What is the reproductive potential of day 7 euploid embryos?

STUDY QUESTION: What is the rate of euploidy and the reproductive potential of embryos biopsied after 6 days of development? SUMMARY ANSWER: Embryos biopsied after 6 days of development have higher rates of aneuploidy; however, day 7 euploid embryos selected at transfer can achieve acceptable pregnancy rates and live birth (LB) outcomes. WHAT IS KNOWN ALREADY: Recent publications have shown promising treatment results after euploid day 7 embryo transfers (ETs), albeit these studies were limited by small sample sizes. Whereas the current clinical standard has been to discard embryos that do not reach expansion by day 6 of development, the lack of robust data surrounding the clinical utility of day 7 embryos warrants further evaluation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from January 2012 to March 2018. A total of 25 775 embryos underwent trophectoderm (TE) biopsy and preimplantation genetic testing for aneuploidy (PGT-A). Additionally, the clinical IVF outcomes of 3824 single, euploid frozen embryo transfer (FET) cycles were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cohorts were segregated by day of TE biopsy following oocyte retrieval (day 5, day 6 or day 7). PGT-A was performed to identify embryonic ploidy rates. Secondly, IVF and LB outcomes after single, euploid FET were evaluated for each cohort. MAIN RESULTS AND THE ROLE OF CHANCE: A total of day 5 (n = 12 535), day 6 (n = 11 939) and day 7 (n = 1298) embryos were included in the study analysis. The rate of embryo euploidy was significantly lower in day 7 blastocysts compared to day 5 or day 6 cohorts (day 7 = 40.5%; day 5 = 54.7%; day 6 = 52.9%; (P < 0.0001)). After adjusting for age, anti-Müllerian hormone, BMI, embryo quality and number of embryos biopsied, there was a significant association between aneuploidy and embryos biopsied on day 7 when compared to day 5 biopsied embryos (OR = 1.34, CI 95% 1.09-1.45, P = 0.001) and day 6 biopsied embryos (OR = 1.26, CI95% 1.07-1.16, P < 0.001).A sub-analysis of subsequent 3824 single, euploid FET cycles (day 5: n = 2321 cycles; day 6: n = 1381 cycles; and day 7: n = 116 cycles) showed significant differences among cohorts in implantation, clinical pregnancy, LB and clinical loss rates. There was a significant decrease in the odds of implantation, clinical pregnancy and LB, but no association with clinical loss or multiple pregnancy rates in patients who utilized day 7-biopsied embryos during treatment. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and potential variability in the study center's laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Additionally, patients who transferred euploid embryos, biopsied on day 7 of development due to an absence of day 5 or day 6 counterparts, may have introduced selection bias in this study. WIDER IMPLICATIONS OF THE FINDINGS: Embryonic developmental stage, morphological grade and ploidy status are paramount factors affecting ET selection and implantation potential. This study reveals that embryos ineligible for TE biopsy on day 5 or day 6 of development may benefit from extended culture to day 7. Our study demonstrates patient benefit when extended culture to day 7 of development is routinely performed for embryos failing to meet biopsy criteria by day 5 or 6. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for the realization of this manuscript. Dr Alan Copperman is Advisor or Board Member of Sema 4 (Stake holder in Data), Progyny and Celmatix. TRIAL REGISTRATION NUMBER: This retrospective analysis was approved by an Institutional Review Board (WIRB PRO NUM: 20161791; Study Number: 1167398).

Blastocyst vitrification, cryostorage and warming does not affect live birth rate, infant birth weight or timing of delivery.

RESEARCH QUESTION: Does vitrification and warming affect live birth rate, infant birth weight and timing of delivery? DESIGN: Retrospective, cohort study comparing outcomes of donor oocyte recipient fresh (n = 25) versus vitrified (n = 86) euploid blastocyst transfers; donor oocyte recipient singleton live births from fresh (n = 100) versus vitrified (n = 102) single embryo transfers (SET); and autologous vitrified euploid SET (n = 1760) (cryostored 21-1671 days). RESULTS: Group 1: fresh and vitrified-warmed blastocysts had similar live birth (OR 1.7; 95% CI 0.5 to 5.9), implantation (OR 0.9; 95% CI 0.2 to 3.9), clinical pregnancy (OR 3.4; 95% CI 0.9 to 13.0) and pregnancy loss (OR 1.2; 95% CI 0.98 to 1.4); group 2: low birth weight (OR 0.44; 95% CI 0.1 to 1.6) and preterm delivery (0.99; 95% CI 0.4 to 2.3) rates were similar in fresh and vitrified-warmed blastocyst transfers; group 3: cryostorage duration did not affect live birth (OR 1.0; 95% CI 1.0 to 1.0), implantation (OR 1.0; 95% CI 0.99 to 1.01), clinical pregnancy (OR 1.0; 95% CI 1.0 to 1.0]), pregnancy loss (OR 0.99; 95% CI 1.0 to 1.0), birth weight (ß = -15.7) or gestational age at delivery (ß = -0.996). CONCLUSIONS: Vitrification and cryostorage (up to 4 years) are safe and effective practices that do not significantly affect clinical outcome after embryo transfer.

The Impact of the Coronavirus Disease 19 Pandemic on Early Pregnancy Outcomes Among Patients Undergoing In Vitro Fertilization Treatment.

Objective: To determine if pregnancy rates (PRs) or pregnancy loss rates (PLRs) were altered in patients undergoing single, euploid frozen-thawed embryo transfer (FET) during the initial peak of the Coronavirus Disease 19 (COVID-19) pandemic. Materials and Methods: This was a retrospective cohort study performed in a single academic center. Patients undergoing single, euploid FET cycles from January to May 2017-2020 were included. Cycles with FET performed in January-May of 2020 ("COVID-surge cohort") were compared to cycles with FET performed in January-May of 2017-2019 ("pre-COVID cohort"). Pregnancy rate (PR), clinical pregnancy rate (CPR), pregnancy loss rate (PLR), and clinical pregnancy loss rate (CLR) were compared between the cohorts. Results: A total of 2629 single, euploid FET cycles were included: 2070 from January to May, 2017-2019 and 559 from January to May 2020. PR was similar when comparing FET performed from January to May 2020 (COVID-surge) to those performed from January to May, 2017-2019 (pre-COVID) (77.6% vs. 73.7%, p = 0.06), while CPR was higher among the COVID-surge compared to the pre-COVID cohort (65.5% vs. 60.0%, p = 0.02). No differences were seen in PLR and CLR among the COVID-surge and pre-COVID cohorts (28.3% vs. 32.0%, p = 0.08; 15.0% vs. 16.5%, p = 0.50). PR, CPR, PLR, and CLR were similar when comparing individual months between the cohorts. Adjusted analysis showed no differences in PR, CPR, PLR, or CLR when comparing the cohorts overall or when comparing corresponding individual months in the two time periods. Conclusion: PRs and PLRs were not decreased when SARS-CoV-2 transmission was widespread in our geographic area, suggesting that high COVID-19 transmission does not compromise early pregnancy outcomes.

Endometrial preparation before the transfer of single, vitrified-warmed, euploid blastocysts: does the duration of estradiol treatment influence clinical outcome?

OBJECTIVE: To investigate whether the duration of estrogen administration before euploid embryo transfer affects clinical outcome. DESIGN: Retrospective cohort study. SETTING: Private, academic fertility center. PATIENT(S): Patients (n = 1,439) undergoing autologous freeze-only in vitro fertilization with preimplantation genetic testing (PGT) followed by endometrial preparation with estrogen and progesterone in a frozen, euploid blastocyst transfer cycle. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome was live birth, and secondary outcomes included implantation, clinical pregnancy, early pregnancy loss, live birth, infant birthweight, low birth weight, infant gestational age at delivery, and preterm birth. RESULT(S): The duration of estrogen administration (mean: 17.5 ± 2.9 days; range: 10-36 days) before frozen embryo transfer did not impact implantation (odds ratio [OR] 0.99; 95% confidence interval [CI], 0.95-1.03), clinical pregnancy (OR 0.98; 95% CI, 0.94-1.01), early pregnancy loss (OR 1.03; 95% CI, 0.95-1.12), or live birth (OR 0.99; 95% CI, 0.95-1.03). The duration of estrogen exposure did not affect infant birthweight (in grams) (ß= -10.65 ± 8.91) or the odds of low birth weight (OR 0.87; 95% CI, 0.68-1.13). For every additional day of estrogen administration, we observed a reduction in gestational age at delivery (in weeks) (ß= -0.07 ± 0.03), but the odds of preterm delivery were not affected (OR 1.05; 95% CI, 0.95-1.17). CONCLUSION(S): Variation in the duration of estradiol supplementation before progesterone initiation does not impact frozen, euploid blastocyst transfer outcome. The duration of estrogen administration was inversely correlated with gestational age at delivery, but this did not translate into an increase in preterm delivery. Further studies are required on the downstream effects of endometrial preparation on the placental-endometrium interface.

Subchorionic hematoma associated with heterotopic pregnancy following in vitro fertilization: a case report.

BACKGROUND: After treatment for infertility using in vitro fertilization (IVF)-embryo transfer, a high index of suspicion must be maintained for early diagnosis and treatment of concurrent ectopic pregnancy; however, the likelihood of a positive outcome for the intrauterine pregnancy remains uncertain. CASE: A subchorionic hematoma threatening an intrauterine gestation noted concurrently with ultrasound diagnosis of a heterotopic IVF pregnancy resolved following laparoscopic salpingectomy. CONCLUSION: Although symptomatic subchorionic hematoma may be associated with an increase in the rate of spontaneous miscarriage for a singleton pregnancy, it may not present a similar risk in the presence of a concurrent heterotopic gestation.

Is what we clearly see really so obvious? Ultrasonography and transcervical embryo transfer--a review.

OBJECTIVE: To critically review the role of ultrasound-guided embryo transfer (ET) and its influence on the outcome of in vitro fertilization (IVF). DESIGN: Medline review of published manuscripts. RESULT(S): Studies evaluating the role of ultrasound-assisted ET have had mixed results, and although meta-analysis of prospective trials suggests an improvement in outcome, limitations in study design may overstate the effect of ultrasonography. Other ET techniques may eliminate the advantages provided by ultrasonography, limiting its benefit to specific clinical scenarios. However, because no trial has demonstrated an adverse effect and because cases that may benefit from its use often cannot be predicted reliably, the routine application of ultrasonography can be justified.

Patient-friendly IVF: how should it be defined?

"Patient-friendly" IVF must be associated with a healthy newborn achieved in a safe, cost-effective, and timely manner. Patients are best served when physicians provide honest appraisal of treatment techniques and outcomes using the evidence available from scientific study.

Low ectopic pregnancy rates after in vitro fertilization: do practice habits matter?

In a 6-year review of ectopic pregnancies (EPs) after fresh and frozen embryo transfers in IVF cycles conducted at a large university-based program, we report an overall 0.9% rate of EP that seems to have increased with the programmatic shift to routine blastocyst transfer, but remains lower than nationally reported rates. Aggressive management of tubal disease may contribute to low rates of EP, whereas blastocyst transfer may increase the rate.

Programmatic implementation of blastocyst transfer in a university-based in vitro fertilization clinic: maximizing pregnancy rates and minimizing triplet rates.

To assess whether the use of extended embryo culture can reduce the incidence of high-order multiple gestations, a retrospective analysis of 7,418 fresh ETs performed in a university-based IVF clinic from 1997-2003 was conducted, comparing program results before and after institution of a protocol to select patients for extended culture of in vitro fertilized embryos. The incidence of triplet pregnancies was significantly reduced in patients at highest risk for high-order multiple gestations, i.e., those at <35 years of age (16.8% versus 6.8%), those at 35-37 years of age (13.0% versus 5.6%), and recipients of donated oocytes (11.2% versus 4.5%).

One at a time.

Review of abstracts presented at the 2004 Annual Meeting of the American Society for Reproductive Medicine clearly demonstrate that good prognosis patients should be given the option of a single embryo transfer.

Transabdominal ultrasound-assisted embryo transfer and pregnancy outcome.

OBJECTIVE: To assess the clinical value of transabdominal ultrasound (TAS)--assisted embryo transfer on outcomes of in vitro fertilization--embryo transfer (IVF-ET) in comparison to the "clinical touch" method of transcervical embryo transfer by one physician and to determine if transabdominal ultrasound should be applied to all cases of embryo transfer in this practice. DESIGN: A retrospective comparison study. SETTING: A university-based IVF practice. PATIENT(S): Two hundred forty-nine patients who underwent transcervical transfer of fresh embryos created using autologous oocytes performed by the same physician from July 1, 2003, to June 30, 2004. INTERVENTION(S): On selected days, at time of embryo transfer, transabdominal ultrasound was performed to guide catheter placement depth approximately 1 cm from the uterine fundus. MAIN OUTCOME MEASURE(S): The presence of at least one gestational sac on ultrasound was compared in the two study groups; additionally, the clinical pregnancy rate (presence of fetal cardiac activity observed on ultrasound), the ectopic pregnancy rate, the biochemical pregnancy rate, and the implantation rate (number of gestational sacs identified on ultrasound per number of embryos transferred) between groups was evaluated. Characteristics of the two cohorts were analyzed to verify similarities between the treatment and control groups, including age of recipient, prior IVF history, day of transfer (day 3 or day 5 after retrieval), difficulty of transfer, the use of a tenaculum, and the quality and number of embryos transferred. RESULT(S): No statistical difference was seen in the presence or number of gestational sacs following embryo transfer with or without transabdominal ultrasound guidance. CONCLUSION(S): No additional advantage is conferred when using transabdominal ultrasound to perform embryo transfer. In experienced hands, the "clinical touch" method of embryo transfer yields equivalent results to transabdominal ultrasound-guided embryo placement. However, in patients with a prior history of difficult uterine sounding or embryo transfer, transabdominal ultrasound guidance may still play a role.