A follow-up study on congenital anomalies in 2208 offspring of three years old born after luteal-phase stimulation.

RESEARCH QUESTION: What is the long-term safety in terms of congenital anomalies of a luteal-phase stimulation (LPS) protocol? DESIGN: In this cohort study, 664 couples and their children born after LPS and 1308 couples and their children born after a short agonist protocol were recruited. To investigate the long-term safety of LPS in terms of the prevalence of congenital anomalies, the physical growth and the health status of the offspring, the follow-up was divided into three steps: preparations before follow-up, first-stage follow-up including four telephone interviews, and second-stage follow-up when the children were aged 3 years. RESULTS: The total prevalence of congenital anomalies did not differ between groups. The detailed classification showed a significantly lower percentage of musculoskeletal system congenital anomalies in singletons (P = 0.020) and an obviously higher percentage of digestive system congenital anomalies in multiple births (P = 0.028), both in the LPS group. In the evaluation of physical growth and health status, no significant differences were discovered between the two groups. CONCLUSIONS: This study showed that offspring born after the LPS protocol did not exhibit an elevated rate of total congenital anomalies up to the age of 3. In addition, indicators regarding physical growth and health status were broadly similar between the two groups. These results have preliminarily confirmed the long-term safety of LPS. A subsequent long-term follow-up with a larger sample size should be carried out to generate more convincing evidence and more accurate conclusions.

Value of endometrial thickness change after human chorionic gonadotrophin administration in predicting pregnancy outcome following fresh transfer in vitro fertilization cycles.

PURPOSE: To study whether the change of endometrial thickness (EMT) between the day of human chorionic gonadotrophin (hCG) administration and the day of embryo transfer has any impact on pregnancy outcome in fresh in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. METHODS: This single-center retrospective cohort study included 2620 patients undergoing their first consecutive autologous IVF/ICSI cycles from January 2003 to December 2012. Patients were categorized into three groups based on the percentage change of post-hCG EMT: > 10% decrease, ± 10% plateau and > 10% increase. The primary outcome was live birth rate. RESULTS: Live birth rates were similar in the EMT decrease, plateau and increase groups (27.4% [174/635], 29.7% [300/1010] and 27.6% [269/975]; P = 0.649). Compared with the plateau group, both EMT decrease (crude odds ratio [cOR] 0.89, 95% confidence interval [CI] 0.72-1.11) and increase (cOR 0.90, 95% CI 0.74-1.10) on the day of transfer did not affect the likelihood of live birth. The non-significant association was maintained after controlling for major confounding factors, with the adjusted OR being 0.92 (95% CI 0.73-1.16) and 0.92 (95% CI 0.75-1.13) for the decrease and increase groups, respectively. CONCLUSION: EMT change after hCG administration did not provide significant prognostic information for pregnancy outcome in fresh IVF/ICSI cycles. This finding should offer reassuring information for patients with decreased EMT on the day of embryo transfer while questioning the necessity of EMT re-measurement prior to transfer as a routine practice.

Adherence to healthy dietary patterns and outcomes of assisted reproduction: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the association between adherence to a healthy dietary pattern and outcomes of assisted reproductive techniques (ARTs). PubMed, Embase and Web of Science were searched for eligible studies through December 2019 according to the population, intervention, comparison, outcome and study design (PICOS) criteria. Eight prospective cohort studies (S) reporting pregnancy outcomes (O) of higher vs lower adherence to a healthy dietary pattern (I/C) in women undergoing ART treatment (P) were included, involving a total of 2229 women with 2067 embryo transfer cycles. The pooled odds ratio (OR) for positive pregnancy test, clinical pregnancy and ongoing pregnancy/live birth was 0.82 (95% confidence interval [CI] 0.65-1.03), 0.99 (95% CI 0.68-1.44) and 1.30 (95% CI 0.81-2.09), respectively. In conclusion, greater adherence to a healthy dietary pattern rich in vegetables, fruits, whole grains, legumes and fish, may not be significantly related to ART success.

Association between peak serum estradiol level during controlled ovarian stimulation and neonatal birthweight in freeze-all cycles: a retrospective study of 8501 singleton live births.

STUDY QUESTION: Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles? SUMMARY ANSWER: Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles. WHAT IS KNOWN ALREADY: Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA). MAIN RESULTS AND THE ROLE OF CHANCE: The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively. LIMITATIONS, REASONS FOR CAUTION: The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations. WIDER IMPLICATIONS OF THE FINDINGS: Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest.

Association between endometrial thickness and neonatal outcomes in intrauterine insemination cycles: a retrospective analysis of 1,016 live-born singletons.

BACKGROUND: Decreased endometrial thickness (EMT) has been suggested to be associated with reduced birthweight of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) newborns. Considering the differences in ovarian stimulation degree and laboratory procedures between IVF/ICSI and IUI treatment, we aim to investigate whether EMT has any influence on IUI infant outcomes as well. METHODS: This was a retrospective cohort study of 1016 patients who had singleton livebirths after IUI treatment cycles from January 2008 to December 2018 at a tertiary-care academic medical center in China. Patients were categorized into three groups by the 10th and 90th percentile of peak EMT: ≤7.6, 7.7-13.0 and ≥ 13.1 mm. The primary outcomes of the study were preterm birth (PTB), low birthweight (LBW) and small-for-gestational age (SGA). Multiple regression analyses were performed after controlling for a variety of potential confounders. RESULTS: No significant differences were found among the three groups in gestational age, birthweight and birthweight Z-score. Compared with the EMT 7.7-13.0 mm group, the incidences of PTB, LBW and SGA were 5.5% (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI] 0.33-2.01), 6.4% (aOR 1.44, 95% CI 0.58-3.58) and 7.3% (aOR 1.21, 95% CI 0.53-2.76) in the EMT ≤7.6 mm group, respectively. Similarly, EMT ≥13.1 mm was not significantly associated with risks of PTB (aOR 0.63, 95% CI 0.24-1.65), LBW (aOR 0.57, 95% CI 0.17-1.95) and SGA (aOR 0.73, 95% CI 0.28-1.92). The odds of other adverse neonatal outcomes, including macrosomia, large-for-gestational age and major congenital malformations, did not show significant differences before and after adjustment in both EMT ≤7.6 and ≥ 13.1 mm groups. CONCLUSIONS: EMT is not independently associated with adverse perinatal outcomes in IUI cycles. This novel finding would provide reassuring information for IUI patients with thin endometrial linings regarding their neonatal health. However, further prospective cohort studies with larger datasets are needed to confirm the conclusion.

Effect of a prior cesarean delivery on pregnancy outcomes of frozen-thawed embryo transfer: A retrospective cohort study in a freeze-all setting.

INTRODUCTION: The association between the mode of previous delivery and subsequent success of assisted reproductive treatment has been poorly understood. By mitigating the detrimental effect of supraphysiologic estradiol levels on endometrial receptivity, a freeze-all strategy provides a novel model to investigate the sole impact of a prior cesarean delivery (CD) on embryo transfer outcomes. MATERIAL AND METHODS: This single-center retrospective cohort study included 2660 patients who underwent their first frozen-thawed embryo transfer cycles after a freeze-all policy from January 2013 to December 2018. Patients with a history of live birth by CD were assigned to the CD group, and those with only vaginal delivery (VD) were categorized into the VD group. The primary outcome measure was live birth. Baseline characteristics of the two groups were balanced by propensity score matching in a ratio of 1:1. Univariate and multivariate logistic regression analyses were performed using the after-matching data. RESULTS: Compared with the VD group, the rates of clinical pregnancy (38.3% vs 44.5%; P = .005) and live birth (27.5% vs 33.4%; P = .003) were significantly lower in women with a history of CD. When adjusted for a number of major confounding factors, the negative association between a prior CD and frozen-thawed embryo transfer success was maintained, with the adjusted odds ratio (OR) being 0.80 (95% CI 0.66-0.96) and 0.78 (95% CI 0.63-0.95) for clinical pregnancy and live birth, respectively. Furthermore, a CD history conferred a marginally increased risk of early miscarriage (crude OR 1.48, 95% CI 1.04-2.11; adjusted OR 1.47, 95% CI 1.01-2.14), whereas the odds of multiple and ectopic pregnancy did not show significant differences before and after adjustment. CONCLUSIONS: A prior CD was associated with a decreased chance of live birth and an increased risk of early miscarriage in frozen-thawed embryo transfer cycles.

Effect of Switching from a Progestin-Primed Ovarian Stimulation Protocol to a Modified Ultra-Long Protocol Among Women Who Had 1 Progestin-Primed Ovarian Stimulation (PPOS) Failure Verses Those Who Had 2 PPOS Failures.

BACKGROUND There is little research on whether normoresponsive patients who produced poor-quality embryos once verses those who produced poor-quality embryos twice when using a single COH protocol should change to a different controlled ovarian hyperstimulation (COH) protocol. MATERIAL AND METHODS In this retrospective study, we enrolled 108 patients with 1 PPOS failure who chose to continue receiving the progestin-primed ovarian stimulation (PPOS) protocol (n=61) versus those who decided to switch to the modified ultra-long protocol (n=47). We also enrolled 131 normoresponsive patients with 2 PPOS failures who chose to continue receiving the PPOS protocol (n=60) versus those who decided to switch to the modified ultra-long protocol (n=71) in the third cycle. RESULTS We found no significant difference in clinical outcomes of patients with 1 PPOS failure who continued using the PPOS protocol verses those who switched to the modified ultra-long protocol in the second cycle, expect for a lower cancelation rate (4.3% vs. 16.4%). However, the patients with 2 PPOS failures had significantly more good-quality embryos (0.9 vs. 0.4), more viable embryos (1.8 vs. 0.9), lower cancelation rates (18.3% vs. 53.3%), and higher pregnancy rates per aspirated cycle (26.8% vs. 10.0%) when switching to the modified ultra-long protocol compared to those who decided to continue receiving the PPOS protocol (P<0.05). Furthermore, the odds of clinical pregnancy (odds ratio [OR] 5.997, 95% confidence interval [CI] 1.476-24.361, P=0.01) were positively associated with switching to the COH protocol in the third cycle. CONCLUSIONS For normoresponsive patients with poor-quality embryos when using the PPOS protocol, switching to the modified ultra-long protocol after having 2 PPOS failures was associated with better ART outcomes.

Delayed versus immediate frozen embryo transfer after oocyte retrieval: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to compare pregnancy outcomes between immediate frozen embryo transfer (FET) performed within the first menstrual cycle after oocyte retrieval and delayed FET following subsequent cycles. METHODS: PubMed, EMBASE, and Web of Science were searched for eligible studies through January 2020. The main outcome measures were clinical pregnancy rate (CPR), live birth rate (LBR), and pregnancy loss rate (PLR). The effect size was estimated as risk ratio (RR) with 95% confidence interval (CI) using a random effects model. Inter-study heterogeneity was assessed by the I2 statistic. RESULTS: Twelve retrospective cohort studies involving 18,230 cycles were included. The pooled results revealed no significant differences between delayed and immediate FET in CPR (RR 0.94, 95% CI 0.87-1.03; I2 = 67.9%), LBR (RR 0.94, 95% CI 0.85-1.03; I2 = 67.5%), and PLR (RR 1.05, 95% CI 0.87-1.26; I2 = 42.7%). Subgroup analyses of freeze-all cycles showed a marginal decrease of CPR in delayed FET (RR 0.93, 95% CI 0.86-1.00; I2 = 53.6%), but no significant changes were observed regarding LBR (RR 0.93, 95% CI 0.85-1.02; I2 = 65.2%) and PLR (RR 1.09, 95% CI 0.84-1.41; I2 = 59.1%). No statistical differences were found in effect estimates among other subgroup analyses by ovarian stimulation protocol, trigger agent, endometrial preparation regimen, and embryo stage. CONCLUSION: Timing of the first FET after oocyte retrieval was not significantly associated with pregnancy outcomes. This finding refutes the current common practice to delay FET after oocyte retrieval and reassures patients who wish to proceed with FET at their earliest convenience. Due to the high heterogeneity and observational nature of included studies, further randomized controlled trials are needed to confirm the results.

Cross-linked hyaluronan gel to improve pregnancy rate of women patients with moderate to severe intrauterine adhesion treated with IVF: a randomized controlled trial.

PURPOSE: To evaluate whether the cross-linked hyaluronan (cHA) gel can improve the clinical pregnancy rate of patients with moderate to severe intrauterine adhesion (IUA) who underwent operative hysteroscopy followed by embryo transfer. METHODS: Women with moderate to severe IUA desiring to undergo embryo transfer were recruited in this randomized controlled trial. The patients were randomized on the day of receiving hysteroscopy. The control group received standard hysteroscopy, while cHA gel was applied to the treatment group at the end of hysteroscopy and 5-7 days after operation. All patients were expected to undergo in vitro fertilization (IVF)/intracytoplasmic sperm injection and frozen-thawed embryo transfer (FET). RESULTS: A total of 306 patients were enrolled in this study, of which 202 were assigned to the treatment group and 104 to the control group. Both the clinical pregnancy rate (26.3% [49/186] vs. 15.3% [13/85], P = 0.045), the implantation rate (17.7% [57/322] vs. 9.8% [15/153], P = 0.025), and the endometrial thickness on the day of embryo transfer (7.97 ± 1.37 vs. 7.50 ± 0.60 mm, P < 0.001) were significantly higher in the treatment group compared to the control group. In addition, histological assessment of the paired endometrial tissues collected before and after operation revealed a relatively higher number of tubular glands after operation (15.1 ± 13.2 vs. 28.8 ± 30.4, P = 0.166). CONCLUSIONS: To conclude, the application of cHA gel in patients with moderate to severe IUA during hysteroscopy can improve the quality of endometrium and uterine receptivity and consequently enhance the clinical pregnancy rate after IVF/CSI and FET.

Effects of pre-pregnancy body mass index on pregnancy and perinatal outcomes in women with PCOS undergoing frozen embryo transfer.

BACKGROUND: Previous studies have shown that among women with polycystic ovary syndrome who have difficulties conceiving, frozen-embryo transfer resulted in increased live birth rates and decreased ovarian hyperstimulation syndrome risk than did fresh-embryo transfer. In the present retrospective analysis, we sought to determine the effect of body mass index (BMI) on pregnancy and perinatal outcomes in women with PCOS undergoing FET. METHODS: Women with PCOS (n = 1556) undergoing FET were divided into groups based on weight, with those with normal weight having a BMI of 18.5-24.9 kg/m2,those who were overweight having a BMI of 25-29.9 kg/m2, and those who were obese having a BMI ≥30 kg/m2. Both pregnancy and perinatal outcomes were compared among these groups. RESULTS: The normal-weight, overweight, or obese groups exhibited similar pregnancy outcomes, including clinical pregnancy rate, miscarriage rate, ongoing pregnancy rate and live birth rate. In singletons, birth characteristics regarding newborn gender, gestational age, birthweight and length at birth were comparable between the three groups. For adverse neonatal outcomes, the three groups showed no significant differences on the rates of low birthweight, very low birthweight, preterm birth, and very preterm birth after adjustment. In addition, the obstetric complications and the frequencies of live-birth defects were also comparable between the three groups except that overweight and obese women were more likely than women of normal weight to have delivered via cesarean section. CONCLUSION: BMI did not affect the pregnancy or perinatal outcomes in women with PCOS undergoing FET.

Pregnancy and neonatal outcomes of artificial oocyte activation in patients undergoing frozen-thawed embryo transfer: a 6-year population-based retrospective study.

PURPOSE: To evaluate the impact of artificial oocyte activation (AOA) in pregnancy and neonatal outcomes in infertile patients undergoing cryopreserved embryo transfer. METHOD: This retrospective study included 5686 patients' transferred embryos from routine intracytoplasmic sperm injection (ICSI) and 194 patients' transferred embryos from ICSI combined with AOA (ICSI-AOA) from January 2011 to December 2016. Pregnancy and neonatal outcomes of couples undergoing routine ICSI or ICSI-AOA were analyzed before and after propensity score matching. Artificial oocyte activation was performed with ionomycin. RESULTS: The pregnancy outcomes showed no significant difference in the rates of biochemical pregnancy, clinical pregnancy, implantation, miscarriage, ectopic pregnancy, multiple pregnancy, and live births between the routine ICSI and ICSI-AOA groups before and after propensity score matching, respectively. The assessment of neonatal outcomes showed no statistically significant differences in the birth defect rate, birth weight, gestational age, preterm birth rate, early-neonatal death rate, and fetal sex ratio between the two groups, and similar results were also observed in the two matched cohorts. CONCLUSION: Artificial oocyte activation with ionomycin does not adversely affect pregnancy and neonatal outcomes in patients undergoing frozen-thawed embryo transfer, which is beneficial to clinicians counseling patients on the risks of artificial oocyte activation.

Dual trigger of final oocyte maturation in poor ovarian responders undergoing IVF/ICSI cycles.

Previous studies show that a dual trigger ovulation regimen significantly improves number and maturity of retrieved oocytes for normal ovarian responders or patients with history of low oocyte yield. The current retrospective cohort study investigated whether dual trigger of final oocyte maturation may benefit IVF outcomes for poor ovarian responders fulfilling the Bologna criteria. Undertaken between May 2014 and August 2016, the study involved 1350 patients undergoing 1389 IVF/intracytoplasmic sperm injection treatment cycles. Patients triggered with 5000 IU human chorionic gonadotrophin (HCG) alone (328 cycles) were compared with those undergoing dual triggering with 5000 IU HCG plus 0.1 mg gonadotrophin-releasing hormone agonist (GnRHa) (386 cycles) and patients triggered with 10,000 IU HCG (363 cycles) were compared with those undergoing dual triggering with 10,000 IU HCG plus 0.1 mg GnRHa (312 cycles). The dual trigger groups showed significantly higher number of oocytes collected and number of mature oocytes compared with their respective HCG trigger group (P < 0.001). Oocyte retrieval rate and percentage of mature oocytes retrieved were also both significantly higher in the dual trigger groups (P < 0.001). Fertilization rate, number of viable embryos, implantation rate, clinical pregnancy rate and miscarriage rate were not significantly different between groups.

Three-Dimensional HyCoSy With Perfluoropropane-Albumin Microspheres as Contrast Agents and Normal Saline Injections Into the Pelvic Cavity for Morphological Assessment of the Fallopian Tube in Infertile Women.

OBJECTIVES: To apply the three-dimensional (3D) hysterosalpingo-contrast sonography (HyCoSy) with perfluoropropane-albumin microspheres as contrast agents and normal saline injections into the pelvic cavity for assessment of the tubal patency and adhesions of fimbrial parts. METHODS: Fifty-five infertile female patients were recruited to undergo 3D HyCoSy with normal saline injected into the pelvic cavity, in which the tubal patency was observed by visualizing the spillage of contrast agents from the fimbriae, and the fimbrial adhesion was confirmed by the finger-like projections of the fimbriae and their floating and moving status. RESULTS: Of the 55 patients, bilateral tubal patency was observed in 44 (80.0%), unilateral tubal patency and the other partial occlusion in 7 (12.7%), unilateral partial occlusion and the other complete occlusion in 3 (5.4%), and bilateral complete occlusion in 1 (1.8%). The fimbrial parts were observed in 105 fallopian tubes, among which 101 were seen with the finger-like fimbriae floated and moved in the pelvic cavity, whereas 4 tubes were not because of adhesion to the pelvic cavity (n = 3) or the ovary and intestine (n = 1). More than three visible, quite long, and distributed evenly finger-like projections were present for the patent fimbrial parts; however, fewer, flat, and not evenly distributed finger-like projections were present for the adhesive tubes. No serious complications occurred during or after this procedure. CONCLUSIONS: Combination of 3D HyCoSy with normal saline injected into the pelvic cavity may be a feasible and safe procedure to assess tubal patency and adhesions of the fimbrial parts.

Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy.

The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle-protrusion-retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal-karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live-born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.

miR-196a-5p-Rich Extracellular Vesicles from Trophoblasts Induce M1 Polarization of Macrophages in Recurrent Miscarriage.

Purpose: Numerous studies have described the presence of crosstalk between trophoblasts and macrophages and the critical role it plays in recurrent miscarriage (RM). However, the mechanism of trophoblast-derived extracellular vesicle (EV) miRNAs and their interactions with decidual macrophages in the pathogenesis of RM remains unclear. Materials and Methods: miRNA-seq was used to identify the differentially expressed miRNAs between RM patients and healthy controls. qPCR and in situ hybridization assays were performed to analyze the expression levels of miR-196a-5p in RM. THP-1 cells were treated with EVs, and qPCR and flow cytometry were performed to explore the polarization of macrophages. To explore the crosstalk between trophoblasts and macrophages, a coculture model and a series of cell function assays were performed. Results: We first demonstrated that miR-196a-5p expression was higher in the cytotrophoblasts of villous tissues and plasma EVs from RM patients. miR-196a-5p derived from trophoblasts could be transferred into macrophages via EVs to induce M1 polarization via IκBα-mediated NF-κB pathway. Moreover, we found that M1 macrophages induced by EV miR-196a-5p derived from trophoblasts conversely regulated the proliferation, migration, and apoptosis of trophoblasts via TNF-α. Conclusions: This study indicated that trophoblast-derived EV miR-196a-5p was positively associated with RM and functioned by regulating the crosstalk between trophoblasts and macrophages. These findings may attribute to identify a novel biomarker specific for RM.

Neonatal outcomes and congenital malformations in children born after progestin-primed ovarian stimulation protocol.

Purpose: The purpose of this study is to assess the safety of progestin-primed ovarian stimulation (PPOS) protocol regarding the neonatal outcomes and congenital malformations in babies born after in vitro fertilization (IVF) and frozen embryo transfer (FET). Methods: In this large retrospective cohort study, a total of 16,493 infants born between 1 September 2013 and 31 July 2021 from IVF and FET cycles after treatment with either PPOS (n = 15,245) or gonadotropin-releasing hormone antagonist (GnRH-ant) (n = 1,248) were finally enrolled. The primary outcome measure was the incidence of congenital malformations. The secondary outcome measures were rates of low birth weight (LBW), very low birth weight (VLBW), preterm birth (PTB), very preterm birth (VPTB), and early neonatal death. Results: Birth characteristics for both singletons and twins regarding the sex of infants, gestational age, birth weight, and birth length were comparable between the PPOS group and the GnRH-ant group. Rates of LBW, VLBW, PTB, VPTB, and early neonatal death were also similar. The reanalysis using propensity score matching (PSM) and multivariable logistic regression indicated that the PPOS protocol could not increase the risk of adverse neonatal outcomes compared with the GnRH-ant protocol. Furthermore, no significant difference was observed in the overall incidence of congenital malformations in live-born babies. After PSM and controlling for all confounders, the results remained insignificant with an adjusted odds ratio of 0.66 [95% confidence interval (CI) 0.32-1.34] and 2.43 [95% CI 0.97-6.06], respectively, for singletons and twins. Conclusions: Our study suggests that compared with GnRH-ant treatment for IVF, the PPOS protocol could not produce a negative effect on the newborn population in terms of neonatal outcomes and congenital malformations.

Differences in Ectopic Pregnancy Rates between Fresh and Frozen Embryo Transfer after In Vitro Fertilization: A Large Retrospective Study.

Ectopic pregnancy (EP) is increasingly found in women treated with in vitro fertilization and embryo transfer (IVF−ET). With the development of the freeze-all policy in reproductive medicine, it is controversial whether frozen embryo transfer (FET) could reduce the rate of EP. In this single-center, large-sample retrospective study, we analyzed 16,048 human chorionic gonadotrophin (hCG)-positive patients who underwent fresh embryo transfer (ET) or FET cycles between January 2013 and March 2022. Throughout the study, the total EP rate was 2.09% (336/16,048), 2.16% (82/3803) in the ET group, and 2.07% (254/12,245) in the FET group. After adjustment for age, infertility causes, and other confounding factors, logistic regression results showed no statistical difference in EP rates between FET and ET groups (odds ratio (OR) 0.93 (0.71−1.22), p > 0.05). However, among the 3808 patients who underwent fresh ET cycles, the OR for EP was significantly lower in the long agonist protocol group than in the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol group (OR 0.45 (0.22−0.93), p < 0.05). Through a large retrospective study, we demonstrated a slightly lower EP rate in FET cycles than in fresh ET cycles, but there was no significant difference. The long agonist protocol in ET cycles had a significantly lower risk of EP than the GnRH-ant protocol.

TIGIT-Fc as a Potential Therapeutic Agent for Fetomaternal Tolerance.

The perfect synchronization of maternal immune-endocrine mechanisms and those of the fetus is necessary for a successful pregnancy. In this report, decidual immune cells at the maternal-fetal interface were detected that expressed TIGIT (T cell immunoreceptor with Ig and ITIM domains), which is a co-inhibitory receptor that triggers immunological tolerance. We generated recombinant TIGIT-Fc fusion proteins by linking the extracellular domain of TIGIT and silent Fc fragments. The treatment with TIGIT-Fc of human decidual antigen presenting cells (APCs), the decidual dendritic cells (dDCs), and decidual macrophages (dMϕs) increased the production of interleukin 10 and induced the decidua APCs to powerfully polarize the decidual CD4+ T cells toward a classic TH2 phenotype. We further proposed that Notch signaling shows a pivotal effect on the transcriptional regulation in decidual immune cell subsets. Moreover, the administration of TIGIT-Fc to CBA/J pregnant mice at preimplantation induced CD4+ forkhead box P3+ (Foxp3+) regulatory T cells and tolerogenic dendritic cells and increased pregnancy rates in an abortion-prone animal model stress. The results suggested the therapeutic potential of the TIGIT-Fc fusion protein in reinstating immune tolerance in failing pregnancies.

Frozen Embryo Transfer in Mildly Stimulated Cycle With Letrozole Compared to Natural Cycle in Ovulatory Women: A Large Retrospective Study.

Objective: To evaluate the clinical effect of mild stimulation with letrozole on pregnancy outcomes in ovulatory women undergoing frozen embryo transfer (FET) compared to natural cycle. Design: Retrospective observational study. Setting: Tertiary care academic medical center. Population: A total of 6,874 infertile women with regular menstrual cycles (21-35 days) met the criteria for this study in the period from 2013 to 2020. Methods: All patients who were prepared for and underwent FET were divided into two groups: a modified natural cycle (NC) group (n=3,958) and a letrozole cycle group (n=2,916). Main Outcome Measures: The primary outcome of the study was clinical pregnancy rate. Secondary outcome measures were endometrial thickness, rates of implantation, positive HCG test, live birth, early miscarriage and ectopic pregnancy. Results: The clinical pregnancy rate was not statistically different between the modified NC-FET group and the letrozole-FFT group before (crude OR 0.99, 95% CI 0.90-1.09, P=0.902>0.05) and after propensity score matching (PSM) (crude OR 1.01, 95% CI 0.91-1.12, P=0.870>0.05). After multivariable logistic regression analysis, the clinical pregnancy rate remained insignificant before (adjusted OR 1.00, 95% CI 0.91-1.10, P=0.979>0.05) and after matching (adjusted OR 1.00, 95% CI 0.89-1.11, P=0.936>0.05), respectively. Similarly, in the crude and adjusted analysis, the positive HCG test, implantation, live birth and early miscarriage rates were also comparable in the letrozole-FFT group and modified NC-FET group before and after matching. Furthermore, the endometrial thickness of letrozole-FFT group was similar to that of modified NC-FET group with adjusted analysis. Conclusion: Our observation suggests that mild stimulation with letrozole could produce similar pregnancy outcomes in ovulatory patients who undergo FET when compared with a natural cycle.

Progesterone affects clinic oocyte yields by coordinating with follicle stimulating hormone via PI3K/AKT and MAPK pathways.

Introduction: As an effective inhibitor of premature ovulation, progestin was introduced to a novel ovarian stimulation regimen for infertility treatment. However, the local action of progestin on the ovary and its effect on clinical outcomes have not been described. Objectives: The influence of progesterone administration on clinical oocyte outcomes and the mechanisms involved in the coordination of progesterone and follicle stimulating hormone (FSH) on follicle growth and oocyte yields were investigated. Methods: Clinical outcomes of patients undergoing ovarian stimulation for in vitro fertilization were analyzed. The murine ovarian stimulation model and follicle culture system were used to evaluate the effects of progesterone on oocyte yield, follicle development, granular cell proliferation, and hormone secretion. Phospho-specific protein microarrays were used to explore involved signaling pathways. Results: Progesterone decreased clinical oocyte yields, and yields were rescued with an increased dose of human menopausal gonadotropin. Administration of progesterone inhibited murine granular cell proliferation and reduced the growth rate of follicles; both of which were rescued by FSH. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) were identified as pivotal signaling pathways to integrate progesterone into the FSH signaling network in granular cells. Conclusion: Progesterone inhibited granular cell proliferation and antral follicle growth during ovarian stimulation, and subsequently influenced oocyte outcomes in the clinical setting. Progesterone coordinated with FSH to regulate follicle growth through PI3K/AKT and MAPK signaling pathways. These findings advance our knowledge regarding the ovarian response to gonadotropins during progestin-primed ovarian stimulation and create an opportunity to manipulate individual oocyte yields.