Soft versus firm catheters for intrauterine insemination
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the pregnancy outcomes of intrauterine insemination (IUI) cycles performed with either soft or firm catheters in subfertile women undergoing IUI.
Background
Description of the condition
At present, 16% of prospective parents seek advice for subfertility. Of all couples presenting with fertility problems, 8% to 28% have no cause of their fertility that can be identified (NICE 2004). Some of these couples will need to undergo intrauterine insemination (IUI) or artificial insemination (AI). This method of assisted reproductive technology is indicated in cases of cervical infertility, relative male factor infertility, anovulation, endometriosis with a healthy fallopian tube and unexplained infertility (Merviel 2010).
Description of the intervention
Intrauterine insemination is a commonly used treatment in couples with unexplained subfertility in spite of the success with newer and more sophisticated assisted reproductive technology (ART) techniques (Verhulst 2009). Even though more advanced fertility treatments such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are available, IUI is a successful, low cost alternative (Iberico 2004). The costs of IUI are considerably lower than for IVF and ICSI with similar pregnancy rates, and the IUI procedure is also less stressful and less invasive than with IVF (Cohlen 2005). A recent Cochrane review recommended the use of IUI in patients with unexplained infertility, as the success rates in this patient population are similar to those achieved with IVF and ICSI (Pandian 2009).
The rationale behind the IUI technique is that the motile spermatozoa are delivered directly into the uterus using a catheter. The cervix acts as a reservoir for sperm and a barrier. With IUI it is bypassed and the spermatozoa are delivered close to the released oocyte (Verhulst 2009).
Higher pregnancy rates can be reached if IUI is combined with ovarian hyperstimulation (OH). The two most commonly used drugs for ovarian hyperstimulation are clomiphene citrate (CC), which is an oral treatment, and gonadotropins administered by subcutaneous injection. The aim of OH is to increase the number of oocytes available for fertilization and to enhance effective timing (Verhulst 2009).
How the intervention might work
Several factors have been accepted as being prognostic of the success of IUI treatment. For a couple these include the woman’s age, cause of infertility, duration of infertility, sperm volume and quality, controlled ovarian stimulation and the type of catheter used (Merviel 2010).
In a recently published systematic review of embryo transfer (ET) catheters, the softness of the ET catheter was found to be a determining factor in the success of ET procedures (Abou‐Setta 2005). The explanation for this is still unclear but it is theorized to be associated with reduced traumatic effects during introduction of the embryo into the uterine cavity with the softer catheter or more significant myometrium contractions with the firmer catheter, or both effects (Kovacs 1999).
Various types of IUI catheters are commercially available. They vary in length, calibre, location of the distal port (end‐ or side‐loading), and degree of rigidity or malleability. All catheters must meet the following criteria: (1) they are easy to use; (2) they must be firm enough to negotiate the cervix without causing trauma to the endocervix or endometrium, or both; and (3) the intrauterine tip of the catheter should occupy a small volume in order to minimize reflux of the inseminated materials (Lavie 1997).
The commercially available IUI catheters can be categorised into two groups, soft or firm. The most widely used IUI catheters are listed in Appendix 1.
Why it is important to do this review
In contrast to the ET catheter, the impact of the choice of IUI catheter in an ART program on the treatment outcome has been poorly investigated and data comparing different types of IUI catheters are limited. Several reports have noted differences in pregnancy rates for the soft and semirigid catheter types used for ET during IVF but few reports exist for IUI (Proctor 2007). Lavie 1997 found that a soft catheter was significantly less damaging for the endometrium than a rigid one but they did not find a statistically significant difference in pregnancy rate.
Currently, rigid catheters are more commonly used for IUI despite the fact that some reports suggest that flexible catheters have favourable results (Proctor 2007).
Objectives
To compare the pregnancy outcomes of intrauterine insemination (IUI) cycles performed with either soft or firm catheters in subfertile women undergoing IUI.
Methods
Criteria for considering studies for this review
Types of studies
Only randomised controlled trials will be eligible for inclusion. Reporting in all languages will be accepted. In addition, cross‐over trials will be included but only the data before the cross over will be included.
Types of participants
Women who meet the criteria for IUI, are undergoing IUI using their male partner's or donor sperm and are randomised to either soft or firm IUI catheter types.
Types of interventions
The use of firm catheter types versus soft catheter types for IUI in subfertile women.
Types of outcome measures
All outcomes are per randomised woman.
Primary outcomes
(1) Live‐birth rate (LBR), defined as delivery of a live fetus after 20 completed weeks of gestation.
Secondary outcomes
(1) Pregnancy rate (PR), defined as evidence of a gestational sac at six to seven weeks; confirmed with ultrasound.
(2) Multiple pregnancy rate (MPR) per randomised woman.
(3) Ease of introduction of the catheter, or difficulty in cannulating the cervix); as assessed by the operator.
Adverse outcomes
(1) Miscarriage
(2) Occurrence of endometrial or cervical trauma, or both, for example denoted by the presence of blood or mucous on the catheter, or bleeding per cervix; as assessed by the operator
(3) Patient discomfort, for example cramping during or immediately after the procedure; as expressed by the woman
Search methods for identification of studies
Electronic searches
Computerized searches will be conducted using the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, and PsycINFO.
We will use the search strategies as described in the following appendices: Appendix 2, Appendix 3, Appendix 4, Appendix 5, and Appendix 6.
The strategies incorporate the following keywords and filters:
Keywords CONTAINS "intracervical insemination" or "Intrauterine Insemination" or "intrautero tuboperitoneal insemination" or "insemination" or "insemination‐artifical by donor" or "insemination‐direct intraperitoneal"or "insemination‐donor" or "insemination, intracervical" or "insemination, intrauterine " or "insemination‐utero tubal" or "IUI" or "artifical insemination by donor" or "artifical insemination by partner" or "artificial insemination" or "insemination‐pericervical" or "utero‐tubal insemination" or Title CONTAINS"intracervical insemination" or "Intrauterine Insemination" or "intrautero tuboperitoneal insemination" or "insemination" or "insemination‐artifical by donor" or "insemination‐direct intraperitoneal"or "insemination‐donor" or "insemination, intracervical" or "insemination, intrauterine " or "insemination‐utero tubal" or "IUI" or "artifical insemination by donor" or "artifical insemination by partner" or "artificial insemination" or "insemination‐pericervical" or "utero‐tubal insemination
AND
Keywords CONTAINS "catheter" or"catheter techniques" or "catheter type" or "catheters" or "insemination catheter" or "insemination techniques" or "catheter change" or "soft‐tipped catheters" or "tom catheter" or "Cook" or "Cook Sydney catheter" or "Sydney Cook catheter" or "Wallace" or "wallace catheter" or "Wallace, Frydman" or "Wallace vs Cook K‐Jet" or Title CONTAINS"catheter" or"catheter techniques" or "catheter type" or "catheters" or "insemination catheter" or "insemination techniques" or "catheter change" or "soft‐tipped catheters" or "tom catheter" or "Cook" or "Cook Sydney catheter" or "Sydney Cook catheter" or "Wallace" or "Wallace catheter" or "Wallace, Frydman" or "Wallace vs Cook K‐Jet"
The MEDLINE search will be combined with the Cochrane highly sensitive search strategy for identifying randomised trials, which appears in the searching chapter of The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). The EMBASE search will be combined with trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN).
Other electronic sources of trials will include: the CINAHL database, trial registers for ongoing and registered trials, citation indexes, conference abstracts in the ISI Web of Knowledge, LILACS database, Clinical Study Results, Google, and the OpenSIGLE database.
Searching other resources
In addition, the reference lists of articles retrieved by the search will be handsearched and personal contact will be made with experts in the field to obtain any additional, relevant data. Any relevant journals and conference abstracts that are not covered in the MDSG Register will be handsearched, in liaison with the MDSG Trial Search Coordinator.
Data collection and analysis
Selection of studies
Titles and abstracts of manuscripts will be reviewed by two independent review authors and those that are very clearly irrelevant will be removed at this stage. The full text of all potentially eligible studies will be retrieved. Two review authors will independently examine the full text articles for compliance with the inclusion criteria and will select studies eligible for inclusion in the review. Any disagreements will be resolved by referral to a third review author and subsequent consensus.
Data extraction and management
Data from eligible studies will be extracted independently by two review authors, using a data extraction form. Where possible, data will be extracted to allow for an intention‐to‐treat analysis, defined as including all randomised participants in the denominator. Any disagreement between these review authors will be resolved by a third review author. Review authors will correspond with study investigators in order to resolve any data queries, as required.
The data extraction forms will include trial characteristics, eligibility, methods, participants, interventions, outcome measures and results. This information will be included in the review following the guidance of the Cochrane Handbook for Systematic Reviews of interventions (Higgins 2008). Data management and analysis will be conducted using Review Manager (RevMan) 5.
Assessment of risk of bias in included studies
The methodological quality of each trial will be assessed in terms of sequence generation; allocation concealment; blinding of the participants, providers and outcome assessors; completeness of outcome data; selective outcome reporting and other potential sources of bias (for example funding). Two review authors will assess these six domains, with any disagreements resolved by consensus or by discussion with a third author. All judgments will be fully described. The conclusions will be presented in a 'Risk of bias' table and will be incorporated into the interpretation of review findings by means of sensitivity analyses.
1) Sequence generation will be considered to be adequate when computer‐generated random number tables, coin‐tossing or shuffled envelopes are used. Quasi‐randomisation is to be considered an inadequate form of randomisation and, therefore, quasi‐randomised studies will not be analysed.
2) Concealment of allocation will be considered adequate if a third‐party system, serially‐numbered sealed opaque envelopes or a similar system has been described. Concealment will be stated as 'uncertain' if sealed envelopes are mentioned without further description, or if no information is available pertaining to allocation concealment.
3) Blinding will be examined with regard to who was blinded in the trial. All levels will be sought and categorized as follows: (i) single blind (only the investigator knew of the allocation); (ii) no blinding (both investigator and participant knew the allocated treatment); (iii) unclear. It is important to note that double blinding will not be sought since it would be impossible to blind the operator with respect to the type of catheter being used. The impossibility of blinding does not affect the risk of bias. There is high risk although this is unavoidable.
4) Completeness of outcome data will be considered adequate if no outcome data are missing or if the missing data are balanced in numbers across intervention groups, with similar reasons for missing data across groups.
5) Selective outcome reporting will be considered adequate if the study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in this review have been reported in the pre‐specified way.
6) Other potential sources of bias, e.g. funding.
Measures of treatment effect
Dichotomous data (for example live birth rates) will be expressed as odds ratios (OR) with 95% confidence intervals (CI).
For continuous data, mean differences between treatment groups will be calculated if all studies report exactly the same outcomes. If continuous data are reported on different scales, the standardized mean difference will be calculated; 95% CIs will be determined for all outcomes.
There are some outcomes that may be recorded using ordinal scales (for example ease of use, patient discomfort). It might be appropriate to treat these as if continuous, but if some are reported as binary and others as short or long ordinal scales then OR methods would be preferable.
Unit of analysis issues
The primary analysis will be per woman randomised. Reported data that do not allow valid analysis (e.g. 'per cycle' rather than 'per woman', where women contribute more than one cycle) will be briefly summarised in an additional table and will not be included in the meta‐analysis. Multiple live births (e.g. twins or triplets) will be counted as one live birth event.
Dealing with missing data
If data from the trial reports are insufficient or missing, we will contact the investigators of individual trials via email, post or by telephone to obtain additional information in order to perform analyses on an intention‐to‐treat basis. We will assume that live birth did not occur in participants with unreported outcomes or with losses to follow up.
In studies reporting sufficient details to calculate mean differences but no details on associated standard deviations (SD), we will assume the outcome to have a standard deviation equal to the highest SD from other studies within the same analysis. We will then perform a sensitivity analysis to determine the impact of this decision upon our final results
Assessment of heterogeneity
Heterogeneity between the results of different studies will be examined in three different ways.
1) Visual inspection of the overlap of the CIs. Where there is poor overlap this will indicate heterogeneity.
2) Using the Chi2 test for heterogeneity, with a 5% level of statistical significance. A low P value (or large Chi2 statistic relative to its degree of freedom) provides evidence of heterogeneity of the intervention effects.
3) Interpreting the I2 statistic in broad terms. The I2 statistic will be used to attempt to quantify any apparent inconsistency:
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0% to 40%, might not be important;
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30% to 60%, may represent moderate heterogeneity;
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50% to 90%, may represent substantial heterogeneity;
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75% to 100%, considerable heterogeneity (Higgins 2008)*.
* The importance of the observed value of the I2 statistic depends on the magnitude of effects and strength of evidence for heterogeneity (for example P value from the Chi2 test) (Higgins 2008).
Assessment of reporting biases
We will attempt to minimize the potential impact of publication and other reporting biases by ensuring a comprehensive search for eligible studies and by being alert for duplication of data. If appropriate (that is there are at least 10 included studies) funnel plots will be included. We will also assess within trial reporting biases by seeking protocols of published studies to check if the planned outcomes have been reported.
Data synthesis
The presence or absence of heterogeneity will be considered before pooling data from different trials. Where it is not appropriate to combine primary studies they will be summarised in a narrative form.
The data from primary studies will be combined using a fixed‐effect model in the comparison of soft versus firm catheters for IUI.
For dichotomous data (for example live births) results from each study will be combined for meta‐analysis with RevMan software using the Peto‐modified Mantel‐Hanzel method. Continuous data will be combined for meta‐analysis with RevMan software using weighted mean difference (WMD) and 95% CI.
Subgroup analysis and investigation of heterogeneity
Where data are available, subgroup analyses will be conducted to determine the evidence within the following subgroups:
1. different stimulation protocols;
2. cause of sub fertility.
Sensitivity analysis
Sensitivity analysis will be used to determine whether the conclusions are robust to arbitrary decisions made regarding the inclusion or exclusion of studies, the nature of the data analysed and the methods of analysis used. These sensitivity analyses will consider whether conclusions would have differed if:
1. eligibility were restricted to studies without a high risk of bias (we expect all studies to have a high risk of bias since it will be impossible to blind the clinicians for this intervention);
2. studies with outlying results had been excluded (we will define outlying results by comparing the CIs and comparing the overlaps between CIs);
3. different imputation strategies of missing values had been adopted;
4. a random‐effects model had been adopted.
