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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.

Background After spontaneous conception, the rate of miscarriage is more common in multiple rather than singleton pregnancies. However, the incidence of miscarriage is lower in in-vitro fertilization twin versus singleton pregnancies. Most patients have little understanding of pregnancy outcomes once they achieve a positive pregnancy test. This study investigated the relationship between multiple pregnancy and miscarriage in women with infertility after fresh and frozen embryo transfer. Methods Retrospective local cohort study of all consecutive patients undergoing in-vitro fertilization at our institution (n = 1130), fresh or frozen embryo transfer, between January 1, 2008 and December 31, 2012. Patient characteristics (age, body mass index, initial hCG, maximum follicle stimulating hormone levels) and in-vitro fertilization parameters (estradiol levels, eggs retrieved, and endometrial thickness) were collected and statistically analyzed using T -test and Chi-square test (Stata version 10). Linear and logistic regression were used when appropriate. Results Overall, live birth rate for all cycles was 30.44% and total pregnancy loss was 6.55% - similar for fresh and frozen cycles despite a higher rate of biochemical pregnancies for frozen cycles. Among all pregnant patients, 62.48% had a live birth. Although clinical pregnancy rate was higher for fresh cycles, live birth rates were similar. In pregnancies where multiple sacs were demonstrated on ultrasound, live birth rates were higher despite 31% of patients losing at least one sac. This finding was comparable between fresh and frozen cycles. However, in patients under age 35 and using donor egg, no live birth advantage was seen in patients with multiple sacs. In fact, transferring more than one embryo did not increase live birth rate either. Conclusions Despite the many maternal and fetal risks of multiple pregnancies, patients who achieve a positive pregnancy test with fresh and frozen in-vitro fertilization and who have more than one pregnancy sac are more likely ultimately to deliver at least one baby. This finding is true of both fresh and frozen embryo transfer cycles. This pregnancy advantage is not seen in young patients and in patients using donor egg, and single embryo transfer maximizes birth outcomes.

Increasing evidence suggests a relationship between in vitro fertilization-embryo transfer (IVF-ET) and placenta accreta spectrum (PAS). Some studies have reported a lower rate of antenatal diagnosis of PAS after IVF-ET compared to PAS with spontaneous conception. This study aimed to review the diagnostic accuracy of PAS after IVF-ET and to explore the relationship between IVF-ET pregnancy and PAS. According to the PRISMA guidelines, a comprehensive systematic review of the literature was conducted through August 31, 2020 to determine the effects of IVF-ET on PAS. In addition, a meta-analysis was conducted to explore the relationship between IVF-ET pregnancy and PAS. Twelve original studies (2011–2020) met the inclusion criteria. Among these, 190,139 IVF-ET pregnancies and 248,534 spontaneous conceptions met the inclusion criteria. In the comparator analysis between PAS after IVF-ET and PAS with spontaneous conception ( n  = 2), the antenatal diagnosis of PAS after IVF-ET was significantly lower than that of PAS with spontaneous conception (22.2% versus 94.7%, P  < 0.01; < 12.9% versus 46.9%, P  < 0.01). The risk of PAS was significantly higher in women who conceived with IVF-ET than in those with spontaneous conception (odds ratio [OR]: 5.03, 95% confidence interval [CI]: 3.34–7.56, P  < 0.01). In the sensitivity analysis accounting for the type of IVF-ET, frozen ET was associated with an increased risk of PAS (OR: 4.60, 95%CI: 3.42–6.18, P  < 0.01) compared to fresh ET. Notably, frozen ET with hormone replacement cycle was significantly associated with the prevalence of PAS compared to frozen ET with normal ovulatory cycle (OR: 5.76, 95%CI 3.12–10.64, P  < 0.01). IVF-ET is associated with PAS, and PAS after IVF-ET was associated with a lower rate of antenatal diagnosis. Therefore, clinicians can pay more attention to the presence of PAS during antenatal evaluation in women with IVF-ET, especially in frozen ET with hormone replacement cycle.

Background The endometrial preparation during frozen embryo transfer (FET) can be performed by natural cycle (NC), hormone replacement therapy (HRT) cycle and cycle with ovulation induction (OI). Whether different FET preparation protocols can affect maternal and neonatal outcomes is still inconclusive. Methods This was a retrospective cohort study that included 6886 women who delivered singleton live birth babies after 28 weeks of pregnancy underwent FET from January, 2015 to July, 2018. Women were divided into three groups according to the protocols used for endometrial preparation during FET: NC group ( N  = 4727), HRT group ( N  = 1642) and OI group ( N  = 517). Results After adjusting for the effect of age, body mass index (BMI), irregular menstruation, antral follicle count (AFC), endometrial thickness, the levels of testosterone, anti-Müllerian hormone (AMH), preconceptional fasting glucose (PFG), systolic and diastolic pressure et al., the HRT group had higher risk of hypertensive disorders of pregnancy (HDP) compared with the NC group (adjusted odds ratio (aOR) 2.00, 95% confidence interval (CI) 1.54–2.60). Singletons born after HRT FET were at increased risk of low birth weight (LBW) compared to NC group (aOR 1.49, 95%CI 1.09–2.06). The risks of preterm birth (PTB) in the HRT and OI group were elevated compared with the NC group (aOR 1.78, 95%CI 1.39–2.28 and aOR 1.51, 95%CI 1.02–2.23, respectively). Conclusions The HRT protocol for endometrial preparation during frozen embryo transfer of blastocysts was associated with increased risk of maternal and neonatal complications, compared to the NC and OI protocol.

Background 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. Methods 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. Results 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. Conclusions 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.

The relationship between blastocyst morphological quality and the risk of congenital malformations in assisted reproductive technology (ART) remains poorly understood, limiting clinical decision-making for embryo selection. We conducted a retrospective cohort study of 3986 frozen embryo transfer cycles (January 2014–June 2023) to evaluate whether blastocyst morphological quality influences the risk of congenital malformations. Blastocysts were classified according to Gardner’s grading system, and 1:2 propensity score matching was applied to control for maternal age, BMI, infertility characteristics, and other potential confounders. After matching, 1743 singleton births were analyzed (1162 good-quality vs. 581 poor-quality blastocysts). Baseline characteristics were well balanced between groups. The risk of congenital malformations was similar between good- and poor-quality groups (aOR 1.14, 95% CI 0.54–2.41, P  = 0.7310; 1.72% vs. 2.07%), with no significant between-group differences in any ICD-10 organ-specific categories (all P > 0.10). Secondary outcomes showed no significant differences: preterm birth (aOR 0.80, 95% CI 0.57–1.12, P  = 0.1976), low birth weight (aOR 1.26, 95% CI 0.72–2.19, P  = 0.4172), other neonatal outcomes, and obstetric complications (aOR 0.89, 95% CI 0.64–1.22, P  = 0.4629). These findings indicate that blastocyst morphological quality does not influence the risk of congenital malformations, supporting the use of morphologically poor blastocysts when high-quality alternatives are unavailable, which may reduce unnecessary discarding of embryos, alleviate patient anxiety, and improve treatment accessibility.

Background Retransferring retained embryos during the embryo transfer (ET) procedure has raised concerns about its adverse effects on assisted reproductive technology (ART) outcomes. Technical challenges associated with embryo retention (ER) may compromise implantation success and lead to increased complications. Objective This systematic review and meta-analysis aimed to evaluate the impact of retransferring retained embryos on key ART outcomes, including clinical pregnancy rate (CPR), biochemical pregnancy rate (BPR), ectopic pregnancy rate (EP), miscarriage rate (MR), and live birth rate (LBR). Methods We conducted a systematic search in PubMed, Scopus, and Cochrane databases from inception to April 11, 2025. ART outcomes were extracted and pooled Mantel–Haenszel odds ratios (OR) with 95% confidence intervals (CI) were calculated under both fixed- and random-effects models. Subgroup analyses were performed based on study design (matched versus non-matched retrospective cohorts) and ET technique (afterload versus direct). Sensitivity analyses were conducted by excluding studies with high or very high risk of bias, as determined by the ROBINS-E tool. Results The overall analysis demonstrated that retransferring retained embryos was associated with a significant reduction in CPR (OR ≈ 0.75, 95% CI: 0.64–0.89, p  < 0.001) and LBR, while substantially increasing the risk of EP (OR ≈ 2.36, p  = 0.036). Subgroup analysis showed that studies with matched designs and those using the afterload ET technique exhibited more pronounced negative outcomes. Sensitivity analyses confirmed the robustness of the primary findings. Conclusion ER negatively impacts ART success, lowering clinical pregnancy and live birth rates and elevating the risk of ectopic pregnancy. These findings highlight the critical need to refine ET protocols and further investigate the biological mechanisms underlying ER. Future well-designed, prospective studies with standardized methodologies are warranted to optimize ER management and improve clinical outcomes.

Ectopic pregnancy (EP) is a common yet fatal complication of in vitro fertilization-embryo transfer (IVF-ET) and intracytoplasmic sperm injection (ICSI). We aim to establish and validate a nomogram in patients undergoing double fresh cleavage-stage embryo transfer, which remains a mainstream strategy in infertile patients. Data from 7456 patients were reviewed and divided into training and validation sets. Logistic analyses were conducted to identify the risk factors, with calibration and decision-curve analyses performed to evaluate model performance. The model divided patients into high- and low-risk groups, showing different 48-h serum beta-human chorionic gonadotropin (HCG) rising thresholds. It showed that Tubal factor infertility (Odds Ratio [OR] = 1.680, 95% Confidence Interval [CI] 1.129–2.500, P  = 0.011), previous tubal surgery (OR = 2.667, 95% CI 1.772–4.015, P  < 0.001), polycystic ovarian syndrome (PCOS) (OR = 1.809, 95% CI 1.169–2.799, P  = 0.008), uterine malformation (OR = 5.663, 95% CI 1.524–21.043, P  = 0.010), endometrial thickness (OR = 0.585, 95% CI 0.522–0.655, P  < 0.001) and serum estradiol levels (OR = 1.000, 95% CI 1.000–1.000, P  < 0.001) on triggering day were independent risk factors for EP after double fresh cleavage-stage embryo transfer. The area under curve (AUC) values for the training and validation sets were 0.768 (95% CI 0.732–0.805, P  < 0.001) and 0.756 (95% CI 0.703–0.810, P  < 0.001), respectively. The nomogram further divided all participants into high EP risk and low EP risk with a cut-off score of 86.1 based on the maximum value of Youden Index in order to investigate different subsequent interventions based on serum HCG level. Patients in high EP risk group suffered significantly higher incidence of EP (OR = 4.902, 95% CI 3.597–6.667, P  < 0.001 and OR = 4.587, 95% CI 2.899–7.246, P  < 0.001). Higher 48-h serum HCG rising thresholds (2.18 vs. 1.74 and 2.10 vs. 1.66) also applied to patients from high EP risk group. The nomogram effectively predicts individual EP probability in patients receiving double fresh cleavage-stage embryo transfer, thereby aiding screening high-risk patients.

Compared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors. This registry-based cohort study with nationwide data from Denmark (1994-2014), Norway (1988-2015), and Sweden (1988-2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (-51 g, 95% CI -58 to -45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (-1.0 days, 95% CI -1.2 to -0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking. We found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias. ClinicalTrials.gov ISRCTN11780826.

ObjectivesNo studies have examined the efficacy of assisted reproductive technology (ART) treatment in women with rheumatoid arthritis. Therefore, we examined the chance of live birth after ART treatment in women with rheumatoid arthritis compared with women without rheumatoid arthritis.MethodsOur cohort study is based on nationwide Danish health registries, comprising all women with an embryo transfer during 1 January 1994 through 30 June 2017. The cohorts comprised 1149 embryo transfers in women with rheumatoid arthritis, and 198 941 embryo transfers in women without rheumatoid arthritis. Our outcome was live birth per embryo transfer, and we controlled for multiple covariates in the analyses. In subanalyses, we examined a chance of biochemical/clinical pregnancy after ART and a possible impact of corticosteroid use prior to embryo transfer.ResultsThe adjusted OR (aOR) for a live birth per embryo transfer in women with rheumatoid arthritis, relative to women without rheumatoid arthritis, was 0.78 (95% CI 0.65 to 0.92). The aORs for biochemical and clinical pregnancies were 0.81 (95% CI 0.68 to 0.95) and 0.82 (95% CI 0.59 to 1.15), respectively. Corticosteroid prescription prior to embryo transfer increased the OR for live birth (aOR=1.32 (95% CI 0.85 to 2.05)).ConclusionsThe chance of a live birth was significantly reduced in women with rheumatoid arthritis receiving ART treatment, relative to women without rheumatoid arthritis, and our result suggested that the problem was related to an impaired chance of embryo implantation. The role of corticosteroid use prior to embryo transfer must be a subject for further research.