The effect of polycystic ovary syndrome without hyperandrogenism on pregnancy-related outcomes: a retrospective cohort study.

OBJECTIVE: To evaluate the effect of polycystic ovary syndrome (PCOS) without hyperandrogenism on pregnancy-related outcomes. DESIGN: A retrospective cohort study. SETTING: Reproductive Medicine Centre of Tongji Hospital. POPULATION: Women without hyperandrogenism undergoing their first single blastocyst transfers in frozen-thawed cycles were divided into a PCOS group and a non-PCOS group according to the Rotterdam criteria. METHODS: The pregnancy-related outcomes of women with and without PCOS were compared. Propensity score matching and multiple logistic regression models were used to eliminate essential impacts on pregnancy-related outcomes. MAIN OUTCOME MEASURES: Pregnancy-related outcomes included pregnancy loss and abnormal perinatal outcomes. RESULTS: A total of 4083 women without hyperandrogenism met the study criteria, among whom 557 met the diagnostic criteria for PCOS. Women with PCOS had higher rates of clinical pregnancy (P = 0.035) and cumulative live births (P = 0.023). However, there were no significant differences in the rates of biochemical pregnancy, twins and pregnancy loss between the two groups. Among women with singleton pregnancies, the incidences of preterm birth, hypertensive disorders of pregnancy, gestational diabetes, placenta praevia, fetal malformation, macrosomia and low birthweight did not differ significantly between the two groups. The results remained unchanged even after adjustments were made for propensity score matching and multiple logistic regression analyses. CONCLUSION: Women with PCOS without hyperandrogenism may achieve higher rates of clinical pregnancy and cumulative live birth than those without PCOS, without increases in their rates of biochemical pregnancy, pregnancy loss or other abnormal perinatal outcomes. TWEETABLE ABSTRACT: PCOS without hyperandrogenism was not associated with abnormal pregnancy-related outcomes.

The depot GnRH agonist protocol improves the live birth rate per fresh embryo transfer cycle, but not the cumulative live birth rate in normal responders: a randomized controlled trial and molecular mechanism study.

STUDY QUESTION: Do cumulative live birth rates (CLBRs) after one complete ART cycle differ between the three commonly used controlled ovarian stimulation (COS) protocols (GnRH antagonist, depot GnRHa (GnRH agonist) and long GnRHa) in normal responders undergoing IVF/ICSI? SUMMARY ANSWER: There were similar CLBRs between the GnRH antagonist, depot GnRHa and long GnRHa protocols. WHAT IS KNOWN ALREADY: There is no consensus on which COS protocol is the most optimal in women with normal ovarian response. The CLBR provides the final success rate after one complete ART cycle, including the fresh and all subsequent frozen-thawed embryo transfer (ET) cycles. We suggest that the CLBR measure would allow for better comparisons between the different treatment protocols. STUDY DESIGN, SIZE, DURATION: A prospective controlled, randomized, open label trial was performed between May 2016 and May 2017. A total of 819 patients were allocated to the GnRH antagonist, depot GnRHa or long GnRHa protocol in a 1:1:1 ratio. The minimum follow-up time from the first IVF cycle was 2 years. To further investigate the potential effect of COS with the GnRH antagonist, depot GnRHa or long GnRHa protocol on endometrial receptivity, the expression of homeobox A10 (HOXA10), myeloid ecotropic viral integration site 1 (MEIS1) and leukemia inhibitory factor (LIF) endometrial receptivity markers was evaluated in endometrial tissue from patients treated with the different COS protocols. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women with normal ovarian response (n = 819) undergoing IVF/ICSI treatment were randomized to the GnRH antagonist, depot GnRHa or long GnRHa protocol. Both IVF and ICSI cycles were included, and the sperm samples used were either fresh or frozen partner ejaculates or frozen donor ejaculates. The primary outcome was the live birth rate (LBR) per fresh ET cycle, and the CLBR after one complete ART cycle, until the birth of a first child (after 28 weeks) or until all frozen embryos were used, whichever occurred first. Pipelle endometrial biopsies from 34 female patients were obtained on Days 7-8 after oocyte retrieval or spontaneous ovulation in natural cycles, respectively, and HOXA10, MEIS1 and LIF mRNA and protein expression levels in the human endometrium was determined by quantitative real-time PCR and western blot, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in CLBRs between the GnRH antagonist, depot GnRHa or long GnRHa protocol (71.4 versus 75.5 versus 72.2%, respectively). However, there was a significantly higher LBR per fresh ET cycle in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (62.6 versus 52.1% versus 45.6%, P < 0.05). Furthermore, HOXA10, MEIS1 and LIF mRNA and protein expression in endometrium all showed significantly higher in the depot GnRHa protocol than in the long GnRHa and GnRH antagonist protocols (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: A limitation of our study was that both our clinicians and patients were not blinded to the randomization for the randomized controlled trial (RCT). An inclusion criterion for the current retrospective cohort study was based on the 'actual ovarian response' during COS treatment, while the included population for the RCT was 'expected normal responders' based on maternal age and ovarian reserve test. In addition, the analysis was restricted to patients under 40 years of age undergoing their first IVF cycle. Furthermore, the endometrial tissue was collected from patients who cancelled the fresh ET, which may include some patients at risk for ovarian hyperstimulation syndrome, however only patients with 4-19 oocytes retrieved were included in the molecular study. WIDER IMPLICATIONS OF THE FINDINGS: The depot GnRH agonist protocol improves the live birth rate per fresh ET cycle, but not the cumulative live birth rate in normal responders. A possible explanation for the improved LBR after fresh ET in the depot GnRHa protocol could be molecular signalling at the level of endometrial receptivity. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by Grant 81571439 from the National Natural Sciences Foundation of China and Grant 2016YFC1000206-5 from the National Key Research & Development Program of China. The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: The RCT trial was registered at the Chinese Clinical Trial Registry, Study Number: ChiCTR-INR-16008220. TRIAL REGISTRATION DATE: 5 April 2016. DATE OF FIRST PATIENT'S ENROLLMENT: 12 May 2016.

Performing ICSI within 4 hours after denudation optimizes clinical outcomes in ICSI cycles.

BACKGROUND: The study aimed to investigate whether and how general and partial time intervals between processes, from human chorionic gonadotrophin (HCG) trigger to intracytoplasmic sperm injection (ICSI), affected the laboratory and reproductive outcomes in ICSI cycles. METHODS: This was a retrospective data analysis of 3602 women who underwent ICSI treatment cycles using partner or donor sperms, performed at Reproduction Medicine Center of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology (Wuhan, China) between October 2016 and September 2018. The clinical pregnancy rate was the major outcome in the study. The fertilization and available embryo rates were secondary outcomes. RESULTS: Data from 3602 consecutive fresh ICSI cycles was analysed. Multivariate linear regression and logistic regression analysis of factors related to fertilization and clinical pregnancy rates showed that fertilization rate (P = 0.001) and clinical pregnancy rate (P = 0.037) were significantly associated with denudation (DN)-ICSI interval. Long DN-ICSI interval was associated with higher rate of fertilization than short DN-ICSI interval but significantly decreased clinical pregnancy rate when the interval is over 4 h (P < 0.05). CONCLUSIONS: DN-ICSI time interval can act as an independent predictor for clinical outcomes in ICSI cycles. The optimal time for ICSI is within 4 h after oocyte denudation for excellent laboratory and reproductive outcomes in ICSI cycles.

Pregnancy and perinatal outcomes in pregnancies resulting from time interval between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer.

BACKGROUND: Adverse obstetric outcomes are correlated with altered circulating hormone levels at the time implantation by the trophectoderm. What' more, embryo freezing process may also have adverse effect on perinatal outcomes. This study aims to evaluate whether increasing interval time between a freeze-all cycle and a subsequent frozen-thawed single blastocyst transfer could have any effect on pregnancy and perinatal outcomes. METHODS: This was a retrospective cohort study included the first single blastocyst transfer in artificially cycles of all patients who underwent a freeze-all cycle between January 1st, 2016 and September 30th, 2018. All patients were divided into two groups according to the time interval between oocyte retrieval and the day of first frozen-thawed embryo transferred (FET): Group 1 (immediate FET cycles) and Group 2 (delayed FET cycles). RESULTS: No significant differences were reported between the two groups regarding the rates of clinical pregnancy, live birth, biochemical pregnancy and pregnancy loss even after adjusting for measured confounding. When accounting for perinatal outcomes, gestational age, birth weight, delivery mode, fetus gender, preterm birth, gestational hypertension, GDM, placenta previa, fetal malformation and low birthweight also did not vary significantly between the two groups. Only the incidence of macrosomia was more frequently in the Group 2 compared with the Group 1 (AOR 3.886, 95%CI 1.153-13.103, P = 0.029) after adjusting with a multiple logistic regression model. CONCLUSIONS: We found delayed FET cycles for blastocyst transfer following freeze-all cycles may not improve the pregnancy outcomes. On the contrary, postponement of FET cycles may increase the risk of macrosomia. Therefore, FET cycles for blastocyst transfer should be done immediately to avoid adverse effects of delayed time on perinatal outcomes.

GnRH antagonist versus follicular-phase single-dose GnRH agonist protocol in patients of normal ovarian responses during controlled ovarian stimulation.

OBJECTIVE: This study aims to explore the differences of the ovarian stimulation (OS) characteristics, laboratory, and clinical outcomes between follicular-phase single-dose gonadotropin-releasing hormone (GnRH) agonist protocol and GnRH antagonist protocol during controlled ovarian hyperstimulation (COH). METHODS: About 1883 consecutive IVF/ICSI fresh cycles of normal ovarian responders were retrospectively analyzed, with 1229 in the single-dose GnRH agonist protocol group and 654 in the GnRH antagonist protocol group at Reproductive Medical Center of Tongji Hospital from 1 January 2014 to 31 December 2017. RESULTS: The follicular-phase single-dose GnRH agonist group showed significantly more oocytes obtained, higher implantation rate and pregnancy rate, as well as lower luteinizing hormone (LH) level and estradiol (E2)/oocyte ratio on the day of human chorionic gonadotropin (hCG) administration. However, differences were not significant in meiosis II (MII) oocyte rate, two pronuclear zygote (2PN) embryo rate, viable embryo rate or high-quality embryo rate, compared with the GnRH antagonist group. Further comparison of clinical outcomes in the first frozen-thawed cycles did not show significant difference in either implantation or clinical pregnancy rate between the two protocol groups. CONCLUSIONS: Follicular-phase single-dose GnRH agonist protocol may achieve better clinical outcomes in normal ovarian responders, which could be explained more by positive effect on endometrial receptivity rather than embryo quality.

The impact of male infertility or intracytoplasmic sperm injection technique on perinatal outcomes.

OBJECTIVE: The aim of this study was to evaluate the impact of male infertility or intracytoplasmic sperm injection (ICSI) technique on perinatal outcomes. MATERIALS AND METHODS: A retrospective cohort study included patients with singleton live births after fresh-cycle embryo transfer that occurred between 1st January 2016 and 31st May 2018. The patients were divided into four groups: (1) IVF treatment without male infertility; (2) ICSI treatment without male infertility; (3) ICSI treatment with male infertility; and (4) IVF treatment with male infertility. RESULT: In total, 2118 patients were analyzed. When comparing perinatal outcomes between the four groups, there were significant differences with regard to gender proportions of offspring and GDM. No statistically significant differences were reported in the incidence of preterm birth, gestational hypertension, placenta previa, fetal malformation, macrosomia, or low birthweight. A separate multiple logistic regression model was performed for each abnormal perinatal outcome to eliminate confounding factors, with the exception of GDM, the above abnormal perinatal outcomes still did not differ significantly when comparing the four groups. However, the incidence of GDM was higher in the third group than it was in the first group. The proportion of male births was significantly decreased in the third and fourth groups. CONCLUSION: The results showed that ICSI may be associated with the risk of GDM in abnormal perinatal outcomes, but the risk is not due to male infertility. However, male infertility may reduce the proportion of male births.

High Serum Anti-Müllerian Hormone Concentrations Are Associated With Poor Pregnancy Outcome in Fresh IVF/ICSI Cycle but Not Cumulative Live Birth Rate in PCOS Patients.

Objective: To investigate the association between baseline serum Anti-Müllerian hormone (AMH) levels and IVF/ICSI outcomes in women with polycystic ovary syndrome (PCOS). Design: Retrospective study. Setting: Reproductive medicine center in a hospital. Population: 2436 PCOS patients (Rotterdam criteria) who underwent their first fresh IVF/ICSI cycles were divided into three groups on the basis of the <25th (Group 1, n=611), 25 to 75th (Group 2, n=1216), or >75th (Group 3, n=609) percentile of baseline serum AMH level. Interventions: Baseline serum AMH levels measured on the 2-3 days of spontaneous menstrual cycle before IVF/ICSI treatment. Main Outcome Measures: Live birth rate (LBR), cumulative live birth rate (CLBR), clinical pregnancy rate (CPR), and normal fertilization rate (FR). Results: The LBR, CPR, and FR were significantly increased in Group 1 than Group 2 and Group 3, however, CLBR was similar between the three groups. The LBR were 46.6%, 40.5%, and 39.4% in Group 1, Group 2, and Group 3 respectively. The CPR were 53.0%, 47.0%, and 45.5%, respectively. The FR was highest in Group 1 (61.7%, P<0.05), but there was no uniform reverse trend with the AMH level. CLBR were 68.7%, 70.4%, and 71.3%, respectively. Although women in Group 1 were older (p < 0.05) and had higher body mass index (BMI) (p < 0.05), binomial logistic regression analysis used age, BMI, FSH, and AMH as independent variables indicated that only AMH was significantly associated with LBR and CPR. Nevertheless, binomial logistic regression analysis used age, BMI, FSH, AMH, and the number of retrieved oocytes as independent variables indicated that only the number of retrieved oocytes was significantly correlated with CLBR. After stratifying by age, the negative relationship between baseline AMH level and LBR and CPR remained only in the patients <30 years old. Conclusions: Higher baseline AMH level in PCOS women resulted in lower LBR, CPR, and FR but did not influence CLBR.

Efficacy of three COS protocols and predictability of AMH and AFC in women with discordant ovarian reserve markers: a retrospective study on 19,239 patients.

BACKGROUND: Recent studies have consistently shown that AFC and serum AMH are good predictors of ovarian response and have shown strong correlations. However, it is not unusual for reproductive medicine specialists to encounter discordance between them. This is the first study to investigate the efficacies of the different COS protocols when the AFC and AMH levels are discordant. Based on the association between COS protocols and pregnancy outcomes, we attempt to explain the controversial results and clarify the predictive value of AMH and AFC in this context. METHODS: 19,239 patients undergoing their first fresh in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles with GnRH antagonist protocols, GnRH-a long protocols or GnRH-a ultra-long protocols between January 1, 2016, and December 31, 2019, were enrolled and then divided into four groups in accordance with the boundaries for the AFC and serum AMH level provided by the Poseidon Classification. Our study was divided into two parts. Firstly, we retrospectively compared the effects of the three COS protocols in patients with discordant AMH and AFC. Multivariate logistic regression models were conducted in a forward manner to exclude the influence of confounding factors. Afterward, to increase comparability between Group 2 (low AMH and normal AFC) and Group 3 (normal AMH and low AFC), propensity score matching (PSM) analysis was performed based on age, BMI, the number of embryos transferred, and COS protocol. IVF intermediate and reproductive outcomes were compared between Group 2 and Group 3. RESULTS: For people with low AMH and normal AFC (Group 2), the number of total oocytes, clinical pregnancy rate (CPR), live birth rate (LBR) and cumulative live birth rate (CLBR) were significantly higher in GnRH-a ultra-long protocol compared with GnRH antagonist protocol. In multivariate logistic regression models, significant associations of COS protocol with fresh LBR and CPR were found after adjusting for age, BMI, AFC, AMH and the number of embryos transferred. Whereas, in patients with normal AMH and low AFC (Group 3), the number of total oocytes, CLBR, LBR and CPR were highest in the long GnRH-a protocol although there was no statistically significant difference. After PSM, the results showed that although oocytes yield and available embryos in patients with normal AMH and low AFC were significantly higher, there was no significant difference in reproductive outcomes between Group 2 and Group 3. CONCLUSIONS: We found that women with normal AFC and low AMH may benefit from the GnRH-a ultra-long protocol. Nevertheless, for women with normal AMH and low AFC, the long GnRH-a protocol seems to be associated with better clinical outcomes. Furthermore, after eliminating the confounding factors including the COS protocol, we found that AMH can only predict the number of oocytes but not the quality of oocytes when there was discordance between AFC and AMH.

Perinatal outcome in young patients with diminished ovarian reserve undergoing assisted reproductive technology.

OBJECTIVE: To investigate the risk of abnormal perinatal outcomes in young patients with diminished ovarian reserve (DOR). DESIGN: A retrospective cohort study. SETTING: Reproductive medicine center in a hospital. PATIENTS: A total of 5,649 young patients (≤35 years) undergoing assisted reproductive technology for fresh-cycle ET between January 1, 2016, and January 31, 2019, were included. The patients were divided into two groups: the non-DOR group (n = 5,295) and the DOR group (n = 354). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Singleton live births were assessed for obstetrical complications and adverse birth outcomes. RESULT(S): There were significantly lower rates of clinical pregnancy, live birth, and singleton live birth among young patients with DOR, without an increase in the rates of clinical pregnancy loss, biochemical pregnancy, and multiple live births compared with young patients without DOR. For young patients with singleton live births, there were no significant differences in the incidence of gestational hypertension, gestational diabetes mellitus, placenta previa, fetal malformation, macrosomia, low birth weight, or preterm birth between the two groups after adjusting with a multiple logistic regression model. CONCLUSION(S): We found that young patients with DOR still had acceptable pregnancy outcomes and similar risks of biochemical pregnancy, pregnancy loss, multiple live births, and abnormal perinatal outcomes compared with young patients with normal ovarian reserve.