News from ESHRE 2018: Endometrial scratch does not result in more pregnancies

Endometrial scratch is often offered as an adjuvant therapy to improve the IVF success rates, but the results of a large randomized control trial have shown that the “add-on” procedure does not improve the pregnancy or live birth rates. The study results were presented at the European Society of Human Reproduction and Embryology (ESHRE) 34^th annual conference in Barcelona, Spain by Dr. Sarah Lensen, a researcher from the University of Auckland, New Zealand.

The study involved 1300 women who underwent IVF across 13 fertility centers in 5 countries (New Zealand, UK, Belgium, Sweden and Australia).

It is proposed that causing injury to the endometrial lining invokes an inflammatory response that helps create a favorable environment for the implantation of the embryo. A survey conducted in Australia, New Zealand, and the UK by Lensen and colleagues in 2016 revealed that about 83% of physician offer endometrial scratch to patients before IVF cycles, especially those who have recurrent implantation failure.

Lensen said in a statement at the conference, "Results from earlier studies have suggested a benefit from endometrial scratching in IVF, 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."

The women in the study group (690) received an endometrial scratch performed by Pipelle cannula between day 3 of the preceding cycle and day 3 of the IVF/embryo transfer cycle, while the control group (674) didn’t receive any such treatment.

In this intent to treat analysis, the 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. No difference was seen in rates of biochemical pregnancy, ectopic pregnancy, or multiple pregnancies among both the groups.

The researchers also looked at other side effects of endometrial scratch and found that the median pain score for the procedure was 3.5. Women also suffered from vasovagal attack, excessive pain, and excessive bleeding. 

“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 underway 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.”

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Endometrial microbiome plays a key role in implantation and pregnancy rates in IVF patients.

Clinical pearls:

• Different bacterial species were detected between vagina and endometrial cavity of the same subjects.
• The microbiota in the endometrial cavity is labelled as Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) or a non-Lactobacillus-dominated microbiota (<90% Lactobacillus spp. with >10% of other bacteria). 
• The composition of endometrial microbiome is not regulated by the hormonal cycle and non-Lactobacillus-dominated microbiota during the receptivity phase correlates with significant decrease in implantation, on-going pregnancy, pregnancy and live birth rates. 

It has been believed since last 50 years that uterine cavity and endometrium is sterile and devoid of microbial habitat in the absence of infection. The sterile womb paradigm was coined by the French pediatrician Henry Tissier and postulated that human infants develop in a sterile environment. [1]

Recent advances in genomics and bioinformatics have led to identifying microbiota in many body organs that were previously thought to be sterile by use of 16S rRNA gene-based bacterial detection and identification techniques. By using this newer advances in microbiology it has been proved that upper genital tract harbors a distinct set of microbiome and is differs considerably in health and disease states.

A study published in the December issue of American journal of Obstetrics and Gynecology (ACOG)  by Moreno et al,[2] not only demonstrated that endometrium harbors microbes and endometrial microbiome has a lot in common with vaginal microbiome.  The study further demonstrated that like vaginal microbiome, the endometrial flora is also divided into Lactobacillus dominant (LD) and non-Lactobacillus dominant (NLD) communities.

The researchers obtained paired samples from vagina and endometrial cavity in 13 fertile women in both receptive and prereceptive phases of the same menstrual cycles. (n=52). To study the hormonal influence on endometrial microbiome during the preparation of endometrium for implantation samples of endometrial aspirate collected from 22 fertile women.

Finally, to study the impact of altered endometrial microbiome on reproduction, the endometrial aspirate was assessed by implantation, miscarriage, ongoing pregnancy, and live birth rates in 35 infertile women undergoing IVF by endometrial receptivity array (ERA).

The study results showed that:

Different bacterial species were detected between vagina and endometrial cavity of the same subjects.

The microbiota in the endometrial cavity is labelled as Lactobacillus-dominated microbiota (>90% Lactobacillus spp.) or a non-Lactobacillus-dominated microbiota (<90% Lactobacillus spp. with >10% of other bacteria). 

The composition of endometrial microbiome is not regulated by the hormonal cycle and non-Lactobacillus-dominated microbiota during the receptivity phase correlates with significant decrease in implantation, on-going pregnancy, pregnancy and live birth rates.

This pilot study has opened the doors for many basic, translational and clinical studies in future. It has also drawn our attention to the fact that reproductive success does not solely rely on endometrial histology and gene expression.

Linda C. Giudice, MD, PhD, Distinguished Professor and reproductive endocrinologist at the University of California San Francisco said in an accompanying editorial “The ongoing revolution in technology, science, multiple omics, and multidimensional data analysis has opened the window of implantation to a greater level of scrutiny. It is time to further investigate the endometrial microbiome and expand research to its virome, fungome, epigenome, and metabolome to increase our understanding the biology of this dynamic tissue and to develop targeted therapies of endometrial disorders that underlie infertility and poor pregnancy outcomes and affect women’s health more broadly. We are indeed on the threshold to transform clinical reproductive medicine and improve reproductive outcomes with precision and personalization for individual patients.”

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[1] https://www.ncbi.nlm.nih.gov/pubmed/23976878/ accessed on 8 December 2016

[2] Moreno, I., Codoñer, F.M., Vilella, F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016; 215: 684–703