High ovarian responders have the highest risk of premature progesterone rise.

OBJECTIVE: Late follicular phase progesterone elevation is a complication that affects approximately 38% of IVF cycles. There is a lack of consensus on the appropriate cut-off levels for progesterone on hCG day. Although premature progesterone rise occurs in all kinds of ovarian responses, there is a knowledge gap regarding the ovarian response with the highest risk of this phenomenon. Our study aims to assess the relative risk of each kind of ovarian response for premature progesterone rise and evaluate the prevalence of premature progesterone rise in each ovarian response. METHODS: A retrospective, cross-sectional, comparative and analytic study was performed at the Reproductive Endocrinology Department in Centro Médico Nacional 20 de Noviembre in Mexico City. All conventional-antagonist cycles were grouped according to their ovarian response and were evaluated from 2015 to 2020. Pearson's Squared-chi, Cramer's V, cross-table and the relative risk were calculated. RESULTS: The prevalence of premature progesterone rise oscillated from 20.8 to 67.9% for low and high ovarian responders, respectively. After calculating the relative risk, high ovarian responders had a 1.38 higher risk for premature progesterone rise than other groups. CONCLUSIONS: High ovarian responders have the highest risk for premature progesterone rise compared to normal and low ovarian responders. High ovarian responders have a 67.9% prevalence of premature progesterone rise.

Association of serum uric acid with women's ovarian reserve: observational study and Mendelian randomization analyses.

OBJECTIVE: To investigate the association between serum uric acid and women's ovarian reserve. DESIGN: Retrospective observational study and Mendelian randomization study. SETTING: University-affiliated in vitro fertilization center. PATIENTS: Observational analyses were undertaken using data from 8,257 women with infertility who finished their first in vitro fertilization treatments between May 2017 and December 2021. Mendelian randomization analyses were based on genome-wide association summary statistics from several biobanks of predominantly European ancestries. INTERVENTIONS: Observational study involved testing log2 transformed serum uric acid levels (for linear, negative regression, and logistic regression analyses); original uric acid levels (for nonlinear association analyses). Mendelian randomization study involved testing genetically predicted uric acid levels. MAIN OUTCOME MEASURES: Biomarkers including antimüllerian hormone, basal antral follicle count, follicle-stimulating hormone, luteinizing hormone, ratio of follicle-stimulating hormone to luteinizing hormone, estradiol; indices of ovarian response to stimulation including poor ovarian response according to different criteria and oocyte yield. RESULTS: In retrospective observational study, all ovarian reserve-related outcomes demonstrated significant differences across serum uric acid quartiles. A two-fold uric acid increase was associated with increased antimüllerian hormone (adjusted ß = 0.69; 95% confidence interval [CI], 0.43-0.95), antral follicle count (adjusted incidence rate ratio = 1.10, 95% CI, 1.05-1.14), luteinizing hormone (adjusted ß = 0.53, 95% CI, 0.28-0.78), decreased risks of Bologna poor ovarian response (adjusted odds ratio = 0.97; 95% CI, 0.95-0.99) and groups 2-4 Poseidon poor ovarian response (group 2: 0.63, 0.56-0.71; group 3: 0.71, 0.65-0.78; group 4: 0.50, 0.46-0.55), whereas an increased risk of group 1 (1.26, 1.13-1.41). Nonlinear analyses showed a common inflection point at 320-340 µmol/L of uric acid. Interactions between uric acid and antimüllerian hormone and antral follicle count were presented in association with oocyte yield. Mendelian randomization results suggested a significant association between genetically predicted uric acid levels and antimüllerian hormone levels (ß = 0.08; 95% CI, 0.04-0.12) but none for uric acid in relation to polycystic ovarian syndrome or other related hormones. CONCLUSION: Higher uric acid levels were associated with better ovarian reserve and increased levels of antimüllerian hormone albeit an increased risk of unexpected poor ovarian response.

Iatrogenic and demographic determinants of the national plural birth increase.

OBJECTIVE: To study the contribution of ovulation induction and ovarian stimulation, in vitro fertilization (IVF), and unassisted conception to the increase in national plural births in the United States, a significant contributor to adverse maternal and infant health outcomes. DESIGN: National and IVF-assisted plural birth data were derived from the Centers for Disease Control and Prevention's National Vital Statistics System (1967-2021, after introduction of Clomiphene Citrate in the United States) and the National Assisted Reproductive Technology Surveillance System (1997-2021), respectively. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): In addition to IVF-assisted plural births, the contributions of unassisted conception to plural births among women aged <35 and ≥35 years were estimated using plural birth rates from 1949-1966 and a Bayesian logistic model with race and age as independent variables. The contribution of ovulation induction and ovarian stimulation was estimated as the difference between national plural births and IVF-assisted and unassisted counterparts. RESULT(S): From 1967-2021, the national twin birth rate increased 1.7-fold to a 2014 high (33.9/1,000 live births), then declined to 31.2/1,000 live births; the triplet and higher order birth rate increased 6.7-fold to a 1998 high (1.9/1,000 live births), then declined to 0.8/1,000 live births. In 2021, the contribution of unassisted conception among women aged <35 years to the national plural births was 56.1%, followed by ovulation induction and ovarian stimulation (19.5%), unassisted conception among women aged ≥35 years (16.8%), and IVF (7.6%). During 2009-2021, the contribution of ovulation induction and ovarian stimulation has remained stable, the contribution of unassisted conception among women aged <35 and ≥35 years has increased, and the contribution of IVF has decreased. CONCLUSION(S): Ovulation induction and ovarian stimulation are leading iatrogenic contributors to plural births. They are, therefore, targets for intervention to reduce the adverse maternal and infant health outcomes associated with plural births. Maternal age of ≥35 years is a significant contributor to the national plural birth increase.

Ovarian response to intraovarian platelet-rich plasma (PRP) administration: hypotheses and potential mechanisms of action.

PURPOSE: Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent literature in both humans and animals suggest that intraovarian PRP administration in the setting of poor ovarian reserve may help ovarian function and increase the chances of pregnancy. METHODS: A comprehensive literature search through PubMed, MEDLINE databases, and recent abstracts published at relevant society meetings was performed and resulted in 25 articles and 2 abstracts published that studied effect of PRP on the ovaries for the purpose of reproduction. RESULTS: This review article presents all the data published to date pertaining to intraovarian PRP injection and pregnancy, both naturally and after in vitro fertilization. It also presents the most recent data on the use of ovarian PRP in in vitro and animal model studies highlighting the possible mechanisms by which PRP could impact ovarian function. CONCLUSIONS: Even though recent commentaries questioned the use of PRP as an "add-on" therapy in fertility treatment because it has not been thoroughly studied, the recent basic science studies presented here could increase awareness for considering more serious research into the efficacy of PRP as an adjunct for women with poor ovarian reserve, premature ovarian insufficiency, and even early menopause who are trying to conceive using their own oocytes. Given its low-risk profile, the hypothetical benefit of PRP treatment needs to be studied with larger randomized controlled trials.

A comparative, observational study evaluating dosing characteristics and ovarian response using the recombinant human follicle-stimulating hormone pen injector with small-dose dial in assisted reproductive technologies treatment in Asia: IMPROVE study.

BACKGROUND: Ovarian stimulation during medically assisted reproduction treatment should be individualized to optimize outcomes and reduce complications. This study assessed whether use of the recombinant human follicle-stimulating hormone (r-hFSH) pen injector allowing small 12.5 IU dose increments resulted in lower r-hFSH dose per oocyte retrieved in a subgroup of patients at risk of OHSS, compared with r-hFSH injection devices allowing only 37.5 IU increments. METHODS: This multicenter, comparative, observational study evaluated patients from a prospective (study group) and historical (control group) cohort. The study group enrolled 1783 patients using the redesigned r-hFSH pen injector (GONAL-f®, Merck Healthcare KGaA, Darmstadt, Germany) from a prospective phase IV, non-interventional, open-label study, conducted in Korea, Vietnam, Indonesia, and China. The control group consisted of 1419 patients from a historical study using r-hFSH devices allowing 37.5 IU increments. In the study group, 397 patients were considered at risk of OHSS; this information was unavailable for the control group, so biomarkers and patient characteristics were used to match 123 patients from the study group and control group. Each center adhered to standard practice; starting dose and intra-cycle dose adjustments were allowed at any point. The primary endpoint, amount of r-hFSH (IU) administered per oocyte retrieved, was assessed in matched patients only. Additional outcomes and safety were assessed in the overall populations. RESULTS: Baseline characteristics were comparable between groups. Mean (SD) total dose of r-hFSH administered per oocyte retrieved in patients at risk of OHSS, was significantly lower in the study group compared with the control group (132.5 [85.2] vs. 332.7 [371.6] IU, P < 0.0001, n = 123). Implantation rate, clinical pregnancy rate, and live birth rates in the overall study and control groups were 30.0 vs. 20.6%, 50.3 vs. 40.7%, and 43.8 vs. 34.0%, respectively. OHSS incidence was significantly lower in the study group compared with the control group (27/1783 [1.5%] vs. 57/1419 [4.0%] patients, P < 0.0001). AEs were reported by 5.0% of patients in the study group. CONCLUSIONS: A significantly lower r-hFSH dose per oocyte retrieved and lower OHSS incidence were observed in patients using the redesigned injector compared with patients using other injection devices.

The association between thrombophilic genes alterations and poor ovarian response in infertile women: a retrospective case-control study.

This research aimed to retrospectively investigate the possible association between poor ovarian stimulation and selected thrombophilia markers in Iranian women with infertility. For this study 100 Iranian infertile women, with a history of at least three Assisted Reproduction Technology (ART) failures (50 with a poor ovarian response and 50 with a normal response), referred to Royan Institute were selected. Targeted genetic variation evaluation for Factor V G1691A, F II Prothrombin G20210A, MTHFR C677T, MTHFR A1298C was performed by PCR-RFLP followed by Sanger Sequencing. The association between these variants and the ovarian response was examined. The results showed an association between Factor V G1691A mutation and poor ovarian response. The heterozygosity rate of the FVL was significantly different between poor responders compared with the normal response group (p-value ≤ 0.05). In conclusion screening of this polymorphism can be used as a genetic determinant of ovarian response functioning through a vascular mechanism. A larger study with bigger sample size is recommended.Impact statementWhat is already known on this subject? Thrombophilia is a multi-genetic disease that is associated with changes in homeostatic mechanisms. Some studies have suggested that thrombophilia has no relationship with poor ovarian response and reduced ovarian reserve in general infertile population undergoing ART.What do the results of this study add? Our results showed a significant association between the FVL heterozygote mutation and poor ovarian response.What are the implications of these findings for clinical practice and/or further research? Screening of FVL polymorphism may be suggested as a predictive test for ovarian stimulation response in infertile women undergoing ART. Further prospective studies with bigger sample size evaluating other thrombophilia markers and ovarian response, as well as further in-vitro studies may help clarify the biological mechanisms behind the effect of the FVL polymorphism on ovarian response, oocyte quality and embryo quality.

A Premature Rise of Luteinizing Hormone Is Associated With a Reduced Cumulative Live Birth Rate in Patients ≥37 Years Old Undergoing GnRH Antagonist In Vitro Fertilization Cycles.

This is a retrospective cohort study included 1021 patients underwent a flexible GnRH antagonist IVF protocol from January 2017 to December 2017 to explore the effect of a premature rise in luteinizing hormone (LH) level on the cumulative live birth rate. All patients included received the first ovarian stimulation and finished a follow-up for 3 years. A premature rise in LH was defined as an LH level >10 IU/L or >50% rise from baseline during ovarian stimulation. The cumulative live birth rate was calculated as the number of women who achieved a live birth divided by the total number of women who had either delivered a baby or had used up all their embryos received from the first stimulated cycle. In the advanced patients (≥37 years), the cumulative live birth rate was reduced in patients with a premature rise of LH (ß: 0.20; 95% CI: 0.05-0.88; p=0.03), compared to patients (≥37 years) without the premature LH rise. The incidence of premature LH rise is associated with decreased rates of cumulative live birth rate in patients of advanced age (≥37 years) and aggravated the reduced potential of embryos produced by the advanced age, not the number of embryos.

Racial disparities in frozen embryo transfer success.

PURPOSE: To compare pregnancy and birth outcomes after frozen embryo transfers (FETs) among White, Black, and Asian women and evaluate the effect of patient, protocol, and cycle characteristics on success. METHODS: A retrospective chart review identified women who underwent an autologous FET at an academic fertility center between January 2013 and March 2020. RESULTS: White, Black, and Asian women completed 1,181 (71.7%), 230 (14.0%), and 235 (14.3%) cycles, respectively. Black women were significantly less likely to achieve a positive hCG level (AOR 0.66, 95% CI 0.49-0.90), clinical pregnancy (AOR 0.71, 95% CI 0.53-0.97), and live birth (AOR 0.65, 95% CI 0.47-0.89) compared to White women after adjusting for possible confounders. There were no differences in the aforementioned outcomes when looking at cycles completed by Asian versus White women. When comparing outcomes by endometrial preparation protocol, significant differences were seen amongst the three groups for live birth rates following natural cycle FETs (52.36%, 25.81%, and 44.19% for White, Black, and Asian women, respectively, p = 0.02), a difference not appreciated after programmed FETs. CONCLUSION: Black race is associated with significantly worse pregnancy and live birth rates following FET when compared to White race. Additionally, significant differences in live birth rates among White, Black, and Asian women exist following natural cycle FET versus programmed FET. These disparities in success are not only important for patient counseling, but also when determining management strategies to improve fertility rates among minority women.

Development and Validation of Prediction Model for High Ovarian Response in In Vitro Fertilization-Embryo Transfer: A Longitudinal Study.

OBJECTIVE: To develop and validate a prediction model for high ovarian response in in vitro fertilization-embryo transfer (IVF-ET) cycles. METHODS: Totally, 480 eligible outpatients with infertility who underwent IVF-ET were selected and randomly divided into the training set for developing the prediction model and the testing set for validating the model. Univariate and multivariate logistic regressions were carried out to explore the predictive factors of high ovarian response, and then, the prediction model was constructed. Nomogram was plotted for visualizing the model. Area under the receiver-operating characteristic (ROC) curve, Hosmer-Lemeshow test and calibration curve were used to evaluate the performance of the prediction model. RESULTS: Antral follicle count (AFC), anti-Müllerian hormone (AMH) at menstrual cycle day 3 (MC3), and progesterone (P) level on human chorionic gonadotropin (HCG) day were identified as the independent predictors of high ovarian response. The value of area under the curve (AUC) for our multivariate model reached 0.958 (95% CI: 0.936-0.981) with the sensitivity of 0.916 (95% CI: 0.863-0.953) and the specificity of 0.911 (95% CI: 0.858-0.949), suggesting the good discrimination of the prediction model. The Hosmer-Lemeshow test and the calibration curve both suggested model's good calibration. CONCLUSION: The developed prediction model had good discrimination and accuracy via internal validation, which could help clinicians efficiently identify patients with high ovarian response, thereby improving the pregnancy rates and clinical outcomes in IVF-ET cycles. However, the conclusion needs to be confirmed by more related studies.

Follitropin alpha versus beta in a first GnRH antagonist ICSI cycle: a retrospective cohort study.

RESEARCH QUESTION: Are cumulative live birth rates (CLBR) after follitropin alpha (Ovaleap®) and follitropin beta (Puregon®) similar when used for ovarian stimulation with ICSI (intracytoplasmic sperm injection) in a first-rank gonadotrophin-releasing hormone (GnRH) antagonist protocol? DESIGN: Retrospective single-centre cohort study including 832 infertile patients undergoing ovarian stimulation with a daily dose of 150-225 IU FSH in their first ICSI cycle at a tertiary referral centre between July 2016 and July 2019. Of those, 349 patients used Ovaleap and 483 patients received Puregon. RESULTS: Baseline characteristics were not statistically different between the groups. The duration of stimulation was slightly longer in the Ovaleap group (10.6 ± 1.7 versus 10.3 ± 1.6 days; P = 0.012). The number of mature oocytes was not statistically different and there was no significant difference in fertilization rate or embryo utilization rate between the two groups. After fresh embryo transfer, biochemical pregnancy rate (137/349 [39.3%] versus 186/483 [38.5%]) as well as clinical pregnancy rate (105/349 [30.1%] versus 152/483 [31.5%]) were comparable (P = 0.83 and 0.67, respectively). Live birth rate (LBR) after fresh embryo transfer (94/349 [26.9%] versus 141/483 [29.2%]; P = 0.48) and CLBR (199/349 [57.0%] versus 287/483 [59.4%]; P = 0.49) were not significantly different. Multivariable regression analysis revealed that the type of gonadotrophin was not associated with CLBR (P = 0.28). CONCLUSION: This retrospective study shows no significant difference in CLBR between Ovaleap and Puregon in patients undergoing their first GnRH antagonist ICSI cycle.

Double daily doses of cetrorelix may raise follicular phase progesterone more compared to single doses in poor ovarian response patients.

PURPOSE: There is evidence that follicular phase progesterone rise [FPPR] adversely affects fresh in vitro fertilization [IVF] cycles. A single daily dose of cetrorelix has been used to prevent early luteinizing Hormone (LH) surge. We speculated that doubling the daily dose might have a positive effect in patients who have early LH surges despite receiving the single daily dose treatment. However, a double daily dose of cetrorelix seems to cause FPPR in poor ovarian response (POR) patients. MATERIALS AND METHODS: On human chorionic gonadotropin [hCG] injection days, the progesterone levels of POR patients who received a single daily dose of cetrorelix (group 1, n = 59) were compared with progesterone levels of the patients who received a double daily dose of cetrorelix (group 2, n = 75). The two groups had statistically similar demographic data. The patients who had FPPR were detected, and a comparison of progesterone levels, using 0.8, 1.0, and 1.2 [ng/mL] of progesterone as cut-off levels, was made between patients of both groups. RESULTS: FPPR patients in group 2 had significantly higher progesterone levels during hCG day, contrary to expectations. When progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 1 patients, 15.3%, 13.6%, and 6.8% of the patients developed FPPR, respectively When the progesterone cut-off levels of 0.8, 1.0, and 1.2 [ng/mL] were used for group 2, the results detected were 45.3%, 30.7%, and 21.3%, respectively. A significant statistical difference in progesterone levels was observed between the groups. CONCLUSION: While the double daily dose of cetrorelix was initially thought to more effectively suppress early LH rise by some authors, we have seen that it increases the FPPR more when compared to a single daily dose regime. We suggest using frozen cycles instead of fresh cycles in order to have better endometrial receptivity in patients who seem to benefit from higher daily doses of cetrorelix.

Variants Ala307Ala and Ser680Ser of 307 and 680 FSHr polymorphisms negatively influence on assisted reproductive techniques outcome and determine high probability of non-pregnancy in Caucasian patients.

PURPOSE: To determine the influence of different genotypes of Ala307Thr and Asn680Ser FSHr polymorphisms on controlled ovarian stimulation (COS) outcome and pregnancy. METHODS: This study collected blood and physiological and clinical parameters of 517 Caucasian patients (Statistical power ≥ 80%) that underwent COS treatment. Genotypes of Ala307Thr and Asn680Ser polymorphisms were determined using PCR amplification followed by Bsu36I and BsrI digestion, respectively. RESULTS: Ala307Ala and Ser680Ser genotypes associated to worse parameters of COS outcome (preovulatory follicles P = 0.05, in both), justifying their lower pregnancy rate than Non-Ala307Ala, P = 0.01 and Non-Ser680Ser, P = 0.004, respectively or together, (P = 0.003). Within the Non-Ala307Ala group, Thr307Thr genotype showed higher number of fertilized oocytes (P = 0.04) and embryos (P = 0.01) than Non-Thr307Thr, but no influence on pregnancy rate. Ala307Ala and Ser680Ser patients doubled probability of non-pregnancy than Non-Ala307Ala (odds ratio = 2.0) and Non-Ser680Ser (odds ratio = 2.11), respectively. Ala307Ala and Ser680Ser genotypes tend to appear together (P < 0.0001), which increases the probability of non-pregnancy. CONCLUSIONS: Ala307Ala and Ser680Ser genotypes of 307 and 680 FSHr polymorphisms associate to worse COS outcome than its respective Non-Ala307Ala and Non-Ser680Ser. Within the Non-Ala307Ala genotypes, Thr307Thr, although shows higher Fertilized Oocytes and Embryos, do not influence on pregnancy rate. Ala307Ala and Ser680Ser genotypes double the probability of Non-Pregnancy than their respective Non-Ala307Ala and Non-Ser680Ser genotypes. Furthermore, the strong tendency of these genotypes to appear together worsens the probability of pregnancy in these patients.

Oocyte accumulation for fertility preservation in women with benign ovarian tumours with a history of previous surgery, multiple or large cysts.

RESEARCH QUESTION: What are ovarian stimulation cycle outcomes and acceptance rates of an oocyte accumulation programme in young women with benign ovarian tumour (BOT)? DESIGN: Retrospective cohort study conducted at the Academic Assisted Reproductive Technology and Fertility Preservation Centre, Lille University Hospital, between January 2016 and December 2019. The number of metaphase II oocytes per cycle and per patient after accumulation were evaluated. Two groups were identified for the analysis: endometrioma ('endometrioma') and dermoid, mucinous or serous cyst ('other cysts'). RESULTS: A total of 113 fertility-preservation cycles were analysed in 70 women aged 27.9 ± 4.8 years. Almost all women had undergone previous ovarian surgery before fertility preservation (89%). Mean anti-Müllerian hormone levels before ovarian stimulation was 12.5 ± 8.7 pmol/l. A total of 6.4 ± 3.4 oocytes were retrieved, and 4.3 ± 3.4 metaphase II (MII) oocytes were vitrified per cycle. All agreed to the oocyte accumulation programme and all underwent at least one cycle. To date, 36 (51%) patients achieved two or three fertility- preservation cycles. After accumulation, 7.0 ± 5.23 MII oocytes were vitrified per patient. No difference was found in ovarian response and oocyte cohort between the 'endometrioma' and 'other cysts' groups. Questionnaires completed after oocyte retrieval revealed abdominal bloating and pelvic pain in most patients, with no difference according to the type of cyst. No serious adverse events occurred. CONCLUSIONS: Oocyte accumulation should be systematically offered to young women with BOT irrespective of histological type, as it seems to be well-tolerated. Long-term follow-up is needed to assess the efficiency of oocyte accumulation to optimize the chances of subsequent pregnancies.

Effects of chromosomal abnormalities on pregnancy outcomes in female undergoing artificial insemination with donor's sperm.

ABSTRACT: This study aimed to evaluate the clinical characteristics, pregnancy outcomes and prognostic factors for pregnancy of female with chromosomal abnormalities (CAs) after artificial insemination with donor's sperm (AID) treatment.A retrospective case-control study was analyzed by using the data of 29 female patients with CA and 116 controlled patients with normal karyotype (1:4 ratio) who underwent AID cycles at Guangdong Family Planning Special Hospital from January 2011 to December 2017. In all cases, reproductive histories were collected, and the cytogenetic analysis was performed by Trypsin-Giemsa banding and karyotyping. The embryos were fertilized via intracervical or intrauterine insemination. Clinical characteristic variables were compared.The prevalence of CA was found to be 0.29% in the whole AID population. The live birth rates of CA group and controlled group were 41.4% and 31.0% (P = .29) respectively. Compared to normal karyotype group, patients with CA showed higher rate of primary infertility (93.1% vs 75.9%, P = .049); Multivariate analysis demonstrated that ovarian stimulation (odds ratio, 3.055; 95% confidence interval, 1.421-6.568; P = .004) was associated with adverse pregnancy outcomes in female patients with AID treatment.For the infertility CA patients who were phenotypically normal, AID was a suitable choice, whereas ovarian stimulation results in an improvement in the pregnancy rate.

Oocyte or embryo number needed to optimize live birth and cumulative live birth rates in mild stimulation IVF cycles.

RESEARCH QUESTION: How many oocytes or embryos are needed to optimize the live birth rate (LBR) per cycle and cumulative LBR (CLBR) following mild stimulation IVF (MS-IVF) in women with uncompromised ovarian reserve? DESIGN: Retrospective analysis of a 4-year database of five fertility centres. The study population included women with normal/high ovarian reserve, who underwent autologous MS-IVF (daily ≤150 IU gonadotrophin) with fresh and subsequent frozen embryo transfer(s) (FET) from surplus embryos. Only the first cycle of each patient was included. Cycles with >150 IU daily average of gonadotrophin were excluded. 'Freeze-all embryo' (FAE) cycles were analysed separately. RESULTS: A total of 862 consecutive cycles fulfilled the inclusion criteria; 592 were eligible for fresh embryo transfer, 239 had non-elective 'freeze-all' cycles. Median age (25-75th percentile) of women who had fresh embryo transfer was 35 (32-37) years, median antral follicle count 19 (14-28) and anti-Müllerian hormone 19.2 (13-28.9) pmol/l. LBR/fresh cycle and CLBR inclusive of FAE cycles in the <35, 35-37, 38-39 and 40-42 year age groups were 37.8% and 45.1%, 36.0% and 41.6%, 18.4% and 29.1%, and 8.9% and 18.1%, respectively. The LBR following fresh embryo transfer plateaued after nine oocytes (40.3%) or four embryos (40.8%). The CLBR optimized when 12 oocytes (42.9%) or nine embryos (53.8%) were obtained. The LBR per oocyte peaked in women under 35 years when <5 oocytes were retrieved (11.4%), then declined with age and with higher oocyte yield. There were no cases of severe ovarian hyperstimulation syndrome (OHSS). CONCLUSION: Nine oocytes, or four embryos, can optimize fresh transfer cycle LBR in MS-IVF. The CLBR are optimized with 12 oocytes, or nine embryos in predicted normal responders, while safeguarding against OHSS.

Association of homocysteine with IVF/ICSI outcomes stratified by MTHFR C677T polymorphisms: a prospective cohort study.

RESEARCH QUESTION: What is the association between homocysteine (Hcy) and IVF/intracytoplasmic sperm injection (ICSI) outcomes, stratified by methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms? DESIGN: This prospective cohort study recruited 1011 infertile women undergoing IVF/ICSI treatment for the first time at the International Peace Maternity and Child Health Hospital between June 2015 and March 2018. RESULTS: The concentration of total serum Hcy was significantly negatively associated with clinical pregnancy and implantation rate. When adjusted for maternal and paternal age and educational level, maternal body mass index, and FSH and oestradiol concentrations, logistic regression analysis showed that women with higher Hcy had a higher risk of unsuccessful pregnancy. After stratification by MTHFR C677T polymorphisms and adjustment for confounding factors, a higher risk of unsuccessful pregnancy and a significantly lower implantation rate only existed in women with higher Hcy concentration in the MTHFR C677T TT genotype. There was no significant association between Hcy concentrations and other ovarian stimulation outcomes (oocytes retrieved, metaphase II stage oocytes, fertilization rate, cleavage rate, high-quality embryo rate) or neonatal outcomes (preterm birth, gestational age at delivery, Caesarean section, birthweight, small for gestational age, large for gestational age or birth defects). CONCLUSIONS: Hcy is highly negatively associated with clinical pregnancy and implantation rate during the first IVF/ICSI cycle, especially in women carrying the MTHFR C677T TT genotype. Other factors with impacts on reproductive outcomes, such as stage of embryo transferred, other factors involved in folate metabolism, preimplantation genetic testing, etc., should be taken into account in further research.

Involvement of single nucleotide polymorphisms in ovarian poor response.

PURPOSE: Unpredictability in acquiring an adequate number of high-quality oocytes following ovarian stimulation is one of the major complications in controlled ovarian hyperstimulation (COH). Genetic predispositions of variations could alter the immunological profiles and consequently be implicated in the variability of ovarian response to the stimulation. DESIGN: Uncovering the influence of variations in AMHR2, LHCGR, MTHFR, PGR, and SERPINE1 genes with ovarian response to gonadotrophin stimulation in COH of infertile women. METHODS: Blood samples of the women with a good ovarian response (GOR) or with a poor ovarian response (POR) were collected. Genomic DNA was extracted, and gene variations were genotyped by TaqMan SNP Genotyping Assays using primer-probe sets or real-time PCR Kit. RESULTS: Except for PGR (rs10895068), allele distributions demonstrate that the majority of POR patients carried minor alleles of AMHR2 (rs2002555, G-allele), LHCGR (rs2293275, G-allele), MTHFR (rs1801131, C-allele, and rs1801133, T-allele), and SERPINE1 (rs1799889, 4G allele) genes compared to the GOR. Similarly, genotypes with a minor allele in AMHR2, LHCGR, MTHFR, and SERPINE1 genes had a higher prevalence among POR patients with the polymorphic genotypes. However, further genotype stratification indicated that the minor alleles of these genes are not associated with poor response. Multivariate logistic analysis of clinical-demographic factors and polymorphic genotypes demonstrated a correlation between FSH levels and polymorphic genotypes of SERPINE1 in poor response status. CONCLUSIONS: Despite a higher prevalence of AMHR2, LHCGR, MTHFR, and SERPINE1 variations in the patients with poor ovarian response, it seems that these variations are not associated with the ovarian response.

Effects of Different Exposure Days to Gonadotropin-Releasing Hormone Agonist (GnRH-a) on Live Birth Rates in the Depot GnRH-a Protocol: A Retrospective Analysis of 7007 Cycles.

BACKGROUND In controlled ovarian hyperstimulation protocols worldwide, depot gonadotropin-releasing hormone agonist (GnRH-a) pretreatment is generally used for pituitary desensitization. The delay between the GnRH-a administration and starting gonadotropin treatment varies greatly, from 25 to 60 days. However, the association between exposure days to GnRH-a before the onset of gonadotropin administration and the clinical outcomes remains unknown. MATERIAL AND METHODS This retrospective study included 7007 patients who underwent fresh embryo transfers between February 2016 and July 2019. The duration of pituitary downregulation was categorized into 3 groups: group 1, ≤30 days; group 2, 31-35 days; and group 3, ≥36 days. The rates of live birth were compared as the main outcome measure. Logistic regression analysis was also performed after controlling for a range of confounders. RESULTS The number of patients in groups 1, 2, and 3 was 2001, 2824, and 2182, respectively. Group 3 (≥36 days) had a noticeably higher live birth rate (48.1%) than the other 2 groups (42.6% and 43.9%, P=0.001). The rate of live birth was remarkably enhanced in group 3 (adjusted odds ratio: 1.264, 95% confidence interval: 1.098, 1.455, P=0.001) after controlling for confounders, while the difference was not found in group 2 (P=0.512) compared with group 1. CONCLUSIONS In the depot GnRH-a protocol, live birth rates are higher among patients needing a longer time to achieve the goal of pituitary downregulation.

PGT or ICSI? The impression of NGS-based PGT outcomes in nonmosaic Klinefelter syndrome.

This retrospective study demonstrates the clinical outcomes of patients with nonmosaic Klinefelter's syndrome (KS) who underwent preimplantation genetic testing (PGT) with frozen-thawed testicular spermatozoa. Microdissection testicular sperm extraction (micro-TESE) was performed for sperm retrieval. Next-generation sequencing (NGS) was conducted for embryo analysis. A total of 18 couples aged ≤35 years were included, and 22 oocyte retrieval cycles were completed. Euploidy was detected in 29 of 45 (64.4%) embryos. Additionally, the numbers of aneuploid and mosaic embryos detected were 8 (17.8%) and 8 (17.8%), respectively, regardless of a lack of sex chromosome abnormalities. Finally, 13 couples with euploid embryos completed 14 frozen embryo transfer (FET) cycles. Ten couples had clinical pregnancies, and 6 of them had already delivered 5 healthy babies and 1 monozygotic twin. There were also 4 ongoing pregnancies and 2 biochemical pregnancies, but no early pregnancy loss was reported. Based on our results, we speculate that for KS patients, when sperm can be obtained by micro-TESE, the cryopreservation strategy makes the ovarian stimulation procedure more favorable for female partners. The paternal genetic risk of sex chromosome abnormalities in their offspring is extremely low in men with KS. In addition to PGT, the intracytoplasmic sperm injection (ICSI) procedure is comparably effective but more economical for young nonmosaic KS couples. ICSI should be offered as an option for such couples, but monitoring by prenatal genetic diagnosis is recommended.

Consecutive ovarian stimulation is beneficial in patients with a poor response to high-dose follicle-stimulating hormone.

OBJECTIVE: To investigate if an immediate additional IVF-ET cycle bear an advantage to patients with poor ovarian response in comparison to a cycle performed at some delay. METHODS: A cohort study including 632 patients who underwent a fresh IVF-ET cycle with high-dose (≥300 IU/d) FSH stimulation that yielded ≤4 oocytes and did not achieve a clinical pregnancy. All underwent a second stimulation and oocyte pick-up (OPU), either consecutively or separately within 180 days (nonconsecutive OPU). The oocyte yield, number of embryos available for transfer, pregnancy live birth rates of the second OPU were compared between patients who had consecutive and nonconsecutive cycles. RESULTS: Consecutive OPU was associated with more mature follicles in the second cycle compared to nonconsecutive OPU (p = .03) in addition to higher peak estradiol level (p < .0001), and more aspirated oocytes (p = .03) and available embryos (p = .023). There was no between-group difference in ongoing pregnancy and live birth rates. In a multivariate analysis of variance controlling for potential confounders, the difference in the number of aspirated oocytes and available embryos was associated significantly only with consecutive performance of the second cycle. CONCLUSION: Immediate sequential stimulation (without an intervening menstrual cycle) in poor responders is advantageous over delayed stimulation in terms of number of aspirated oocytes and available embryos. The administration of high-dose FSH in the first cycle may benefit follicular recruitment also in the subsequent cycle. Although the effect is modest, given that each additional oocyte aspirated contributes to the outcome, it might be of significance especially in younger patients.