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Background Evidence referring to the trade-offs between the benefits and risks of single embryo transfer (SET) versus double embryo transfer (DET) following assisted reproduction technology are insufficient, especially for those women with a defined embryo quality or advanced age. Methods A systematic review and meta-analysis was conducted according to PRISMA guidelines. PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov were searched based on established search strategy from inception through February 2021. Pre-specified primary outcomes were live birth rate (LBR) and multiple pregnancy rate (MPR). Odds ratio (OR) with 95% confidence interval (CI) were pooled by a random-effects model using R version 4.1.0. Results Eighty-five studies (14 randomized controlled trials and 71 observational studies) were eligible. Compared with DET, SET decreased the probability of a live birth (OR = 0.78, 95% CI: 0.71–0.85, P <  0.001, n  = 62), and lowered the rate of multiple pregnancy (0.05, 0.04–0.06, P <  0.001, n  = 45). In the sub-analyses of age stratification, both the differences of LBR (0.87, 0.54–1.40, P  = 0.565, n  = 4) and MPR (0.34, 0.06–2.03, P  = 0.236, n  = 3) between SET and DET groups became insignificant in patients aged ≥40 years. No significant difference in LBR for single GQE versus two embryos of mixed quality [GQE + PQE (non-good quality embryo)] (0.99, 0.77–1.27, P =  0.915, n  = 8), nor any difference of MPR in single PQE versus two PQEs (0.23, 0.04–1.49, P =  0.123, n  = 6). Moreover, women who conceived through SET were associated with lower risks of poor outcomes, including cesarean section (0.64, 0.43-0.94), antepartum haemorrhage (0.35, 0.15-0.82), preterm birth (0.25, 0.21-0.30), low birth weight (0.20, 0.16-0.25), Apgar1 < 7 rate (0.12, 0.02-0.93) or neonatal intensive care unit admission (0.30, 0.14-0.66) than those following DET. Conclusions In women aged < 40 years or if any GQE is available, SET should be incorporated into clinical practice. While in the absence of GQEs, DET may be preferable. However, for elderly women aged ≥40 years, current evidence is not enough to recommend an appropriate number of embryo transfer. The findings need to be further confirmed.

Elective single embryo transfer (eSET) has been increasingly advocated, but concerns about the lower pregnancy rate after reducing the number of embryos transferred have encouraged transfer of multiple embryos. Extended embryo culture combined with electively freezing all embryos and undertaking a deferred frozen embryo transfer might increase pregnancy rate after eSET. We aimed to establish whether elective frozen single blastocyst transfer improved singleton livebirth rate compared with fresh single blastocyst transfer. This multicentre, non-blinded, randomised controlled trial was undertaken in 21 academic fertility centres in China. 1650 women with regular menstrual cycles undergoing their first cycle of in-vitro fertilisation were enrolled from Aug 1, 2016, to June 3, 2017. Eligible women were randomly assigned to either fresh or frozen single blastocyst transfer. The randomisation sequence was computer generated, with block sizes of two, four, or six, stratified by study site. For those assigned to frozen blastocyst transfer, all blastocysts were cryopreserved and a delayed frozen-thawed single blastocyst transfer was done. The primary outcome was singleton livebirth rate. Analysis was by intention to treat. This trial is registered at the Chinese Clinical Trial Registry, number ChiCTR-IOR-14005405. 825 women were assigned to each group and included in analyses. Frozen single blastocyst transfer resulted in higher rates of singleton livebirth than did fresh single blastocyst transfer (416 [50%] vs 329 [40%]; relative risk [RR] 1·26, 95% CI 1·14–1·41, p<0·0001). The risks of moderate or severe ovarian hyperstimulation syndrome (four of 825 [0·5%] in frozen single blastocyst transfer vs nine of 825 [1·1%] in fresh single blastocyst transfer; p=0·16), pregnancy loss (134 of 583 [23·0%] vs 124 of 481 [25·8%]; p=0·29), other obstetric complications, and neonatal morbidity were similar between the two groups. Frozen single blastocyst transfer was associated with a higher risk of pre-eclampsia (16 of 512 [3·1%] vs four of 401 [1·0%]; RR 3·13, 95% CI 1·06–9·30, p=0·029). Frozen single blastocyst transfer resulted in a higher singleton livebirth rate than did fresh single blastocyst transfer in ovulatory women with good prognosis. The increased risk of pre-eclampsia after frozen blastocyst transfer warrants further studies. The National Key Research and Development Program of China.

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

Background: Embryo quality may affect birth weight among neonates born through assisted reproductive technology. There are very limited studies assessing the adverse effect of transferring a poor-quality embryo with a good-quality one on neonatal outcomes. Objective: The aim of this study was to evaluate the effect of double embryo transfer (DET) with one good-quality embryo (GQE) plus a poor-quality one on the birth weight of newborns conceived by in vitro fertilization in both fresh and frozen-thawed embryo transfer cycles. Materials and Methods: This study was conducted at Yazd Reproductive Sciences Institute, Yazd, Iran. A total of 626 women were classified into three groups according to the embryo quality: single embryo transfer with a GQE (group A); DET using two GQEs (group B); and DET using one good-quality and one poor-quality embryo (group C). The primary outcome was singleton birth weight which was compared between the three groups among fresh and frozen-embryo transfer cycles. A comparative analysis was also performed regarding the effect of vitrification procedures on neonatal birth weight within each of the three embryo quality-based groups. Results: The mean birth weight and the rate of preterm birth were similar between the three groups (p = 0.45 and 0.32, respectively). There were also no significant differences found in the vitrification comparative analysis between and within the groups with regard to birth weight. Conclusion: Our results showed that a poor-quality embryo did not have a significant influence on a good-quality one regarding neonatal birth weight when transferred together. Key words: Embryo quality, Birth weight, Frozen-embryo transfer, Fresh embryo transfer, Single embryo transfer, Double embryo transfer.

Background Comparative neonatal outcomes with respect to singleton births from blastocyst transfers or cleavage-state embryo transfers are controversial with respect to which method is superior. Many studies have yielded contradictory results. We performed a systematic review and meta-analysis for the purpose of comparing neonatal outcomes in single births following IVF/ICSI. Methods We searched the Medline, Embase and Cochrane Central Register of Clinical Trials (CCTR) databases until October 2016. Studies and trials that contained neonatal outcomes for singleton births were included. Data were extracted in 2 × 2 tables. The analysis was performed using Rev Man 5.1 software. Risk ratios (RRs) and risk differences, with 95% confidence intervals, were calculated to assess the results of each outcome. Subgroups were applied in all outcomes. Newcastle-Ottawa scale (NOS) checklists were used to assess the quality of the referenced studies. Results Twelve studies met the criteria in this meta-analysis. There was a high risk of preterm birth after blastocyst embryo transfer versus the risk after cleavage-stage transfer (RR: 1.11, 95% CI: 1.01–1.22). For the “only fresh” subgroup, the outcome was coincident (RR: 1.16, 95% CI: 1.06–1.27). For the “fresh and frozen” and “only frozen” subgroups, there were no differences. Patients who received fresh blastocyst embryo transfers had a high risk of very preterm births (RR: 1.16, 95% CI: 1.02–1.31). Finally, cleavage-stage embryo transfers were associated with a high risk of infants who were small for gestational age (0.83, 95% CI: 0.76–0.92) and a low risk of those who were large for gestation age (1.14, 95% CI: 1.04–1.25). Conclusions The risks of preterm and very preterm births increased after fresh blastocyst transfers versus the risks after fresh cleavage-stage embryo transfers. However, in frozen embryo transfers, there were no differences. Blastocyst embryo transfers resulted in high risks of infants who were large for gestational age, and cleavage-stage embryo transfers resulted in high risks of infants who were small for gestational age.

Background Sequential embryo transfer has been proposed as a way to improve embryo implantation in women for in vitro fertilization (IVF), but the effect on pregnancy outcomes remains ambiguous. This systematic review was conducted to investigate the efficacy of sequential embryo transfer on IVF outcomes. Methods A literature search was performed in the PubMed, Web of Science, Cochrane Library, ScienceDirect and Wanfang databases. Data were pooled using a random- or fixed-effects model according to study heterogeneity. The results are expressed as relative risks (RRs) with 95% confidence intervals (CIs). Heterogeneity was evaluated by the I 2 statistic. The study protocol was registered prospectively on INPLASY, ID: INPLASY202180019. Results Ten eligible studies with 2658 participants compared sequential embryo transfer and cleavage transfer, while four studies with 513 participants compared sequential embryo transfer and blastocyst transfer. The synthesis results showed that the clinical pregnancy rate was higher in the sequential embryo transfer group than in the cleavage embryo transfer group (RR 1.42, 95% CI 1.26–1.60, P < 0.01) for both women who did experience repeated implantation failure (RIF) (RR 1.58, 95% CI 1.17–2.13, P < 0.01) and did not experience RIF (Non-RIF) (RR 1.44, 95% CI 1.20–1.66, P < 0.01). However, sequential embryo transfer showed no significant benefit over blastocyst embryo transfer. Conclusion The current systematic review demonstrates that sequential cleavage and blastocyst embryo transfer improve the clinical pregnancy rate over conventional cleavage embryo transfer. For women with adequate embryos, sequential transfer could be attempted following careful consideration. More high-grade evidence from prospective randomized studies is warranted.

Background Endometrial preparation with hormone replacement therapy (HRT) is the preferred regimen for clinicians due to the opportunity to schedule the day of embryo transfer and for patients due to the requirement of fewer visits for frozen-warmed embryo transfers (FET). The increasing number of FETs raises the question of the serum P levels required to optimize the pregnancy outcome on the embryo transfer day. Methods This prospective cohort study includes patients who underwent single euploid FET. All patients received HRT with oestradiol valerate (EV) and 100 mg of intramuscular (IM) progesterone (P). FET was scheduled 117–120 h after the first IM administration of 100 mg P. The serum P level was analyzed 1 h before the embryo transfer (ET). In all cycles, only embryos that were biopsied on day 5 were utilized for FET. Next generation sequencing (NGS) was used for comprehensive chromosomal analysis. Results Overall, the ongoing pregnancy rate (OPR) was 58.9% (99/168). Data were then categorized according to the presence (Group I; n  = 99) or the absence (Group II; n  = 69) of an ongoing pregnancy. No significant differences regarding, female age, body mass index (BMI), number of previous miscarriages, number of previous live birth, sperm concentration, number of oocytes retrieved, number of mature oocytes (MII), rate of fertilized oocytes with two pronuclei (2PN), trophectoderm score, inner cell mass (ICM) score, endometrial thickness (mm), oestrodiol (E 2 ) and P levels prior to IM P administration were found between two groups. The P levels on the day of ET (ng/ml) were significantly higher in Group I (28 (5.6–76.4) vs 16.4 (7.4–60) p  = 0.039). The P level on the day of ET was a predictor of a higher OPR ( p  < 0.001 OR: 1.033 95%CI [1.009–1.056]) after multivariate analysis. The ROC curve showed a significant predictive value of serum P levels on the day of ET for OPR, with an AUC (95%CI) = 0.716 (0.637–0.795). The optimal cut-off value for prediction of the OPR was a P level of 20.6 ng/ml (71.7% sensitivity, 56.5% specificity). Conclusions The present study suggests a minimum threshold of the serum P value on the day of ET that needs to be reached in HRT cycles to optimize the clinical outcome. Individualization of the P dosage should be evaluated in further studies.

AbstractObjectiveTo compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment.DesignMulticentre, randomised controlled superiority trial.SettingOutpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain.Participants460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection.InterventionsWomen were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure.Main outcome measuresThe primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle.ResultsOngoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) v 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group.ConclusionsIn women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present.Trial registrationClinicaltrials.gov NCT02746562.

To assess the value of deep learning in selecting the optimal embryo for in vitro fertilization, a multicenter, randomized, double-blind, noninferiority parallel-group trial was conducted across 14 in vitro fertilization clinics in Australia and Europe. Women under 42 years of age with at least two early-stage blastocysts on day 5 were randomized to either the control arm, using standard morphological assessment, or the study arm, employing a deep learning algorithm, intelligent Data Analysis Score (iDAScore), for embryo selection. The primary endpoint was a clinical pregnancy rate with a noninferiority margin of 5%. The trial included 1,066 patients (533 in the iDAScore group and 533 in the morphology group). The iDAScore group exhibited a clinical pregnancy rate of 46.5% (248 of 533 patients), compared to 48.2% (257 of 533 patients) in the morphology arm (risk difference −1.7%; 95% confidence interval −7.7, 4.3; P  = 0.62). This study was not able to demonstrate noninferiority of deep learning for clinical pregnancy rate when compared to standard morphology and a predefined prioritization scheme. Australian New Zealand Clinical Trials Registry (ANZCTR) registration: 379161 . A randomized controlled trial evaluating the selection of a single blastocyst for transfer by deep learning did not demonstrate noninferiority in clinical pregnancy rates when compared to trained embryologists using standard morphology criteria.

The studies posits that there is not sufficient evidence to support the use of intrauterine platelet-rich plasma (PRP) infusion in patients with recurrent implantation failure (RIF). This study aims to investigate the effects of infusion of PRP on patients with unexplained-RIF in fresh and frozen embryo transfer (ET) cycles. A total of 80 participants were included in this study. The participants were randomly assigned to one of two groups with and without PRP infusion. Each of the PRP and control groups were also divided into fresh and frozen ET subgroups. ET outcomes were compared between groups. Clinical pregnancy rate was significantly higher in Frozen ET in PRP group than other subgroups ( p  < 0.0001). Miscarriage rate were significantly lower in PRP group than control group. Pregnancy complications and preterm labor were significantly higher in PRP group than control group ( p  < 0.0001). Live birth and healthy baby rate were significantly higher in PRP group than control group ( p  < 0.0001). The intrauterine infusion of 0.8-1 ml of PRP 48 h before blastocyst ET at fresh and frozen cycles can be an efficient treatment option for u-RIF patients. Also, results indicated that the clinical pregnancy rate was equal to the live birth rate at fresh ET cycles, whereas the live birth rate was lower than the clinical pregnancy rate at frozen ET cycles. Therefore, considering the superiority of fresh cycles over freeze cycles, the infusion of PRP into the uterus of patients with RIF is recommended to be done at fresh ET cycles. Trial registration : NCT, NCT03996837. Registered 25/06/2019. Retrospectively registered, http://www.clinicaltrial.gov/ NCT03996837.