria as the study patients and who underwent IVF during the same time period. Neonatal data on all newborns was also collected. RESULTS: From October 2009 until November 2010, a total of 17 patients were enrolled in this study (mean age 31.9 +/- 2.9 years). Three subjects withdrew prior to retrieval and one subject did not have a transfer from vitrified oocytes. A total of 164 metaphase II (MII) oocytes were retrieved (mean 11.7 +/- 3.7), 83 were vitrified with 86.7% survival. Fertilization rate was similar between vitrified and fresh oocytes (69.4 vs 78.2%, P = 0.8). Cleavage on day two, however, was lowerin the vitrified oocytes (88% vs 100%, P = 0.004). Implantation rate (IR) was 25% (7/28) with a mean number of 2.0 +/- 0.5 embryos transferred. Live birth rate/embryo transfer (ET) was 46.1% (6/13) after transferring embryos derived only from vitrified oocytes, (six live births, seven babies,one set of twins). One additional ongoing pregnancy has been established after transfer of a cryopreserved blastocyst derived from a vitrified oocyte (combined pregnancy rate/ ET: 50%; 7/14). CONCLUSIONS: This study provides a viable model to quickly assess the efficacy of a newly established egg vitrification program following American Society for Reproductive Medicine (ASRM) guidelines in an investigational protocol. Embryos resulting from oocyte vitrification resulted in optimal live birth and implantation rate. The lower cleavage rate noted in this study may indicate a possible detrimental effect of the vitrification process, which may be overcome with additional experience and refinement of the technique.

Macroprolactinemia: a mini-review and update on clinical practice.

Hyperprolactinemia is common among infertile patients, with up to 15%-20% of women with oligomenorrhea having hyperprolactinemia. Suppression of the hypothalamic-pituitary-gonadal axis via inhibition of pulsatile gonadotropin releasing hormone because of hyperprolactinemia is a common endocrine etiology of infertility. There are 3 forms of human prolactin (PRL): monomeric PRL, dimeric PRL, and macro-PRL. Also known as big-big PRL, macro-PRL has a molecular weight >150 kDa and normally comprises 5%-10% of circulating PRL. When the predominant form of circulating PRL is macro-PRL, macroprolactinemia is diagnosed. Among patients with hyperprolactinemia, 10%-46% have macroprolactinemia. Patients with macroprolactinemia are at risk of unnecessary pituitary imaging and treatment with dopamine agonists if not correctly diagnosed. Given the high prevalence of macroprolactinemia among patients with elevated PRL levels and the different management of patients with macroprolactinemia vs true monomeric hyperprolactinemia, all patients with persistently elevated PRL levels should be screened for macro-PRL.

Pregnancy outcomes after frozen-thawed embryo transfer using letrozole ovulation induction, natural, or programmed cycles.

OBJECTIVE: To evaluate and compare pregnancy outcomes between letrozole ovulation induction, natural, and programmed frozen-thawed embryo transfer (FET) cycles in a population based in the United States. DESIGN: Retrospective cohort study. SETTING: Single university-affiliated infertility practice. PATIENT(S): A total of 3,148 FET cycles consisting of patients aged ≤45 years transferring blastocysts that were created from autologous oocytes between January 2015 and July 2021. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was the ongoing pregnancy rate (OPR) or live birth rate (LBR). The secondary outcomes included clinical pregnancy and clinical loss rates (CLRs). RESULT(S): The OPR/LBR was higher among letrozole FETs than among programmed FETs (adjusted risk ratio [aRR] 1.11, 95% confidence interval [CI] 1.02-1.21) but comparable to natural FETs (aRR 1.05, 95% CI 0.96-1.14). The OPR/LBR was comparable between natural and programmed FETs (aRR 1.06, 95% CI 0.99-1.13). The CLR was lower in the natural FET group than in the programmed FET group (aRR 0.62, 95% CI 0.46-0.84). There were no differences in CLRs between letrozole and programmed FETs and between letrozole and natural FETs. Among ovulatory women, the OPR/LBR among letrozole FETs was higher than that among programmed FETs (aRR 1.16, 95% CI 1.05-1.28). The CLR among ovulatory women was significantly lower in both letrozole FETs (aRR 0.44, 95% CI 0.22-0.87) and natural FETs (aRR 0.59, 95% CI 0.43-0.80) than in programmed FETs. Among anovulatory women, the OPR/LBR in the letrozole FET group was similar to that in the programmed FET group (aRR 0.95, 95% CI 0.79-1.13). CONCLUSION(S): Letrozole and natural FET clinical outcomes were improved compared with programmed FET outcomes.

Black race associated with lower live birth rate in frozen-thawed blastocyst transfer cycles: an analysis of 7,002 Society for Assisted Reproductive Technology frozen-thawed blastocyst transfer cycles.

OBJECTIVE: To evaluate if racial/ethnic differences in pregnancy outcomes persisted in frozen-thawed embryo transfer (FET) cycles on a national level. DESIGN: Retrospective cohort study. SETTING: Clinic-based data. PATIENT(S): A total of 189,000 Society for Assisted Reproductive Technology FET cycles from 2014-2016 were screened, of which 12,000 cycles had available fresh cycle linkage information and ultimately, because of missing data, 7,002 FET cycles were included. Cycles were stratified by race (White, Black, Asian, and Hispanic). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was live birth rate. Secondary outcomes were implantation rate, clinical pregnancy rate, multiple pregnancy rate, and clinical loss rate (CLR). RESULT(S): Live birth rate was significantly lower in the Black vs. White and Asian, but not Hispanic group. Implantation rate was also significantly lower and CLR higher in the Black group compared with all other groups (all P<.01). Black women had a lower risk of live birth (adjusted risk ratio, 0.82; 95% confidence interval [CI], 0.73-0.92) and a higher risk of clinical loss (adjusted risk ratio, 1.59; 95% CI, 1.28-1.99) compared with White women. There was no significant difference between groups in clinical pregnancy rate or multiple pregnancy rate. When the analysis was limited to preimplantation genetic testing FET cycles, there remained a significantly lower implantation rate in the Black group compared with all other groups (all P<.01). CONCLUSION(S): Black race remains an independent predictor of reduced live birth rate in FET cycles, likely because of higher CLR.