Frozen-thawed Embryo Transfer Research Articles

P-286 Comparative study of frozen-thawed embryo transfer with modified natural cycle versus HRT cycle in previously cancelled true natural cycle patients

Abstract Study question Is there any difference in outcome of frozen embryo transfer(FET) between hormone replacement therapy(HRT) and modified natural cycle(MNC) in previously cancelled true natural cycle patients Summary answer In patients with previous history of cancelled true natural cycle, MNC results in higher clinical pregnancy rates after FET, when compared to HRT cycle What is known already Preparation of endometrium lays down the foundation for conception and subsequent successful pregnancy.There has been a plethora of endometrial preparation protocols described in the literature. The established protocols are true natural cycle,MNC with or without luteal phase support(LPS) and HRT cycle with or without gonadotrophin releasing hormone agonist(GnRha) suppression. Nevertheless,there is no consensus on protocol which may provide the best outcome in patients who have had cancelled true natural cycle.In such situations,HRT cycle may be considered as an easy option as the cancellation rate is low.However,HRT treatment is known for higher early pregnancy and obstetric complications,compared to MNC Study design, size, duration Prospective observational study,where 155 patients undergoing FET who had minimum one true natural cycle cancellation were recruited.They were divided into group A undergoing HRT cycle(n = 77) and group B for MNC cycle(n = 78).The study was conducted in a fertility unit over six months from June-November 2023.Primary outcome measures were serum betaHCG estimation and ultrasonographic documentation of intrauterine pregnancy.Results were analysed using statistical software SPSS version25 and p value of less than 0.05 was considered statistically significant Participants/materials, setting, methods HRT patients received injectable GnRha 3.75 mg on day21 of previous cycle.Oral estradiol valerate 6mg daily started on day2 of menses. When ET was minimum 7mm, luteal phase support(LPS) was started with daily oral and vaginal progesterone(30mg and 600mcg respectively),followed by FET. MNC patients received Letrozole 5mg daily from day 2-6 of menstruation.rhCG 250mcg was given subcutaneously,when ET was at least 7mm,dominant follicle 16-18mm and progesterone(P4) less than 1ng/ml.LPS(vaginal progesterone600mcg) was started 36hours after rHCG,followed by FET Main results and the role of chance Mean ET in MNC group was 8.92mm ± SD1.38, which was higher than HRT group (8.31 mm ± SD0.89). This difference was statistically significant with a p value of 0.014.Serum beta HCG estimation was done 2weeks after FET. In HRT group beta HCG was positive in 41 out of 77(53.25%) and in MNC group positivity was higher being 48 out of 78(61.54%). However, this difference was not statistically significant. Transvaginal ultrasonography(TVS) was done to confirm intrauterine pregnancy 2weeks after beta HCG assay. Clinical pregnancy rate(CPR) was higher in MNC group with 32 out of 78(41.03%),compared to 18 out of 77(23.38%) in HRT group. This difference is statistically significant with p value of 0.019 Limitations, reasons for caution Relatively small population in this study may be the reason for caution to interpret the statistical data. Study with higher numbers may bring about more robust conclusions Wider implications of the findings Patients with failed true natural cycles may be considered for modified natural cycle(MNC) stimulation for FET, without attempt of another true natural cycle stimulation Trial registration number NOT APPLICABLE

O-276 Implantation failure is not associated with seven different vaginal bacterial community-state types; however, a distinct signature, including Ureaplasma parvum, is strongly linked to treatment failure

Abstract Study question Is microbial diversity or vaginal bacterial composition associated with embryonic implantation in women undergoing frozen-thawed embryo transfer? Summary answer While global diversity measures of microbial composition do not correlate with positive implantation, specific taxa may serve as predictors of treatment outcomes. What is known already Clinical studies have indicated a reduced likelihood of embryo implantation in women diagnosed with microbial dysbiosis. The application of Next-Generation Sequencing for microbiota analysis has significantly advanced our understanding of vaginal microbiome composition. Recent studies have proposed distinct vaginal microbiome patterns as potential predictors of IVF treatment success or failure. However, the evidence regarding the biological basis of test algorithms (such as the independent association of distinct community state types with outcomes) and the reliability of diagnostic test performance (including replicability and external validity) in predicting implantation success or failure in women undergoing embryo transfer remains less robust. Study design, size, duration In a prospective, single-centre observational cohort study (05/2017-03/2019, NCT03507673, local ethical approval reference no.18-005), conducted at a university-affiliated centre for reproductive medicine in Germany, vaginal swab samples were collected from infertile, asymptomatic female patients (n = 260), aged 18-45, undergoing frozen-thawed embryo transfer. Patients, each contributing a single treatment cycle, received sequential oral estradiol and oral estradiol/dydrogesterone in an HRT regimen for FET. Vaginal swabs were taken from baseline visit before transfer day and stored at –80 °C. Participants/materials, setting, methods 16S rRNA gene amplicon sequencing was performed targeting V3/V4 hypervariable region using Illumina MiSeq platform. Raw data assembly, filtering and taxonomic assignment were performed using mothur against EzBioCloud database. Statistical analyses, and visualization were conducted using R. Community structure via hierarchical clustering, alpha and beta diversity, and indicator species via LefSe analysis were assessed. Main results and the role of chance Based on a hierarchical clustering using the 25 most abundant bacterial taxa, seven separate community state types (CSTs) being either dominated by species of the genus Lactobacillus (CST-A, CST-B, CST-C, CST-E, CST-G) or Gardnerella (CST-F) or presenting a variable community composition (CST-D) were identified. A community state type dominated by Lactobacillus fornicalis was found in a small fraction of women and enhanced resolution among the Gardnerella genus impacts CST definitions in this sample. Embryonic implantation had no significant association to either alpha diversity measures or CST distribution; likewise, the previously suggested ratio of relative abundances of Lactobacillus iners vs. Lactobacillus crispatus was not associated with implantation. Lactobacillus fornicalis is positively linked to implantation, while Lactobacillus iners and Ureaplasma parvum were linked to implantation failure: above 50% relative abundance of Lactobacillus fornicalis, was associated with 75% positive implantation. Conversely, just 0.5% relative abundance of Ureaplasma parvum was associated with a decrease in implantation rate to approximately 20%. LefSe and binary regression analysis identified a relatively rare (6% in our sample) microbiome signature, mostly from CST-C (Lactobacillus iners dominated) with a very low likelihood of implantation, with Ureaplasma parvum as the common denominator. Limitations, reasons for caution Studies on the vaginal microbiome in IVF face issues such as study design variability, small sample-sizes, limited control for temporal dynamics, and patient heterogeneity. Attempts at establishing causal relationships through interventional studies in IVF have been limited and inconclusive. Understanding the microbiome’s functional aspects is crucial for reproductive outcome elucidation. Wider implications of the findings Current study findings don’t confirm previously reported associations between common vaginal bacterial CSTs and outcome. Therefore, screening for vaginal microbiome composition in asymptomatic women with subfertility is not recommended outside research. Signatures/taxae with an independent and strong negative association with implantation are likely to be rare yet deserve further attention. Trial registration number NCT03507673

P-201 Embryo prioritization through an AI-powered evaluation system improves the clinical outcome in IVF cycles

Abstract Study question How can the implantation rate be improved through the prioritization of embryos, particularly in the context of elective single embryo transfer (eSET)? Summary answer Based on the retrospective data of IVF treatment using 965 embryos, the AI-powered embryo-evaluation system, icONE, was developed to provide unbiased selection with promising accuracy. What is known already Over the past decade, numerous predictive models guiding IVF treatments for frozen-thawed embryo transfer (FET) success have emerged. However, most are unidimensional, focusing on factors like patient characteristics (e.g., age, reproductive hormones), embryo quality (e.g., morphokinetics), or biomarkers (e.g., genes, microRNAs). Despite efforts, many models exhibit limited AUROC (area under the receiver operating characteristic curve) values of 0.70∼0.77, suggesting a need for comprehensive consideration of maternal and embryonic factors to enhance predictive accuracy. Study design, size, duration The current study aims to develop an AI-assisted embryo prediction system. Nine hundred and sixty-five embryos from 232 patients (ages ranging from 24 to 50 years old, mean age = 36.9 years) who underwent IVF treatment during 2015–2018 were enrolled for developing an embryo prediction system. The clinical information and detail of IVF procedures of each patient and embryo were recorded and integrated to explore their impact on clinical outcomes. Participants/materials, setting, methods Pregnant outcomes were followed, including hCG examination, sac formation, and live birth. Whole genome sequencing (WGS) analysis using TE biopsy was performe. Genetic features extracted from WGS data and maternal clinicopathological characteristics were integrated and calculated by decision tree algorithm and machine learning algorithms, including Random Forest, XGBoost, LightGBM, Tabnet, etc. Main results and the role of chance To reduce the number of IVF cycles, diminish the risk associated with multiple pregnancy, and maximize the efficacy of IVF treatment, we analyzed genetic data generated from the preimplantation genetic screenings and developed a prototype of an AI-assisted program to evaluate the viability and quality of each embryo. The “intelligent cOmputing Noble Embryo” (icONE) program integrates genetic data and maternal clinical features. icONE showed classification accuracy and prediction specificity of 0.81 and 0.83, respectively, and the overall prediction accuracy of successful implantation reached to 92%. Random Forest outperformed other machine learning tools with overall positive predictive value, negative predictive value, specificity, and sensitivity of 91.8%, 91.0%, 90.3%, and 92.4%, respectively. The overall prediction accuracy of successful implantation reaches was 91.4%. Notably, the preliminary results of a randomized prospective clinical trial showed that the clinical pregnancy rate reached 77.3% (n = 81) based on the icONE’s evaluation, which was significantly higher than that of 50% (n = 85) in the non-icONE group. Patients of both advanced and young age benefited from icONE. Taken together, these results endorse the efficacy of icONE in prioritizing embryos for clinicians in IVF treatment. Limitations, reasons for caution It is noticed that our study is limited by the small sample size and all the data are collected from a single IVF center. The uniform and controlled operation of IVF cycles in a single center may cause selection bias. Wider implications of the findings Given the shift towards eSET in reproductive medicine, prioritizing embryos for implantation potential is vital in infertility treatment. The AI-powered model established in this study enhances clinical practice, optimizing parenthood chances for those facing fertility issues. Trial registration number not applicable

P-329 Evaluating Implansera, autologous platelet-derived growth factors, to improve clinical pregnancy and live birth rates in frozen embryo transfer for women with recurrent implantation failure

Abstract Study question Can Implansera, Autologous Platelet-Derived Growth Factors, serve as a promising adjuvant therapy in assisted reproductive techniques to enhance endometrial thickness and implantation rates? Summary answer Use of Implansera significantly increased clinical pregnancy and Live Birth Rate In Patients With repeated implantation failure during FET cycles. What is known already Insufficient endometrial thickness and receptivity contribute to Recurrent Implantation Failure (RIF), prompting consideration of surrogacy. Despite global rise in Frozen Embryo Transfer (FET), quest for an optimal implantation protocol persists. Recent research highlights platelet-rich plasma (PRP) as promising solution for thin endometrium and RIF cases, attributing positive outcomes to PRP’s high growth factor concentration. Recognizing the need for precise platelet and growth factor concentrations, Implansera—a specialized platelet-derived growth factor concentrate—was developed. This innovation addresses the challenge of unresponsive endometrium, offering tailored solution to maximize therapeutic efficacy and improve pregnancy outcomes for patients facing RIF issues. Study design, size, duration Conducted from May 2021 to December 2023, this prospective interventional self-controlled study focused on 21 women (aged 30-48) experiencing recurrent IVF failure due to stubborn thin endometrium. Selected after negative hysteroscopic and bacteriologic screenings, and unsuccessful pregnancies despite multiple immune therapy regimens, such as intralipid and granulocyte colony-stimulating factor infusions, steroids, and endometrial scratching. The subjects underwent Implansera treatment, aiming to address refractory thin endometrium and potentially enhance their chances of successful conception. Participants/materials, setting, methods After obtaining informed consent women with at least two previous unexplained RIF, who were candidates for frozen-thawed embryo transfer were treated with intrauterine infusion of 0.8 ml of Implansera was infused into uterine cavity in addition to standard HRT protocols 2 days before ET. Clinical pregnancy was determined by positive serum β-HCG, 2weeks after ET and presence of fetal heart beat in trans-vaginal ultrasound 5weeks after ET. Main results and the role of chance Among 21 women, 10 achieved pregnancy (47.6%), while 11 did not conceive (52.4%). Clinical outcomes varied: 1 woman (4.8%) experienced chemical pregnancy, 3 (14.3%) miscarried before 6-12 weeks, 3 (14.3%) delivered healthy full-term babies, and 3 (14.3%) are in the 24th week of uneventful gestation accounts for 28.6% cumulative successful pregnancy outcomes. Implansera treatment yielded no reported adverse effects.Implansera, prepared through a patented proprietary process, standardized to contain 6-9 times higher growth factors than peripheral blood, particularly implantation-friendly and anti-inflammatory cytokines, addresses the crucial angiogenic and anti-inflammatory requirements for successful implantation. Tailored for the cyclical demands of endometrial proliferation, secretion, and implantation phases, it efficiently restores impaired uterine environments.Beyond efficacy, Implansera’s safety, reproducibility, and effectiveness in emulating natural tissue repair and regeneration processes are noteworthy. Studies underscore the significance of creating an environment conducive to successful implantation, and Implansera’s composition aligns with these requirements. Its capacity to mimic natural processes positions it as a promising solution, offering a comprehensive approach to enhancing endometrial receptivity, thus optimizing conditions for successful pregnancies. Limitations, reasons for caution This self-controlled prospective study, albeit with small sample size and lacking randomized control group, aligns with published data in demonstrating Implansera’s benefits. Proposing larger studies, particularly with unexplained RIF, to establish Implansera as routine IVF adjuvant. Further investigations aim to identify active molecules influencing implantation and suggest targeted recommendations. Wider implications of the findings Implansera improved implantation, pregnancy, and live birth rates (LBR) in unexplained RIF patients which indicates clearly endometrial thickness and receptivity improvement and motivated us to plan randomized controlled studies to confirm the results and provide opportunity for women with unexplained RIF to conceive and deliver in lesser number of cycles. Trial registration number Not applicable

P-295 Impact of septate uteri on pregnancy and neonatal outcomes of IVF/ICSI–frozen embryo transfer

Abstract Study question What is the impact of septate uteri on reproductive and neonatal outcomes of IVF/ICSI–frozen embryotransfer? Summary answer septate uteri are associated with lower birthweight and worse fertility outcomes including lower Intrauterine implantation rate and lower live birth rates. What is known already Several studies have investigated the negative effects of septate uteri on pregnancy outcomes.However, an all-round and definitive conclusion has not been reached yet owing to the relatively low incidence of the disease and theheterogeneity of study populations, especially among women undergoing ART. Study design, size, duration This was a retrospective cohort study including 149 women with septate uteri and 13921 women with a normal uterus who underwent first frozen-thawed embryo transfer cycles of IVF/ICSI from january 2016 to December 2022. We compared reproductive outcomes. Participants/materials, setting, methods Reproductive outcomes of women with septate uteri were studied through propensity score-matched comparisons (patients with septate uterus respectively along with corresponding control group without uterine malformations). We also comparedpregnancy and neonatal outcomes. Main results and the role of chance Compared to the matched control group, women with septate uterus had asignificantly lower LBR(37.58% versus 50.56%, odds ratio (OR) 1.698 [95% CI: 1.161, 2.484], P = 0.006) and Intrauterine implantation rate(36.31% versus 45.67%, odds ratio (OR) 1.474 [95% CI: 1.06, 2.06], P = 0.021) Limitations, reasons for caution This was a single-centre, retrospective study in which neonatal data were extracted fromparental questionnaires. In patientswith uterine malformations, the number of babies with birth defects and twin pregnancies was relatively small, limiting the power of thestudy. Wider implications of the findings Compared to patients with a normal uterus, women with septate uterus have poorer reproductive outcomes. Pregnant women with a septate uterus need to be managed as high-risk pregnancies and followed withappropriate obstetric review. Trial registration number not applicable

P-706 The pregnancy rates in a large cohort of patients with thin endometrium when stratified according to estradiol levels on the day of triggering

Abstract Study question Is there any difference in ongoing pregnancy rate in women with thin endometrium (<8 mm) when scrutinized based on estradiol levels on triggering day? Summary answer Either with a low, moderate, or high estradiol level on the day of triggering, ongoing pregnancy rates do not change in patients with thin endometrium. What is known already Endometrial thickness has been argued to be one of the proxy determinants of endometrial receptivity. In that context, although the optimal thickness has been widely stated to be between 8-14 mm, the negative effect of thin endometrium on pregnancy outcome is still controversial in in-vitro-fertilization (IVF) cycles. Nevertheless, particularly lack of large sample size of women with thin endometrium among the available literature, is the leading factors that avoids to solid conclusion.Furthermore, it might be hypothesized that patients with thin endometrium and accompanying low estradiol might be distinct from women with thin endometrium despite relatively high estradiol level. Study design, size, duration A retrospective cohort study was designed among patients that has undergone in-vitro fertilization (IVF) treatment between January-2018 and June-2023 in Bahceci Health Group. Only patients having an endometrial thickness <8 mm on the day of triggering were recruited. Other inclusion criteria was having at least one blastocyst to be transferred. All frozen-thawed embryo transfer cycles were excluded. Female age and body mass index were not considered as an exclusion criterion. Participants/materials, setting, methods During the study period, a total of 3076 IVF cycles with fresh ET were employed. Of them, 814 had an endometrial thickness of < 8 mm on the day of triggering. Among 814 IVF cycles, 25th, 50th and 75th quartiles of estradiol levels on the day of triggering referred to 322.8, 755.7 and 1310.5 pg/ml, respectively. The number of IVF-ET cycles in the 1st, 2nd, 3th and 4th quartiles were 203, 204, 204 and 203. Main results and the role of chance The mean (SD) age of women recruited in the final analyses was 36.5 (5.5) years and endometrial thickness was 7.2 (0.8) mm. The pregnancy rates per ET with regard to 1st, 2nd, 3th and 4th quartiles were 37.6%, 33.0%, 37.3% and 44.3%, respectively without any statistical significance (p = 0.134). However, the respective ongoing pregnancy rates were 26.1%, 18.1%, 22.1%, 31.0 % and the highest quartile had a statistically superior ongoing pregnancy rates than the second (p = 0.003) and third quartiles (p = 0.022). When binary logistic regression analysis was performed by inserting the female age, body-mass index, duration of infertility and quartiles of estradiol levels on the day of triggering, only female age remained as an independent factor for the prediction of an ongoing pregnancy (RR: 0.92 CI95%: 0.87 to 0.98, p = 0.008). Utilization of estradiol level as a continuous variable in the same model also failed to present the independent validity of it to predict an ongoing pregnancy. Notably, the lowest thickness of a positive pregnancy resulting with an ongoing pregnancy was 4.7 mm. Limitations, reasons for caution The inherent risks cannot be excluded due to the retrospective nature of the current study, which had been efforted to overcome with regression analysis. Wider implications of the findings The current study includes one of the largest numbers of experience particularly with thin endometrium on the day of triggering. However, having a thin endometrium despite low or relatively high estradiol level does yield any prediction for the pregnancy outcome. Trial registration number Not Applicable

P-545 Early pregnancy outcomes associated with age and AMH following Next-Generation Sequencing(NGS)-based Preimplantation Genetic Testing for Aneuploidy(PGT-A) in single euploid embryo transfers for advanced age patients

Abstract Study question Does age and AMH impact early pregnancy outcomes in euploid single embryo transfers using NGS-based PGT-A for individuals aged 35 and above? Summary answer In this NGS-based PGT-A study, no significant differences in early pregnancy rates were observed based on age or AMH among individuals aged 35 and above. What is known already A recent meta-analysis suggest a decline in pregnancy rates with advancing age in the context of euploid embryo transfer following PGT-A. However, it’s crucial to acknowledge variations in PGT-A techniques across studies. While individuals with low AMH levels may encounter challenges in obtaining euploid embryos, the precise impact of AMH on pregnancy rates post-embryo acquisition remains unclear. Study design, size, duration A retrospective cohort study was conducted on 428 cycles of single euploid embryo transfers in patients aged 35 and above, performed at the single infertility center from January to December 2022. Participants/materials, setting, methods The study examined frozen-thawed embryo transfer cycles in patients aged 35 and above, analyzing early pregnancy outcomes in single euploid embryo transfers. Participants were grouped by age(35-38, 38-42, 42 and above) and AMH levels(<1, 1-3, >3 ng/ml). NGS-based PGT-A conducted embryo biopsy. The analysis aimed to detect differences in initial pregnancy rates among age and AMH subgroups. The differences between groups were compared using Pearson’s chi-squared test. Main results and the role of chance The average age at transfer was 39.05 ± 2.53 years, with a mean AMH of 2.60 ± 1.86(ng/ml). The mean number of prior frozen embryo transfer (FET) cycles was 1.9 ± 2.04, with 119 patients (27.8%) having undergone three or more transfer cycles. Transfer cycles comprised 363 (84.8%) artificial cycles and 65 (15.2%) ovulatory cycles, with an average endometrial thickness of 8.95 ± 1.73 mm at the time of transfer. The β-hCG positive rate was 57.7% (247/428), and the clinical pregnancy rate was 53.5% (229/428). When analyzing positive b-hCG results by age, rates were 59.9% (82/137) for ages 35-38, 55.5% (121/218) for ages 38-42, and 60.3% (44/73) for ages 42 and above (p = 0.641). In terms of AMH, β-hCG positive rates were 52.1% (37/71) for <1, 59.1% (120/203) for 1-3, and 58.0% (83/143) for ≥3, with no statistically significant differences (p = 0.584). Clinical pregnancy rates were 54.0% for ages 35-38, 51.8% for ages 38-42, and 57.5% for ages 42 and above. For AMH, rates were 50.7% for <1, 53.2% for 1-3, and 54.5% for ≥3, with no statistically significant differences (p = 0.869). Limitations, reasons for caution Being a retrospective study analyzing patients undergoing embryo transfer, our study overlooks variables related to oocyte retrieval. Given the challenges of obtaining euploid embryos in advanced age, further investigation is warranted to explore the probability and duration of embryo acquisition in this population. Wider implications of the findings In this study, utilizing NGS-based PGT-A after generating euploid embryos, no significant differences in early pregnancy outcomes were observed for women aged 35 and older, considering age and AMH levels. The study suggests further research is needed to explore if NGS-based PGT-A can address limitations of traditional chromosomal testing methods. Trial registration number not applicable

Racial disparities in the outcomes of euploid single frozen-thawed embryo transfer cycles – analysis of the Clinical Outcome Reporting System of the Society for Assisted Reproductive Technology 2016–2018 data

ObjectiveTo evaluate if in pregnancies conceived with the transfer of single genetically tested embryos, maternal race and ethnicity relate to pregnancy outcome. DesignRetrospective cohort. SubjectsAutologous frozen -thaw embryo transfer (FET) cycles with transfer of single genetically tested embryo in SART-CORS for years 2016-2018; cycles associated with diagnoses of recurrent pregnancy loss, gestational carrier, donor egg and donor embryo were excluded. ExposureInformation on race and ethnicity linked with in vitro fertilization and FET cycles available in the SART-CORS. Main Outcome MeasuresMultivariable analyses utilizing generalized estimating equation examined the relationship between categories of race and ethnicity with the following outcomes: Pregnancy (+βhCG following FET), clinical pregnancy, pregnancy loss (early [at gestation <13 weeks] and late [loss between ≥13 and <20 weeks]), preterm (<37 weeks), term (≥37 weeks) and live birth. Covariates adjusted for included age, BMI, AMH, infertility diagnosis and smoking history. Results79,416 FET cycles met the eligibility criteria. Information on race and ethnicity was specified for 50,820 (64.0%) and was not known in 28, 723 (36%) of the cycles . The population was predominantly non-Hispanic White (NHW, 44%). Non-Hispanic Black [NHB] comprised 2.7%, Asian 12.3%, Hispanic 3.4%, American Indian, Pacific Islander, Hawaiian and Alaskan [AI_AL_PI_H] 0.2%. Nearly 1.0 % self-identified with more than one race. On multivariable analyses, pregnancies in NHB and in Hispanic women (compared to NHWs) were significantly more likely to result in in preterm birth (p<0.001). Compared to NHW women, the likelihood of live birth was significantly lower in NHBs (p<0.01), Asian (p=0.04), Hispanic (<0.01) and AI_AL_PI_H women (p<0.01). . The likelihood for delivery by Cesarean was also disproportionately higher in the NHB (p=0.047), Hispanic (p=0.007) and in women identifying with more than one race (0.023)compared to NHWs . ConclusionRacial and ethnic differentials are apparent in the outcomes of FET conceived pregnancies resulting from the transfer of single genetically tested embryos.

International Committee for Monitoring Assisted Reproductive Technology world report: assisted reproductive technology, 2015 and 2016

ObjectiveTo report utilization, effectiveness, and safety of assisted reproductive technologies in 2015 and 2016. DesignRetrospective, cross-sectional survey of 3103 assisted reproductive technology clinics in 74 countries in 2015 and 3249 clinics in 79 countries in 2016 that submitted cycle and pregnancy outcome data through national and regional registries. SubjectsPatients undergoing assisted reproductive technology procedures. ExposureAssisted reproductive technology. Main Outcome MeasuresOutcomes on country, regional, and global levels. ResultsReported for 2015: 2,358,239 cycles with 548,652 babies born; for 2016: 2,807,963 cycles with 647,188 babies born. Estimated in 2015, ≥2,683,677 cycles resulted in >675,134 babies; in 2016, ≥3,100,448 cycles resulted in ≥723,026 babies. Reported cycles represent approximately 80% of global utilization. In 2015 and 2016, 27.6% and 27.8%, respectively, of women undergoing fresh autologous cycles were age ≥40 years. Frozen-thawed embryo transfer cycles accounted for 47.0% and 51.9%, respectively, of all embryo transfers in 2015 and 2016. Oocyte donation cycles accounted for 6.7% and 7.1% of all embryo transfers in 2015 and 2016. Intracytoplasmic sperm injection was performed in 57.7% and 56.4% of autologous aspiration cycles in 2015 and 2016, respectively. The cumulative delivery rate per aspiration cycle for fresh and frozen-thawed embryo transfer was 32.4% in 2015 and 33.1% in 2016, respectively. The average number of transferred embryos was 1.70 in 2015 and 1.69 in 2016. The proportion of single embryo transfers in fresh autologous cycles increased from 42.1% in 2015 to 44.0% in 2016. The twin delivery rate decreased from 16.0% in 2015 to 14.7% in 2016, and the triplet rate decreased from 0.6% in 2015 to 0.4% in 2016. The proportion of single embryo transfers in frozen-thawed embryo transfer autologous cycles was 62.2% in 2015 and 64.2% in 2016, with twin and triplet rates of 10.1% and 0.3% in 2015 and 10.0% and 0.2% in 2016, respectively. ConclusionUtilization of assisted reproductive technology and births per cycle increased from 2015 to 2016 while multiple births were reduced . Increasing proportion of frozen-thawed embryo transfer cycles, continuing wide variation in use of intracytoplasmic sperm injection, and increase in single embryo transfer rates are reported.

Does Serum Estradiol Prior to Progesterone Administration in Programmed Frozen Embryo Transfer Cycle Impacts Live Birth Rate: A Prospective Cohort Study

Background: There is a paucity of data on the optimal threshold of oestradiol (E2) levels required for successful implantation as this is a valid question to be answered, considering that significant number of in vitro fertilisation cycles are deferred for FET cycles. Aim: The aim of this study is to investigate the serum E2 levels before starting exogenous progesterone in artificial autologous frozen thawed embryo transfers on pregnancy outcomes. Settings and Design: This was a cohort study wherein clinical data of 213 artificial autologous programmed hormone-regulated frozen embryo transfer (HR-FET) cycles were collected. Materials and Methods: The HR-FET cycles were divided into three groups based on the E2 levels before starting progesterone: Group A: E2 ≤300 pg/mL, Group B: E2 301–500 pg/mL and Group C: E2 &gt;500 pg/mL. After adequate endometrial stripe was appreciated by transvaginal ultrasonography, single blastocyst transfer was performed in all the cycles. Statistical Analysis Used and Results: The clinical pregnancy rate (CPR) in Groups A, B and C were 41.8%, 73.5% and 0.95%, respectively (P = 0.0001). The live birth rate (LBR) in Groups A, B and C was 18.1%, 62.2% and 0%, respectively (P = 0.0001). The miscarriage rate (MR) was significantly lower (15.3%) when E2 was between 301 and 500 pg/mL (P = 0.001). At both the extremes of serum E2 values, the rate of miscarriage increased. If serum E2 levels were ≤300 pg/mL or &gt;500 pg/mL, the rate of miscarriage was 56.5% and 100%, respectively. Conclusion: Serum E2 levels in the range of 301–500 pg/mL before starting progesterone in programmed FET cycle are associated with an improved CPR and LBR and also decreased MR as compared to the extreme values of E2 ≤300 pg/mL or &gt;500 pg/mL.

THE EFFECT OF LASER-ASSISTED HATCHING ON PREGNANCY OUTCOMES OF VITRIFICATION FROZEN EMBRYO TRANSFER

Highlights LAH might effectively increase pregnancy outcomes for frozen-thawed embryo transfer. Zona pellucida drilling might help increase pregnancy outcomes in FET. Abstract Background: Zona Pellucida (ZP) thickness of less than 16 mm is better for embryo implantation inside the endometrium. Laser Assisted Hatching (LAH) is commonly used, especially in non-contact mode, using a 1.48-um infrared diode laser beam because of its short exposure time, accurate positioning, simple operation, indirect contact, safety, and effectiveness. Objective: This paper describes the potential of laser-assisted hatching in biochemical pregnancy outcomes in Frozen Embryo Thawed transfers. Material and Method: The total number of patients enrolled in this study was 141. Patients were prospectively treated during embryo transfers at Pusat Fertilitas Bocah Indonesia, Primaya Hospital at Tangerang, Indonesia, from December 2020 until December 2021. Result: There were no significant differences between the LAH and no-LAH groups regarding average age, infertility duration, infertility type, and etiology of infertility (p&gt;0.05). In the same line, the blastocyst (0.76 ± 0.87; 1.25 ± 1.08) compared with cleavage (0.72 ± 0.84; 0.67 ± 0.98) (p&lt;0.534 and p&lt; .032). There was no significant difference, even though clinically, the proportions of live births, multiple pregnancies, biochemical pregnancies, and ongoing pregnancies in the LAH group were not exceptions to the outcomes of failures and miscarriages. Conclusion: LAH did not appear to increase the pregnancy rate in this study. However, the methodology seems to reduce bias in this study by considering methodology for selecting FET embryos based on the cryopreserved condition, embryo quality, and precise LAH.

Obstetrical and Neonatal Outcomes of in vitro Fertilization Twins after Fresh Embryo Transfer versus Frozen-Thawed Embryo Transfer.

The limited data regarding obstetrical outcomes in multiple pregnancies following both fresh embryo transfer and frozen-thawed embryo transfer (FET), along with the association between multiple pregnancies and increased pregnancy complications compared to singleton pregnancies, highlight the need for research on this topic. Therefore, this study aimed to compare obstetrical and neonatal outcomes of twin pregnancies after fresh embryo transfer versus FET. This was a retrospective single-center study. There were in vitro fertilization (IVF) dichorionic twin pregnancies ≥23 weeks of gestation during 2010-2022. This retrospective study was based on data recorded at Galilee Medical Center, a tertiary-care university-affiliated hospital, Israel. We conducted a comparative analysis of obstetrical and neonatal outcomes between IVF dichorionic twin pregnancies after fresh embryo transfer and those after FET. This analysis included variables such as gestational age at delivery, birthweight, preterm birth rates, low birthweight rates, neonatal intensive care unit admissions, and complications related to prematurity. The study included 389 IVF twin pregnancies: 253 after fresh embryo transfer and 136 after FET. Following fresh embryo transfer compared to FET, the mean gestational age at delivery was earlier (34 + 6 vs. 35 + 5 weeks, p = 0.001) and the rate of preterm birth (&lt;37 weeks) was higher (70.4% vs. 53.7%, p = 0.001). This difference in gestational age at delivery remained significant after adjustment for maternal age, parity, and BMI (OR = 2.11, 95% CI: 2.11-3.27, p = 0.001). Similarly, the difference in preterm birth rates remained significant after adjustment of the same variables (p = 0.001). For the fresh embryo transfer compared to the FET group, the mean birthweight was lower (2,179.72 vs. 2,353.35 g, p = 0.003); and low birthweight and very low birthweight rates were higher (71.2% vs. 56.3%, p &lt; 0.001 and 13.5% vs. 6.7%, p = 0.004, respectively). For the fresh embryo transfer compared to the FET group, the proportions were higher of neonates admitted to the neonatal intensive care unit (23.3% vs. 16.0%, p = 0.019), of neonates with respiratory distress syndrome (10.5% vs. 5.9%, p = 0.045) and those needing phototherapy (23.3% vs. 16.0%, p = 0.019). Limitations of the study include its retrospective nature. Furthermore, we were unable to adjust for some confounders, such as the number of eggs retrieved, the number of embryos transferred, and methods for ovarian stimulation or preparation of the endometrium for embryo transfer. Obstetrical and neonatal outcomes of twin pregnancies were worse after fresh embryo transfer than after FET. The findings support favorable fetal outcomes after FET and support the current trend of shifting from fresh embryo transfer to FET. Prospective studies are needed to support our results.

Combined analysis of estradiol and β-hCG to predict the early pregnancy outcome of FET: a retrospective study

BackgroundThe accurate prediction of pregnancy outcomes in in vitro fertilization (IVF) cycles is crucial. While several studies have been conducted on the predictive power of serum estradiol (E2) and β-hCG concentrations post-embryo transfer (ET) for pregnancy outcomes, there is debate on the predictive value of E2. The objective of this study was to investigate the predictive efficacy of combining serum E2 and β-hCG levels on early reproductive outcomes 12 days after embryo transfer.MethodsA total of 1521 patients with β-hCG positive values on day 12 following frozen-thawed embryo transfer (FET) with natural endometrial preparation cycles (NCs) were gathered in affiliated Women’s Hospital of Jiangnan University. Using logistic regression, the relationship between pregnancy outcome and early serum E2 and β-hCG concentrations was examined. The receiver-operating characteristic (ROC) analysis was used to assess the predictive accuracy of the serum E2 and β-hCG concentrations.ResultsNotable distinctions were observed in the serum E2 and β-hCG levels on the twelfth day following FET with NCs between the groups classified as clinical pregnancy group (CP Group) and biochemical pregnancy group (BP Group). In addition, the cutoff values for E2 and β-hCG on day 12 following FET with NCs in cleavage embryo group (CE Group) were 129.25 pg/mL and 156.60 mIU/mL, respectively. The threshold values for E2 and β-hCG for the blastocyst group (B Group) were 174.45 pg/mL and 217.70 mIU/mL. Serum E2 day12 and β-hCG day12 were found to be substantially linked with clinical pregnancy by logistic regression analysis.ConclusionsSerum E2 and β-hCG concentrations were found to be significantly different between the CP Group and BP Group in infertility women underwent FET with NCs. Our retrospective cohort study’s findings suggest that the combination of early E2 and β-hCG levels on day 12 post-FET could be used as a predictive tool to evaluate the likelihood of both positive and negative pregnancy outcomes in FET with NCs.

The role of age and AMH on cumulative live birth rates over multiple frozen-thawed embryo transfer cycles: a study based on low prognosis patients of POSEIDON 3 and 4 groups

BackgroundAmong the POSEIDON criteria, group 3 and group 4 have an expected low prognosis. For those patients with inadequate ovary reserve, embryo accumulated from consecutive oocyte retrieval cycles for multiple frozen-thawed embryo transfers (FET) has become more common. It is necessary to inform them of the pregnancy outcomes after single or multiple FET cycles before the treatment. However few studies about cumulative live birth rate (CLBR) for those with low prognosis have been reported.MethodsThis retrospective study included 4712 patients undergoing frozen embryo transfer cycles from July 2015 to August 2020. Patients were stratified as POSEIDON group 3, group 4, control 1 group (< 35 years) and control 2 group (≥ 35 years). The primary outcome is CLBRs up to six FET cycles and the secondary outcomes were LBRs per transfer cycle. Optimistic approach was used for the analysis of CLBRs and the depiction of cumulative incidence curves.ResultsUnder optimistic model analyses, control 1 group exhibited the highest CLBR (93.98%, 95%CI 91.63-95.67%) within 6 FET cycles, followed by the CLBR from women in POSEIDON group 3(92.51%, 95%CI 77.1-97.55)was slightly lower than that in control 1 group. The CLBR of POSEIDON group 4(55% ,95%CI 39.34-70.66%)was the lowest and significantly lower than that of control 2 group(88.7%, 95%CI 80.68-96.72%). Further, patients in POSEIDON group 4 reached a CLBR plateau after 5 FET cycles.ConclusionsThe patients of POSEIDON group 3 may not be considered as traditional “low prognosis” in clinical practice as extending the number of FET cycles up to 6 can archive considerably CLBR as control women. While for the POSEIDON group 4, a simple repeat of the FET cycle is not recommended after four failed FET cycles, some strategies such as PGT-A may be beneficial.

Letrozole ovulation regimen for frozen-thawed embryo transfer in women with polycystic ovary syndrome: study protocol for a randomized controlled trial

BackgroundWomen with polycystic ovary syndrome (PCOS) are usually selected to undergo an ovulation induction regimen or a programmed regimen for endometrial preparation in the frozen-thawed embryo transfer (FET) during their IVF/ICSI treatment. The programmed regimen permits flexible scheduling of embryo transfer but requires long-term usage of exogenous estrogen and higher dosages of luteal support while the letrozole ovulation regimen needs lower dosages of luteal support only. Recently, multiple studies have shown that the letrozole ovulation regimen can improve pregnancy outcomes of FET in women with PCOS compared with the programmed regimen. However, most of these studies are retrospective, and prospective studies are urgently needed the evidence from the perspective study is insufficient.Methods/designWe are undertaking a multicentre, randomized, controlled clinical trial of an endometrial preparation regimen for FET in women with PCOS. The eligible women are randomly assigned to either the letrozole ovulation regimen or the programmed regimen for endometrial preparation. The primary outcome is the clinical pregnancy rate.DiscussionThe results of this study will provide evidence for whether the letrozole ovulation regimen for endometrial preparation could improve pregnancy outcomes in PCOS women undergoing FET.Trial registrationChinese Clinical Trial Registry ChiCTR2200062244. Registered on 31 July 2022.

Impact of different progesterone timings on live birth rates for blastocyst frozen embryo transfer cycles

Research questionThe optimal timing of progesterone use before blastocyst transfer in frozen-thawed embryo transfer (FET) cycles remains unknown. Does the different timing of progesterone administration for day 5 and day 6 blastocysts affect the live birth rate (LBR) of artificial FET cycles? DesignThis retrospective cohort study included 1362 patients who underwent artificial FET cycles. The effects of 6 and 7 days of progesterone administration prior to blastocyst transfer on clinical outcomes were compared in day 5 and day 6 blastocysts, respectively. Univariable and multivariable regression analyses were used. ResultsIn the univariable and multivariable regression models for all patients, LBRs were comparable between the two groups (51.8% vs. 47.9%). For day 6 blastocysts, after adjusting for confounders, the 7-day progesterone regimen resulted in a significantly higher LBR (44.8% vs. 36.4%; adjusted OR=1.494; 95% CI, 1.060-2.106) and lower pregnancy loss rate (15.4% vs. 25.2%; adjusted OR=0.472; 95% CI, 0.260-0.856) compared to the 6-day progesterone regimen. For day 5 blastocysts, there was no significant difference in pregnancy outcomes between the two groups, but the rate of low birthweight was higher with the 7-day progesterone regimen than with the 6-day regimen (13.9% vs. 6.7%). ConclusionsIn all blastocyst analyses, there was no difference in LBR between 6 and 7 days of progesterone use prior to blastocyst transfer in artificial FET cycle. For day 6 blastocysts, the LBR was significantly higher with the 7-day progesterone regimen than with the 6-day regimen, whereas for day 5 blastocysts, pregnancy outcomes were comparable between the two groups.

Oil-soluble contrast medium bathing attenuated endometrial inflammation and improved endometrial receptivity in women with recurrent implantation failure: a descriptive study

BackgroundThe oil-soluble contrast medium used in hysterosalpingography has been shown to have a fertility-enhancing effect, but the underlying mechanism is unclear, especially regarding the role of window of implantation (WOI). This study aimed to assess the endometrial immunological impact of the WOI before and after bathing with the oil-soluble contrast medium in women with recurrent implantation failure (RIF).MethodsThis descriptive study involved two medical centers between December 18, 2019, and December 30, 2020. We included infertile women who underwent three or more transfer cycles, cumulative transplantation of at least four high-quality cleavage-stage embryos or three high-quality blastocysts without clinical pregnancy, and high-quality frozen embryos that were still available for implantation. Patients received 5 ml of ethiodized poppyseed oil bathing, endometrial biopsy around bathing, and frozen-thawed embryo transfer (FET) within four menstrual cycles after bathing. Patients were excluded if failure to complete anyone. Data on the baseline characteristics and clinical data of the FET cycles were collected, and endometrial biopsy specimens were collected in the luteal phase before and after bathing and subjected to immunohistochemistry. The number of CD56 and CD138 positive cells and H-score of expression of ανβ-3 and HOXA10 in endometrium were collected.ResultsThirty-four patients were initially enrolled in the study; ultimately, twelve patients with a median age of 32.5 years (range 27–40 years) completed the research. The median number of embryo transfer cycles was three (range 3–8). A total of 4 of 12 women (33.33%) were diagnosed with chronic endometritis before oil-soluble contrast bathing. After bathing, the median numbers of CD138-positive cells in endometrium decreased from 0.75 (range 0–13.5) to 0.65 (range 0–6), P = 0.035; additionally, the H-score of expression of ανβ-3 in endometrium increased from 148.50 ± 31.63 to 175.58 ± 31.83, P < 0.001. The thickness of the endometrium also significantly increased (8.90 ± 1.45 mm vs.10.11 ± 1.98 mm, P = 0.005). However, no consistent changes were found in the expression of CD56 and HOXA10 in the endometrium. Five patients experienced biochemical pregnancies (41.67%), four had clinical pregnancies (33.33%), and three achieved live births following oil-soluble contrast bathing (25%).ConclusionsThese results suggest that oil-soluble contrast medium bathing decreased CD138-positive cells and upregulated expression of ανβ-3 during WOI in patients with RIF. This histological impact of endometrium may result in enhanced fertility during FET cycles. Investigating the ability of intrauterine bathing with lower-dosage oil-soluble contrast to improve pregnancy in the RIF population is warranted.

Effect of different endometrial preparation methods on pregnancy outcome of FET in women with a normal menstrual cycle

ABSTRACT Objective: This study aims to explore the relationship between different endometrial preparations and pregnancy outcomes among patients with regular ovulatory cycles in order to find the best endometrial preparation methods in the freeze–thaw embryo transfer (FET) cycle. Materials and Methods: This is a retrospective study to investigate FET pregnancy outcomes in women who had a regular menstrual cycle, were younger than 35 years old, and underwent a modified natural cycle (mNC), ovulation induction (OI), or a hormone replacement treatment (HRT) cycle. A total of 1071 frozen cycles were included for analysis. Results: The implantation rate and live birth rate (LBR) in the OI group show a significant difference when compared to the mNC and HRT groups (P &lt; 0.01). After adjusting for confounding factors, the logistic regression analysis revealed that the number of embryos transferred, the embryo stage, and quality were significantly associated with clinical pregnancy rate and LBR. The LBR was additionally affected by the mode of the endometrial preparation; the OI cycle could increase LBR. Conclusions: Endometrial preparation methods affect the LBR in women with a regular menstrual cycle. The OI cycle had an advantage in the LBR of FET.

Clinical Outcomes of Oral vs. Transdermal Estrogen for Endometrial Preparation for Frozen Thawed Embryo Transfer in HRT-FET Cycles: A Systematic Review and Meta-Analysis

Background and Purpose: Among different routes of estrogen formulations, the transdermal route has obtained popularity in recent years for endometrial preparation in hormone replacement (HRT) frozen embryo transfer (FET) cycles. However, no clear evidence is available regarding clinical outcome of the transdermal route. This meta-analysis investigated the clinical outcomes of oral versus transdermal estrogen for endometrial preparation for FET in HRT-FET cycles. Methods: A comprehensive literature search was performed for all published randomized controlled trials (RCTs) before May 30, 2022, in electronic databases, including PubMed, Cochrane Library, Embase, CINAHL, Trip Database, Worldwide Science, and Google Scholar. Outcomes, including endometrial thickness, implantation rate (IR), miscarriage rate (MR), clinical pregnancy rate (CPR), and live birth rate (LBR), were measured using pooled odds ratio (OR) or standardized mean difference (SMD) with 95% confidence intervals (CIs). Results: Seven studies involving a total of 898 IVF patients were included in the meta-analysis. In a pooled analysis, endometrial thickness (ET) was more in the transdermal group as compared to the oral estrogen group ([Formula: see text]; 95% [Formula: see text]–0.31). However, no significant association for IR ([Formula: see text]; 95% [Formula: see text]–1.38), CPR ([Formula: see text]; 95% [Formula: see text]–1.31), MR ([Formula: see text]; 95% [Formula: see text]–2.06), and LBR ([Formula: see text]; 95% [Formula: see text]–1.23) was found between oral versus transdermal estrogen groups. Conclusions: In HRT-FET cycles using oral or transdermal estrogen, no significant difference was seen in clinical outcomes of IR, CPR, and LBR rates; however, a trend for a higher endometrial thickness was noted in the transdermal group.

What is the optimal number of embryos to transfer for POSEIDON group 1 and group 2? A retrospective study

BackgroundThe 2016 Patient-Oriented Strategy Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria redefined the poor responders as low prognosis patients. The embryo transfer strategy for POSEIDON patients remained to be addressed. This study aimed to investigate the optimized number of embryos to transfer for unexpected low-prognosis patients (POSEIDON Group 1 and Group 2) with blastocyst transfer in their first frozen cycle.MethodsA retrospective cohort study of 2970 patients who underwent frozen-thawed embryo transfer (FET) between January 2018 and December 2021. Patients from POSEIDON Group 1 (N = 219) and Group 2 (N = 135) who underwent blastocyst transfer in their first FET cycles were included and divided into the elective single embryo transfer (eSET) group and the double embryo transfer (DET) group.ResultsFor POSEIDON Group 1, the live birth rate per embryo transfer of the DET group was slightly higher than the eSET group (52.17% vs 46.15%, OR 0.786, 95% CI 0.462–1.337, P = 0.374; adjusted OR (aOR) 0.622, 95% CI 0.340–1.140, P = 0.124), while a significant increase of 20.00% in the multiple birth rate was shown. For Group 2, higher live birth rates were observed in the DET group compared to the eSET group (38.46% vs 20.48%, OR 0.412, 95% CI 0.190–0.892, P = 0.024; aOR 0.358, 95% CI 0.155–0.828, P = 0.016). The difference in the multiple birth rate was 20.00% without statistical significance. Univariate and multivariate analyses revealed that age (OR 0.759, 95% CI .624–0.922, P = 0.006 and OR 0.751, 95% CI 0.605–0.932, P = 0.009) and the number of transferred embryos (OR 0.412, 95% CI 0.190–0.892, P = 0.024 and OR 0.367, 95% CI 0.161–0.840, P = 0.018) were significant variables for the live birth rate in POSEIDON Group 2.ConclusionsThe findings in the present study showed that eSET was preferred in the first frozen cycle for POSEIDON Group 1 to avoid unnecessary risks. Double embryo transfer strategy could be considered to improve the success rate for POSEIDON Group 2 with caution. Further stratification by age is needed for a more scientific discussion about the embryo transfer strategy for POSEIDON patients.