Impact of double trophectoderm biopsy on reproductive outcomes following single euploid blastocyst transfer.

OBJECTIVES: To study the effect of double trophectoderm biopsy on clinical outcomes following single euploid blastocyst transfer. STUDY DESIGN: Retrospective cohort study of 2046 single euploid frozen-thawed blastocyst transfers from January 2015 to June 2022 in a single centre. All patients undergoing a frozen-thawed embryo transfer (FTET) cycle with euploid blastocysts, biopsied for any indication, were included. The outcomes were compared for blastocysts which were biopsied and vitrified once (Group 1, n = 1684), biopsied once but vitrified twice (Group 2, n = 312) and biopsied and vitrified twice (Group 3n = 50). We adjusted for confounders and performed subgroup analysis for PGT-A, PGT-M and PGT-SR cycles. The primary outcome was live birth rate. Secondary outcomes included pregnancy, clinical pregnancy, birthweight and sex ratio. RESULTS: After adjusting for confounders (previous failed euploid implantations, embryo quality and day of biopsy), embryos which were biopsied twice had lower OR for clinical pregnancy (0.48, CI 0.26-0.88, p = 0.019) and for live birth (0.50 CI 0.27-0.92, p = 0.025) compared to controls. Embryos which were biopsied once but vitrified twice had no different ORs for all reproductive outcomes compared to controls. No significant difference was observed for neonatal birthweight or sex ratio amongst the three groups. This is a retrospective single centre study with inherent bias and results may not be transferable to all settings. CONCLUSION: This study is the largest to date assessing the outcomes of FTET cycles following double trophectoderm biopsy. The results are in keeping with the existing literature and can be incorporated into patient counselling. Whilst double biopsy seems to adversely impact LBR, it is only one of the many factors that can affect success rates. The subfertility background and embryo characteristics should not be overlooked. This study provides reassuring evidence since double biopsied embryos still result in live births with no difference in sex ratio or birthweight. However, long term follow up of the off-springs is lacking and should be reported in future studies.

Intrauterine instillation of human chorionic gonadotropin at the time of blastocyst transfer: Systematic review and meta-analysis.

Intrauterine instillation (IU) of Human Chorionic Gonadotropin (hCG) before embryo transfer (ET) has been proposed to enhance implantation success rates. This is the first meta-analysis to evaluate the effect at the blastocyst-stage. A systematic literature search was performed using Medline, Embase, Cochrane Library and Google. Randomized clinical trials (RCTs) were included. The primary outcome combined live birth rate (LBR) and ongoing pregnancy rate (OPR). The secondary outcomes were clinical pregnancy rate (CPR), implantation rate (IR) and miscarriage rate (MR). 93 citations were identified, of which there were seven eligible RCTs. 2499 participants were included in the meta-analysis; 1331 were assigned to an experimental group and 1168 were assigned to the control group. The overall effect of IU hCG instillation on LBR and OPR was not significant: risk ratio (RR) 1.00 (95% CI, 0.90-1.12). Analysis of secondary outcomes found the effect of IU hCG instillation was not significant. Analysis of the data suggests that the studies conducted have too much heterogeneity to identify whether a specific cohort may have a significant benefit. The findings of this meta-analysis demonstrate that there is insufficient evidence at present to support the use of IU hCG instillation prior to blastocyst-stage ET.

Systematic review and meta-analysis: does pre-implantation genetic testing for aneuploidy at the blastocyst stage improve live birth rate?

PURPOSE: To establish if preimplantation genetic testing for aneuploidy (PGT-A) at the blastocyst stage improves the composite outcome of live birth rate and ongoing pregnancy rate per embryo transfer compared to conventional morphological assessment. METHODS: A systematic literature search was conducted using PubMed, EMBASE and Cochrane database from 1st March 2000 until 1st March 2022. Studies comparing reproductive outcomes following in vitro fertilisation using comprehensive chromosome screening (CCS) at the blastocyst stage with traditional morphological methods were evaluated. RESULTS: Of the 1307 citations identified, six randomised control trials (RCTs) and ten cohort studies fulfilled the inclusion criteria. The pooled data identified a benefit between PGT-A and control groups in the composite outcome of live birth rate and ongoing pregnancy per embryo transfer in both the RCT (RR 1.09, 95% CI 1.02-1.16) and cohort studies (RR 1.50, 95% CI 1.28-1.76). Euploid embryos identified by CCS were more likely to be successfully implanted amongst the RCT (RR 1.20, 95% CI 1.10-1.31) and cohort (RR 1.69, 95% CI 1.29-2.21) studies. The rate of miscarriage per clinical pregnancy is also significantly lower when CCS is implemented (RCT: RR 0.73, 95% CI 0.56-0.96 and cohort: RR 0.48, 95% CI 0.32-0.72). CONCLUSIONS: CCS-based PGT-A at the blastocyst biopsy stage increases the composite outcome of live births and ongoing pregnancies per embryo transfer and reduces the rate of miscarriage compared to morphological assessment alone. In view of the limited number of studies included and the variation in methodology between studies, future reviews and analyses are required to confirm these findings.

Live birth rate following a euploid blastocyst transfer is not affected by double vitrification and warming at cleavage or blastocyst stage.

PURPOSE: To compare reproductive outcomes following a euploid embryo transfer, between those embryos vitrified-warmed twice to those vitrified-warmed once. METHODS: We retrospectively analysed 694 single euploid frozen embryo transfer cycles following preimplantation genetic testing for aneuploidy (PGT-A). For cycles in group 1 (N = 451), embryos were biopsied for PGT-A at blastocyst stage and vitrified. For cycles in group 2 (N = 146), embryos were vitrified at blastocyst stage, before being warmed and biopsied for PGT-A and vitrified again. For cycles in group 3 (N = 97), embryos were vitrified on day-3, before being warmed, cultured to day-5 and biopsied for PGT-A and re-vitrified. RESULTS: The pregnancy, clinical pregnancy and livebirth rate in group 2 were not statistically different to group 1 (pregnancy rate, adjusted OR 1.09, 95% CI 0.62-1.91; clinical pregnancy, aOR 0.89, 95% CI 0.58-1.37; live birth rate, aOR 0.85, 95% CI 0.56-1.28). There was also no significant difference between group 3 and group 1, with similar pregnancy rate (aOR 1.22, 95% CI 0.74-1.99), clinical pregnancy rate (aOR 1.21, 95% CI 0.75-1.96) and live birth rate (aOR 1.15, 95% CI, 0.73-1.80). There was no significant difference in miscarriage rates between all three groups. The age at the oocyte collection, embryo quality and day of biopsy were associated with pregnancy, clinical pregnancy and live birth rate. CONCLUSION: This study suggests that vitrifying and warming embryos twice at blastocyst or at cleavage and then blastocyst stage, can lead to similar reproductive outcomes to embryos vitrified-warmed once, after a single euploid embryo transfer.

Adding a low-quality blastocyst to a high-quality blastocyst for a double embryo transfer does not decrease pregnancy and live birth rate.

INTRODUCTION: The effect of embryo quality on clinical outcomes of assisted reproductive technology following a double transfer is not well defined, with some studies suggesting that a low-quality embryo transferred with a high-quality embryo decreases the live birth rate (LBR), compared with transferring a single high-quality embryo. Our study examined whether the quality of a second blastocyst transferred affects the outcome, controlling for the number of the available high-quality blastocysts (HQB). MATERIAL AND METHODS: A historical cohort study of 2346 fresh blastocyst transfers in a single fertility clinic between 2013 and 2019. The main outcomes were pregnancy, miscarriage, live birth, and multiple gestation rates. Outcomes were compared between single embryo transfers with a high-quality blastocyst (SET-H), double embryo transfers with two HQBs (DET-HH), and transfers with one high-quality and one low-quality blastocyst (DET-HL). Outcomes were also assessed between SET and DET when only low-quality blastocysts were available. RESULTS: With one HQB available, DET-HL increased LBR (adjusted odds ratio [OR] 1.65, 95% CI 1.09-2.49) compared with SET-H, but increased multiple gestation rate (aOR 23.1, 95% CI 3.0-177.6). With two HQBs available, DET-HH was associated with a higher LBR (aOR 1.62, 95% CI 1.28-2.04) and lower miscarriage rate (aOR 0.56, 95% CI 0.40-0.80), but very high twin rate (aOR 49.8, 95% CI 24.3-102.1) compared with SET-H. A SET-H with at least one or more HQB available to freeze, compared with a SET-H with no other HQB available, had a higher LBR (aOR 1.69, 95% CI 1.17-2.45). When there were no HQBs available, compared with SET-L, a DET-LL had a higher live birth (aOR 3.20, 95% CI 1.78-7.703) and twin rate (aOR 3.72 × 1010 ) and a lower miscarriage rate (aOR 0.24, 95% CI 0.10-0.58). CONCLUSIONS: When there is one HQB available, transferring an additional low-quality blastocyst would only slightly increase the LBR, but significantly increase the twin rate, therefore SET should be recommended. When two or more HQBs are available, SET-H would have a reasonably good chance of success without the very high twin rate associated with DET-HH. DET-LL when compared with SET-L, would increase the LBR, but increase the risk of multiple gestation.

The Association Between Elevated Progesterone Level on Day of hCG Trigger and Live Birth Rates in ART Cycles: A Single Centre Observational Study.

BACKGROUND: The advent of ovarian stimulation within an in vitro fertilization (IVF) cycle has resulted in modifying the physiology of stimulated cycles and has helped optimize pregnancy outcomes. In this regard, the importance of progesterone (P4) elevation at time of human chorionic gonadotrophin (hCG) administration within an IVF cycle has been studied over several decades. Our study aimed to evaluate the association of P4 levels at time of hCG trigger with live birth rate (LBR), clinical pregnancy rate (CPR) and miscarriage rate (MR) in fresh IVF or IVF-ICSI cycles. METHODS: This was a retrospective cohort study (n=170) involving patients attending the Centre for Reproductive and Genetic Health (CRGH) in London. The study cohort consisted of women undergoing controlled ovarian stimulation using GnRH antagonist or GnRH agonist protocols. Univariate and multiple logistic regression analyses were used to evaluate the association of clinical outcomes. Differences were considered statistically significant if p≤0.05. RESULTS: As serum progesterone increased, a decrease in LBR was observed. Following multivariate logistical analyses, LBR significantly decreased with P4 thresholds of 4.0 ng/ml (OR 0.42, 95% CI:0.17-1.0) and 4.5 ng/ml (OR 0.35, 95% CI:0.12-0.96). CONCLUSION: P4 levels are important in specific groups and the findings were statistically significant with a P4 threshold value between 4.0-4.5 ng/ml. Therefore, it seems logical to selectively measure serum P4 levels for patients who have ovarian dysfunction or an ovulatory cycles and accordingly prepare the individualized management packages for such patients.

Live birth and miscarriage rate following intracytoplasmic morphologically selected sperm injection vs intracytoplasmic sperm injection: An updated systematic review and meta-analysis.

INTRODUCTION: Intracytoplasmic morphologically selected sperm injection (IMSI) is one of the sperm selection techniques used for assisted reproduction which has been applied for a variety of indications including previously failed fertilization with intracytoplasmic sperm injection (ICSI). A Cochrane review1 found no difference in outcomes between either modality of sperm selection. Since the Cochrane review was published there have been a further two randomized controlled trials comparing IMSI and ICSI. This systematic review and meta-analysis aims to compare IMSI with ICSI as insemination methods regarding live birth rate and miscarriage rate. MATERIAL AND METHODS: Systematic review of randomized controlled trials, observational studies and similar reviews in electronic databases published before January 2018. RESULTS: We found nine randomized controlled trials, evaluating 1610 cycles of in vitro fertilization and 15 observational studies evaluating 1243 cycles of in vitro fertilization. Meta-analysis of the included randomized controlled trials showed no difference in the live birth rate or miscarriage rate between the ICSI and IMSI groups. Meta-analysis of five observational studies showed a significantly higher number of live births in the IMSI group than ICSI group (live birth rate odds ratio 1.47, 95% confidence interval 1.16-4.07), with a moderate degree of heterogeneity (I2  = 41%). Additionally, from six observational studies, a significantly lower miscarriage rate was observed in the IMSI group than in the ICSI group (odds ratio 0.51, 95% confidence interval 0.37-0.70, I2  = 0%). CONCLUSIONS: Meta-analysis of randomized studies comparing IMSI to ICSI has not shown any difference in live birth rate and miscarriage rate. Meta-analysis of observational studies, which must be interpreted with caution, revealed an increased live birth rate and decreased miscarriage rate with IMSI vs ICSI.

Live birth after blastocyst transfer following only 2 days of progesterone administration in an agonadal oocyte recipient.

In oocyte donation cycles where hormone replacement is given to recipients, progesterone administration is necessary to induce the luteal phase and synchronize the endometrium with the embryo stage. Most studies suggest that 5-7 days of progesterone are needed to prepare the endometrium for a day-5 embryo transfer and provide optimal implantation rate. This paper reports a case where an agonadal oocyte recipient received only 2 days of progesterone prior to the embryo transfer of a day-5 embryo. She subsequently had a clinical pregnancy and a live birth.