Trophectoderm grade is associated with the risk of placenta previa in frozen-thawed single-blastocyst transfer cycles.

STUDY QUESTION: Do obstetric and perinatal complications vary according to different blastocyst developmental parameters after frozen-thawed single-blastocyst transfer (SBT) cycles? SUMMARY ANSWER: Pregnancies following the transfer of a blastocyst with a grade C trophectoderm (TE) were associated with an increased risk of placenta previa compared to those with a blastocyst of grade A TE. WHAT IS KNOWN ALREADY: Existing studies investigating the effect of blastocyst morphology grades on birth outcomes have mostly focused on fetal growth and have produced conflicting results, while the risk of obstetric complications has rarely been reported. Additionally, growing evidence has suggested that the appearance of TE cells could serve as the most important parameter for predicting implantation and live birth. Given that the TE ultimately develops into the placenta, it is plausible that this independent predictor may also impact placentation. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study at a tertiary-care academic medical center included 6018 singleton deliveries after frozen-thawed SBT cycles between January 2017 and December 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singleton pregnancies were grouped into two groups according to blastocyst developmental stage (Days 5 and 6), four groups according to embryo expansion (Stages 3, 4, 5, and 6), three groups according to inner cell mass (ICM) quality (A, B, and C), and three groups according to TE quality (A, B, and C). The main outcomes included pregnancy-induced hypertension, preeclampsia, gestational diabetes mellitus, preterm premature rupture of membrane, placenta previa, placental abruption, placenta accreta, postpartum hemorrhage, preterm birth, low birth weight, small for gestational age, and birth defects. Multivariate logistic regressions were performed to evaluate the effect of blastocyst developmental stage, embryo expansion stage, ICM grade, and TE grade on measured outcomes adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: No association was found between blastocyst developmental stage and obstetric or perinatal outcomes both before and after adjusting for potential confounders, and similar results were found with regard to embryo expansion stage and ICM grade. Meanwhile, the incidence of placenta previa derived from a blastocyst with TE of grade C was higher compared with those derived from a blastocyst with TE of grade A (1.7%, 2.4%, and 4.0% for A, B, and C, respectively, P = 0.001 for all comparisons). After adjusting for potential covariates, TE grade C blastocysts had 2.81 times the likelihood of resulting in placenta previa compared to TE grade A blastocysts (adjusted odds ratio 2.81, 95% CI 1.11-7.09). No statistically significant differences were detected between any other measured outcomes and TE grades both before or after adjustment. LIMITATIONS, REASONS FOR CAUTION: The study is limited by its retrospective, single-center design. Additionally, although the sample size was relatively large for the study group, the sample size for certain subgroups was relatively small and lacked adequate power, particularly the ICM grade C group. Therefore, these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The study extends our knowledge of the potential downstream effect of TE grade on placental abnormalities. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2023YFC2705501, 2023YFC2705505, 2019YFA0802604); National Natural Science Foundation of China (82130046, 82320108009, 82371660, 32300710); Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SHSMU-ZLCX20180401), Shanghai Jiaotong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), and Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effects of SARS-COV-2 infection during the frozen-thawed embryo transfer cycle on embryo implantation and pregnancy outcomes.

STUDY QUESTION: Does severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the frozen-thawed embryo transfer (FET) cycle affect embryo implantation and pregnancy rates? SUMMARY ANSWER: There is no evidence that SARS-CoV-2 infection of women during the FET cycle negatively affects embryo implantation and pregnancy rates. WHAT IS KNOWN ALREADY: Coronavirus disease 2019 (COVID-19), as a multi-systemic disease, poses a threat to reproductive health. However, the effects of SARS-CoV-2 infection on embryo implantation and pregnancy following fertility treatments, particularly FET, remain largely unknown. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study, included women who underwent FET cycles between 1 November 2022 and 31 December 2022 at an academic fertility centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who tested positive for SARS-CoV-2 during their FET cycles were included in the COVID-19 group, while those who tested negative during the same study period were included in the non-COVID-19 group. The primary outcome was ongoing pregnancy rate. Secondary outcomes included rates of implantation, biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy. Multivariate logistic regression models were applied to adjust for potential confounders including age, body mass index, gravidity, vaccination status, and endometrial preparation regimen. Subgroup analyses were conducted by time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) and by level of fever (no fever, fever <39°C, or fever ≥39°C). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 243 and 305 women were included in the COVID-19 and non-COVID-19 group, respectively. The rates of biochemical pregnancy (58.8% vs 62.0%, P = 0.46), clinical pregnancy (53.1% vs 54.4%, P = 0.76), implantation (46.4% vs 46.2%, P = 0.95), early pregnancy loss (24.5% vs 26.5%, P = 0.68), and ongoing pregnancy (44.4% vs 45.6%, P = 0.79) were all comparable between groups with or without infection. Results of logistic regression models, both before and after adjustment, revealed no associations between SARS-CoV-2 infection and rates of biochemical pregnancy, clinical pregnancy, early pregnancy loss, or ongoing pregnancy. Moreover, neither the time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) nor the level of fever (no fever, fever <39°C, or fever ≥39°C) was found to be related to pregnancy rates. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study is subject to possible selection bias. Additionally, although the sample size was relatively large for the COVID-19 group, the sample sizes for certain subgroups were relatively small and lacked adequate power, so these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The study findings suggest that SARS-CoV-2 infection during the FET cycle in females does not affect embryo implantation and pregnancy rates including biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy, indicating that cycle cancellation due to SARS-CoV-2 infection may not be necessary. Further studies are warranted to verify these findings. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2019YFA0802604), National Natural Science Foundation of China (82130046, 82101747), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SSMU-ZLCX20180401), Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai Sailing Program (21YF1425000), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161413). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Elevated SAA1 promotes the development of insulin resistance in ovarian granulosa cells in polycystic ovary syndrome.

BACKGROUND: Insulin resistance (IR) contributes to ovarian dysfunctions in polycystic ovarian syndrome (PCOS) patients. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver in response to inflammation. In addition to its role in inflammation, SAA1 may participate in IR development in peripheral tissues. Yet, expressional regulation of SAA1 in the ovary and its role in the pathogenesis of ovarian IR in PCOS remain elusive. METHODS: Follicular fluid, granulosa cells and peripheral venous blood were collected from PCOS and non-PCOS patients with and without IR to measure SAA1 abundance for analysis of its correlation with IR status. The effects of SAA1 on its own expression and insulin signaling pathway were investigated in cultured primary granulosa cells. RESULTS: Ovarian granulosa cells were capable of producing SAA1, which could be induced by SAA1 per se. Moreover, the abundance of SAA1 significantly increased in granulosa cells and follicular fluid in PCOS patients with IR. SAA1 treatment significantly attenuated insulin-stimulated membrane translocation of glucose transporter 4 and glucose uptake in granulosa cells through induction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression with subsequent inhibition of Akt phosphorylation. These effects of SAA1 could be blocked by inhibitors for toll-like receptors 2/4 (TLR 2/4) and nuclear factor kappa light chain enhancer of activated B (NF-κB). CONCLUSIONS: Human granulosa cells are capable of feedforward production of SAA1, which significantly increased in PCOS patients with IR. Excessive SAA1 reduces insulin sensitivity in granulosa cells via induction of PTEN and subsequent inhibition of Akt phosphorylation upon activation of TLR2/4 and NF-κB pathway. These findings highlight that elevation of SAA1 in the ovary promotes the development of IR in granulosa cells of PCOS patients.

The impact of embryo quality on singleton birthweight in vitrified-thawed single blastocyst transfer cycles.

STUDY QUESTION: Does the quality of a single transferred blastocyst affect singleton birthweight in frozen-embryo transfer (FET) cycles? SUMMARY ANSWER: The transfer of a poor-quality blastocyst was associated with lower mean birthweight and gestation-adjusted birthweight (Z-scores) when compared with the transfer of an excellent-quality blastocyst during FET cycles. WHAT IS KNOWN ALREADY: Embryo quality is a strong predictor of IVF success rates. However, very few studies have examined the effect of embryo quality on singleton birthweight. STUDY DESIGN, SIZE, DURATION: This retrospective study involved singleton live births born to women undergoing frozen-thawed single blastocyst transfers during the period from January 2010 to December 2017 at a tertiary care centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1207 women who fulfilled the inclusion criteria were included and were grouped into four groups depending on the blastocyst quality: excellent, good, average and poor. The primary outcome measure was singleton birthweight. The Z-score was employed to calculate the birthweight adjusted for gestational age and newborn gender. Multiple linear regression analysis was performed to investigate the relationship between embryo quality and neonatal birthweight after adjustment for some potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary multivariable model, singletons from the poor-quality blastocyst group weighed 183.5 g less than those from the excellent-quality blastocyst group (95% CI: -295.1 to -71.9 g, P = 0.001) in terms of mean birthweight after accounting for patient characteristics, IVF treatment parameters, the year of treatment and newborn gender. Likewise, poor-quality blastocyst transfer was associated with lower gestation-adjusted Z-scores than the transfer of excellent-quality blastocysts (ß = -0.35, 95% CI: -0.59 to -0.12, P = 0.003). LIMITATIONS AND REASONS FOR CAUTION: The current study was limited by its retrospective design and the fact that our analysis was restricted to women with singleton births from single blastocyst transfers. Future prospective studies are required to confirm our findings. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide new insight into the relationship between embryo quality and neonatal outcomes by showing that poor-quality blastocyst transfer was associated with a decrease in singleton birthweight. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (grant no. 2018YFC1003000), the National Natural Science Foundation of China (grant nos. 81771533, 81571397 and 31770989), and the China Postdoctoral Science Foundation (Grant no. 2018M630456). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Effect of maternal body mass index on neonatal outcomes in women with endometriosis undergoing IVF.

RESEARCH QUESTION: Does preconception body mass index (BMI) affect neonatal outcomes in women with endometriosis who conceive with IVF? DESIGN: This retrospective study included 7086 women who delivered a singleton live birth through IVF between December 2006 and December 2017. Of these, 1111 women were diagnosed with endometriosis by laparoscopy or laparotomy, while 5975 women received IVF treatment due to tubal factor or male factor infertility. Women were categorized according to predefined BMI groups (<18.5 kg/m2, BMI 18.5-24.9 kg/m2, ≥25 kg/m2). All comparisons performed were between women undergoing cryopreserved embryo transfer. RESULTS: After stratification by BMI, underweight women with endometriosis showed higher preterm birth (PTB) rates compared with controls (14.61% versus 3.28%, P < 0.001), whereas normal weight and overweight/obese endometriotic women had similar PTB rates to controls. There was a significant interactive effect of endometriosis and maternal BMI on preterm delivery (P for interaction <0.05). After adjustment for potential confounding factors, the PTB rate remained consistently higher in the low BMI subgroup of women with endometriosis (adjusted odds ratio 4.66, 95% confidence interval 2.54-8.57), whereas this difference was not observed for the other BMI categories. Additionally, we noted no differences in the rate of early PTB, low birthweight, macrosomia, small for gestational age and large for gestational age between women with endometriosis and controls with respect to any preconception category of BMI. CONCLUSIONS: Endometriotic patients who were underweight before conception (BMI <18.5 kg/m2) had a higher rate of PTB than women without endometriosis, but the difference was not observed in the other BMI categories.

Association between the number of oocytes retrieved and neonatal outcomes after freeze-all IVF cycles.

STUDY QUESTION: Is there any association between the number of oocytes retrieved and neonatal outcomes following IVF/ICSI treatment for patients using a freeze-all strategy? SUMMARY ANSWER: There was no increased risk of adverse neonatal outcomes in cycles with high number of oocytes retrieved (≥ 16) compared to those with 10-15 oocytes retrieved in freeze-all cycles. WHAT IS KNOWN ALREADY: Recent studies have found that there is an increased risk of preterm birth (PTB, <37 weeks gestation) and low birth weight (LBW, <2500 g) following IVF in women with a high number (>20) of oocytes retrieved in fresh embryo transfer (ET) cycles. Other studies have found that there is an association between the number of oocytes retrieved and placenta praevia. However, the association between the number of oocytes retrieved and neonatal outcomes when using a freeze-all strategy is unknown. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included 14 170 women with singleton deliveries achieved by a freeze-all strategy performed between November 2006 and December 2017 in China. Only the first delivery from one episode of ovarian stimulation was included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only cycles using a freeze-all strategy performed during the study period and resulting in singleton live births were included. Patients were categorized into five groups according to the number of oocytes retrieved: 1-3, 4-9, 10-15, 16-20 or >20 oocytes. In univariate and multivariate logistic regression analysis of the association between ovarian response and the outcomes of PTB, early PTB, LBW and other neonatal outcomes, the 10 to 15 oocyte category was used as a reference and other four groups were analysed as dummy variables. Multiple linear regression analysis was used to evaluate possible associations of birth weight z-scores and the number of oocytes retrieved (analysed as a continuous variable) with other confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusted for confounding factors, no significant differences were observed in the risk of PTB (P = 0.837), LBW (P = 0.974), early PTB (P = 0.341), very LBW (P = 0.848), congenital malformation (P = 0.916) and other adverse neonatal outcome among patients with different number of oocytes retrieved. There was a higher risk of early PTB among women with a poor ovarian response (1-3 oocytes) compared with women with a normal response (10-15 oocytes) (1.5% vs 0.8%), crude odds ratio (OR): 2.001, 95% CI: 1.159-3.465, P = 0.013. However, the difference was not significant after adjusting for confounders, adjusted OR: 1.753, 95% CI: 0.997-3.081, P = 0.051. LIMITATIONS, REASONS FOR CAUTION: Data on some known confounders such as smoking and medical history of gestational diabetes mellitus and preeclampsia were lacking. As with any retrospective study, unknown confounders may affect outcomes. WIDER IMPLICATIONS OF THE FINDINGS: In the freeze-all cycles, there was no association between number of oocytes retrieved and adverse neonatal outcomes. This is a reassuring finding for both clinicians and patients who are planning to use freeze-all cycles for a variety of indications. STUDY FUNDING/COMPETING INTEREST(S): Grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare.

N6-methyladenosine RNA methylation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, and hyperglycemic memory associated with diabetes carries the risk of disease occurrence, even after the termination of blood glucose injury. The existence of hyperglycemic memory supports the concept of an epigenetic mechanism involving n6-methyladenosine (m6A) modification. Several studies have shown that m6A plays a key role in the pathogenesis of DKD. This review addresses the role and mechanism of m6A RNA modification in the progression of DKD, including the regulatory role of m6A modification in pathological processes, such as inflammation, oxidative stress, fibrosis, and non-coding (nc) RNA. This reveals the importance of m6A in the occurrence and development of DKD, suggesting that m6A may play a role in hyperglycemic memory phenomenon. This review also discusses how some gray areas, such as m6A modified multiple enzymes, interact to affect the development of DKD and provides countermeasures. In conclusion, this review enhances our understanding of DKD from the perspective of m6A modifications and provides new targets for future therapeutic strategies. In addition, the insights discussed here support the existence of hyperglycemic memory effects in DKD, which may have far-reaching implications for the development of novel treatments. We hypothesize that m6A RNA modification, as a key factor regulating the development of DKD, provides a new perspective for the in-depth exploration of DKD and provides a novel option for the clinical management of patients with DKD.

Network Pharmacology and Experimental Analysis to Explore the Effect and Mechanism of Modified Buyang Huanwu Decoction in the Treatment of Diabetic Nephropathy.

Purpose: Preventing and treating diabetic nephropathy (DN) are global challenges due to the complexity and diversity of its causes and manifestations. It is important to find effective medications to treat DN. Patients and Methods: Gene expression files of DN were downloaded from the GEO database to identify the differentially expressed genes. Network pharmacology and molecular docking were used to explore the possible mechanisms of modified Buyang Huanwu Decoction (mBHD) in treating DN. Biochemical, histopathological, and real-time PCR analyses were conducted in both in vivo and in vitro DN models to investigate the effects of mBHD. Results: A total of 336 active ingredients and 124 potential targets of mBHD associated with DN were identified. Among them, 8 hub genes were found to be important targets for mBHD in treating DN and were significantly correlated with the infiltration status of six immune cells. Partially, the active ingredients of mBHD demonstrated good stability in binding to CASP3 and TP53. mBHD treatment significantly reduced levels of total cholesterol, triglyceride, blood urea nitrogen, serum creatinine, and microalbumin in db/db mice. HE and Masson's staining results showed that mBHD attenuated renal injury in db/db mice. Additionally, mBHD treatment could significantly alter the expression of CASP3, CCL2, TP53, ALB, and HMOX1. Conclusion: mBHD may be involved in the treatment of DN through multiple ingredients, targets, and pathways. In addition, mBHD could alleviate renal injury in db/db mice, possibly involving CASP3, CCL2, TP53, ALB, and HMOX1.

Empagliflozin attenuating renal interstitial fibrosis in diabetic kidney disease by inhibiting lymphangiogenesis and lymphatic endothelial-to-mesenchymal transition via the VEGF-C/VEGFR3 pathway.

Renal interstitial fibrosis (RIF) is a significant pathological change in diabetic kidney disease (DKD) that can be induced by endothelial-to-mesenchymal transition (EndMT). Lymphangiogenesis, mediated by the vascular endothelial growth factor-C (VEGF-C)/vascular endothelial growth factor receptor-3 (VEGFR-3) pathway, plays a crucial role in the development of RIF in DKD. Although numerous studies have demonstrated the efficacy of empagliflozin in treating renal injury, its effects on lymphangiogenesis in DKD-related RIF and the underlying mechanisms remain unclear. In the present study, significant lymphangiogenesis was assessed in the renal interstitium of patients with DKD. We subsequently explored the relationship between DKD-related RIF and lymphangiogenesis in mouse models, high-glucose (HG)-stimulated renal HK-2 cell lines, and human lymphatic endothelial cells (hLECs). Additionally, we evaluated the effects of empagliflozin on these processes. The results revealed that HG induces lymphangiogenesis, which exacerbates RIF by promoting inflammatory responses. Furthermore, hLECs directly contributed to the progression of DKD-related RIF through EndMT. Further analysis revealed that tubular epithelial cells (TECs) act as effector cells for VEGF-C, with the epithelial-to-mesenchymal transition (EMT) of TECs occurring concurrently with the EndMT of lymphatic vessels. Empagliflozin inhibited RIF in DKD by suppressing the VEGF-C/VEGFR3 pathway and reducing lymphangiogenesis. In conclusion, this study elucidates the interplay between lymphangiogenesis, EndMT, and RIF in DKD and provides new insights into the mechanism by which empagliflozin treats DKD.

Role of SAA1 in endometrial extracellular matrix remodeling in polycystic ovary syndrome: implication for pregnancy loss.

CONTEXT: Abnormal endometrial extracellular matrix (ECM) remodeling compromises endometrial receptivity and diminishes the probability of a successful live birth. Serum amyloid A1 (SAA1), a modulator of inflammation, is elevated in the circulation of polycystic ovary syndrome (PCOS) patients and involved in ECM remodeling during tissue repair. However, the specific role of SAA1 in endometrial ECM remodeling and subsequent risk of pregnancy loss in PCOS patients remains unclear. OBJECTIVE: To examine the role and underlying mechanism of SAA1 in ECM remodeling in the endometrium of PCOS patients. DESIGN: Serum samples from PCOS and control patients were utilized to investigate the relationship between the abundance of SAA1 and pregnancy loss. Human endometrial tissues and primary human endometrial stromal cells were used to examine the role and underlying mechanism of SAA1 in ECM remodeling. RESULTS: Serum SAA1 concentration was elevated and could serve as an independent risk of pregnancy loss in PCOS patients. Increased SAA1 abundance was also observed in endometrium obtained from these patients. Further mechanistic studies showed that SAA1 stimulated collagen I chains synthesis (COL1A1 and COL1A2) in endometrial stromal cells, suggesting excessive SAA1 may contribute to endometrial ECM remodeling, resulting in a non-supportive environment for ongoing pregnancy. This effect was abolished by either a toll-like receptors 2/4 antagonist or a nuclear factor κB inhibitor. CONCLUSIONS: The locally elevated levels of SAA1 in endometrium contribute to ECM over-deposition by inducing collagen I synthesis in PCOS patients, which may hamper embryo implantation and increase the risk of pregnancy loss. These observations highlight the crucial role of heightened SAA1 in orchestrating endometrial dysfunction and shed light on potential therapeutic avenues for improving reproductive outcomes in PCOS patients.

The effect of peak serum estradiol level during ovarian stimulation on cumulative live birth and obstetric outcomes in freeze-all cycles.

Objective: To determine whether the peak serum estradiol (E2) level during ovarian stimulation affects the cumulative live birth rate (CLBR) and obstetric outcomes in freeze-all cycles. Methods: This retrospective cohort study involved patients who underwent their first cycle of in vitro fertilization followed by a freeze-all strategy and frozen embryo transfer cycles between January 2014 and June 2019 at a tertiary care center. Patients were categorized into four groups according to quartiles of peak serum E2 levels during ovarian stimulation (Q1-Q4). The primary outcome was CLBR. Secondary outcomes included obstetric and neonatal outcomes of singleton and twin pregnancies. Poisson or logistic regression was applied to control for potential confounders for outcome measures, as appropriate. Generalized estimating equations were used to account for multiple cycles from the same patient for the outcome of CLBR. Results: A total of 11237 patients were included in the analysis. Cumulatively, live births occurred in 8410 women (74.8%). The live birth rate (LBR) and CLBR improved as quartiles of peak E2 levels increased (49.7%, 52.1%, 54.9%, and 56.4% for LBR; 65.1%, 74.3%, 78.4%, and 81.6% for CLBR, from the lowest to the highest quartile of estradiol levels, respectively, P<0.001). Such association remained significant for CLBR after accounting for potential confounders in multivariable regression models, whereas the relationship between LBR and peak E2 levels did not reach statistical significance. In addition, no significant differences were noticed in adverse obstetric and neonatal outcomes (gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, placental disorders, preterm birth, low birthweight, and small for gestational age) amongst E2 quartiles for either singleton or twin live births, both before and after adjustment. Conclusion: In freeze-all cycles, higher peak serum E2 levels during ovarian stimulation were associated with increased CLBR, without increasing the risks of adverse obstetric and neonatal outcomes.

Ambient air pollution on fecundity and live birth in women undergoing assisted reproductive technology in the Yangtze River Delta of China.

BACKGROUND: Ambient air pollution has adverse effects on the reproductive system. However, inconsistent conclusions were reached from different studies with regard to air pollutants and pregnancy outcomes, especially the livebirth rate in assisted reproductive technology (ART) in different windows of exposure. METHODS: A retrospective cohort study was conducted on 12,665 women who underwent first fresh or frozen embryo transfer cycle in the Yangtze River Delta of China. Daily average levels of six air pollutants in four different periods were obtained: Period 1 and 2: 90 days or one year prior to oocyte retrieval; Period 3 and 4: the day of oocyte retrieval or one year prior to oocyte retrieval to the day of serum hCG test or to the end of the pregnancy. A multiple logistic regression model was used to investigate the association between air pollutant exposure and pregnancy outcomes. Stratified analyses were conducted to explore potential modifier effects. RESULTS: The one year exposure window (Period 2) before oocyte retrieval had a more evident negative association with pregnancy outcomes. Each IQR increase in ambient PM10 (OR: 0.89, 95% CI: 0.84-0.93), PM2.5 (OR: 0.82, 95% CI: 0.77-0.87), SO2 (OR: 0.87, 95% CI: 0.83-0.91) and CO (OR: 0.91, 95% CI: 0.87-0.96) was associated with a respective 11%, 18%, 13% and 9% decrease in the likelihood of live birth. In entire exposure window of Period 4, all air pollutants except for O3 were associated with a decreased likelihood of live birth. Stratified analyses showed that women undergoing frozen embryo transfer cycles, especially those with two embryos transferred, were more vulnerable to air pollutant exposure. CONCLUSION: This study indicates a negative association between air pollutant exposure before oocyte retrieval and livebirth rate in ART. The adverse impact was more evident in one year exposure compared to three-month refresh cycle of the gametes. Additional protection from air pollution should be undertaken at least one year before ART, particularly for those with frozen embryo transfer cycles.

Impact of Day 7 Blastocyst Transfer on Obstetric and Perinatal Outcome of Singletons Born After Vitrified-Warmed Embryo Transfer.

BACKGROUND: Extended embryo culture has been reported to affect perinatal outcome regarding higher risks of large for gestational age (LGA) and preterm birth (PTB) yet decreased risk of small for gestational age (SGA). However, existing data about the obstetric outcome and the safety for offspring resulting from the transfer of day 7 blastocysts is rare. OBJECTIVES: To compare obstetric and perinatal outcome using embryos vitrified on day 7 with those vitrified on day 3, day 5, and day 6. METHODS: Data were collected from 4489 infertile women who gave birth to live-born singletons after vitrified-warmed embryo transfer cycles from January 1, 2006 to December 31, 2017. Singletons were compared depending on the age of embryos. Main perinatal outcome parameters included PTB (gestational age < 37 weeks), very PTB (VPTB, gestational age < 32 weeks), LGA (birthweights > 90th percentiles), and SGA (birthweights < 10th percentiles). Obstetric outcomes included gestational diabetes (GDM), pregnancy-induced hypertension (PIH), preterm premature rupture of membranes (PPROM), pre-eclampsia, placenta previa, placental abruption, and postpartum hemorrhage. Propensity score matching (PSM) was used to adjust the confounding factors across groups and then analyze the association between in vitro culture period and the outcome measures. RESULTS: After PSM, the transfer of day 7 blastocysts was associated with higher birth weight Z-scores and increased incidence of very large for gestational age (VLGA) compared with the transfer of day 3 cleavage-stage embryos while the incidence of PTB, low birth weight (LBW), SGA did not reach statistical significance. Moreover, comparable perinatal outcome was found in the comparison of day 7 vs. day 5 and day 7 vs. day 6. Day 7 blastocysts did not result in adverse obstetric outcome compared with day 3, day 5, and day 6 embryos, respectively. CONCLUSION: In vitrified-warmed transfer cycles, day 7 blastocysts were associated with adverse perinatal outcome regarding higher risk of VLGA compared with day 3 cleavage-stage embryo, while blastocysts with diverse growth rates embrace similar developmental viability regardless of blastocysts vitrified on day 5, day 6, or day 7.

Poor Embryo Quality Is Associated With A Higher Risk of Low Birthweight in Vitrified-Warmed Single Embryo Transfer Cycles.

BACKGROUND: Previous studies have reported the association between embryo quality and perinatal outcomes in fresh cycles, after cleavage-stage or blastocyst embryo transfer, and found no significant difference. However, in terms of vitrified-warmed embryo transfer cycles, the impact of embryo quality on neonatal and maternal outcomes has not been evaluated. OBJECTIVES: To explore the association between the quality of a single vitrified-warmed embryo and perinatal outcomes. METHODS: This retrospective study included 2403 live-born singletons derived from single vitrified-warmed embryo transfer cycles during January 2006 and July 2018. Neonatal and maternal outcomes were compared between singletons resulting from the use of single good quality embryo (GQE) (n = 1854) and single poor quality embryo (PQE) (n = 549) and analyzed in the group of cleavage-stage embryo transfer and the group of blastocyst transfer, respectively. RESULTS: A significantly higher risk of low birthweight (LBW, birthweight <2500 g) was observed in the singletons derived from the transfer of single PQE compared with those derived from the transfer of single GQE both in cleavage and blastocyst stages (cleavage-stage, AOR 2.62, 95% CI 1.27-5.37; blastocyst stage, AOR 1.98, 95% CI 1.06-3.70). An increased risk of preterm birth (PTB, gestational age <37 weeks) was also observed in singletons born after transfer of a PQE of cleavage-stage compared with those after a GQE of cleavage-stage (AOR 2.40, 95% CI 1.28-4.49). The transfer of single poor quality blastocyst was associated with a higher risk of placenta previa compared with the transfer of single good quality blastocyst (AOR 2.65, 95% CI 1.26-5.57). Other maternal complications, neonatal malformations, and neonatal complications were similar between compared groups. CONCLUSION: In vitrified-warmed cycles with single embryo transfer, poor embryo quality would result in a significantly higher risk of LBW, regardless of cleavage-stage or blastocyst embryo transfer. Meanwhile, the transfer of poor cleavage-stage embryo was also associated with an increased incidence of PTB.

Fertility and Neonatal Outcomes of Freeze-All vs. Fresh Embryo Transfer in Women With Advanced Endometriosis.

Background: Eutopic endometrium from women with endometriosis has functional changes in several aspects, which may largely account for the decrease in the quality of endometrial receptivity. It is of utmost importance to know whether freeze-all strategy can restore optimal receptivity in endometriotic women leading to the better ART outcomes. Methods: Retrospective study involved patients with advanced endometriosis undergoing first embryo transfer cycles during the period from March 2006 to March 2017 at a tertiary care center. After propensity score matching, there were 506 women in the freeze-all group and 255 women in fresh group. Our main outcomes included the rates of implantation, clinical pregnancy, and live birth. Subgroup analyses were performed after stratification by the number of oocytes retrieved and fertilization method. Neonatal outcomes included gestational age and birth weight z-score for singletons and multiple births. Results: In our matched cohort, the implantation, clinical pregnancy and live birth rates were statistically significantly higher in the freeze-all group compared with fresh transfer groups (34.4 vs. 25.5%, 51.8 vs. 38.8%, and 45.3 vs. 31.8%, all P < 0.001, respectively). A more beneficial effect of freeze-all cycles was found in patients who got more than 15 oocytes. Additionally, when ICSI insemination techniques were used to achieve fertilization, the advantage of freeze-all strategy was not obvious. Assessment of 382 babies showed no statistically significant difference in the mode of delivery, sex of live-born, gestational age, unadjusted median birth weight, and z-score between two study groups. Conclusion: Freeze-all strategy is an attractive option to improve the outcomes of ART for women with advanced endometriosis.