The effect of hyaluronic acid in embryo transfer media in donor oocyte cycles and autologous oocyte cycles: a systematic review and meta-analysis
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Abstract STUDY QUESTION Does the addition of hyaluronic acid (HA) to embryo transfer medium improve pregnancy outcomes in both autologous and oocyte donation IVF cycles? SUMMARY ANSWER The best available evidence indicates that the addition of HA to embryo transfer medium is clinically beneficial in cycles with autologous oocytes. WHAT IS KNOWN ALREADY There is a known clinical benefit of HA addition to embryo transfer media but it is not known if HA affects donor and autologous oocyte cycles differently. STUDY DESIGN, SIZE, DURATION A systematic review with meta-analysis was performed. The Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL via Cochrane Register of Studies Online (CRSO), MEDLINE, Embase and PsycINFO electronic databases (until 8 January 2020) were searched for randomized controlled trials (RCTs) examining the effect of HA in embryo transfer medium on pregnancy outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS RCTs with separate donor and autologous oocyte data that compared embryo transfer medium with functional HA concentrations (0.5 mg/ml) to those containing no or low HA concentrations (0.125 mg/ml) were included. Two review authors independently selected trials for inclusion, extracted data and assessed the included studies using the Cochrane risk of bias assessment tool. Pooled risk ratios and 95% CIs were calculated. A summary of findings table was generated using Grading of Recommendations, Assessment, Development and Evaluation criteria. Judgements about evidence quality were justified and incorporated into the reported results for each outcome. MAIN RESULTS AND THE ROLE OF CHANCE Fifteen studies, totalling 4686 participants, were analysed. In autologous oocyte cycles, live birth increased from 32% to 39% when embryo transfer media contained functional HA concentrations (risk ratio (RR) 1.22, 95% CI 1.11–1.34; nine studies, 3215 participants, I2 = 39%, moderate-quality evidence (number needed to treat (NNT) 14). HA-enriched media increased clinical pregnancy and multiple pregnancy rates by 5% and 8%, respectively (RR 1.11, 95% CI 1.04–1.18; 13 studies, 4014 participants, I2 = 0%, moderate-quality evidence, NNT 21) and (RR 1.49, 95% CI 1.27–1.76; 5 studies, 2400 participants, I2 = 21%, moderate-quality evidence, number needed to harm 13). Conversely, in donor oocyte cycles, HA addition showed little effect on live birth and clinical pregnancy (RR 1.12 95% CI 0.86–1.44; two studies, 317 participants, I2 = 50%, low-quality evidence) and (RR 1.06, 95% CI 0.97–1.28; three studies, 351 participants, I2 = 23%, low-quality evidence). There was insufficient available information on multiple pregnancy in donor oocyte cycles and on total adverse effects in both groups to draw conclusions. LIMITATIONS, REASONS FOR CAUTION There were limited studies with separate data on donor oocyte cycles and limited information on oocyte quality. Additionally, one-third of the included studies did not include the main outcome, live birth rate. WIDER IMPLICATIONS OF THE FINDINGS There is a moderate level of evidence to suggest that functional HA concentration in embryo transfer medium increases clinical pregnancy, live birth and multiple pregnancy rates in IVF cycles using autologous oocytes. This effect was not seen in donor oocyte cycles, indicating either intrinsic differences between donor and autologous oocytes or lack of statistical power. The combination of HA addition to transfer media in cycles using autologous oocytes and a single embryo transfer policy might yield the best combination, with higher clinical pregnancy and live birth rates without increasing the chance of multiple pregnancies. STUDY FUNDING/COMPETING INTEREST(S) No financial assistance was received. The authors have no competing interests. REGISTRATION NUMBER N/A.Keywords:
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Single Embryo Transfer
To investigate whether the day of embryo transfer (day 2 or day 3) affects clinical pregnancy outcomes in poor responder patients.We retrospectively analyzed the pregnancy rates of 265 initial fresh cycles of in vitro fertilization-embryo transfer (IVF-ET), all transferred on day 2 (n = 169) or day 3 (n = 96) irrespective of quality because of an extremely low number of available embryos.Among the poor responders aged < 35 years, a higher rate of clinical pregnancy was achieved in the day-3 than in the day-2 group (50% vs 32.43% ; RR = 0.65, 95% CI: 0.43 - 0.99), and among those aged years, the two groups showed similar pregnancy outcomes.Shortening the time of embryo culture has no obvious benefit for the pregnancy outcome. For the poor responders under 35 years of age, day-3 embryo transfer may afford an even higher rate of clinical pregnancy.
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Ovarian hyperstimulation syndrome
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Single Embryo Transfer
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Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection
The traditional reliance on the transfer of multiple embryos during in vitro fertilisation (IVF) in order to maximise the chance of pregnancy, has resulted in increasing rates of multiple pregnancies. Women undergoing IVF had a 20 - fold increased risk of twins and 400 - fold increased risk of higher order pregnancies (Martin 1998). The maternal and perinatal morbidity and mortality as well as national health service costs associated with multiple pregnancies is significantly high in comparison with singleton births (Luke 1992; Callahan 1994; Goldfarb 1996). Single embryo transfer is now being considered as an effective means of reducing this iatrogenic complication. This systematic review evaluates the effectiveness of elective two embryo transfer in comparison with single and more than two embryo transfer following IVF and ICSI (intra cytoplasmic sperm injection) treatment.The aim of this review is to determine, whether in couples who undergo IVF/ICSI: (1) the elective transfer of two embryos improves the probability of livebirth compared with: (a) Single embryo transfer, (b) Three embryo transfer or (c) Four embryo transfer.(2) the elective transfer of three embryos improves the probability of livebirth compared with: (a) Single embryo transfer, or (b) Four embryo transfer,We searched the Cochrane Menstrual Disorders and Subfertility Group's trials register (searched June 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 4, 2003), MEDLINE (1970 to 2003), EMBASE (1985 to 2003) and reference lists of articles. We also handsearched relevant conference proceedings and contacted researchers in the field.Only randomised controlled trials were included.Two reviewers independently assessed eligibility and quality of trials.We found no studies that compared a policy of transferring multiple embryos on one cycle versus a policy of cryo- preservation and transfer of a single embryo over multiple cycles. We also found no trials comparing transfer of two versus three embryos. Three small, poorly reported trials compared transfer of two versus one embryo in a single cycle, and one small, poorly reported trial compared transfer of two versus four embryos in a single cycle. The clinical pregnancy rate per woman/couple associated with two embryo transfer was significantly higher compared to single embryo transfer (OR 2.08, 95% CI 1.24 to 3.50; test for overall effect p = 0.006). The live birth rate per woman/couple associated with two embryo transfer was also significantly higher than that associated with single embryo transfer (OR 1.90, 95% CI 1.12 to 3.22, test for overall effect p=0.02). The multiple pregnancy rate was significantly lower in women who had single embryo transfer (OR 9.97, 95% CI 2.61 to 38.19; p = 0.0008). The effectiveness of double embryo transfer versus four embryo transfer was tested in a single trial. There was no statistically significant differences in the clinical pregnancy rate (OR 0.75, 95% CI 0.26 to 2.16; p=0.6), and multiple pregnancy rates (OR 0.44. 95% CI 0.10 to 1.97; p = 0.28) between the two groups. The livebirth rate in the four embryo transfer group was higher compared to the two embryo transfer group, but the results were not statistically significant (OR 0.35, 95% CI 0.11 to 1.05; p = 0.06).The results of this systematic review suggest that live birth and pregnancy rates following single embryo transfer are lower than those following double embryo transfer as are the chances of multiple pregnancy including twins. As such, it is unlikely that the conclusions are robust enough to catalyse a change in clinical practice. The studies included are limited by their small sample size, so that even large differences might be hidden. Cumulative livebirth rates are seldom reported. The data were inadequate to draw conclusions about single embryo transfer and first frozen single embryo transfer (1FZET) or subsequent single frozen embryo transfers. Until more evidence is available single embryo transfer may not be the preferred choice for all patients undergoing IVF/ICSI. Clinicians may need to individualise protocols for couples based on their risks of multiple pregnancy. A definitive pragmatic, large multi centre randomised controlled trial comparing single embryo versus double embryo transfer in terms of clinical and cost effectiveness as well as acceptability is required. The primary outcome measured should be cumulative livebirth per woman/couple.
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Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection
Background Multiple embryo transfer during IVF has increased multiple pregnancy rates (MPR) causing maternal and perinatal morbidity. Elective single embryo transfer (SET) is now being considered as an effective means of reducing this iatrogenic complication. Objectives To determine in couples undergoing IVF/ICSI (intra‐cytoplasmic sperm injection) whether: (1) elective transfer of two embryos improves the probability of livebirth compared with: (a) elective single embryo transfer, (b) three embryo transfer (TET) or (c) four embryo transfer (FET). (2) elective transfer of three embryos improves the probability of livebirth compared with: (a) elective single embryo transfer, or (b) elective four embryo transfer. Search methods We searched the Cochrane Menstrual Disorders and Subfertility Group's trials register (searched March 2008), the Cochrane Central Register of Controlled Trials (Cochrane Library, Issue 1, 2008), MEDLINE (1970 to 2008), EMBASE (1985 to 2008) and reference lists of articles. Relevant conference proceedings were hand‐searched and researchers in the field contacted. Selection criteria Randomised controlled trials were included. Data collection and analysis Two reviewers independently assessed eligibility and quality of trials. Main results For the update in 2008 five trials compared DET with SET. DET versus TET and DET versus FET were evaluated in a single small trial each. The difference in cumulative livebirth rates (CLBR) after DET and those after SET followed by transfer of a single frozen thawed embryo (1FZET) was not statistically significant (OR 0.81, 95% CI 0.59 to 1.11; p=0.18). There was no statistically significant difference in CLBR after a single fresh cycle of DET versus two fresh cycles of SET (OR 1.23, 95% CI 0.56 to 2.69, p= 0.60 ). The live birth rate (LBR) per woman in a single fresh treatment was higher following DET than SET (OR 2.10, 95% CI 1.65 to 2.66, p<0.00001). The MPR was lower following SET (OR 0.04, 95% CI 0.01 to 0.11; p< 0.00001). The CLBR following two fresh cycles of DET versus two fresh cycles of TET (OR 0.77, 95%CI 0.22 to 2.65, p=0.67) and CLBR after three fresh cycles of DET versus three fresh cycles of TET showed no statistically significant differences (OR 0.77, 95% CI 0.24 to 2.52; p=0.67). There were no statistically significant differences between DET and TET in terms of LBR (OR 0.40, 95%CI 0.09 to 1.85; p=0.24) and MPR (OR 0.17, 95%CI 0.01 to 3.85; p= 0.27). DET led to lower LBR than FET but the difference was not statistically significant (OR 0.35, 95% CI 0.11 to 1.05; p = 0.06). Authors' conclusions In a single fresh IVF cycle, SET is associated with a lower LBR than DET. However there is no significant difference in CLBR following SET+ 1FZET and the LBR following a single cycle of DET. MPR are lowered following SET compared with other transfer policies. There are insufficient data on the outcome of two versus three and four embryo transfer policies.
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Single Embryo Transfer
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Abstract Study question Does the selection of blastocysts for single embryo transfer, through the diagnosis of aneuploidy, improves the live birth rate in patients undergoing in vitro fertilization? Summary answer There seems to be no statistical difference in live birth rates between embryos with preimplantational genetic diagnosis (PGD) and those without. What is known already: Initial reports indicate that reproductive results improve after the selection of embryos to be transfer after performing a biopsy of the blastomeres, or trophectoderm cells, with the subsequent comprehensive analysis of the chromosomes. However, these results are now questioned. Reports in the literature are contrasting, so the real utility of selecting all embryos through comprehensive chromosome analysis calls for a more careful analysis that compares the risks, costs, and benefits of these techniques and their actual utility in reproductive results of patients treated with in vitro fertilization. Specifically results related to live birth rate. Study design, size, duration A systematic review of prospective studies evaluating live birth rate after embryo transfer of embryos selected by blastocyst biopsy for aneuploidy analysis compared with reproductive outcomes in embryo transfers of embryos selected morphologically, without biopsy nor screening for aneuploidies. Participants/materials, setting, methods A literature search was performed in PubMed, EmBase, and the Cochrane library (from January 2000 to december 2019). A cumulative meta-analysis and evaluation of heterogeneity was performed for the clinical pregnancy rate. The quality of the included studies was assessed using Cochrane’s Risk of Bias tool and ROBINS I for observational studies Main results and the role of chance Seven studies were included, three were randomized controlled trials and four were non-randomized studies of intervention (NRSI). The included studies were published between 2013 and 2019. For the preimplantational genetic diagnosis, three studies used array comparative genomic hybridization, three studies used next generation sequencing and only one study used qPCR. A total of 1638 patients were included, only two studies excluded patients with advanced maternal age (>35 years), two studies studied patients with recurrent implantation failure and three studies patients with recurrent pregnancy loss. Regarding the assisted reproduction techniques (ART), only studies where embryos where biopsied after day five for the genetic diagnosis where considered, most used ICSI and performed frozen-thawed transfer of up to two embryos, only one study allowed patients to be transferred with more than two embryos per cycle. Reproductive outcomes (live birth rate, miscarriage rate, clinical pregnancy) were extracted considering the events per embryo transfer and calculating the pooled odds ratios (OR) with 95% confidence intervals (95%CI) as our main outcome, sensitivity analyses will be performed using the events per cycles to assess the robustness of the effect estimate. Preliminary meta-analyses resulted in a pooled OR of 1.45 (95%CI 0.24–8.78) for NRSI and 1.34 (95%CI 0.85–2.11) for RCT. Limitations, reasons for caution The main limitation was the quantity of studies with acceptable methodology. This generated heterogeneity, hindering the evaluation of the true impact of PGD in ART outcomes. The use of events per embryo transfer as a main outcome could bias the results favoring PGD as less embryos are usually transferred. Wider implications of the findings: Our results show that there are too few studies with adequate methodology to generate a conclusion about the true benefit of PGD. However, a slight tendency favoring the reproductive outcomes of PGD was found. Trial registration number PROSPERO CRD42020198866
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Blastocyst Transfer
Single Embryo Transfer
Live birth
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Embryo cryopreservation
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Introduction: This study investigated the differences in clinical pregnancy rate (CPR), live birth rate (LBR) and multiple pregnancy rate (MPR) between double cleavage-stage embryo transfers compared to single and double blastocysts stage embryo transfers in a single academic medical centre. Materials and Methods: This was a retrospective cohort study performed at the KK Women’s and Children’s Hospital In Vitro Fertilisation (KKIVF) Centre of all women who underwent fresh-cycle in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles over a 5-year period. The outcome measures were CPR, LBR and MPR. The study included 5294 cycles, of which 539 patients underwent single embryo transfer (SET); 4533 patients underwent double embryo transfer (DET); 84 patients underwent double blastocyst transfer (DBT); and 65 patients underwent single blastocyst transfer (SBT). Results: The mean age of patients undergoing single blastocysts stage embryo transfer was lower than the other 2 groups. The DET, single and double blastocysts stage embryo transfer groups achieved similar LBR (33.9%, 38.7%, 35.4%, P >0.05) and CPR (42.4%, 46.2%, 46.9%). Conclusion: We found that single blastocysts stage embryo transfer is associated with similar LBR and CPR compared to double blastocysts stage embryo transfer and DET, with lower MPRs, and should be offered as standard practice, where possible. Key words: Infertility, Pregnancy outcomes
Blastocyst Transfer
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