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To estimate the aneuploidy rates in young women with diminished ovarian reserve (DOR) before treatment and poor ovarian response (POR) postretrieval.Retrospective cohort study.A single academically-affiliated fertility clinic.Autologous frozen embryo transfer cycles from December 2014 to June 2020 were reviewed. Demographic and clinical factors that impact outcomes were used for propensity score matching (PSM) in a ratio of 2:1 and 4:1 for preimplantation genetic testing for aneuploidy pre-cycle DOR and POR after stimulation, respectively.None.Aneuploid rates, defined as the number of aneuploid blastocysts divided by the number of biopsied blastocysts per cycle. No euploid embryos to transfer, defined as all cohorts of embryos being aneuploid.A total of 383 women diagnosed with DOR were compared with matched controls. Aneuploid rates did not differ significantly between the two groups (42.2% vs. 41.7%; RR = 1.06; 95% CI, 0.95-1.06). No differences were identified in live birth rates per transfer between women with and without DOR after euploid single-embryo transfers (56.0% and 60.5%, respectively). An additional PSM analysis to assess aneuploidy rates for patients with POR (5 oocytes) vs. those without it, resulted in similar rates of aneuploidy between the two comparison groups (41.1% vs. 44%, R = 1.02; 95% CI, 0.91-1.14). The prevalence of cycles with "no euploid embryos" in the POR cohort was higher (26% vs. 13%); however, rates of cases with a single embryo available for biopsy were lower in the DOR group, relative to controls (11% vs. 31%).Young women diagnosed with DOR or POR exhibited equivalent aneuploidy rates and live birth rates per euploid embryo transfer in a large matched population, based on age, body mass index, and IVF cycle initiation. The lower percentage of cycles with no euploid embryo available for transfer in DOR and POR patients is because of the decreased total number of oocytes/developing embryos and not because of increased aneuploidy rates in these groups.

Objective To compare gestational age, birth weight (BW), and live birth rates in gestational carriers (GC) after the transfer of 1 or 2 frozen embryo(s) with or without preimplantation genetic testing for aneuploidy (PGT-A), with the understanding that several social and economic factors may motivate intended parents to request the transfer of 2 embryos and/or PGT-A when using a GC. Design Retrospective cohort study Setting An assisted reproductive technology practice. Patient(s) All frozen blastocyst transfers with GCs from 2009–2018. Intervention(s) One or 2 embryo frozen embryo transfers with and without PGT-A. Main Outcome Measure(s) Live birth, preterm birth, and low BW. Results A total of 583 frozen embryo transfer cycles with vitrified high-grade blastocysts (grade BB or higher) to GCs were analyzed. Although the live birth rate was significantly greater in frozen embryo transfers with 2 embryos, after single embryo transfer (SET), the mean gestational age and BW of live births were statistically significantly greater than those of double embryo transfer (DET). The rate of multiple births was 1.9% for SET compared to 20.0% for DET per transfer. Only 3.8% of live births from SET experienced low BW and 0.6% had very low or extremely low BW. By comparison, 12.5% of DET live births were low BW and 5% were very low BW. After SET, 13.4% of live births were preterm, compared with 40% in DET. The analysis also included a total of 194 transfers with PGT-A compared to 389 cycles without. Overall, live births per transfer were not significantly different between these latter 2 subgroups. Conclusion Frozen embryo transfer cycles in GCs with DET were associated with more preterm births and lower birth weights compared with those of SET. Intended parents and GCs should be counseled that DET is associated with greater risks of adverse pregnancy and perinatal outcomes, which mitigates higher live birth rates. The use of PGT-A did not appear to improve the live birth rate.

Objective To investigate the association of endometrium preparation with perinatal outcomes. Design Retrospective cohort study. Setting University-affiliated fertility center. Patient(s) Twenty-one thousand six hundred and forty-eight women who underwent frozen single-blastocyst transfer from January 2013 to March 2019. Intervention(s) None. Main Outcome Measure(s) Cesarean delivery, preterm delivery (PTD), vaginal PTD, very preterm delivery (VPTD), postterm delivery, low birth weight (LBW), macrosomia, small for gestational age (SGA), large for gestational age (LGA), hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), premature rupture of membrane (PROM), placenta previa, and congenital abnormality. Result(s) Compared with natural cycles, hormone replacement cycles were associated with an increased risk of PTD, VPTD, cesarean delivery, macrosomia, PROM, and HDP. There was a trend toward an increased risk of vaginal PTD and LGA in hormone replacement cycles. Stimulated cycles were associated with an increased risk of postterm delivery and GDM. There was no statistically significant difference in the rate of SGA, placenta previa, or congenital abnormality among the three endometrium preparation methods. Conclusion(s) Hormone replacement cycles are associated with an increased risk of PTD, VPTD, cesarean delivery, LBW, macrosomia, PROM, and HDP. Stimulated cycles are associated with an increased risk of postterm delivery and GDM.

Objective To evaluate the risk of ectopic pregnancies (EPs) for fresh cycles according to different ovarian stimulation protocols. Design Registry-based retrospective cohort study. Setting Not applicable. Patient(s) A total of 68,851 clinical pregnancies after fresh single embryo transfer between 2007 and 2015. Intervention (s) None Main Outcome Measure(S) Ectopic pregnancies. Odds ratios and 95% confidence intervals for EPs were calculated by using generalized estimating equations adjusted for potential maternal and treatment characteristics. Result(s) Among 68,851 clinical pregnancies, 1,049 (1.46%) cases of EP were reported. Compared with natural cycles, all ovarian stimulation protocols were associated with a significantly increased risk of EP. Ovarian stimulation with clomiphene (CC) demonstrated the highest odds ratios for EPs. Significant associations between ovarian stimulation protocols and EP compared with natural cycles were prominent when the number of retrieved oocytes was low (1–3) to moderate (4–7), but there were no significant associations when the number of retrieved oocytes was high (≥8). Conclusion(s) Ovarian stimulation protocols were significantly associated with an increased risk of EP. In particular, ovarian stimulation with CC had the highest risk of EP compared with other stimulation protocols. Further studies are essential to investigate possible confounding factors for different ovarian stimulation protocols, especially CC, and the risk of EP.

The health of children born through assisted reproductive technologies (ART) is particularly vulnerable to policy decisions and market forces that play out before they are even conceived. ART treatment is costly, and public and third-party funding varies significantly between and within countries, leading to considerable variation in consumer affordability globally. These relative cost differences affect not only who can afford to access ART treatment, but also how ART is practiced in terms of embryo transfer practices, with less affordable treatment creating a financial incentive to transfer more than one embryo to maximize the pregnancy rates in fewer cycles. One mechanism for reducing the burden of excessive multiple pregnancies is to link insurance coverage to the number of embryos that can be transferred; another is to combine supportive funding with patient and clinician education and public reporting that emphasizes a "complete" ART cycle (all embryo transfers associated with an egg retrieval) and penalizes multiple embryo transfers. Improving funding for fertility services in a way that respects clinician and patient autonomy and allows patients to undertake a sufficient number of cycles to minimize moral hazard improves outcomes for mothers and babies while reducing the long-term economic burden associated with fertility treatments.

Objective To assess whether the calculated difference in endometrial thickness from the end of the estrogen phase to the day of ET (after 6 days of P in hormonally prepared cycles) is associated with ongoing pregnancy rates in euploid frozen ETs (FETs). Design An observational cohort study. Setting Single tertiary care medical center. Patient(s) Ultrasound images from 234 hormonally prepared FET cycles were assessed. All the transfers were elective single ETs of a euploid embryo, post–preimplantation genetic testing for aneuploidy (PGT-A). Intervention(s) Ultrasound measurements of peak endometrial thickness at the end of the estrogen phase and again after 6 days of P at the time of ET. Main Outcome Measure(s) Ongoing pregnancy rate in relation to the delta between endometrial thickness at the end of estrogen phase and at the time of ET. Result(s) We calculated the ongoing pregnancy rate in cycles where the endometrial lining decreased (compacted) after addition of P by 5%, 10%, 15%, and 20% and demonstrated a significantly higher pregnancy rate after all rates of compaction of the endometrial lining in comparison with cycles where the endometrial lining did not compact. The ongoing pregnancy rate in this cohort, after compaction of 15% or more, was 51.5%, compared with 30.2% in cycles where the endometrial lining did not compact. Conclusion(s) There is a significant correlation between endometrial lining compaction and ongoing pregnancy rate in FET cycles of euploid embryos. These findings help to explain why some euploid embryos may fail to implant.

Objective To examine the differences in live birth rates (LBRs), with single embryo transfer (SET), using oocytes from program generated egg donors vs. commercial egg bank donors and other factors affecting LBRs using donor oocytes. Design Retrospective cohort study. Setting Not applicable. Patient(s) A total of 40,485 in vitro fertilization cycles using donor oocytes reported to the Society for Assisted Reproductive Technology registry in 2016–2018. Intervention(s) None. Main Outcome Measure(s) Live birth rate and cumulative LBR for SET using donor oocytes. Result(s) Multivariate results from the first SET from 19,128 cycles, including 15,429 from program generated egg donors and 3,699 from commercial egg banks, showed, when controlling for all other variables, the following: the LBR in the first SET cycle using commercial egg banks was 53.3% compared with 55.4% using program recruited egg donors (odds ratio [OR], 0.92); a reduction in the LBR with increasing recipient age, ages 40–44 years (OR, 0.80), 45–49 years (OR, 0.77), and >49 years (OR, 0.65); a steady decline in the LBR with increases in recipient body mass index above normal; and a steady increase in the LBR in association with >16 oocytes retrieved. Double embryo transfer increased the LBR (SET, 52%, vs. double embryo transfer, 58%) but also significantly increased the multiple pregnancy LBR, with 43% twins and 0.9% triplets. Blastocyst transfer had a higher LBR than cleavage stage embryos (52.5% vs. 39.5%). Intracytoplasmic sperm injection vs. conventional insemination when using fresh oocytes from program donors had similar LBRs. Conclusion(s) When performing in vitro fertilization using donor oocytes with SET, the LBR is affected by oocyte source, recipient age, recipient body mass index, stage of embryo at transfer, and number of oocytes retrieved.

Objective To determine whether increased endometrial B-cell lymphoma 6 (BCL6) expression is associated with live birth in a normal responder in vitro fertilization (IVF) population. Design Case-control study. Setting University-affiliated infertility center. Patient(s) Two groups of women undergoing IVF with preimplantation genetic testing for aneuploidy followed by warmed, single, euploid embryo transfer. Group 1 consisted of women who failed to achieve live birth, and group 2 consisted of women who achieved live birth. Intervention(s) None. Main Outcome Measure(s) Endometrial BCL6 expression measured by immunohistochemistry in endometrial tissue samples. Overexpression was defined by mean HSCORE with a cutoff of positivity of >1.4, as previously described in the literature. Result(s) Twenty-seven patients who achieved live birth and 23 patients who failed to achieve live birth were included. B-cell lymphoma 6 expression/HSCORE and live birth rate were not associated (Odds ratio [OR], 0.78 [0.24–2.55]). Using a cutoff of >1.4 for positivity, 8 of 23 samples were positive for BCL6 in the no live birth group, whereas 7 of 27 were positive in the live birth group. There was no significant association between BCL6 positivity and live birth (OR, 0.66 [0.19–2.21]). Conclusion(s) The proportion of patients with BCL6 positivity did not significantly differ between those who achieved live birth and those who did not. In the population of patients at our center, who compromise of women who respond normally to IVF stimulation, BCL6 overexpression was not associated with IVF success. Physicians implementing BCL6 testing as a diagnostic tool for clinical decision making should counsel patients that results may have limited utility in predicting IVF outcomes in this population.

Objective: To develop a random forest model (RFM) to predict implantation potential of a transferred embryo and compare it with a multivariate logistic regression model (MvLRM), based on data from a large cohort including in vitro fertilization (IVF) patients treated with the use of single-embryo transfer (SET) of blastocyst-stage embryos. Design: Retrospective study of a 2-year single-center cohort of women undergoing IVF or intracytoplasmatic sperm injection (ICSI). Setting: Academic hospital. Patient(s): Data from 1,052 women who underwent fresh SET in IVF or ICSI cycles were included. Intervention(s): None. Main Outcome Measure(s): The performance of both RFM and MvLRM to predict pregnancy was quantified in terms of the area under the receiver operating characteristic (ROC) curve (AUC), classification accuracy, specificity, and sensitivity. Result(s): ROC analysis resulted in an AUC of 0.74 ± 0.03 for the proposed RFM and 0.66 ± 0.05 for the MvLRM for the prediction of ongoing pregnancies of ≥11 weeks. This RFM approach and the MvLRM yielded, respectively, sensitivities of 0.84 ± 0.07 and 0.66 ± 0.08 and specificities of 0.48 ± 0.07 and 0.58 ± 0.08. Conclusion(s): The performance to predict ongoing implantation will significantly improve with the use of an RFM approach compared with MvLRM.

Objective To evaluate which clinical characteristics influence early maternal β-human chorionic gonadotropin (hCG) and progesterone levels in in vitro fertilization (IVF) pregnancies. Design Retrospective cohort analysis. Setting Academic medical center. Patient(s) Women with a live birth after single-blastocyst embryo transfer in either a fresh or frozen cycle between 2004 and 2017, comprising 1,282 pregnancies in 1,057 patients. Intervention(s) None. Main Outcome Measure(s) The initial human chorionic gonadotropin concentration (β-hCG1) measured a mean of 10 days (range: 9–12 days) after embryo transfer, the rate of increase in β-hCG concentrations, and progesterone concentration, with all analyses controlled for number of days between the embryo transfer and the β-hCG1 measurement. Result(s) The clinical factor that positively influenced the β-hCG1 level in the fresh cycle was the stimulation type (antagonist cycle higher than long agonist cycle). The clinical factors that negatively influenced both fresh and frozen cycle β-hCG1 were lower embryo quality and increasing body weight. Increasing weight negatively impacted progesterone levels in both fresh and frozen cycles. A 100 lb (45.4 kg) difference in weight was associated with a 34.8% reduction in β-hCG1 for both fresh and frozen cycle pregnancies. The rate of increase in β-hCG was unaffected by body weight. A 100 lb (45.4 kg) difference in weight was associated with a 53.3% and a 32.8% reduction in progesterone in fresh and frozen cycles, respectively. Conclusion(s) Increasing body weight is associated with significantly lower β-hCG and progesterone concentrations in early pregnancy after blastocyst single-embryo transfer in both fresh and frozen cycles. Clinicians should consider this when evaluating these hormone levels for prognostic and diagnostic purposes.

To analyze the performance of an annotation-free embryo scoring system on the basis of deep learning for pregnancy prediction after single vitrified blastocyst transfer (SVBT) compared with the performance of other blastocyst grading systems dependent on annotation or morphology scores.A single-center large cohort retrospective study from an independent validation test.Infertility clinic.Patients who underwent SVBT cycles (3,018 cycles, mean ± SD patient age 39.3 ± 4.0 years).None.The pregnancy prediction performances of each embryo scoring model were compared using the area under curve (AUC) for predicting the fetal heartbeat status for each maternal age group.The AUCs of the35 years age group (n = 389) for pregnancy prediction were 0.72 for iDAScore, 0.66 for KIDScore, and 0.64 for the Gardner criteria. The AUC of iDAScore was significantly greater than those of the other two models. For the 35-37 years age group (n = 514), the AUCs were 0.68, 0.68, and 0.65 for iDAScore, KIDScore, and the Gardner criteria, respectively, and were not significantly different. The AUCs of the 38-40 years age group (n = 796) were 0.67 for iDAScore, 0.65 for KIDScore, and 0.64 for the Gardner criteria, and there were no significant differences. The AUCs of the 41-42 years age group (n = 636) were 0.66, 0.66, and 0.63 for iDAScore, KIDScore, and the Gardner criteria, respectively, and there were no significant differences among the pregnancy prediction models. For the42 years age group (n = 389), the AUCs were 0.76 for iDAScore, 0.75 for KIDScore, and 0.75 for the Gardner criteria, and there were no significant differences. Thus, iDAScore AUC was either the highest or equal to the highest AUC for all age groups, although a significant difference was observed only in the youngest age group.Our results showed that objective embryo assessment by a completely automatic and annotation-free model, iDAScore, performed as well as or even better than more traditional embryo assessment or annotation-dependent ranking tools. iDAScore could be an optimal pregnancy prediction model after SVBT, especially in young patients.

Objective To identify the risk of stillbirth from in vitro types of assisted reproductive technologies compared with spontaneous conception (SC), limited to singleton births. Design Systematic literature search and search chaining on online databases: PubMed, Embase, and Scopus. Setting Not applicable. Patient(s) Singleton pregnancies from in vitro fertilization (IVF) or fertilization by IVF and intracytoplasmic sperm injection (IVF-ICSI). Intervention(s) Not applicable. Main Outcome Measure(s) Adjusted odds ratio for stillbirth or prevalence of stillbirth in case–control groups of IVF/IVF-ICSI singletons and SCs, respectively, in matched studies. Result(s) A total of 19 studies were included, and study quality was mixed. Ten studies qualified for inclusion to the meta-analysis, which revealed a significantly increased risk of stillbirth in IVF/IVF-ICSI compared with that in SC (odds ratio [95% confidence interval]: 1.82 [1.37–2.42]), and there was no evidence of publication bias. Conclusion(s) In vitro fertilization and IVF-ICSI treatment increases the risk of stillbirth compared with natural conception. Clinical Trial Registration Number PROSPERO 216768.

In the early years of in vitro fertilization, overall pregnancy rates were low, and it was considered necessary to transfer more than one embryo to increase the chances of pregnancy. It was not until advances in assisted reproductive technologies resulting in increased pregnancy rates that the concept of transferring just one embryo was considered possible. A consequence of improvements in implantation rates was also an increase in multiple pregnancies when more than one embryo was transferred. Although some countries have reduced the number of embryos transferred, international data show that in many parts of the world high twin and higher order multiple pregnancy rates still exist. Even in developed countries these problems persist depending on clinical practice, funding of health services, and patient demands. Perinatal and other outcomes are significantly worse with twins compared with singleton pregnancies and there is an urgent need to reduce multiple pregnancy rates to at least 10%. This has been achieved in several countries and clinics by introducing single embryo transfer but there are many barriers to the introduction of this technique in most clinics worldwide. We discuss the background to the high multiple rate in assisted reproduction and the factors that contribute to its persistence even in excellent clinics and in high-quality health services. Practices that may promote single embryo transfer are discussed.

Multiple pregnancies following fertility treatments typically occur in 30% of women in whom more than one embryo is transferred. Worldwide, fewer than 20 countries have fully funded public fertility treatments, and many women utilizing assisted reproduction technologies are transferring more than one embryo for financial reasons because they consider it will be cheaper to have two embryos transferred in the one procedure. Yet, there is a large body of evidence for the poorer health, economic, and social outcomes for mother and baby from multiple pregnancies. Some countries have reduced the multiple pregnancy rate to less than 5% by linking the funding of ART to policies where the large majority of transfers are single embryos.

To evaluate the efficacy of two different in vitro fertilization culture media for blastocyst development, pregnancy, and live birth rate. Global (GB) medium (used without refreshment) and G-TL medium (designed specifically for culture in time-lapse incubators) were compared.Prospective randomized study of sibling embryo culture in two culture media.In vitro fertilization clinic.Women undergoing fresh or frozen cycles using autologous or donor oocytes.None.The primary endpoints were implantation, pregnancy, and live birth rate (LBR) after single blastocyst transfer. Secondary endpoints included embryo morphokinetics, development of good-quality blastocysts, and euploidy rate.Kinetic data from 10,768 sibling pronucleate embryos cultured in the EmbryoScope were compared. GB embryos initiated compaction earlier and formed morula sooner than their G-TL counterparts. The mean timing for start of blastulation did not differ. The interval between start of blastulation and time of blastocyst formation was observed to be12 hours for proportionately more GB compared with G-TL-cultured embryos. Despite a higher rate of observed dysmorphisms in GB embryos, the euploidy rate among biopsied blastocysts did not differ between media. A total of 820 single-embryo transfer cycles were performed. Implantation rates were similar between media, independent of whether the embryo transferred was fresh (GB 58.7% vs. G-TL 61.7%) or frozen (GB 64.1% vs. G-TL 60.5%). Live birth rates were also not different. With GB medium, the LBR for fresh and frozen transfers was 54.2% and 53.1%, respectively, as compared with 51.1% and 50%, respectively, with G-TL.Uninterrupted culture in a time-lapse incubator without medium refreshment was well supported by both media tested. Differences in morphokinetics did not necessarily dictate the superiority of one media over the other. Both pregnancy and LBR were not significantly influenced by choice of culture medium. The euploidy rate was also independent of culture medium.

Objective To study the impact of both controlled ovarian hyperstimulation (COH) length and total gonadotropin (GN) dose individually and in concert on live birth rates (LBR) in both fresh and freeze-all in vitro fertilization embryo transfer (IVF-ET) cycles. Design Historical cohort study. Setting Not applicable. Patient(s) The U.S. national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System from 2014 to 2015 was used to identify patients undergoing autologous GN stimulation IVF cycles with the use of GnRH antagonist–based suppression protocols where a single embryo transfer was performed as part of a fresh IVF-ET cycle (fresh, n = 14,866) or the first frozen embryo transfer after a freeze-all cycle (frozen, n = 2,964), and not including preimplantation genetic testing cycles. The patients’ demographic and cycle characteristics, duration of COH, total GN dose, and pregnancy outcomes were extracted. Binomial regression models estimated trend and relative risk of live birth with respect to days of stimulation and total GN dose singularly, and after adjustment for a priori confounders including age, parity, body mass index, diagnosis, and maximum follicle-stimulating hormone in both fresh and frozen embryo transfer cycles. Both days of stimulation and total GN dose were then added to the multivariate model to show whether they were independently associated with LBR. Intervention(s) Not applicable. Main outcome measure(s) Live birth rate. Results In both fresh and frozen cycles, length of COH was significantly associated with total GN dose. On univariate analysis, LBR decreased significantly with increasing length of stimulation and increasing total GN dose in both fresh and frozen cycles. On multivariable analysis including both days of stimulation and total GN dose, days of stimulation was no longer significantly correlated with LBR, whereas total GN dose remained significantly correlated with LBR in fresh cycles only. When total GN doses ranging from 5,000 IU were compared, a significant improvement in live birth rate was noted with lower total GN doses. Specifically, GN doses 5,000 IU. For GN dose groups up to 4,000 IU, the estimated effect on LBR was similar. There was a marginal improvement (13%) in LBR with GN doses of 4,000 IU to 5,000 IU compared with >5,000 IU. When the multivariate model was applied to the frozen cycles, neither total GN dose nor days of stimulation was significantly associated with LBR. Conclusions High total GN dose but not prolonged COH is associated with decreasing LBRs in fresh cycles, whereas neither factor significantly affects LBR in frozen cycles. Consideration should be given to minimizing the total GN dose when possible in fresh autologous cycles, either by decreasing the daily dose or by limiting the length of stimulation to improve LBRs. In freeze-all cycles, the use of higher GN doses does not seem to adversely affect the LBR of the first frozen embryo transfer. High total GN dose likely exerts a negative impact on the endometrium and/or oocyte/embryo unrelated to the length of stimulation. The differential effect of total GN dose on LBR in fresh and frozen cycles may imply a greater impact exerted on the endometrium rather than the oocyte.

Objective To evaluate the impact of a poor quality embryo (PQE) during double ET (DET) with a top quality embryo (TQE) on IVF outcome. Design A review of prospectively collected data. Setting Tertiary level fertility clinic. Patient(s) All patients undergoing blastocyst transfers as part of fresh IVF (n = 939) and frozen ET (n = 1,009) cycles performed between 2010 and 2016. Intervention(s) Single ET (SET) with TQE (group 1) was set as control and compared with outcomes for SET with PQE (group 2), DET with 2 TQEs (group 3), PQE plus TQE (group 4), and 2 PQE (group 5). Main Outcome Measure(s) Live births and multiple births. Result(s) The live birth rates for group 4 were statistically similar to group 1 during fresh IVF (26.5% vs. 33.7%; odds ratio [OR], 0.95; 95% confidence interval [CI] 0.53–1.7) and frozen ET (24.2% vs. 32.7%; OR, 0.75; 95% CI 0.48–1.2), although there was a trend for lower success. Conversely, multiple births were higher in group 4 for fresh IVF (19% vs. 4.7%; OR, 2.9; 95% CI 1.3–6.6) and frozen ET (10.3% vs. 2.6%; OR, 2.4; 95% CI 1.2–4.9). The live birth rates for group 2 (12.2% for fresh IVF and 14.6% for frozen ET) and group 5 (21.2% for fresh IVF and 14% for frozen ET) were lower and for group 3 were higher (40.8% for fresh IVF and 40.3% for frozen ET) when compared with group 1. Multiple births were significantly higher with DET. Conclusion(s) This study does not support DET with one PQE along with a TQE, when there is only one TQE and one or more PQEs available for fresh IVF or frozen ET.

Objective To determine if transferring a lower-quality embryo with a good-quality blastocyst is detrimental, given that evidence suggests that embryos can signal the endometrium and that embryo quality may affect negatively endometrial receptivity. Design Retrospective cohort study. Setting In vitro fertilization center. Intervention(s) Single- versus double-embryo transfer. Patient(s) Patients with a double-embryo transfer of a good-quality blastocyst plus a lower-quality blastocyst, early blastocyst, or morula were compared with patients receiving a single good-quality blastocyst. Main Outcome Measure(s) Live birth, multiple gestation. Result(s) In this study, 4,640 in vitro fertilization cycles were analyzed. In none of the analyses did transferring a second lower-quality embryo negatively affect birth rate. In the primary analysis, transferring a second lower-quality embryo increased live birth by 10% and the multiple birth rate by 15%. The addition of a fair- or poor-quality blastocyst or early blastocyst markedly increased the twin birth rate by 22%–27% with an 8%–12% increase in live birth. The addition of a morula did not increase live birth but resulted in 12% more multiples. In women younger than 38 years, adding a lower-quality embryo increased the birth rate by 7% but resulted in 18% increase in multiples. In women 38 years or older, adding a lower-quality embryo increased the live birth rate by 9% with a 15% increase in multiples. Conclusion(s) Addition of a lower-quality embryo does not have a detrimental effect on a good-quality blastocyst and results in a small increase in live births. However, this is at the expense of a marked increase in the likelihood of multiple gestations.

To study the effect of frozen embryo transfer (FET) preparation protocol on incidence of subchorionic hematoma (SCH) and serum hormone levels.Retrospective cohort study.University-affiliated fertility center.Patients who underwent FET at the New York University Langone Fertility Center.None.The primary outcome was incidence of SCH by protocol in FET cycles.There were 1,273 FET cycles that met criteria for inclusion. The frequency of SCH was lower in natural compared with programmed cycles (P.05; relative risk = 0.4 [0.27-0.78]; odds ratio = 0.4 [0.23-0.75]). Serum estrogen level was higher in programmed compared with natural cycles on day of progesterone initiation (P.001) and cycle day 28 (P.001). However, serum estrogen levels at the same time points were not associated with formation of SCH in programmed or natural cycles.This is the first study to evaluate the formation of SCHs by FET protocol type. Our results highlight that high serum estradiol levels do not independently lead to an increase in rate of SCH. Further research must be done to understand other clinical, or perhaps molecular, differences between natural and programmed FET cycle preparations that can be better associated with SCH formation.

The high incidence of multiple embryo transfers is evidence of the need for better methods of embryo selection. Additionally, methods to determine the reproductive competence of unfertilized oocytes are critically needed to inform the growing population of patients undergoing fertility preservation. The ideal method of oocyte and embryo selection would be noninvasive, inexpensive, and able to be incorporated into embryology workflow with minimal disruption. Methods to assess the biomechanical properties of cells offer many of these traits, and there is a growing body of evidence in multiple cell types demonstrating the biomechanical properties of cells are reflective of a cell's intrinsic health. The associations with these properties are not mere coincidence, as many of the biomechanical properties are critical to cellular function. The biomechanical properties of oocytes and embryos undergo a dynamic, characteristic transformation from oocyte maturation through blastocyst formation, lending itself to biomechanical assessment. Many of the assessments made by embryologists, from ease of microinjection during intracytoplasmic sperm injection to degree of blastocyst expansion, are direct proxies for cellular biomechanics. Newer, objective and quantitative methods of biomechanical assessment are being applied to oocyte and embryo selection, with early use supporting their application in assisted reproduction.

The need to identify the most viable embryo following in vitro fertilization (IVF) was established early in the history of human IVF. The stalwart of identifying the best embryos has been morphology. Other techniques have however seen wide acceptance, including the use of preimplantation genetic screening, even though concerns exist over the invasive nature of the technique. Alternatively, noninvasive assessment technologies have tried to determine an embryo's viability through measurements of factors in the media or by imaging of the embryo. We present data showing that the metabolic blueprint of an embryo is linked to viability, and argue that analysis of metabolic function, using either spent medium or by novel microscopies, could provide the basis for selecting the embryo with the highest viability. This review therefore asks, "Will noninvasive methods surpass invasive for assessing gametes and embryos?" We examine the current state of research on noninvasive technologies, including novel optical methods, and conclude noninvasive embryo viability assessment will assist in embryo selection for transfer.

Objective To investigate the association between ABO blood type and live-birth outcomes in patients undergoing IVF with day 5 single-embryo transfer (SET). Design Retrospective cohort study. Setting University-affiliated center. Patient(s) Normal responders, Intervention(s) None. Main Outcome Measure(s) Live-birth rate was the primary outcome. Secondary outcomes were birth weight and gestational age at delivery. Univariate and multivariable logistic regression was used to examine the association between blood type and live birth, while controlling for confounders. Odds ratios (OR) with 95% confidence intervals (CI) for live birth were estimated. Result(s) A total of 2,329 patients were included. The mean age of the study cohort was 34.6 ± 4.78 years. The distribution of blood types was as follows: A=897 (38.5%); B=397 (17.0%); AB=120 (5.2%); and, O=1,915 (39.3%) patients. There was no difference in the baseline demographics, ovarian stimulation, or embryo quality parameters between the blood types. The unadjusted ORs for live birth when comparing blood type A (referent) with blood types B, AB, and O were 0.96 (95% CI, 0.6–1.7), 0.72 (95% CI, 0.4–1.2), and 0.96 (95% CI. 0.6–1.7), respectively. The adjusted ORs for live birth remained not significant when comparing blood type A to blood types B, AB, and O individually. No difference in birth weight or gestational age at delivery was noted among the four blood types. Conclusion(s) Our findings suggest that ABO blood type is not associated with live-birth rate, birth weight, or gestational age at delivery in patients undergoing IVF with day 5 SET.

To examine outcomes of singleton pregnancies conceived without assisted reproductive technology (non-ART) compared with singletons conceived with ART by elective single-embryo transfer (eSET), nonelective single-embryo transfer (non-eSET), and double-embryo transfer with the establishment of 1 (DET -1) or ≥2 (DET ≥2) early fetal heartbeats.Retrospective cohort using linked ART surveillance data and vital records from Florida, Massachusetts, Michigan, and Connecticut.Not applicable.Singleton live-born infants.None.Preterm birth (PTB37 weeks), very preterm birth (VPTB32 weeks), small for gestational age birth weight (10th percentile), low birth weight (LBW2,500 g), very low birth weight (VLBW1,500 g), 5-minute Apgar score7, and neonatal intensive care unit (NICU) admission.After controlling for maternal characteristics and employing a weighted propensity score approach, we found that singletons conceived after eSET were less likely to have a 5-minute Apgar7 (adjusted odds ratio [aOR] 0.33; 95% CI, 0.15-0.69) compared with non-ART singletons. There were no differences among outcomes between non-ART and non-eSET infants. We found that PTB, VPTB, LBW, and VLBW were more likely among DET -1 and DET ≥2 compared with non-ART infants, with the odds being higher for DET ≥2 (PTB aOR 1.58; 95% CI, 1.09-2.29; VPTB aOR 2.46; 95% CI, 1.20-5.04; LBW aOR 2.17; 95% CI, 1.24-3.79; VLBW aOR 3.67; 95% CI, 1.38-9.77).Compared with non-ART singletons, singletons born after eSET and non-eSET did not have increased risks whereas DET -1 and DET ≥2 singletons were more likely to have adverse perinatal outcomes.

To investigate whether the morphodynamic characterization of a euploid blastocyst's development allows a higher prediction of a live birth after single-embryo-transfer (SET).Observational cohort study conducted in two phases: training and validation.Private in vitro fertilization centers.Euploid blastocysts: 511 and 319 first vitrified-warmed SETs from 868 and 546 patients undergoing preimplantation genetic testing for aneuploidies (PGT-A) in the training and validation phase, respectively.Data collected from time of polar body extrusion to time of starting blastulation, and trophectoderm and inner-cell-mass static morphology in all embryos cultured in a specific time-lapse incubator with a continuous medium. Logistic regressions conducted to outline the variables showing a statistically significant association with live birth. In the validation phase, these variables were tested in an independent data set.Live births per SET.The average live birth rate (LBR) in the training set was 40% (N = 207/511). Only time of morulation (tM) and trophectoderm quality were outlined as putative predictors of live birth at two IVF centers. In the validation set, the euploid blastocysts characterized by tM80 hours and high-quality trophectoderm resulted in a LBR of 55.2% (n = 37/67), while those with tM ≥ 80 hours and a low-quality trophectoderm resulted in a LBR of 25.5% (N = 13/51).Time of morulation and trophectoderm quality are better predictors of a euploid blastocyst's reproductive competence. Our evidence was reproducible across different centers under specific culture conditions. These data support the crucial role of morulation for embryo development, a stage that involves massive morphologic, cellular, and molecular changes and deserves more investigation.

Objective To evaluate the benefit of next-generation sequencing (NGS)–based preimplantation genetic testing for aneuploidy (PGT-A) for embryo selection in frozen-thawed embryo transfer. Design Randomized controlled trial. Setting Not applicable. Patient(s) Women aged 25–40 years undergoing IVF with at least two blastocysts that could be biopsied. Intervention(s) Randomization for single frozen-thawed embryo transfer with embryo selection based on PGT-A euploid status versus morphology. Main Outcome Measure(s) Ongoing pregnancy rate (OPR) at 20 weeks' gestation per embryo transfer. Result(s) A total of 661 women (average age 33.7 ± 3.6 years) were randomized to PGT-A (n = 330) or morphology alone (n = 331). The OPR was equivalent between the two arms, with no significant difference per embryo transfer (50% [137/274] vs. 46% [143/313]) or per intention to treat (ITT) at randomization (41.8% [138/330] vs. 43.5% [144/331]). Post hoc analysis of women aged 35–40 years showed a significant increase in OPR per embryo transfer (51% [62/122] vs. 37% [54/145]) but not per ITT. Conclusion(s) PGT-A did not improve overall pregnancy outcomes in all women, as analyzed per embryo transfer or per ITT. There was a significant increase in OPR per embryo transfer with the use of PGT-A in the subgroup of women aged 35–40 years who had two or more embryos that could be biopsied, but this was not significant when analyzed by ITT. Clinical Trial Registration Number NCT02268786.

Objective To evaluate the outcomes of embryo transfer with the use of monopronuclear (1PN) zygotes, and the risks of congenital malformations and postpartum developmental disorders. Design Retrospective cohort study. Setting Tertiary-care academic medical center. Patient(s) This study included patients who underwent single embryo transfer of 1PN frozen-thawed cleavage- or blastocyst-stage embryos. Seventy-six singletons were assessed for congenital malformations and defects in psychomotor development. Intervention(s) Monopronuclear frozen-thawed cleavage-stage or blastocyst embryos were compared with 2PN frozen-thawed cleavage-stage and blastocyst frozen embryos, in frozen-thawed embryo transfer (FET) cycles. Neonates from 2PN FET constituted the control group. Main Outcome Measure(s) Implantation rate (IR), clinical pregnancy rate (PR), miscarriage rate, live birth rate, congenital malformations, and motor and language development status were compared. Result(s) The cohort comprised 186, 676, 133, and 502 patients consenting to FET with, respectively, 1PN cleavage-stage, 2PN cleavage-stage, 1PN blastocystocyst, and 2PN blastocystocyst embryos. The IR, PR, and live birth rate were lower in 1PN than with 2PN cleavage-stage FET, but similar between 1PN and 2PN blastocystocysts. Miscarriage rates did not differ significantly between 1PN and 2PN cleavage-stage or blastocystocyst FET. Risk of congenital malformations and defects in psychomotor development did not differ significantly within 2 years postpartum with the use of 1PN or 2PN FET. Conclusion(s) The present results suggest that the value of 1PN blastocyst FET is similar to that of 2PN blastocyst FET, without an increased risk of miscarriage rate, congenital malformations, or defects of psychomotor development.

Objective To determine the effect of elective single ET (eSET) on live birth and multiple birth rates by a cycle-level and clinic-level analysis. Design Retrospective cohort study. Setting Not applicable. Patient(s) Patient ages Intervention(s) None. Main Outcome Measure(s) Clinics were divided into groups based on eSET rate for each age group and aggregate rates of live birth per ET and multiple birth per delivery were calculated. A cycle-level analysis comparing eSET and double ET (DET) live birth and multiple birth rates was also performed, stratified based on total number (2, 3, or 4+) of embryos available, embryo stage, and patient age. Result(s) There was a linear decrease in multiple birth rate with increasing eSET rate and no significant difference in clinic-level live birth rates for each age group. Cycle-level analysis found slightly higher live birth rates with double ET, but this was mainly observed in women aged 35–37 years or with four or more embryos available for transfer, and confirmed the marked reduction in multiple births with eSET. Conclusion(s) Our study showed a marked and linear reduction in multiple birth rates, and important, little to no effect on clinic-level live birth rates with increasing rates of eSET supporting the growing evidence that eSET is effective in decreasing the high multiple birth rates associated with IVF and suggests that eSET should be used more frequently than is currently practiced.

Objective To analyze donor oocyte cycles in the Society for Assisted Reproductive Technology (SART) registry to determine: 1) how many cycles complied with the 2009 American Society for Reproductive Medicine/SART embryo transfer guidelines; and 2) cycle outcomes according to the number of embryos transferred. For donor oocyte IVF with donor age Design Retrospective cohort study of United States national registry information. Setting Not applicable. Patient(s) A total of 13,393 donor-recipient cycles from 2011 to 2012. Intervention(s) Embryos transferred in donor IVF cycles. Main Outcome Measure(s) Percentage of compliant cycles, multiple pregnancy rate. Result(s) There were 3,157 donor cleavage-stage transfers and 10,236 donor blastocyst transfers. In the cleavage-stage cycles, 88% met compliance criteria. The multiple pregnancy rate (MPR) was significantly higher in the noncompliant cycles. In a subanalysis of compliant cleavage-stage cycles, 91% transferred two embryos and only 9% single embryos. In those patients transferring two embryos, the MPR was significantly higher (33% vs. 1%). In blastocyst transfers, only 28% of the cycles met compliance criteria. The MPR was significantly higher in the noncompliant blastocyst cohort at 53% (compared with 2% in compliant cycles). Conclusion(s) The majority of donor cleavage-stage transfers are compliant with current guidelines, but the transfer of two embryos results in a significantly higher MPR compared with single-embryo transfer. The majority of donor blastocyst cycles are noncompliant, which appears to be driving an unacceptably high MPR in these cycles.

Objective To determine whether oocyte retrieval from nondominant small follicles supplies mature oocytes and increases live births in natural cycle IVF and embryo transfer (IVF-ET). Design Retrospective cohort study. Setting Private assisted reproductive technology practice. Patient(s) Seven hundred seventy-one infertile women who underwent natural cycle IVF between 2011 and 2013. Intervention(s) The LH surge was triggered via nasal buserelin when the dominant follicle reached 16–18 mm during nonstimulated cycles, and as many oocytes as possible were retrieved from nondominant small follicles (a diameter of 3–10 mm) after retrieval from the large (dominant) follicle. The embryos were cryopreserved once they had yielded good-quality blastocysts and then transferred (one per cycle) during subsequent cycles. Main Outcome Measure(s) Number of mature oocytes (metaphase II) and resulting live births yielded via oocyte retrieval from the initial cycle of treatment. Result(s) Among 771 women, nondominant small follicle puncture yielded 902 metaphase II oocytes and 78 live births, whereas large dominant follicle puncture yielded 466 metaphase II oocytes and 90 live births. Successes in oocyte retrieval and live births resulting from small follicle puncture were positively correlated with ovarian reserve but did not depend on the outcomes of the dominant follicle puncture. Conclusion(s) Nondominant small follicles are a promising supplementary source of mature oocytes for natural cycle IVF.

To evaluate the effect of semen quality on human sex ratio in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI).Retrospective cohort study.Not applicable.A total of 27,158 singleton infants born between 2007 and 2012 after fresh single-embryo transfer.None.Proportion of male infants among liveborn infants.There were 14,996 infants born after IVF, 12,164 infants born after ICSI with ejaculated sperm, and 646 infants born after ICSI with nonejaculated sperm. The sex ratio of IVF was 53.1% (95% confidence interval [CI], 52.3-53.9); the sex ratio of ICSI with ejaculated and nonejaculated sperm demonstrated as statistically significant reduction (48.2%; 95% CI, 47.3-49.1 and 47.7%; 95% CI, 43.8-51.6, respectively). In IVF, lower sperm motility, including asthenozoospermia (sperm motility40%), was associated with a statistically significantly lower sex ratio compared with normal sperm (51.0%; 95% CI, 48.6-53.3 vs. 53.4%; 95% CI, 52.5-54.3). In ICSI with ejaculated sperm, there was no association between sperm motility and sex ratio. Sperm concentration was not associated with sex ratio in both IVF and ICSI.In IVF, lower sperm motility was associated with a statistically significant reduction in sex ratio; ICSI with either ejaculated or nonejaculated sperm was associated with a statistically significant reduction in sex ratio regardless of semen quality.

To determine live-birth rates (LBRs) at various ages in very poor prognosis patients, who are defined as poor responders under the Bologna criteria.Retrospective cohort study.Academically affiliated private fertility center.Among 483 patients, who under the Bologna criteria (three or fewer oocytes,40 years of age, and/or antimüllerian hormone [AMH]1.1 ng/mL [2/3 criteria minimum]) were poor responders, 278 (381 fresh IVF cycles) qualified for the study because they had at least one embryo on day 3 for transfer.IVF cycles in women with low functional ovarian reserve, involving androgen and CoQ10 supplementation and ovarian stimulation with daily gonadotropin dosages of 300-450 IU of FSH and 150 IU of hMG in microdose agonist cycles.Age-specific LBRs per ET.Ages did not differ between nonelective (ne) single ET (SET), ne2-ET, and ne ≥ 3-ET cycles (41.3 ± 3.9, 41.7 ± 3.1, and 42.4 ± 2.1 years, respectively). Patients with neSETs demonstrated significantly lower AMH and higher FSH levels and required higher gonadotropin dosages than ne2-ET and ne ≥ 3-ET patients. LBRs declined with age. Above age 42, three or more embryos are required to achieve reasonable LBRs and two or more to avoid futility under American Society for Reproductive Medicine (ASRM) guidelines.Very poor prognosis patients can still achieve acceptable pregnancy rates at least till their mid-40s if they reach ET. The degree to which egg donation is emphasized as the only treatment option in such patients, therefore, requires reconsideration. Above age 42, at least two, and preferably three embryos, are however required to exceed futility, as defined by ASRM.