CME Author: Vicki Brower
Study Authors: Sarah Lensen, Diana Osavlyuk, et al.
Target Audience and Goal Statement:
Obstetrician/gynecologists and assisted fertility specialists
The goal was to determine whether endometrial scratching before in vitro fertilization (IVF) results in higher rates of embryo implantation, pregnancy, and live births compared with no intervention.
- Does endometrial scratching before IVF increase the odds of live births in women (primary endpoint)?
- Does this procedure result in ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy, biochemical pregnancy, miscarriage, stillbirth, pregnancy termination, pain during the procedure, bleeding the day after the procedure, and maternal and neonatal outcomes (secondary endpoints)?
Study Synopsis and Perspective:
Endometrial scratching before in vitro fertilization (IVF), while intended to improve pregnancy rates, did not improve live birth rates over no treatment in any subgroup, according to a large, international randomized trial.
The intervention yielded a live birth in 26.1% of women compared with 26.1% among controls (adjusted OR 1.00, 95% CI 0.78-1.27), reported Sarah Lensen, PhD, of the University of Auckland in New Zealand, and colleagues.
Moreover, there were no significant differences in any other pregnancy outcomes, such as rates of clinically confirmed pregnancy, ectopic pregnancy, or miscarriage, the authors wrote in the New England Journal of Medicine. The current findings are in line with what the same researchers presented at the 2018 European Society of Human Reproduction and Embryology meeting in Barcelona.
Lensen and colleagues randomized 1,364 women over 3 years at 13 sites (2014-2017): 690 to receive endometrial scratching from day 3 of the cycle preceding the IVF cycle, and day 3 of the IVF cycle, and 674 to serve as controls. Twenty-five percent of the women in the study had undergone two or more previous unsuccessful embryo transfers.
There was no significant difference between groups in live births or in any examined pregnancy outcome. The live-birth rate was 180 of 690 in the treated group, and 176 of the 674 control group, with no significant differences in primary or secondary outcomes.
In two subgroups of particular interest — women in whom implantation had failed at least twice or women in whom it had failed no more than once — there was also no evidence of benefit, the authors said. They noted that “subgroup analyses did not identify any populations of women who might benefit.” However, treated women did experience pain (median was 3.5 on a 10-point scale), and 14 had adverse reactions, such as dizziness, nausea, and excessive bleeding.
Regarding the ubiquity of the procedure among patients undergoing IVF, a recent survey found that 83% of fertility clinicians in the U.K., Australia, and New Zealand offer or recommend endometrial scratching, which can cost patients approximately $500.
In an accompanying editorial, Ben W. Mol, MD, of Monash University in Victoria, Australia, and Kurt T. Barnhart, MD, of the University of Pennsylvania in Philadelphia, pointed out that the trial failed to meet the primary outcome, and showed no “suggestion of benefit” in any secondary outcome.
The procedure reflects current standards of care, and the population — including women undergoing IVF for the first time and women with previous failed cycles treated in centers in several countries — was generalizable to populations with infertility across the world, they wrote, stating that “As a consequence, the results of this trial should be trusted.”
These results contrast with a 2016 Cochrane review that suggested that overall, there was an increased probability of clinical pregnancy with endometrial scratching. Lensen’s group warned that most of the trials included in that review had a high risk of bias. Mol and Barnhart also assessed the quality of that evidence as “moderate,” noting a host of limitations to the trials in the Cochran review, including not prospectively registered, showing an unrealistic large effect in limited sample sizes, using suboptimal randomization techniques, or having been stopped prematurely.
Overall, the success rate of IVF remains “modest,” holding at about 25-30% per cycle, Lensen and colleagues said.
The theory behind endometrial scratching is that a small injury to the endometrium may facilitate embryo implantation via inflammatory and immunologic mechanisms, they added. Previous trial results are far from unanimous in indicating efficacy, with one larger trial “with a robust design” showing a lack of benefit, whereas a subgroup analysis suggested lower pregnancy rates with this procedure. Pooled results from the Cochrane review suggested benefit especially in women in whom IVF had previously failed.
Mol and Barnhart emphasized that the current “well-conducted” trial reinforced the idea that all adjuvants to fertility treatments and IVF should be carefully evaluated prior to being offered to patients who “may be receptive to anything that might hypothetically increase their chance of having a baby.”
Source References: New England Journal of Medicine, Jan. 24, 2019; DOI:10.1056/NEJMoa1808737
Editorial: New England Journal of Medicine, Jan. 24, 2019; DOI:10.1056/NEJMe1815042
Study Highlights: Explanation of Findings
This pragmatic randomized trial conducted across five countries improves the “generalizability” of the results that endometrial scratching had no impact on live birth rates, according to the study authors. The editorialists agreed, suggesting that it was “Time to Stop” scratching the endometrium in IVF.
“Despite continual advances in techniques and technology since the introduction of IVF more than 40 years ago, [endometrial scratching] is successful in fewer than half of initiated cycles,” the authors wrote, adding that there is no current regulatory framework that considers such procedures (27 per a recent Cochrane review), yet that review identified endometrial scratching “as the only one for which there was evidence of higher live-birth rates.”
Yet, “this simple and cheap procedure has been widely adopted by infertility specialists and used in tens of thousands of women around the world, for a usual fee of $200 to $500 U.S.,” Lensen and colleagues pointed out.
They criticized the Cochrane review meta-analysis’ design flaws, and noted that the first “appropriately conducted” randomized trial evaluating this procedure showed a relative risk of 0.83 (95% CI, 0.59 to 1.19) for the primary end of pregnancy. The only “solace” the current trial offers is that it “caused no harm” other than pain and bleeding, they stated.
This study underscores that all adjuvants to IVF, and fertility treatments in general, should be evaluated carefully before being offered to infertile couples who may be receptive to anything that might hypothetically increase their chances of having a baby, according to the editorialists.
“An unanswered public health question is whether IVF clinics and doctors around the world should continue to offer unevaluated adjuvants, recognizing the likelihood that they will be proven ineffective once properly evaluated and that some might cause harm,” they wrote.
“Misleading information on the effectiveness of adjuvants is already the topic of legal disputes involving couples who have used IVF,” they added, referring to a couple who became the first in the U.K. to sue an IVF clinic for selling them “worthless and unproven” extra interventions. Rather, fertility specialists should “do no harm, and do not offer false hope or sell snake oil,” they concluded.