Endometrial injury in women undergoing assisted reproductive techniques

Review question

To assess the safety and efficacy of performing an endometrial injury (such as endometrial biopsy) on reproductive outcomes in women undergoing ART.

Background

Couples who have trouble getting pregnant may seek fertility treatments to help them conceive. These treatments are known as assisted reproductive techniques (ART), such as in vitro fertilisation (IVF). In ART, eggs are collected from the woman and are combined with semen in the laboratory to create embryos. Embryos are transferred back into the womb in the hope that they will establish a pregnancy. Implantation is the process by which an embryo is embedded in the lining of the womb; it is the first step toward establishing a successful pregnancy. It has been suggested that the chances of implantation are increased by intentional endometrial scratching, such as by endometrial biopsy or curettage, before replacement of the embryo.

Study characteristics

Cochrane authors included 14 clinical trials (2128 women) evaluating the effects of endometrial injury on outcomes of ART. Thirteen of these trials studied endometrial injury during the menstrual cycle before embryo transfer. One trial studied endometrial injury on the day of oocyte retrieval, which is just a few days before the day the embryo is transferred into the womb. Whether participants had undergone previous embryo transfers varied among the included studies. The evidence is current to January 2015.

Key results

The included studies suggest that endometrial injury performed sometime during the month before the start of ovarian stimulation as part of ART improves the chances that a woman will achieve live birth and clinical pregnancy. Moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with this intervention. Contrary to this, endometrial injury performed on the day the eggs are picked up reduces the chances of pregnancy.

We are still uncertain about the effect of endometrial injury on adverse events such as miscarriage, multiple pregnancy or vaginal bleeding. However, the endometrial injury procedure does appear to cause some pain, although this is short lived.

Quality of the evidence

Evidence that endometrial injury performed in the cycle before ART increases the probability of live birth and clinical pregnancy is of moderate quality. For all other outcomes the evidence is of low or very low quality. The quality of the evidence is reduced because insufficient participants were included in the studies, and because a large proportion of the included studies have important limitations in the methods that they used.

Authors' conclusions: 

Moderate-quality evidence indicates that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle is associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There is no evidence of an effect on miscarriage, multiple pregnancy or bleeding. The procedure is mildly painful. Endometrial injury on the day of oocyte retrieval is associated with a reduction of clinical and ongoing pregnancy rates.

Although current evidence suggests some benefit of endometrial injury, we need evidence from well-designed trials that avoid instrumentation of the uterus in the preceding three months, do not cause endometrial damage in the control group, stratify the results for women with and without recurrent implantation failure (RIF) and report live birth.

Read the full abstract...
Background: 

Implantation of an embryo within the endometrial cavity is a critical step in assisted reproductive techniques (ART). Previous research has suggested that endometrial injury - intentional damage to the endometrium - can increase the probability of pregnancy in women undergoing ART.

Objectives: 

To assess the effectiveness and safety of endometrial injury performed before embryo transfer in women undergoing ART.

Search strategy: 

We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Latin American Caribbean Health Sciences Literature (LILACS) and ClinicalTrials.gov. The original search was performed in November 2011, and further searches were done in March 2014 and January 2015.

Selection criteria: 

Randomised controlled trials comparing intentional endometrial injury before embryo transfer in women undergoing ART, versus no intervention or a sham procedure.

Data collection and analysis: 

Two independent review authors screened studies and extracted data which were checked by a third review author. Two review authors independently assessed risk of bias. We contacted and corresponded with study investigators as required and analysed data using risk ratio (RR) and a random-effects model. We assessed the quality of the evidence by using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria.

Main results: 

We included 14 trials that included 1063 women in the intervention groups and 1065 women in the control groups. Thirteen studies compared endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle versus no injury, and one study compared endometrial injury on the day of oocyte retrieval versus no injury. Overall, eight of the 14 included studies were deemed to be at high risk of bias in at least one domain.

In studies comparing endometrial injury performed between day 7 of the previous cycle and day 7 of the ET cycle versus no intervention or a sham procedure, endometrial injury was associated with an increase in live birth or ongoing pregnancy rate: RR 1.42, 95% confidence interval (CI) 1.08 to 1.85; P value 0.01; nine RCTs; 1496 women; I² = 53%; moderate-quality evidence. In other words, moderate-quality evidence suggests that if 26% of women achieve live birth without endometrial injury, between 28% and 48% will achieve live birth with endometrial injury. A sensitivity analysis removing the studies at high risk of bias showed no difference in effect.

There was no evidence of an effect on miscarriage, however the evidence is of low-quality: RR 0.99, 95% CI 0.63 to 1.53; P value 0.06; eight RCTs; 500 clinical pregnancies; I² = 10%; low-quality evidence.

Endometrial injury was also associated with an increased clinical pregnancy rate: RR 1.34, 95% CI 1.21 to 1.61; P value 0.002; 13 RCTs; 1972 women; I² = 45%; moderate-quality evidence. This suggests that if 30% of women achieve clinical pregnancy without endometrial injury, between 33% and 48% will achieve clinical pregnancy with this intervention.

Endometrial injury was associated with increased pain, however the evidence was of very low quality. One study reported pain on a VAS scale: MD 4.60, 95% CI 3.98 to 5.22; P value < 0.00001; one RCT; 158 women. Two studies reported the number of pain complaints after the procedure; one recorded no events in either group, and the other reported that endometrial injury increased pain complaints: OR 8.65, 95% CI 2.49 to 30.10; P value 0.0007; one RCT; 101 women.

Results from the only randomised controlled trial (RCT) comparing endometrial injury on the day of oocyte retrieval versus no injury, reported that this endometrial injury markedly decreased live birth (RR 0.31, 95% CI 0.14 to 0.69; P value 0.004; 156 women; low-quality evidence) and clinical pregnancy (RR 0.36, 95% CI 0.18 to 0.71; P value 0.003; one RCT; 156 women; low-quality evidence).

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