Association between endometrial thickness before ovulation, live birth, and placenta previa rates in clomiphene citrate-treated cycles.

BACKGROUND: Although a recent study reported that the pregnancy outcomes in the first trimester were more correlated with endometrial thickness on the day of the trigger than with endometrial thickness on the day of single fresh-cleaved embryo transfer, it remains unclear whether endometrial thickness on the day of the trigger can predict live birth rate after a single fresh-cleaved embryo transfer. OBJECTIVE: This study aimed to examine whether endometrial thickness on the trigger day is associated with live birth rates and whether modifying the single fresh-cleaved embryo transfer criteria to reflect endometrial thickness on the trigger day improved the live birth rate and reduced maternal complications in a clomiphene citrate-based minimal stimulation cycle. STUDY DESIGN: This was a retrospective study of the outcomes of 4440 treatment cycles of women who underwent single fresh-cleaved embryo transfer on day 2 of the retrieval cycle. From November 2018 to October 2019, single fresh-cleaved embryo transfer was performed when endometrial thickness on the day of single fresh-cleaved embryo transfer was ≥8 mm (criterion A). From November 2019 to August 2020, single fresh-cleaved embryo transfer was conducted when endometrial thickness on the day of the trigger was ≥7 mm (criterion B). RESULTS: A multivariate logistic regression analysis revealed that increased endometrial thickness on the trigger day was significantly associated with an improvement in the live birth rate after single fresh-cleaved embryo transfer (adjusted odds ratio, 1.098; 95% confidence interval, 1.021-1.179). The live birth rate was significantly higher in the criterion B group than in the criterion A group (22.9% and 19.1%, respectively; P=.0281). Although endometrial thickness on the day of single fresh-cleaved embryo transfer was sufficient, the live birth rate tended to be lower when endometrial thickness on the trigger day was <7.0 mm than when endometrial thickness on the day of the trigger was ≥7.0 mm. The risk for placenta previa was reduced in the criterion B group when compared with the criterion A group (4.3% and 0.6%, respectively; P=.0222). CONCLUSION: This study demonstrated an association of decreased endometrial thickness on the trigger day with low birth rate and a high incidence of placenta previa. A modification of the criteria for a single fresh-cleaved embryo transfer based on endometrial thickness may improve pregnancy and maternal outcomes.

Letrozole-induced endometrial preparation improved the pregnancy outcomes after frozen blastocyst transfer compared to the natural cycle: a retrospective cohort study.

BACKGROUND: Letrozole treatment is considered an effective option in endometrial preparation for frozen embryo transfers in patients with ovulation disorders or irregular menstruation; however, the effectiveness of letrozole-induced endometrial preparation remains unclear in ovulatory patients. Furthermore, there is no comparative study reporting on pregnancy complications and congenital anomalies after frozen embryo transfers comparing natural and letrozole-assisted cycles. This study examined whether letrozole-induced endometrial preparation affected pregnancy outcomes, perinatal outcomes, and congenital anomalies after single vitrified-warmed blastocyst transfers (SVBTs) in ovulatory patients, as compared with the natural cycle. METHODS: This historic cohort study included only patients with unexplained infertility. Overall, 14,611 patients who underwent SVBTs between July 2015 and June 2020, comprising both natural and letrozole-assisted cycles, were included. Multiple covariates that impact outcomes were used for propensity score matching; 1,911 patients in the letrozole group were matched to 12,700 patients in the natural group, and the clinical records of 1,910 patients in each group were retrospectively analysed. Cycle characteristics, pregnancy outcomes (clinical pregnancy, ongoing pregnancy, and live birth), and incidence of pregnancy complications and congenital anomalies were statistically compared between the two groups. RESULTS: Multivariate logistic regression analysis showed that letrozole administration during SVBT cycles significantly improved the live birth rate (P = 0.0355). Gestational age, birth length, birth weight, and infant sex, as well as the incidence of pregnancy complications and birth defects, were statistically comparable between the two groups. Furthermore, multivariate logistic regression analysis revealed that the perinatal outcomes were not affected by letrozole-induced endometrial preparation. CONCLUSIONS: Letrozole-induced endometrial preparation improved the live birth rate compared with the natural cycle, without adverse effects on perinatal outcomes and congenital anomalies after SVBTs. Therefore, letrozole-induced endometrial preparation might be a safe and more effective strategy, especially for patients with insufficient luteal function.

Endometrial preparation and maternal and obstetrical outcomes after frozen blastocyst transfer.

BACKGROUND: Two types of endometrial preparation protocols are used for frozen embryo transfers in current practice: hormone replacement and the natural cycle. Endometrial preparation in the natural cycle reportedly increases the chances of live birth and decreases early pregnancy loss compared with that in the hormone replacement cycle. However, the influence of endometrial preparation on maternal and neonatal health remains unclear. OBJECTIVE: This study aimed to investigate whether the differences between hormone replacement cycle and natural cycle influence perinatal outcomes and risk of congenital anomalies in frozen-thawed blastocyst transfer fetuses or births. STUDY DESIGN: Perinatal outcomes and congenital abnormalities were compared between the natural and hormone replacement cycles. According to the timing of ovulation, frozen-thawed blastocyst transfers in the natural cycle were classified into 2 patterns: on day 4.5 (ovulation 4.5) or day 5 (ovulation 5.0) after ovulation. When the serum luteinizing hormone level was not increased on the day of the trigger, a single vitrified-warmed blastocyst transfer was performed on day 7 after the trigger (ovulation 5.0). When the luteinizing hormone level was slightly increased on the day of trigger, single vitrified-warmed blastocyst transfer was performed on day 6 after the trigger (ovulation 5.0). In total, 67,018 cycles (ovulation 4.5, 29,705 cycles; ovulation 5.0, 31,995 cycles; hormone replacement, 5318 cycles) of frozen-thawed blastocyst transfer between January 2008 and December 2017 at Kato Ladies Clinic were retrospectively analyzed. During the study period, embryo cryopreservation was performed using a vitrification method in all cycles. RESULTS: Hormone replacement cycles were associated with a higher occurrence of hypertensive disorders of pregnancy (adjusted odds ratio, 2.16; 95% confidence interval, 1.66-2.81) and placenta accreta (adjusted odds ratio, 4.14; 95% confidence interval, 1.64-10.44) compared with the natural cycle. The risks of cesarean delivery (adjusted odds ratio, 1.93; 95% confidence interval, 1.78-2.18), preterm birth (adjusted odds ratio, 1.55; 95% confidence interval, 1.25-1.93), and low birthweight (adjusted odds ratio, 1.42; 95% confidence interval, 1.18-1.73) were also higher for hormone replacement cycles. No significant difference in the risk of congenital anomalies was observed between the 2 cycles. CONCLUSION: The risk of hypertensive disorders of pregnancy, placenta accreta, cesarean delivery, preterm delivery, and low birthweight was higher in hormone replacement cycles than in natural cycles, whereas the risk of congenital anomalies was similar between both cycles. Further follow-up is needed to investigate these risks and to explore alternative endometrial preparation methods.

Perinatal outcomes and congenital anomalies associated with letrozole and natural cycles in single fresh cleaved embryo transfers: A single-center, 10-year cohort study.

Objective: To investigate and compare the safety of letrozole and natural cycles in fresh early embryo transfers. Design: A retrospective cohort study. Setting: A large fertility treatment center. Patients: Women who underwent natural and letrozole cycles during fresh early embryo transfer at Kato Ladies Clinic between January 2008 and December 2017. Interventions: None. Main Outcome measures: Perinatal complications and congenital anomalies. Results: No significant differences were observed in pregnancy complications, gestational age, birth weight, small for gestational age, large for gestational age, and congenital anomalies between the the women who underwent natural and letrozole cycles. Conclusions: The perinatal outcomes and congenital anomaly rates associated with letrozole and natural cycles in fresh early embryo transfers were comparable. Therefore, our data support the safe use of letrozole in fresh early embryo transfers in assisted reproductive technology.

Maternal and obstetric outcomes are influenced by developmental stage and cryopreservation of transferred embryos after clomiphene citrate-based minimal stimulation IVF.

STUDY QUESTION: Is the embryo transfer (ET) method associated with maternal and perinatal outcomes after minimal stimulation IVF using clomiphene citrate (CC)? SUMMARY ANSWER: The incidence of pregnancy complications and adverse perinatal outcomes was influenced by the developmental stage (cleavage versus blastocyst stages) and cryopreservation (fresh versus vitrified) of the transferred embryos. WHAT IS KNOWN ALREADY: Pregnancies resulting from IVF are associated with higher risks of adverse perinatal outcomes compared to natural conceptions; therefore, the next focus in reproductive medicine should be to assess whether these increased risks are attributable to IVF. Pregnancy complications and perinatal outcomes should be considered in addition to pregnancy outcomes when selecting the ET method, however, studies that describe the influence of transfer methods on perinatal and maternal outcomes are limited. STUDY DESIGN SIZE DURATION: This study retrospectively analysed a large single-centre cohort. The clinical records of 36 827 women who underwent oocyte retrieval (during a CC-based minimal stimulation cycle) followed by their first ET at the fertility treatment centre between January 2008 and December 2017 were retrospectively analysed. The patients underwent a single fresh cleavage-stage ET (SFCT), single vitrified-warmed cleavage-stage ET (SVCT) or single vitrified-warmed blastocyst transfer (SVBT). This study only included one cycle per patient. PARTICIPANTS/MATERIALS SETTING METHODS: Oocyte retrieval was performed following CC-based minimal ovarian stimulation. The embryos were transferred 2-3 days after retrieval or vitrified at the cleavage or blastocyst stage. The vitrified embryos were then warmed and transferred within the natural cycles. Pregnancy complications and perinatal outcomes were stratified according to the transfer methods used. Multivariate logistic regression analysis was performed to evaluate the effect of ET methods on the prevalence of pregnancy complications and congenital anomalies. MAIN RESULTS AND THE ROLE OF CHANCE: The rates of clinical pregnancy and delivery were significantly different among the groups. We analysed pregnancy complications in 7502 singleton births (SFCT, 3395 cycles; SVCT, 586 cycles; and SVBT, 3521 cycles). Multivariate logistic regression analysis revealed that the adjusted odds ratio (AOR) for hypertensive disorders in pregnancy was significantly lower in the SVBT group than in the SFCT group [AOR, 0.72; 95% CI, 0.56-0.92]. The AOR for low-lying placenta was lower in the SVBT group than in the SFCT group (AOR, 0.34; 95% CI, 0.19-0.60). The AOR for placenta previa was lower in the SVCT and SVBT groups than in the SFCT group (AOR, 0.21; 95% CI, 0.07-0.58 versus AOR, 0.53; 95% CI, 0.38-0.75, respectively). A total of 7460 follow-up data on neonatal outcomes was analysed. The AOR for preterm delivery was lower in the SVBT group than in the SFCT group (AOR, 0.78; 95% CI, 0.64-0.94). The AOR for low birthweight was significantly lower after SVCT and SVBT than after SFCT (AOR, 0.68; 95% CI, 0.46-0.98 versus AOR, 0.57; 95% CI, 0.48-0.66, respectively). The AOR for small for gestational age was lower in the SVCT and SVBT groups than in the SFCT group (AOR, 0.68; 95% CI, 0.46-0.98 versus AOR, 0.44; 95% CI, 0.36-0.55, respectively). The AOR for large for gestational age babies was higher in the SVBT group than in the SFCT group (AOR, 1.88; 95% CI, 1.62-2.18). The incidence of each congenital anomaly was similar among the groups. LIMITATIONS REASONS FOR CAUTION: The study data were collected through self-reported parental questionnaires on maternal and neonatal outcomes. Our findings were not compared with the incidence of pregnancy complications and congenital anomalies in natural pregnancies. Furthermore, this study was retrospective in nature; therefore, further studies are required to ascertain the generalizability of these findings to other clinics with different protocols and/or different patient demographics. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated reassuring outcomes for SVBT (in terms of a lower incidence of pregnancy complications) compared to SFCT. Our findings provide valuable knowledge that will help improve perinatal and maternal outcomes in CC-based stimulation and inform couples of the possible benefits and risks of each type of ET method. STUDY FUNDING/COMPETING INTERESTS: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Early and late paternal effects of reactive oxygen species in semen on embryo development after intracytoplasmic sperm injection.

Although reactive oxygen species in semen are associated with unfavorable results with respect to assisted reproductive technology, their effects based on the detailed stages of embryo development are unclear. We investigated the relationship between reactive oxygen species in semen and the oocyte fertilization rate, cleavage rate, and blastulation rate of intracytoplasmic sperm injections. This retrospective study enrolled 77 couples who underwent intracytoplasmic sperm injection and analyzed 887 eggs from 141 cycles of intracytoplasmic sperm injection. The reactive oxygen species level in semen was compared between the fertilized and nonfertilized groups, between the good-cleavage-embryo and non-developed-embryo groups, and between the good-quality-blastocyst and poor-quality-blastocyst groups. The cut-off level of reactive oxygen species was calculated to predict good-cleavage-embryo and good-quality-blastocyst development. The fertilization rate was 65.4%, and the mean reactive oxygen species levels were not significantly different between the fertilized and nonfertilized groups. The reactive oxygen species level was significantly higher in the non-developed-embryo group than in the good-cleavage-embryo group (P = 0.0026) and was significantly lower in the good-quality-blastocyst group than in the poor-quality-embryo group (P = 0.015). Cleavage embryos and blastocysts were divided into high- and low-reactive-oxygen-species groups using a cut-off value of 6601 and 4926 relative light units, as calculated from the receiver operating characteristic curve. The rates of good-cleavage embryos and good-quality blastocysts were lower in the high-reactive-oxygen-species group than in the low-reactive-oxygen-species group, which were both statistically significant. To conclude, reactive oxygen species in semen is considered to have an adverse effect on both the early and late stages of embryo development in intracytoplasmic sperm injection.Abbreviations: GnRH, gonadotropin-releasing hormone; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; LPO, lipid peroxidation; NADPH, nicotinamide adenine dinucleotide phosphate; RLU, relative light units; ROC, receiver operating characteristic; ROS, reactive oxygen species.

Impact of single embryo transfer policy on perinatal outcomes in fresh and frozen cycles-analysis of the Japanese Assisted Reproduction Technology registry between 2007 and 2012.

OBJECTIVE: To investigate whether the introduction of single embryo transfer (SET) policy in Japan has improved perinatal outcomes. DESIGN: A retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 140,718 live births and 510 stillbirths (after 22 weeks of gestation) conceived by assisted reproductive technology in Japan between 2007 and 2012 were reviewed. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Preterm birth (PTB), low birth weight (LBW), very low birth weight (VLBW), small for gestational age (SGA), large for gestational age (LGA), perinatal mortality, and other pregnancy complications. RESULT(S): The rate of SET increased significantly from 52.2% in 2007 to 82.6% in 2012, while the rate of multiple pregnancy decreased significantly from 10.7% to 4.1% over the same period. The rates of PTB, LBW, and SGA decreased significantly, while that of LGA increased. Perinatal mortality decreased from 0.70% to 0.40% in fresh cycles, while that of frozen cycles did not change. Double ET or more was associated with a significantly increased risk for multiple pregnancy, placenta accreta, preterm premature rupture of membrane, cesarean section (CS), PTB, LBW, SGA, and early neonatal death compared with SET. Compared with before the SET policy was launched, the risks of multiple pregnancy, CS, early PTB before 32 weeks, LBW, VLBW, and SGA were significantly decreased after the policy was launched, with significant interactions of fresh/frozen status. CONCLUSION(S): The results suggest that the SET policy improved perinatal outcomes in Japan. The impact of SET policy was different in fresh and frozen cycles for several perinatal outcomes.

Efficacy, safety, and trends in assisted reproductive technology in Japan-analysis of four-year data from the national registry system.

PURPOSE: This study aimed to evaluate the efficacy, safety, and trends in assisted reproductive technology (ART) in Japan. METHODS: Data pertaining to treatment cycles, pregnancy rate, live birth rate, age distribution, single embryo transfer rate, and multiple pregnancy rate were analyzed for patients registered in the national ART registry system of Japan from 2007 to 2010. RESULTS: The total number of treatment cycles was 161,164, 190,613, 213,800, and 242,161 in 2007, 2008, 2009, and 2010, respectively. The number of ART treatments administered to patients aged ≥40 years was 31.2 %, 32.1 %, 33.4 %, and 35.7 %, respectively, showing an increasing trend from 2007 to 2010. In each of these years, the total pregnancy rate per embryo transfer was 24.4 %, 21.9 %, 22.3 %, and 21.9 % for fresh cycles, respectively, and 32.0 %, 32.1 %, 32.5 %, and 33.7 % for frozen cycles, respectively. The single embryo transfer rate was 49.9 %, 63.6 %, 70.6 %, and 73.0 %, respectively, showing an increasing trend, while the multiple pregnancy rate was 11.5 %, 6.8 %, 5.3 %, and 4.8 %, respectively, showing a decreasing trend. CONCLUSIONS: From 2007 to 2010 in Japan, the number of ART treatment cycles, number of elderly patients treated, and the single embryo transfer rate increased, while the multiple pregnancy rate decreased. However, the overall pregnancy rate remained stable during the study period.