Medically Assisted Reproduction and Risk of Cancer Among Offspring.

Importance: Cancer is a leading cause of death among children worldwide. Treatments used for medically assisted reproduction (MAR) are suspected risk factors because of their potential for epigenetic disturbance and associated congenital malformations. Objective: To assess the risk of cancer, overall and by cancer type, among children born after MAR compared with children conceived naturally. Design, Setting, and Participants: For this cohort study, the French National Mother-Child Register (EPI-MERES) was searched for all live births that occurred in France between January 1, 2010, and December 31, 2021 (and followed up until June 30, 2022). The EPI-MERES was built from comprehensive data of the French National Health Data System. Data analysis was performed from December 1, 2021, to June 30, 2023. Exposure: Use of assisted reproduction technologies (ART), such as fresh embryo transfer (ET) or frozen ET (FET), and artificial insemination (AI). Main Outcomes and Measures: The risk of cancer was compared, overall and by cancer type, among children born after fresh ET, FET, or AI and children conceived naturally, using Cox proportional hazards regression models adjusted for maternal and child characteristics at birth. Results: This study included 8 526 306 children with a mean (SD) age of 6.4 (3.4) years; 51.2% were boys, 96.4% were singletons, 12.1% were small for gestational age at birth, and 3.1% had a congenital malformation. There were 260 236 children (3.1%) born after MAR, including 133 965 (1.6%) after fresh ET, 66 165 (0.8%) after FET, and 60 106 (0.7%) after AI. A total of 9256 case patients with cancer were identified over a median follow-up of 6.7 (IQR, 3.7-9.6) years; 165, 57, and 70 were born after fresh ET, FET, and AI, respectively. The overall risk of cancer did not differ between children conceived naturally and those born after fresh ET (hazard ratio [HR], 1.12 [95% CI, 0.96 to 1.31]), FET (HR, 1.02 [95% CI, 0.78 to 1.32]), or AI (HR, 1.09 [95% CI, 0.86 to 1.38]). However, the risk of acute lymphoblastic leukemia was higher among children born after FET (20 case patients; HR 1.61 [95% CI, 1.04 to 2.50]; risk difference [RD], 23.2 [95% CI, 1.5 to 57.0] per million person-years) compared with children conceived naturally. Moreover, among children born between 2010 and 2015, the risk of leukemia was higher among children born after fresh ET (45 case patients; HR, 1.42 [95% CI, 1.06 to 1.92]; adjusted RD, 19.7 [95% CI, 2.8 to 43.2] per million person-years). Conclusions and Relevance: The findings of this cohort study suggest that children born after FET or fresh ET had an increased risk of leukemia compared with children conceived naturally. This risk, although resulting in a limited number of cases, needs to be monitored in view of the continuous increase in the use of ART.

Does recurrent implantation failure exist? Prevalence and outcomes of five consecutive euploid blastocyst transfers in 123 987 patients.

STUDY QUESTION: What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures in the absence of another known factor that affects implantation? SUMMARY ANSWER: The fourth and fifth euploid blastocyst transfers resulted in similar live birth rates of 40% and 53.3%, respectively, culminating in a cumulative live birth rate of 98.1% (95% CI = 96.5-99.6%) after five euploid blastocyst transfers. WHAT IS KNOWN ALREADY: The first three euploid blastocysts have similar implantation and live birth rates and provide a cumulative live birth rate of 92.6%. STUDY DESIGN, SIZE, DURATION: An international multi-center retrospective study was conducted at 25 individual clinics. The study period spanned between January 2012 and December 2022. A total of 123 987 patients with a total of 64 572 euploid blastocyst transfers were screened for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with a history of any embryo transfer at another clinic, history of any unscreened embryo transfer at participating clinics, parental karyotype abnormalities, the use of donor oocytes or a gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital uterine anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior to initiating of progesterone, use of testicular sperm due to non-obstructive azoospermia in the male partner, transfer of an embryo with a reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles for monogenic disorders, or structural chromosome rearrangements were excluded. Ovarian stimulation protocols and embryology laboratory procedures including trophectoderm biopsy followed the usual practice of each center. The ploidy status of blastocysts was determined with comprehensive chromosome screening. Endometrial preparation protocols followed the usual practice of participating centers and included programmed cycles, natural or modified natural cycles. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 105 (0.085% of the total population) patients met the criteria and underwent at least one additional euploid blastocyst transfer after failing to achieve a positive pregnancy test with three consecutive euploid blastocyst transfers. Outcomes of the fourth and fifth euploid blastocyst transfers were similar across participating centers. Overall, the live birth rate was similar with the fourth and fifth euploid blastocysts (40% vs 53.3%, relative risk = 1.33, 95% CI = 0.93-1.9, P value = 0.14). Sensitivity analyses excluding blastocysts biopsied on Day 7 postfertilization, women with a BMI >30 kg/m2, cycles using non-ejaculate or donor sperm, double-embryo transfer cycles, and cycles in which the day of embryo transfer was modified due to endometrial receptivity assay test result yielded similar results. Where data were available, the fourth euploid blastocyst had similar live birth rate with the first one (relative risk = 0.84, 95% CI = 0.58-1.21, P = 0.29). The cumulative live birth rate after five euploid blastocyst transfers was 98.1% (95% CI = 96.5-99.6%). LIMITATIONS, REASONS FOR CAUTION: Retrospective design has its own inherent limitations. Patients continuing with a further euploid embryo transfer and patients dropping out from treatment after three failed euploid transfers can be systematically different, perhaps with regard to ovarian reserve or economic status. WIDER IMPLICATION OF THE FINDINGS: Implantation failure seems to be mainly due to embryonic factors. Given the stable and high live birth rates up to five euploid blastocysts, unexplained recurrent implantation failure should have a prevalence of <2%. Proceeding with another embryo transfer can be the best next step once a known etiology for implantation failure is ruled out. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Association of duration of embryo culture with risk of large for gestational age delivery in cryopreserved embryo transfer cycles.

OBJECTIVE: To examine the relationship between the day of embryo cryopreservation and large for gestational age (LGA) infants in women undergoing frozen embryo transfers (FETs) after cryopreservation on days 2-7 after fertilization and to compare the risk of the day of embryo cryopreservation to other possible risk factors of LGA after FET cycles. DESIGN: Retrospective cohort study. SETTING: Society of Assisted Reproduction Clinical Outcomes Reporting System. PATIENTS: Women undergoing FET cycles. INTERVENTION: Day of cryopreservation. MAIN OUTCOME MEASURE: Singleton LGA infant. RESULTS: A total of 33,030 (18.2%) FET cycles in the study group (n = 181,592) resulted in LGA infants during the study period of 2014-2019. There was an increase in LGA risk when cryopreservation was performed from day 2 (13.7%) to days 3-7 (14.4%, 15.0%, 18.2%, 18.5%, and 18.9%). In the log-binomial model, the risk increased compared with days 2-3 combined when cryopreservation was performed on days 5-7 (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.22-1.44 for day 5, aRR 1.34, 95% CI 1.23-1.46 for day 6, and aRR 1.42, 95% CI 1.25-1.61 for day 7). Other factors most associated with LGA risk in the log-binomial model were preterm parity of >3 compared with 0 (aRR 1.82, 95% CI 1.24-2.69) and body mass index (BMI) of >35 kg/m2 compared with normal weight (aRR 1.94, 95% CI 1.88-2.01). Increasing gravity, parity, BMI, number of oocytes, and embryo grade were also associated with LGA in this model. Asian, Black, Hispanic, and combined Hawaiian and Pacific Islander were protective factors in the model compared with White patients. Low BMI (<18.5 kg/m2) was also considered a protective factor in the model compared with normal BMI. CONCLUSION: Duration of embryo culture was associated with an increased risk of LGA in this study cohort when controlling for known confounders such as maternal BMI and parity. This study sheds new light on the possible link between FET and LGA infants.

Cumulative live birth rates for low-prognosis women over 5 years or 9 frozen-thawed embryo transfer cycles.

BACKGROUND: For heterogeneous populations of low-prognosis women, it remains unclear as to how long individuals should continue undergoing ART when attempting to have a baby, as there have been insufficient studies to date tracking the cumulative live birth rates (CLBRs) for these women over the entire course of their ART treatment, particularly over extended time periods. METHODS: This was a retrospective analysis of 17,698 women at a tertiary care academic medical center who had begun undergoing IVI/ICSI cycles using a progestin-primed ovarian stimulation (PPOS) approach between January 2013 and January 2019. Low-prognosis patients were stratified into four groups based upon POSEIDON criteria, with patients exhibiting normal or high ovarian reserves and response to stimulation (defined as AFC ≥5, > 9 oocytes retrieved) being included as controls (group 5). The CLBR within 5 years or 9 FET cycles from the ovum pick-up (OPU) day of the first cycle was the primary endpoint for this study, including all repetitive oocyte retrieval cycles and subsequent FET cycles. Optimistic and conservative approaches were used for the analysis of CLBRs and the depiction of cumulative incidence curves. RESULTS: Under both optimistic and conservative model analyses, normal and good responders exhibited the highest CLBR within 5 years or 9 FET cycles, followed by younger unexpected poor responders, younger expected poor responders, older unexpected poor responders, and older expected poor responders. Upward trends in CLBRs were evident across the five groups with the prolongation of time or an increase in FET cycle counts. Within the first 2 years or 3 FET cycles, the CLBRs rose rapidly, followed by more moderate increases over the following 2-3.5 years or 4-6 cycles, with expected poor responders exhibiting the most obvious improvements. All Patients reached a CLBR plateau after 3.5 years or 6 FET cycles. CONCLUSIONS: All low-prognosis women should undergo ART treatment for a minimum of 2 years or 3 FET cycles, and exhibit better outcomes when extending ART treatment to 3.5 years or 6 FET cycles (particularly for POSEIDON groups 3 and 4), but should consider ceasing further treatment thereafter due to a lack of apparent benefit.

Effect of previous wedge resection for interstitial pregnancy on pregnancy and neonatal outcomes following frozen-thawed embryo transfer (FET) cycles of IVF/ICSI: a retrospective study.

OBJECTIVE: The present study aimed to evaluate pregnancy and neonatal outcomes in women, with a previous history of wedge resection for interstitial pregnancy, in frozen-thawed embryo transfer (FET) cycles of IVF/ICSI. METHODS: The present study involved a retrospective case-control assessment of 75 cases and 375 control subjects over 6 years in a single center. To compare pregnancy and neonatal outcomes between cases, treated using wedge resection, and controls without any previous history of ectopic pregnancy, propensity score matching (1:5) was utilized. The study also compared subgroups in the case group. RESULTS: Women with previous wedge resection exhibited higher rates of ectopic pregnancy and uterine rupture rate as compared to control subjects (9.1% vs 1.3%, P = 0.025 and 4.5% vs 0%, P = 0.035, respectively). No statistically significant differences were recorded between the two cohorts with regard to clinical pregnancy rate, live birth rate, and neonatal outcomes. For pregnancy type subgroup analysis, Z-score and rates of large for gestational age were recorded to be significantly lower in twin pregnancy subgroup when compared with singleton pregnancy subgroup (0.10 (- 0.59, 0.25) vs 0.50 (- 0.97, 1.39), P = 0.005; 4.5% vs 26.1%, P = 0.047, respectively). CONCLUSION: The results of the present study indicated that previous wedge resection correlated to a higher risk of ectopic pregnancy and uterine rupture. However, it might not be related to an increased risk of adverse neonatal outcomes. The study recommended cesarean section in these patients. Further studies are required to verify the validity of current recommendations.

Informative predictors of pregnancy after first IVF cycle using eIVF practice highway electronic health records.

The aim of this study is to determine the most informative pre- and in-cycle variables for predicting success for a first autologous oocyte in-vitro fertilization (IVF) cycle. This is a retrospective study using 22,413 first autologous oocyte IVF cycles from 2001 to 2018. Models were developed to predict pregnancy following an IVF cycle with a fresh embryo transfer. The importance of each variable was determined by its coefficient in a logistic regression model and the prediction accuracy based on different variable sets was reported. The area under the receiver operating characteristic curve (AUC) on a validation patient cohort was the metric for prediction accuracy. Three factors were found to be of importance when predicting IVF success: age in three groups (38-40, 41-42, and above 42 years old), number of transferred embryos, and number of cryopreserved embryos. For predicting first-cycle IVF pregnancy using all available variables, the predictive model achieved an AUC of 68% + /- 0.01%. A parsimonious predictive model utilizing age (38-40, 41-42, and above 42 years old), number of transferred embryos, and number of cryopreserved embryos achieved an AUC of 65% + /- 0.01%. The proposed models accurately predict a single IVF cycle pregnancy outcome and identify important predictive variables associated with the outcome. These models are limited to predicting pregnancy immediately after the IVF cycle and not live birth. These models do not include indicators of multiple gestation and are not intended for clinical application.

Embryo attrition in planned PGT-A: predicting the number of available blastocysts for transfer.

PURPOSE: During a typical IVF cycle, there is unavoidable attrition from oocytes retrieved to blastocysts formed. Some patients will not have blastocysts available to biopsy or embryos for transfer. The purpose of this study was to predict the number of transferable blastocysts available for patients based on their age and number of 2pn zygotes. METHODS: This was a retrospective cohort study of all fresh autologous IVF and ICSI cycles in which PGT-A was planned from 1/2012 to 3/2020. In total, 746 cycles from 571 patients were analyzed. Patient cycles were stratified into two groups: less than four 2pn zygotes (n = 85) and at least four 2pn zygotes (n = 661). Cycles were then stratified by patient age. Cycle outcomes, including number of cleavage-stage embryos, blastocysts, euploid blastocysts, and low level mosaic blastocysts, were determined. RESULTS: Cleavage-rate was independent of age and number of 2pn zygotes and ranged between 96 and 100%. Blastocyst conversion and euploid blastocyst conversion rates were directly correlated to age, ranging from 52 to 83% for blastocyst conversion and 0-28% for euploid blastocyst conversion. For patients above the age of 40 years with less than four 2pn zygotes, the risk of having no transferable embryos was 99.7%. CONCLUSION: While the literature demonstrates higher live birth rates with the use of PGT-A in women of advancing age, this is inconsequential if there is no embryo available to transfer. Women over 40 years with less than four 2pn zygotes should consider transfer of one or more untested embryos either on day 3 or on day 5.

Sex ratio imbalance following blastocyst transfer is associated with ICSI but not with IVF: an analysis of 14,892 single embryo transfer cycles.

PURPOSE: Assisted reproductive technology (ART) has an impact on secondary sex ratio (SSR), which is seemed to be elevated after blastocyst transfer (BT) but decreased following ICSI procedure. We aim to assess whether the higher SSR associated with BT could be influenced by fertilization method used. METHODS: All consecutive IVF/ICSI cycles (fresh and frozen) involving single embryo transfer (SET) resulting in a live birth between 2015 and 2019 were retrospective analyzed. Logistic regression was used to model the effect on the SSR of maternal and specific ART characteristics. RESULTS: Six thousand nine hundred twenty-two women were included with the crude SSR of 54.8%. The impact of BT on SSR is influenced by the fertilization method used. After adjustment for potential confounders, the SSR in the ICSI BT group was significantly higher when compared to ICSI cleavage-stage embryo SET (aOR 1.24; 95% CI 1.10-1.40, P < 0.001). However, this effect was not detected among SBT with IVF treatment (aOR 1.04; 95% CI 0.97-1.12, P = 0.260). Assessing blastocyst morphological parameters, high trophectoderm quality was significantly associated with elevated SSR (aOR 1.76, 95% CI 1.34-2.31 [A vs. C], and aOR 1.28, 95% CI 1.14-1.44 [B vs. C]). No significant difference was shown in expansion, inner cell mass, or days of blastocyst formation between male and female blastocysts. CONCLUSIONS: The impact of BT on SSR could be influenced by the fertilization method used. The higher SSR was observed after BT with ICSI procedures but not with IVF. Interpretation of the findings is limited by the potential for selection and confounding bias.

Effects of the Zishen Yutai Pill Compared With Placebo on Live Births Among Women in a Fresh Embryo Transfer Cycle: A Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy of the Zishen Yutai Pill compared with placebo on live birth rates among women after fresh embryo transfer cycles. METHODS: We conducted a double-blind, multicenter, placebo-controlled, randomized trial to investigate whether administration of the Zishen Yutai Pill would improve pregnancy outcomes among women undergoing fresh embryo transfer after in vitro fertilization or intracytoplasmic sperm injection. The primary outcome was live birth rate. Secondary outcomes were rates of implantation, biochemical pregnancy, clinical pregnancy, pregnancy loss, cycle cancellation, and maternal, fetal, and neonatal complications. A total sample size of 2,265 women (1:1 in two groups) was used to detect a live birth rate difference between the Zishen Yutai Pill and placebo. Participants were enrolled and randomized to receive 5 g of the Zishen Yutai Pill or placebo orally, three times per day during the study. RESULTS: Recruitment was completed between April 2014 and June 2017, with 2,580 patients screened. Two thousand two hundred sixty-five patients were randomized: 1,131 to the Zishen Yutai Pill and 1,134 to placebo. Characteristics were similar between groups. In intention-to-treat analysis, the rates of live birth in the Zishen Yutai Pill (ZYP) group and placebo group were 26.8% and 23.0% (rate ratio [RR], 1.16; 95% CI 1.01-1.34; P=.038), respectively. The implantation rates were 36.8% and 32.6% in the ZYP and placebo groups, respectively (RR 1.13; 95% CI 1.01-1.25; P=.027). The biochemical pregnancy rate for the ZYP group was 35.5% compared with 31.1% in the placebo group (RR 1.14; 95% CI 1.02-1.28; P=.026). The rates of clinical pregnancy in the ZYP and placebo groups were 31.2% compared with 27.3%, respectively (RR 1.14; 95% CI 1.00-1.30; P=.043). There were no significant between-group differences in the rates of pregnancy loss, maternal, or neonatal complications (all P>.05). CONCLUSION: The Zishen Yutai Pill increased the rate of live birth after fresh embryo transfer compared with placebo. CLINICAL TRIAL REGISTRATION: Chictr.org.cn, Chictr-TRC-14004494.

Impact of body mass index (BMI) on the success rate of fresh embryo transfer in women undergoing first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment.

OBJECTIVE: To investigate the impact of body mass index (BMI) on the success rate and prenatal outcomes of fresh embryo transfer in women undergoing their first in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment. METHODS: It is a post-hoc analysis of a prospective observational cohort study. 2569 Chinese women were grouped in quintiles of BMI and according to the official Chinese classification of body weight. IVF/ICSI and pregnancy outcomes were compared between groups. RESULTS: BMI was not associated with IVF/ICSI pregnancy outcomes including hCG positive rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, ongoing pregnancy rate, early miscarriage rate, and live birth rate. However, it was negatively related to some pregnancy complications such as gestational diabetes mellitus (GDM) and hypertension. Additionally, the proportion of Cesarean-section was increased with BMI. As for prenatal outcomes, the current results showed no statistical difference in the number of male and female newborn, the proportion of low live birth weight (<2500 g), macrosomia (≥4000 g) (both in all live birth and full-term live birth), and premature delivery (<37 weeks). CONCLUSIONS: The current study showed that BMI was not associated with embryo transfer outcomes after fresh embryo transfer in women undergoing their first IVF/ICSI treatment, whereas BMI was associated with GDM and gestational hypertension.

Outcomes of embryo transfers performed by Reproductive Endocrinology and Infertility fellows vs. faculty: an 11-year retrospective review.

OBJECTIVE: To compare the clinical pregnancy rate (CPR) and live birth rate (LBR) of embryo transfer episodes (ETEs) performed by Reproductive Endocrinology and Infertility fellows vs. those of ETEs performed by faculty physicians. DESIGN: Retrospective cohort analysis. SETTING: Academic reproductive endocrinology and infertility practice. PATIENT(S): In total, 3,073 ETEs for 1,488 unique patients were performed by fellows or faculty physicians between January 2009 and January 2020. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate and LBR. RESULT(S): Fifteen fellows performed 1,225 (39.9%) of 3,073 ETEs after completing 30 mock transfers. On comparing outcomes among fellowship years (FY1, FY2, and FY3), CPR (44.1% vs. 43.2% vs. 45.7%, respectively, P = .83) and LBR (39.1% vs. 38.1% vs. 38.4%, respectively, P = .97) were not significantly different. Fellowship year 1 fellows' initial 30 ETEs vs. all the remaining FY1 ETEs had a significantly higher CPR (48.1% vs. 40.5%, respectively, P = .030) and LBR (45.4% vs. 34.3%, respectively, P = .001). There were no significant differences between faculty versus fellow ETEs in terms of CPR (43.0% vs. 45.0%, respectively, P = .30) or LBR (37.3% vs. 39.8%, respectively, P = .16), even after adjusting for patient age, body mass index, primary infertility diagnosis, autologous vs. donor oocyte, fresh vs. frozen embryo, number of embryos transferred, type of transfer catheter, and year of transfer (P = .32 for CPR, P = .22 for LBR). CONCLUSION(S): Appropriately trained FY1 fellows had success rates maintained throughout all FYs. There were no significant differences in clinical outcomes between fellow- and faculty-performed transfers. These data demonstrated that allowing fellows to perform live embryo transfers is not detrimental to clinical outcomes.

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience.

PURPOSE: To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer. METHODS: The present retrospective observational study analyzed 4,613 single embryo transfers (SET) (646 fresh and 3,967 frozen) from January 1, 2014, to December 31, 2018. Fresh embryo transfer at blastocyst stage was considered according to the age of the patient and her prognosis. In case of the risk of ovarian hyperstimulation syndrome, premature progesterone rise, non-optimal endometrial growth, or supernumerary embryos, cryopreservation with subsequent frozen embryo transfer (FET) was indicated. RESULTS: No differences in LBR were recorded. Fresh embryo transfers yielded an increase both in neonatal complications OR 2.15 (95% CI 1.20-3.86, p 0.010), with a higher prevalence of singletons weighting below the 5th percentile (p 0.013) and of intrauterine growth retardation (p 0.015), as well as maternal complications, with a higher placenta previa occurrence OR 3.58 (95% CI 1.54-8.28, p 0.003), compared to FET. CONCLUSION: LBR appears not to be affected by the transfer procedure preferred. Fresh embryo transfer is associated with higher risk of neonatal complications (specifically a higher prevalence of singletons weighting below the 5th percentile and of intrauterine growth retardation) and placenta previa. Reflecting on the increased practice of ART procedures, it is imperative to understand whether a transfer procedure yields less complications than the other and if it is time to switch to a "freeze-all" procedure as standard practice. TRIAL REGISTRATION: Clinical Trial Registration Number: NCT04310761. Date of registration: March 17, 2020, retrospectively registered.

Racial disparities in frozen embryo transfer success.

PURPOSE: To compare pregnancy and birth outcomes after frozen embryo transfers (FETs) among White, Black, and Asian women and evaluate the effect of patient, protocol, and cycle characteristics on success. METHODS: A retrospective chart review identified women who underwent an autologous FET at an academic fertility center between January 2013 and March 2020. RESULTS: White, Black, and Asian women completed 1,181 (71.7%), 230 (14.0%), and 235 (14.3%) cycles, respectively. Black women were significantly less likely to achieve a positive hCG level (AOR 0.66, 95% CI 0.49-0.90), clinical pregnancy (AOR 0.71, 95% CI 0.53-0.97), and live birth (AOR 0.65, 95% CI 0.47-0.89) compared to White women after adjusting for possible confounders. There were no differences in the aforementioned outcomes when looking at cycles completed by Asian versus White women. When comparing outcomes by endometrial preparation protocol, significant differences were seen amongst the three groups for live birth rates following natural cycle FETs (52.36%, 25.81%, and 44.19% for White, Black, and Asian women, respectively, p = 0.02), a difference not appreciated after programmed FETs. CONCLUSION: Black race is associated with significantly worse pregnancy and live birth rates following FET when compared to White race. Additionally, significant differences in live birth rates among White, Black, and Asian women exist following natural cycle FET versus programmed FET. These disparities in success are not only important for patient counseling, but also when determining management strategies to improve fertility rates among minority women.

Impact of maternal education level on live birth rate after in vitro fertilization in China: a retrospective cohort study.

PURPOSE: To assess the association between maternal education level and live birth after in vitro fertilization (IVF). METHODS: We studied women who underwent the first cycle of fresh or frozen-thawed embryo transfer between 2014 and 2019. Women were divided into four educational categories according to the level of education received (elementary school graduate or less, middle school graduate, high school graduate, college graduate or higher). The live birth rate was compared between different education level groups. We used logistic regression to analyze the association between maternal education level and live birth after IVF. RESULTS: We studied 41,546 women, who were grouped by maternal educational level: elementary school graduate or less (n = 1590), middle school graduate (n = 10,996), high school graduate (n = 8354), and college graduate or higher (n = 20,606). In multivariable logistic regression analysis, we did not demonstrate a statistically significant relationship between educational level and live birth in middle school graduate (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.84-1.09), high school graduate (AOR 1.01; 95% CI, 0.87-1.14) or college graduate or higher (AOR 1.01; 95% CI, 0.88-1.14) patients, with elementary school graduate or less as the reference group. CONCLUSIONS: Maternal educational level was not associated with the likelihood of live birth in patients undergoing fresh or frozen embryo transfer.

Effects of half-dose and full-dose GnRH antagonists on IVF-ET outcomes: a retrospective study.

BACKGROUND: Gonadotropin-releasing hormone antagonist(GnRH-ant) has been shown to have a negative effect on endometrial receptivity. Therefore, the use of lower doses of GnRH-ant during controlled ovarian stimulation (COS) may improve endometrial receptivity and clinical pregnancy rate. However, the GnRH-ant dose is relatively flexible and there is no fixed requirement for guidance. In this retrospective study, we determined the effects of half-dose and full-dose GnRH-ant on IVF-ET outcomes. METHODS: Of the 316 cycles in the 314 patients analyzed in this study, 149 received GnRH-ant half-dose (Group1), while 167 received GnRH-ant full-dose (Group2). The groups were further classified based on age and BMI. Age subgroups, were divided as age ≤ 35(subgroup A) and age > 35(subgroup B): 180 cycles in subgroup A (107 cycles in subgroup A1,73 cycles in subgroup A2), 136 cycles in subgroup B (42 cycles in subgroup B1,94 cycles in subgroupB2). The subgroups based on BMI were divided as BMI < 25 (subgroup C)and BMI ≥ 25 (subgroup D):208 cycles in subgroup C (94 cycles in subgroup C1,114 cycles in subgroup C2), 108 cycles in subgroup D (55 cycles in subgroup D1,53 cycles in subgroup D2). RESULTS: The number of fertilized oocytes, superior-quality embryos, clinical pregnancy rate, and live birth rate differed significantly between the two groups. However, the number of retrieved oocytes and available embryos were significantly higher in Group 1 than Group 2 (8.17 ± 4.10 vs. 7.07 ± 4.05, 2.96 ± 2.03 vs. 2.52 ± 1.62, respectively,p<0.05). Differences between the age subgroups were not statistically significant. However, in the subgroups based on BMI, the fertilized oocytes, available embryos, the number of superior-quality embryos, and the live birth rate differed significantly between the four subgroups. The number of retrieved oocytes was higher in subgroup C1 than in subgroup C2 (8.24 ± 4.04 vs. 6.83 ± 3.92,p < 0.05), In addition, the clinical pregnancy rate was slightly higher in subgroup D1 than in subgroup D2(45.45 vs. 24.53%, P < 0.05). CONCLUSIONS: The results showed that half-dose GnRH-ant was as effective as full-dose GnRH-ant for most patients. Moreover, half-dose GnRH-ant may be more suitable in patients with BMI greater than or equal to 25. The findings of this study need to be validated in a large sample RCT. TRIAL REGISTRATION: Retrospectively registered.

CD19 and intraglandular CD163-positivity as prognostic indicators of pregnancy outcome in CD138-negative women with a previous fresh-embryo-transfer failure.

Many factors impede embryonic implantation, and excluding obvious known factors such as chronic endometritis, the immune status of the endometrium may be related to pregnancy. Although an abundantly large number of immune cells infiltrate the endometrium during the secretory phase, whether these immune cells can be used as a predictor of prognosis in ART has not yet been clarified. In the present study we therefore retrospectively analyzed 97 CD138-negative women with a previous fresh-embryo-transfer failure. We assessed the expression of CD56+ uNK cells, CD16+ NK cells, CD57+ NK cells, CD68+ pan-macrophages, CD163+ M2 macrophages, CD4+T cells, CD8+T cells, FOXP3+ regulatory T cells, and CD19+ B cells in the endometrium by IHC to evaluate mid-luteal endometrial immune cells as prognostic indicators of pregnancy outcome in the next frozen-embryo-transfer cycle. CD19-positive cells and the intraglandular CD163-positivity rate increased significantly in the clinically non-pregnant group (0.47 % vs. 0.20 %, P = 0.021; 61 % vs. 30 %, P = 0.017). The ratios of CD4/CD8 were also higher in the non-pregnant group (1.96 vs. 1.45, P = 0.005).The area under the ROC curve of CD19 cell number alone, the intraglandular CD163-positivity alone, and CD19 number combined with the intraglandular CD163-positivity were 0.692 (95 % CI, 0.55-0.834), 0.661 (95 % CI, 0.514-0.809), and 0.748 (95 % CI, 0.614-0.882), respectively. The optimal cut-off value of CD19 was 0.464 %, and the clinical pregnancy rate and live-birth rate diminished significantly when the CD19 level was above this cut-off value. Our study suggests that CD19-positive cells and intraglandular CD163-positivity can be used as prognostic indicators of pregnancy outcome in CD138-negative patients who experienced first-fresh-embryo transfer failure.

Childhood growth of term singletons born after frozen compared with fresh embryo transfer.

RESEARCH QUESTION: Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? DESIGN: Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. RESULTS: Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. CONCLUSIONS: Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.

Sequential cleavage and blastocyst embryo transfer and IVF outcomes: a systematic review.

BACKGROUND: Sequential embryo transfer has been proposed as a way to improve embryo implantation in women for in vitro fertilization (IVF), but the effect on pregnancy outcomes remains ambiguous. This systematic review was conducted to investigate the efficacy of sequential embryo transfer on IVF outcomes. METHODS: A literature search was performed in the PubMed, Web of Science, Cochrane Library, ScienceDirect and Wanfang databases. Data were pooled using a random- or fixed-effects model according to study heterogeneity. The results are expressed as relative risks (RRs) with 95% confidence intervals (CIs). Heterogeneity was evaluated by the I2 statistic. The study protocol was registered prospectively on INPLASY, ID: INPLASY202180019. RESULTS: Ten eligible studies with 2658 participants compared sequential embryo transfer and cleavage transfer, while four studies with 513 participants compared sequential embryo transfer and blastocyst transfer. The synthesis results showed that the clinical pregnancy rate was higher in the sequential embryo transfer group than in the cleavage embryo transfer group (RR 1.42, 95% CI 1.26-1.60, P< 0.01) for both women who did experience repeated implantation failure (RIF) (RR 1.58, 95% CI 1.17-2.13, P< 0.01) and did not experience RIF (Non-RIF) (RR 1.44, 95% CI 1.20-1.66, P< 0.01). However, sequential embryo transfer showed no significant benefit over blastocyst embryo transfer. CONCLUSION: The current systematic review demonstrates that sequential cleavage and blastocyst embryo transfer improve the clinical pregnancy rate over conventional cleavage embryo transfer. For women with adequate embryos, sequential transfer could be attempted following careful consideration. More high-grade evidence from prospective randomized studies is warranted.

Do live birth rate and obstetric outcomes vary between immediate and delayed embryo transfers following freeze-all cycles?

RESEARCH QUESTION: Do live birth rates (LBR), obstetric and perinatal outcomes vary between women who underwent frozen embryo transfer (ET) in the immediately subsequent menstrual cycle, and with those who underwent delayed frozen ET. DESIGN: Retrospective cohort study (n = 198) consisting of 119 women who underwent immediate transfer within 30 days of oocyte retrieval (OR) and 79 women who underwent delayed transfer which was performed after >30 days following OR. Either flexible antagonist or flexible progestin-primed ovarian stimulation protocols were started after a baseline ultrasonography on the second or third day of menstrual cycle. Only freeze all cycles were included in the study and all transfers were with hormonal endometrial preparation. Main outcome measures were LBR, birth weight, gestational day at birth and pregnancy complications. RESULTS: Peak estradiol level on trigger day (2746 vs 2081 pg/ml) and number of metaphase-two oocytes (13 vs 10) were significantly higher in the immediate transfer group. Clinical pregnancy rate per ET was similar between the groups (50.4% vs 44.3%). However, miscarriage rate per positive pregnancy was significantly higher (12.3% vs 31.1%) while LBR per ET was significantly lower (42.9% vs 26.6%) in the delayed transfer group. Median gestational age at delivery were 267.5 and 268 days in the immediate and delayed transfer groups. Median birthweight was significantly higher in the delayed transfer group (3520 vs 3195 g). Adjusted analyses also suggest similar LBR with immediate and delayed transfer. CONCLUSION(S): Frozen ET in the immediate menstrual cycle and delayed ET, after a freeze all strategy did not show significant difference in terms of LBR after adjustment. Obstetric and perinatal outcomes of frozen ET in the immediate menstrual cycle appear reassuring.

Objective sleep duration and timing predicts completion of in vitro fertilization cycle.

PURPOSE: To examine associations between objectively measured sleep duration and sleep timing with odds of completion of an in vitro fertilization (IVF) cycle. METHODS: This prospective cohort study enrolled 48 women undergoing IVF at a large tertiary medical center between 2015 and 2017. Sleep was assessed by wrist-worn actigraphy, 1-2 weeks prior to initiation of the IVF cycle. Reproductive and IVF cycle data and demographic and health information were obtained from medical charts. Sleep duration, midpoint, and bedtime were examined in relation to IVF cycle completion using logistic regression models, adjusted for age and anti-Müllerian hormone levels. A sub-analysis excluded women who worked non-day shifts to control for circadian misalignment. RESULTS: The median age of all participants was 33 years, with 29% of women >35 years. Ten women had an IVF cycle cancelation prior to embryo transfer. These women had shorter sleep duration, more nocturnal awakenings, lower sleep efficiency, and later sleep timing relative to those who completed their cycle. Longer sleep duration was associated with lower odds of uncompleted IVF cycle (OR = 0.88; 95%CI 0.78, 1.00, per 20-min increment of increased sleep duration). Women with later sleep midpoint and later bedtime had higher odds of uncompleted cycle relative to those with earlier midpoint and earlier bedtime; OR = 1.24; 95%CI 1.09, 1.40 and OR = 1.33; 95%CI 1.17, 1.53 respectively, for 20-min increments. These results were independent of age, anti-Müllerian hormone levels, or sleep duration, and remained significant after exclusion of shift-working women. CONCLUSIONS: Shorter sleep duration and later sleep timing increase the odds of uncompleted cycles prior to embryo transfer.