Body mass index modified the effectiveness of low dose aspirin treatment on frozen-thawed embryo transfer outcome: a propensity score-matched study.

Background: Low-dose aspirin is one of the widely used adjuvants in assisted reproductive technologies with the hope of improving the live birth rate. However, the studies regarding its effects are conflicting. The study aimed to investigate the association between aspirin administration and live birth following frozen-thawed embryo transfer (FET) in patients with different body mass index (BMI). Methods: A retrospective cohort study was performed on 11,993 patients receiving FET treatments. 644 of which received a low-dose aspirin (100 mg/day) during endometrial preparation until 10 weeks after transfer. Propensity score matching was performed to avoid selection biases and potential confounders. Results: The clinical pregnancy rate and live birth rate were similar before matching (54.4% versus 55.4%, RR: 1.02, 95%CI: 0.95-1.09, and 46.3 versus 47.8, RR: 1.03, 95%CI: 0.95-1.12 respectively). A weak association in favor of aspirin administration was found in the matched cohort (49.5% versus 55.4%, RR: 1.12, 95%CI: 1.01-1.24, and 41.9% versus 47.8%, RR: 1.14, 95%CI: 1.01-1.29 respectively). However, when stratified the patients with WHO BMI criteria, a significant increase in live birth rate associated with aspirin treatment was found only in patients with low BMI (<18.5 kg/m2) in either unmatched (46.4% versus 59.8%, RR:1.29, 95%CI:1.07-1.55) or matched cohort (44% versus 59.8%, RR: 1.36, 95%CI: 1.01-1.83) but not in patients with higher BMI categories. With the interaction analysis, less association between aspirin and live birth appeared in patients with normal BMI (Ratio of OR:0.49, 95%CI: 0.29-0.81) and high BMI (Ratio of OR:0.57, 95%CI: 0.27-1.2) compared with patients with low BMI. Conclusion: BMI may be considered when evaluating aspirin's effect in FET cycles.

Indications affect neonatal outcomes following early rescue ICSI: a retrospective study.

PURPOSE: To investigate the impact of heterogeneity in patient indications or insemination protocols on neonatal outcomes of singletons following early rescue ICSI (rICSI) treatments. METHODS: A retrospective study was conducted. Propensity score matching and multivariable logistic regression were used to adjust for confounders and biases. RESULTS: A total of 9095 IVF patients, 2063 ICSI patients, and 642 early rICSI patients were included in the study. No differences were detected in neonatal outcomes except small for gestational age (SGA) which increased in early rICSI patients compared with both unmatched and matched IVF groups with the risk ratio (RR) of 1.31 (95% CI: 1.05, 1.64) and 1.49 (95% CI: 1.05, 2.12). Further analysis showed that SGA increased significantly in partial fertilization failure (PFF) cycles with RRs of 1.56 (95% CI: 1.08, 2.27) and 1.78 (95% CI: 1.22, 2.59) compared with both unmatched and matched IVF patients but not in TFF patients. A positive association between fertilization rate via IVF and birth weight z-score was revealed in the PFF patients. CONCLUSION: Early rICSI in patients with total fertilization failure (TFF) appeared to be safe in terms of neonatal outcomes. However, when expanding the indications of rICSI to PFF patients, the SGA in the offspring increased, suggesting a potential effect on long-term health. Since other treatment options, such as using only the IVF-origin embryos still exist for these patients, further studies were needed to confirm the optimal decision for these patients.

Pretreatment prediction for IVF outcomes: generalized applicable model or centre-specific model?

STUDY QUESTION: What was the performance of different pretreatment prediction models for IVF, which were developed based on UK/US population (McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model), in wider populations? SUMMARY ANSWER: For a patient in China, the published pretreatment prediction models based on the UK/US population provide similar discriminatory power with reasonable AUCs and underestimated predictions. WHAT IS KNOWN ALREADY: Several pretreatment prediction models for IVF allow patients and clinicians to estimate the cumulative probability of live birth in a cycle before the treatment, but they are mostly based on the population of Europe or the USA, and their performance and applicability in the countries and regions beyond these regions are largely unknown. STUDY DESIGN, SIZE, DURATION: A total of 26 382 Chinese patients underwent oocyte pick-up cycles between January 2013 and December 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: UK/US model performance was externally validated according to the coefficients and intercepts they provided. Centre-specific models were established with XGboost, Lasso, and generalized linear model algorithms. Discriminatory power and calibration of the models were compared as the forms of the AUC of the Receiver Operator Characteristic and calibration curves. MAIN RESULTS AND THE ROLE OF CHANCE: The AUCs for McLernon 2016 model, Luke model, Dhillon model, and McLernon 2022 model were 0.69 (95% CI 0.68-0.69), 0.67 (95% CI 0.67-0.68), 0.69 (95% CI 0.68-0.69), and 0.67 (95% CI 0.67-0.68), respectively. The centre-specific yielded an AUC of 0.71 (95% CI 0.71-0.72) with key predictors including age, duration of infertility, and endocrine parameters. All external models suggested underestimation. Among the external models, the rescaled McLernon 2022 model demonstrated the best calibration (Slope 1.12, intercept 0.06). LIMITATIONS, REASONS FOR CAUTION: The study is limited by its single-centre design and may not be representative elsewhere. Only per-complete cycle validation was carried out to provide a similar framework to compare different models in the sample population. Newer predictors, such as AMH, were not used. WIDER IMPLICATIONS OF THE FINDINGS: Existing pretreatment prediction models for IVF may be used to provide useful discriminatory power in populations different from those on which they were developed. However, models based on newer more relevant datasets may provide better calibrations. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China [grant number 22176159], the Xiamen Medical Advantage Subspecialty Construction Project [grant number 2018296], and the Special Fund for Clinical and Scientific Research of Chinese Medical Association [grant number 18010360765]. TRIAL REGISTRATION NUMBER: N/A.

Does cleavage stage morphology increase the discriminatory power of prediction in blastocyst transfer outcome?

PURPOSE: To evaluate the contribution of the cleavage stage morphological parameters to the prediction of blastocyst transfer outcomes. METHODS: A retrospective study was conducted on 8383 single-blastocyst transfer cycles including 2246 fresh and 6137 vitrified-warmed cycles. XGboost, LASSO, and GLM algorithms were employed to establish models for assessing the predictive value of the cleavage stage morphological parameters in transfer outcomes. Four models were developed using each algorithm: all-in model with or without day 3 morphology and embryo quality-only model with or without day 3 morphology. RESULTS: The live birth rate was 48.04% in the overall cohort. The AUCs of the models with the algorithm of XGboost were 0.83, 0.82, 0.63, and 0.60; with LASSO were 0.66, 0.66, 0.61, and 0.60; and with GLM were 0.66, 0.66, 0.61, and 0.60 respectively. In models 1 and 2, female age, basal FSH, peak E2, endometrial thickness, and female BMI were the top five critical features for predicting live birth; In models 3 and 4, the most crucial factor was blastocyst formation on D5 rather than D6. In model 3, incorporating cleavage stage morphology, including early cleavage, D3 cell number, and fragmentation, was significantly associated with successful live birth. Additionally, the live birth rates for blastocysts derived from on-time, slow, and fast D3 embryos were 49.7%, 39.5%, and 52%, respectively. CONCLUSIONS: The value of cleavage stage morphological parameters in predicting the live birth outcome of single blastocyst transfer is limited.

Association between ambient air pollutants and birthweight of singletons following assisted reproductive technologies.

OBJECTIVE: To investigate the associations between exposure to ambient air pollutants and birthweight following ART treatment. DESIGN: Retrospective cohort study. METHODS: We included 11,599 singletons derived from fresh cycles or frozen-thawed embryo transfer (FET) cycles between Jan 2013 and Dec 2019. Exposure to six air pollutants (SO2, NO2, CO, O3, PM2.5, and PM10) at patients` residences and the clinic site were estimated using the inverse distance weighting interpolation method based on data obtained from monitor sites. The daily mean levels of pollutants were estimated in potential exposure windows (the period from three months before treatment to oocyte retrieval, the period of ovarian stimulation, the period of in vitro culture, the period from embryo transfer to hCG test, the period of entire pregnancy, the 1st, 2nd, and 3rd trimester) were calculated. Generalized additive models adjusted for confounders including maternal age, BMI, and parity were used to evaluate the association between exposures and birthweight. Interaction of exposures and ART-associated factors, such as supraphysiologic estradiol and frozen-thawed, were explored in an XGboost model. MAIN OUTCOME MEASURES: Birthweight and z-score of singletons. RESULTS: In fresh cycles, O3 exposure during the period from three months before treatment to oocyte retrieval and SO2 exposure during in vitro culture at the ART clinic showed a linear association with birthweight (7.24, 95% CI: 1.18-13.31 g per 10 µg/m3 increase in O3; 25.92, 95% CI: 8.26-43.58 g per 10 µg/m3 increase in SO2, respectively). For patients receiving single blastocyst transfer with exposures below the China standard of 20 µg/m3, an increase of 10 µg/m3 in SO2 was associated with a 61.52 (95% CI: 1.13-121.91) g increase in birthweight. In FET cycles, no significant association was found between air pollution and birthweight. XGboost model did not reveal a strong interaction between the exposures and ART-related factors, except for the interactions between O3 exposure and BMI. However, none of the interactions reached a higher rank of importance. CONCLUSIONS: Air pollution exposure during ART treatment may affect the birthweight of the offspring.

Oocyte degeneration in a cohort adversely affects clinical outcomes in conventional IVF cycles: a propensity score matching study.

Background: Oocyte degeneration was mostly described in intracytoplasmic sperm injection (ICSI) cycles; there is no report showing the relationship between oocyte degeneration and clinical outcomes in conventional in vitro fertilization (IVF) cycles. This retrospective study using the propensity score (PS) matching method aimed to explore whether the presence of oocyte degeneration in conventional IVF cycles would affect the sibling embryo development potential and clinical outcomes. Methods: Patients with at least one oocyte degenerated after short-term insemination and stripping were defined as the degeneration (DEG) group, while patients with no oocyte degenerated were defined as the non-degeneration (NONDEG) group. The PS matching method was used to control for potential confounding factors, and a multivariate logistic regression analysis was made to evaluate whether the presence of oocyte degeneration would affect the cumulative live birth rate (CLBR). Results: After PS matching, basic characteristics were similar between the two groups, oocyte yield was significantly higher in the DEG group than the NON-DEG group (P < 0.05), mature oocyte number, 2 pronuclear (2PN) embryo number, 2PN embryo clearage rate, "slow" embryo number, "accelerated" embryo number, rate of cycles with total day 3 embryo extended culture, number of frozen embryo transfer (FET) cycles, transferred embryo stage, transferred embryo number, and live birth rate in fresh embryo transfer cycles were all similar between the two groups (P > 0.05), but the 2PN fertilization rate, available embryo number, high-quality embryo number, "normal" embryo number, frozen embryo number, blastocyst formation rate, and no available embryo cycle rate were all significantly lower in the DEG group than the NON-DEG group (P < 0.05). The cumulative live birth rate was also significantly lower in the DEG group than in the NON-DEG group (70.2% vs. 74.0%, P = 0.0019). Multivariate logistic regression analysis further demonstrated that the presence of oocyte degeneration in conventional IVF cycles adversely affects the CLBR both before (OR = 0.83, 95% CI: 0.75-0.92) and after (OR = 0.82, 95% CI: 0.72-0.93) PS matching. Conclusion: Our findings together revealed that the presence of oocyte degeneration in a cohort of oocytes may adversely affect subsequent embryo development potential and clinical outcomes in conventional IVF cycles.

Predicting the unexpected total fertilization failure in conventional in vitro fertilization cycles: What is the role of semen quality?

Background: Male and female gametes factors might contribute to the total fertilization failure (TFF). In first in vitro fertilization (IVF) cycles, decision-making of insemination protocol was mainly based on semen quality for the contribution of female clinical characteristics to TFF remained obscure. The purpose of the study was to evaluate the role of semen quality in predicting unexpected TFF. Methods: A single-center retrospective cohort analysis was performed on 19539 cycles between 2013 and 2021. Two algorithms, a Least Absolute Shrinkage and Selection Operator (LASSO) and an Extreme Gradient Boosting (Xgboost) were used to create models with cycle characteristics parameters. By including semen parameters or not, the contribution of semen parameters to the performance of the models was evaluated. The area under the curve (AUC), the calibration, and the net reclassification index (NRI) were used to evaluate the performance of the models. Results: The prevalence of TFF were .07 (95%CI:0.07-0.08), and .08 (95%CI:0.07-0.09) respectively in the development and validation group. Including all characteristics, with the models of LASSO and Xgboost, TFF was predicted with the AUCs of .74 (95%CI:0.72-0.77) and .75 (95%CI:0.72-0.77) in the validation group. The AUCs with models of LASSO and Xgboost without semen parameters were .72 (95%CI:0.69-0.74) and .73 (95%CI:0.7-0.75). The models of LASSO and Xgboost with semen parameters only gave the AUCs of .58 (95%CI:0.55-0.61) and .57 (95%CI:0.55-0.6). For the overall validation cohort, the event NRI values were -5.20 for the LASSO model and -.71 for the Xgboost while the non-event NRI values were 10.40 for LASSO model and 0.64 for Xgboost. In the subgroup of poor responders, the prevalence was .21 (95%CI:0.18-0.24). With refitted models of LASSO and Xgboost, the AUCs were .72 (95%CI:0.67-0.77) and .69 (95%CI:0.65-0.74) respectively. Conclusion: In unselected patients, semen parameters contribute to limited value in predicting TFF. However, oocyte yield is an important predictor for TFF and the prevalence of TFF in poor responders was high. Because reasonable predicting power for TFF could be achieved in poor responders, it may warrant further study to prevent TFF in these patients.

Low BMI is associated with poor IUI outcomes: a retrospective study in 13,745 cycles.

PURPOSE: To evaluate the association between body mass index (BMI) and pregnancy outcomes in women receiving intrauterine insemination (IUI) treatment. METHODS: The study included 6407 women undergoing 13,745 IUI cycles stratified by BMI. Cox regression was used to analyze the association between BMI and cumulative live births across multiple IUI cycles. A generalized estimating equation (GEE) was used to analyze the live birth rate per cycle. RESULTS: Compared with normal-weight women (n = 4563), underweight women (n = 990) had a lower cumulative pregnancy and live birth rate (20.71% vs 25.93% and17.17% vs 21.61%, respectively), while overweight women (n = 854) had a higher cumulative pregnancy and live birth rate (31.97%, 26.58%). Adjusted for confounders, the hazard ratio (HR) for achieving live birth following up to a maximum of four IUI cycles was 0.80 (95% CI: 0.67-0.95), comparing underweight with normal weight. In the GEE analyses, low BMI was also associated with a lower per-cycle birth rate (OR 0.79, 95% CI: 0.66-0.95), with adjustment for cycle-specific parameters, including ovarian stimulation, endometrial thickness, and follicular diameter. CONCLUSION: Low BMI is associated with poor IUI outcomes.

Day-3-embryo fragmentation is associated with singleton birth weight following fresh single blastocyst transfer: A retrospective study.

Background: Previous studies have arguably associated poor embryo morphology with low birth weight in singletons following single embryo transfer. However, the association between birth weight and specific morphological features in the cleavage stage remains less known. The purpose of the study was to investigate whether morphological features of embryos at the cleavage stage affect birth weight following blastocyst transfer. Methods: The single-center retrospective cohort study included 4,226 singletons derived from fresh single cleavage-stage embryo transfer (ET; n = 1,185), fresh single blastocyst transfer (BT; n = 787), or frozen-thawed single blastocyst transfer (FBT; n = 2,254) between 2016 and 2019. Morphological parameters including early cleavage, day-3 fragmentation, symmetry, blastomere number, and blastocyst morphology were associated with neonatal birth weight and birth weight z-score in multivariate regression models. The models were adjusted for maternal age, body mass index (BMI), parity, peak estradiol level, endometrial thickness, insemination protocol, female etiologies, order of transfer, mode of delivery, and year of treatment. Results: Adjusted for confounders, day-3 fragmentation was the only morphological feature associated with birth weight and birth weight z-score, while early cleavage, symmetry, blastomere number, and blastocyst morphology were not. Day-3 fragmentation increased the birth weight in both the ET (115.4 g, 95% CI: 26.6-204.2) and BT groups (168.8 g, 95% CI: 48.8-288.8) but not in the FBT group (7.47 g, 95% CI: -46.4 to 61.3). The associations between birth weight and these morphological parameters were confirmed through birth weight z-score analyses. The adjusted odds of large for gestational age (LGA) and high birth weight were also significantly greater in singletons following the transfer of fragmented embryos in the BT group [odds ratio (OR) 3, 95% CI: 1.2-7.51 and OR 3.65, 95% CI: 1.33-10, respectively]. The presence of fragmentation at the cleavage stage also affected the association between the blastocyst morphology and birth weight. Inner cell mass grades were negatively associated with birth weight in blastocysts with day-3 fragmentation but not in blastocysts without. Conclusions: The birth weight following blastocyst transfer was found to be positively associated with fragmentation at the cleavage stage. The data did not support the argument that transferring a poor-looking embryo may increase the risks of low birth weight. However, concerns for LGA infants remain.

Uterine factors modify the association between embryo transfer depth and clinical pregnancy.

The embryo transfer depth may affect the chance of pregnancy. However, embryo dislodging caused by uterine contraction may occur after the transfer. The aim of the retrospective study was to investigate whether the factors associated with uterine contractilities, such as endometrial thickness and progesterone elevation, affect the association between transfer depth and implantation. A total of 7849 fresh transfer cycles on conventional stimulation in a single in vitro fertilization (IVF) center during the period 2013-2015 was reviewed. Patients were categorized according to quartiles of embryo transfer depth (≤ 9 mm, n = 1735, 9.1-11 mm, n = 2557, 11.1-14 mm, n = 1933, ≥ 1.4 mm, n = 1624, respectively). Adjusted for confounding factors, the adjusted odds ratio (aOR) (95% confidence interval, CI) for clinical pregnancy was 0.90 (0.79-1.02), 0.86 (0.74-0.99), and 0.70 (0.60-0.82) respectively in quartiles 2 through 4, comparing with quartile 1. However, the aORs were significantly increased when the endometrial thickness was < 8 mm. In comparison with that in the cycles with a normal endometrial thickness (8-11 mm), the aORs comparing quartiles 2 through 4 with quartile 1 in the cycles with an endometrial thickness < 8 mm increased from 0.78 (95% CI 0.65-0.93), 0.79 (95% CI 0.65-0.97), and 0.64 (95% CI 0.51-0.81) to 1.73 (95% CI 1.21-2.47), 1.04 (95% CI 0.69-1.56), and 1.45 (95% CI 0.91-2.31), respectively. In the cycles with elevated progesterone and blastocyst stage transfer, the aORs comparing quartiles 4 with quartile 1 decreased from 0.73 (95% CI 0.62-0.87) and 0.74 (95% CI 0.63-0.87) to 0.58 (95% CI 0.40-0.84) and 0.42 (95% CI 0.25-0.73) than those in the cycles without. However, only blastocyst transfer showed a significant interaction with transfer depth (p = 0.043). Our data suggested that endometrial thickness and blastocyst transfer significantly affect the association between embryo transfer depth and clinical pregnancy.

Does conventional morphological evaluation still play a role in predicting blastocyst formation?

BACKGROUND: Advanced models including time-lapse imaging and artificial intelligence technologies have been used to predict blastocyst formation. However, the conventional morphological evaluation of embryos is still widely used. The purpose of the present study was to evaluate the predictive power of conventional morphological evaluation regarding blastocyst formation. METHODS: Retrospective evaluation of data from 15,613 patients receiving blastocyst culture from January 2013 through December 2020 in our institution were reviewed. Generalized estimating equations (GEE) were used to establish the morphology-based model. To estimate whether including more features regarding patient characteristics and cycle parameters improve the predicting power, we also establish models including 27 more features with either LASSO regression or XGbosst. The predicted number of blastocyst were associated with the observed number of the blastocyst and were used to predict the blastocyst transfer cancellation either in fresh or frozen cycles. RESULTS: Based on early cleavage and routine observed morphological parameters (cell number, fragmentation, and symmetry), the GEE model predicted blastocyst formation with an AUC of 0.779(95%CI: 0.77-0.787) and an accuracy of 74.7%(95%CI: 73.9%-75.5%) in the validation set. LASSO regression model and XGboost model based on the combination of cycle characteristics and embryo morphology yielded similar predicting power with AUCs of 0.78(95%CI: 0.771-0.789) and 0.754(95%CI: 0.745-0.763), respectively. For per-cycle blastocyst yield, the predicted number of blastocysts using morphological parameters alone strongly correlated with observed blastocyst number (r = 0.897, P < 0.0001) and predicted blastocyst transfer cancel with an AUC of 0.926((95%CI: 0.911-0.94). CONCLUSION: The data suggested that routine morphology observation remained a feasible tool to support an informed decision regarding the day of transfer. However, models based on the combination of cycle characteristics and embryo morphology do not increase the predicting power significantly.

The effect of epididymal sperm cryopreservation on neonatal birthweight following PESA-ICSI.

PURPOSE: To compare the neonatal birthweight of singletons derived from ICSI cycles with fresh or frozen-thawed epididymal sperm in patients with obstructive azoospermia. METHODS: A total of 436 singletons derived from ICSI cycles with fresh (n = 220) or frozen-thawed (n = 216) epididymal sperm in obstructive azoospermia evaluated from 2012 to 2018 in the retrospective study. Multivariate generalized linear model was used to analyze the association between epididymal sperm cryopreservation and neonatal birthweight. RESULTS: The crude birthweight and z-score in neonates derived from frozen-thawed epididymal sperm were significantly lower than those from fresh epididymal sperm (3186.57 g vs 3303.61 g and - 0.18 vs 0.08, respectively), with a mean difference of 117.04 (95% CI 32.36-201.72) g and 0.25 (95% CI 0.06-0.45). Adjusted for confounders including parental age and BMI, maternal ovarian reserve, paternal FSH and T levels, peak E2 during OPU cycles, frozen-thawed embryo transfer, embryo development stage, gestational age, maternal parity and child gender, the multivariate model suggested that singletons conceived from ICSI with fresh epididymal sperm was on average 91.21 g heavier than those conceived from ICSI with frozen-thawed epdidiymal sperm (95% CI 12.72 to 166.7, P = 0.016). CONCLUSION: Cryopreservation of epididymal sperm may negatively affect birthweight.

Does the transfer of a poor quality embryo with a good quality embryo benefit poor prognosis patients?

BACKGROUND: While single embryo transfer (SET) is widely advocated, double embryo transfer (DET) remains preferable in clinical practice to improve IVF success rate, especially in poor prognosis patients with only poor quality embryos (PQEs) available in addition to one or no good quality embryos (GQEs). Furthermore, previous studies suggest PQE might adversely affect the implantation of a GQE when transferred together. This study aims to evaluate the effect of transferring an additional PQE with a GQE on the outcomes in poor prognosis patients. METHODS: A total of 5037 frozen-thawed blastocyst transfer (FBT) cycles between January 2012 and May 2019 were included. Propensity score matching was applied to control for potential confounders, and we used generalized estimating equations (GEE) models to identify the association between the effect of an additional PQE and the outcomes. RESULTS: Overall, transferring a PQE with GQE (Group GP) achieved significantly higher pregnancy rate (PR), live birth rate (LBR) and multiple pregnancy rate (MPR) than GQE only (group G). The addition of a PQE increased LBR in patients aged 35 and over and in patients who received over 3 cycles of embryo transfer (ET) (48.1% vs 27.2%, OR:2.56, 95% CI: 1.3-5.03 and 46.6% vs 35.4%, OR:1.6, 95% CI: 1.09-2.35), but not in women under 35 and in women who received less than 3 cycles of ET (48.7% vs 43.9%, OR:1.22, 95% CI: 0.93-1.59 and 48.3% vs 41.4%, OR:1.33, 95% CI: 0.96-1.85). Group GP resulted in significantly higher MPR than group G irrespective of age and the number of previous IVF cycles. CONCLUSIONS: An additional PQE does not negatively affect the implantation potential of the co-transferred GQE. Nevertheless, the addition of a PQE contributes to both live birth and multiple birth in poor prognosis patients. Physicians should still balance the benefits and risks of DET.

Ambient outdoor air pollutants and sex ratio of singletons born after in vitro fertilization: the effect of single blastocyst transfer.

OBJECTIVE: To evaluate the impact of air pollution on the sex ratio in singletons after IVF treatment and to evaluate the influence of the number of and the developmental stage of transferred embryos on the sex ratio. DESIGN: Retrospective cohort study. SETTING: University-affiliated IVF unit. PATIENT(S): A total of 7,004 singletons born after fresh transfer or frozen-thawed embryo transfer (FET) between January 2013 and December 2017. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Male-to-female ratio in live-born singletons. RESULT(S): The estimated medians (interquartile range) of particle matter (PM)10, PM2.5, CO, NO2, O3, and SO2 at the IVF site were 51.4 (39.5-64.6), 27.7 (20.7-37.4), 0.62 (0.5-0.72), 32.5 (25.4-40.1), 79.6 (63.3-96.6), and 11.9 (9.3-15.9) µg/m3, respectively. Multivariate analysis indicated that SO2 was the only pollutant clearly associated with sex ratio. In singletons from single blastocyst transfer (SBT), as indicated by the generalized additive model, the SO2 concentration and sex ratio showed an inverted-U-shape association. In singletons after non-SBT, a monotonic decreasing in the sex ratio was observed with increased SO2 concentration. Compared with the referent category (SO2 < 7.57 µg/m3), the sex ratio at the 5th decile of SO2 (10.81-11.94 µg/m3) was increased by 2.1-fold (95% confidence interval [CI], 1.3-3.14) after adjusting covariates. In singletons born from non-SBT, the sex ratio significantly decreased only in the 9th (odds ratio = 0.69; 95% CI, 0.53-0.90) and 10th (OR = 0.74, 95% CI, 0.56-0.98) deciles. CONCLUSION(S): Low concentrations of SO2 showed an association with increased sex ratio in singletons of SBT, while in singletons born from another ET system the sex ratios did not show an association at low concentrations of SO2.

Prosaposin in seminal plasma on the day of oocyte retrieval is associated with normal fertilization and embryo development in in vitro fertilization cycles.

The prospective study including 166 participants aims to evaluate the association between seminal prosaposin and the outcomes of in vitro fertilization (IVF) cycles in humans. The generalized linear model (GLM) was used to analyze the associations between seminal prosaposin concentrations and normal fertilization rates and good embryos proportion. The generalized estimating equation (GEE) was used to evaluate the association between embryo parameters and the prosaposin concentrations. Each model was adjusted for age of the couples, female basal FSH, AFC and BMI, starting dose and oocyte yield of IVF cycles and smoker. GLM models suggested that prosaposin was significantly associated with fertilization rate (P = 0.005) and good embryo proportion (P = 0.038) while none of the semen parameters (sperm concentration, motility, progressive motility, normal morphology rate, postwash sperm concentration and motility) was significantly associated with the parameters in the cohort. Using GEE, it was also shown that prosaposin was positively associated with the occurrence of early cleavage and negatively associated with uneven cleavage pattern on day 3. In both the overall population and the normozoospermia patients, the prosaposin was significantly associated with pregnancy with adjustment with covariates. In conclusion, our data suggested that seminal prosaposin concentration could provide more information regarding normal fertilization and embryo development in IVF than traditional semen parameters.

Association between outdoor air pollution during in vitro culture and the outcomes of frozen-thawed embryo transfer.

STUDY QUESTION: Does outdoor air pollution differentially affect the outcomes of frozen-thawed embryo transfer (FET) and fresh transfer in IVF treatment? SUMMARY ANSWER: Increased SO2 and O3 levels at the site of IVF unit were significantly associated with lower live birth rates following FET but did not affect the contemporary fresh transfer outcomes. WHAT IS KNOWN ALREADY: Ambient air pollution has been associated with human infertility and IVF outcomes. However, most of the studies excluded FET cycles. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 11148 patients contributing to 16290 transfer cycles between January 2013 and December 2016 was carried out. PARTICIPANTS/MATERIALS, SETTING, METHODS: The average age of the cohort was 31.51 ± 4.48 years and the average BMI was 21.14 ± 2.37 kg/cm2. Inverse distance weighting interpolation was used to estimate the daily ambient exposures to six pollutants (PM2.5, PM10, SO2, NO2, CO, O3) at an IVF clinical site, according to the data from fixed air quality monitoring stations in the city. The exposures of each cycle were presented as average daily concentrations of pollutants from oocyte retrieval to embryo transfer/cryopreservation. Exposures were analyzed in quartiles. A generalized estimating equation was used to evaluate the association between pollutants and IVF outcomes, adjusted for important confounding factors including maternal age, infertility diagnosis, BMI, endometrial status and embryo transfer policy. MAIN RESULTS AND THE ROLE OF CHANCE: The clinical pregnancy rate and live birth rate of the cycles was 55.1% (8981/16290) and 47.1% (7672/16290), respectively. Among the included cycles, 4013 patients received 5299 FET cycles, resulting in 2263 live births (42.7% per ET), whereas 9553 patients received 10991 fresh transfer cycles, resulting in 5409 live births (49.2% per ET). SO2 and O3 levels were significantly associated with live birth rates in FET cycles, whereas none of the pollutants were significantly associated with IVF outcomes in contemporary fresh transfer cycles. The FET cycles in the highest quartile of SO2 and O3 exposure had significantly lower live birth rates (adjusted odds ratio (OR) 0.63, 95%CI 0.53-0.74; 0.69, 95% CI 0.58-0.82, respectively) in comparison with those in the lowest quartile. Models involving all transfer cycles and interaction terms (FET×exposures) suggested that FET significantly enhanced the effects of SO2 and O3 exposure on IVF outcomes (P < 0.001). Multi-pollutant models gave consistent results for the association between SO2 and live birth in FET cycles. Accounting for all six pollutants, women in the highest quartile of SO2 still had the lowest live birth rates (OR 0.61, 95%CI 0.47-0.80). LIMITATIONS, REASONS FOR CAUTION: The study was limited by its retrospective nature. The exposure data were estimated according to monitoring data rather than measured directly from the IVF unit. Unknown confounding factors may skew the results. WIDER IMPLICATIONS OF THE FINDINGS: Our data implied that embryos undergoing FET may be more vulnerable to a suboptimal environment than those undergoing fresh transfer. In heavily polluted sites or seasons, fluctuation in FET outcomes may be partially explained by the dynamic changes of ambient gaseous air pollutant. STUDY FUNDING/COMPETING INTEREST(S): National Natural Science Foundation (81302454). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Day 6 blastocyst is associated with increased birth weight in full-term singleton newborns after frozen-thawed transfer.

PURPOSE: The purpose of the study is to compare the newborns weight in singleton term birth following transfer of thawed blastocysts-frozen on either day 5 or day 6 after in vitro fertilization. METHOD: The retrospective study included 1444 frozen-thawed blastocyst transfer (FBT) cycles resulting in live singleton births between Jan 2013 and Dec 2016. The main outcomes measured were absolute birth weight, z-score adjusted for gestational age and gender, and incidence of large-for-gestational-age (LGA) newborns. Generalized linear model (GLM) and logistic regression were used in multivariate analyses. RESULT(S): Both the absolute birth weight (3416.49 ± 404.74 vs 3349.22 ± 416.17) and the z-score (0.6 ± 0.93 vs 0.41 ± 0.93) were significantly higher on day 6 FBT in comparison with day 5 FBT. The incidence of LGA newborns was also increased on day 6 FBT (22.8 vs 14.7%, P = 0.006). Adjusted for maternal age, BMI, PCOS diagnosis, present of vanishing twin, and embryo quality, the odds ratio (95% confidence interval) for LGA on day 6 FBT comparing with day 5 FBT was 1.76 (1.18-2.64). CONCLUSION(S): Day 6 FBT is associated with increased birth weight and contributes to the incidence of LGA newborns in FBT.

Differential response of AMH to GnRH agonist among individuals: the effect on ovarian stimulation outcomes.

PURPOSE: The purpose of this study is to investigate whether individual response of anti-Mullerian hormone (AMH) to gonadotropin-releasing hormone (GnRH) treatment is associated with difference in ovarian stimulation outcomes. METHODS: The retrospective study included 1058 non-polycystic ovary syndrome (PCOS) women undergoing long agonist protocol in a single in vitro fertilization unit from January 1, 2016, through December 31, 2016. Patients were grouped according to AMH changes from day 3 to the day of stimulation (group 1, change < 1 ng/ml, n = 714; group 2, decrease ≥ 1 ng/ml, n = 143; group 3, increase ≥ 1 ng/ml, n = 201). A generalized linear model including Poisson distribution and log link function was used to evaluate the association between AMH response and the number of oocytes retrieved. RESULTS: Group 2 was characterized by higher basal AMH level and increased AMH to AFC ratio in comparison with two other groups. However, the number of oocytes and ovarian sensitivity index in group 2 was significantly lower than group 3. Adjusted for age, BMI, ovarian reserve markers, and stimulation parameters, the population marginal means (95% confidence interval) of oocyte number in groups 1 through 3 were 9.51 (9.17, 9.86), 8.04 (7.54, 8.58), and 10.65 (10.15, 11.18), respectively. For patients from group 2 and group 3, basal AMH is no longer significantly associated with oocyte yield. CONCLUSIONS: AMH change in response to GnRH agonist varies among individuals; for those undergoing significant changes in AMH following GnRH agonist treatment, basal AMH may not be a reliable marker for ovarian response in long agonist protocol.