Application of seminal plasma to female genital tract prior to embryo transfer in assisted reproductive technology cycles (IVF, ICSI and frozen embryo transfer).

Ata B ，Abou-Setta AM ，Seyhan A ，Buckett W ... -  《Cochrane Database of Systematic Reviews》

Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction.

Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. The injection of embryo culture supernatant in the endometrial cavity can be undertaken at various time intervals before embryo transfer. It provides an altered endometrial environment through the secretion of factors considered to facilitate implantation. It is proposed that injection of the supernatant into the endometrial cavity prior to embryo transfer will stimulate the endometrium and provide better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking. To evaluate the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART. Our search strategies were designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist. We sought to identify all published and unpublished randomised controlled trials (RCTs) meeting inclusion criteria. Searches were performed on 2 December 2019. We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, CINAHL, trials registries and grey literature. We made further searches in the UK National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with searches of PubMed and Google for any recent trials that have not yet been indexed in the major databases. We had no language or location restrictions. We included RCTs testing the use of endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle, compared with the non-use of this intervention, the use of placebo or the use of any other similar drug. Two review authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We pooled studies using a fixed-effect model. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods. We found five RCTs suitable for inclusion in the review (526 women analysed). We made two comparisons: embryo culture supernatant use versus standard care or no intervention; and embryo culture supernatant use versus culture medium. All studies were published as full-text articles. Data derived from the reports or through direct communication with investigators were available for the final meta-analysis performed. The GRADE evidence quality of studies ranged from very low-quality to moderate-quality. Factors reducing evidence quality included high risk of bias due to lack of blinding, unclear risk of publication bias and selective outcome reporting, serious inconsistency among study outcomes, and serious imprecision due to wide confidence intervals (CIs) and low numbers of events. Comparison 1. Endometrial injection of embryo culture supernatant before embryo transfer versus standard care or no intervention: One study reported live birth only and two reported the composite outcome live birth and ongoing pregnancy. We are uncertain whether endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle improves live birth/ongoing pregnancy rates compared to no intervention (odds ratio (OR) 1.11, 95% CI 0.73 to 1.70; 3 RCTs; n = 340, I2 = 84%; very low-quality evidence). Results suggest that if the chance of live birth/ongoing pregnancy following placebo or no treatment is assumed to be 42%, the chance following the endometrial injection of embryo culture supernatant before embryo transfer would vary between 22% and 81%. We are also uncertain whether the endometrial injection of embryo culture supernatant could decrease miscarriage rates, compared to no intervention (OR 0.89, 95% CI 0.44 to 1.78, 4 RCTs, n = 430, I2 = 58%, very low-quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 9%, the chance following injection of embryo culture supernatant would vary between 3% and 30%. Concerning the secondary outcomes, we are uncertain whether the injection of embryo culture supernatant prior to embryo transfer could increase clinical pregnancy rates (OR 1.13, 95% CI 0.80 to 1.61; 5 RCTs; n = 526, I2 = 0%; very low-quality evidence), decrease ectopic pregnancy rates (OR 0.32, 95% CI 0.01 to 8.24; n = 250; 2 RCTs; I2 = 41%; very low-quality evidence), decrease multiple pregnancy rates (OR 0.70, 95% CI 0.26 to 1.83; 2 RCTs; n = 150; I2 = 63%; very low-quality evidence), or decrease preterm delivery rates (OR 0.63, 95% CI 0.17 to 2.42; 1 RCT; n = 90; I2 = 0%; very low-quality evidence), compared to no intervention. Finally, there may have been little or no difference in foetal abnormality rates between the two groups (OR 3.10, 95% CI 0.12 to 79.23; 1 RCT; n = 60; I2 = 0%; low-quality evidence). Comparison 2. Endometrial injection of embryo culture supernatant versus endometrial injection of culture medium before embryo transfer We are uncertain whether the use of embryo culture supernatant improves clinical pregnancy rates, compared to the use of culture medium (OR 1.09, 95% CI 0.48 to 2.46; n = 96; 1 RCT; very low-quality evidence). No study reported live birth/ongoing pregnancy, miscarriage, ectopic or multiple pregnancy, preterm delivery or foetal abnormalities. We are uncertain whether the addition of endometrial injection of embryo culture supernatant before embryo transfer as a routine method for the treatment of women undergoing ART can improve pregnancy outcomes. This conclusion is based on current available data from five RCTs, with evidence quality ranging from very low to moderate across studies. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of endometrial injection of embryo culture supernatant before embryo transfer.

Siristatidis CS ，Sertedaki E ，Karageorgiou V ，Vaidakis D ... -  《Cochrane Database of Systematic Reviews》

Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection.

Brown J ，Daya S ，Matson P 《Cochrane Database of Systematic Reviews》

Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection.

Transfer of more than one embryo during in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) increases multiple pregnancy rates resulting in an increased risk of maternal and perinatal morbidity. Elective single embryo transfer offers a means of minimising this risk, but this potential gain needs to be balanced against the possibility of jeopardising the overall live birth rate (LBR). To evaluate the effectiveness and safety of different policies for the number of embryos transferred in infertile couples undergoing assisted reproductive technology cycles. We searched the Cochrane Gynaecology and Fertility Group specialised register of controlled trials, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform from inception to March 2020. We handsearched reference lists of articles and relevant conference proceedings. We also communicated with experts in the field regarding any additional studies. We included randomised controlled trials (RCTs) comparing different policies for the number of embryos transferred following IVF or ICSI in infertile women. Studies of fresh or frozen and thawed transfer of one to four embryos at cleavage or blastocyst stage were eligible. Two review authors independently extracted data and assessed trial eligibility and risk of bias. The primary outcomes were LBR and multiple pregnancy rate. The secondary outcomes were clinical pregnancy and miscarriage rates. We analysed data using risk ratios (RR), Peto odds ratio (Peto OR) and a fixed effect model. We included 17 RCTs in the review (2505 women). The main limitation was inadequate reporting of study methods and moderate to high risk of performance bias due to lack of blinding. A majority of the studies had low numbers of participants. None of the trials compared repeated single embryo transfer (SET) with multiple embryo transfer. Reported results of multiple embryo transfer below refer to double embryo transfer. Repeated single embryo transfer versus multiple embryo transfer in a single cycle Repeated SET was compared with double embryo transfer (DET) in four studies of cleavage-stage transfer. In these studies the SET group received either two cycles of fresh SET (one study) or one cycle of fresh SET followed by one frozen SET (three studies). The cumulative live birth rate after repeated SET may be little or no different from the rate after one cycle of DET (RR 0.95, 95% CI (confidence interval) 0.82 to 1.10; I² = 0%; 4 studies, 985 participants; low-quality evidence). This suggests that for a woman with a 42% chance of live birth following a single cycle of DET, the repeated SET would yield pregnancy rates between 34% and 46%. The multiple pregnancy rate associated with repeated SET is probably reduced compared to a single cycle of DET (Peto OR 0.13, 95% CI 0.08 to 0.21; I² = 0%; 4 studies, 985 participants; moderate-quality evidence). This suggests that for a woman with a 13% risk of multiple pregnancy following a single cycle of DET, the risk following repeated SET would be between 0% and 3%. The clinical pregnancy rate (RR 0.99, 95% CI 0.87 to 1.12; I² = 47%; 3 studies, 943 participants; low-quality evidence) after repeated SET may be little or no different from the rate after one cycle of DET. There may be little or no difference in the miscarriage rate between the two groups. Single versus multiple embryo transfer in a single cycle A single cycle of SET was compared with a single cycle of DET in 13 studies, 11 comparing cleavage-stage transfers and three comparing blastocyst-stage transfers.One study reported both cleavage and blastocyst stage transfers. Low-quality evidence suggests that the live birth rate per woman may be reduced in women who have SET in comparison with those who have DET (RR 0.67, 95% CI 0.59 to 0.75; I² = 0%; 12 studies, 1904 participants; low-quality evidence). Thus, for a woman with a 46% chance of live birth following a single cycle of DET, the chance following a single cycle of SET would be between 27% and 35%. The multiple pregnancy rate per woman is probably lower in those who have SET than those who have DET (Peto OR 0.16, 95% CI 0.12 to 0.22; I² = 0%; 13 studies, 1952 participants; moderate-quality evidence). This suggests that for a woman with a 15% risk of multiple pregnancy following a single cycle of DET, the risk following a single cycle of SET would be between 2% and 4%. Low-quality evidence suggests that the clinical pregnancy rate may be lower in women who have SET than in those who have DET (RR 0.70, 95% CI 0.64 to 0.77; I² = 0%; 10 studies, 1860 participants; low-quality evidence). There may be little or no difference in the miscarriage rate between the two groups. Although DET achieves higher live birth and clinical pregnancy rates per fresh cycle, the evidence suggests that the difference in effectiveness may be substantially offset when elective SET is followed by a further transfer of a single embryo in fresh or frozen cycle, while simultaneously reducing multiple pregnancies, at least among women with a good prognosis. The quality of evidence was low to moderate primarily due to inadequate reporting of study methods and absence of masking those delivering, as well as receiving the interventions.

Kamath MS ，Mascarenhas M ，Kirubakaran R ，Bhattacharya S ... -  《Cochrane Database of Systematic Reviews》

Granulocyte-colony stimulating factor administration for subfertile women undergoing assisted reproduction.

Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART). To evaluate the effectiveness and safety of G-CSF in women undergoing ART. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings. Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment. Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria. We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.

Kamath MS ，Kirubakaran R ，Sunkara SK 《Cochrane Database of Systematic Reviews》