Cleavage-stage Embryo Transfer Research Articles

Association between the length of in vitro embryo culture, mode of ART, and the initial endogenous hCG rise in ongoing singleton pregnancies.

Is there an association between the length of in vitro culture, mode of ART and the initial endogenous hCG rise, in cycles with a foetal heartbeat after single embryo transfer (ET) and implantation? Both the length of in vitro culture and the mode of ART have an impact on the initial endogenous rise in hCG in singleton pregnancies. Different factors have been identified to alter the kinetics of hCG in pregnancies. Current studies show conflicting results regarding the kinetics of hCG after different types of ART (fresh vs frozen ET (FET)), the inclusion or not of preimplantation genetic testing (PGT), and the length of time in in vitro culture. This was a multicentre cohort study, using prospectively collected data derived from 4938 women (5524 treatment cycles) undergoing IUI (cycles, n = 608) or ART (cycles, n = 4916) treatments, resulting a in singleton ongoing pregnancy verified by first-trimester ultrasound scan. Data were collected from the Danish Medical Data Centre, used by the three participating Danish public fertility clinics at Copenhagen University hospitals: Herlev Hospital, Hvidovre Hospital, and Rigshospitalet, from January 2014 to December 2021. The fresh ET cycles included cleavage-stage (2 or 3 days in vitro) and blastocyst (5 days in vitro) transfers. FET cycles included cleavage-stage (3 days in vitro before cryopreservation) or blastocyst (5 or 6 days in vitro before cryopreservation) transfers. The IUI cycles represented no time in vitro. To attain a comparable interval for serum-hCG (s-hCG), the ovulation induction time was identical: 35-37 h before oocyte retrieval or IUI. The conception day was considered as: the insemination day for pregnancies conceived after IUI, the oocyte retrieval day for fresh ET, or the transfer day minus 3 or 5 as appropriate for FET of Day 3 or 5 embryos. Multiple linear regression analysis was used, including days post-conception for the hCG measurement as a covariate, and was adjusted for the women's age, the cause of infertility, and the centre. For FET, a sensitivity analysis was used to adjust for endometrial preparation. The study totally includes 5524 cycles: 2395 FET cycles, 2521 fresh ET cycles, and 608 IUI cycles. Regarding the length of in vitro culture, with IUI as reference (for no time in in vitro culture), we found a significantly lower s-hCG in pregnancies achieved after fresh ET (cleavage-stage ET or blastocyst transfer). S-hCG was 18% (95% CI: 13-23%, P < 0.001) lower after fresh cleavage-stage ET, and 23% (95% CI: 18-28%, P < 0.001) lower after fresh blastocyst transfer compared to IUI. In FET cycles, s-hCG was significantly higher after blastocyst transfers compared to cleavage-stage FET, respectively, 26% (95% CI: 13-40%, P < 0.001) higher when cryopreserved on in vitro Day 5, and 14% (95% CI: 2-26%, P = 0.02) higher when cryopreserved on in vitro Day 6 as compared to Day 3. Regarding the ART treatment type, s-hCG after FET blastocyst transfer (Day 5 blastocysts) cycles was significantly higher, 33% (95% CI: 27-45%, P < 0.001), compared to fresh ET (Day 5 blastocyst), while there was no difference between cleavage-stage FET (Days 2 + 3) and fresh ET (Days 2 + 3). S-hCG was 12% (95% CI: 4-19%, 0.005) lower in PGT FET (Day 5 blastocysts) cycles as compared to FET cycles without PGT (Day 5 blastocysts). The retrospective design is a limitation which introduces the risk of possible bias and confounders such as embryo score, parity, and ovarian stimulation. This study elucidates how practices in medically assisted reproduction treatment are associated with the hCG kinetics, underlining a potential impact of in vitro culture length and mode of ART on the very early embryo development and implantation. The study provides clinicians knowledge that the type of ART used may be relevant to take into account when evaluating s-hCG for the prognosis of the pregnancy. No funding was received for this study. AP has received consulting fees, research grants, or honoraria from the following companies: Preglem, Novo Nordisk, Ferring Pharmaceuticals, Gedeon Richter, Cryos, Merck A/S, and Organon. AZ has received grants and honoraria from Gedeon Richter. NLF has received grants from Gedeon Richter, Merck A/S, and Cryos. MLG has received honoraria fees or research grants from Gedeon Richter, Merck A/S, and Cooper Surgical. CB has received honoraria from Merck A/S. MB has received research grants and honoraria from IBSA. MPR, KM, and PVS all report no conflicts of interest. The study was registered and approved by the Danish Protection Agency, Capital Region, Denmark (Journal-nr.: 21019857). No approval was required from the regional ethics committee according to Danish law.

Maternal and obstetric outcomes following the transfer of embryos warmed with fatty acid-supplemented solutions

BackgroundVitrification procedures decrease intracytoplasmic lipid content and impair developmental competence. Adding fatty acids (FAs) to the warming solution has been shown to recover the lipid content of the cytoplasm and improve developmental competence and pregnancy outcomes. However, the influence of the FA supplementation on live birth rates after embryo transfers and perinatal outcomes remains unknown. In the present study, we examined the influence of FA-supplemented warming solutions on live birth rates, pregnancy complications, and neonatal outcomes after single vitrified-warmed cleavage-stage embryo transfers (SVCTs).MethodsThe clinical records of 701 treatment cycles in 701 women who underwent SVCTs were retrospectively analyzed. Vitrified embryos were warmed using solutions (from April 2022 to June 2022, control group) or FA-supplemented solutions (from July 2022 to September 2022, FA group). The live birth rate, pregnancy complications, and perinatal outcomes were compared between the control and FA groups.ResultsThe live birth rate per transfer was significantly higher in the FA group than in the control group. Multivariate logistic regression analysis further demonstrated a higher probability of live births in the FA group than in the control group. Miscarriage rates, the incidence and types of pregnancy complications, the cesarean section rate, gestational age, incidence of preterm delivery, birth length and weight, incidence of low birth weight, infant sex, and incidence of birth defects were all comparable between the control and FA groups. Multivariate logistic regression analysis further demonstrated no adverse effects of FA-supplemented warming solutions.ConclusionsFA-supplemented warming solutions improved live birth rates after SVCTs without exerting any adverse effects on maternal and obstetric outcomes. Therefore, FA-supplemented solutions can be considered safe and effective for improving clinical outcomes and reducing patient burden.

Trade-off between double cleavage-stage embryos transfer and single blastocyst-stage embryo transfer in patients with few good quality embryos in antagonist cycles: a retrospective study using a propensity score matching analysis

ObjectiveThis study aimed to compare the per OPU clinical outcomes for transfer of Day 3 double cleavage-stage embryos (DET) and Day 5 single blastocyst-stage (SBT) in patients with five or fewer good quality embryos on day 3 per occyte pick-up cycle (OPU) in antagonist cycles with consideration of blastocyst formation failure.MethodsThis was a retrospective, observational cohort study of 2,116 cases of OPU treated with antagonist protocol in the affiliated Chenggong Hospital of Xiamen University between January 2013 and December 2020. DET was performed in 1,811cycles and SBT was performed in 305 cycles. The DET group was matched to the SBT group by propensity score (PS) matching according to multiple maternal baseline covariates. After PS matching, there were 303 ET cycles in each group. The primary outcomes were the cumulative live birth rate (CLBR), cumulative multiple pregnancy rate(CMPR)per OPU and the number of ET to achieve live birth per OPU. Secondary outcomes were the percentage of clinical pregnancy(CPR), live birth rate(LBR), multiple pregnancy rate(MPR).ResultsFollowing PS mating, the CLBR was slightly higher (48.8% versus 40.3% ; P = 0.041) and the CMPR was significantly higher in the DET group compared to SBT group(44.2% versus 7.9%, P < 0.001). The CPR, LBR and MPR per fresh transfer were higher in DET group compared to SBT group(50.2% versus 28.7%; 41.3% versus 21.5%;29.6% versus 0%, P < 0.001). The number of ET to achieve live birth per OPU in SBT group was obiviously more than in DET group(1.48 ± 0.578 versus 1.22 ± 0.557 ,P < 0.001).ConclusionWith a marginal difference cumulative live birth rate, the lower live birth rate per fresh transfer and higher number of ET per OPU in the SBT group suggested that it might take longer time to achieve a live birth with single blastocyst strategy. A trade-off decision should be made between efficiency and safety.

A retrospective comparative study of double cleavage-stage embryo transfer versus single blastocyst in frozen-thawed cycles

BackgroundThis retrospective study aimed to compare the outcomes of day 3 double embryo transfer (DET) with single blastocyst transfer (SBT) during frozen embryo transfer (FET) cycles. A total of 999 women below the age of 38 years who underwent FET at Malaysia’s KL Fertility and Gynaecology Centre from January 2019 to December 2021 were analyzed. Patients with autologous eggs were recruited in the study. All the eggs were inseminated by intracytoplasmic sperm injection. The embryos were vitrified on day 3 cleavage-stage or blastocyst stage with Cryotop® method. The FET was performed following natural cycle (NC), modified natural cycle (m-NC), or hormone replacement therapy (HRT) cycles. The NC and m-NC groups received oral dydrogesterone for luteal phase support.ResultsThere were no statistical differences in the rates of positive pregnancy, clinical pregnancy, and ongoing pregnancy between the two groups. However, implantation rates were significantly higher in the SBT group (50.1% versus 37.6%, p < 0.05). The day 3 DET group had significantly higher multiple pregnancy rates (28.7% versus 1.1%, p < 0.05). Subgroup analysis of embryo transfers performed following NC, m-NC, or HRT cycles showed similar results.ConclusionsThis study suggests that SBT is the better choice for embryo transfers as it had higher implantation rates and its pregnancy rates were similar to day 3 DET. The SBT also significantly reduced the incidence of multiple pregnancies without compromising pregnancy rates.

The effect of an extended culture period on birth weight among singletons born after single or double vitrified embryo transfer.

To evaluate the effect of an extended culture period on birth weight among singletons born after vitrified-warmed embryo transfer. A retrospective cohort study was performed among 12400 women who gave birth to 1015, 1027, 687, and 9671 singletons after single blastocyst transfer, single cleavage-stage embryo transfer, double blastocyst transfer, and double cleavage-stage embryo transfer, respectively. The unadjusted birth weight of singletons born after vitrified blastocyst transfer were heavier than those born after cleavage-stage transfer (β=30.28, SE=13.17, P=0.022), as were the adjusted birth weights (β=0.09, SE=0.03, P=0.007). In addition, there was a 37% increased odd of having an infant with high birth weight after vitrified blastocyst transfer compared with vitrified cleavage stage transfer (OR=1.37, 95% CI:1.07-1.77). The unadjusted and adjusted birth weight and odds of having an infant with high birth weight significantly increased after blastocyst transfer compared with cleavage-stage embryo transfer in vitrified-warmed cycles.

Clinical outcomes of frozen-thawed embryo transfer in natural cycles with luteinized unruptured follicles

ObjectiveTo assess the effect of luteinized unruptured follicles (LUF) on frozen–thawed embryo transfer cycles performed in natural cycles (FET-NC). MethodsRetrospective cohort study, held in a university hospital with 3415 cycles for frozen-thawed embryo transfer, performed between June 2019 and September 2022. Using propensity score matching, 242 patients with a diagnosis of LUF (LUF group) were matched with 484 ovulated patients (ovulation group). Stratified by the type of embryo transferred, the LUF group included 168 blastocyst transfer patients (blastocyst group) and 74 cleavage-stage embryo transfer patients (cleavage-embryo group). The ovulation group included 324 patients with blastocyst transfer (blastocyst group) and 160 patients with transferred cleavage-stage embryos. Clinical pregnancy rate was retrospectively analyzed between the LUF and ovulation groups, as well as between each subgroup. ResultsAfter using propensity score matching, the general characteristics of the LUF and ovulation groups were similar. The implantation and clinical pregnancy rates in the LUF group were not significantly different from those in the ovulation group (44.98 % vs. 45.29 %, p = 0.93; 53.72 % vs. 52.48 %, p = 0.75). The implantation and pregnancy rates of transferred cleavage-stage embryos in the LUF group were also not significantly different from those in the ovulation group (32.39 % vs. 36.40 %, p = 0.42; 47.30 % vs. 47.50 %, p = 0.98). The implantation and pregnancy rates of transferred blastocysts in the LUF group were also not significantly different from those in the ovulation group (53.11 % vs. 52.03 %, p = 0.82; 56.55 % vs. 54.94 %, p = 0.73). There was also no significant difference in the miscarriage rate between the groups. ConclusionIn the natural cycle, LUF does not affect the clinical pregnancy outcomes of FET. If adequate luteal support is given, the clinical pregnancy outcomes were similar between the LUF group and ovulation group.

Effect of frozen-thawed embryo transfer with a poor-quality embryo and a good-quality embryo on pregnancy and neonatal outcomes.

To evaluate the impact of embryo quality and quantity, specifically a poor quality embryo (PQE) in combination with a good quality embryo (GQE), by double embryo transfer (DET) on the live birth rate (LBR) and neonatal outcomes in patients undergoing frozen-thawed embryo transfer (FET) cycles. A study on a cohort of women who underwent a total of 1462 frozen-thawed cleavage or blastocyst embryo transfer cycles with autologous oocytes was conducted between January 2018 and December 2021. To compare the outcomes between single embryo transfer (SET) with a GQE and DET with a GQE and a PQE, propensity score matching (PSM) was applied to control for potential confounders, and a generalized estimating equation (GEE) model was used to determine the association between the effect of an additional PQE and the outcomes. Subgroup analysis was also performed for patients stratified by female age. After PS matching, DET-GQE + PQE did not significantly alter the LBR (adjusted odds ratio [OR] 1.421, 95% CI 0.907-2.228) compared with SET-GQE in cleavage-stage embryo transfer but did increase the multiple birth rate (MBR, [OR] 3.917, 95% CI 1.189-12.911). However, in patients who underwent blastocyst-stage embryo transfer, adding a second PQE increased the live birth rate by 7.8% ([OR] 1.477, 95% CI 1.046-2.086) and the multiple birth rate by 19.6% ([OR] 28.355, 95% CI 3.926-204.790), and resulted in adverse neonatal outcomes. For patients who underwent cleavage-stage embryo transfer, transferring a PQE with a GQE led to a significant increase in the MBR ([OR] 4.724, 95% CI 1.121-19.913) in women under 35 years old but not in the LBR ([OR] 1.227, 95% CI 0.719-2.092). The increases in LBR and MBR for DET-GQE + PQE compared with SET-GQE in women older than 35 years were nonsignificant toward. For patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE had a greater LBR ([OR] 1.803, 95% CI 1.165-2.789), MBR ([OR] 24.185, 95% CI 3.285-178.062) and preterm birth rate (PBR, [OR] 4.092, 95% CI 1.153-14.518) than did SET-GQE in women under 35 years old, while no significant impact on the LBR ([OR] 1.053, 95% CI 0.589-1.884) or MBR (0% vs. 8.3%) was observed in women older than 35 years. The addition of a PQE has no significant benefit on the LBR but significantly increases the MBR in patients who underwent frozen-thawed cleavage-stage embryo transfer. However, for patients who underwent blastocyst-stage embryo transfer, DET-GQE + PQE resulted in an increase in both the LBR and MBR, which may lead to adverse neonatal outcomes. Thus, the benefits and risks of double blastocyst-stage embryo transfer should be balanced. In patients younger than 35 years, SET-GQE achieved satisfactory LBR either in cleavage-stage embryo transfer or blastocyst-stage embryo transfer, while DET-GQE + PQE resulted in a dramatically increased MBR. Considering the low LBR in women older than 35 years who underwent single cleavage-stage embryo transfer, selective single blastocyst-stage embryo transfer appears to be a more promising approach for reducing the risk of multiple live births and adverse neonatal outcomes.

A comparative analysis of the clinical pregnancy and perinatal outcomes between oocyte vitrification and embryo vitrification based on the propensity score matching method.

This study investigated the safety and effectiveness of oocyte vitrification by comparing the clinical pregnancy and perinatal outcomes between transfer cycles of vitrified oocytes and those of vitrified embryos. A retrospective cohort study was conducted to analyze the clinical data of patients who underwent cleavage-stage embryo transfer at the Department of Reproductive Medicine between January 2011 and June 2021. Seventy-seven transfer cycles of fresh cleavage-stage embryos developed from vitrified-thawed oocytes (oocyte vitrification group) and 2170 transfer cycles of vitrified-thawed cleavage-stage embryos developed from fresh oocytes (embryo vitrification group) were included. Further, 293 cases were selected from the embryo vitrification group after applying propensity score matching at 1:4. The primary outcomes were miscarriage rate, live birth rate, and neonatal birth weight. No statistically significant differences were observed in the baseline data, pregnancy, perinatal outcomes, or neonatal outcomes for either singleton or twin births between the two groups after matching. Backwards stepwise regression was used to analyze the length of gestation. The age of female participants (β = - 0.410, 95% CI = - 1.339 ~ - 0.620, P < 0.001) had a statistically significant effect. Oocyte vitrification results in similar clinical pregnancy and perinatal outcomes as does embryo vitrification; hence, it is a relatively safe assisted reproductive technique.

Does The Culture of Post-Thawed Cleavage-Stage Embryos to Blastocysts Improve Infertility Treatment Outcomes of Frozen-Thawed Embryo Transfer Cycles? A Randomised Clinical Trial.

There is a definite shift in assisted reproductive centres from cleavage-stage embryo transfer (ET) to blastocyst transfer that is attributed to improvements in laboratory environments and advances in the development of embryo culture media. The aim of the study was to investigate the reproductive outcomes of thawed cleavage-stage ET versus blastocysts derived from an extended culture of these embryos. This open-label, randomised, parallel group clinical trial study enrolled 182 women aged ≤37 years who underwent frozen-thawed ET from November 2015 to June 2020 at Royan Institute Research Centre, Tehran, Iran. The women were randomly assigned to either the thawed cleavage ET group (n=110) or the post-thaw extended culture blastocysts group (n=72). The primary outcome measure was the clinical pregnancy rate. Secondary outcome measures were implantation rate, live birth rate (LBR), and miscarriage rate. A P<0.05 indicated statistical significance. There were no significant differences between the two groups in terms of demographic characteristics. Both the mean numbers of embryos transferred and good quality embryos transferred were significantly lower in the postthaw extended culture blastocysts group compared to thawed cleavage-stage ET cycles. However, the post-thaw extended culture blastocysts group had higher clinical pregnancy (56.94 vs. 40.91%, P=0.034), implantation (34.43 vs. 19.84%, P=0.001) and live birth (49.3 vs. 33.63%, P=0.036) rates compared to the thawed cleavage-stage ET group. Miscarriage and multiple gestations rates were comparable between the groups. These results allow us to take a position in favour of post-thaw extended culture blastocysts; thus, it is important to improve the post-thawing extended culture technique (registration number: NCT02681029).

Perinatal outcomes of frozen-thawed embryo transfer following blastocyst-stage embryo transfer compared to those of cleavage-stage embryo transfer: Analysis of 9,408 singleton newborns using propensity score analysis

Objective: Regarding frozen-thawed embryo transfer (FET), there is limited consensus on whether extending embryo culture from the cleavage stage to the blastocyst stage affects perinatal outcomes. This study aimed to compare perinatal outcomes of singletons between blastocyst-stage transfer (BT) and cleavage-stage transfer (CT) in FET. Methods: A total of 9,408 FET cycles that met the inclusion criteria were included in this retrospective cohort study between 2019 and 2022. Blastocyst-stage embryo transfers were performed in the BT group, and cleavage-stage embryo transfers were performed in the CT group. Multivariate logistic regression analyses were performed, as well as propensity score matching (PSM) to adjust for confounders. Results: After PSM, a higher risk of preterm birth (PTB) (OR 1.23, 95% CI 1.00–1.50, P=0.048) and being large for gestational age (LGA) (OR 1.16, 95% CI 1.00–1.35, P=0.050) was observed in the BT group compared to that in the CT group. After stratified PSM, in the subgroup under 35 years of age, only an increased risk of LGA was observed in the BT group compared to the CT group. Perinatal outcomes in the double-embryo transfer subgroup were similar to those in the unstratified group. However, in the subgroup beyond 35 years of age and the single-embryo transfer subgroup, perinatal outcomes were not statistically different between the BT and CT groups (P&gt;0.05). Conclusions: In FET, prolonged embryo culture to the blastocyst stage increased the risk of PTB and LGA in single fetuses. However, stratified analysis based on age and the number of transferred embryos yielded different results, necessitating further mechanistic studies.

Risk factors of ectopic pregnancy after in vitro fertilization-embryo transfer in Chinese population: A meta-analysis.

The prevalence of ectopic pregnancy after assisted reproduction is notably high, posing a significant threat to the life safety of pregnant women. Discrepancies in published results and the lack of a comprehensive description of all risk factors have led to ongoing uncertainties concerning ectopic pregnancy after assisted reproduction. This study aimed to understand the risk factors for ectopic pregnancy after in vitro fertilization-embryo transfer in the Chinese population and provide a reference for targeted prevention and treatment. A comprehensive search of the China National Knowledge Infrastructure, Wang fang Database, China Science Technology Journal Database, Chinese Biomedical Literature Database, PubMed, Web of Science, and Embase was conducted to identify relevant literature on the risk factors for ectopic pregnancy in Chinese women after assisted reproductive technology in Chinese women. A meta-analysis of the included studies was performed using Stata17. Overall, 34 articles were included in the analysis. The risk factors for ectopic pregnancy after in vitro fertilization-embryo transfer in the Chinese population included a thin endometrium on the day of HCG administration and embryo transplantation, a history of ectopic pregnancy, secondary infertility, a history of induced abortion, polycystic ovary syndrome, decreased ovarian reserve, tubal factor infertility, cleavage stage embryo transfer, fresh embryo transfer, artificial cycle protocols, elevated estradiol levels on the day of human chorionic gonadotropin administration, a history of tubal surgery, two or more number of embryo transfers, previous pregnancy history, and a history of pelvic surgery. This study clarified the factors influencing ectopic pregnancy after in vitro fertilization and embryo transfer in the Chinese population, focusing on high-risk groups. Targeted and personalized intervention measures should be adopted to prevent and detect the disease early to reduce its incidence and harm. The protocol for this view was registered in PROSPERO (CRD42023414710).

Effect of sequential embryo transfer on in vitro fertilization and embryo transfer outcomes: a systematic review and meta-analysis.

Sequential embryo transfer has been recognized as a strategy to increase pregnancy rates in women undergoing in vitro fertilization and embryo transfer (IVF-ET). However, its impact on assisted reproductive outcomes remains to be substantiated by robust evidence. This systematic review aims to summarize and analyze the available evidence to investigate the effect of sequential embryo transfer on assisted reproductive outcomes. A comprehensive literature search was executed across the Pubmed, Cochrane Library, Web of Science, and Scopus databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were aggregated utilizing a random effects model, and the resultant outcomes were articulated as odds ratios (ORs) along with their 95% confidence intervals (CIs). The pooled results revealed a statistically significant enhancement in reproductive outcomes for infertile patients undergoing sequential embryo transfer as evidenced by elevated rates of chemical pregnancy (OR = 1.67, 95% CI = 1.23-2.27), clinical pregnancy (OR = 1.78, 95% CI = 1.43-2.21), and ongoing pregnancy (OR = 1.54, 95% CI = 1.03-2.31). Compared with cleavage-stage embryo transfer, sequential transfer yielded superior outcomes in terms of chemical pregnancy rate (OR = 2.08, 95% CI = 1.35-3.19) and clinical pregnancy rate (OR = 1.78, 95% CI = 1.37-2.31). Furthermore, among the repeated implantation failure (RIF) cohort, sequential embryo transfer surpassed blastocyst-stage transfer, delivering a heightened chemical pregnancy rate (OR = 1.66, 95% CI = 1.19-2.53) and clinical pregnancy rate (OR = 1.65, 95% CI = 1.19-2.27). Our meta-analysis indicates that sequential transfer may enhance clinical pregnancy rate in a small subgroup of well-selected women. While promising, further evidence from prospective studies is needed.

Effect of Elevated Progesterone Levels on hCG Trigger Day on Clinical Pregnancy Outcome in Short-Acting GnRHa Downregulated Cycles.

Previous studies suggested higher serum progesterone (P) levels were strongly associated with a lower clinical pregnancy rate (CPR) for in vitro fertilization-embryo transfer (IVF-ET). However, the effect of increased serum P levels on the day of human chorionic gonadotropin (hCG) administration on clinical outcomes in short-acting gonadotropin-releasing hormone agonist (GnRHa) downregulated IVF-ET cycles remains unclear. We conducted a retrospective cohort study from January 2017 to December 2021, which included a total of 1664 patients receiving their first short-acting GnRHa IVF-ET cycles at our reproductive medicine centre of Nanjing Drum Tower Hospital. The smooth curve fitting and interaction analysis were employed to analyse the association between the CPR and the serum P levels with different embryo types (cleavage-stage embryo or blastocyst). In addition, total cycles were grouped according to different P levels on the trigger day of hCG administration for further analysis. The CPR of patients with increased serum P level (higher than 1.5 ng/mL) on the hCG day did not decrease. A smoothing curve fitting showed that the CPR did not change obviously with the increase in serum P levels. Subgroup analysis of different types of embryos transferred showed that no correlation was observed between the CPR and serum P levels on the day of hCG administration in cleavage-stage embryo transfer cycles. However, the CPR of patients receiving blastocyst transfer showed a downward trend with the increase in serum P levels. At the same time, an interaction analysis also confirmed that the CPR of blastocyst transfer was more likely to be affected by elevated serum P levels on the hCG day. In the luteal phase short-acting GnRHa downregulated IVF-ET cycles, the elevated serum P levels on the hCG day did not affect the CPR of cleavage-stage embryo transfer but reduced the CPR of blastocyst transfer.

Effect of endometrial thickness on the risk of ectopic pregnancy for frozen embryo transfer

Objective: Few studies have explored the suitability of endometrial thickness (EMT) as a predictor of ectopic pregnancy (EP) in frozen embryo transfer (FET) cycles. Our study aimed to investigate the association between EMT and EP and explore the cutoff value of EMT to predict EP. Methods: This retrospective cohort study included women aged 20 - 45 years undergoing FET between March 2015 and September 2021. The primary outcomes and measured variables were ectopic pregnancy and endometrial thickness, respectively. The threshold effect of EMT on EP was calculated based on a constructed smooth curve fitting. The patients were divided into two groups based on the threshold for comparison. A subgroup analysis was conducted to examine whether the relationship between EMT and EP remained consistent across the different subgroups. Additionally, a generalized linear model was used to analyze the interactions between the treatment factors and EMT in EP. Results: In total, 27,549 FET cycles were included, with 27,086 intrauterine and 463 ectopic pregnancies. The risk of EP in the EMT ≤ 8.7 mm group was 3.36 times higher than that in the EMT &gt;8.7 mm group (OR: 3.36, 95% CI 2.57-4.05). Subgroup analysis further indicated that a thin EMT was a risk factor for EP, independent of other risks. We also noted that diminished ovarian reserve, tubal factor infertility, transfer of two embryos, or transfer of cleavage-stage embryos may further enhance the risk of EP in patients with thin endometrium. Conclusions: Thin endometrium was associated with an increased risk of EP. Patients with EMT less than 8.7 mm need close medical observation and management after embryo transfer. In addition, diminished ovarian reserve, tubal factor infertility, transfer of two embryos, or transfer of cleavage-stage embryos may significantly enhance the effect of a thin endometrium on the risk of EP.

Factors affecting male-to-female ratio at birth in frozen-thawed embryo transfer cycles: a large retrospective cohort study.

ICSI (intracytoplasmic sperm injection) leads to a reduced male-to-female ratio at birth, whereas blastocyst transfer results in an increased male-to-female ratio. However, limited knowledge exists regarding the impact of these factors on the live birth rate for each gender. This study aimed to investigate the influence of patient characteristics and treatment parameters on the live birth rate for each gender, as well as the ultimate male-to-female ratio at birth in frozen-thawed embryo transfer (FET) cycles. This retrospective cohort study involved a total of 28,376 FET cycles and 9,217 subsequent deliveries, spanning from January 2003 to December 2015. The study consisted of two parts. First, logistic regression models were constructed to determine the factors influencing the male-to-female ratio among babies born after FET. Second, we aimed to investigate the mechanisms underlying this sex ratio imbalance by analyzing data from all transfer cycles. Generalized estimated equations were employed to assess the impact of risk factors on rates of male and female live births separately. ICSI resulted in a lower proportion of male offspring compared to in vitro fertilization (IVF) (50.1% vs. 53.7%, aOR: 0.87, 95% CI: 0.80-0.96). Conversely, blastocyst transfer yielded a higher proportion of male offspring than cleavage-stage embryo transfer (58.7% vs. 51.6%, aOR: 1.32, 95% CI: 1.17-1.48). Analysis of all cycles indicated that ICSI resulted in a reduced likelihood of male live birth in comparison to IVF (19.8% vs. 21.6%, aOR: 0.90, 95% CI: 0.83-0.97). However, the transfer of blastocysts rather than cleavage-stage embryos not only increased the chance of male live birth (26.9% vs. 20.2%, aOR: 1.70, 95% CI:1.56-1.85) but also facilitated female live birth (20.3% vs. 19.3%, aOR: 1.26, 95% CI: 1.15-1.39). ICSI was associated with a reduction in the male-to-female sex ratio and a lower rate of male live births, while blastocyst transfer was associated with an increased male-to-female sex ratio at birth and a higher rate of male live births.

Sequential embryo transfer versus double cleavage-stage embryo or double blastocyst transfer in patients with recurrent implantation failure with frozen-thawed embryo transfer cycles: a cohort study.

Recurrent implantation failure (RIF) is more common among patients receiving assisted reproductive treatment. Many efforts have been made to increase the incidence of clinical pregnancy among patients with RIF. The effect of the sequential transfer procedure, a two-step interval transfer of a cleavage-stage embryo followed by a blastocyst in one transfer cycle, on the clinical outcomes of RIF patients remains controversial. In total, 1774 frozen-thawed embryo transfer (FET) cycles in RIF patients were included. Of these cycles, 302 were sequential embryo transfer (ET) cycles, 979 were double day 3 cleavage-stage ET cycles, and 493 were double blastocyst ET cycles. The primary outcomes were the rates of implantation, clinical pregnancy and multiple pregnancy, and the secondary outcomes were the rates of hCG positive, early miscarriage and ectopic pregnancy. The implantation, hCG positive, and clinical pregnancy rates in the sequential ET group (32.1%, 58.9%, 50.7%) were significantly higher than those in the day 3 cleavage-stage ET group (24.9%, 46.5%, 40.4%) and were similar to those in the blastocyst transfer group (30.1%, 56.4%, 47.1%). The early miscarriage rate in the blastocyst transfer group was significantly higher than that in the cleavage-stage ET group (17.2% vs. 8.1%, P <0.05), while the ectopic pregnancy rate in the blastocyst transfer group was significantly lower than that in the cleavage-stage ET group (0.4% vs. 3.0%, P <0.05). The multiple pregnancy rate in the sequential ET group was significantly lower than that in the cleavage-stage ET group (17.0% vs. 25.5%, P <0.05) and the blastocyst transfer group (17.0% vs. 27.6%, P <0.05). When cycles of blastocyst culture failure were excluded, the clinical pregnancy rate was significantly higher (55.7% vs. 47.1%, P <0.05), and the early miscarriage rate and multiple pregnancy rate were significantly lower (8.5% vs. 17.2%, 17.7% vs. 27.6%; P <0.05, respectively) in the sequential ET group than in the double blastocyst ET group. Sequential embryo transfer in FET cycles could improve the clinical outcomes of patients with RIF.

The influence of embryo stage on obstetric complications and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis.

To investigate the effect of embryo stage at the time of transfer on obstetric and perinatal outcomes in programmed frozen-thawed embryo transfer (FET) versus natural FET cycles. Systematic review and meta-analysis. Not applicable. Women with programmed frozen-thawed embryo transfer (FET) and natural FET. The PubMed, MEDLINE, and EMBASE databases and the Cochrane Central Register of Controlled Trials (CCRT) were searched from 1983 to October 2022. Twenty-three observational studies were included. The primary outcomes were hypertensive disorders of pregnancy (HDPs), gestational hypertension and preeclampsia (PE). The secondary outcomes were gestational diabetes mellitus (GDM), placenta previa, postpartum haemorrhage (PPH), placental abruption, preterm premature rupture of membranes (PPROM), large for gestational age (LGA), small for gestational age (SGA), macrosomia, and preterm delivery (PTD). The risk of HDP (14 studies, odds ratio (OR) 2.17; 95% confidence interval (CI) 1.95-2.41; P<0.00001; I2 = 43%), gestational hypertension (11 studies, OR 1.38; 95% CI 1.15-1.66; P=0.0006; I2 = 19%), PE (12 studies, OR 2.09; 95% CI 1.88-2.32; P<0.00001; I2 = 0%), GDM (20 studies, OR 1.09; 95% CI 1.02-1.17; P=0.02; I2 = 8%), LGA (18 studies, OR 1.11; 95% CI 1.07-1.15; P<0.00001; I2 = 46%), macrosomia (12 studies, OR 1.15; 95% CI 1.07-1.24; P=0.0002; I2 = 31%), PTD (22 studies, OR 1.21; 95% CI 1.15-1.27; P<0.00001; I2 = 49%), placenta previa (17 studies, OR 1.2; 95% CI 1.02-1.41; P=0.03; I2 = 11%), PPROM (9 studies, OR 1.19; 95% CI 1.02-1.39; P=0.02; I2 = 40%), and PPH (12 studies, OR 2.27; 95% CI 2.02-2.55; P <0.00001; I2 = 55%) were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer. Blastocyst transfer had a higher risk of HDP (6 studies, OR 2.48; 95% CI 2.12-2.91; P<0.00001; I2 = 39%), gestational hypertension (5 studies, OR 1.87; 95% CI 1.27-2.75; P=0.002; I2 = 25%), PE (6 studies, OR 2.23; 95% CI 1.93-2.56; P<0.00001; I2 = 0%), GDM (10 studies, OR 1.13; 95% CI 1.04-1.23; P=0.005; I2 = 39%), LGA (6 studies, OR 1.14; 95% CI 1.07-1.21; P<0.0001; I2 = 9%), macrosomia (4 studies, OR 1.15; 95% CI 1.05-1.26; P<0.002; I2 = 68%), PTD (9 studies, OR 1.43; 95% CI 1.31-1.57; P<0.00001; I2 = 22%), PPH (6 studies, OR 1.92; 95% CI 1.46-2.51; P<0.00001; I2 = 55%), and PPROM (4 studies, OR 1.45; 95% CI 1.14-1.83; P=0.002; I2 = 46%) in programmed FET cycles than in natural FET cycles. Cleavage-stage embryo transfers revealed no difference in HDPs (1 study, OR 0.81; 95% CI 0.32-2.02; P=0.65; I2 not applicable), gestational hypertension (2 studies, OR 0.85; 95% CI 0.48-1.51; P=0.59; I2 = 0%), PE (1 study, OR 1.19; 95% CI 0.58-2.42; P=0.64; I2not applicable), GDM (3 study, OR 0.79; 95% CI 0.52-1.20; P=0.27; I2 = 21%), LGA (1 study, OR 1.15; 95% CI 0.62-2.11; P=0.66; I2not applicable), macrosomia (1 study, OR 1.22; 95% CI 0.54-2.77; P=0.64; I2 not applicable), PTD (2 studies, OR 1.05; 95% CI 0.74-1.49; P=0.79; I2 = 0%), PPH (1 study, OR 1.49; 95% CI 0.85-2.62; P=0.17; I2not applicable), or PPROM (2 studies, OR 0.74; 95% CI 0.46-1.21; P=0.23; I2 = 0%) between programmed FET cycles and natural FET cycles. The risks of HDPs, gestational hypertension, PE, GDM, LGA, macrosomia, SGA, PTD, placenta previa, PPROM, and PPH were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer and blastocyst transfer, but the risks were not clear for cleavage-stage embryo transfer.

Elevated estradiol levels on hCG trigger day adversely effects on the clinical pregnancy rates of blastocyst embryo transfer but not cleavage-stage embryo transfer in fresh cycles: a retrospective cohort study.

Elevated estradiol (E2) levels are an inevitable outcome of the controlled ovulation hyperstimulation. However, the effect of this change on pregnancy is still uncertain. Our study aimed to analyze the impact of increased serum E2 at the day of human chorionic gonadotropin (hCG) administration on the clinical outcomes of women with fresh embryo transfer (ET) cycles. This study included 3,009 fresh ET cycles from October 2015 to September 2021. Based on the stage of embryos transferred, these cycles were categorized into the cleavage group and blastocyst group. Both groups were then divided into four sets according to E2 levels when hCG was administered: set 1 (E2 ≤ 2,000 pg/ml), set 2 (E2 = 2,001-3,000 pg/ml), set 3 (E2 = 3,001-4,000 pg/ml), and set 4 (E2 > 4,000 pg/ml). The primary outcome was the clinical pregnancy rate (CPR). Binary logistics regression analysis was established to explore the association between CPR and E2 levels. Specifically, the threshold effect of serum E2 on CPR was revealed using the two-piecewise linear regression analyses. The multivariate regression model in the cleavage group showed that patients' CPR in set 4 was 1.59 times higher than those in reference set 1, but the statistical difference was insignificant (P=0.294). As for the blastocyst group, patients in set 4 had a lower CPR with adjusted ORs of 0.43 (P=0.039) compared to patients in set 1. The inflection point for the blastocyst group was 39.7 pg/dl according to the results of the two-piecewise linear regression model. When E2 levels were over the point, the CPR decreased by 17% with every 1 pg/dl increases in serum E2 (adjusted OR = 0.83, 95% CI [0.72-0.96], P=0.012). Elevated E2 levels (>39.7 pg/dl) on hCG trigger day were associated with decreased CPR in patients with fresh blastocyst ET. However, it had no similar effect on the CPR of patients with fresh cleavage-stage ET.

Impaired in vitro fertilization outcomes following testosterone treatment improve with washout in a mouse model of gender-affirming hormone treatment

The impact of gender-affirming testosterone on fertility is poorly understood, with ovarian histopathologic studies showing variable results, some with a detrimental effect on reproductive capacity and uncertain reversibility. Assisted reproductive outcome data are restricted to small case series that lack the ability to inform clinical practice guidelines and limit fertility preservation counseling for transgender and nonbinary individuals. This study aimed to determine the impact of current testosterone and testosterone washout on invitro fertilization outcomes in a mouse model for gender-affirming hormone treatment. We hypothesized that current or previous testosterone treatment would not affect invitro fertilization outcomes. C57BL/6N female mice (n=120) were assigned to 4 treatment groups: (1) current control, (2) current testosterone, (3) control washout, and (4) testosterone washout. Testosterone implants remained in situ for 6 or 12 weeks, representing the short- and long-term treatment arms, respectively. Current treatment groups underwent ovarian stimulation with implants in place, and washout treatment groups were explanted and had ovarian stimulation after 2 weeks. Oocytes were collected, fertilized, and cultured invitro, with one arm continuing to the blastocyst stage and the other having transfer of cleavage-stage embryos. Statistical analysis was performed using GraphPad Prism, version 9.0 and R statistical software, version 4.1.2, with statistical significance defined by P<.05. Current long-term testosterone treatment impaired invitro fertilization outcomes, with fewer mature oocytes retrieved (13.7±5.1 [standard deviation] vs 28.6±7.8 [standard deviation]; P<.0001) leading to fewer cleavage-stage embryos (12.1±5.1 vs 26.5±8.2; P<.0001) and blastocysts (10.0±3.2 vs 25.0±6.5; P<.0001). There was recovery of invitro fertilization outcomes following washout in the short-term treatment cohort, with incomplete reversibility in the long-term cohort. Testosterone did not negatively affect maturity, fertilization, or blastulation rates. In a mouse model of gender-affirming hormone treatment, testosterone negatively affected oocyte yield without affecting oocyte quality. Our findings suggest that testosterone reversibility is duration-dependent. These results demonstrate the feasibility of invitro fertilization without testosterone discontinuation while supporting a washout period for optimization of mature oocyte yield.

Embryo development, pregnancy and live birth outcomes following IVF treatment were not compromised during the COVID-19 pandemic.

To evaluate whether outcomes of in vitro fertilization (IVF) are affected during the coronavirus disease-19 (COVID-19) pandemic. This was a single-center, retrospective study. Embryo development, pregnancy, and live birth outcomes were compared between COVID-19 and pre-COVID-19 groups. Blood samples from patients during the COVID-19 pandemic were tested for COVID-19. After 1:1 random matching, 403 cycles for each group were included in the study. The rates of fertilization, normal fertilization, and blastocyst formation were higher in the COVID-19 group than in the pre-COVID-19 group. No difference was observed in the rates of day 3 good-quality embryos and good-quality blastocysts between the groups. A multivariate analysis showed that the live birth rate in the COVID-19 group was higher than that in the pre-COVID-19 group (51.4% vs. 41.4%, P = 0.010). In fresh cleavage-stage embryo and blastocyst transfer cycles, there were no differences between the groups in terms of pregnancy, obstetric, and perinatal outcomes. In the freeze-all cycles, the live birth rate was higher during the COVID-19 pandemic (58.0% vs. 34.5%, P = 0.006) than during the pre-COVID-19 period following frozen cleavage stage embryo transfer. The rate of gestational diabetes during the COVID-19 pandemic was higher than that during the pre-COVID-19 period (20.3% vs. 2.4%, P = 0.008) following frozen blastocyst transfer. All the serological results of the patients during the COVID-19 pandemic were negative. Our results indicate that embryo development, pregnancy, and live birth outcomes in uninfected patients were not compromised during the COVID-19 pandemic at our center.