Assessment of reproductive outcomes of fresh versus cryopreserved ejaculated sperm samples-a retrospective analysis of 44 423 oocyte donation ICSI cycles.

STUDY QUESTION: Does the use of frozen sperm affect live birth rate (LBR) and cumulative LBR (CLBR) compared to fresh sperm samples in oocyte donation ICSI cycles? SUMMARY ANSWER: Although there were slight decreases in pregnancy rates (PRs) and LBR, as well as CLBR per embryo replaced and per embryo transfer (ET), when frozen sperm samples were used compared to fresh ejaculates, their clinical impact was limited. WHAT IS KNOWN ALREADY: Sperm cryopreservation is part of the daily routine in reproduction clinics worldwide because of its many advantages in cycle planning. Nonetheless, there is a lack of agreement in terms of its impact on the outcomes of ICSI cycles. Previous studies showed conflicting conclusions and focused on different populations, which makes reaching consensus on the impact of sperm freezing-thawing complicated. Moreover, classical parameters are used to assess cycle success: pregnancy, live birth and miscarriage rates per ET. This study reports those measurements plus CLBR, which more accurately reflects the impact of the technique on the likelihood of achieving a newborn. STUDY DESIGN, SIZE, DURATION: A retrospective multicenter observational cohort study, including data from 37 041 couples and 44 423 ICSI procedures from January 2008 to June 2022, was carried out. The group using frozen sperm included 23 852 transferred embryos and 108 661 inseminated oocytes, whereas the fresh sample group comprised 73 953 embryos replaced and 381 509 injected oocytes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Outcomes measured per first ET and per ET were compared between groups using Fisher's exact test and Chi-squared test, as appropriate. Binary-logistics regression models were used to adjust the analyses according to clinically relevant co-variables. Kaplan-Meier curves plotted the CLBR per oocyte inseminated, per embryo replaced and per ET, and compared between groups using the Mantel-Cox test. Cox regressions were employed for the multivariate analyses of CLBR. MAIN RESULTS AND THE ROLE OF CHANCE: The frozen sperm group showed a slightly lower biochemical (3.55% and 2.56%), clinical (3.68% and 3.54%) and ongoing (3.63% and 3.15%) PR compared to the cycles using fresh sperm, respectively, both per first ET and per ET. LBR was 4.57% lower per first ET and 3.95% lower per ET in the frozen sperm group than the fresh sperm group. There was also a subtle increase of 2.66% in biochemical miscarriage rate per ET when using frozen versus fresh sperm. All these differences remained statistically significant after the multivariate analysis (adjusted P ≤ 0.001). There were statistically significant differences in CLBR per embryo replaced and per ET but not per oocyte used (adjusted P = 0.071). Despite the statistical significance of the differences between the groups, those using frozen sperm required only 0.54 more oocytes injected, 0.45 more embryos transferred and 0.41 more ET procedures, on average, to achieve a live birth compared to the fresh samples. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study subjects the data to biases or potential errors during annotation on the source clinical and cycle records. This study uses multivariate analyses to control biases as much as possible. Using the oocyte donation model also contributes to reducing heterogeneity in the oocyte quality factor. WIDER IMPLICATIONS OF THE FINDINGS: The large sample sizes included in this study allowed for the detection of small changes in cycle success rates between groups. Although statistically significant, the decrease in PRs, LBR, and CLBR when using frozen sperm can be clinically overlooked in favor of the many benefits of sperm cryopreservation. STUDY FUNDING/COMPETING INTEREST(S): None declared. TRIAL REGISTRATION NUMBER: Not applicable.

A history of recurrent pregnancy loss is associated with increased perinatal complications, but not necessarily a longer birth interval: a population study spanning 18 years.

STUDY QUESTION: Is there a difference in the time interval between the first and second live births among individuals with and without recurrent pregnancy loss (RPL)? SUMMARY ANSWER: Primary RPL (two or more pregnancy losses before the first live birth) is associated with a shorter time interval between the first and second live births compared with individuals without RPL, but this association is reversed in patients with secondary RPL (RPL patients with no or one pregnancy loss before the first live birth). WHAT IS KNOWN ALREADY: There is limited information regarding the ability to have more than one child for patients with RPL. Previous studies have investigated the time to live birth and the live birth rate from the initial presentation to clinical providers. Most of the previous studies have included only patients treated at specialized RPL clinics and thus may be limited by selection bias, including patients with a more severe condition. STUDY DESIGN, SIZE, DURATION: We conducted a population-based retrospective cohort study of 184 241 participants who delivered in British Columbia, Canada, and had at least two recorded live births between 2000 and 2018. The aim was to study the differences in the time interval between the first and second live births and the prevalence of pregnancy complications in patients with and without RPL. Additionally, 198 319 individuals with their first live birth between 2000 and 2010 were studied to evaluate cumulative second live birth rates. PARTICIPANTS/MATERIALS, SETTING, METHODS: Among individuals with at least two recorded live births between 2000 and 2018, 12 321 patients with RPL and 171 920 participants without RPL were included. RPL was defined as at least two pregnancy losses before 20 weeks gestation. Patients with primary RPL had at least two pregnancy losses occurring before the first live birth, while patients with secondary RPL had no or one pregnancy loss before the first live birth. We compared the time interval from the first to second live birth in patients with primary RPL, those with secondary RPL, and participants without RPL using generalized additive models to allow for a non-linear relationship between maternal age and time interval between first and second live births. We also compared prevalence of pregnancy complications at the first and second live births between the groups using non-parametric Kruskal-Wallis H test and Fisher's exact test for continuous and categorical variables, respectively. We assessed the cumulative second live birth rates in patients with primary RPL and those without RPL, among participants who had their first live birth between 2000 and 2010. Cox proportional hazards model was used to estimate and compare hazard ratios between the two groups using a stratified modelling approach. MAIN RESULTS AND THE ROLE OF CHANCE: The adjusted time interval between the first and second live births was the longest in patients with secondary RPL, followed by individuals without RPL, and the shortest time interval was observed in patients with primary RPL: 4.34 years (95% CI: 4.09-4.58), 3.20 years (95% CI: 3.00-3.40), and 3.05 years (95% CI: 2.79-3.32). A higher frequency of pregnancy losses was associated with an increased time interval between the first and second live births. The prevalence of pregnancy complications at the first and second live births, including gestational diabetes, hypertensive disorder of pregnancy, preterm birth, and multiple gestations was significantly higher in patients with primary RPL compared with those without RPL. The cumulative second live birth rate was significantly lower in patients with primary RPL compared with individuals without RPL. LIMITATIONS, REASONS FOR CAUTION: This study may be limited by its retrospective nature. Although we adjusted for multiple potential confounders, there may be residual confounding due to a lack of information about pregnancy intentions and other factors, including unreported pregnancy losses. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study provide information that will help clinicians in the counselling of RPL patients who desire a second child. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by a grant from the Canadian Institutes of Health Research (CIHR): Reference Number W11-179912. M.A.B. reports research grants from CIHR and Ferring Pharmaceutical. He is also on the advisory board for AbbVie, Pfizer, and Baxter. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT04360564.

Does growth hormone supplementation of in vitro fertilization/intracytoplasmic sperm injection improve cumulative live birth rates in women with poor embryonic development in the previous cycle?

BACKGROUND: Growth hormone (GH) has been proposed as an adjunct in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles, especially in women with poor ovarian response. However, it is unclear whether GH supplementation is effective in women with poor embryonic development in the previous IVF cycle. The aim of this study was to evaluate the effectiveness of GH supplementation in IVF/ICSI cycles in women with poor embryonic development in the previous cycle. METHODS: This is a retrospective cohort study from a public fertility center in China, in which we performed propensity score-matching (PSM) for female age and AFC in a ratio of 1:1. We compared the cumulative live birth rate per started cycle, as well as a series of secondary outcomes. We included 3,043 women with poor embryonic development in the previous IVF/ICSI cycle, of which 1,326 had GH as adjuvant therapy and 1,717 had not. After PSM, there were 694 women in each group. RESULTS: After PSM, multivariate analyses showed the cumulative live birth rate to be significantly higher in the GH group than the control group [N = 694, 34.7% vs. N = 694, 27.5%, risk ratio (RR): 1.4 (95%CI: 1.1-1.8)]. Endometrial thickness, number of oocytes retrieved, number of embryos available, and number of good-quality embryos were significantly higher in the GH group compared to controls. Pregnancy outcomes in terms of birth weight, gestational age, fetal sex, preterm birth rate, and type of delivery were comparable. When we evaluated the impact of GH on different categories of female age, the observed benefit in the GH group did not appear to be significant. When we assessed the effect of GH in different AFC categories, the effect of GH was strongest in women with an AFC5-6 (32.2% versus 19.5%; RR 2.0; 95% CI 1.2-3.3). CONCLUSIONS: Women with poor embryonic quality in the previous IVF/ICSI cycles have higher rates of cumulative live birth with GH supplementation.

Predicting personalized cumulative live birth rate after a complete in vitro fertilization cycle: an analysis of 32,306 treatment cycles in China.

BACKGROUND: The cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations. METHODS: This retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation. RESULTS: Predictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05. CONCLUSIONS: This study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator ( https://h5.eheren.com/hcyc/pc/index.html#/home ). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

Patients with low prognosis in ART: a Delphi consensus to identify potential clinical implications and measure the impact of POSEIDON criteria.

BACKGROUND: Currently, there is no consensus on the optimal management of women with low prognosis in ART. In this Delphi consensus, a panel of international experts provided real-world clinical perspectives on a series of literature-supported consensus statements regarding the overall relevance of the POSEIDON criteria for women with low prognosis in ART. METHODS: Using a Delphi-consensus framework, twelve experts plus two Scientific Coordinators discussed and amended statements and supporting references proposed by the Scientific Coordinators (Round 1). Statements were distributed via an online survey to an extended panel of 53 experts, of whom 36 who voted anonymously on their level of agreement or disagreement with each statement using a six-point Likert-type scale (1 = Absolutely agree; 2 = More than agree; 3 = Agree; 4 = Disagree; 5 = More than disagree; 6 = Absolutely disagree) (Round 2). Consensus was reached if > 66% of participants agreed or disagreed. RESULTS: The extended panel voted on seventeen statements and subcategorized them according to relevance. All but one statement reached consensus during the first round; the remaining statement reached consensus after rewording. Statements were categorized according to impact, low-prognosis validation, outcomes and patient management. The POSEIDON criteria are timely and clinically sound. The preferred success measure is cumulative live birth and key management strategies include the use of recombinant FSH preparations, supplementation with r-hLH, dose increases and oocyte/embryo accumulation through vitrification. Tools such as the ART Calculator and Follicle-to-Oocyte Index may be considered. Validation data from large, prospective studies in each POSEIDON group are now needed to corroborate existing retrospective data. CONCLUSIONS: This Delphi consensus provides an overview of expert opinion on the clinical implications of the POSEIDON criteria for women with low prognosis to ovarian stimulation.

Impact of a positive Chlamydia trachomatis serology on cumulative IVF live birth rate.

RESEARCH QUESTION: Does positive Chlamydia trachomatis serology have an impact on the cumulative live birth rate from IVF? DESIGN: A retrospective matched cohort study compared women with positive Chlamydia trachomatis serology (group A) who underwent IVF treatment between January 2016 and December 2021 with a control group of women with negative Chlamydia trachomatis serology (group B). The main outcome measures were the cumulative live birth rate per IVF cycle and the live birth rate per embryo transfer. Secondary outcomes were the cumulative rates of clinical pregnancy, ectopic pregnancy and pregnancy loss calculated per IVF cycle and per embryo transfer. RESULTS: A total of 151 women in group A were matched 1:2 to 302 women in group B, representing 220 and 440 IVF cycles, respectively. Women with a history of Chlamydia trachomatis infection had a significantly higher rate of tubal obstruction (P < 0.001), excluded or operated hydrosalpinx (P = 0.002) and/or history of chronic endometritis (P < 0.001). There were no statistically significant differences between the two groups in the mean number of mature oocytes retrieved, fertilization rate or implantation rate. The IVF cumulative live birth rate per cycle was similar in the two groups (36.7% in group A versus 34.9% in group B, P = 0.692). The cumulative rates of clinical pregnancy, pregnancy loss, biochemical pregnancy and ectopic pregnancy were comparable between the two groups. CONCLUSION: Positive Chlamydia trachomatis serology has no impact on IVF pregnancy outcomes.

Acrosin activity negatively influences the cumulative live birth rate in patients undergoing IVF treatment.

RESEARCH QUESTION: Is acrosin activity related to cumulative live birth rate (CLBR) over 1 year after IVF, intracytoplasmic sperm injection (ICSI) treatment or both? DESIGN: Retrospective monocentric cohort study of 5704 couples who started IVF/ICSI treatments between 2016 and 2021. Acrosin activity was determined by a modified Kennedy method using a commercial kit. Patients were divided into two groups according to their acrosin activity: below 25 µIU/106 spermatozoa; and an acrosin activity 25 µIU/106 spermatozoa or above. Primary outcome was the CLBR, defined as an ongoing pregnancy leading to live birth that had arisen from all embryo transfers carried out within 1 year after the first ovum retrieval. Both conservative and optimistic methods were used for estimating CLBRs. RESULTS: The CLBRs of patients with an acrosin activity below 25 µIU/106 spermatozoa were found to be significantly lower than those of patients with an acrosin activity 25 µIU/106 spermatozoa or above by conservative (48.5% versus 55.4%, P = 0.02) and optimistic (63.7% versus 70.3%, P = 0.047) methods after adjusting for confounders. When acrosin activity was regarded as a continuous variable, significant negative relationships between acrosin activity and CLBR were identified in subgroups: young couples (men and women aged younger than 30 years) and couples from whom no more than 10 eggs were retrieved. CONCLUSION: Low acrosin activity levels were correlated with decreasing CLBRs over 1 year. These findings suggest that acrosin activity can be used as a predictor for CLBRs before starting IVF/ICSI treatment to enhance the effectiveness of counselling.

The ovarian stimulation regimen does not affect aneuploidy or blastocyst rate.

RESEARCH QUESTION: Could the total dose (<3000 IU or ≥3000 IU) and type of exogenous gonadotrophin (i.e. recombinant FSH and/or human menopausal gonadotrophin [HMG]) influence aneuploidy and blastulation rates and produce different reproductive outcomes? DESIGN: This retrospective, observational, multicentre cohort study included a total of 8466 patients undergoing IVF using autologous oocytes and preimplantation genetic testing for aneuploidies. Participants were divided according to the dosage of total gonadotrophins and stratified by maternal age. RESULTS: The aneuploidy rates, pregnancy outcomes and cumulative live birth rates (CLBR) were similar among women who received total gonadotrophin dosages of <3000 or ≥3000 IU. No statistical differences were reported in the blastulation rate with lower or higher gonadotrophin dosages. Women receiving a higher amount of HMG during ovarian stimulation had a lower aneuploidy rate (P = 0.02); when stratified according to age, younger women with a higher HMG dosage had lower aneuploidy rates (P< 0.001), while no statistical differences were observed in older women with higher or lower HMG dosages. No significant differences were observed in IVF outcomes or CLBR. CONCLUSIONS: High doses of gonadotrophins were not associated with rate of aneuploidy. However, an increased fraction of HMG in younger women was associated with a lower aneuploidy rate. The study demonstrated that the total gonadotrophin dosage did not influence aneuploidy, reproductive outcomes or CLBR. The increased gonadotrophin and HMG dosages used for ovarian stimulation did not precede aneuploidy, and the use of HMG should be evaluated on a case-by-case basis, according to the individual's characteristics and infertility type.

Association between pre-gravid body mass index and clinical outcomes in in vitro fertilization: a multicentered retrospective cohort study.

BACKGROUND: With the increasing incidence of obesity and the childbearing-age delay among women, a debate over obesity's impacts on pregnancy and neonatal outcomes becomes hot. The potential negative effects of obesity and aging on fertility lead to an idea, whether an obese female pursuing IVF treatment can benefit from an ideal BMI achieved over a long-time weight loss process at the cost of aging? We aimed to assess the association between body mass index (BMI) and clinical or neonatal outcomes in patients undergoing in vitro fertilization (IVF) treatment, for answering whether it is necessary to lose weight first for obese patients, particularly those at advanced age. METHODS: A retrospective cohort study was performed using multicentered data from China. The women were stratified into 5 groups in terms of pre-gravid BMI (kg/m2) with the WHO obesity standard (group 1: BMI < 18.5; group 2: 18.5 ≤ BMI < 23.0; group 3: 23.0 ≤ BMI < 25.0; group 4: 25.0 ≤ BMI < 30.0; group 5: BMI ≥ 30.0). The primary outcome was cumulative live birth rate (CLBR), and other clinical and neonatal outcomes were weighed as secondary outcomes. Multivariate logistic regression analyses were carried to evaluate the association between BMI and the CLBR, or between BMI and some neonatal outcomes. Furthermore, we implemented a machine-learning algorithm to predict the CLBR based on age and BMI. RESULTS: A total of 115,287 women who underwent first IVF cycles with autologous oocytes from January 2013 to December 2017 were included in our study. The difference in the CLBR among the five groups was statistically significant (P < 0.001). The multivariate logistic regression analysis showed that BMI had no significant impact on the CLBR, while women's age associated with the CLBR negatively. Further, the calculation of the CLBR in different age stratifications among the five groups revealed that the CLBR lowered with age increasing, quantitatively, it decreased by approximately 2% for each one-year increment after 35 years old, while little difference observed in the CLBR corresponding to the five groups at the same age stratification. The machine-learning algorithm derived model showed that BMI's effect on the CLBR in each age stratification was negligible, but age's impact on the CLBR was overwhelming. The multivariate logistic regression analysis showed that BMI did not affect preterm birth, low birth weight infant, small for gestational age (SGA) and large for gestational age (LGA), while BMI was an independent risk factor for fetal macrosomia, which was positively associated with BMI. CONCLUSIONS: Maternal pre-gravid BMI had no association with the CLBR and neonatal outcomes, except for fetal macrosomia. While the CLBR was lowered with age increasing. For the IVF-pursuing women with obesity plus advanced age, rather than losing weight first, the sooner the treatment starts, the better. A multicentered prospective study with a large size of samples is needed to confirm this conclusion in the future.

Impact of thyroid autoimmunity on the cumulative live birth rates after IVF/ICSI treatment cycles.

BACKGROUND: Cumulative live birth rate (CLBR) is considered as the most important endpoint for assessing the probability of having a baby in a complete in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment cycle. Many previous studies have focused on the association between thyroid autoimmunity (TAI) and live birth rate after first embryo transfer cycle, however, evidence on whether the presence of TAI affects the CLBR is lacking. The purpose of this study is to investigate the impact of TAI on the CLBR in a complete IVF/ICSI cycle. METHODS: This retrospective study included 12,796 women who underwent their first IVF/ICSI treatment between January 2019 and February 2021. Based on the levels of thyroid antibodies, 2,603 women were assigned to the TAI group, and 10,193 women were assigned to the control group. Subgroup analysis was performed according to the different causes of infertility (including male factor only, ovulation disorder, tubal factor, endometriosis and unexplained infertility) and different types and titres of thyroid antibodies. The primary outcome in this study was CLBR, which included live births from the fresh embryo transfer cycle and all subsequent frozen-thawed embryo transfer cycles performed before December 2021. RESULTS: There was no significant difference in the CLBR between the TAI and control groups, even after adjusting for relevant confounders including age, body mass index, cause of infertility, thyroid function, protocols of controlled ovarian stimulation, type of transfer (fresh vs. frozen), type of transferred embryo (cleavage-stage embryo vs. blastocyst), and fertilization method (IVF vs. ICSI) (cumulative live birth: 50.6% vs. 52.1%, OR 0.94, 95% CI 0.86-1.02, adjusted OR 0.97, 95%CI 0.89-1.06). Subgroup analysis showed that no significant difference was observed in CLBR between the TAI and control groups for all causes of infertility, except for infertility attributed to endometriosis. Among women with endometriosis, the CLBR was significantly lower in the TAI group than that in the control group; however, this difference was not significant after adjusting for potential confounders including age, body mass index, thyroid function, protocols of controlled ovarian stimulation, type of transfer (fresh vs. frozen), type of transferred embryo (cleavage-stage embryo vs. blastocyst), and fertilization method (IVF vs. ICSI) (cumulative live births: 43.1% vs. 51.0%, OR 0.73, 95% CI 0.53-0.99, adjusted OR 0.74, 95% CI 0.53-1.02). Another subgroup analysis demonstrated that the type and titre of thyroid antibody did not affect CLBR in women with TAI. CONCLUSIONS: In our study, there was no significant difference in the CLBR between women with TAI and those without TAI, which suggests that TAI did not affect the chances of having a baby in a complete IVF/ICSI treatment cycle.

A heatmap for expected cumulative live birth rate in preimplantation genetic testing for monogenic disorders and chromosomal structural rearrangements.

PURPOSE: Our objective is to predict the cumulative live birth rate (CLBR) and identify the specific subset within the population undergoing preimplantation genetic testing for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR) which is likely to exhibit a diminished expected CLBR based on various patient demographics. METHODS: We performed a single-centre retrospective cohort study including 1522 women undergoing 3130 PGT cycles at a referral centre for PGT. A logistic regression analysis was performed to predict the CLBR per ovarian stimulation in women undergoing PGT-M by polymerase chain reaction (PCR) or single-nucleotide polymorphism (SNP) array, and in women undergoing PGT-SR by SNP array, array comparative genomic hybridization (CGH) or next-generation sequencing (NGS). RESULTS: The mean age of women was 32.6 years, with a mean AMH of 2.75 µg/L. Female age and AMH significantly affected the expected CLBR irrespective of the inheritance mode or PGT technology. An expected CLBR < 10% was reached above the age of 42 years and AMH ≤ 1.25 µg/L. We found no significant difference in outcome per ovarian stimulation between the different PGT technologies, i.e. PCR, SNP array, array CGH and NGS. Whereas per embryo transfer, we noticed a significantly higher probability of live birth when SNP array, array CGH and NGS were used as compared to PCR. CONCLUSION: In a PGT-setting, couples with an unfavourable female age and AMH should be informed of the prognosis to allow other reproductive choices. The heatmap produced in this study can be used as a visual tool for PGT couples.

Early cumulus cell removal increases cumulative live birth rate while having no negative effect on the malformation rate in in vitro fertilization: a propensity score-matched cohort study.

PURPOSE: The aim of this study was to investigate the efficacy and safety of early cumulus cell removal (ECCR) during human in vitro fertilization (IVF). METHODS: A retrospective analysis was performed between January 2011 and December 2019. The study enrolled 1131 couples who underwent IVF treatment with ECCR. After propensity score matching at a 1:1 ratio, 1131 couples who underwent overnight coincubation of gametes were selected. The main outcome measure was the cumulative live birth rate. Secondary outcome measures included the cumulative pregnancy rate, polyspermy rate, available embryo rate, miscarriage rate, malformation rate, time to live birth, and oocyte-to-baby rate. RESULTS: There were no significant differences found between the two groups in the polyspermy rate, available embryo rate, miscarriage rate, time to live birth, oocyte-to-baby rate, and neonatal congenital anomalies rate. The results of the study showed that ECCR was associated with a significantly higher cumulative live birth rate and cumulative pregnancy rate, along with a significantly lower fertilization rate. CONCLUSIONS: ECCR tended to confer increased cumulative live birth rate and had no negative effect on the neonatal malformation rate.

Required number of blastocysts transferred, and oocytes retrieved to optimize live and cumulative live birth rates in the first complete cycle of IVF for autologous and donated oocytes.

PURPOSE: To investigate live birth rate (LBR) and cumulative live birth rate (CLBR) to achieve the first newborn per blastocyst transferred and oocyte retrieved in the first complete IVF cycle of autologous and donated oocytes and identify the possible success factors. METHODS: This was a retrospective cohort study of a private IVF center. There were 1867 cycles, 1241 of which were fresh transfers and 626, their subsequent thawing transfers. RESULTS: We found significant variables by binary logistic regression. For LBR, female infertility and the day of blastocyst transferred were relevant; however, for CLBR, the numbers of blastocysts available for future transfers, oocyte age, and maternal age were more critical. Oocyte age is a negative factor that begins to affect CLBR gradually beyond 36 years; from that age, there are significant worse results in polycystic ovary syndrome and poor responder patients. CONCLUSION: The LBR and CLBR were optimized for oocyte recipients when eight oocytes were retrieved (63.6%; 87.9%); at most, fourteen oocytes should be assigned to avoid freezing surplus blastocysts. Thirteen autologous oocytes (69.2%; 92.3%) were ideal for optimization. CLBR optimized after three blastocysts in donor oocytes (81.8%) and four for autologous oocyte patients (80.9%). Our outcomes are valuable for doctors and infertile couples, and they give us information on what we can expect from a first complete IVF cycle.

A clinical predictive model for live birth in women of advanced age undergoing PGT cycles.

PURPOSE: The trend of delaying childbirth has resulted in a growing number of advanced-aged women who are opting for preimplantation genetic testing (PGT) to screen for monogenic diseases or structural chromosomal rearrangements (PGT-M and PGT-SR). This increase in demand necessitates the development of a clinical predictive model for live birth outcomes in these women. Therefore, the objective of this study is to construct a comprehensive predictive model that assesses the likelihood of achieving a successful live birth in advanced-aged women undergoing PGT-M and PGT-SR treatments. METHODS: A retrospective cohort study of 37-45-year-old women undergoing preimplantation genetic testing for monogenic disease or structural chromosomal rearrangement cycles from 2010 to 2021 was conducted at a university hospital reproductive centre. The purpose was to develop a clinical predictive model for live birth in these women. The main outcome studied was the cumulative live birth rate in the first or subsequent cycles. Developing a decision tree enabled a comprehensive study of clinical parameters and expected outcomes. RESULTS: The analysis included 158 women undergoing 753 preimplantation genetic testing cycles. The cumulative live birth rate was 37.342% (59/158). Decision tree analysis revealed that women aged ≤ 40.1 or women > 40.1 with one or more top-quality transferable embryos in their first cycle had the best chance for a live baby (56% and 41%, respectively). Those older than 40.1 without top-quality embryos and seven or fewer dominant follicles had no live births. A Kaplan-Meier curve showed that for autosomal dominant diseases, there was a negligible increase in live birth rate after three cycles, compared to six cycles in autosomal recessive inheritance. CONCLUSION: In older women, the chance of delivering after repeated cycles is higher in those with at least one top-quality unaffected embryo in their first preimplantation genetic testing cycle. Additional preimplantation genetic testing cycles after three in carriers of an autosomal dominant disorder and six in those with an autosomal recessive disorder should be considered prudently.

Exploring the efficacy and beneficial population of preimplantation genetic testing for aneuploidy start from the oocyte retrieval cycle: a real-world study.

BACKGROUND: Preimplantation genetic testing for aneuploidy (PGT-A) is widely used as an embryo selection technique in in vitro fertilization (IVF), but its effectiveness and potential beneficiary populations are unclear. METHODS: This retrospective cohort study included patients who underwent their first oocyte retrieval cycles at CITIC-Xiangya between January 2016 and November 2019, and the associated fresh and thawed embryo transfer cycles up to November 30, 2020. PGT-A (PGT-A group) and intracytoplasmic sperm injection (ICSI)/IVF (non-PGT-A group) cycles were included. The numbers of oocytes and embryos obtained were unrestricted. In total, 60,580 patients were enrolled, and baseline data were matched between groups using 1:3 propensity score matching. Sensitivity analyses, including propensity score stratification and traditional multivariate logistic regression, were performed on the original unmatched cohort to check the robustness of the overall results. Analyses were stratified by age, body mass index, ovarian reserve/responsiveness, and potential indications to explore benefits in subgroups. The primary outcome was cumulative live birth rate (CLBR). The other outcomes included live birth rate (LBR), pregnancy loss rate, clinical pregnancy rate, pregnancy complications, low birth weight rate, and neonatal malformation rate. RESULTS: In total, 4195 PGT-A users were matched with 10,140 non-PGT-A users. A significant reduction in CLBR was observed in women using PGT-A (27.5% vs. 31.1%; odds ratio (OR) = 0.84, 95% confidence interval (CI) 0.78-0.91; P < 0.001). However, women using PGT-A had higher first-transfer pregnancy (63.9% vs. 46.9%; OR = 2.01, 95% CI 1.81-2.23; P < 0.001) and LBR (52.6% vs. 34.2%, OR = 2.13, 95% CI 1.92-2.36; P < 0.001) rates and lower rates of early miscarriage (12.8% vs. 20.2%; OR = 0.58, 95% CI 0.48-0.70; P < 0.001), preterm birth (8.6% vs 17.3%; P < 0.001), and low birth weight (4.9% vs. 19.3%; P < 0.001). Moreover, subgroup analyses revealed that women aged ≥ 38 years, diagnosed with recurrent pregnancy loss or intrauterine adhesions benefited from PGT-A, with a significant increase in first-transfer LBR without a decrease in CLBR. CONCLUSION: PGT-A does not increase and decrease CLBR per oocyte retrieval cycle; nonetheless, it is effective in infertile populations with specific indications. PGT-A reduces complications associated with multiple gestations.

The combined effect of BMI and age on ART outcomes.

STUDY QUESTION: For a woman with infertility and overweight/obesity, can infertility treatment be postponed to first promote weight loss? SUMMARY ANSWER: Advice regarding a delay in IVF treatment to optimize female weight should consider female age, particularly in women over 38 years for whom only substantial weight loss in a short period of time (3 months) seems to provide any benefit. WHAT IS KNOWN ALREADY: Body weight excess and advanced age are both common findings in infertile patients, creating the dilemma of whether to promote weight loss first or proceed to fertility treatment immediately. Despite their known impact on fertility, studies assessing the combined effect of female age and BMI on cumulative live birth rates (CLBRs) are still scarce and conflicting. STUDY DESIGN, SIZE, DURATION: We performed a multicentre retrospective cohort study including 14 213 patients undergoing their first IVF/ICSI cycle with autologous oocytes and subsequent embryo transfers, between January 2013 and February 2018 in 18 centres of a multinational private fertility clinic. BMI was subdivided into the following subgroups: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obesity (≥30.0 kg/m2). PARTICIPANTS/MATERIALS, SETTING, METHODS: The primary outcome was CLBR. The secondary outcome was time to pregnancy. To assess the influence of female age and BMI on CLBR, two multivariable regression models were developed with BMI being added in the models as either an ordinal categorical variable (Model 1) or a continuous variable (Model 2) using the best-fitting fractional polynomials. CLBR was estimated over 1-year periods (Model 1) and shorter timeframes of 3 months (Model 2). We then compared the predicted CLBRs according to BMI and age. MAIN RESULTS AND THE ROLE OF CHANCE: When compared to normal weight, CLBRs were lower in women who were overweight (adjusted odds ratio (aOR) 0.86, 95% CI 0.77-0.96) and obese (aOR 0.74, 95% CI 0.62-0.87). A reduction of BMI within 1 year, from obesity to overweight or overweight to normal weight would be potentially beneficial up to 35 years old, while only a substantial reduction (i.e. from obesity to normal BMI) would be potentially beneficial in women aged 36-38 years. Above 38 years of age, even considerable weight loss did not compensate for the effect of age over a 1-year span but may be beneficial in shorter time frames. In a timeframe of 3 months, there is a potential benefit in CLBR if there is a loss of 1 kg/m2 in BMI for women up to 33.25 years and 2 kg/m2 in women aged 33.50-35.50 years. Older women would require more challenging weight loss to achieve clinical benefit, specifically 3 kg/m2 in women aged 35.75-37.25 years old, 4 kg/m2 in women aged 37.50-39.00 years old, and 5 kg/m2 or more in women over 39.25 years old. LIMITATIONS, REASONS FOR CAUTION: This study is limited by its retrospective design and lower number of women in the extreme BMI categories. The actual effect of individual weight loss on patient outcomes was also not evaluated, as this was a retrospective interpatient comparison to estimate the combined effect of weight loss and ageing in a fixed period on CLBR. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that there is potential benefit in weight loss strategies within 1 year prior to ART, particularly in women under 35 years with BMI ≥25 kg/m2. For those over 35 years of age, weight loss should be considerable or occur in a shorter timeframe to avoid the negative effect of advancing female age on CLBR. A tailored approach for weight loss, according to age, might be the best course of action. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. All authors have no conflicts to declare. TRIAL REGISTRATION NUMBER: N/A.

Impact of moderate-to-severe endometriosis on IVF cumulative live birth rate: a retrospective matched cohort study.

RESEARCH QUESTION: Does moderate-to-severe endometriosis have an impact on cumulative live birth rates (cLBR) and IVF outcomes? DESIGN: In this retrospective matched cohort study, women with moderate-to-severe endometriosis undergoing IVF or intracytoplasmic sperm injection treatment from January 2015 to December 2020 were matched 1:2 to women with other causes of infertility (control group). The main outcome was cLBR per cycle and per woman, and secondary outcomes were number of oocytes retrieved and number of mature oocytes, fertilization rate, total number of embryos and usable embryos, implantation rate, clinical pregnancy rate and miscarriage rate per cycle. RESULTS: In total, 195 women with endometriosis were matched with 390 women without endometriosis (323 and 646 cycles, respectively). Women with endometriosis had significantly fewer oocytes retrieved than women in the control group (P=0.003) despite higher doses of gonadotropins, but had a similar number of mature oocytes, fertilization rate, and total number of embryos and usable embryos. cLBR per cycle and per women did not differ significantly between the endometriosis group and the control group (19.8% versus 24.3%, P = 0.12; 32.3% versus 37.2%, P = 0.24, respectively). In women with endometrioma, a history of cystectomy did not impact cLBR per cycle (28.3% versus 31.9%, P = 0.68). We did not observe any significant impact of tobacco use in the endometriosis group compared with the control group (16.4% versus 25.9%, P = 0.13). CONCLUSION: This matched cohort study did not observe a significant impact of moderate-to-severe endometriosis on cLBR among women undergoing IVF. These data are reassuring for the counselling of infertile women with endometriosis before IVF.

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%.

Association between sequence variants in the FSHR gene and reproductive outcomes following IVF in predicted normoresponders.

RESEARCH QUESTION: Is there an association between FSHR sequence variants and reproductive outcomes following IVF in predicted normoresponders? DESIGN: Multicentre prospective cohort study conducted from November 2016 to June 2019 in Vietnam, Belgium and Spain including patients aged <38 years, and undergoing IVF with a predicted normal response with fixed-dose 150 IU rFSH in an antagonist protocol. Genotyping was performed for three FSHR (c.919A>G, c.2039A>G, c.-29G>A) and one FSHB sequence variants (c.-211G>T). Clinical pregnancy rate (CPR), live birth rate (LBR) and miscarriage rate in the first embryo transfer and cumulative live birth rate (CLBR) were compared between the different genotypes. RESULTS: A total of 351 patients underwent at least one embryo transfer. Genetic model analysis that adjusted for patient age, body mass index, ethnicity, type of embryo transfer, embryo stage and number of top-quality embryos transferred revealed a higher CPR for homozygous patients for the variant allele G of c.919A>G when compared to patients with genotype AA (60.3% versus 46.3%, adjusted odds ratio [ORadj] 1.96, 95% confidence interval [CI] 1.09-3.53). Also, c.919A>G genotypes AG and GG presented a higher CPR and LBR when compared with genotype AA (59.1% versus 46.3%, ORadj 1.80, 95% CI 1.08-3.00, and 51.3% versus 39.0%, ORadj 1.69, 95% CI 1.01-2.80, respectively). Cox regression models revealed a statistically significantly lower CLBR for c.2039A>G genotype GG in the codominant model (hazard ratio [HR] 0.66, 95% CI 0.43-0.99). CONCLUSION: These results demonstrate a previously unreported association between variant c.919A>G genotype GG and higher CPR and LBR in infertile patients and reinforce a potential role for genetic background in predicting the reproductive prognosis following IVF.

Analysis of cumulative live birth rate outcomes of three ovarian stimulation protocols in patients after laparoscopic cystectomy of ovarial endometrioma: a retrospective cohort study.

BACKGROUND: Previous studies have reported that after laparoscopic cystectomy of ovarial endometrioma, the ovarian response to gonadotropin (Gn) significantly decreased. However, for patients with diminished ovarian reserve (DOR) after ovarian surgery, how to choose the most appropriate controlled ovarian hyperstimulation protocol has not been concluded. Compared with the traditional agonist regimen, the gonadotropin (Gn)-releasing hormone (GnRH) antagonist, microstimulation, and progestin-primed ovarian stimulation (PPOS) protocols are simple to operate and have a shorter cycle, which are often used in patients with DOR. So the purpose of our study is to compare the assisted reproductive outcomes of these three controlled ovarian hyperstimulation protocols in patients with DOR following laparoscopic cystectomy of ovarial endometrioma. METHODS: In this retrospective cohort study, 89 patients with DOR who had undergone in vitro fertilisation/intracytoplasmic sperm injection at the Department of Reproductive Medicine at the Third Affiliated Hospital of Zhengzhou University from 1 to 2018 to 31 December 2020 were included. According to the controlled ovarian hyperstimulation protocols employed, the patients were divided into GnRH antagonist (38 patients), PPOS (27 patients), and microstimulation (24 patients) groups. The basic data and clinical outcomes of the three groups were compared. The main outcome measure was the cumulative live birth rate. RESULTS: No significant differences in the age of the female patients and their spouses and female patients' body mass index and basal endocrine levels (follicle-stimulating hormone and oestradiol) were noted among the three groups (P > 0.05). The GnRH antagonist group had higher antral follicle counts, greater endometrial thickness on the human chorionic Gn injection day, greater number of oocytes retrieved, and higher two pronuclear embryo counts than did the other two groups. However, the starting dosage of Gn was lower in the GnRH antagonist group than in the other two groups. The microstimulation group had a significantly higher oocyte output rate and high-quality embryo rate than did the other two groups (P < 0.05). No significant differences in the total dosage of Gn, cumulative pregnancy rate, cumulative live birth rate, viable embryo rate, and blastocyst formation rate were observed among the three groups (P > 0.05). CONCLUSION: In conclusion, for patients aged under 40 years who experienced DOR after laparoscopic cystectomy of ovarial endometrioma, GnRH antagonist protocol and PPOS protocol can obtain better ovulation induction outcomes and cumulative live birth rate than microstimulation protocol, and are more suitable ovulation induction protocols.