The place of intrauterine insemination in the management of infertility

Transcription

1 CURRENT PAPERS Keywords control led ovarian hyperstimulation (COH), intrauterine insemination (IUI), in witro fertilisation (IVF), male factor i n f e rt i I it y, su bfert i I ity. The place of intrauterine insemination in the management of infertility Tariq Miskry, Michael Chapman Many fertility units now offer a range of different treatments for subfertile couples. In couples with unexplained infertility or mild/moderate male factor infertility it may be possible to avoid the more invasive and expensive treatments options, such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). Many clinics now offer intrauterine insemination (IUI) either in the presence or absence of controlled ovarian hyperstimulation (COH). This article reviews some of the current literature examining the importance of patient selection and the role of COH in the role of IUI in managing i nf erti I ity. Author details Tariq Mirkry MRCOG, Fellow in Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, St George Hospital, Gray Street, Kogarah 2217, NSW, Australia. miskryohotmail.com (corresponding author) Michael Chapman mo FRCOG FRCAOG OIEI, Professor and Consultant Obstetrician and Gynaecologis?, St George Hospital, Kogarah, NSW, Australia. I nt rod uct i on Involuntary infertility affects up to 15% of couples. In an attempt to improve upon a spontaneous conception rate of only 2% per cycle, various forms of artificial insemination have been practised in the last 200 years. Recently, the most refined of these techniques, intrauterine insemination (IUI), has gained increasing attention. The aim of IUI is to place a small volume preparation of motile sperm high in the uterine cavity, on the day of ovulation. In many units IUI is often combined with controlled ovarian hyperstimulation (COH) or ovulation induction. In this way the best sperm are introduced at the right time in the cycle, physically close to the fallopian tubes and bypassing cervical mucus, while the number of available oocytes at ovulation is increased. Despite success rates of % per cycle,. the place of IUI, especially in relation to in vitro fertilisation (IVF) techniques, remains controversial. There are also wide variations between units in indications for treatment, patient selection and cycle regimens. For example, in Australia, not all units offer IUI for male factor subfertility or to women over the age of 40 years of age, while there is an enormous range of drug regimens used for COH.5 A literature search using intrauterine insemination as a keyword found 39 citations in the Cochrane Controlled Trials Register and 114 English-language citations on Medline since 1998 alone. In this review of current papers we have chosen four papers that have attempted to resolve what, to us, are the most fundamental issues: patient selection and the place of COH. In critically appraising these papers we have judged them against the accepted gold standard study design of double-blind randomised trials and we have highlighted both their strengths and weaknesses. Selection of patients for intrauterine insemination Timed intercourse versus in t ra ti t e r i ne ins emi na t i on with or without ovarian hyper s ti mu la ti on for subfertility in men. Cohlen BJ,Vandekerckhove P, tevelde ER, Habbema JDE Cochrane Database Syst Rev 2000;(3). The basis for this comprehensive review and meta-analysis was that although IUI is less invasive than IVF its effectiveness in male factor infertility remains controversia1.to justify the use of IUI it must be clear that the technique confers a significant advantage over cycle monitoring with timed intercourse alone. Whether the addition of COH provides further benefit was also examined. Randomised controlled trials assessing IUI and timed intercourse with male factor infertility were identified and examined using established Cochrane search and analysis strategies.this review was last updated in January 38 Q 2003 Royal College of Obstetricians and Gynaecologists

2 1999. In total, 17 trials comparing 3775 treatment cycles were analysed. Despite the problems inherent in pooling results ftom studies with clinical heterogeneity, many with poor methodology, the authors were able to arrive at some firm conclusions. After combining data for meta-analysis, IUI in natural cycles and IUI with COH were found to significantly improve the probability of conception (OR 2.43; 95% CI ) compared with timed intercourse alone (OR 6.23; 95% CI ). This difference was greatest in couples with severe semen defects (e.g. less than 10 million sperm/ml). IUI with COH was also superior to timed intercourse with COH (OR 2.14; 95% CI ). Finally, although the authors noted a strong trend towards higher pregnancy rates (12.6%) versus 7.3%) in favour of COH with IUI versus IUI alone (four trials) this did not reach statistical significance (OR 1.79; 95% CI ). Interestingly, when studies using gonadotrophins rather than clomiphene citrate were analysed separately (two trials) there was a statistically significant increase in pregnancy rates associated with the use of COH compared with IUI alone (OR 2.0; 95% CI ).The multiple pregnancy rate (reported in six studies) associated with COH was 5.5%. all of which were twin pregnancies, while the incidence of ovarian hyperstimulation syndrome (OHSS) (reported in six studies) was 0.8% - all occurring in a single study where a dose of 150 iu human menopausal gonadotrophin (hmg) per day was used (a relatively high dose). The authors concluded from these results that, for the treatment of male subfertility, IUI in natural cycles should be the treatment of choice in cases of severe semen defect and advised the use of IUI with COH using low-dose gonadotrophins in couples with less severe defects only. This advice is rationalised by postulating that subfertility in couples with mild semen abnormalities may be more likely to have a contributory female factor problem, correctable by ovarian stimulation. Nevertheless, we suspect that many clinicians would be reluctant to limit the use of gonadotrophins in IUI to this subgroup, given the strong trend towards increased pregnancy rates associated with COH against relatively low rates of multiple pregnancy and OHSS, particularly with low-dose regimens, reported in this review. Ideally, of course, such use should be as part of clinical trials and indeed the authors recommended further prospective, randomised trials into the role of COH. Sadly, one of the take-home messages from this review is that many published infertility studies suffer from basic methodological problems ranging from study design flaws (such as inadequate randomisation) to inconsistencies in definitions and reporting of complications (such as OHSS). In particular, the authors underlined the need for a universally accepted method of expressing pregnancy rates to allow valid comparison of results. Intrauterine insemination or it? oitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost effectiveness analysis. Goverde AJ, McDonnell J,Vermeiden JPW, Schats R, Rutten FFH, Schoemaker J. Lancet 2000:355: Long-term unexplained or male factor infertility is associated with a low spontaneous pregnancy rate of 2% per cycle. Both IUI and IVF with superovulation increase the chance of pregnancy but have associated risks of OHSS and multiple pregnancy, while IVF in particular is expensive. To justify the use of IVF it should be demonstrably better than IUI. This prospective study from Holland assessed the cost effectiveness of IUI (with and without COH) and IVF and makes recommendations on which option should be considered first-line treatment. After an appropriate power calculation, 258 couples with idiopathic subfertility of over three years or male factor infertility (with at least one million progressively motile spermatozoa after sperm preparation) of one year were adequately randomised after stratification (e.g. for age and duration of infertility) to a maximum of six cycles of IUI alone, IUI and COH or IVE In spontaneous cycles, IUI followed hours after detection of an urinary luteinising hormone (LH) surge (checked twice daily). In stimulated cycles, patients received 75 iu hmg daily and were triggered with human chorionic gonadotrophin (hcg) on detection of the LH surge or on follicle size (> 18 mm) on ultrasound, and IUI performed hours later, depending on the indication for trigger. Monofollicular growth prompted an increase in dose of human menopausal gonadotrophin (hmg) in subsequent cycles. IVF cycles followed a standard long protocol (short protocol in women over 38 years) and oocyte retrieval was performed under regional anaesthesia. It was not clear from the text whether fertilisation relied on conventional IVF or intracytoplasmic sperm injection (ICSI), which is certainly relevant, particularly in male factor infertility. Two embryos were transferred in women aged under 81 Gynaecologist 2003;5:

3 Gynaeco ogist 35 years and three in those over 35 years. For the purposes of analysis, three outcomes were considered: pregnancy resulting in at least one live birth; no pregnancy after treatment and censored. Included in the censored group were couples who dropped out of treatment before completion, pregnancy resulting in miscarriage or stillbirth and those who had not completed treatment at the time of analysis.the rationale for including those who were censored in the denominator for calculating pregnancy rates is that the probability of success of a treatment depends not only on the diagnosis and treatment itself but the likelihood of continuation of treatment in the face of a previous failed cycle (i.e. even if a couple had only a single cycle they contributed to the cumulative pregnancy rate per couple quoted for the full six cycle treatment). The pregnancy rate per started cycle was 7.4% for IUI, 8.7% for IUI with COH and 12.2% for IVF. These low figures reflect the use of including only those pregnancies that resulted in a live birth in the analysis. This translated as cumulative pregnancy rates of 31% for IUI, 37% for IUI with COH and 38% for IVE These differences did not reach statistical significance. Age had the biggest impact on the probability of pregnancy with a woman of 38 years having a 50% lower chance of pregnancy than a woman aged 28 years.the multiple pregnancy rates were 29% and 21% for IUI with COH and IVF, respectively. Two women in the stimulated IUI group (0.6% per cycle) had mild OHSS, compared with three (1.2%) who had severe OHSS requiring admission in the IVF group. The cost per pregnancy was US$4,035 for IUI alone, US$5,108 for IUI with COH and US$13,131 for IVE The authors concluded that IUI was as effective as IVF at one-third of the cost per pregnancy. As IUI with COH did not have a significant impact on pregnancy rates but is more expensive and associated with increased health risks, unstimulated IUI should be considered the firstline treatment option in idiopathic and male factor infertility. This was without doubt a well-designed trial with basically sound methodology. However, we had some problems with their data analysis. First, as the authors conceded they chose to include censored patients as an outcome measure, with the result that the number of patients who completed treatment fell below that required of their power calculation. This is important as, if more couples had completed treatment, the trend in favour of COH with IUI over IUI alone may have reached statistical significance. Second, this paper may underestimate the cumulative pregnancy rate for IVF as they did not assess the impact of frozen embryo transfers following failed fresh cycles. Finally, the authors only included live births in their calculations, whereas the majority of reports express clinical pregnancy rates. Although live births are arguably a more meaningful measure of success, it is dificult to compare these results with other studies. Despite these limitations, this is an extremely important paper that demonstrates that acceptable pregnancy rates, approaching those of IVF, are achievable with IUI. Given the financial and emotional cost of IVF, this paper provides good evidence in favour of IUI as the first-line treatment in unexplained and male factor infertility. As the number of patients completing treatment was lower than expected this study failed to answer whether IUI should be combined with COH. Ovulation induction and intrauterine insemination Eficacy of superovulation arid intrauterine insemination in the treatment of infertility. Guzick DS, Carson SA, Coutifaris C, Overstreet JW, Factor-Litvak P, Steinkampf MP, et al. N Engl] Med 1999;340: This large, prospective, randomised, niulticentre study from the National Cooperative Reproductive Medicine Network in the USA attempted to definitively establish the relative merits of superovulation and IUI both independently and in combination. Women under the age of 40 years with previously untreated idiopathic or male factor subfertility (only men with complete absence of motile sperm were excluded) were randomised to four cycles of treatment within four study groups: timed ICSI (regarded as a control group) timed IUI COH and intracervical insemination (regarded as COH alone) COH and IUI. Women undergoing COH received 150 iu follicle-stimulating hormone (FSH) daily and were triggered when at least two follicles were greater than 18 mm. In this study, pregnancy was defined as a rise in quantitative P-human chorionic gonadotrophin (P-hCG) between days 15 and 17 following insemination. Extensive quality control measures (e.g. internal audits and training of technical stam were employed both for comparability of laboratory analyses and data 40

4 collection, in order to niinimise some of the problems associated with multicentre trials. A total of 932 couples were recruited and underwent 2678 treatment cycles.the cumulative pregnancy rate per couple was 33% for IUI and COH, compared with 19% for ICSI and COH, 18% for IUI alone and 10% for ICSI alone. Couples undergoing COH and IUI were more than three times as likely to become pregnant as the control group (OR 3.2; 95%1 CI 2.C-5.3) and nearly twice as likely as following IUI alone (OR 1.7; 95% CI ). These differences were highly statistically significant and remained true after adjusting for age, duration of infertility and semen characteristics. Interestingly, the largest effect of IUI was seen in couples with the most severe semen abnormalities while, in this same subgroup, COH had the least effect. These finding provide support for the Cochrane review conclusion that superovulation in combination with IUI should be reserved for moderate semen defects and unexplained infertility. Worryingly, the multiple pregnancy rate in those undergoing COH was nearly 3(:)'%1 of all live births and included three quadruplet and four triplet pregnancies. Although the women with higher-order pregnancies underwent fetal reduction, 16% of women treated with COH had a preterm delivery compared with 6'%1 undergoing insemination only.these figures had to be calculated from the data presented and, surprisingly, were not discussed by the authors. In this study, women undergoing COH had their cycles cancelled only if the serum oestrogen was greater than pinol/l on day three and not on the number of follicles. This is a significant criticism of this study design, as a less aggressive policy of ovarian stimulation with stricter cancellation criteria could have limited the number of multiple (especially higher-order) pregnancies. Six women had severe OHSS requiring admission. The frequency of mild and moderate OHSS was not reported. A major criticism of this paper is that the authors f:iiled to present either a power calculation or a trial profile, as recommended by the CONSOKT guidelines for reporting of randoniised trials."this underinines the overall quality of an otherwise well designed and implemented study. A further criticisin is in the authors' choice of control group. It could be argued that a single act of ICSI is not comparable to several acts of timed intercourse and this may have unfairly exaggerated the treatment effects reported here. Nonetheless, this study provides good evidence that COH provides an independent positive effect on pregnancy rates when combined with IUI. A randomised prospective study comparing pregnancy rates after clotniphene citrate and human menopausal gonadotrophin before in t ra 11 t e r i n e ins e 111 in at i on. Ecochard R, Mathieu C, Royere D, Blache G, Kabilloud M, Czyba J. Fertil Steril 2000;73:90-3. Among the disadvantages of gonadotrophins for COH are the need for frequent injections and the level of monitoring required to reduce the incidence of OHSS and multiple pregnancies. As a result, cloniiphene citrate is used in some units as a simpler alternative. However, there is little evidence to suggest that pregnancy rates with IUI and cloniiphene are better than IUI alone. This study set out to determine the relative eficacy of clomiphene citrate compared with gonadotrophins. The authors carried out a randomised prospective crossover study comparing nig ofcloniiphene citrate in days three to seven of the cycle, with four doses of 150 iu hmg alternate daily from day four. Both treatment arms had identical cycle monitoring with daily transvaginal ultrasound and serum oestradiol and luteinising hormone (LH) estimation from day ten. Ovulation was triggered with hcg on follicle size or detection of the LH surge. A total of 58 couples under the age of 39 years with female factor (ovulatory dysfunction, cervical factor, endonietriosis), male factor (at least three million motile spermatozoa after preparation) or idiopathic infertility of more than two years were randomised to two cycles of clomiphene citrate followed by two cycles of hmg or vice versa. This represented a total of 97 clomiphene citrate and 86 hmg cycles.they achieved a per cycle pregnancy rate of7.14'% for hmg and 14.4% for clomiphene and cumulative pregnancy rates of 25.4% and 51.4'%1, respectively. These differences failed to reach statistical significance.the authors therefore concluded that clomiphene is at least as effective as hmg. Unfortunately, the methodology in this study has several flaws.the regimen of hmg chosen by the authors was slightly unusual and different from regimens previously reported by other groups, which niay have adversely affected the pregnancy rate in the hmg group. Indeed, the authors admitted that their results were lower than predicted from the literature. Conversely, their results following clomiphene citrate were higher than expected. In part, the authors attribute this to the same close monitoring and use of an HCG trigger as in the hmg group. Paradoxically, of course, such intensive monitoring removes one of 41

5 ~ ~~ References the principle advantages of clomiphene. The fundamental problem with this paper however, is that the power of this study was only 30% to detect a difference in cumulative pregnancy rates. In fact, assuming a cumulative pregnancy rate of 25% for IUI with gonadotrophins, 200 couples would be required in each arm for a power of 80% to detect a difference of 10% in pregnancy rates.as a result, it is difficult to agree with the authors conclusion that this paper demonstrates that clomiphene citrate is as effective as hh4g. Of the studies that we have presented, this was certainly the weakest and illustrates the need for better trial design. A larger, preferably parallel study is certainly required to definitively answer the question of efficacy of clomiphene citrate for COH in IUI programmes. Conclusion In the current climate of evidence-based medicine, the case for IUI with or without COH as the first-line treatment for unexplained and mild or moderate male factor infertility appears to be strong. Even in the presence of severe semen defects, IUI improves pregnancy rates and is an option for the couple who wish to avoid IVF/ICSI. Although pregnancy may not occur as quickly, a policy of initial treatment by IUI will probably save 20% of couples from moving on to IVF, which is universally accepted as being more invasive and expensive both financially and emotionally. There are still questions to be answered, however, such as the optimuni dose regimen of gonadotrophins and the place of clomiphene for COH. These issues will only be resolved by high-quality prospective trials with adequate power, preferably with standardised reporting of success and complication rates. 1. Teiiipleton A. Frdser C:.Thnnipson l3.the epideiiiioloh?. of infertility in Aberderii. R,U/ I1)Yl);301:I1X Urinsden R, Marcus S. An overview ofiiitraiiterinc insemination. In: Meniru GI. editor..4 Hmrdliook!/ Iiirrmrrrrbrr Ii~~~~iiri~r~~riu~i. (:mibridge: (:aiiihridge University Press: IYY7. p. I-X. 3. Stone l3a.vargy.s JM. I\itiglcr GE. Stcin AL. Marrc 1. KI? I)eterminants of outcome of intrauterine inseiiiiiiation: Analysis of outconire of 9963 consecutive cycles. Ani J Olisrcr Cyiiem/ 1 Y9Y;180: Kaplan I F. Austin DJ, Freund R. Subcutaneous hunian nienopausal gonadotropin administration for controlled ovarian hyperctimulation with intrauterine inseniinatioii cycles. Am J Obssrrr Gynrrnl ; 182: Miskry T. Chapman M.The use of intrauterine insemination in Australia and New Zealand. Hirni Rcprod 2002:17: Uegg C, Cho M. Eastwood S, Horton R, Moher D. Olkin I, e! a/. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1 YY6;276: