Impact of different progesterone timings on live birth rates for blastocyst frozen embryo transfer cycles.

RESEARCH QUESTION: Do different timings of progesterone administration for day 5 and day 6 blastocysts affect the live birth rate (LBR) of artificial frozen embryo transfer (FET) cycles? DESIGN: This retrospective cohort study included 1362 patients who underwent artificial FET cycles. The effects of 6 and 7 days of progesterone administration prior to blastocyst transfer on clinical outcomes were compared in day 5 and day 6 blastocysts. Univariable and multivariable regression analyses were undertaken. RESULTS: In all patients, LBR was comparable between the two groups (51.8% versus 47.9%, P = 0.165). For day 6 blastocysts, after adjusting for confounders, the 7-day progesterone regimen resulted in a significantly higher LBR (44.8% versus 36.4%, P = 0.039, adjusted OR = 1.494, 95% CI 1.060-2.106) and lower pregnancy loss rate (15.4% versus 25.2%, P = 0.031, adjusted OR = 0.472, 95% CI 0.260-0.856) compared with the 6-day progesterone regimen. For day 5 blastocysts, there were no significant differences in pregnancy outcomes between the two regimens, but the rate of low birthweight was higher with the 7-day progesterone regimen than with the 6-day progesterone regimen (13.9% versus 6.7%, P = 0.032). CONCLUSIONS: In all blastocyst analyses, no difference in LBR was found between the 6- and 7-day progesterone regimens in artificial FET cycles. For day 6 blastocysts, LBR was significantly higher with the 7-day progesterone regimen than with the 6-day progesterone regimen, whereas for day 5 blastocysts, pregnancy outcomes were comparable between the two regimens.

Comparison of Cumulative Live Birth Rates Between Progestin and GnRH Analogues in Preimplantation Genetic Testing Cycles.

CONTEXT: Progestins have recently been used as an alternative for gonadotropin-releasing hormone (GnRH) analogues to prevent premature luteinizing hormone surge due to the application of vitrification technology. However, the long-term efficacy and safety of a progestin-primed ovarian stimulation (PPOS) regimen, including oocyte competence, cumulative live birth rate (LBR), and offspring outcomes, remain to be investigated. OBJECTIVE: To compare cumulative LBR of preimplantation genetic testing (PGT) cycles between a PPOS regimen and GnRH analogues. METHODS: This was a retrospective cohort study at a tertiary academic medical center. A total of 967 patients with good prognosis were categorized into 3 groups, of which 478 patients received a long GnRH agonist, 248 patients received a GnRH antagonist, and 250 received a PPOS regimen. Medroxyprogesterone 17-acetate was the only progestin used in the PPOS regimen. The primary outcome was cumulative LBR. Secondary outcomes included time to live birth, cumulative rates of biochemical and clinical pregnancy and pregnancy loss, and perinatal outcomes. RESULTS: The PPOS regimen was negatively associated with cumulative LBR compared with GnRH antagonists and GnRH agonists (28.4% vs 40.7% and 42.7%). The average time to live birth was significantly shorter with GnRH antagonists than with the PPOS regimen. The cumulative biochemical and clinical pregnancy rates were also lower in the PPOS regimen than GnRH analogues, while cumulative pregnancy loss rates were similar across groups. Furthermore, the number and ratio of good-quality blastocysts were significantly reduced in the PPOS regimen compared with GnRH analogues. In addition, perinatal outcomes were comparable across 3 groups. CONCLUSION: A PPOS regimen may be adversely affect cumulative LBR and blastocyst quality in women with good prognosis compared with GnRH analogues in PGT cycles.

High anti-Mullerian hormone level is adversely associated with cumulative live birth rates of two embryo transfers after the first initiated cycle in patients with polycystic ovary syndrome.

Objective: Anti-Mullerian hormone (AMH) has been recently identified as a potential predictor of live birth rates (LBRs) following assisted reproductive technology (ART) treatment. This study aimed to investigate the association between AMH levels and the outcomes of in vitro fertilization (IVF) in patients with polycystic ovary syndrome (PCOS). Methods: Patients with PCOS initiating their first ovarian stimulation under the gonadotropin-releasing hormone antagonist protocol at the Guangdong Women and Children Hospital, China, were enrolled from November 2014 to September 2018. A total of 157 patients who underwent fresh embryo transfer (ET) cycles were included in group A, whereas 187 patients who underwent frozen-thawed ET cycles were included in group B. After the failure of the first ET cycle, 94 patients underwent the second ET cycle with frozen-thawed embryos. Of these 94 patients, 52 had failed the first fresh ET cycle (group C) and 42 had failed the first frozen-thawed ET cycle (group D). Successful embryo transfer was defined as live birth. This retrospective cohort study addressed the association between AMH levels and pregnancy outcomes using logistic regression approaches. After adjusting for age, body mass index, antral follicle counts, baseline follicle-stimulating hormone levels and baseline progesterone levels, LBRs were compared among the four groups and the cumulative live birth rate after two embryo transfers (TCLBR) was calculated. Results: The LBRs showed no differences among the four groups. Higher serum AMH levels were found to be associated with a lower TCLBR [adjusted OR 0.937 (0.888-0.987), P = 0.015]. In patients who underwent the second ET cycle, LBRs were inversely proportional to AMH levels [crude OR 0.904 (0.828-0.986), P = 0.022 versus adjusted OR 0.845 (0.754-0.946), P = 0.004, respectively]. In addition, the LBR was approximately 61%-78% lower in the group with AMH levels of >12 ng/mL [crude OR 0.391 (0.168-0.912), P = 0.030 versus adjusted OR 0.217 (0.074-0.635), P = 0.005, respectively]. Conclusions: Among PCOS patients high AMH level (>12 ng/ml) is found to be associated with low TCLBR and low LBR of the second embryo transfer cycles. The results provide limited clinical inferences and warrant further investigation.

Comparison of cumulative live birth rates between progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in different populations.

Objective: To compare cumulative live birth rate (LBR) between progestin-primed ovarian stimulation (PPOS) and GnRH antagonist protocols of preimplantation genetic testing (PGT) cycles in different populations. Methods: This was a retrospective cohort study. A total of 865 patients were enrolled and separate analyses were performed for three populations: 498 patients with predicted normal ovarian response (NOR), 285 patients with PCOS, and 82 patients with predicted poor ovarian response (POR). The primary outcome was cumulative LBR for one oocyte retrieval cycle. The results of response to ovarian stimulation were also investigated, including numbers of oocytes retrieved, MII oocytes, 2PN, blastocysts, good-quality blastocysts, and usable blastocysts after biopsy, as well as rates of oocyte yield, blastocyst formation, good-quality blastocysts, and moderate or severe OHSS. Univariable and multivariable logistic regression analyses were used to identify potential confounders that may be independently associated with cumulative live birth. Results: In NOR, the cumulative LBR of PPOS protocol was significantly lower than that of GnRH antagonists (28.4% vs. 40.7%; P=0.004). In multivariable analysis, the PPOS protocol was negatively associated with cumulative LBR (adjusted OR=0.556; 95% CI, 0.377-0.822) compared to GnRH antagonists after adjusting for potential confounders. The number and ratio of good-quality blastocysts were significantly reduced in PPOS protocol compared to GnRH antagonists (2.82 ± 2.83 vs. 3.20 ± 2.79; P=0.032 and 63.9% vs. 68.5%; P=0.021), while numbers of oocytes, MII oocytes and 2PN did not show any significant difference between GnRH antagonist and PPOS protocols. PCOS patients had similar outcomes as NOR. The cumulative LBR of PPOS group appeared to be lower than that of GnRH antagonists (37.4% vs. 46.1%; P=0.151), but not significantly. Meanwhile, the proportion of good-quality blastocysts in PPOS protocol was also lower compared to GnRH antagonists (63.5% vs. 68.9%; P=0.014). In patients with POR, the cumulative LBR of PPOS protocol was comparable to that of GnRH antagonists (19.2% vs. 16.7%; P=0.772). There was no statistical difference in the number and rate of good-quality blastocysts between the two protocols in POR, while the proportion of good-quality blastocysts appeared to be higher in PPOS group compared to GnRH antagonists (66.7% vs. 56.3%; P=0.182). In addition, the number of usable blastocysts after biopsy was comparable between the two protocols in three populations. Conclusion: The cumulative LBR of PPOS protocol in PGT cycles is lower than that of GnRH antagonists in NOR. In patients with PCOS, the cumulative LBR of PPOS protocol appears to be lower than that of GnRH antagonists, albeit lacking statistical difference, whereas in patients with diminished ovarian reserve, the two protocols were comparable. Our findings suggest the need for caution when choosing PPOS protocol to achieve live births, especially for normal and high ovarian responders.

Letrozole + Ziwu Liuzhu Transcutaneous Electrical Acupoint Stimulation Improves Ovulation-Induced Pregnancy Rate in Obese Women with Polycystic Ovary Syndrome: A Prospective Cohort Study.

Objective: This study investigated the effect of letrozole with/without meridian-infusion percutaneous electrical stimulation on the rates of ovulation-induced pregnancy in patients with obese polycystic ovary syndrome (obPCOS). Materials and Methods: Patients with obPCOS, ages 20-40, each with a body mass index (BMI) ≥24 kg/m2, and/or waist circumference ≥80 cm, and at least 1 side tubal patency were enrolled at the Guangdong Women and Children Hospital, Guangzhou, China. They were divided into 2 groups: ZLT [Ziwu Liuzhu + transcutaneous electrical acupoint stimulation] and control. Baseline conditions and pregnancy status were collected for all patients. Multivariate Cox regression analysis and sensitivity analysis of propensity score matching (PSM) were performed for the groups after multiple interpolations. Results: From July 2021 to September 2022, 345 patients with obPCOS were recruited: 53 cases/69 cycles in the ZLT group and 292 cases/396 cycles in the control group. The 2 sets of baselines were flush. The anovulatory cycle rates were: ZLT, 2.89% (2/69); and control, 1.77% (7/396); P > 0.05. Multifollicle growth-cycle rates were: ZLT, 0% (0/69); and control, 0.76% (3/396); P > 0.05. Multivariate COX regression analysis showed adjusted hazard ratio (aHR) 95% confidence interval (CI): 2.11 (1.19, 3.73); P = 0.011. Multivariate Cox regression analysis with multiple imputation showed aHR 95% CI: 2.11 (1.19, 3.73); P = 0.013. In the overweight group (24-28 kg/m2), the pregnancy rate of the control and ZLT groups were 20.2% and 32.3%, respectively, aHR 95% CI: 1.76 (0.87,3.55); P = 0.113. In the obese cohort (≥ 28 kg/m2), the control and ZLT groups, pregnancy rates were 10.7% and 27.3%, respectively, aHR 95% CI: 3.46 (1.21, 9.92); P = 0.021; (Pfor interaction = 0.369). The caliper value was set as 0.2 for BMI and antral-follicle count, and PSM was performed at 1:1, aHR 95%CI: 2.45 (1.01, 5.96); P = 0.048. Conclusions: Letrazole + ZLT had a positive effect on ovulation-induced pregnancy rates in patients with obPCOS.

The impact of different cycle regimens on birthweight of singletons in frozen-thawed embryo transfer cycles of ovulatory women.

OBJECTIVE: To investigate whether different endometrial preparation regimens affect neonatal outcomes after frozen-thawed embryo transfer (FET). DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: A total of 3,639 patients with live-born singletons were categorized into three groups on the basis of the type of endometrial preparation regimens. Of these, 1,225, 2,136, and 278 live-born singletons were conceived through natural cycle FET, artificial cycle FET, and stimulated cycle FET, respectively. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The main outcomes were the measures of birthweight including the absolute mean birthweight, Z-score, low birthweight, high birthweight (HBW), small for gestational age, and large for gestational age (LGA). RESULTS: After controlling for a variety of covariates, singletons from the artificial cycle FET group had a higher mean birthweight and Z-score than those from the natural cycle FET group and stimulated cycle FET group. The risk of LGA infants significantly increased in the artificial cycle group (14.0%) than that in the natural cycle group (10.3%) and stimulated cycle group (7.6%). The risk of hypertensive disorders of pregnancy in the artificial cycle group (4.4%) was significantly higher than that in the natural cycle group (2.5%). The stimulated cycle FET singletons had a higher risk of low birthweight than the natural cycle FET singletons. The other perinatal outcomes, including the incidence of preterm birth, small for gestational age, and gestational diabetes mellitus, were comparable between the groups before or after adjustment for confounders. CONCLUSIONS: Singletons from artificial cycle FET were associated with a higher risk of LGA infants, and natural cycle FET may be a better regimen for ovulatory women. Our results indicate a link between the absence of the corpus luteum and adverse perinatal outcomes, and further studies are needed to detect the underlying mechanism.

Association between baseline LH/FSH and live-birth rate after fresh-embryo transfer in polycystic ovary syndrome women.

This study aimed to retrospectively analyse the effect of the baseline luteinising hormone/follicle-stimulating hormone ratio (bLH/FSH) on the live-birth rate per fresh-embryo transfer cycle (LBR/ET) in infertile women with polycystic ovary syndrome (PCOS) who received a fresh-embryo transfer. A total of 424 patients with PCOS who underwent the first cycle of in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) fresh-embryo transfer at our hospital was enrolled. Univariate and multivariate logistic regression analyses, along with curve fitting and a threshold effect analysis, were performed. Baseline LH/FSH levels were a significant (P < 0.05) independent risk factor affecting live birth. In the first IVF/ICSI antagonist treatment cycles, LBR/ET after fresh-embryo transfer was relatively flat, until bLH/FSH was 1.0; thereafter, it started to decrease by 17% for every 0.1-unit bLH/FSH increase. Considering the decline in LBR/ET, it is recommended that PCOS women with bLH/FSH > 1.0 carefully consider fresh-embryo transfer during their first IVF/ICSI.

Association between endogenous LH level prior to progesterone administration and live birth rate in artificial frozen-thawed blastocyst transfer cycles of ovulatory women.

STUDY QUESTION: Is there an association between serum LH levels prior to progesterone administration and live birth rate (LBR) in artificial frozen-thawed embryo transfer (FET) cycles? SUMMARY ANSWER: : Low serum LH levels on the day before progesterone initiation in artificial frozen-thawed blastocyst transfer cycles of ovulatory women are associated with a lower LBR. WHAT IS KNOWN ALREADY: In artificial FET cycles, exogenous oestrogen and progesterone are administered sequentially to mimic the serum hormone pattern similar to the natural cycle. In oestrogen-only phase, the supplemental oestrogen causes thickening of the endometrium and is sometimes accompanied by a rise in serum LH. However, whether the endogenous LH level in artificial FET cycles is related to clinical outcomes remains unclear. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study including 3469 artificial frozen-thawed blastocyst transfer cycles was conducted at a tertiary-care academic medical centre between February 2014 and January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3469 frozen blastocyst transfer cycles were stratified into four groups based on the quartiles of serum LH level before progesterone initiation: <25th percentile (LH < 8.79 mIU/ml), 25-50th percentile (8.79 ≤ LH ≤ 13.91 mIU/ml), 51-75th percentile (13.91 < LH ≤ 20.75 mIU/ml) and >75th percentile (LH > 20.75 mIU/ml). The serum LH level >75th percentile group was considered as the reference group. Patients with polycystic ovarian syndrome or other ovulatory disorders were excluded from the study. We also excluded cycles with an endometrial thickness <7 mm before progesterone initiation and patients with intrauterine adhesions and uterine abnormalities. In order to avoid the interference of BMI, all patients were divided into two categories based on the overweight threshold: BMI <25 kg/m2 and ≥25 kg/m2, and the impacts of serum LH levels on LBR were investigated separately. Univariable and multivariable logistic regression analysis were performed to adjust for potential confounders. EmpowerStats software and R-project were used to build smooth curve fitting models. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with the reference group, the implantation rate significantly decreased with low LH levels (<25th percentile) on the day before progesterone initiation (odds ratio [OR] = 0.74; 95% CI, 0.64-0.86; P = 0.001). Accounting for major covariates, low LH levels were associated with a relatively lower LBR (adjusted OR = 0.649; 95% CI, 0.531-0.794; P < 0.001), mainly due to a lower implantation rate, lower clinical pregnancy rate and higher pregnancy loss rate. Moreover, in the patients with BMI <25 kg/m2, low LH was associated with a lower LBR (P < 0.001); while in the overweight subgroup, LBR and LH were not correlated (P = 0.823). LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Owing to the relatively small number in the overweight group, the results of the overweight subgroup should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The evidence provided in this study shows the importance of serum LH levels on the day before progesterone initiation in patients undergoing artificial FET cycles. Hypothalamic dysfunction may be one of the important causes of a relatively low LH, which is related to impaired pregnancy outcomes. Serum LH levels may be used as one of the clinical indicators to predict pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): No funding and no competing interest were involved in this study. TRIAL REGISTRATION NUMBER: NA.

Gestational Folic Acid Administration Alleviated Maternal Postpartum Emotional and Cognitive Dysfunction in Mice.

Gestational folic acid (FA) supplementation has been widely recognized for its benefits in preventing offspring defects, but its effect on postpartum females has not yet been adequately assessed. The occurrence of emotional and cognitive dysfunction is common in postpartum women, and its treatment remains limited. Considering the promising results of FA in various psychiatric disorders both in human and redents, we tested the effect of gestational FA administration on postpartum psychiatric behavioral phenotypes and the implicated brain-related mechanisms in a murine model. FA was administered orally in both the hormone-stimulated-pregnancy (HSP) model and pregnant mice at doses of 1 and 5 mg/kg. Postpartum behavioral results showed that the disorders of cognitive performance, depressive, and anxiety-related behaviors were all alleviated in the 5 mg/kg FA group. However, the general development of their offspring remained unaffected. Immunofluorescence and immunoblot results revealed that FA pretreatment significantly activated the maternal hippocampal BDNF-related pathway. Morphological studies have confirmed that FA promotes hippocampal neurogenesis. Moreover, synaptic plasticity and synaptic transmission are enhanced. All of these hippocampal changes play critical roles in rescuing neuronal function and behaviors. Thus, our data suggest that gestational FA administration has a therapeutic effect that improves cognition and reduces depression and anxiety in a murine postpartum model. This may be developed as a preventive and adjuvant therapeutic option for pregnant women.