Endometrial injury in women undergoing in vitro fertilisation (IVF).
Implantation of an embryo within the endometrial cavity is a critical step in the process of in vitro fertilisation (IVF). Previous research has suggested that endometrial injury (also known as endometrial scratching), defined as intentional damage to the endometrium, can increase the chance of pregnancy in women undergoing IVF.
To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing in vitro fertilisation (IVF) including intracytoplasmic sperm injection (ICSI) and frozen embryo transfer.
In June 2020 we searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, LILACS, DARE and two trial registries. We also checked the reference sections of relevant studies and contacted experts in the field for any additional trials.
Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing IVF, versus no intervention or a sham procedure.
We used standard methodological procedures recommended by Cochrane. Two independent review authors screened studies, evaluated risk of bias and assessed the certainty of the evidence by using GRADE (Grading of Recommendation, Assessment, Development and Evaluation) criteria. We contacted and corresponded with study investigators as required. Due to the high risk of bias associated with many of the studies, the primary analyses of all review outcomes were restricted to studies at a low risk of bias for selection bias and other bias. Sensitivity analysis was then performed including all studies. The primary review outcomes were live birth and miscarriage.
Endometrial injury versus control (no procedure or a sham procedure) A total of 37 studies (8786 women) were included in this comparison. Most studies performed endometrial injury by pipelle biopsy in the luteal phase of the cycle before the IVF cycle. The primary analysis was restricted to studies at low risk of bias, and included eight studies. The effect of endometrial injury on live birth is unclear as the result is consistent with no effect, or a small reduction, or an improvement (odds ratio (OR) 1.12, 95% confidence interval (CI) 0.98 to 1.28; participants = 4402; studies = 8; I2 = 15%, moderate-certainty evidence). This suggests that if the chance of live birth with IVF is usually 27%, then the chance when using endometrial injury would be somewhere between < 27% and 32%. Similarly, the effect of endometrial injury on clinical pregnancy is unclear (OR 1.08, 95% CI 0.95 to 1.23; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence). This suggests that if the chance of clinical pregnancy from IVF is normally 32%, then the chance when using endometrial injury before IVF is between 31% and 37%. When all studies were included in the sensitivity analysis, we were unable to conduct meta-analysis for the outcomes of live birth and clinical pregnancy due to high risk of bias and statistical heterogeneity. Endometrial injury probably results in little to no difference in chance of miscarriage (OR 0.88, 95% CI 0.68 to 1.13; participants = 4402; studies = 8; I2 = 0%, moderate-certainty evidence), and this result was similar in the sensitivity analysis that included all studies. The result suggests that if the chance of miscarriage with IVF is usually 6.0%, then when using endometrial injury it would be somewhere between 4.2% and 6.8%. Endometrial injury was associated with mild to moderate pain (approximately 4 out of 10), and was generally associated with some minimal bleeding. The evidence was downgraded for imprecision due to wide confidence intervals and therefore all primary analyses were graded as moderate certainty. Higher versus lower degree of injury Only one small study was included in this comparison (participants = 129), which compared endometrial injury using two different instruments in the cycle prior to the IVF cycle: a pipelle catheter and a Shepard catheter. This trial was excluded from the primary analysis due to risk of bias. In the sensitivity analysis, all outcomes reported for this study were graded as very-low certainty due to risk of bias, and as such we were not able to interpret the study results.
The effect of endometrial injury on live birth and clinical pregnancy among women undergoing IVF is unclear. The results of the meta-analyses are consistent with an increased chance, no effect and a small reduction in these outcomes. We are therefore uncertain whether endometrial injury improves the chance of live birth or clinical pregnancy in women undergoing IVF. Endometrial injury does not appear to affect the chance of miscarriage. It is a somewhat painful procedure associated with a small amount of bleeding. In conclusion, current evidence does not support the routine use of endometrial injury for women undergoing IVF.
Lensen SF
，Armstrong S
，Gibreel A
，Nastri CO
，Raine-Fenning N
，Martins WP
... -
《Cochrane Database of Systematic Reviews》
Endometrial injury for pregnancy following sexual intercourse or intrauterine insemination.
Intentional endometrial injury is being proposed as a technique to improve the probability of pregnancy in women undergoing assisted reproductive technologies (ART) such as in vitro fertilisation (IVF). Endometrial injury is often performed by pipelle biopsy and is a common gynaecological procedure with established safety. However, it causes a moderate degree of discomfort/pain and requires an additional pelvic examination. The effectiveness of this procedure outside of ART, in women or couples attempting to conceive via sexual intercourse or with intrauterine insemination (IUI), remains unclear.
To assess the effectiveness and safety of intentional endometrial injury performed in infertile women or couples attempting to conceive through sexual intercourse or intrauterine insemination (IUI).
The Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, ISI Web of Knowledge, and clinical trial registries were searched from inception to 21 May 2020, as were conference abstracts and reference lists of relevant reviews and included studies.
We included randomised controlled trials (RCTs) that evaluated any kind of intentional endometrial injury in women planning to undergo IUI or attempting to conceive spontaneously (with or without ovarian stimulation (OS)) compared to no intervention, a mock intervention, or intentional endometrial injury performed at a different time or to a higher/lower degree.
We used standard methodological procedures recommended by Cochrane. Primary outcomes were live birth/ongoing pregnancy and pain experienced during the procedure. Due to high risk of bias associated with many of the studies, primary analyses of all review outcomes were restricted to studies at low risk of bias. Sensitivity analysis including all studies was then performed.
We included 23 RCTs (4035 women). Most of these studies included women with unexplained infertility. Intentional endometrial injury versus either no intervention or a sham procedure The primary analysis was restricted to studies at low risk of bias, which left only one study included. We are uncertain whether endometrial injury has an effect on the probability of live birth, as only one study is included in the analysis and the confidence interval is wide (risk ratio (RR) 1.11, 95% confidence interval (CI) 0.78 to 1.59; 1 RCT, 210 participants). Evidence suggests that if the chance of live birth with no intervention/a sham procedure is assumed to be 34%, then the chance with endometrial injury would be 27% to 55%. When all studies were included in the sensitivity analysis, we were uncertain whether endometrial injury improves live birth/ongoing pregnancy, as the evidence was of very low quality (RR 1.71, 95% CI 1.32 to 2.21; 8 RCTs, 1522 participants; I² = 16%). Evidence suggests that if the chance of live birth/ongoing pregnancy with no intervention/a sham procedure is assumed to be 13%, then the chance with endometrial injury would be 17% to 28%. A narrative synthesis conducted for the other primary outcome of pain during the procedure included studies measuring pain on a zero-to-ten visual analogue scale (VAS) or grading pain as mild/moderate/severe, and showed that most often mild to moderate pain was reported (6 RCTs, 911 participants; very low-quality evidence). Higher versus lower degree of intentional endometrial injury Evidence was insufficient to show whether there is a difference in ongoing pregnancy rates (RR 1.29, 95% CI 0.71 to 2.35; 1 RCT, 332 participants; low-quality evidence) between hysteroscopy with endometrial injury and hysteroscopy alone. Evidence suggests that if the chance of ongoing pregnancy with hysteroscopy alone is 10%, then the chance with hysteroscopy with endometrial injury would be 7% to 24%. This study did not report the primary outcomes of live birth and pain during the procedure. Timing of intentional endometrial injury Four trials compared endometrial injury performed in the cycle before IUI to that performed in the same cycle as IUI. None of these studies reported the primary outcomes of live birth/ongoing pregnancy and pain during the procedure. One study compared endometrial injury in the early follicular phase (EFP; Day 2 to 4) to endometrial injury in the late follicular phase (LFP; Day 7 to 9), both in the same cycle as IUI. The primary outcome live birth/ongoing pregnancy was not reported, but the study did report the other primary outcome of pain during the procedure assessed by a zero-to-ten VAS. The average pain score was 3.67 (standard deviation (SD) 0.7) when endometrial injury was performed in the EFP and 3.84 (SD 0.96) when endometrial injury was performed in the LFP. The mean difference was -0.17, suggesting that on average, women undergoing endometrial injury in the EFP scored 0.17 points lower on the VAS as compared to women undergoing endometrial injury in the LFP (95% CI -0.48 to 0.14; 1 RCT, 110 participants; very low-quality evidence).
Evidence is insufficient to show whether there is a difference in live birth/ongoing pregnancy between endometrial injury and no intervention/a sham procedure in women undergoing IUI or attempting to conceive via sexual intercourse. The pooled results should be interpreted with caution, as the evidence was of low to very low quality due to high risk of bias present in most included studies and an overall low level of precision. Furthermore, studies investigating the effect of timing of endometrial injury did not report the outcome live birth/ongoing pregnancy; therefore no conclusions could be drawn for this outcome. Further well-conducted RCTs that recruit large numbers of participants and minimise bias are required to confirm or refute these findings. Current evidence is insufficient to support routine use of endometrial injury in women undergoing IUI or attempting to conceive via sexual intercourse.
Bui BN
，Lensen SF
，Gibreel A
，Martins WP
，Torrance H
，Broekmans FJ
... -
《Cochrane Database of Systematic Reviews》
Autologous platelet-rich plasma for assisted reproduction.
Autologous platelet-rich plasma (PRP) consists of plasma and a concentrate of platelets extracted from fresh whole blood of the person being treated. Research has suggested that intrauterine or intraovarian infusion/injection of PRP before embryo transfer may improve endometrial receptivity and response to ovarian stimulation in women undergoing assisted reproduction. We compared these interventions to standard treatment, placebo, or other interventions (mechanical or pharmacological).
To assess the effectiveness and safety of intrauterine and intraovarian infusion/injection of platelet-rich plasma in infertile women undergoing assisted reproductive technology cycles.
We searched the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and the Epistemonikos database in January 2023. We also searched the reference lists of relevant articles and contacted the trial authors and experts in the field for any additional trials.
We included randomized controlled trials (RCTs) that evaluated the application of PRP in the uterine cavity, ovaries, or both versus no intervention, placebo, or any other intervention (either mechanical or pharmacological) in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles.
We followed standard methodological procedures recommended by Cochrane, including use of the updated risk of bias tool (RoB 2). The primary outcomes were live birth (or ongoing pregnancy) and miscarriage. The secondary outcomes were clinical pregnancy, complications of the procedure, multiple pregnancy, ectopic pregnancy, fetal growth restriction, preterm delivery, and fetal abnormality. We estimated the average effect of the interventions by fitting a Der Simonian-Laird's random-effects meta-analysis model. We reported pooled odds ratios (ORs) with 95% confidence intervals (CIs). We restricted the primary analyses to trials at low risk of bias for the outcomes and performed sensitivity analyses that included all studies.
We included 12 parallel-group RCTs that recruited a total of 1069 women. We identified three different comparison groups. Using GRADE, we assessed the certainty of evidence as very low for almost all outcomes. Intrauterine injection/infusion of platelet-rich plasma versus no intervention or placebo Nine studies evaluated intrauterine PRP versus no intervention or placebo. Eight included women with at least two or three previous implantation failures. Only one was assessed at low risk of bias for each outcome. This study provided very low-certainty evidence about the effect of intrauterine PRP injection versus no intervention on live birth (OR 1.10, 95% CI 0.38 to 3.14; 94 women) and miscarriage (OR 0.96, 95% CI 0.13 to 7.09; 94 women). If the likelihood of live birth following no intervention is assumed to be 17%, then the likelihood following intrauterine PRP would be 7% to 40%; and if the risk of miscarriage following no intervention is 4%, then the risk following intrauterine PRP would be 1% to 24%. When we analyzed all studies (regardless of risk of bias), we found very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on live birth or ongoing pregnancy (OR 2.38, 95% CI 1.16 to 4.86; I² = 54%; 6 studies, 564 women) and miscarriage (OR 1.54, 95% CI 0.59 to 4.01; I² = 0%; 5 studies, 504 women). The study at low risk of bias provided very low-certainty evidence about the effect of intrauterine PRP compared with no intervention on clinical pregnancy (OR 1.55, 95% CI 0.64 to 3.76; 94 women) and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 94 women). The synthesis of all studies provided very low-certainty evidence about the effect of intrauterine PRP compared with placebo or no intervention on clinical pregnancy (OR 2.22, 95% CI 1.50 to 3.27; I² = 24%; 9 studies, 824 women), multiple pregnancy (OR 2.68, 95% CI 0.81 to 8.88; I² = 0%; 2 studies, 240 women), and ectopic pregnancy (OR 2.94, 95% CI 0.12 to 73.95; 1 study, 94 women; very low-certainty evidence). Intrauterine infusion of PRP may increase the risk of preterm delivery compared with no intervention (OR 8.02, 95% CI 1.72 to 37.33; 1 study, 120 women; low-certainty evidence). No studies reported pain, infection, allergic reaction, fetal growth restriction, or fetal abnormality. Intrauterine infusion of platelet-rich plasma versus intrauterine infusion of granulocyte colony-stimulating factor Two RCTs evaluated intrauterine PRP versus intrauterine granulocyte colony-stimulating factor (G-CSF); both included women with thin endometrium, and neither was judged at low risk of bias for any outcome. We are uncertain about the effect of intrauterine PRP compared with intrauterine G-CSF on live birth (OR 0.88, 95% CI 0.43 to 1.81; 1 study, 132 women; very low-certainty evidence), miscarriage (OR 1.94, 95% CI 0.63 to 5.96; 1 study, 132 women; very low-certainty evidence), and clinical pregnancy (OR 1.24, 95% CI 0.66 to 2.35; 2 studies, 172 women; very low-certainty evidence). Neither study reported adverse outcomes other than miscarriage. Intraovarian injection of platelet-rich plasma versus no intervention One RCT evaluated PRP injection into both ovaries versus no intervention; it was judged at high risk of bias for the two outcomes it reported. We are uncertain about the effect of intraovarian PRP injection compared with no intervention on ongoing pregnancy (OR 1.09, 95% CI 0.33 to 3.63; 73 women; very low-certainty evidence) and clinical pregnancy (OR 0.90, 95% CI 0.31 to 2.60; 73 women; very low-certainty evidence). The study examined no safety outcomes.
We are uncertain about the effect of intrauterine or intraovarian administration of PRP on outcomes of assisted reproduction technology in infertile women. The pooled results should be interpreted with caution. Only one of the 12 included studies was judged at low risk of bias. Other limitations of the included trials were failure to report live birth, poor reporting of methods, lack of prospective protocol registration, low precision due to the small number of enrolled participants, indirectness due to the specific subpopulations and settings studied, and insufficient or absent safety data.
Vaidakis D
，Papapanou M
，Siristatidis CS
《Cochrane Database of Systematic Reviews》
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