Sarah F Lensen, Marlies Manders, Carolina O Nastri, Ahmed Gibreel, Wellington P Martins, Gabriella E Templer, Cindy Farquhar

Intentional endometrial injury is currently 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 or a similar technique, and is a common, simple, gynaecological procedure that has an established safety profile. However, it is also known to be associated with 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 low complexity fertility treatments such as intrauterine insemination (IUI) and ovulation induction (OI), remains unclear. To evaluate the effectiveness and safety of intentional endometrial injury in subfertile women and couples attempting to conceive through sexual intercourse or intrauterine insemination (IUI). We searched the Cochrane Gyanecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, DARE, ISI Web of Knowledge and ClinicalTrials.gov; as well as reference lists of relevant reviews and included studies. We performed the searches from inception to 31 October 2015. 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 OI) compared to no intervention, a mock intervention or intentional endometrial injury performed at a different time or to a higher/lower degree. Two review authors independently selected trials, extracted data and assessed trial quality using GRADE methodology. The primary outcomes were live birth/ongoing pregnancy and pain experienced during the procedure. Secondary outcomes were clinical pregnancy, miscarriage, ectopic pregnancy, multiple pregnancy and bleeding secondary to the procedure. We combined data to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. Nine trials, which included a total of 1512 women, met the inclusion criteria of this Cochrane review. Most of these studies included women with unexplained infertility. In seven studies the women were undergoing IUI and in two studies the women were trying to conceive from sexual intercourse. Eight trials compared intentional endometrial injury with no injury/placebo procedure; of these two trials also compared intentional endometrial injury in the cycle prior to IUI with intentional endometrial injury in the IUI cycle. One trial compared higher vs. lower degree of intentional endometrial injury. Intentional endometrial injury vs. either no intervention or a sham procedureWe are uncertain whether endometrial injury improves live birth/ongoing pregnancy as the quality of the evidence has been assessed as very low (risk ratio (RR) 2.22, 95% confidence interval (CI) 1.56 to 3.15; six RCTs, 950 participants; I² statistic = 0%, very low quality evidence). When we restricted the analysis to only studies at low risk of bias the effect was imprecise and the evidence remained of very low quality (RR 2.64, 95% CI 1.03 to 6.82; one RCT, 105 participants; very low quality evidence). Endometrial injury may improve clinical pregnancy rates however the evidence is of low quality (RR 1.98, 95% CI 1.51 to 2.58; eight RCTs, 1180 participants; I² statistic = 0%, low quality evidence).The average pain experienced by participants undergoing endometrial injury was 6/10 on a zero-10 visual analogue scale (VAS)(standard deviation = 1.5). However, only one study reported this outcome. Higher vs. lower degree of intentional endometrial injuryWhen we compared hysteroscopy with endometrial injury to hysteroscopy alone, there was no evidence of a difference in ongoing pregnancy rate (RR 1.29, 95% CI 0.71 to 2.35; one RCT, 332 participants; low quality evidence) or clinical pregnancy rate (RR 1.15, 95% CI 0.66 to 2.01; one RCT, 332 participants, low quality evidence). This study did not report the primary outcome of pain during the procedure. Timing of intentional endometrial injuryWhen endometrial injury was performed in the cycle prior to IUI compared to the same cycle as the IUI, there was no evidence of a difference in ongoing pregnancy rate (RR 0.65, 95% CI 0.37 to 1.16, one RCT, 176 participants; very low quality evidence) or clinical pregnancy rate (RR 0.82, 95% CI 0.50 to 1.36; two RCTs, 276 participants; very low quality evidence). Neither of these studies reported the primary outcome of pain during the procedure.In all three comparisons there was no evidence of an effect on miscarriage, ectopic pregnancy or multiple pregnancy. No studies reported bleeding secondary to the procedure. It is uncertain whether endometrial injury improves the probability of pregnancy and live birth/ongoing pregnancy in women undergoing IUI or attempting to conceive via sexual intercourse. The pooled results should be interpreted with caution as we graded the quality of the evidence as either low or very low. The main reasons we downgraded the quality of the evidence were most included studies were at a high risk of bias and had an overall low level of precision. Further well-conducted RCTs that recruit large numbers of participants and minimise internal bias are required to confirm or refute these findings.