Endometrial injection of embryo culture supernatant for subfertile women in assisted reproduction

Review question:

Researchers in the Cochrane Collaboration reviewed the evidence about the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing assisted reproduction.

Background:

Assisted reproduction techniques (ART) includes techniques used for treating subfertility, and in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) are the most common. Despite both clinical and laboratory efforts and improvements in the success of these treatments, pregnancy rates remain relatively low. In IVF, eggs are retrieved from a woman's ovaries and placed in a dish with sperm from her partner or from a donor, in a liquid called embryo culture medium. In ICSI, a single sperm cell is injected into a woman's egg, and then the egg goes into the culture medium.

Various factors allow a communication of embryo with maternal tissues. These could affect the receptivity of the lining of the womb (endometrium). Researchers have proposed that injecting the upper layer of the embryo culture's liquid, called supernatant, into the womb before embryo transfer, might stimulate the lining of the womb and facilitate the embryo's attachment to it. This could improve live birth rates and other ART outcomes.

Although injection before embryo transfer seems to be an encouraging procedure, its effectiveness and safety remain controversial, as there is not much available evidence about outcomes. In this Cochrane Review, we summarised the relevant evidence. We aimed for our conclusions to be as robust as possible, and also to identify any limitations to the evidence.

Study characteristics:

In consultation with the Cochrane Gynaecology and Fertility Group Information Specialist, we performed a comprehensive literature search of the standard medical databases, from each databases' earliest records to December 2019. We searched for all randomised controlled trials (RCTs) (studies in which participants are assigned to a treatment group using a random method) that investigated the effectiveness of endometrial injection of embryo culture supernatant before embryo transfer, during a cycle with IVF or ICSI, versus any other intervention or no intervention (usual care). IVF and ICSI are the two major modalities of ART. We searched for studies irrespective of language and country of origin. Two review authors independently selected and evaluated studies, extracted data, and attempted to contact the authors of studies for which data were missing. Five studies comprising 526 women met our review's inclusion criteria. We identified no ongoing studies.

Key results:

We are uncertain whether the routine use of endometrial injection of embryo culture supernatant before embryo transfer has a positive effect in women undergoing assisted reproduction, compared to usual care, for improving both live birth or ongoing pregnancy and miscarriage rates. We found that the live birth or ongoing pregnancy rate with usual care was 42%, but it varied between 35% and 55% when supernatant was injected. The risk of miscarriage was found to be 9% for usual care, and between 4% and 15% with the injection. We found similar conclusions for the rates of clinical pregnancy, multiple pregnancy and ectopic pregnancy, as well as for preterm delivery and foetal abnormalities. No single outcome measure in our review's included RCTs demonstrated a clear benefit with its use. There is also insufficient evidence to support the routine use of endometrial injection of embryo culture supernatant compared to culture media before embryo transfer.

Quality of the evidence:

The quality of the evidence was very low for nearly all outcomes. Evidence quality was low for foetal abnormalities. The main limitations of the included RCTs were poorly reported study methods, wide variations in the characteristics of the included studies and statistical imprecision due to the small study numbers and few numbers of events reported.

Authors' conclusions: 

We are uncertain whether the addition of endometrial injection of embryo culture supernatant before embryo transfer as a routine method for the treatment of women undergoing ART can improve pregnancy outcomes. This conclusion is based on current available data from five RCTs, with evidence quality ranging from very low to moderate across studies. Further large well-designed RCTs reporting on live births and adverse clinical outcomes are still required to clarify the exact role of endometrial injection of embryo culture supernatant before embryo transfer.

Read the full abstract...
Background: 

Despite substantial improvements in the success of assisted reproduction techniques (ART), live birth rates may remain consistently low, and practitioners may look for innovative treatments to improve the outcomes. The injection of embryo culture supernatant in the endometrial cavity can be undertaken at various time intervals before embryo transfer. It provides an altered endometrial environment through the secretion of factors considered to facilitate implantation. It is proposed that injection of the supernatant into the endometrial cavity prior to embryo transfer will stimulate the endometrium and provide better conditions for implantation to take place. An increased implantation rate would subsequently increase rates of clinical pregnancy and live birth, but current robust evidence on the efficacy of injected embryo culture supernatant is lacking.

Objectives: 

To evaluate the effectiveness and safety of endometrial injection of embryo culture supernatant before embryo transfer in women undergoing ART.

Search strategy: 

Our search strategies were designed with the help of the Cochrane Gynaecology and Fertility Group Information Specialist. We sought to identify all published and unpublished randomised controlled trials (RCTs) meeting inclusion criteria. Searches were performed on 2 December 2019.

We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, CINAHL, trials registries and grey literature. We made further searches in the UK National Institute for Health and Care Excellence (NICE) fertility assessment and treatment guidelines. We handsearched reference lists of relevant systematic reviews and RCTs, together with searches of PubMed and Google for any recent trials that have not yet been indexed in the major databases. We had no language or location restrictions.

Selection criteria: 

We included RCTs testing the use of endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle, compared with the non-use of this intervention, the use of placebo or the use of any other similar drug.

Data collection and analysis: 

Two review authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We pooled studies using a fixed-effect model. Our primary outcomes were live birth/ongoing pregnancy and miscarriage. We performed statistical analysis using Review Manager 5. We assessed evidence quality using GRADE methods.

Main results: 

We found five RCTs suitable for inclusion in the review (526 women analysed). We made two comparisons: embryo culture supernatant use versus standard care or no intervention; and embryo culture supernatant use versus culture medium.

All studies were published as full-text articles. Data derived from the reports or through direct communication with investigators were available for the final meta-analysis performed. The GRADE evidence quality of studies ranged from very low-quality to moderate-quality. Factors reducing evidence quality included high risk of bias due to lack of blinding, unclear risk of publication bias and selective outcome reporting, serious inconsistency among study outcomes, and serious imprecision due to wide confidence intervals (CIs) and low numbers of events.

Comparison 1. Endometrial injection of embryo culture supernatant before embryo transfer versus standard care or no intervention:

One study reported live birth only and two reported the composite outcome live birth and ongoing pregnancy. We are uncertain whether endometrial injection of embryo culture supernatant before embryo transfer during an ART cycle improves live birth/ongoing pregnancy rates compared to no intervention (odds ratio (OR) 1.11, 95% CI 0.73 to 1.70; 3 RCTs; n = 340, I2 = 84%; very low-quality evidence). Results suggest that if the chance of live birth/ongoing pregnancy following placebo or no treatment is assumed to be 42%, the chance following the endometrial injection of embryo culture supernatant before embryo transfer would vary between 22% and 81%.

We are also uncertain whether the endometrial injection of embryo culture supernatant could decrease miscarriage rates, compared to no intervention (OR 0.89, 95% CI 0.44 to 1.78, 4 RCTs, n = 430, I2 = 58%, very low-quality evidence). Results suggest that if the chance of miscarriage following placebo or no treatment is assumed to be 9%, the chance following injection of embryo culture supernatant would vary between 3% and 30%.

Concerning the secondary outcomes, we are uncertain whether the injection of embryo culture supernatant prior to embryo transfer could increase clinical pregnancy rates (OR 1.13, 95% CI 0.80 to 1.61; 5 RCTs; n = 526, I2 = 0%; very low-quality evidence), decrease ectopic pregnancy rates (OR 0.32, 95% CI 0.01 to 8.24; n = 250; 2 RCTs; I2 = 41%; very low-quality evidence), decrease multiple pregnancy rates (OR 0.70, 95% CI 0.26 to 1.83; 2 RCTs; n = 150; I2 = 63%; very low-quality evidence), or decrease preterm delivery rates (OR 0.63, 95% CI 0.17 to 2.42; 1 RCT; n = 90; I2 = 0%; very low-quality evidence), compared to no intervention. Finally, there may have been little or no difference in foetal abnormality rates between the two groups (OR 3.10, 95% CI 0.12 to 79.23; 1 RCT; n = 60; I2 = 0%; low-quality evidence).

Comparison 2. Endometrial injection of embryo culture supernatant versus endometrial injection of culture medium before embryo transfer

We are uncertain whether the use of embryo culture supernatant improves clinical pregnancy rates, compared to the use of culture medium (OR 1.09, 95% CI 0.48 to 2.46; n = 96; 1 RCT; very low-quality evidence). No study reported live birth/ongoing pregnancy, miscarriage, ectopic or multiple pregnancy, preterm delivery or foetal abnormalities.

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