Intra‐uterine insemination for unexplained subfertility
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of this review is to determine whether, for couples with unexplained subfertility, IUI improves the live birth rate compared with timed intercourse, both with and without ovarian hyperstimulation.
Background
Of all couples presenting with fertility problems, 8‐28% have no cause that can be identified for their subfertility (NICE 2004). Intra‐uterine insemination (IUI) is a commonly used treatment in couples with unexplained subfertility. The rationale for performing IUI is that the motile spermatozoa, which are morphologically normal, can be concentrated in a small volume and placed directly into the uterus, close to the released oocyte. In this way the cervix is bypassed. IUI can be performed with or without ovarian hyperstimulation (OH). The two widely used drugs for ovarian hyperstimulation are clomiphene citrate (CC), which is an oral treatment; and gonadotropins, administered by injection. The aim of OH is to increase the number of available oocytes for fertilization.
The role of IUI in fertility treatment is often debated in particular in terms of whether or not it is superior to timed intercourse (TI) and whether or not OH should be used at the same time (Hughes 2003; Stewart 2003). The first randomized controlled trial of IUI was published in 1984 and reported a favourable outcome for IUI compared with timed intercourse (TI), for male factor infertility (Kerin 1984). However for unexplained subfertility, many trials have studied the efficacy of IUI since then, with various results.
Subsequent RCTs have compared IUI with timed intercourse (TI), with or without OH, and suggested a benefit of OH in combination with IUI (Hughes 1997). Goverde and colleagues reported that mild ovarian hyperstimulation of IUI cycles did not yield higher pregnancy rates (Goverde 2000), though this treatment is more cost‐effective compared with in vitro fertilisation (IVF). Others stated that IUI alone did not appear to be efficacious without some form of ovarian hyperstimulation (Guzick 1998). Some studies suggested that both OH and IUI contributed independently to increased pregnancy rates (Aboulghar 2003; Hughes 1997). There is insufficient evidence to suggest that either one of the used OH‐treatments (CC or gonadotropins) is superior or inferior to the other (Athaullah 2002).
Although ovarian hyperstimulation seems to result in higher pregnancy rates, it also increases the incidence of multiple pregnancy and ovarian hyperstimulation syndrome (OHSS). These are both associated with high risks to the health of both mother and baby (Gleicher 2000; Nan 1994). Recently the NICE Fertility guidelines recommended IUI without OH for couples with unexplained subfertility, because of the increased risk of multiple pregnancies and OHSS (NICE 2004).
This systematic review will assess the evidence on the benefits and harms of IUI with or without OH in couples with unexplained subfertility, compared to timed intercourse.
Objectives
The aim of this review is to determine whether, for couples with unexplained subfertility, IUI improves the live birth rate compared with timed intercourse, both with and without ovarian hyperstimulation.
Methods
Criteria for considering studies for this review
Types of studies
Only truly randomised controlled trials will be included. The method of allocation will be assessed to determine whether a study is truly randomised or quasi randomised. The author of the article will be contacted if the randomisation or allocation method is unclear.
Trials that do not report separate data specifically for women with unexplained subfertility, and where such data are not obtainable from the authors, will be excluded. Trials that also include couples with a mild semen defect, probably resembling unexplained subfertility, and where it seems impossible to extract the data from those couples with unexplained subfertility may be included.
Crossover trials will only be included when data from before crossover can be obtained. In the absence of parallel trials or pre‐crossover data, data from crossover trials will be displayed separately, without being pooled.
Types of participants
Participants who will be included:
1. Couples with unexplained subfertility with evidence of the following:
ovulatory status (measured by either biphasic basal body temperature chart, normal luteal progesterone or in phase endometrial biopsy);
tubal patency (measured by hysterosalpingography or laparoscopy, or both);
a normal semen sample according to WHO criteria current at the time of trial;
sperm concentration of at least 20 x 106 per ml;
total motility of at least 50%;
normal morphology in at least 30% (WHO 1987: at least 50%) or Kruger criteria ;
no anti‐sperm antibodies.
2. Couples who have tried to conceive for at least one year.
Participants who will be excluded:
1. couples with a known cause of infertility, including male factor, moderate to severe endometriosis (according to the ASRM classification), tubal disease and cervical factor. (Authors will be contacted to obtain the raw data. If the relevant data cannot be extracted separately, the study will be excluded);
2. couples known to have had previously failed fertility treatments such as assisted reproductive techniques (ART) and IUI. (Authors will be contacted. A subgroup analysis will be performed for studies with patients known to have had previous treatment, studies with only first treatment patients included, and trials with mixed or unknown previous treatment).
Types of interventions
The following will be included.
-
Trials with at least one of the following comparisons:
‐ intra‐uterine insemination (IUI) versus timed intercourse (TI), both in natural cycles;
‐ IUI with ovarian hyperstimulation (OH) versus TI in natural cycles;
‐ IUI in natural cycles versus TI with OH;
‐ IUI with OH versus TI with OH;
‐ IUI in natural cycles versus IUI with OH
-
Where OH is achieved with either clomiphene citrate or gonadotrophins.
Interventions that will be excluded:
-
intra‐cervical insemination, because we consider this a different treatment modality (Ripps 1994) and it is the topic of an other review (O'Brien 2000);
-
donor insemination
Types of outcome measures
Main outcome:
‐ live birth rate per couple (at end of the trial).
Secondary outcomes:
‐ live birth per couple after one treatment cycle;
‐ pregnancy rate per couple at the end of the trial;
‐ pregnancy rate per couple after one treatment cycle.
Adverse events:
‐ ovarian hyperstimulation syndrome (OHSS) rate per woman or per cycle;
‐ multiple pregnancy rate per couple;
‐ miscarriage rate per couple;
‐ ectopic pregnancy rate per couple.
Pregnancy is defined by the presence of an intra‐uterine gestational sac or fetal heartbeat, visualised by ultrasound scan. Only biochemically confirmed pregnancies only are to be excluded. When pregnancy is not further defined, and remains unclear even after contacting the author, the pregnancy will be assumed to be clinical. Ongoing pregnancy is defined as a pregnancy beyond 12 weeks of gestation, confirmed by ultrasound or delivery.
Data on moderate or severe ovarian hyperstimulation syndrome (OHSS) will be collected.
Multiple pregnancy should be confirmed by ultrasound and will include pregnancies where selective reduction is undertaken.
An intention‐to‐treat analysis will be used whenever possible. Women who dropped out or were excluded after randomisation will be assumed not to be pregnant. Women who were excluded because they got pregnant before receiving treatment will be included in the ITT analysis as a success.
Search methods for identification of studies
We will search the following for all reports which describe (or might describe) randomised controlled trials of IUI: the Cochrane Menstrual Disorder and Subfertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to March 2005), EMBASE (1980 to March 2005), SCIsearch and reference lists of articles. We will handsearch abstracts of the American Society for Reproductive Medicine (ASRM), European Society for Human Reproduction and Embryology (ESHRE), and the American Fertility Society (AFS). Experts in the field will be contacted world wide.
We will use the search strategy developed by the Menstrual Disorder and Subfertility Group (see Review group details in the Cochrane Library for more information). The specific search string used for MEDLINE will be as follows.
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 Randomized controlled trials/
4 random allocation/
5 double‐blind method/
6 single‐blind method/
7 or/1‐6
8 clinical trial.pt.
9 exp clinical trials/
10 (clin$ adj25 trial$).ti,ab,sh.
11 ((singl$ or doubl$ or tripl$ or trebl$) adj25 (blind$ or mask$)).ti,ab,sh.
12 placebos/
13 placebo$.ti,ab,sh.
14 random$.ti,ab,sh.
15 Research design/
16 or/8‐15
17 animal/ not (human/ and animal/)
18 7 or 16
19 18 not 17
20 insemination/
21 inseminat$.tw.
22 IUI.tw.
23 or/20‐22
24 subfertil$.tw.
25 (unexplain$ adj5 infertil$).tw.
26 infertil$.tw.
27 or/24‐26
28 19 and 23 and 27 (274)
Data collection and analysis
SM Verhulst and BJ Cohlen will independently select the trials to be included according to the above‐mentioned criteria. Disagreements will be resolved by discussion with Professor E Hughes, as referee.
Included trials will be analysed for the following quality criteria and methodological details.
Trial characteristics:
1. method of randomization;
2. quality of allocation concealment. (An allocation score will be given, according to the Cochrane standards. Only allocation score A and B will be included in the meta‐analysis.);
3. cross‐over or parallel design;
4. number of couples randomised, excluded or lost to follow up;
5. details on dropouts;
6. whether an intention‐to‐treat analysis was done or can be extracted;
7. percentage of cancelled cycles;
8. the presence of a power calculation;
9. duration, timing and location of the study.
Types of participants:
1. couples with unexplained subfertility;
2. duration of infertility;
3. women's age;
4. previous administered treatment(s).
Interventions:
1. maximum treatment cycles offered per couple;
2. method of ovarian stimulation, with or without luteinising hormone (LH) test;
3. timing of insemination;
4. number of inseminations per cycle;
5. sperm characteristics.
Outcomes:
Data that will be sought are: number of couples who started and completed cycles for each treatment modality, number of live births, number of clinical (total and ongoing) pregnancies, number of cycles with OHSS, and number of multiple pregnancies.
Statistical analysis will follow the guidelines of the Cochrane Menstrual Disorders and Subfertility group.
The dichotomous data results for each study will be summarised in a two‐by‐two table and expressed as an odds ratio with 95% confidence interval.
Heterogeneity between the results of different studies will be examined by inspecting the scatter in the data points on the graphs and the overlap in their confidence intervals, and by checking the I2 statistic. If strong heterogeneity is detected (I2 greater than 75 %) or if trials differ markedly with respect to clinical or design characteristics, then sensitivity analyses will be undertaken.
Specific differences we plan to explore are as follows:
1.trials with adequate methodology versus those of poor methodology, where adequate methodology is defined for this purpose as adequate allocation concealment, analysis by intention‐to‐treat and losses to follow up of less than 20%;
2.trials which might differ from the others with respect to their participants, interventions or clinical criteria for defining outcomes.
If appropriate, the data will be pooled and a meta‐analysis will be performed with RevMan software (using the Peto‐modified Mantel‐Haenszel method) using both a fixed‐effect and random‐effects model. Published graphs will display the results of the fixed effect approach.
Crossover trials will only be pooled with parallel trial data when pre‐crossover data are available. In the absence of parallel trials or pre‐crossover data from crossover trials, data from crossover trials will be analysed separately.
We will perform a subgroup analysis regarding the method of ovarian hyperstimulation: trials using clomiphene citrate will be analysed separately from those using gonadotrophins.
To detect publication bias, a funnel graph, plotting sample size versus effect size will be performed.
This review will be updated every two years. Comments by others that might improve the quality of this review will be included.
