Comparison of pregnancy outcomes between 4th day morula and 5th day blastocyst after embryo transfer: a retrospective cohort study.

BACKGROUND: This study was designed to evaluate pregnancy outcomes between morulae transferred on day 4 (D4) and blastocysts transferred on day 5 (D5). METHODS: From September 2017 to September 2020, 1963 fresh transfer cycles underwent early follicular phase extra-long protocol for assisted conception in our fertility center were divided into D4 (324 cases) and D5 (1639 cases) groups, and the general situation and other differences of patients in both groups were compared. To compare the differences in pregnancy outcomes, the D4 and D5 groups were further divided into groups A and B based on single and double embryo transfers. Furthermore, the cohort was divided into two groups: those with live births (1116 cases) and those without (847 cases), enabling a deeper evaluation of the effects of D4 or D5 transplantation on assisted reproductive outcomes. RESULTS: In single embryo transfer, there was no significant difference between groups D4A and D5A (P > 0.05). In double embryo transfer, group D4B had a lower newborn birthweight and a larger proportion of low birthweight infants (P < 0.05). The preterm delivery rate, twin delivery rate, cesarean delivery rate, and percentage of low birthweight infants were lower in the D5A group than in the D5B group (P < 0.05). Analysis of factors influencing live birth outcomes further confirmed the absence of a significant difference between D4 and D5 transplantation in achieving live birth (P > 0.05). CONCLUSION: When factors such as working life and hospital holidays are being considered, D4 morula transfer may be a good alternative to D5 blastocyst transfer. Given the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) success rate and risk of twin pregnancy, D4 morula transfer requires an adapted decision between single and double embryo transfer, although a single blastocyst transfer is recommended for the D5 transfer in order to decrease the twin pregnancy rate. In addition, age, endometrial thickness and other factors need to be taken into account to personalize the IVF program and optimize pregnancy outcomes.

The construction of machine learning-based predictive models for high-quality embryo formation in poor ovarian response patients with progestin-primed ovarian stimulation.

OBJECTIVE: To explore the optimal models for predicting the formation of high-quality embryos in Poor Ovarian Response (POR) Patients with Progestin-Primed Ovarian Stimulation (PPOS) using machine learning algorithms. METHODS: A retrospective analysis was conducted on the clinical data of 4,216 POR cycles who underwent in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) at Sichuan Jinxin Xinan Women and Children's Hospital from January 2015 to December 2021. Based on the presence of high-quality cleavage embryos 72 h post-fertilization, the samples were divided into the high-quality cleavage embryo group (N = 1950) and the non-high-quality cleavage embryo group (N = 2266). Additionally, based on whether high-quality blastocysts were observed following full blastocyst culture, the samples were categorized into the high-quality blastocyst group (N = 124) and the non-high-quality blastocyst group (N = 1800). The factors influencing the formation of high-quality embryos were analyzed using logistic regression. The predictive models based on machine learning methods were constructed and evaluated accordingly. RESULTS: Differential analysis revealed that there are statistically significant differences in 14 factors between high-quality and non-high-quality cleavage embryos. Logistic regression analysis identified 14 factors as influential in forming high-quality cleavage embryos. In models excluding three variables (retrieved oocytes, MII oocytes, and 2PN fertilized oocytes), the XGBoost model performed slightly better (AUC = 0.672, 95% CI = 0.636-0.708). Conversely, in models including these three variables, the Random Forest model exhibited the best performance (AUC = 0.788, 95% CI = 0.759-0.818). In the analysis of high-quality blastocysts, significant differences were found in 17 factors. Logistic regression analysis indicated that 13 factors influence the formation of high-quality blastocysts. Including these variables in the predictive model, the XGBoost model showed the highest performance (AUC = 0.813, 95% CI = 0.741-0.884). CONCLUSION: We developed a predictive model for the formation of high-quality embryos using machine learning methods for patients with POR undergoing treatment with the PPOS protocol. This model can help infertility patients better understand the likelihood of forming high-quality embryos following treatment and help clinicians better understand and predict treatment outcomes, thus facilitating more targeted and effective interventions.

Derivation and validation of the first web-based nomogram to predict the spontaneous pregnancy after reproductive surgery using machine learning models.

Objective: Infertility remains a significant global burden over the years. Reproductive surgery is an effective strategy for infertile women. Early prediction of spontaneous pregnancy after reproductive surgery is of high interest for the patients seeking the infertility treatment. However, there are no high-quality models and clinical applicable tools to predict the probability of natural conception after reproductive surgery. Methods: The eligible data involving 1013 patients who operated for infertility between June 2016 and June 2021 in Yantai Yuhuangding Hospital in China, were randomly divided into training and internal testing cohorts. 195 subjects from the Linyi People's Hospital in China were considered for external validation. Both univariate combining with multivariate logistic regression and the least absolute shrinkage and selection operator (LASSO) algorithm were performed to identify independent predictors. Multiple common machine learning algorithms, namely logistic regression, decision tree, random forest, support vector machine, k-nearest neighbor, and extreme gradient boosting, were employed to construct the predictive models. The optimal model was verified by evaluating the model performance in both the internal and external validation datasets. Results: Six clinical indicators, including female age, infertility type, duration of infertility, intraoperative diagnosis, ovulation monitoring, and anti-Müllerian hormone (AMH) level, were screened out. Based on the logistic regression model's superior clinical predictive value, as indicated by the area under the receiver operating characteristic curve (AUC) in both the internal (0.870) and external (0.880) validation sets, we ultimately selected it as the optimal model. Consequently, we utilized it to generate a web-based nomogram for predicting the probability of spontaneous pregnancy after reproductive surgery. Furthermore, the calibration curve, Hosmer-Lemeshow (H-L) test, the decision curve analysis (DCA) and clinical impact curve analysis (CIC) demonstrated that the model has superior calibration degree, clinical net benefit and generalization ability, which were confirmed by both internal and external validations. Conclusion: Overall, our developed first nomogram with online operation provides an early and accurate prediction for the probability of natural conception after reproductive surgery, which helps clinicians and infertile couples make sensible decision of choosing the mode of subsequent conception, natural or IVF, to further improve the clinical practices of infertility treatment.

Multiple collapses of blastocysts after full blastocyst formation is an independent risk factor for aneuploidy - a study based on AI and manual validation.

BACKGROUND: The occurrence of blastocyst collapse may become an indicator of preimplantation embryo quality assessment. It has been reported that collapsing blastocysts can lead to higher rates of aneuploidy and poorer clinical outcomes, but more large-scale studies are needed to explore this relationship. This study explored the characteristics of blastocyst collapse identified and quantified by artificial intelligence and explored the associations between blastocyst collapse and embryo ploidy, morphological quality, and clinical outcomes. METHODS: This observational study included data from 3288 biopsied blastocysts in 1071 time-lapse preimplantation genetic testing cycles performed between January 2019 and February 2023 at a single academic fertility center. All transferred blastocysts are euploid blastocysts. The artificial intelligence recognized blastocyst collapse in time-lapse microscopy videos and then registered the collapsing times, and the start time, the recovery duration, the shrinkage percentage of each collapse. The effects of blastocyst collapse and embryo ploidy, pregnancy, live birth, miscarriage, and embryo quality were studied using available data from 1196 euploid embryos and 1300 aneuploid embryos. RESULTS: 5.6% of blastocysts collapsed at least once only before the full blastocyst formation (tB), 19.4% collapsed at least once only after tB, and 3.1% collapsed both before and after tB. Multiple collapses of blastocysts after tB (times ≥ 2) are associated with higher aneuploid rates (54.6%, P > 0.05; 70.5%, P < 0.001; 72.5%, P = 0.004; and 71.4%, P = 0.049 in blastocysts collapsed 1, 2, 3 or ≥ 4 times), which remained significant after adjustment for confounders (OR = 2.597, 95% CI 1.464-4.607, P = 0.001). Analysis of the aneuploid embryos showed a higher ratio of collapses and multiple collapses after tB in monosomies and embryos with subchromosomal deletion of segmental nature (P < 0.001). Blastocyst collapse was associated with delayed embryonic development and declined blastocyst quality. There is no significant difference in pregnancy and live birth rates between collapsing and non-collapsing blastocysts. CONCLUSIONS: Blastocyst collapse is common during blastocyst development. This study underlined that multiple blastocyst collapses after tB may be an independent risk factor for aneuploidy which should be taken into account by clinicians and embryologists when selecting blastocysts for transfer.

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.

Effect of the degree of follicular diameter ≥18mm differentiation on the day of hCG administration to the outcome of controlled ovarian hyperstimulation (COH).

Objective: To explore the impact of the level of differentiation in a minimum of two follicles with a diameter of ≥18 mm on the outcome of controlled ovarian hyperstimulation on the day of human chorionic gonadotropin (hCG) administration. Methods: Single-center data from January 2018 to December 2021 was retrospectively analyzed for 1,199 patients with fresh embryo transfer for assisted reproduction. The absolute value of the standard deviation of the follicle size of at least 2 follicles ≥18 mm in diameter in both ovaries on the day of hCG was taken as the degree of differentiation of the dominant follicle after ovulation induction, based on the standard deviation response to the degree of dispersion of the data. The degree of follicular differentiation was divided into 3 groups according to the size of the value, and the general clinical conditions, laboratory indexes, and clinical outcomes of the patients in the 3 groups were compared. Results: Among the three groups, the body mass index (BMI) of the ≤1s group was lower than that of the other two groups (P< 0.05), while the follicle-stimulating hormone (FSH) and Anti-Mullerian hormone (AMH) were higher (P< 0.05), and the implantation rate and clinical pregnancy rate were significantly higher than those of the other two groups (P< 0.01). After multifactorial logistic regression to correct for confounding factors, with the ≤1s group as the reference, the implantation rate, hCG-positive rate, clinical pregnancy rate and live birth rate of embryo transfer in the ≥2S group were significantly lower (P< 0.01). The results of curve fitting analysis showed that the live birth rate decreased gradually with the increase of the absolute standard deviation (P=0.0079). Conclusion: Differences in follicle diameters ≥18 mm on the day of hCG injection did not have an impact on embryo quality, but had an impact on pregnancy outcomes. The less the variation in follicle size, the more homogeneous the follicle development and the higher the likelihood of live births.

Individualized luteal phase support in frozen-thawed embryo transfer after intramuscular progesterone administration might rectify live birth rate.

Background: The serum P concentrations are suggested to have an impact on pregnancy outcome. However there is no consensus about the optimal progesterone cut-off during the luteal phase. Few studies evaluated the effectiveness of a "rescue protocol" for low serum P concentrations and most of these studies used vaginal progesterone administration. There is paucity of data on the effectiveness of rescue protocol using intramuscular progesterone (IM-P) in frozen-thawed embryo transfer (FET). Methods: This study is a retrospective cohort study included 637 single or double blastocyst FETs with artificially prepared endometrium receiving 100 mg IM progesterone (P) after incremental estrogen treatment. Serum P concentrations were evaluated using blood samples obtained 117-119 hours after the first IM-P administration and 21 ± 2 hours after the last IM-P administration. Patients with serum P concentrations <20.6 ng/ml on the ET day were administrated 400 mg vaginal progesterone for rescue. Results: Demographic and cycle characteristics were similar between patients receiving rescue vaginal P (embryo transfer (ET)-day P concentration < 20.6 ng/ml) and patients who did not need rescue vaginal P (ET-day P concentration ≥ 20.6 ng/ml). Clinical pregnancy, miscarriage, and live birth rates were similar between two groups: 52.9%(45/85) vs 59.6%(326/552), p=0.287; 11.1%(5/45) vs 14.1%(46/326), p=0.583; and 47.1%(40/85) vs 50.7%(280/552), p=0.526, respectively. Logistic regression analysis revealed that the female age (p = 0.008, OR=0.942, 95% CI = 0.902-0.984) and embryo quality (ref: good quality for moderate: p=0.02, OR=0.469, 95% CI =0.269-0.760; for poor: p=0.013, OR= 0.269, 95% CI = 0.092-0.757) were independent variables for live birth. Following rescue protocol implementation, ET-day P concentration was not a significant predictor of live birth. Conclusions: Rescue vaginal P administration for low ET day serum P concentrations following IM-P yields comparable live birth rates.

The fertility outcome of assisted oocyte activation combined with spindle view-assisted intracytoplasmic sperm injection in patients with low fertilization rate.

OBJECTIVE: To examine the possible synergic effect of spindle view-assisted intracytoplasmic sperm injection (SV-ICSI) with assisted oocyte activation (AOA) for low fertilization rate. MATERIALS AND METHODS: A single-center retrospective study from 2019/09-2023/06, a total of 47 patients, autologous IVF cycle, and low fertilization rate history, including control group (SV-ICSI, 33 patients) and intervention group (AOA-SV-ICSI, 14 patients), comparing fertilization rate, blastocyst formation rate, and clinical pregnancy rate. RESULTS: The blastocyst formation rate was significantly higher (p = 0.020) in the AOA-SV-ICSI group than in the SV-ICSI group. The fertilization rate (P = 0.468) and clinical pregnancy rate (p = 0.057) were non-significant between groups. CONCLUSION: The AOA-SV-ICSI group's blastocyst formation rate significantly improved in patients with previous low fertilization rates, which might help them obtain more useable embryos for further embryo implantation.

Uterine tone: A neglected criterion for the selection of bovine embryo transfer recipients.

This study evaluated the relationship between CL features assessed by ultrasound (luteal tissue area and blood flow, BF) or rectal palpation (size), uterine tone (UT), plasma progesterone (P4) concentration on Day 7 (D7) and subsequent pregnancy outcomes in bovine embryo recipients. A total of 163 cows and heifers were included in this study. The expected day of ovulation after the synchronization protocol was designated as D0. On D7, ovaries and uterus were examined by ultrasonography and rectal palpation, and subjective scores (1-3 scale) were assigned for CL size, area and BF, and for UT. Blood samples were collected for further P4 analysis. Each embryo recipient then received a grade I frozen-thawed in vivo-produced blastocyst, which was transferred to the uterine horn ipsilateral to the CL. Pregnancy diagnosis was performed on D35, and the results were retrospectively compared with the assigned scores for CL and UT. We observed a significant (p < .02) interaction between CL size and UT, with a progressive increase in the likelihood of pregnancy for recipients bearing a large CL among those with turgid UT. Ultrasound scoring of the CL using B-mode and Doppler-mode did not significantly predict pregnancy rates on D35 (p < .6 and p < .5, respectively). However, logistic regression analysis revealed a trend towards a quadratic effect (p < .08 and p < .06) indicating that the probability of pregnancy varied according to the area of luteal tissue and P4 concentrations, respectively. No significant (p > .05) association was found between the probability of pregnancy and the BF area of the CL. In summary, UT before embryo transfer may reflect successful recipient synchronization. Elevated P4 levels, assessed by CL size, may offset uterine contractility, mitigating adverse effects. Additionally, the CL area may be more important than its vascularization area when evaluating recipients D7 after ovulation.

Effects of obesity on clinical outcomes in diminished ovarian reserve patients undergoing intracytoplasmic sperm injection cycles.

The aim of this study is to evaluate the effects of obesity on clinical outcomes in diminished ovarian reserve (DOR) patients undergoing intracytoplasmic sperm injection cycles. In this retrospective observational cross-sectional study, women admitted to current clinic with DOR undergoing intracytoplasmic sperm injection were divided into 2 groups according to the obesity. Patient age, body mass index, anti-mullerian hormone, baseline follicle stimulating hormone and baseline estradiol levels, antral follicle count, total gonadotropin dose, day of stimulation, number of mature (MII) oocytes, and clinical pregnancy were evaluated. There were no statistically significant differences between groups in terms of age, anti-mullerian hormone, baseline follicle stimulating hormone, baseline estradiol levels, antral follicle count, and clinical pregnancy (P > .05). Total gonadotropin dose, the days of ovarian stimulation were higher and number of MII oocyte were less in the obese group (P < .05). Logistic regression analyses also revealed that the days of ovarian stimulation and number of MII oocyte were significant factors in the study group. ROC curve analysis showed obesity is a negatively affecting factor in DOR patients. Obesity causes more gonadotropin dose longer days of stimulation, and less number of MII oocyte. However clinical pregnancy rate is not negatively affected by obesity according to the current study.

In vitro fertilization results of GNRH antagonists and medroxyprogesterone acetate used to prevent premature LH surge during ovarian hyperstimulation.

The aim of this study was to evaluate the effects of medroxyprogesterone acetate (MPA) treatment in comparison to those of gonadotropin releasing hormone (GnRH) antagonists for the prevention of premature luteinizing hormone surges during controlled ovarian hyperstimulation (OS) and the impact of these effects on developing embryos and pregnancy outcomes. Data from 757 cycles of GnRH antagonist treatment and 756 cycles of MPA treatment were evaluated at the Akdeniz University Faculty of Medicine Assisted Reproductive Treatment Center between October 2018 and April 2022. Patient records were obtained from the electronic database of the centre and analysed. In our centre, GnRH antagonist protocols were used between 2018 and 2020, and MPA protocols were used between 2020 and 2022. We chose our study population by year. Our study is a comparative retrospective study. All methods in this study were performed in accordance with the relevant guidelines and regulations. Patients using MPA were significantly older (33.9 ± 5.6 vs. 32.6 ± 5.6, p < 0.001) and had a lower number of antral follicles (AFC) (10.7 ± 8.6 vs. 11.9 ± 10.8, p = 0.007) than those using GnRH antagonists. Both MPA (2.9%) and GnRH antagonists (2.2%) had similar effectiveness in preventing premature ovulation (p = 0.415). There was no significant difference between the two groups in terms of the number of total developed embryos (1.3 ± 1.3 vs. 1.2 ± 1.2, p = 0.765). There was no significant difference in the clinical pregnancy rates with the first ET (%35.4 vs. %30.1, p = 0.074), per total number of transfers (35.3% vs. 30.1%, p = 0.077). MPA was found to be effective at preventing premature ovulation during OS treatment, and the incidence of developing embryo and pregnancy outcomes in patients using MPA were similar to those in patients using GnRH antagonists. Therefore, the use of MPA instead of GnRH antagonists during OS may be a viable alternative for patients not scheduled for fresh ET.

Improvement of early miscarriage rates in women with adenomyosis via oxytocin receptor antagonist during frozen embryo transfer-a propensity score-matched study.

BACKGROUND: Dysfunctional uterine peristalsis seems to play a pivotal role in hindering embryo implantation among women diagnosed with adenomyosis. This research aims to investigate whether administering an oxytocin receptor antagonist during a frozen embryo transfer (FET) cycle using a hormone replacement therapy (HRT) protocol can enhance in vitro fertilization (IVF) outcomes for infertile women affected by adenomyosis. METHODS: Between January 2018 and June 2022, our reproductive center conducted IVF-FET HRT cycles for infertile women diagnosed with adenomyosis. Propensity score matching was employed to select matched subjects between the two groups in a 1:1 ratio. Following this, 168 women received an oxytocin receptor antagonist during FET, constituting the study group, while the matched 168 women underwent FET without this antagonist, forming the control group. We conducted comparative analyses of baseline and cycle characteristics between the two groups, along with additional subgroup analyses. RESULTS: The study group exhibited notably lower rates of early miscarriage compared to the control group, although there were no significant differences in clinical pregnancy rates, ongoing pregnancy rates, and live birth rates between the two groups. Multivariate analysis revealed a negative correlation between the use of oxytocin receptor antagonists and early miscarriage rates in women with adenomyosis. Subgroup analyses, categorized by age, infertility types, and embryo transfer day, showed a substantial decrease in early miscarriage rates within specific subgroups: women aged ≥ 37 years, those with secondary infertility, and individuals undergoing day 3 embryo transfers in the study group compared to the control group. Furthermore, subgroup analysis based on adenomyosis types indicated significantly higher clinical pregnancy rates, ongoing pregnancy rates and live birth rates in the study group compared to the control group among women with diffuse adenomyosis. CONCLUSIONS: Administering an oxytocin receptor antagonist during FET may reduce the early miscarriage rates in women with adenomyosis.

Combined traditional Chinese medicine therapy for the treatment of infertility with polycystic ovary syndrome: A network meta-analysis of randomized controlled trials.

BACKGROUND: Polycystic ovary syndrome (PCOS) infertility has attracted great attention from researchers due to its high incidence. Numerous studies have shown that Chinese medicine is effective in treating this disease, but there is a wide variety of Chinese medicine therapies available, and there is a lack of comparative evaluation of the efficacy of various Chinese medicine combination therapies in the clinic, which requires further in-depth exploration. This study aims to evaluate the efficacy of a combined traditional Chinese medicine (TCM) therapy for the treatment of infertility with PCOS using network meta-analysis (NMA). METHODS: In PubMed, web of Science, Cochrane Library, Embase, China Knowledge Network, Wanfang Data, VIP Database, China Biomedical Literature Database (SinoMed) databases, searchs were conducted for information about the randomized controlled trials (RCTs) of combined TCM therapy for the treatment of infertility with PCOS. Quality evaluation was performed using the Cochrane 5.3 risk of bias assessment tool, and NMA using Stata 16.0. RESULTS: This study comprised 28 RCTs using 8 combined TCM therapies in total. The results of the NMA showed that moxibustion + herbal, fire acupuncture + herbal, acupuncture + herbal, electroacupuncture + herbal, and acupoint application + herbal improved the clinical pregnancy rate better than acupuncture, herbal, and western medicines monotherapy (P < .05). Additionally, ear point pressure + herbal enema + herbal, acupuncture and moxibustion + herbal, fire acupuncture + herbal, and acupuncture + herbal improved the ovulation rate better than acupuncture, herbal, and western medicines monotherapy (P < .05). Moxibustion + herbal, fire acupuncture + herbal, and acupuncture + herbal are the 3 most effective therapies for improving the clinical pregnancy rate. Fire acupuncture + herbal, acupuncture + herbal, and ear point pressure + herbal enema + herbal are the 3 most effective therapies for improving the ovulation rate. CONCLUSION: The combined TCM therapy demonstrated better efficacy for the treatment of infertility with PCOS compared to acupuncture, herbal, and western medicines monotherapy. However, the optimal treatment therapy varied depending on the outcome indicators. Further large sample, high-quality, and standardized RCTs are needed to verify these findings.

Co-administration of GnRH-agonist and hCG (double trigger) for final oocyte maturation increases the number of top-quality embryos in patients undergoing IVF/ICSI cycles.

BACKGROUND: The utilization of a double trigger, involving the co-administration of gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) for final oocyte maturation, is emerging as a novel approach in gonadotropin-releasing hormone antagonist (GnRH-ant) protocols during controlled ovarian hyperstimulation (COH). This protocol involves administering GnRH-a and hCG 40 and 34 h prior to ovum pick-up (OPU), respectively. This treatment modality has been implemented in patients with low/poor oocytes yield. This study aimed to determine whether the double trigger could improve the number of top-quality embryos (TQEs) in patients with fewer than three TQEs. METHODS: The stimulation characteristics of 35 in vitro fertilization (IVF) cycles were analyzed. These cycles were triggered by the combination of hCG and GnRHa (double trigger cycles) and compared to the same patients' previous IVF attempt, which utilized the hCG trigger (hCG trigger control cycles). The analysis involved cases who were admitted to our reproductive center between January 2018 and December 2022. In the hCG trigger control cycles, all 35 patients had fewer than three TQEs. RESULTS: Patients who received the double trigger cycles yielded a significantly higher number of 2PN cleavage embryos (3.54 ± 3.37 vs. 2.11 ± 2.15, P = 0.025), TQEs ( 2.23 ± 2.05 vs. 0.89 ± 0.99, P < 0.001), and a simultaneously higher proportion of the number of cleavage stage embryos (53.87% ± 31.38% vs. 39.80% ± 29.60%, P = 0.043), 2PN cleavage stage embryos (43.89% ± 33.01% vs. 27.22% ± 27.13%, P = 0.014), and TQEs (27.05% ± 26.26% vs. 14.19% ± 19.76%, P = 0.019) to the number of oocytes retrieved compared with the hCG trigger control cycles, respectively. The double trigger cycles achieved higher rates of cumulative clinical pregnancy (20.00% vs. 2.86%, P = 0.031), cumulative persistent pregnancy (14.29% vs. 0%, P < 0.001), and cumulative live birth (14.29% vs. 0%, P < 0.001) per stimulation cycle compared with the hCG trigger control cycles. CONCLUSION: Co-administration of GnRH-agonist and hCG for final oocyte maturation, 40 and 34 h prior to OPU, respectively (double trigger) may be suggested as a valuable new regimen for treating patients with low TQE yield in previous hCG trigger IVF/intracytoplasmic sperm injection (ICSI) cycles.

Iodine and other factors associated with fertility outcome following oil-soluble contrast medium hysterosalpingography: a prospective cohort study.

Objective: To examine factors associated with fertility following hysterosalpingography (HSG) using an oil-soluble contrast medium (OSCM). Design: In a prospective cohort study on 196 women undergoing OSCM HSG, we showed that iodine excess was almost universal (98%) and mild subclinical hypothyroidism was frequent (38%). Here, we report the analyses of secondary outcomes examining factors associated with the likelihood of pregnancy following the HSG. Setting: Auckland, New Zealand (2019-2021). Sample: 196 women with primary or secondary infertility who underwent OSCM HSG. Methods: Baseline and serial urine iodine concentrations (UIC) and thyroid function tests were measured over six months following the HSG. Pregnancy and treatment with levothyroxine during the study period were documented. Results: Following OSCM HSG, pregnancy rates were 49% in women aged <40 years (77/158) but considerably lower (16%) among those ≥40 years (6/38). Similarly, live birth rates were markedly lower in women ≥40 years (17%; 1/6) versus <40 years (73%; 56/77). 29% of participants were iodine deficient at baseline despite advice recommending iodine fortification. Following HSG, the likelihood of pregnancy in women with moderate iodine deficiency was 64% higher than in women with normal iodine levels (p=0.048). Among women aged <40 years who had subclinical hypothyroidism (n=75), levothyroxine treatment was associated with higher pregnancy rates compared to untreated women [63% (26/48) vs 37% (10/27), respectively; p=0.047]. Conclusion: OSCM HSG was associated with higher pregnancy rates in women ≤40 than in those aged >40 years. Iodine deficiency was relatively common in this cohort, and increased iodine levels from OSCM exposure may contribute to the improved fertility observed with this procedure. Trial registration: This study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR: 12620000738921) https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000738921.

Effect of oral glucose tolerance test-based insulin resistance on embryo quality in women with/without polycystic ovary syndrome.

Objective: To explore the effects of insulin resistance (IR) on embryo quality and pregnancy outcomes in women with or without polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Methods: A retrospective cohort study concerning patients with/without PCOS who received gonadotropin-releasing hormone (GnRH)-antagonist protocol for IVF/ICSI from January 2019 to July 2022 was conducted. All the patients included underwent oral glucose tolerance test plus the assessment of insulin release within 6 months before the controlled ovarian stimulation. The Matsuda Index was calculated to diagnose IR. Two populations (PCOS and non-PCOS) were included and each was divided into IR and non-IR groups and analyzed respectively. The primary outcome was the high-quality day 3 embryo rate. Results: A total of 895 patients were included (751 with PCOS and 144 without PCOS). For patients with PCOS, the IR group had a lower high-quality day 3 embryo rate (36.8% vs. 39.7%, p=0.005) and available day 3 embryo rate (67.2% vs. 70.6%, p<0.001). For patients without PCOS, there was no significant difference between the IR and non-IR groups in high-quality day 3 embryo rate (p=0.414) and available day 3 embryo rate (p=0.560). There was no significant difference in blastocyst outcomes and pregnancy outcomes for both populations. Conclusion: Based on the diagnosis by the Matsuda Index, IR may adversely affect the day 3 embryo quality in patients with PCOS but not pregnancy outcomes. In women without PCOS, IR alone seems to have less significant adverse effects on embryo quality than in patients with PCOS. Better-designed studies are still needed to compare the differences statistically between PCOS and non-PCOS populations.

The impact of clomiphene citrate on the endometrium in comparison to gonadotropins in intrauterine insemination cycles: is it thinner and does it matter?

Objective: To determine whether endometrial thickness (EMT) differs between i) clomiphene citrate (CC) and gonadotropin (Gn) utilizing patients as their own controls, and ii) patients who conceived with CC and those who did not. Furthermore, to investigate the association between late-follicular EMT and pregnancy outcomes, in CC and Gn cycles. Methods: Retrospective study. Three sets of analyses were conducted separately for the purpose of this study. In analysis 1, we included all cycles from women who initially underwent CC/IUI (CC1, n=1252), followed by Gn/IUI (Gn1, n=1307), to compare EMT differences between CC/IUI and Gn/IUI, utilizing women as their own controls. In analysis 2, we included all CC/IUI cycles (CC2, n=686) from women who eventually conceived with CC during the same study period, to evaluate EMT differences between patients who conceived with CC (CC2) and those who did not (CC1). In analysis 3, pregnancy outcomes among different EMT quartiles were evaluated in CC/IUI and Gn/IUI cycles, separately, to investigate the potential association between EMT and pregnancy outcomes. Results: In analysis 1, when CC1 was compared to Gn1 cycles, EMT was noted to be significantly thinner [Median (IQR): 6.8 (5.5-8.0) vs. 8.3 (7.0-10.0) mm, p<0.001]. Within-patient, CC1 compared to Gn1 EMT was on average 1.7mm thinner. Generalized linear mixed models, adjusted for confounders, revealed similar results (coefficient: 1.69, 95% CI: 1.52-1.85, CC1 as ref.). In analysis 2, CC1 was compared to CC2 EMT, the former being thinner both before [Median (IQR): 6.8 (5.5-8.0) vs. 7.2 (6.0-8.9) mm, p<0.001] and after adjustment (coefficient: 0.59, 95%CI: 0.34-0.85, CC1 as ref.). In analysis 3, clinical pregnancy rates (CPRs) and ongoing pregnancy rates (OPRs) improved as EMT quartiles increased (Q1 to Q4) among CC cycles (p<0.001, p<0.001, respectively), while no such trend was observed among Gn cycles (p=0.94, p=0.68, respectively). Generalized estimating equations models, adjusted for confounders, suggested that EMT was positively associated with CPR and OPR in CC cycles, but not in Gn cycles. Conclusions: Within-patient, CC generally resulted in thinner EMT compared to Gn. Thinner endometrium was associated with decreased OPR in CC cycles, while no such association was detected in Gn cycles.

Rectal versus vaginal progesterone administration for luteal phase support in the hormone replacement therapy frozen embryo transfer (HRT-FET) cycle: protocol for a non-inferiority randomised controlled trial.

INTRODUCTION: This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly. METHODS AND ANALYSIS: This study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled. ETHICS AND DISSEMINATION: The trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal. TRIAL REGISTRATION NUMBER: EUCT number: 2023-504616-15-02.

Melatonin improves fertilization rate in assisted reproduction: Systematic review and meta-analysis.

BACKGROUND: Melatonin is a hormone produced by the pineal gland and it has antioxidant properties. AIM: This study aimed to evaluate the effects of melatonin on assisted reproductive technologies through a systematic review and a meta-analysis. MATERIALS AND METHODS: Search strategies were used in PubMed and in other databases covering the last 15 years. After screening for eligibility, 17 articles were selected for the systematic review. For the meta-analysis statistics, two groups were formed, the treatment group (with melatonin) and the control group (without melatonin) for various assisted reproduction outcomes. RESULTS: The main results were that no statistical differences were found concerning the clinical pregnancy outcome (p = 0.64), but there was a statistical difference with respect to Mature Oocytes (MII) (p = 0.001), antral follicle count (p = 0.0002), and the fertilization rate (p ≤ 0.0001). CONCLUSIONS: Melatonin had beneficial effects such as the improvement in the fertilization rate, although the authors did not obtain significance in the clinical pregnancy rate.

Effect of different treatment protocols on in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes in adenomyosis women: a systematic review and meta-analysis.

OBJECTIVES: Pregnancy outcomes of different ovarian stimulation protocols for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in patients with adenomyosis are not explicit. This meta-analysis aimed to systematically evaluate the effects of different IVF/ICSI protocols on pregnancy outcomes. DESIGN: Meta-analysis. DATA SOURCES: PubMed, Web of Science and Cochrane library were searched up to October 2023. ELIGIBILITY CRITERIA: Comparative studies on IVF/ICSI outcomes in the adenomyosis population were eligible. Studies on preimplantation genetic testing, reviews, case reports and animal experiments were excluded. DATA EXTRACTION AND SYNTHESIS: Valid information was extracted by two independent authors according to a standard data format. All analyses were conducted using Review Manager (RevMan, V.5.3). RESULTS: Compared with the non-adenomyosis population, adenomyosis was responsible for a 26% reduction in clinical pregnancy rate (CPR; 42.47% vs 55.89%, OR: 0.74, 95% CI: 0.66 to 0.82, p<0.00001), a 35% reduction in live birth rate (LBR; 30.72% vs 47.77%, OR: 0.65, 95% CI: 0.58 to 0.73, p<0.00001) and a 1.9-fold increase in miscarriage rate (MR; 27.82% vs 13.9%, OR: 1.90, 95% CI: 1.56 to 2.31, p<0.00001). Subgroup analysis suggested that, in fresh embryo transfer (ET) cycles, the CPR (34.4% vs 58.25%) in the long/short/antagonist protocol group was poorer than that in the ultralong protocol group. In frozen ET (FET) cycles, there were no statistical differences in CPR ((GnRHa+FET) AM(adenomyosis) vs non-AM: 51.32% vs 43.48%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 50.25% vs 60.10%, p=0.82), MR ((GnRHa+FET) AM vs non-AM:12.82% vs 12.50%, p=0.97; (non-GnRHa+FET) AM vs non-AM: 30.5% vs 15.54%, p=0.15) and LBR ((GnRHa+FET) AM vs non-AM:44.74% vs 36.96%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 34.42% vs 50.25%, p=0.28). The MR in the adenomyosis group was high in the fresh ET and FET cycles. CONCLUSIONS: FET might be a better choice for women with adenomyosis, especially those pretreated with GnRHa. In fresh ET cycles, pregnancy outcomes of the long/short/antagonist protocols were poorer than those of the ultralong protocol. TRIAL REGISTRATION NUMBER: CRD42022340743.