Pregnancy outcome and cost-effectiveness comparisons of artificial cycle-prepared frozen embryo transfer with or without GnRH agonist pretreatment for polycystic ovary syndrome: a randomised controlled trial.

OBJECTIVE: To compare the live birth rate and cost effectiveness of artificial cycle-prepared frozen embryo transfer (AC-FET) with or without GnRH agonist (GnRH-a) pretreatment for women with polycystic ovary syndrome (PCOS). DESIGN: Open-label, randomised, controlled trial. SETTING: Reproductive centre of a university-affiliated hospital. SAMPLE: A total of 343 women with PCOS, aged 24-40 years, scheduled for AC-FET and receiving no more than two blastocysts. METHODS: The pretreatment group (n = 172) received GnRH-a pretreatment and the control group (n = 171) did not. Analysis followed the intention-to-treat (ITT) principle. MAIN OUTCOME MEASURES: The primary outcome measure was live birth rate. Secondary outcome measures included clinical pregnancy rate, implantation rate, early pregnancy loss rate and direct treatment costs per FET cycle. RESULTS: Among the 343 women randomised, 330 (96.2%) underwent embryo transfer and 328 (95.6%) completed the protocols. Live birth rate according to ITT did not differ between the pretreatment and control groups [85/172 (49.4%) versus 92/171 (53.8%), absolute rate difference -4.4%, 95% CI -10.8% to 2.0% (P = 0.45). Implantation rate, clinical pregnancy rate and early pregnancy loss rate also did not differ between groups, but median direct cost per FET cycle was significantly higher in the pretreatment group (7799.2 versus 4438.9 RMB, OR = 1.9, 95%CI 1.2-3.4, P < 0.001). Median direct cost per live birth was also significantly higher in the pretreatment group (15663.1 versus 8189.9 RMB, odds ratio [OR] = 1.9, 95% CI 1.2-3.8, P < 0.001). CONCLUSIONS: Pretreatment with GnRH-a does not improve pregnancy outcomes for women with PCOS receiving AC-FET, but significantly increases patient cost. TWEETABLE ABSTRACT: For women with PCOS, artificial cycle-prepared FET with GnRH agonist pretreatment provides no pregnancy outcome benefit but incurs higher cost.

Perinatal outcomes of neonates born from different endometrial preparation protocols after frozen embryo transfer: a retrospective cohort study.

BACKGROUND: Previous studies have focused on pregnancy outcomes after frozen embryo transfer (FET) performed using different endometrial preparation protocols. Few studies have evaluated the effect of endometrial preparation on pregnancy-related complications. This study was designed to explore the association between different endometrial preparation protocols and adverse obstetric and perinatal complications after FET. METHODS: We retrospectively included all FET cycles (n = 12,950) in our hospital between 2010 and 2017, and categorized them into three groups, natural cycles (NC), hormone replacement therapy (HRT) and ovarian stimulation (OS) protocols. Pregnancy-related complications and subsequent neonatal outcomes were compared among groups. RESULTS: Among all 12,950 FET cycles, the live birth rate was slightly lower for HRT cycles than for NC (HRT vs. NC: 28.15% vs. 31.16%, p < 0.001). The pregnancy loss rate was significantly higher in OS or HRT cycles than in NC (HRT vs. NC: 17.14% vs. 10.89%, p < 0.001; OS vs. NC: 16.44% vs. 10.89%, p = 0.001). Among 3864 women with live birth, preparing the endometrium using OS or HRT protocols increased the risk of preeclampsia, and intrahepatic cholestasis of pregnancy (ICP) in both singleton and multiple deliveries. Additionally, OS and HRT protocols increased the risk of low birth weight (LBW) and small for gestational age (SGA) in both singletons and multiples after FET. CONCLUSION: Compared with HRT or OS protocols, preparing the endometrium with NC was associated with the decreased risk of pregnancy-related complications, as well as the decreased risk of LBW and SGA after FET.

Live birth rate of twin pregnancies after frozen embryo transfer: natural cycle versus ovulation induction regimens.

PURPOSE: Ovulation induction (OI) using letrozole or human menopausal hormone (hMG) is recently developed for endometrium preparation in frozen embryo transfer (FET) cycles. The purpose of this study is to compare the live birth rate of twin pregnancies between modified natural and OI regimens for endometrium preparation in FET cycles. STUDY DESIGN: This study included all consecutive twin pregnancies following FET with modified natural cycle (mNC-FET) or OI (OI-FET) regimen for endometrium preparation between January 2015 to June 2019. Primary outcome was the live birth of at least one twin per pregnancy. Multivariable logistic regression analysis was used to evaluate the potential association of endometrium preparation regimen and live birth. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. RESULTS: During the study period, 269 twin pregnancies after mNC-FET and 177 twin pregnancies after OI-FET were included. The live birth rate of at least one twin per pregnancy was not significantly different between mNC-FET and OI-FET groups, 92.2% vs 90.4%; aOR 0.65; 95%CI 0.32-1.34. The multivariable regression analysis showed that twin pregnancies after OI-FET had decreased odds for gestational diabetes mellitus (aOR 0.37; 95% CI 0.16-0.87) in comparison to twin pregnancies after mNC-FET. In subgroup analysis, we found that the rate of live birth of at least one twin per pregnancy was significantly higher in OI-FET cycles using letrozole compared to those using hMG (94% vs 83.3%; aOR 3.45; 95%CI 1.24-9.57). CONCLUSION: The live birth rate in twin pregnancies after FET is comparable between mNC or OI regimens for endometrium preparation.

Association Between Pregnancy Outcomes and the Time of Progesterone Exposure of D6 Single-Blastocyst Transfer in Frozen-Thawed Cycles: A Retrospective Cohort Study.

Purpose: The objective of this study was to assess reproductive outcomes of D6 blastocysts transferred on day 6 in comparison to those transferred on day 7 of progesterone exposure in frozen-thawed embryo transfer cycles. Patients and Methods: This retrospective cohort study included 2029 D6 single blastocysts from the first frozen-thawed embryo transfer cycles of patients at the Hospital for Reproductive Medicine Affiliated to Shandong University from February 2017 to January 2020. Participants were divided into Group A (blastocyst transferred on the 6th day of progesterone exposure, n=1634) and Group B (blastocyst transferred on the 7th day of progesterone exposure, n=395). Results: The live birth rate was comparable between Group A and Group B (38.7% versus 38.7%, P=0.999). Subgroup analysis revealed a significantly higher preterm birth rate in D6 single blastocysts transferred on the 7th day than in those transferred on the 6th day of progesterone exposure for natural cycle frozen-thawed embryo transfer (5.2% versus 11.3%, P=0.020). After adjustment for potential confounders, the differences in the preterm birth rate in natural cycles persisted (adjusted odds ratio 2.347, 95% confidence interval 1.129-4.877, P=0.022). Conclusion: In frozen-thawed embryo transfer cycles, transferring on the 6th or 7th day of progesterone exposure of D6 blastocysts did not affect the live birth rate; however, when a natural cycle protocol is adopted, the possible preterm risk of transferring D6 blastocysts on the 7th day of progesterone exposure should be noted.

Effect of GnRH agonist down-regulation combined with hormone replacement treatment on reproductive outcomes of frozen blastocyst transfer cycles in women of different ages.

Objective: To investigate the effect of GnRH agonist (GnRH-a) down-regulation prior to hormone replacement treatment (HRT) to prepare the endometrium in frozen embryo transfer (FET) cycles in women of different ages. Methods: This was a retrospective study, and after excluding patients with adenomyosis, endometriosis, severe endometrial adhesions, polycystic ovary syndrome (PCOS), and repeated embryo implantation failures, a total of 4,091 HRT cycles were collected. Patients were divided into group A (<35 years old) and group B (≥35 years old), and each group was further divided into HRT and GnRHa-HRT groups. The clinical outcomes were compared between groups. Results: There was no statistically significant difference in clinical outcomes between the HRT and GnRHa-HRT groups among women aged <35 years. In women of advanced age, higher rates of clinical pregnancy and live birth were seen in the GnRHa-HRT group. Logistic regression analysis showed that female age and number of embryos transferred influenced the live birth rate in FET cycles, and in women aged ≥ 35 years, the use of GnRH-a down-regulation prior to HRT improved pregnancy outcomes. Conclusions: In elderly woman without adenomyosis, endometriosis, PCOS, severe uterine adhesions, and RIF, hormone replacement treatment with GnRH agonist for pituitary suppression can improve the live birth rate of FET cycles.

Obstetric and neonatal outcomes after programmed frozen embryo transfer with or without GnRH agonist for polycystic ovary syndrome: secondary analysis results from a randomized controlled trial.

BACKGROUND: Recent studies have reported higher risks of adverse maternal and neonatal outcomes, such as hypertensive disorders of pregnancy, after programmed frozen embryo transfer, especially in cycles with gonadotropin-releasing hormone agonist pretreatment. It remains unclear if GnRH agonist pretreatment before programmed frozen embryo transfer further increases the risk for obstetrical complications among women with polycystic ovary syndrome. OBJECTIVE: This study aimed to compare the obstetrical and neonatal complications of singleton and twin pregnancies after programmed frozen embryo transfer with or without gonadotropin-releasing hormone-a pretreatment among women with polycystic ovary syndrome. STUDY DESIGN: This was a secondary analysis of a single-center, randomized controlled trial comparing the live birth rate and cost-effectiveness of programmed cycle-prepared frozen embryo transfers with or without gonadotropin-releasing hormone agonist pretreatment among women with polycystic ovary syndrome. The analysis was restricted to women with polycystic ovary syndrome, aged 24 to 40 years, who delivered live neonates after frozen-thawed blastocyst transfer. The obstetrical and neonatal outcomes were compared between programmed cycles with and those without gonadotropin-releasing hormone agonist pretreatment. The adjusted odds ratios with 95% confidence intervals were calculated and adjustments were made for relevant confounders. RESULTS: The maternal and neonatal complications associated with 177 live single births and 38 twin births (253 newborns in total) were analyzed. There were no significant differences in the frequencies of obstetrical complications, including hypertensive disorders of pregnancy, between the gonadotropin-releasing hormone agonist pretreatment and no pretreatment group for both singleton and twin pregnancies. However, there was a significantly greater incidence of having a low birthweight neonate among singleton infants born after gonadotropin-releasing hormone agonist pretreatment when compared with no pretreatment (10.2% vs 1.3%; P=0.042), and a low birthweight among singleton infants was still more likely after adjusting for confounders (relative ratio, 3.85; 95% confidence interval, 1.13-7.11; P=.024). Other neonatal complications were all comparable between the pretreatment and no pretreatment groups for both singleton and twin pregnancies. CONCLUSION: For women with polycystic ovary syndrome, programmed frozen embryo transfer cycles with gonadotropin-releasing hormone agonist pretreatment could lead to a greater risk of having a low birthweight singleton neonate.

Hormonal Replacement Treatment for Frozen-Thawed Embryo Transfer With or Without GnRH Agonist Pretreatment: A Retrospective Cohort Study Stratified by Times of Embryo Implantation Failures.

Objective: To evaluate the efficacy of the long-acting gonadotropin-releasing hormone agonist (GnRH-a) administration before hormone replacement treatment for frozen-thawed embryo transfer in women with different times of embryo implantation failures. Methods: A retrospective cohort study was performed between January 2015 and December 2019. A total of 9263 women who underwent frozen-thawed embryo transfer were included in the study. The study is divided into three parts based on the times of embryo implantation failures. The sample sizes were 4611 for no implantation failure, 3565 for one failure and 1087 for multiple failures. Two endometrium preparation protocols, HRT and HRT with GnRH-a pretreatment (G-HRT), were compared. Confounding factors were treated by propensity score matching and generalized estimation equation. Results: For women with no failure of embryo implantation, the live birth rate was not statistically different when they underwent HRT and G-HRT (HRT: 42.75% [498/1165], G-HRT: 45.24% [527/1165], P=0.2261). Similar outcome also appeared in women with one failure of embryo implantation (HRT: 47.22% [535/1133], G-HRT: 50.31% [570/1131], P=0.1413). For women with multiple failures of embryo implantation, the live birth rate was significantly difference (HRT: 38.74% [117/302], G-HRT: 45.48% [357/785], P=0.0449). When stratified by age, the live birth rate is similar for women older than 37 years. Generalized estimation equation showed that GnRH agonist pretreatment was independently associated with the live birth rate for women with multiple failures (adjust OR: 1.5, 95%CI: [1.12-2.00]). Conclusion: For women with no/one failure of embryo implantation, the live birth rate is similar between HRT and G-HRT protocols. For women with multiple failure of embryo implantation, GnRH agonist pretreatment is beneficial to raise the live birth rate.

A comparison of the effects of three different estrogen used for endometrium preparation on the outcome of day 5 frozen embryo transfer cycle.

OBJECTIVE: To evaluate the effects of three different estrogen used for endometrium preparation on pregnancy rate, as well as hormone profile on day 5 frozen embryo transfer (FET) cycles. METHODS: Retrospective, observational study. Setting: A tertiary teaching and research private reproductive medicine center. Patients: Ninety patients who were undergoing endometrium preparation for day five frozen embryo transfer cycle (FET). Intervention(s): The women were divided in three groups according to the administration route of estrogen (E2): oral (Primogyna), transdermal patches (Estradot), or transdermal gel (Oestrogel Pump). These administration routines of estrogen are equivalent to 6mg of estradiol daily. All women received 600mg of vaginal progesterone (P) per day (Utrogestan) for luteal phase support. We drew blood samples on starting P day, as well as on beta hCG day for E2 and P measurements. Main Outcome Measure(s): Clinical pregnancy rates (PR). RESULTS: Patient features in the three groups were comparable. There were no significant differences concerning implantation rate, clinical PR, miscarriage rate, multiple-pregnancy rate, or E2 and P levels on starting P day and on beta hCG day. CONCLUSIONS: In FET cycles with oral (Primogyna) or transdermal patches (Estradot), or transdermal gel (Oestrogel Pump), there was no significant difference on pregnancy rates.

Letrozole for Female Infertility.

Letrozole, an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, has been used in the applications of a wide range of infertility settings. It has been more than 20 years since the initial clinical trial of letrozole for ovulation induction. In light of the accumulating clinical and basic evidence, the efficacy and safety of letrozole have been identified. This mini review focuses on our current knowledge of the applications and mechanisms of letrozole for female infertility and various questions are put forward about how letrozole could be more effectively used.

Programming the endometrium for deferred transfer of cryopreserved embryos: hormone replacement versus modified natural cycles.

Over the last decade the use of frozen-thawed embryo transfer has substantially increased, and currently up to one in two embryos transferred has been cryopreserved. To support implantation, endometrial and embryo maturity are required to be synchronized. This can be achieved in various ways. The most commonly applied endometrial preparation methods are the "natural cycle," in which the sequential estrogen and P necessary for endometrial maturation are derived from the developing follicle, and the "artificial" cycle, in which these are sequentially administered. Review of the published data comparing these approaches does not identify a superior approach in terms of clinical outcomes. However, although the "natural cycle" avoids the need for luteal support, the artificial cycle provides more control over timing of ET, and the "modified" natural cycle, in which ovulation is triggered exogenously, may offer both of these advantages. The optimal monitoring strategy for freeze-thaw cycles remains unclear, because only a few studies have addressed this question. Further studies are also required to determine the ideal dosage, method of administration, and duration of estrogen and P supplementation in artificial cycle frozen embryo transfer.

Effects of three kinds of endometrial preparation on pregnancy outcomes of patients with frozen-thawed embryo transfer / 吉林大学学报(医学版)

Objective: To investigate the effects of three kinds of endometrial preparation (normal hormone replacement, half- and full-dose of long-acting gonadotropin-releasing hormone agonist (GnRH-a) down-regulation combined with hormone replacement) on the pregnancy outcomes in the frozen-thawed embryo transfer (FET) cycle in the patients with endometriosis (E M T), adenomyosis or repeated implantation failure (RIF) for unknown reasons, and to provide a basis for the selection of clinical endometrial preparation method. Methods: A total of 191 patients with EMT, adenomyosis or RIF for unknown reasons underwent FET treatment were selected. The patients were divided into normal hormone replacement group (n=63), half-dose GnRH-a group (n=61) and full-dose GnRH-a group (n=67) according to the endometrial preparation method. The clinical data of patients in each group such as age, body mass index (BMI), duration of infertility, the number of embryo transfer cycles, the number of embryos transferred, the endometrial thickness on the day of conversion and transplantation, the rate of high-quality embryos transferred, the intrauterine clinical pregnancy rate and the embryo implantation rate were analyzed retrospectively and compared. Results: There were no significant differences of the general clinical data of the patients in FET cycles in three groups such as age, BMI, duration of infertility, the number of embryo transfer cycles, the number of embryos transferred, the endometrial thickness on the day of conversion and transplantation, and the rate of high-quality embryos transferred (P