Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To investigate whether the intrauterine administration of hCG around the time of ET improves the clinical outcomes in subfertile women undergoing assisted reproduction.
Background
Description of the condition
Subfertility is defined as the inability of a couple to conceive spontaneously following 12 months of regular unprotected sexual intercourse. It is estimated that 15% of couples are affected by subfertility of different causes (female factor, male factor, unexplained). Assisted reproduction refers to procedures involving the in vitro (in a laboratory dish) handling of both human gametes (sperm and eggs) with the objective of establishing a pregnancy (Zegers‐Hochschild 2009). The most vulnerable step of assisted reproduction is the embryo transfer (ET) (Schoolcraft 2001). Most women undergoing assisted reproduction treatment will reach the stage of ET due to important improvements in ovarian stimulation protocols and laboratory technology but the proportion of embryos that implant following ET has remained small (less than one third) over the last 20 years (Kupka 2014).
The process of implantation involves a reciprocal interaction between the embryo and endometrium, culminating in a small reception‐ready phase of the endometrium during which implantation can occur. This interaction is dependent on the temporal differentiation of endometrial cells to attain uterine receptivity. Implantation failure is thought to occur as a consequence of impairment of the embryo developmental potential or impairment of uterine receptivity, or both, and the embryo–uterine dialogue (Diedrich 2007).
Many interventions have been attempted, with varying degrees of success, before ET (endometrial injury (Nastri 2012), dummy ET (Mansour 1990), endometrial preparation (Derks 2009), peri‐implantation heparin (Akhtar 2013), aspirin (Siristatidis 2011)), during ET (ultrasound guidance (Brown 2010), cervical mucus removal (Craciunas 2014)) and after ET (fibrin sealant, bed rest (Abou‐Setta 2014)) in order to optimise the embryo‐endometrial interaction and improve outcomes.
Description of the intervention
Human chorionic gonadotropin (hCG) is a hormone synthesised and released by the syncytiotrophoblast. It stimulates the ovarian production of progesterone during the first trimester of pregnancy. Intrauterine administration of synthetic or natural hCG around the time of embryo transfer is a novel approach that has recently been suggested to improve the outcomes of assisted reproduction treatment based on the fundamental role of hCG in embryo implantation and the early stages of pregnancy (Cole 2010). The intervention involves the intrauterine administration of hCG via an ET catheter during a mock procedure (a trial of the actual ET without using an embryo, performed to assess the difficulty of the ET) using the lowest level of medium before the conventional ET. The hCG sources for medical treatments include extraction from the urine of pregnant women (natural) or from cultures of genetically modified bacteria using recombinant DNA (synthetic).
How the intervention might work
The hCG may promote peritrophoblastic immune tolerance, which facilitates trophoblast invasion by inducing an increase in endometrial T cell apoptosis (Kayisli 2003). It also supports trophoblast apposition (the first stage of implantation, loose alignment of the trophoblast to the decidua) and adhesion (second stage of implantation, closer attachment of the trophoblast to the decidua) to the endometrium by regulating proteins involved in implantation (Racicot 2014). Intrauterine injection of urinary hCG alters endometrial secretory parameters (Licht 1998), while cell proliferation and migration are increased in the presence of hCG (Bourdiec 2013).
Why it is important to do this review
Subfertility affects a relatively large proportion of couples, while assisted reproduction treatments remain costly and stressful.All the effort should be directed towards increasing the success rates of infertility treatment and primary research should be translated into clinical practice in an efficient and timely manner. Intrauterine administration of hCG around the time of ET has the potential to improve the outcome of assisted reproduction treatments and randomised and non‐randomised trials have reported varying results (Mansour 2011; Hong 2014). Different studies have evaluated variable circumstances of intrauterine hCG administration in terms of stage of the embryo at transfer (cleavage versus blastocyst), source of hCG (urine versus recombinant), dose of hCG, embryo processing (fresh versus frozen‐thawed) and number of embryos transferred, leading to real uncertainties about the role of the intervention.
Objectives
To investigate whether the intrauterine administration of hCG around the time of ET improves the clinical outcomes in subfertile women undergoing assisted reproduction.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials (RCTs) evaluating intrauterine administration of hCG around the time of ET will be included in this review irrespective of language and country of origin. Only data from the first phase of crossover RCTs will be included in meta‐analyses.
Types of participants
All women undergoing ET as part of their assisted reproduction treatment.
Types of interventions
RCTs comparing intrauterine administration of hCG around the time of ET versus any other active intervention, no intervention or placebo will be eligible for inclusion.
Types of outcome measures
Primary outcomes
1. Live birth (the delivery of a live fetus after 24 completed weeks of gestational age) rate per women or couple randomised
2. Miscarriage (the loss of the pregnancy before 24 completed weeks of gestational age) rate per woman or couple randomised
Secondary outcomes
3. Clinical pregnancy (the presence of a gestational sac on ultrasound scan) rate per woman or couple randomised
4. Complication rate per woman or couple randomised, including ectopic pregnancy, intrauterine growth restriction, fetal or congenital defects, pelvic infection or other adverse events, reported as an overall complication rate and/or as individual outcomes (as reported by individual studies).
Search methods for identification of studies
All published and unpublished RCTs of intrauterine hCG administration around the time of ET will be sought in consultation with the Menstrual Disorders and Subfertility Group (MDSG) Trials Search Co‐ordinator. We will use the following search strategy, without any language restriction.
Electronic searches
The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying RCTs, which appears in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.0.2, chapter 6, 6.4.11). The EMBASE and CINAHL searches will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (http://www.sign.ac.uk/methodology/filters.html#random).
The search terms used for the Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsycINFO are presented in the Appendices (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6).
We will search The World Health Organization International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/Default.aspx) and ClinicalTrials.gov for ongoing and registered trials. OpenGrey (http://www.opengrey.eu/) and Google Scholar (http://scholar.google.co.uk/) will be searched for grey literature. The abstracts published following major conferences (for example the American Society for Reproductive Medicine (ASRM), European Society of Human Reproduction and Embryology (ESHRE)) organised in the last five years will be handsearched to find additional studies not yet published in full.
Searching other resources
We will screen the references lists of all included studies and relevant reviews to identify further articles for possible inclusion.
Data collection and analysis
Review Manager (RevMan 5.3) will be used for input of data and statistical analysis will be conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
Two of the present authors will independently screen the title, abstract and keywords for each publication in order to exclude the studies that are irrelevant for the objective of this review. The remaining publications will be retrieved in full text and appraised independently by the same two authors in order to identify the RCTs suitable for inclusion. Any potential disagreement related to study eligibility will be resolved by discussion with a third review author. The selection process will be documented with a PRISMA flow chart.
Data extraction and management
Two authors will independently extract data using a pre‐designed and pilot‐tested data extraction form. For studies with multiple publications we will use the main RCT report as the reference and we will supplement it with additional data from secondary publications. Author correspondence will be attempted where published data are insufficient. Potential disagreements will be resolved by involving a third author. Data will be entered into RevMan by one author and a second author will check the data against the data extraction form.
Assessment of risk of bias in included studies
The Cochrane risk of bias assessment tool will be used to assess the included studies for: selection, performance, detection, attrition, reporting and other bias. A third author will be involved in case of potential disagreements. We will include the risk of bias table in the table 'Characteristics of included studies', describing the judgements in detail.
Measures of treatment effect
All outcomes are expected to be dichotomous. We will calculate Mantel‐Haenszel risk ratios (RRs) with 95% confidence intervals (CI) using the numbers of events in the intervention and control groups of each study. For outcomes with event rates below 1% the Peto one‐step odds ratio (OR) method will be used to calculate the combined outcome with 95% CI.
Unit of analysis issues
We will only perform analysis per woman or couple randomised for live birth, clinical pregnancy, miscarriage and complication rates. Only first‐phase data from crossover RCTs will be included. Data not included in the meta‐analysis (for example per cycle data) will be summarised in an additional table. Multiple live births (twins, triplets) will be counted as a single live birth event.
Dealing with missing data
We will attempt to contact the RCT authors to obtain missing data in order to perform analyses on an intention‐to‐treat basis. In the case of unobtainable data, imputation of individual values will be undertaken for the live birth rate only. Live births will be assumed not to have occurred in participants without a reported outcome. For other outcomes, we will analyse only the available data. We will subject any imputation undertaken to a sensitivity analysis.
Assessment of heterogeneity
We will identify heterogeneity by visual inspection of the forest plots and by using a standard Chi2 test with significance set at P < 0.1. The I2 statistic will be used to estimate the total variation across RCTs that is due to heterogeneity, where I2 > 50% indicates substantial heterogeneity.
Assessment of reporting biases
A comprehensive search will be conducted in order to minimise the potential impact of publication bias and other reporting biases. We will use a funnel plot to explore the possibility of small study effects when the number of included RCTs exceeds 10.
Data synthesis
We will combine the data from similar RCTs comparing similar treatments using a random‐effects model. We will display an increase in the odds of an outcome to the right of the centre line and a decrease in the odds of an outcome to the left of the centre line. In the event of substantial clinical, methodological or statistical heterogeneity (I2 > 75%), RCTs results will not be combined in a meta‐analysis. Where data are incomplete and cannot be presented in the analyses, we will report available data in narrative form.
Subgroup analysis and investigation of heterogeneity
Where data are available, we will conduct subgroup analyses to investigate the efficacy of intrauterine hCG administration around the time of ET depending on:
1. stage of the embryo at transfer (cleavage versus blastocyst);
2. source of hCG (urine versus recombinant);
3. embryo processing (fresh versus frozen‐thawed);
4. number of embryos transferred.
If we detect substantial heterogeneity, we will explore possible explanations in sensitivity analyses. Factors to be considered will include treatment indication, the age of the women, ovarian stimulation protocol, response to ovarian stimulation, timing of hCG administration, hCG dose and volume of infused medium, method of hCG administration (that is type of catheter), embryo quality, endometrial thickness, source of oocytes (that is donated, own) and ET difficulty.We will take any statistical heterogeneity into account when interpreting the results, especially if there is any variation in the direction of effect.
Sensitivity analysis
We will perform sensitivity analysis to examine the stability and robustness of the results in relation to the following eligibility and analysis factors.
1. Inclusion of RCTs without high risk of bias.
2. Publication type (abstract versus full text).
3. The use of a random‐effects model.
4. Calculation of risk ratio (RR).
5. Imputation of outcomes.
Overall quality of the body of evidence: summary of findings table
We will prepare a summary of findings table using GRADEpro or Guideline Development Tool software. This table will evaluate the overall quality of the body of evidence for the main review outcomes (live birth rate, miscarriage and clinical pregnancy rate) using GRADE criteria (study limitations (that is risk of bias), consistency of effect, imprecision, indirectness and publication bias). Judgements about evidence quality (high, moderate or low) will be justified, documented and incorporated into reporting of results for each outcome.
