The effect of administering pregnancy hormone in the womb of subfertile women undergoing assisted reproduction

Review question

Does administering pregnancy hormone into the womb of subfertile women undergoing assisted reproduction have any benefit?

Background

Subfertility affects 15% of couples and represents the inability to conceive (become pregnant) naturally following 12 months of regular unprotected sexual intercourse. Assisted reproduction refers to procedures involving handling of both sperm and eggs in the laboratory in a petri dish to create embryos that will be transferred into the womb (embryo transfer (ET)). It is a key option for many subfertile couples who want to have a baby. Most women undergoing assisted reproduction treatment will reach the stage of ET but the proportion of embryos that survive following ET has remained small since the mid-1990s. The pregnancy hormone (human chorionic gonadotropin) is released by the embryo and has an important role in the early stages of pregnancy. Administering natural or synthetic pregnancy hormone in the womb of subfertile women undergoing assisted reproduction treatment is a novel approach that has been suggested to increase the chance of having a baby.

Study characteristics

Cochrane authors performed a comprehensive literature search of the standard medical databases (from inception to 10 November 2015) in consultation with the Cochrane Gynaecology and Fertility Group Trials Search Co-ordinator, for all randomised studies (clinical studies where people are randomly put into one of two or more treatment groups) investigating the effect of administering pregnancy hormone in the womb of subfertile women undergoing assisted reproduction. Searches and inclusion were irrespective of language and country of origin. Two authors independently selected studies, evaluated them, extracted data and attempted to contact the authors where data were missing.

We found 12 studies (4038 women) that met our inclusion requirements. The natural or synthetic pregnancy hormone was administered in variable doses at different times before the ET.

Key results

There was an increase in live birth rate in a post-hoc analysis (after the study was finished) of a subgroup of women having day three ETs with a pregnancy hormone dose of 500 IU or greater compared to women having day three ETs without pregnancy hormone (moderate quality evidence from three studies involving 914 women). In a clinic with a live birth rate of 25% per cycle then the use of a pregnancy hormone dose of 500 IU or greater would be associated with a live birth rate that varies from 33% to 46%. There was no significant effect on live birth in any of the other subgroups (e.g. lower doses of pregnancy hormone).

Miscarriage was not influenced by administration of pregnancy hormone into the womb, irrespective of embryo stage at transfer or dose of pregnancy hormone (very low quality evidence from seven studies involving 3395 women). Other complications reported in the included studies were ectopic pregnancy (where the embryo develops outside the womb), heterotopic pregnancy (where embryos develop inside and outside the womb), death of embryo while in the womb and triplets. There was no evidence of a difference between the groups, but there were too few events to allow any conclusions to be drawn and the evidence was very low quality.

The pregnancy outcome for day three ETs using a pregnancy hormone dose of 500 IU or greater is promising. However, given the small size and the variable quality of the studies and the fact that the positive finding was from only the 500 IU or greater group, the current evidence for pregnancy hormone treatment does not support its use in assisted reproduction cycles. A definitive large study with live birth as the primary outcome of interest is recommended.

Quality of the evidence

The evidence was of very low to moderate quality.

Authors' conclusions: 

The pregnancy outcome for cleavage-stage ETs using an IC-hCG dose of 500 IU or greater is promising. However, given the small size and the variable quality of the trials and the fact that the positive finding was from a subgroup analysis, the current evidence for IC-hCG treatment does not support its use in assisted reproduction cycles. A definitive large clinical trial with live birth as the primary outcome is recommended. There was no evidence that miscarriage was influenced by intrauterine hCG administration, irrespective of embryo stage at transfer or dose of IC-hCG. There were too few events to allow any conclusions to be drawn with regard to other complications.

Read the full abstract...
Background: 

Subfertility affects 15% of couples and represents the inability to conceive naturally following 12 months of regular unprotected sexual intercourse. Assisted reproduction refers to procedures involving the in vitro handling of both human gametes and represents a key option for many subfertile couples. Most women undergoing assisted reproduction treatment will reach the stage of embryo transfer (ET) but the proportion of embryos that successfully implant following ET has remained small since the mid-1990s. Human chorionic gonadotropin (hCG) is a hormone synthesised and released by the syncytiotrophoblast and has a fundamental role in embryo implantation and the early stages of pregnancy. Intrauterine administration of synthetic or natural hCG via an ET catheter during a mock procedure around the time of ET is a novel approach that has recently been suggested to improve the outcomes of assisted reproduction.

Objectives: 

To investigate whether the intrauterine administration of hCG around the time of ET improves the clinical outcomes in subfertile women undergoing assisted reproduction.

Search strategy: 

We performed a comprehensive literature search of the Cochrane Gynaecology and Fertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, registers of ongoing trials and reference lists of all included studies and relevant reviews (from inception to 10 November 2015), in consultation with the Cochrane Gynaecology and Fertility Group Trials Search Co-ordinator.

Selection criteria: 

We included all randomised controlled trials (RCTs) evaluating intrauterine administration of hCG around the time of ET in this review irrespective of language and country of origin.

Data collection and analysis: 

Two authors independently selected studies, assessed risk of bias, extracted data from studies and attempted to contact the authors where data were missing. We performed statistical analysis using Review Manager 5 in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. We assessed evidence quality using GRADE methods.

Main results: 

Twelve RCTs investigated the effect of intrauterine administration of hCG for 4038 subfertile women undergoing assisted reproduction. The intra-cavity hCG (IC-hCG) was administered in variable doses at different timings before the ET. The source of hCG was from the urine of pregnant women or from cell cultures using recombinant DNA technology.

Most of the studies (9/12) were at high risk of bias in at least one of the seven domains assessed. Common problems were unclear reporting of study methods and lack of blinding. The main limitations in the overall quality of the evidence were high risk of bias and serious imprecision.

For the analyses of live birth and clinical pregnancy, there was considerable heterogeneity (I2 greater than 75%) and we did not undertake a meta-analysis. Exploration for the sources of heterogeneity identified two key pre-specified variables as important determinants: stage of ET (cleavage versus blastocyst stage) and dose of IC-hCG (less than 500 international units (IU) versus 500 IU or greater). We then performed meta-analysis for these analyses within the subgroups defined by stage of embryo and dose of IC-hCG.

There was an increase in live birth rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (risk ratio (RR) 1.57, 95% confidence interval (CI) 1.32 to 1.87, three RCTs, n = 914, I2 = 0%, moderate quality evidence). In a clinic with a live birth rate of 25% per cycle then the use of IC-hCG -500 IU or greater would be associated with a live birth rate that varies from 33% to 46%. We did not observe a significant effect on live birth in any of the other subgroups.

The was an increase in clinical pregnancy rate in the subgroup of women having cleavage-stage ETs with an IC-hCG dose of 500 IU or greater compared to women having cleavage-stage ETs with no IC-hCG (RR 1.41, 95% CI 1.25 to 1.58, seven RCTs, n = 1414, I2 = 0%, moderate quality evidence). We did not observe a significant effect on clinical pregnancy in either of the other subgroups.

There was no evidence that miscarriage was influenced by intrauterine hCG administration (RR 1.09, 95% CI 0.83 to 1.43, seven RCTs, n = 3395, I2 = 0%, very low quality evidence).

Other complications reported in the included studies were ectopic pregnancy (three RCTs, n = 915, three events overall), heterotopic pregnancy (one RCT, n = 495, one event), intrauterine death (two RCTs, n = 978, 21 events) and triplets (one RCT, n = 48, three events). There was no evidence of a difference between the groups, but there were too few events to allow any conclusions to be drawn and the evidence was very low quality.

Share/Save
Health topics: