Mitigating multiples, less is more: examining trends in multifetal gestation rates with assisted reproductive technology.

PURPOSE: Multifetal gestation (MFG) is much more common in pregnancies that utilize assisted reproductive technologies (ART). We assessed how these rates have changed over the previous decade and the impact on live birth rates (LBR). METHODS: This retrospective cohort study uses the National Summary Reports of the Society for Assisted Reproductive Technology (SART) from 2014 to 2020. Data points included only autologous cycles. The data were divided into five age groups as reported in the database: < 35, 35-37, 38-40, 41-42, and > 42 years old. Descriptive statistics and a two-tailed T-test were used to determine the trends and statistical significance (p < 0.05). RESULTS: Rates of twin births decreased substantially from 2014 to 2020 for autologous embryo transfers across all age groups and diagnoses. Surprisingly, the overall LBR for autologous IVF cycles decreased at similar rates from 2014 to 2020 in all age groups. The mean number of embryos transferred has dramatically reduced, especially across age groups < 42. CONCLUSION: Rates of twin and higher-level gestations have decreased substantially over the past decade; the effect correlates with the increased utilization of eSET and PGT. The cause of infertility did not significantly impact the rate of MFG.

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

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

Predictors of success after in vitro fertilization.

The last few decades have witnessed a rise in the global uptake of in vitro fertilization (IVF) treatment. To ensure optimal use of this technology, it is important for patients and clinicians to have access to tools that can provide accurate estimates of treatment success and understand the contribution of key clinical and laboratory parameters that influence the chance of conception after IVF treatment. The focus of this review was to identify key predictors of IVF treatment success and assess their impact in terms of live birth rates. We have identified 11 predictors that consistently feature in currently available prediction models, including age, duration of infertility, ethnicity, body mass index, antral follicle count, previous pregnancy history, cause of infertility, sperm parameters, number of oocytes collected, morphology of transferred embryos, and day of embryo transfer.

Perinatal outcomes of singleton live births after preimplantation genetic testing during single frozen-thawed blastocyst transfer cycles: a propensity score-matched study.

OBJECTIVE: To determine whether singleton pregnancy achieved after preimplantation genetic testing (PGT) is associated with a higher risk of adverse perinatal outcomes than in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) singleton pregnancy. DESIGN: A retrospective cohort study. SETTING: A university-affiliated fertility center. PATIENT(S): This cohort study included singleton live births resulting from PGT (n = 232) and IVF/ICSI singleton pregnancies (n = 2,829) with single frozen-thawed blastocyst transfer. Multiple baseline covariates were used for propensity score matching, yielding 214 PGT singleton pregnancies matched to 617 IVF/ICSI singleton pregnancies. INTERVENTION(S): Trophectoderm biopsy. MAIN OUTCOME MEASURE(S): The primary outcome was gestational hypertension, and various clinical perinatal secondary outcomes related to maternal and neonatal health were measured. RESULT(S): Compared with IVF/ICSI singleton pregnancy, PGT singleton pregnancy was associated with a significantly higher risk of gestational hypertension (adjusted odds ratio, 2.58; 95% confidence interval, 1.32, 5.05). In the matched sample, the risk of gestational hypertension remained higher with PGT singleton pregnancy (odds ratio, 2.33; 95% confidence interval, 1.04, 5.22) than with IVF/ICSI singleton pregnancy. No statistical differences were noted in any other measured outcomes between the groups. CONCLUSION(S): The perinatal outcomes of PGT and IVF/ICSI singleton pregnancies were similar except for the observed potentially higher risk of gestational hypertension with PGT singleton pregnancy. However, because the data on PGT singleton pregnancies are limited, this conclusion warrants further investigation.

The impact of different cycle regimens on birthweight of singletons in frozen-thawed embryo transfer cycles of ovulatory women.

OBJECTIVE: To investigate whether different endometrial preparation regimens affect neonatal outcomes after frozen-thawed embryo transfer (FET). DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: A total of 3,639 patients with live-born singletons were categorized into three groups on the basis of the type of endometrial preparation regimens. Of these, 1,225, 2,136, and 278 live-born singletons were conceived through natural cycle FET, artificial cycle FET, and stimulated cycle FET, respectively. INTERVENTION(S): None. MAIN OUTCOME MEASURES: The main outcomes were the measures of birthweight including the absolute mean birthweight, Z-score, low birthweight, high birthweight (HBW), small for gestational age, and large for gestational age (LGA). RESULTS: After controlling for a variety of covariates, singletons from the artificial cycle FET group had a higher mean birthweight and Z-score than those from the natural cycle FET group and stimulated cycle FET group. The risk of LGA infants significantly increased in the artificial cycle group (14.0%) than that in the natural cycle group (10.3%) and stimulated cycle group (7.6%). The risk of hypertensive disorders of pregnancy in the artificial cycle group (4.4%) was significantly higher than that in the natural cycle group (2.5%). The stimulated cycle FET singletons had a higher risk of low birthweight than the natural cycle FET singletons. The other perinatal outcomes, including the incidence of preterm birth, small for gestational age, and gestational diabetes mellitus, were comparable between the groups before or after adjustment for confounders. CONCLUSIONS: Singletons from artificial cycle FET were associated with a higher risk of LGA infants, and natural cycle FET may be a better regimen for ovulatory women. Our results indicate a link between the absence of the corpus luteum and adverse perinatal outcomes, and further studies are needed to detect the underlying mechanism.

Whither cryopreservation? The landscape gets colder.

The increase in utilization and changing legal landscape has made the field of embryo and gamete cryopreservation fraught with potential future challenges and liabilities. Clinics should be aware of the current state of the science, potential legal ramifications of what is currently routine practice, and long-term ethical implications of our work.

The association between season, day length, and temperature on clinical outcomes after cryopreserved embryo transfer.

OBJECTIVE: To investigate whether there is an association between season, temperature, and day length at oocyte retrieval and/or embryo transfer (ET) and clinical outcomes in frozen ET cycles. DESIGN: Retrospective cohort study. SETTING: Large academically affiliated research hospital. PATIENT(S): A total of 3,004 frozen ET cycles from 1,937 different women with oocyte retrieval and transfer between 2012 and 2017. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, spontaneous abortion, and live birth. RESULT(S): Frozen ETs with oocyte retrieval dates in summer had 45% greater odds of clinical pregnancy (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.15-1.82) and 42% greater odds of live birth (OR, 1.42; 95% CI, 1.13-1.79) compared with those with oocyte retrieval dates in winter. A 41% greater odds of clinical pregnancy (OR, 1.41; 95% CI, 1.16-1.71) and 34% greater odds of live birth (OR, 1.34; 95% CI, 1.10-1.62) were observed among transfers with an average temperature at oocyte retrieval in the highest tertile (17.2-33.3 °C) compared with those in the lowest tertile (-17.2-6.7 °C). There were no consistent associations between clinical outcomes and day length at oocyte retrieval or between season, day length, or temperature at transfer of thawed embryos. CONCLUSION(S): Warmer temperatures at oocyte retrieval are associated with higher odds of clinical pregnancy and live birth among frozen ET cycles. The consistent associations seen with oocyte retrieval dates and the lack of associations observed with ET dates suggest that any seasonality effects on in vitro fertilization success are related to ovarian function and not uterine receptivity.

Characteristics of the cytoplasmic halo during fertilisation correlate with the live birth rate after fresh cleaved embryo transfer on day 2 in minimal ovarian stimulation cycles: a retrospective observational study.

BACKGROUND: Information regarding the influence of cytoplasmic events during fertilisation on the clinical outcome remains limited. The cytoplasmic halo is one of these events. A previous study that used time-lapse technology found an association of the presence and morphokinetics of the cytoplasmic halo with cleavage patterns, development to the blastocyst stage, and the ongoing pregnancy rate after blastocyst transfer. Therefore, the cytoplasmic halo may be a useful predictor of the pregnancy outcome after cleaved embryo transfer. This study evaluated the ability of the cytoplasmic halo to predict a live birth after fresh cleaved embryo transfer on day 2, and sought to identify factors potentially influencing the presence and morphokinetics of the halo. METHODS: A total of 902 embryos cultured in the EmbryoScope+® time-lapse system and subjected to single fresh cleaved embryo transfer were retrospectively analysed. The presence and duration of a cytoplasmic halo were annotated. The initial positions of the pronuclei were also observed. The correlation between the cytoplasmic halo and live birth was evaluated and the association of the cytoplasmic halo with patient, cycle, and embryonic characteristics was determined. RESULTS: Absence of a cytoplasmic halo was associated with a significant decrease in the likelihood of a live birth after fresh cleaved embryo transfer. Prolongation of the halo, especially the duration of central repositioning of cytoplasmic granules, had an adverse impact on the live birth rate. The characteristics of the cytoplasmic halo were not affected by the ovarian stimulation method used, female age, the serum steroid hormone level on the day of trigger, or semen quality. However, the cytoplasmic halo was significantly affected by male age, oocyte diameter, and the initial position of the male pronucleus. CONCLUSIONS: Absence or prolongation of the cytoplasmic halo was negatively correlated with the live birth rate after fresh cleaved embryo transfer. The characteristics of the cytoplasmic halo were strongly associated with oocyte diameter, male age, and the initial position of the male pronucleus. These findings indicate that the characteristics of the cytoplasmic halo can be used to select more competent embryos for transfer at the cleavage stage.

Defining recurrent implantation failure: a profusion of confusion or simply an illusion?

Recurrent implantation failure (RIF) is a poorly defined clinical scenario marked by failure to achieve pregnancy after multiple embryo transfers. The causes and definitions of implantation failure are heterogeneous, posing limitations on study design as well as the interpretation and application of findings. Recent studies suggest a novel, personalized approach to defining RIF. Here, we review the implantation physiology and definitions of the implantation rate, failure, and RIF.

Novel therapeutic options for treatment of recurrent implantation failure.

Despite the challenges in studying recurrent implantation failure, progress is currently being made in therapeutic options to help those who suffer from recurrent implantation failure. Three of the most promising therapeutic options for recurrent implantation failure include immune therapies such as peripheral blood mononuclear cells, platelet rich plasma and subcutaneous granulocyte-colony stimulating factor.

A review of the pathophysiology of recurrent implantation failure.

Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment.

Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?

OBJECTIVE: To determine whether the epigenetic control of imprinted genes (IGs) and transposable elements (TEs) differs at birth between fresh or frozen embryo transfers and natural conceptions. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): A total of 202 singleton births were divided into three groups: 84 natural pregnancies (controls), 66 in vitro fertilization/intracytoplasmic sperm injection with fresh embryo transfers, and 52 vitro fertilization/intracytoplasmic sperm injection with frozen embryo transfers. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pyrosequencing was used to assess the DNA methylation profiles of three IGs (H19/IGF2:IG-DMR [two sequences], KCNQ1OT1:TSS-DMR, and SNURF:TSS-DMR) and two TEs (LINE-1 and HERV-FRD) in cord blood and placenta. The quantitative reverse transcriptase polymerase chain reaction was used to study the transcription of three IGs (H19, KCNQ1, and SNRPN) and two TEs (LINE-1 and ORF2). RESULT(S): After adjustment, the placental DNA methylation levels of H19/IGF2 were lower in the fresh embryo transfer group than in the control (H19/IGF2-seq1) and frozen embryo transfer (H19/IGF2-seq2) groups. The DNA methylation rate for LINE-1 was lower in placentas from the fresh embryo transfer group than in placentas from the control and frozen embryo transfer groups and for HERV-FRD compared with controls. In cord blood, DNA methylation levels were not significantly associated with the mode of conception. The relative expression of LINE-1 and ORF2 was decreased in both cord blood and placental tissues from fresh embryo transfer conceptions compared with natural conceptions and frozen embryo transfer conceptions. CONCLUSION(S): Compared with natural conceptions and frozen embryo transfers, fresh embryo transfers were associated with methylation and/or transcription changes in some TEs and IGs, mostly in placental samples, which could indicate altered placental epigenetic regulation resulting from ovarian stimulation protocols.

Endometrial thickness changes after progesterone administration do not affect the pregnancy outcomes of frozen-thawed euploid blastocyst transfer: a retrospective cohort study.

OBJECTIVE: To evaluate whether the change in endometrial thickness from progesterone administration day to transfer day is related to pregnancy outcomes in single frozen-thawed euploid blastocyst transfer cycles. DESIGN: Observational cohort study. SETTING: Single reproductive medical center. PATIENT(S): All patients were transferred with a single biopsied euploid blastocyst, and their endometrium was prepared with hormone replacement therapy (HRT). INTERVENTION(S): The endometrial thickness on the day of blastocyst transfer and progesterone administration was measured by transvaginal ultrasound, and the difference between them and the change ratio were calculated. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates and live birth rates. RESULT(S): Endometrial ultrasound images of 508 euploid blastocyst transfer cycles using HRT were evaluated by transvaginal ultrasound. Overall, pregnancy outcomes were comparable in different groups of endometrial thickness changes. The results of multiple logistic regression showed that the clinical pregnancy rate and live birth rate did not significantly increase with the increase in endometrial thickness change ratios (per 10%) in the fully adjusted model as a continuous variable. In the adjustment model as a categorical variable, there was no statistical difference in pregnancy outcomes among the groups with changes in endometrial thickness. Interaction analysis showed that after adjusting for confounders, there was no statistically significant interaction between the endometrial thickness change ratio and pregnancy outcomes in all subgroups. CONCLUSION(S): In the euploid blastocyst transfer cycle of preparing the endometrium with HRT, the endometrial thickness change ratio after progesterone administration was not related to pregnancy outcomes.