An add-on treatment commonly offered to female IVF patients to improve their chance of success has been shown in a large randomised trial to be of no value. “Endometrial scratch,” a technique whereby a small scratch or tissue biopsy is made to the lining of the uterus prior to IVF, was associated with no improvements in pregnancy or live birth rates, and should, say an international team of investigators, be abandoned as a procedure by fertility clinics.
The results of the study were presented at the 34th Annual Meeting of ESHRE by Dr Sarah Lensen, a researcher from the University of Auckland, New Zealand.
The study was a large randomised trial performed at 13 fertility centres in five countries (New Zealand, UK, Belgium, Sweden and Australia) and involving more than 1,300 women having IVF. One half were randomly assigned to endometrial scratching and the other to no adjuvant procedure. The scratch was performed with a Pipelle cannula, a small flexible plastic tube commonly used for performing uterine biopsy for a variety of indications. In IVF, where some studies have shown a benefit in outcome, it’s been proposed that injury to the lining of the uterus causes an inflammatory response conducive to implantation following embryo transfer.
“Results from earlier studies have suggested a benefit from endometrial scratching in IVF,” explained Lensen, “especially in women with previous implantation failure.
However, many of these studies had a high risk of bias in their design or conduct and did not provide strong evidence. There was still uncertainty about the validity of a beneficial effect.”
Women in the endometrial scratch arm of the study had a Pipelle biopsy between day 3 of the preceding cycle and day 3 of the IVF/embryo transfer cycle. Controls had no intervention. Results showed that clinical pregnancy rate in the endometrial scratch group was 31.4% and in the control group 31.2%; live birth rates were 26.1% in the former and 26.1% in the latter. The probabilities of pregnancy were still comparable after controlling for variables and sub-group analysis, which included patients with a history of implantation failure in IVF (defined as two or more unsuccessful embryo transfers). This group in earlier studies has appeared to gain particular benefit from the procedure.
This latest study also measured pain discomfort score associated with endometrial scratch and found “a moderate amount of pain and bleeding.” This too, said the investigators, was further reason why endometrial scratch should be abandoned and removed from the list of IVF adjuvant options.
Endometrial scratch is a reportedly common add-on treatment in fertility clinics. A survey of clinics in Australia, New Zealand and UK performed by Lensen and colleagues in 2016 found that 83% of clinicians would recommend endometrial scratching prior to IVF, especially to women with recurrent implantation failure.
“Our results contradict those of many studies published previously,” said Lensen, “and, although our trial was the largest and most robust study undertaken so far, it can be difficult for one trial to change practice. However, there are other trials under way at the moment, including two large studies from the Netherlands and UK. Nevertheless, even based just on our results, I think clinics should now reconsider offering endometrial scratch as an adjuvant treatment.”
Study question: Does endometrial scratching delivered by an endometrial pipelle biopsy, increase the probability of live-birth in women undergoing IVF/embryo transfer? Summary answer: Endometrial scratching was not associated with any improvement in live birth rate. What is known already: Endometrial scratching has been suggested to improve the probability of embryo implantation, and therefore pregnancy, in women undergoing IVF. It is proposed that the mechanical disruption to the endometrium results in a favourable inflammatory response, increasing the endometrial receptivity. Pooled results from randomised trials suggest benefit from endometrial scratching prior to an IVF cycle, especially in women with previous implantation failure. However, many of the studies had a high risk of bias secondary to study design, such as exposure of controls to endometrial disruption and lack of allocation concealment. Therefore, there is uncertainty about the validity of a beneficial effect.
Study design, size, duration: A pragmatic, multi-centre, open-label, randomised trial was conducted between June 2014 and June 2017 in 13 centres across five countries. Women were randomised 1:1 to either endometrial scratching or no procedure, using an online trial-specific database which ensured allocation concealment. Sample-size was calculated separately in women with recurrent implantation failure (≥2 unsuccessful embryo transfers, 15% increase live-birth rate anticipated) and without (8% increase). At 80% power and a 5% significance level, 1300 women were required.
Participants/materials, setting, methods: Eligible women were undergoing embryo transfer (fresh or frozen) using their own oocytes, with no recent exposure to disruptive intrauterine instrumentation. Women in the endometrial scratching arm underwent a pipelle biopsy between day 3 of the preceding cycle and day 3 of the IVF/embryo transfer cycle. The primary outcome was live-birth using an intention-to-treat approach. Risk ratio and 95% confidence intervals were calculated, and logistic regression was used to test for subgroup differences. Main results and the role of chance: A total of 1364 women were randomised: 690 to endometrial scratching and 674 to control. Baseline and cycle characteristics were similar between the two groups. Endometrial scratching was not associated with any improvement in live birth rate 26.1% (180/690) vs 26.1% (176/674), odds ratio =1.00 (0.78 to 1.27). The effect remained similar after adjusting for protocol deviations and the observation that fewer women in the control arm underwent an embryo transfer. There was no difference in the rate of biochemical pregnancy, ectopic pregnancy, ongoing pregnancy, clinical pregnancy or multiple pregnancy between the two groups. Subgroup analysis did not identify any subpopulations that may benefit from endometrial scratching; there was no evidence of a benefit in women: with recurrent implantation failure, undergoing fresh or frozen cycles, or depending on the timing of the scratch in relation to the embryo transfer. The median pain score from endometrial scratching was 3.5/10 (IQR 1.9-6.0). There were 14 adverse events related to endometrial scratching: 7 vasovagal reactions, 2 excessive bleeding and 5 excessive pain.
Limitations, reasons for caution: Although a higher proportion of women in the endometrial scratching arm underwent embryo transfer, this did not impact the results. The definition of recurrent implantation failure was two or more previous unsuccessful embryo transfers, with no consideration for the stage or quality of the previously transferred embryos.
Wider implications of the findings: This was a large trial and the pragmatic design increases the generalisability of the results. As the beneficial effects reported previously were not confirmed by this trial, and the procedure caused a moderate amount of pain and bleeding, the current use of endometrial scratching in fertility clinics should be abandoned.
S Lensen, D Osavyluk, S Armstrong, E Napier, L Sadler, A Hennes, C Stadelmann, H Hamoda, Y Khalaf, L Webber, P Bhide, WT Teh, S Wakeman, L Searle, C Farquhar
European Society of Human Reproduction and Embryology material
ESHRE 2018 abstract (PDF file)