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Gonadotrophin ovarian stimulation and intrauterine insemination for unexplained infertility
RBMOnline - Vol 9. No 6. 2004 664-672 Reproductive BioMedicine Online; www.rbmonline.com/Article/1560 on web 2 November 2004
Article Gonadotrophin ovarian stimulation and intrauterine insemination for unexplained infertility
Dr Juan Balasch
Juan Balasch obtained his MD degree (1974) and the speciality degree in Obstetrics and Gynaecology (1977) at the Faculty of Medicine-Hospital Clínic, University of Barcelona in Spain. The PhD degree was granted to him at the same University in 1979. At present he is full professor in Obstetrics and Gynaecology and Head of the Fertility Unit at the Faculty of Medicine-Hospital Clinic, University of Barcelona. Professor Balasch is Past President of the Spanish Fertility Society and has more than 200 publications in international journals and books; in a series of studies he and his team developed a new hypothesis on the pathogenesis of the ovarian hyperstimulation syndrome. He serves as ad-hoc reviewer or is on the Editorial Board of different international journals dealing with fertility, gynaecological endocrinology and human reproduction. Professor Balasch’s current research interests include assisted reproduction, repeated abortion, implantation failure and ovarian (hyper)stimulation.
Juan Balasch Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine, University of Barcelona, Barcelona, Spain Correspondence: Institut Clinic of Gynecology, Hospital Clínic, C/Casanova 143, 08036-Barcelona, Spain. Tel: +34 93 2275534; Fax: +34 93 2275454; e-mail: [email protected]
Abstract Over the past 15 years, there has been a marked increase in the use of ovulation induction and intrauterine insemination (IUI) for the treatment of unexplained infertility. However, although ovulation induction and IUI have rapidly gained popularity, clinical use is based largely on practical experience rather than on well-designed scientific studies. This article summarizes the evidence in this area. Despite clinical heterogeneity and different methodological qualities of the trials, it can be concluded that ovulation induction significantly improves the probability of conception in couples with unexplained infertility, particularly when associated with IUI. It is remarkable, though, that there has been only one large-scale, randomized trial of ovulation induction plus IUI in the treatment of unexplained infertility in which one of the study arms is an untreated control group. For couples requiring treatment, the complication rate must be minimized, particularly the occurrence of high-order multiple pregnancy. Evaluation of the effectiveness and safety of low-dose gonadotrophin administration in patients with unexplained infertility is limited and further studies are warranted. Keywords: gonadotrophins, intrauterine insemination, ovarian stimulation, unexplained infertility
Introduction The efficacy of treatment for infertility disorders may be assessed easily and objectively by the resulting pregnancy rates. Cycle fecundity after IVF and embryo transfer in women who have had their Fallopian tubes surgically removed provides a good indication of the efficacy of IVF for that condition. Similarly, in partners of azoospermic males undergoing artificial insemination with donor semen, the cycle fecundity is a good indicator of the suitability of this therapeutic approach.
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The underlying assumption in the analysis of efficacy for any infertility treatment is that the likelihood of pregnancy without treatment is negligible. However, most couples seeking
therapy for infertility are not truly sterile, but have some degree of subfertility (i.e. the couples have conditions associated with a relative decrease in the monthly likelihood of conception) and can achieve pregnancy without treatment (Collins et al., 1983; Evers, 2002). Thus, in contrast to the treatment of sterility, it cannot be assumed that the pregnancy that occurs after treatment for subfertility is attributable solely to the treatment, because it could have occurred by chance. Such treatment independent pregnancies are more likely in couples designated as having unexplained infertility. Despite advances in the diagnosis of causes of subfertility, inability to conceive remains unexplained in 25–30% of fully investigated couples (Evers, 2002). In these couples, the delay in conception may represent a chance delay or may be, in many cases, the result of an as yet undetected abnormality in the
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reproductive process. Cumulative pregnancy rates of 60% may be achieved within 2 years; however, for infertility of greater than 3 years duration, monthly fecundity rates in untreated couples are 1–2% (Hull, 1992; Collins et al., 1995). Therefore, designing and assessing the efficacy (or lack thereof) of treatment of unexplained infertility is rather challenging for several reasons (Hull et al., 1985; Hull, 1992; ESHRE Capri Workshop, 1996; Evers, 2002): (i) There is a lack of consistency in the literature in defining the condition and couples with only mild endometriosis are frequently considered to have unexplained infertility. (ii) Therapy of unexplained infertility does not fit standard practice for medical decision making. Such standard practice requires a specific pathophysiological rationale that allows the correction of a biological defect. Because no such defect is known in unexplained infertility, treatment approaches are usually empiric. (iii) Given the high probability for conception in such couples with observation alone, especially with infertility lasting less than 3 years, a decrease in the time to conception may be seen rather than an increase in the absolute number of couples conceiving. (iv) There is a paucity of prospective, randomized, controlled trials evaluating pregnancy rates in treated and untreated patients with unexplained infertility. During the past 15 years, there has been a marked increase in the use of two treatments (used alone or in combination) for unexplained infertility: induction of ovulation induction, in which the ovaries are stimulated with exogenous gonadotrophins to develop several dominant follicles, and intrauterine insemination (IUI), in which motile spermatozoa are suspended in culture medium and injected transcervically into the uterine cavity. However, although IUI and/or ovulation induction have rapidly gained popularity, clinical practice is based largely on practical experience rather than well-designed scientific studies (Collins, 2003; Hughes, 2003; Stewart, 2003). This report summarizes the evidence regarding the efficacy of gonadotrophin treatment associated with IUI for unexplained infertility. In this report, FSH was used as synonymous with ovarian stimulation with gonadotrophins, i.e. HMG or FSH.
Ovulation induction and IUI for unexplained infertility: is there a rationale? Taking into account the above considerations, what might be the rationale for administering gonadotrophins to stimulate follicular development in patients with unexplained infertility, who by definition have regular, ovulatory menstrual cycles? Why introduce washed spermatozoa into the uterine cavity in situations in which the semen analysis is normal and there is no cervical factor present? With respect to ovarian stimulation, two explanations have been offered (Collins, 1990; Guzick et al., 1998): (i) it may overcome a subtle defect in ovulatory function not uncovered by conventional testing, and (ii) it may enhance the likelihood of pregnancy by increasing the number of eggs available for fertilization. According to the latter rationale, ovarian stimulation might improve the monthly pregnancy rate by simply increasing the number of oocytes available for fertilization and implantation. In fact, ovulation induction therapy was developed as a result of a
fortuitous clinical observation. Some patients who received FSH in preparation for an IVF or gamete intra-Fallopian transfer (GIFT) cycle had their oocyte retrieval procedure cancelled (because of inadequate numbers of follicles or endogenous LH surge) but became pregnant anyway (Haney et al., 1987; Curole et al., 1989). This observation suggested that multiple follicular recruitment and egg release might be the most critical element contributing to pregnancy. The direct relationship found between the intensity of stimulation protocols used for ovulation induction and IUI and the multiple pregnancy rates further supports this contention (Nan et al., 1994; Gleicher et al., 2000). Along similar lines of thinking, by increasing the density of motile spermatozoa with a high proportion of normal forms available to these oocytes by IUI might further increase the monthly probability of pregnancy. In addition, timing the insemination as close to ovulation as possible optimizes the likelihood for gamete interaction (Stewart, 2003). Thus, by increasing the numbers of gametes at the site of fertilization, the probability of conception can be increased. In fact, this is also the rationale behind IUI in couples with moderate male factor subfertility where sperm morphology using strict criteria and the inseminating motile sperm count after sperm preparation are the two most important sperm parameters related to IUI success (Ombelet, 2003).
Efficacy of ovulation induction alone or in combination with IUI for unexplained infertility: analysis of the literature In order to allow firm conclusions to be drawn on whether ovulation induction, with or without IUI, significantly improves the probability of conception in cases of unexplained infertility compared with timed intercourse (TI), and to address the question of what are the independent effects of gonadotrophins and IUI, four comparisons should be performed in randomized clinical trials (Cohlen et al., 1995, 2004a). First, IUI should be compared with TI in natural cycles (comparison 1) and in stimulated ovulation cycles (comparison 2). Whether ovulation induction in combination with TI improves the probability of conception should be investigated in a trial comparing TI in stimulated cycles with TI in natural cycles (comparison 3). Whether ovulation induction in combination with IUI improves the probability of conception should be investigated in a trial comparing IUI in stimulated cycles with IUI in natural cycles (comparison 4). The aim of this analysis of the literature is to determine, after performing the four above-mentioned comparisons, whether, for unexplained infertility, ovulation induction improves the probability of conception compared with TI, and whether IUI improves the results any further. The following studies [four meta-analysis, two analysis of combined data from the literature, and three large, randomized clinical trials (two multicentre trials)] in the literature were considered relevant in this regard.
Meta-analysis by Cohlen (1998) This study is the basis for a Cochrane Review (protocol) (Cohlen et al., 2004a) and presents preliminary data from 18 randomized clinical trials in which ovulation induction was achieved with FSH (alone in most treatment cycles and associated with
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clomiphene citrate in others; as these are preliminary results, the actual studies have not been described) (Table 1). These results indicate that IUI in natural cycles does not improve the probability of conception in couples with unexplained infertility. However, when ovulation induction is applied, IUI has an independent positive effect. Therefore, it seems that, in the case of unexplained infertility, ovulation induction is more important compared with IUI. It is thus postulated that the worse the semen factor the more important IUI becomes, and the better the semen factor, the more important ovulation induction becomes. It seems logical to suggest that the better the semen quality, the more likely female factors are to influence the subfertility of the couple (Dunphy et al., 1990; Cohlen et al., 1998). As previously discussed, ovarian stimulation might overcome these subtle factors, as well as increasing the number of available oocytes. The above hypothesis is further supported by a Cochrane Review (Cohlen et al., 2004b) analysing TI versus IUI with or without ovarian stimulation for subfertility in men and concluding that in both natural and stimulated cycles IUI significantly improves the probability of conception compared with TI. However, whereas IUI in cycles with ovarian stimulation improved the probability of conception compared with IUI in natural cycles, significance was not reached.
Meta-analysis by Zeyneloglu et al. (1998) Seven prospective randomized trials of couples with unexplained infertility were eligible for inclusion in this metaanalysis. The quality of the individual studies was assessed with the use of a method modified by Chalmers et al. (1981). The mean validity score for trials selected was 60%. A total of 980 cycles were evaluated when all studies were combined. There were 49 pregnancies resulting from 431 cycles with TI (11.37%), compared with 110 pregnancies from 549 IUI cycles (20.04%). For individual studies, the odds ratios (OR) for pregnancy for cycles with IUI versus TI ranged from 0.98 to 3.57, and confidence intervals (CI) ranged from 0.22 to 43.01. Only two studies reported significantly increased benefit from addition of IUI to ovarian stimulation, whereas the remaining studies failed to show a significant effect of IUI versus TI. The common OR (1.84; 95% CI: 1.30–2.62), however, revealed a significant effect of IUI. The analysis showed that the studies were homogeneous, with a Breslow–Day score of 8.97 (df = 6; not statistically significant). From this meta-analysis, it was concluded that couples treated for unexplained infertility could benefit from the addition of IUI to ovulation induction. The authors propose that the use of IUI in combination with FSH will help many couples to avoid the stress and cost of more invasive technologies.
Meta-analysis by Hughes (1997)
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This is a systematic review evaluating the effectiveness of IUI with or without ovarian stimulation in the treatment of unexplained infertility. Relevant randomized, controlled trials were identified by a diverse strategy, including a hand search of 43 core journals since 1966. Two approaches to meta-analysis were used to summarize the data. First, using a standard Mantel–Haenszel approach, eight trials comparing FSH/IUI with FSH/TI for unexplained infertility were combined. The common OR for pregnancy per treatment cycle was 2.37 (95%
CI, 1.43–3.90), suggesting a significant improvement with IUI following ovulation induction in this patient group. Although the data were statistically homogeneous (the Breslow–Day test of heterogeneity was not statistically significant), clinically significant heterogeneity was present. Second, the independent effects of treatment with FSH and IUI were assessed using stepwise logistic regression. Based on 4516 cycles reported in 22 trials, the adjusted OR for pregnancy associated with FSH use was 2.35 (95% CI, 1.87–2.94) and for IUI 2.82 (95% CI 2.18–3.66) (Table 2). Thus, when compared with untreated cycles, the average level of fecundity is more than two-fold higher in a cycle with either treatment and approximately fivefold higher when both treatments are combined.
Meta-analysis by the European Society for Human Reproduction and Embryology (ESHRE) – The ESHRE Capri Workshop Group (1996) Data from 13 randomized clinical trials were assembled in a meta-analysis to estimate the independent effects of ovarian stimulation and IUI in patients with unexplained infertility. The common element in this analysis was IUI treatment. All trials either compared IUI treatment with TI or IUI treatment was the active control treatment. Based on 2065 non-stimulated cycles and 956 gonadotrophin-stimulated cycles, the unadjusted aggregate results indicated that the pregnancy rate per cycle was 3% in cycles of observation with TI, 6% in FSH cycles and 14% in cycles of FSH and IUI (Table 3). From the logistic regression analysis, the effects of IUI and FSH treatment were similar: each treatment significantly increased the likelihood of conception approximately two-fold.
Analysis of data by Guzick et al. (1998) This work was conducted during 1996 when the investigators were members of a subcommittee of the ASRM Practice Committee. The subcommittee was convened to write evidence-based guidelines on the use of assisted reproduction in the treatment of unexplained infertility. After reviewing the literature and working with the data, it was concluded that the dearth of randomized, controlled trials in this area precluded the writing of guidelines that were strictly evidence-based. However, in view of the need for clinicians to make reasoned judgments about treatment alternatives, a summary of evidence was collected regarding the efficacy of alternative treatments for unexplained infertility. Aggregate data from 45 published reports involving expectant management, IUI, ovulation induction, GIFT, and IVF for unexplained infertility were presented. Some studies reported data pertaining to only one treatment, whereas others reported data on two or more treatments. Each study was assigned a quality score based on its strengths and weaknesses. Studies could have received a total score ranging from 6 to 20. The actual point scores for the studies reviewed ranged from 6 to 19 [mean (±SD) score 12.7 ± 3.2]. Quality-adjusted pregnancy rates were calculated by applying quality scores of studies to their pregnancy rate data. Combined pregnancy rates per initiated cycle, adjusted for study quality, are summarized in Table 4. Based on the highest level of evidence found in the data, it may be concluded that IUI does not appear to be efficacious without some form of ovulation induction.
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Table 1. Preliminary results combining 18 randomized clinical trials in patients with unexplained infertility. Comparison
OR
(95% CI)
IUI versus TI FSH + IUI versus FSH + TI FSH + TI versus TI FSH + IUI versus IUI
1.3 1.9 1.9 4.4
(0.37–4.6) (1.4–2.6) (1.1–3.1) (1.9–10)
Adapted from Cohlen et al. (1998).
Table 2. Crude aggregate data from 22 relevant trials (4516 cycles) of FSH versus no stimulation for IUI or timed intercourse as treatment for unexplained infertility.
Ovulation stimulation No stimulation FSH
No. (%) of pregnancies per cycle IUI TI
OR (95% CI)
80/1306 (6) 171/1156 (15)
2.82 (2.18–3.66) 2.35 (1.87–2.94)
27/1354 (2) 47/700 (7)
Adapted from Hughes (1997).
Table 3. Aggregate pregnancy rates in trials of IUI with and without ovarian stimulation for unexplained infertility.
Ovarian stimulation No stimulation FSH
No. (%) of pregnancies per cycle IUI TI
OR (95% CI)
61/1102 (6) 90/625 (14)
2.09 (1.35–3.22) 2.19 (1.45–3.32)
25/963 (3) 21/331 (6)
Adapted from the ESHRE Capri Workshop Group (1996).
Table 4. Aggregate data for alternative treatments for unexplained infertility. Treatment
No. of studies
No. (%) of pregnancies per initiated cycle
Control groups Control groups, randomized studies IUI FSH FSH + IUI
11
64/3539 (1.8)
6 9 13 14
23/597 (3.9) 15/378 (4.0) 139/1806 (7.7) 207/1133 (18.3)
Percentage of qualityadjusted pregnancies per initiated cycle 1.3
4.1 3.8 7.7 17.1
Adapted from Guzick et al. (1998).
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Study by Aboulghar et al. (2003) In this study, the results of different randomized controlled trials comparing ovulation induction and IUI versus ovulation induction and TI (n = 13 studies), ovulation induction and IUI versus IUI alone (n = 5 studies), and ovulation induction and IUI versus ovulation induction and cervical insemination (n = 4 studies) in patients with unexplained infertility were analysed. Aggregate analysis of the extracted data does suggest that combined ovarian stimulation and IUI has more beneficial effect than ovarian stimulation alone (Table 5). The results of trials comparing ovulation induction plus IUI versus IUI alone showed that the pregnancy rate in the first treatment group was significantly higher than that obtained using IUI alone. From these data, the authors assumed that both ovarian stimulation and IUI were independent positive factors in achieving better pregnancy rate in unexplained infertility. The optimum number of ovarian stimulation/IUI cycles in the treatment of unexplained infertility was investigated by the authors (Aboulghar et al., 2001), who performed an observational prospective study in which 594 couples with unexplained infertility were treated by ovulation induction and IUI for up to 3 cycles before trying IVF. One to three cycles of ovarian stimulation/IUI were performed in 594 patients undergoing 1112 cycles. Up to three further trials (cycles 4–6) of ovulation induction/IUI were then done in 91 of these women, a total of 161 cycles. In the first three treatment cycles a cycle fecundity of 16.4% was achieved, as compared with 5.6% in cycles 4–6, a highly significant difference. The authors concluded that in unexplained infertility, IVF should be tried after failure of three trials of ovarian stimulation/IUI. The aggregate analysis of randomized controlled trials comparing ovulation induction/IUI versus ovulation induction/cervical insemination demonstrated that the former association has a significantly higher pregnancy rate than the latter (Table 5).
Study by Crosignani et al. (1991) Nineteen European fertility centres participated in a controlled, randomized trial aimed at comparing the effectiveness of five methods for the treatment of unexplained infertility: ovulation induction alone, and ovulation induction together with one of the following procedures: IUI, intraperitoneal insemination, GIFT and IVF. By the end of the trial, 444 patients had been treated in a total of 649 cycles. Because of unavoidable practical difficulties, the experimental design eventually obtained was severely unbalanced. Nevertheless, objective statistical comparisons were possible among the five treatments, using non-orthogonal analysis of variance. There was some statistical evidence that the pregnancy rate obtained from ovulation induction alone was inferior to that obtained by using ovulation induction together with one of the methods of assisted conception. The pregnancy rate in each method of the assisted conception groups was found to be vastly better than various estimates of the spontaneous pregnancy rates cited in the literature.
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This multicentre randomized trial was conducted by the Reproductive Medicine Network of the National Institute of Child Health and Development. The overall hypothesis of the
study was that induction of ovulation induction with FSH or IUI would result in a higher pregnancy rate among infertile couples than would no treatment. No treatment was defined as intracervical insemination timed to a surge in the urinary excretion of LH to ensure that spermatozoa were present in the cervix and vaginal fornix at the time of ovulation. The study included 932 couples, in which the woman had no identifiable infertility factor and the man had motile spermatozoa (i.e. unexplained infertility or male factor infertility). The couples were randomly assigned to receive intracervical insemination, IUI, ovulation induction and intracervical insemination, or ovulation induction and IUI. Treatment continued for four cycles, unless pregnancy was achieved. The 231 couples in the group treated with ovulation induction and IUI had a higher rate of pregnancy (33%) than the 234 couples in the IUI group (18%), the 234 couples in the group treated with ovulation induction and intracervical insemination (19%), or the 233 couples in the intracervical insemination group (10%). Stratified, discrete-time, Cox proportionalhazards analysis showed that the couples in the group treated with ovulation induction and IUI were 3.2 times more likely to become pregnant than those in the intracervical insemination group (95% CI, 2.0–5.3) and 1.7 times more likely to become pregnant than those in the IUI group (95% CI, 1.2–2.6). The couples in the IUI group and in the group treated with ovulation induction and intracervical insemination were nearly twice as likely to conceive as those in the intracervical insemination group. The effects of ovulation induction and IUI on pregnancy for the whole study population appear to be independent and additive, with both techniques contributing equally to the likelihood of pregnancy. However, among couples in which the man had sperm values in the lowest quartile, more or less corresponding to a diagnosis of male subfertility, induction of ovulation induction had little effect and IUI had a greater positive effect.
Study by Goverde et al. (2000) In this prospective, randomized trial, 258 couples with idiopathic subfertility or male subfertility were treated for a maximum of six cycles of either IUI in a spontaneous cycle (IUI alone) (n = 86), IUI after mild ovarian stimulation with FSH (n = 85), or IVF (n = 87). Although the pregnancy rate per cycle was higher in the IVF group than in the IUI groups (12.2 versus 7.4 and 8.7% respectively; not statistically significant), the cumulative pregnancy rate for IVF was not significantly better than that for IUI. Also, IUI was a more cost-effective treatment than IVF. The authors concluded that IUI in the spontaneous cycle carries fewer health risks than IUI after mild hormonal stimulation and is, therefore, the treatment of first-choice. However, a feature of the trial design deserves comment. The combination of two diagnostic groups (idiopathic and male subfertility) is justified from a pragmatic point of view, because the same treatment was offered to both groups, but combination of the groups does affect the interpretation of the results. In this trial, the sample size of 80 in each group was chosen to allow detection of a significant difference in outcome between the intervention groups, but was insufficient
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to do so for each diagnostic category. In fact, when patients with unexplained infertility and male factor infertility were considered separately, pregnancy rates in the former group tended to be higher when IUI was used in combination with ovulation induction (37%), as compared with IUI alone (26%). In contrast, in patients with male subfertility, pregnancy rates in the groups undergoing IUI alone and IUI plus ovulation induction were very similar (42 and 37% respectively).
Concluding remarks and future perspectives Despite clinical heterogeneity and different methodological qualities of the trials comparing efficacy of treatment for unexplained infertility, based on the evidence found in the analysed data (Table 6) the following recommendations can be made. In couples with unexplained infertility, ovulation induction with gonadotrophins significantly improves the
probability of conception, particularly when associated with IUI. It is remarkable, however, that in all the years that FSH and IUI has been in widespread use, there has been only one large-scale, randomized trial of gonadotrophin use plus IUI in the treatment of unexplained infertility in which one of the study arms is an untreated control group (Guzick et al., 1999). In this study, however, timed intracervical insemination with prepared semen was adopted as the baseline, or control, (non)treatment. For two reasons, this approach may not truly reflect actual non-treatment, leading to an overestimation of the therapeutic value of IUI and ovulation induction (te Velde and Cohlen, 1999). First, spermatozoa ejaculated during normal intercourse may be of better quality than those obtained by masturbation. Second, the probability of conception during the fertile period increases if there are several acts of intercourse rather than the single insemination used in the study by Guzick et al. (1999). Thus, further studies of FSH plus IUI versus no treatment are needed.
Table 5. Aggregate pregnancy rates of 20 randomized controlled trials comparing alternative treatments for unexplained infertility. Figures in parentheses are percentages. Comparison
No. (%) of pregnancies per cycle
OR (95% CI)
FSH + IUI versus FSH + TI FSH + IUI versus IUI FSH + IUI versus FSH + cervical insemination
170/929 (18) versus 76/711 (11) 107/478 (22) versus 59/466 (13) 127/476 (27) versus 74/517 (14)
1.71 (1.28–2. 28) 1.77 (1.26–2.49) 1.86 (1.36–2.54)
Adapted from Aboulghar et al. (2003).
Table 6. Summary of reported results of treatment for unexplained infertility in the studies included in this paper. Study
IUI versus TI
FSH + IUI versus FSH + TI
Result
FSH + TI versus TI
Result
FSH + IUI versus IUI
Result
Cohlen et al. (1998) Zeyneloglu et al. (1998) Hughes (1997) ESHRE Capri Workshop group (1996) Guzick et al. (1998) Crosignani et al. (1991) Guzick et al. (1999) Goverde et al. (2000) Aboulghar et al. (2003)
No difference
FSH + IUI
Better
FSH + TI
Better
FSH + IUI
Better
–
FSH + IUI
Better
–
IUI better IUI better
FSH + IUI FSH + IUI
Better Better
FSH + TI FSH + TI
Better Better
FSH + IUI FSH + IUI
Better Better
No difference
FSH + IUI
Better
FSH + TI
Better
FSH + IUI
Better
–
FSH + IUI
Better
–
IUI better
FSH + IUI
Better
FSH + TI
–
FSH + IUI
Better
–
FSH + IUI
Better
–
– Better
FSH + IUI
Better
–
FSH + IUI
Better
–
FSH + IUI
Better
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On the other hand, for couples for whom treatment does become necessary, the complication rate must be minimized. Traditionally, intense levels of ovarian stimulation in IUI cycles have been used, leading the more aggressive protocols to higher monthly fecundity rates but also to more multiple pregnancies and an unacceptably high rate of triplets (Nan et al., 1994; Gleicher et al., 2000). Interestingly, according to population-based studies, as many as two-thirds of iatrogenic multiple pregnancies, mainly high-order gestations (triplets or more), may be attributable to ovulation-inducing drugs without IVF or related techniques (Levene et al., 1992; Derom et al., 1993; Evans et al., 1995; Corchia et al., 1996; Wilcox et al., 1996). As multiple gestations of triplets or more represent the majority of the risk usually associated with multiple births, ovarian stimulation seems acceptable only when it leads to a singleton pregnancy or, occasionally, twin pregnancies. Clomiphene citrate could be postulated as a treatment option in this regard, but its use in women with unexplained infertility is associated with a small absolute effect on treatment per cycle (Hughes et al., 2001) and pregnancy rates obtained are lower in comparison with FSH treatment, mainly when ovarian stimulation is associated with IUI (Balasch et al., 1994; ESHRE Capri Workshop Group, 1996; Hughes, 1997; Cohlen et al., 1998a; Matorras et al., 2002; Costello, 2004). Very recently, however, the place of IUI in association with ovulation induction has been brought into focus by the NICE Fertility Guidelines (National Collaborating Centre for Women’s and Children’s Health, 2004) when stressing that ‘where IUI is used to manage unexplained infertility problems, both stimulated and unstimulated IUI are more effective than no treatment. However, ovarian stimulation should not be offered, even though it is associated with higher pregnancy rates than unstimulated IUI, because it carries a risk of multiple pregnancy’. Thus, the main objection to using IUI and gonadotrophin ovarian stimulation as the initial treatment in unexplained infertility has been the multiple pregnancy rate (Stewart, 2003). In fact, it has recently been suggested that IVF should be offered as first-line therapy as opposed to IUI and ovulation induction with gonadotrophins for the treatment of unexplained infertility (Gleicher et al., 2000; Gleicher and Karande, 2001).
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In response to this argument, others (Collins, 2003; Hughes, 2003) regretted the lack of good quality, large, prospective randomized trials to settle the argument. Notably, Homburg (Homburg 2003; Homburg and Insler, 2002) has critically and thoughtfully analysed this subject using the results of randomized controlled trials wherever possible, live birth rates rather than pregnancy rates and taking into account efficacy; complications, especially multiple pregnancy rates; patient compliance and cost efficiency. The efficiency of the IVF is still limited; although less efficient on a per-cycle basis, findings are consistent in concluding that IUI and ovulation induction are nevertheless capable of producing a pregnancy and delivery within a reasonable time. There is little doubt that IVF is a much more invasive procedure than IUI and that ovulation induction and IUI are unequivocally less complicated and safer compared with IVF. In fact, the cumulative drop-out rate in an IVF programme is significantly higher than that for IUI. Ovulation induction coupled with IUI is more cost-effective than IVF (Homburg, 2003; Homburg and Insler, 2002). The cost of an IVF cycle is approximately four times higher than the cost of a cycle of FSH/IUI treatment
(Collins, 2003). Cost–effectiveness, which is the ratio of cost to success, tends to decrease when success is better and increase when costs go up. Thus, given the four- to five-fold higher cost of IVF, the live birth rate with a cycle of IVF would have to be four-fold greater than the live birth rate with a cycle of FSH/IUI to achieve a similar level of cost-effectiveness (Collins, 2003). On the other hand, because FSH/IUI is more tolerable and less expensive than IVF, repeated cycles are possible, further increasing the absolute number of pregnancies associated with these treatments (Hughes, 2003). As stressed above, the main objection to using IUI and ovulation induction in the treatment of unexplained infertility has been the multiple pregnancy rate, especially high-order multiple pregnancies (Gleicher et al., 2000; Stewart, 2003), which in both medical and social terms can have highly negative consequences (Jones, 2003). The recent study by Gleicher et al. (2000) supports the idea that specific ultrasonographic and oestradiol parameters do not prevent high-order multiple pregnancies. In fact, that study concluded that current criteria result in an unacceptably high incidence of high-order multiple pregnancies after the induction of ovulation with gonadotrophins and the authors suggested that better criteria cannot easily be developed without negatively affecting overall pregnancy rates (Gleicher et al., 2000). In other words, according to those authors, gonadotrophin stimulation that is less intensive than is currently customary may reduce the incidence of high-order multiple pregnancy in fertile women, though only to a limited extent and at the expense of overall pregnancy rate (Gleicher et al., 2000). However, more recent work (Dickey et al., 2001; Tur et al., 2001) has suggested that certain factors are associated with high-order gestations after gonadotrophin stimulation and if relatively conservative limits for follicular development and oestradiol serum concentrations are rigorously applied, the number of high-order multiple pregnancies that result from ovulation induction with exogenous gonadotrophins might be significantly reduced. In the study by Tur et al. (2001), a large series of 1878 consecutive pregnancies obtained in cycles stimulated with gonadotrophins was retrospectively analysed. Of the 1878 conceptional cycles, 1493 resulted from IUI with husband’s (n = 1041) or donor frozen–thawed (n = 452) spermatozoa and the remaining 385 followed ovulation induction and TI. Employing univariate, multivariate and receiver-operating characteristic analysis, a three-variable model was developed to identify patients at high risk for highorder multiple pregnancies in ovulation induction cycles. It was found that the risk of high-order multiple implantation correlated significantly with increasing total number of follicles and was significantly increased in women with a serum oestradiol >862 pg/ml and aged ≤32 years (Tur et al., 2001). Very recently (Tur et al., 2005), the effectiveness in clinical practice of such a prediction model has been determined prospectively in a series of 849 consecutive infertile patients undergoing a total of 1542 treatment cycles. Women were either anovulatory (n = 196 cycles) or were undergoing ovarian stimulation on an empirical basis, usually in conjunction with IUI (n = 1346 cycles) with husband’s (n = 1138 cycles) or donor frozen–thawed (n = 208 cycles) spermatozoa. It was found that the use of the prediction model
Article - Unexplained infertility - J Balasch
(implying cancellation of all cycles at high risk for high-order multiple pregnancies) would result in an 8% (95% CI, 6.8–9.2%) reduction of overall pregnancy rate but also in a 285% (95% CI, 279–291%) reduction of high-order multiple pregnancies (Tur et al., 2005). By using this prediction model, it was possible to maintain a low risk of high-order multiple gestations with a good pregnancy rate in patients receiving gonadotrophin ovarian stimulation or induction of ovulation without IVF. Thus, in conclusion, recognizing the importance of certain variables (i.e. woman’s age, oestradiol serum concentrations, and follicular development) in predicting multiple pregnancies in gonadotrophin stimulated cycles, appropriate guidelines should be established in each individual centre. It should be noted that in a prospective study (Tur et al., 2005), the regimen of gonadotrophin administration was the chronic low-dose step-up regimen where the starting dose of recombinant or highly purified FSH was 75 IU/day for most women (>85%) (37.5 IU/day in previous high responders and 150 IU/day for those women aged ≥40 years or for previous poor responders). The effectiveness and safety of low-dose administration of FSH in WHO group II anovulatory infertile women are well established (Balasch et al., 1996; White et al., 1996; Homburg and Howles, 1999), but evaluation of this therapeutic option for treatment of patients with non-ovulatory disorders, including unexplained infertility, has been limited (Balasch et al., 1994; Hughes et al., 1998; Sengoku et al., 1999). As stressed by the ESHRE Capri Workshop Group (2000), prevention is the most important means of decreasing multiple gestation rates, and multiple gestation rates in ovulation induction and ovulation induction cycles can be reduced by using lower dosage gonadotrophin regimens. Thus, large-scale studies investigating the clinical efficacy of lowdose FSH administration combined with IUI for unexplained infertility are warranted. Notably, a very recent large observational study (Papageorgiou et al., 2004) including 3219 IUI cycles (334, or 10%, of them resulting in pregnancies) in 1256 patients receiving minimal ovarian stimulation with recombinant FSH (50 or 75 IU daily from day 4 to 7 and then the dose was adjusted according to oestradiol concentrations in order to achieve a maximum of two follicles >15 mm in diameter on the day of HCG injection) has shown that minimal recombinant FSH stimulation in IUI cycles may reduce the rates of twins (<10% of all pregnancies) and high order multiples (<0.5% of all viable pregnancies) while maintaining acceptable pregnancy rates. Prospective randomized studies comparing IUI with minimal ovarian stimulation and IUI with more aggressive stimulation are needed in order to confirm these results.
Acknowledgements This work was supported in part by grants from the Instituto de Salud Carlos III (RCMN C03/08), and the Comissionat per a Universitat i Recerca-Generalitat de Catalunya (2001SGR 00372).
References Aboulghar MA, Mansour RT, Serour GI et al. 2001 Controlled ovarian hyperstimulation and intrauterine insemination for
treatment of unexplained infertility should be limited to a maximum of three trials. Fertility and Sterility 75, 88–91. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG 2003 Diagnosis and management of unexplained infertility: an update. Archives of Gynecology and Obstetrics 267, 177–188. Balasch J, Ballescá JL, Pimentel C et al. 1994 Late low-dose pure follicle stimulating hormone for ovarian stimulation in intrauterine insemination cycles. Human Reproduction 9, 1863–1866. Balasch J, Tur R, Peinado JA 1996 The safety and effectiveness of stepwise and low-dose administration of follicle stimulating hormone in WHO group II anovulatory infertile women: evidence from a large multicenter study in Spain. Journal of Assisted Reproduction and Genetics 13, 551–556. Chalmers TC, Smith H Jr, Blackburn B et al. 1981 A method for assessing the quality of a randomized control trial. Controlled Clinical Trials 2, 31–49. Cohlen BJ 1998 Intrauterine insemination and controlled ovarian hyperstimulation. In: Templeton A, Cooke I, O’Brien PMS (eds) Evidence-Based Fertility Treatment. RCOG Press, London, pp. 205–216. Cohlen BJ, te Velde ER, van Kooij RJ 1995 Is there still a place for intra-uterine insemination as a treatment for male subfertility? International Journal of Andrology 18 (suppl. 2), 72–75. Cohlen BJ, te Velde ER, van Kooij RJ et al. 1998 Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study. Human Reproduction 13, 1553–1558. Cohlen BJ, Hughes E, te Velde ER 2004a Intra-uterine insemination for unexplained infertility (protocol for a Cochrane Review). In: The Cochrane Library, Issue 3. Wiley, Chichester. Cohlen BJ, Vandekerckhove P, te Velde ER, Habbema JDF 2004b Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men (Cochrane Review). In: The Cochrane Library, Issue 3. Wiley, Chichester. Collins JA 1990 Ovulation induction in the treatment of unexplained infertility. Seminars in Reproductive Endocrinology 8, 165–173. Collins JA 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. Current best evidence for the advanced treatment of unexplained subfertility. Human Reproduction 18, 907–912. Collins JA, Wrixon W, Janes LB, Wilson EH 1983 Treatmentindependent pregnancy among infertile couples. New England Journal of Medicine 309, 1201–1206. Collins JA, Burrows EA, Willan AR 1995 The prognosis for live birth among untreated infertile couples. Fertility and Sterility 64, 22–28. Corchia C, Mastroiacovo P, Lanni R et al. 1996 What proportion of multiple births are due to ovulation induction? A register-based study in Italy. American Journal of Public Health 86, 851–854. Costello MF 2004 Systematic review of the treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination. Australian and New Zealand Journal of Obstetrics and Gynaecology 44, 93–102. Crosignani PG, Walters DE, Soliani A 1991 The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report. Human Reproduction 6, 953–958. Curole DN, Dickey RP, Taylor SN et al. 1989 Pregnancies in cancelled gamete intrafallopian transfer cycles. Fertility and Sterility 51, 363–364. Derom C, Derom R, Vlietinck R et al. 1993 Iatrogenic multiple pregnancies in East Flanders, Belgium. Fertility and Sterility 60, 493–496. Dickey RP, Taylor SN, Lu PY, Sartor BM et al. 2001 Relationship of follicle numbers and estradiol levels to multiple implantation of 3606 intrauterine insemination cycles. Fertility and Sterility 75, 69–78. Dunphy BC, Li TC, Macleod JC et al. 1990 The interaction of parameters of male and female fertility in couples with previously unexplained infertility. Fertility and Sterility 54, 824–827. ESHRE Capri Workshop Group 1996 Guidelines to the prevalence,
671
Article - Unexplained infertility - J Balasch
672
diagnosis, treatment and management of infertility, 1996. Human Reproduction 11, 1775–1807. ESHRE Capri Workshop Group 2000 Multiple gestation pregnancy. Human Reproduction 15, 1856–1864. Evans MI, Littman L, St Louis L et al. 1995 Evolving patterns of iatrogenic multifetal pregnancy generation: implications for aggressiveness of infertility treatments. American Journal of Obstetrics and Gynecology 172, 1750–1755. Evers JLH 2002 Female subfertility. Lancet 360, 151–159. Gleicher N, Karande V 2001 Forget about ovulation induction! Proceed directly to IVF. In: Ben-Rafael Z, Shoham Z, Frydman R (eds) Proceedings of the 2nd World Congress on Controversies in Obstetrics and Gynecology. Monduzzi Editore, Bologna, pp. 211–215. Gleicher N, Oleske DM, Tur-Kaspa I et al. 2000 Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. New England Journal of Medicine 343, 2–7. Goverde AJ, McDonnell J, Vermeiden JPW et al. 2000 Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 355, 13–18. Guzick DS, Sullivan MW, Adamson GD et al. 1998 Efficacy of treatment for unexplained infertility. Fertility and Sterility 70, 207–213. Guzick DS, Carson SA, Coutifaris C et al. for the National Cooperative Reproductive Medicine Network 1999 Efficacy of ovulation induction and intrauterine insemination in the treatment of infertility. New England Journal of Medicine 340, 177–183. Haney AF, Hughes CL, Whitesides DB, Dodson WC 1987 Treatment-independent, treatment-associated and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer. Fertility and Sterility 47, 634–638. Homburg R 2003 The case for initial treatment with intrauterine insemination as opposed to in vitro fertilization for idiopathic infertility. Human Fertility (Cambridge) 6, 122–124. Homburg R, Howles CM 1999 Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Human Reproduction Update 5, 493–499. Homburg R, Insler V 2002 Ovulation induction in perspective. Human Reproduction Update 8, 449–462. Hughes EG 1997 The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Human Reproduction 12, 1865–1872. Hughes EG 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. ‘Effective treatment’ or ‘not a natural choice’? Human Reproduction 18, 912–914. Hughes EG, Collins JA, Gunby J 1998 A randomized controlled trial of three low-dose gonadotrophin protocols for unexplained infertility. Human Reproduction 13, 1527–1531. Hughes EG, Collins J, Vandekerckhove P 2001 Clomiphene citrate for unexplained subfertility in women (Cochrane Review I). The Cochrane Library, Issue 2. Update Software, Oxford. Hull MGR 1992 Infertility treatment: relative effectiveness of conventional and assisted conception methods. Human Reproduction 7, 785–796. Hull MGR, Glazener CMA, Kelly NJ et al. 1985 Population study of causes, treatment, and outcome of infertility. British Medical Journal 291, 1693–1697. Jones HW 2003 Multiple births: how are we doing? Fertility and Sterility 79, 17–21. Levene MI, Wild J, Steer P 1992 Higher multiple births and the modern management of infertility in Britain. British Journal of Obstetrics and Gynaecology 99, 607–613. Matorras R, Díaz T, Corcostegui B et al. 2002 Ovarian stimulation in intrauterine insemination with donor sperm: a randomized study comparing clomiphene citrate in fixed protocol versus highly purified urinary FSH. Human Reproduction 17, 2107–2111. Nan PM, Cohlen BJ, te Velde ER et al. 1994 Intra-uterine insemination or timed intercourse after ovarian stimulation for
male subfertility? A controlled study. Human Reproduction 9, 2022–2026. National Collaborating Centre for Women’s and Children’s Health 2004 Fertility: Assessment and Treatment for People with Fertility Problems. Intrauterine insemination. Commissioned by the National Institute for Clinical Excellence. RCOG Press, London, pp. 75–80. Ombelet W 2003 Semen quality and intrauterine insemination. Reproductive BioMedicine Online 7, 485–492. Papageorgiou TC, Guibert J, Savale M et al. 2004 Low dose recombinant FSH treatment may reduce multiple gestations caused by controlled ovarian hyperstimulation and intrauterine insemination. British Journal of Obstetrics and Gynaecology 111, 1277–1282. Sengoku K, Tamate K, Takaoka Y et al. 1999 The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility. Human Reproduction 14, 349–353. Stewart JA 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. Should the guidelines be changed? Human Reproduction 18, 903–907. te Velde ER, Cohlen BJ 1999 The management of infertility. New England Journal of Medicine 340, 224–226. Tur R, Barri PN, Coroleu B et al. 2001 Risk factors for high-order multiple implantation after ovarian stimulation with gonadotrophins: evidence from a large series of 1878 consecutive pregnancies in a single centre. Human Reproduction 16, 2124–2129. Tur R, Barri PN, Coroleu B et al. 2005 The use of a prediction model for high-order multiple implantation after ovarian stimulation with gonadotropins. Fertility and Sterility 2005, in press. White DM, Polson DW, Kiddy D et al. 1996 Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. Journal of Clinical Endocrinology and Metabolism 81, 3821–3824. Wilcox LS, Kiely JL, Melvin CL, Martin MC 1996 Assisted reproductive technologies: estimates of their contribution to multiple births and newborn hospital days in the United States. Fertility and Sterility 65, 361–366. Zeyneloglu HB, Arici A, Olive DL, Duleba AJ 1998 Comparison of intrauterine insemination with timed intercourse in superovulated cycles with gonadotropins: a meta-analysis. Fertility and Sterility 69, 486–491.
Received 24 September 2004; refereed 15 October 2004; accepted 21 October 2004.
Article Gonadotrophin ovarian stimulation and intrauterine insemination for unexplained infertility
Dr Juan Balasch
Juan Balasch obtained his MD degree (1974) and the speciality degree in Obstetrics and Gynaecology (1977) at the Faculty of Medicine-Hospital Clínic, University of Barcelona in Spain. The PhD degree was granted to him at the same University in 1979. At present he is full professor in Obstetrics and Gynaecology and Head of the Fertility Unit at the Faculty of Medicine-Hospital Clinic, University of Barcelona. Professor Balasch is Past President of the Spanish Fertility Society and has more than 200 publications in international journals and books; in a series of studies he and his team developed a new hypothesis on the pathogenesis of the ovarian hyperstimulation syndrome. He serves as ad-hoc reviewer or is on the Editorial Board of different international journals dealing with fertility, gynaecological endocrinology and human reproduction. Professor Balasch’s current research interests include assisted reproduction, repeated abortion, implantation failure and ovarian (hyper)stimulation.
Juan Balasch Institut Clínic of Gynecology, Obstetrics and Neonatology, Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine, University of Barcelona, Barcelona, Spain Correspondence: Institut Clinic of Gynecology, Hospital Clínic, C/Casanova 143, 08036-Barcelona, Spain. Tel: +34 93 2275534; Fax: +34 93 2275454; e-mail: [email protected]
Abstract Over the past 15 years, there has been a marked increase in the use of ovulation induction and intrauterine insemination (IUI) for the treatment of unexplained infertility. However, although ovulation induction and IUI have rapidly gained popularity, clinical use is based largely on practical experience rather than on well-designed scientific studies. This article summarizes the evidence in this area. Despite clinical heterogeneity and different methodological qualities of the trials, it can be concluded that ovulation induction significantly improves the probability of conception in couples with unexplained infertility, particularly when associated with IUI. It is remarkable, though, that there has been only one large-scale, randomized trial of ovulation induction plus IUI in the treatment of unexplained infertility in which one of the study arms is an untreated control group. For couples requiring treatment, the complication rate must be minimized, particularly the occurrence of high-order multiple pregnancy. Evaluation of the effectiveness and safety of low-dose gonadotrophin administration in patients with unexplained infertility is limited and further studies are warranted. Keywords: gonadotrophins, intrauterine insemination, ovarian stimulation, unexplained infertility
Introduction The efficacy of treatment for infertility disorders may be assessed easily and objectively by the resulting pregnancy rates. Cycle fecundity after IVF and embryo transfer in women who have had their Fallopian tubes surgically removed provides a good indication of the efficacy of IVF for that condition. Similarly, in partners of azoospermic males undergoing artificial insemination with donor semen, the cycle fecundity is a good indicator of the suitability of this therapeutic approach.
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The underlying assumption in the analysis of efficacy for any infertility treatment is that the likelihood of pregnancy without treatment is negligible. However, most couples seeking
therapy for infertility are not truly sterile, but have some degree of subfertility (i.e. the couples have conditions associated with a relative decrease in the monthly likelihood of conception) and can achieve pregnancy without treatment (Collins et al., 1983; Evers, 2002). Thus, in contrast to the treatment of sterility, it cannot be assumed that the pregnancy that occurs after treatment for subfertility is attributable solely to the treatment, because it could have occurred by chance. Such treatment independent pregnancies are more likely in couples designated as having unexplained infertility. Despite advances in the diagnosis of causes of subfertility, inability to conceive remains unexplained in 25–30% of fully investigated couples (Evers, 2002). In these couples, the delay in conception may represent a chance delay or may be, in many cases, the result of an as yet undetected abnormality in the
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reproductive process. Cumulative pregnancy rates of 60% may be achieved within 2 years; however, for infertility of greater than 3 years duration, monthly fecundity rates in untreated couples are 1–2% (Hull, 1992; Collins et al., 1995). Therefore, designing and assessing the efficacy (or lack thereof) of treatment of unexplained infertility is rather challenging for several reasons (Hull et al., 1985; Hull, 1992; ESHRE Capri Workshop, 1996; Evers, 2002): (i) There is a lack of consistency in the literature in defining the condition and couples with only mild endometriosis are frequently considered to have unexplained infertility. (ii) Therapy of unexplained infertility does not fit standard practice for medical decision making. Such standard practice requires a specific pathophysiological rationale that allows the correction of a biological defect. Because no such defect is known in unexplained infertility, treatment approaches are usually empiric. (iii) Given the high probability for conception in such couples with observation alone, especially with infertility lasting less than 3 years, a decrease in the time to conception may be seen rather than an increase in the absolute number of couples conceiving. (iv) There is a paucity of prospective, randomized, controlled trials evaluating pregnancy rates in treated and untreated patients with unexplained infertility. During the past 15 years, there has been a marked increase in the use of two treatments (used alone or in combination) for unexplained infertility: induction of ovulation induction, in which the ovaries are stimulated with exogenous gonadotrophins to develop several dominant follicles, and intrauterine insemination (IUI), in which motile spermatozoa are suspended in culture medium and injected transcervically into the uterine cavity. However, although IUI and/or ovulation induction have rapidly gained popularity, clinical practice is based largely on practical experience rather than well-designed scientific studies (Collins, 2003; Hughes, 2003; Stewart, 2003). This report summarizes the evidence regarding the efficacy of gonadotrophin treatment associated with IUI for unexplained infertility. In this report, FSH was used as synonymous with ovarian stimulation with gonadotrophins, i.e. HMG or FSH.
Ovulation induction and IUI for unexplained infertility: is there a rationale? Taking into account the above considerations, what might be the rationale for administering gonadotrophins to stimulate follicular development in patients with unexplained infertility, who by definition have regular, ovulatory menstrual cycles? Why introduce washed spermatozoa into the uterine cavity in situations in which the semen analysis is normal and there is no cervical factor present? With respect to ovarian stimulation, two explanations have been offered (Collins, 1990; Guzick et al., 1998): (i) it may overcome a subtle defect in ovulatory function not uncovered by conventional testing, and (ii) it may enhance the likelihood of pregnancy by increasing the number of eggs available for fertilization. According to the latter rationale, ovarian stimulation might improve the monthly pregnancy rate by simply increasing the number of oocytes available for fertilization and implantation. In fact, ovulation induction therapy was developed as a result of a
fortuitous clinical observation. Some patients who received FSH in preparation for an IVF or gamete intra-Fallopian transfer (GIFT) cycle had their oocyte retrieval procedure cancelled (because of inadequate numbers of follicles or endogenous LH surge) but became pregnant anyway (Haney et al., 1987; Curole et al., 1989). This observation suggested that multiple follicular recruitment and egg release might be the most critical element contributing to pregnancy. The direct relationship found between the intensity of stimulation protocols used for ovulation induction and IUI and the multiple pregnancy rates further supports this contention (Nan et al., 1994; Gleicher et al., 2000). Along similar lines of thinking, by increasing the density of motile spermatozoa with a high proportion of normal forms available to these oocytes by IUI might further increase the monthly probability of pregnancy. In addition, timing the insemination as close to ovulation as possible optimizes the likelihood for gamete interaction (Stewart, 2003). Thus, by increasing the numbers of gametes at the site of fertilization, the probability of conception can be increased. In fact, this is also the rationale behind IUI in couples with moderate male factor subfertility where sperm morphology using strict criteria and the inseminating motile sperm count after sperm preparation are the two most important sperm parameters related to IUI success (Ombelet, 2003).
Efficacy of ovulation induction alone or in combination with IUI for unexplained infertility: analysis of the literature In order to allow firm conclusions to be drawn on whether ovulation induction, with or without IUI, significantly improves the probability of conception in cases of unexplained infertility compared with timed intercourse (TI), and to address the question of what are the independent effects of gonadotrophins and IUI, four comparisons should be performed in randomized clinical trials (Cohlen et al., 1995, 2004a). First, IUI should be compared with TI in natural cycles (comparison 1) and in stimulated ovulation cycles (comparison 2). Whether ovulation induction in combination with TI improves the probability of conception should be investigated in a trial comparing TI in stimulated cycles with TI in natural cycles (comparison 3). Whether ovulation induction in combination with IUI improves the probability of conception should be investigated in a trial comparing IUI in stimulated cycles with IUI in natural cycles (comparison 4). The aim of this analysis of the literature is to determine, after performing the four above-mentioned comparisons, whether, for unexplained infertility, ovulation induction improves the probability of conception compared with TI, and whether IUI improves the results any further. The following studies [four meta-analysis, two analysis of combined data from the literature, and three large, randomized clinical trials (two multicentre trials)] in the literature were considered relevant in this regard.
Meta-analysis by Cohlen (1998) This study is the basis for a Cochrane Review (protocol) (Cohlen et al., 2004a) and presents preliminary data from 18 randomized clinical trials in which ovulation induction was achieved with FSH (alone in most treatment cycles and associated with
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clomiphene citrate in others; as these are preliminary results, the actual studies have not been described) (Table 1). These results indicate that IUI in natural cycles does not improve the probability of conception in couples with unexplained infertility. However, when ovulation induction is applied, IUI has an independent positive effect. Therefore, it seems that, in the case of unexplained infertility, ovulation induction is more important compared with IUI. It is thus postulated that the worse the semen factor the more important IUI becomes, and the better the semen factor, the more important ovulation induction becomes. It seems logical to suggest that the better the semen quality, the more likely female factors are to influence the subfertility of the couple (Dunphy et al., 1990; Cohlen et al., 1998). As previously discussed, ovarian stimulation might overcome these subtle factors, as well as increasing the number of available oocytes. The above hypothesis is further supported by a Cochrane Review (Cohlen et al., 2004b) analysing TI versus IUI with or without ovarian stimulation for subfertility in men and concluding that in both natural and stimulated cycles IUI significantly improves the probability of conception compared with TI. However, whereas IUI in cycles with ovarian stimulation improved the probability of conception compared with IUI in natural cycles, significance was not reached.
Meta-analysis by Zeyneloglu et al. (1998) Seven prospective randomized trials of couples with unexplained infertility were eligible for inclusion in this metaanalysis. The quality of the individual studies was assessed with the use of a method modified by Chalmers et al. (1981). The mean validity score for trials selected was 60%. A total of 980 cycles were evaluated when all studies were combined. There were 49 pregnancies resulting from 431 cycles with TI (11.37%), compared with 110 pregnancies from 549 IUI cycles (20.04%). For individual studies, the odds ratios (OR) for pregnancy for cycles with IUI versus TI ranged from 0.98 to 3.57, and confidence intervals (CI) ranged from 0.22 to 43.01. Only two studies reported significantly increased benefit from addition of IUI to ovarian stimulation, whereas the remaining studies failed to show a significant effect of IUI versus TI. The common OR (1.84; 95% CI: 1.30–2.62), however, revealed a significant effect of IUI. The analysis showed that the studies were homogeneous, with a Breslow–Day score of 8.97 (df = 6; not statistically significant). From this meta-analysis, it was concluded that couples treated for unexplained infertility could benefit from the addition of IUI to ovulation induction. The authors propose that the use of IUI in combination with FSH will help many couples to avoid the stress and cost of more invasive technologies.
Meta-analysis by Hughes (1997)
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This is a systematic review evaluating the effectiveness of IUI with or without ovarian stimulation in the treatment of unexplained infertility. Relevant randomized, controlled trials were identified by a diverse strategy, including a hand search of 43 core journals since 1966. Two approaches to meta-analysis were used to summarize the data. First, using a standard Mantel–Haenszel approach, eight trials comparing FSH/IUI with FSH/TI for unexplained infertility were combined. The common OR for pregnancy per treatment cycle was 2.37 (95%
CI, 1.43–3.90), suggesting a significant improvement with IUI following ovulation induction in this patient group. Although the data were statistically homogeneous (the Breslow–Day test of heterogeneity was not statistically significant), clinically significant heterogeneity was present. Second, the independent effects of treatment with FSH and IUI were assessed using stepwise logistic regression. Based on 4516 cycles reported in 22 trials, the adjusted OR for pregnancy associated with FSH use was 2.35 (95% CI, 1.87–2.94) and for IUI 2.82 (95% CI 2.18–3.66) (Table 2). Thus, when compared with untreated cycles, the average level of fecundity is more than two-fold higher in a cycle with either treatment and approximately fivefold higher when both treatments are combined.
Meta-analysis by the European Society for Human Reproduction and Embryology (ESHRE) – The ESHRE Capri Workshop Group (1996) Data from 13 randomized clinical trials were assembled in a meta-analysis to estimate the independent effects of ovarian stimulation and IUI in patients with unexplained infertility. The common element in this analysis was IUI treatment. All trials either compared IUI treatment with TI or IUI treatment was the active control treatment. Based on 2065 non-stimulated cycles and 956 gonadotrophin-stimulated cycles, the unadjusted aggregate results indicated that the pregnancy rate per cycle was 3% in cycles of observation with TI, 6% in FSH cycles and 14% in cycles of FSH and IUI (Table 3). From the logistic regression analysis, the effects of IUI and FSH treatment were similar: each treatment significantly increased the likelihood of conception approximately two-fold.
Analysis of data by Guzick et al. (1998) This work was conducted during 1996 when the investigators were members of a subcommittee of the ASRM Practice Committee. The subcommittee was convened to write evidence-based guidelines on the use of assisted reproduction in the treatment of unexplained infertility. After reviewing the literature and working with the data, it was concluded that the dearth of randomized, controlled trials in this area precluded the writing of guidelines that were strictly evidence-based. However, in view of the need for clinicians to make reasoned judgments about treatment alternatives, a summary of evidence was collected regarding the efficacy of alternative treatments for unexplained infertility. Aggregate data from 45 published reports involving expectant management, IUI, ovulation induction, GIFT, and IVF for unexplained infertility were presented. Some studies reported data pertaining to only one treatment, whereas others reported data on two or more treatments. Each study was assigned a quality score based on its strengths and weaknesses. Studies could have received a total score ranging from 6 to 20. The actual point scores for the studies reviewed ranged from 6 to 19 [mean (±SD) score 12.7 ± 3.2]. Quality-adjusted pregnancy rates were calculated by applying quality scores of studies to their pregnancy rate data. Combined pregnancy rates per initiated cycle, adjusted for study quality, are summarized in Table 4. Based on the highest level of evidence found in the data, it may be concluded that IUI does not appear to be efficacious without some form of ovulation induction.
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Table 1. Preliminary results combining 18 randomized clinical trials in patients with unexplained infertility. Comparison
OR
(95% CI)
IUI versus TI FSH + IUI versus FSH + TI FSH + TI versus TI FSH + IUI versus IUI
1.3 1.9 1.9 4.4
(0.37–4.6) (1.4–2.6) (1.1–3.1) (1.9–10)
Adapted from Cohlen et al. (1998).
Table 2. Crude aggregate data from 22 relevant trials (4516 cycles) of FSH versus no stimulation for IUI or timed intercourse as treatment for unexplained infertility.
Ovulation stimulation No stimulation FSH
No. (%) of pregnancies per cycle IUI TI
OR (95% CI)
80/1306 (6) 171/1156 (15)
2.82 (2.18–3.66) 2.35 (1.87–2.94)
27/1354 (2) 47/700 (7)
Adapted from Hughes (1997).
Table 3. Aggregate pregnancy rates in trials of IUI with and without ovarian stimulation for unexplained infertility.
Ovarian stimulation No stimulation FSH
No. (%) of pregnancies per cycle IUI TI
OR (95% CI)
61/1102 (6) 90/625 (14)
2.09 (1.35–3.22) 2.19 (1.45–3.32)
25/963 (3) 21/331 (6)
Adapted from the ESHRE Capri Workshop Group (1996).
Table 4. Aggregate data for alternative treatments for unexplained infertility. Treatment
No. of studies
No. (%) of pregnancies per initiated cycle
Control groups Control groups, randomized studies IUI FSH FSH + IUI
11
64/3539 (1.8)
6 9 13 14
23/597 (3.9) 15/378 (4.0) 139/1806 (7.7) 207/1133 (18.3)
Percentage of qualityadjusted pregnancies per initiated cycle 1.3
4.1 3.8 7.7 17.1
Adapted from Guzick et al. (1998).
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Study by Aboulghar et al. (2003) In this study, the results of different randomized controlled trials comparing ovulation induction and IUI versus ovulation induction and TI (n = 13 studies), ovulation induction and IUI versus IUI alone (n = 5 studies), and ovulation induction and IUI versus ovulation induction and cervical insemination (n = 4 studies) in patients with unexplained infertility were analysed. Aggregate analysis of the extracted data does suggest that combined ovarian stimulation and IUI has more beneficial effect than ovarian stimulation alone (Table 5). The results of trials comparing ovulation induction plus IUI versus IUI alone showed that the pregnancy rate in the first treatment group was significantly higher than that obtained using IUI alone. From these data, the authors assumed that both ovarian stimulation and IUI were independent positive factors in achieving better pregnancy rate in unexplained infertility. The optimum number of ovarian stimulation/IUI cycles in the treatment of unexplained infertility was investigated by the authors (Aboulghar et al., 2001), who performed an observational prospective study in which 594 couples with unexplained infertility were treated by ovulation induction and IUI for up to 3 cycles before trying IVF. One to three cycles of ovarian stimulation/IUI were performed in 594 patients undergoing 1112 cycles. Up to three further trials (cycles 4–6) of ovulation induction/IUI were then done in 91 of these women, a total of 161 cycles. In the first three treatment cycles a cycle fecundity of 16.4% was achieved, as compared with 5.6% in cycles 4–6, a highly significant difference. The authors concluded that in unexplained infertility, IVF should be tried after failure of three trials of ovarian stimulation/IUI. The aggregate analysis of randomized controlled trials comparing ovulation induction/IUI versus ovulation induction/cervical insemination demonstrated that the former association has a significantly higher pregnancy rate than the latter (Table 5).
Study by Crosignani et al. (1991) Nineteen European fertility centres participated in a controlled, randomized trial aimed at comparing the effectiveness of five methods for the treatment of unexplained infertility: ovulation induction alone, and ovulation induction together with one of the following procedures: IUI, intraperitoneal insemination, GIFT and IVF. By the end of the trial, 444 patients had been treated in a total of 649 cycles. Because of unavoidable practical difficulties, the experimental design eventually obtained was severely unbalanced. Nevertheless, objective statistical comparisons were possible among the five treatments, using non-orthogonal analysis of variance. There was some statistical evidence that the pregnancy rate obtained from ovulation induction alone was inferior to that obtained by using ovulation induction together with one of the methods of assisted conception. The pregnancy rate in each method of the assisted conception groups was found to be vastly better than various estimates of the spontaneous pregnancy rates cited in the literature.
Study by Guzick et al. (1999) 668
This multicentre randomized trial was conducted by the Reproductive Medicine Network of the National Institute of Child Health and Development. The overall hypothesis of the
study was that induction of ovulation induction with FSH or IUI would result in a higher pregnancy rate among infertile couples than would no treatment. No treatment was defined as intracervical insemination timed to a surge in the urinary excretion of LH to ensure that spermatozoa were present in the cervix and vaginal fornix at the time of ovulation. The study included 932 couples, in which the woman had no identifiable infertility factor and the man had motile spermatozoa (i.e. unexplained infertility or male factor infertility). The couples were randomly assigned to receive intracervical insemination, IUI, ovulation induction and intracervical insemination, or ovulation induction and IUI. Treatment continued for four cycles, unless pregnancy was achieved. The 231 couples in the group treated with ovulation induction and IUI had a higher rate of pregnancy (33%) than the 234 couples in the IUI group (18%), the 234 couples in the group treated with ovulation induction and intracervical insemination (19%), or the 233 couples in the intracervical insemination group (10%). Stratified, discrete-time, Cox proportionalhazards analysis showed that the couples in the group treated with ovulation induction and IUI were 3.2 times more likely to become pregnant than those in the intracervical insemination group (95% CI, 2.0–5.3) and 1.7 times more likely to become pregnant than those in the IUI group (95% CI, 1.2–2.6). The couples in the IUI group and in the group treated with ovulation induction and intracervical insemination were nearly twice as likely to conceive as those in the intracervical insemination group. The effects of ovulation induction and IUI on pregnancy for the whole study population appear to be independent and additive, with both techniques contributing equally to the likelihood of pregnancy. However, among couples in which the man had sperm values in the lowest quartile, more or less corresponding to a diagnosis of male subfertility, induction of ovulation induction had little effect and IUI had a greater positive effect.
Study by Goverde et al. (2000) In this prospective, randomized trial, 258 couples with idiopathic subfertility or male subfertility were treated for a maximum of six cycles of either IUI in a spontaneous cycle (IUI alone) (n = 86), IUI after mild ovarian stimulation with FSH (n = 85), or IVF (n = 87). Although the pregnancy rate per cycle was higher in the IVF group than in the IUI groups (12.2 versus 7.4 and 8.7% respectively; not statistically significant), the cumulative pregnancy rate for IVF was not significantly better than that for IUI. Also, IUI was a more cost-effective treatment than IVF. The authors concluded that IUI in the spontaneous cycle carries fewer health risks than IUI after mild hormonal stimulation and is, therefore, the treatment of first-choice. However, a feature of the trial design deserves comment. The combination of two diagnostic groups (idiopathic and male subfertility) is justified from a pragmatic point of view, because the same treatment was offered to both groups, but combination of the groups does affect the interpretation of the results. In this trial, the sample size of 80 in each group was chosen to allow detection of a significant difference in outcome between the intervention groups, but was insufficient
Article - Unexplained infertility - J Balasch
to do so for each diagnostic category. In fact, when patients with unexplained infertility and male factor infertility were considered separately, pregnancy rates in the former group tended to be higher when IUI was used in combination with ovulation induction (37%), as compared with IUI alone (26%). In contrast, in patients with male subfertility, pregnancy rates in the groups undergoing IUI alone and IUI plus ovulation induction were very similar (42 and 37% respectively).
Concluding remarks and future perspectives Despite clinical heterogeneity and different methodological qualities of the trials comparing efficacy of treatment for unexplained infertility, based on the evidence found in the analysed data (Table 6) the following recommendations can be made. In couples with unexplained infertility, ovulation induction with gonadotrophins significantly improves the
probability of conception, particularly when associated with IUI. It is remarkable, however, that in all the years that FSH and IUI has been in widespread use, there has been only one large-scale, randomized trial of gonadotrophin use plus IUI in the treatment of unexplained infertility in which one of the study arms is an untreated control group (Guzick et al., 1999). In this study, however, timed intracervical insemination with prepared semen was adopted as the baseline, or control, (non)treatment. For two reasons, this approach may not truly reflect actual non-treatment, leading to an overestimation of the therapeutic value of IUI and ovulation induction (te Velde and Cohlen, 1999). First, spermatozoa ejaculated during normal intercourse may be of better quality than those obtained by masturbation. Second, the probability of conception during the fertile period increases if there are several acts of intercourse rather than the single insemination used in the study by Guzick et al. (1999). Thus, further studies of FSH plus IUI versus no treatment are needed.
Table 5. Aggregate pregnancy rates of 20 randomized controlled trials comparing alternative treatments for unexplained infertility. Figures in parentheses are percentages. Comparison
No. (%) of pregnancies per cycle
OR (95% CI)
FSH + IUI versus FSH + TI FSH + IUI versus IUI FSH + IUI versus FSH + cervical insemination
170/929 (18) versus 76/711 (11) 107/478 (22) versus 59/466 (13) 127/476 (27) versus 74/517 (14)
1.71 (1.28–2. 28) 1.77 (1.26–2.49) 1.86 (1.36–2.54)
Adapted from Aboulghar et al. (2003).
Table 6. Summary of reported results of treatment for unexplained infertility in the studies included in this paper. Study
IUI versus TI
FSH + IUI versus FSH + TI
Result
FSH + TI versus TI
Result
FSH + IUI versus IUI
Result
Cohlen et al. (1998) Zeyneloglu et al. (1998) Hughes (1997) ESHRE Capri Workshop group (1996) Guzick et al. (1998) Crosignani et al. (1991) Guzick et al. (1999) Goverde et al. (2000) Aboulghar et al. (2003)
No difference
FSH + IUI
Better
FSH + TI
Better
FSH + IUI
Better
–
FSH + IUI
Better
–
IUI better IUI better
FSH + IUI FSH + IUI
Better Better
FSH + TI FSH + TI
Better Better
FSH + IUI FSH + IUI
Better Better
No difference
FSH + IUI
Better
FSH + TI
Better
FSH + IUI
Better
–
FSH + IUI
Better
–
IUI better
FSH + IUI
Better
FSH + TI
–
FSH + IUI
Better
–
FSH + IUI
Better
–
– Better
FSH + IUI
Better
–
FSH + IUI
Better
–
FSH + IUI
Better
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On the other hand, for couples for whom treatment does become necessary, the complication rate must be minimized. Traditionally, intense levels of ovarian stimulation in IUI cycles have been used, leading the more aggressive protocols to higher monthly fecundity rates but also to more multiple pregnancies and an unacceptably high rate of triplets (Nan et al., 1994; Gleicher et al., 2000). Interestingly, according to population-based studies, as many as two-thirds of iatrogenic multiple pregnancies, mainly high-order gestations (triplets or more), may be attributable to ovulation-inducing drugs without IVF or related techniques (Levene et al., 1992; Derom et al., 1993; Evans et al., 1995; Corchia et al., 1996; Wilcox et al., 1996). As multiple gestations of triplets or more represent the majority of the risk usually associated with multiple births, ovarian stimulation seems acceptable only when it leads to a singleton pregnancy or, occasionally, twin pregnancies. Clomiphene citrate could be postulated as a treatment option in this regard, but its use in women with unexplained infertility is associated with a small absolute effect on treatment per cycle (Hughes et al., 2001) and pregnancy rates obtained are lower in comparison with FSH treatment, mainly when ovarian stimulation is associated with IUI (Balasch et al., 1994; ESHRE Capri Workshop Group, 1996; Hughes, 1997; Cohlen et al., 1998a; Matorras et al., 2002; Costello, 2004). Very recently, however, the place of IUI in association with ovulation induction has been brought into focus by the NICE Fertility Guidelines (National Collaborating Centre for Women’s and Children’s Health, 2004) when stressing that ‘where IUI is used to manage unexplained infertility problems, both stimulated and unstimulated IUI are more effective than no treatment. However, ovarian stimulation should not be offered, even though it is associated with higher pregnancy rates than unstimulated IUI, because it carries a risk of multiple pregnancy’. Thus, the main objection to using IUI and gonadotrophin ovarian stimulation as the initial treatment in unexplained infertility has been the multiple pregnancy rate (Stewart, 2003). In fact, it has recently been suggested that IVF should be offered as first-line therapy as opposed to IUI and ovulation induction with gonadotrophins for the treatment of unexplained infertility (Gleicher et al., 2000; Gleicher and Karande, 2001).
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In response to this argument, others (Collins, 2003; Hughes, 2003) regretted the lack of good quality, large, prospective randomized trials to settle the argument. Notably, Homburg (Homburg 2003; Homburg and Insler, 2002) has critically and thoughtfully analysed this subject using the results of randomized controlled trials wherever possible, live birth rates rather than pregnancy rates and taking into account efficacy; complications, especially multiple pregnancy rates; patient compliance and cost efficiency. The efficiency of the IVF is still limited; although less efficient on a per-cycle basis, findings are consistent in concluding that IUI and ovulation induction are nevertheless capable of producing a pregnancy and delivery within a reasonable time. There is little doubt that IVF is a much more invasive procedure than IUI and that ovulation induction and IUI are unequivocally less complicated and safer compared with IVF. In fact, the cumulative drop-out rate in an IVF programme is significantly higher than that for IUI. Ovulation induction coupled with IUI is more cost-effective than IVF (Homburg, 2003; Homburg and Insler, 2002). The cost of an IVF cycle is approximately four times higher than the cost of a cycle of FSH/IUI treatment
(Collins, 2003). Cost–effectiveness, which is the ratio of cost to success, tends to decrease when success is better and increase when costs go up. Thus, given the four- to five-fold higher cost of IVF, the live birth rate with a cycle of IVF would have to be four-fold greater than the live birth rate with a cycle of FSH/IUI to achieve a similar level of cost-effectiveness (Collins, 2003). On the other hand, because FSH/IUI is more tolerable and less expensive than IVF, repeated cycles are possible, further increasing the absolute number of pregnancies associated with these treatments (Hughes, 2003). As stressed above, the main objection to using IUI and ovulation induction in the treatment of unexplained infertility has been the multiple pregnancy rate, especially high-order multiple pregnancies (Gleicher et al., 2000; Stewart, 2003), which in both medical and social terms can have highly negative consequences (Jones, 2003). The recent study by Gleicher et al. (2000) supports the idea that specific ultrasonographic and oestradiol parameters do not prevent high-order multiple pregnancies. In fact, that study concluded that current criteria result in an unacceptably high incidence of high-order multiple pregnancies after the induction of ovulation with gonadotrophins and the authors suggested that better criteria cannot easily be developed without negatively affecting overall pregnancy rates (Gleicher et al., 2000). In other words, according to those authors, gonadotrophin stimulation that is less intensive than is currently customary may reduce the incidence of high-order multiple pregnancy in fertile women, though only to a limited extent and at the expense of overall pregnancy rate (Gleicher et al., 2000). However, more recent work (Dickey et al., 2001; Tur et al., 2001) has suggested that certain factors are associated with high-order gestations after gonadotrophin stimulation and if relatively conservative limits for follicular development and oestradiol serum concentrations are rigorously applied, the number of high-order multiple pregnancies that result from ovulation induction with exogenous gonadotrophins might be significantly reduced. In the study by Tur et al. (2001), a large series of 1878 consecutive pregnancies obtained in cycles stimulated with gonadotrophins was retrospectively analysed. Of the 1878 conceptional cycles, 1493 resulted from IUI with husband’s (n = 1041) or donor frozen–thawed (n = 452) spermatozoa and the remaining 385 followed ovulation induction and TI. Employing univariate, multivariate and receiver-operating characteristic analysis, a three-variable model was developed to identify patients at high risk for highorder multiple pregnancies in ovulation induction cycles. It was found that the risk of high-order multiple implantation correlated significantly with increasing total number of follicles and was significantly increased in women with a serum oestradiol >862 pg/ml and aged ≤32 years (Tur et al., 2001). Very recently (Tur et al., 2005), the effectiveness in clinical practice of such a prediction model has been determined prospectively in a series of 849 consecutive infertile patients undergoing a total of 1542 treatment cycles. Women were either anovulatory (n = 196 cycles) or were undergoing ovarian stimulation on an empirical basis, usually in conjunction with IUI (n = 1346 cycles) with husband’s (n = 1138 cycles) or donor frozen–thawed (n = 208 cycles) spermatozoa. It was found that the use of the prediction model
Article - Unexplained infertility - J Balasch
(implying cancellation of all cycles at high risk for high-order multiple pregnancies) would result in an 8% (95% CI, 6.8–9.2%) reduction of overall pregnancy rate but also in a 285% (95% CI, 279–291%) reduction of high-order multiple pregnancies (Tur et al., 2005). By using this prediction model, it was possible to maintain a low risk of high-order multiple gestations with a good pregnancy rate in patients receiving gonadotrophin ovarian stimulation or induction of ovulation without IVF. Thus, in conclusion, recognizing the importance of certain variables (i.e. woman’s age, oestradiol serum concentrations, and follicular development) in predicting multiple pregnancies in gonadotrophin stimulated cycles, appropriate guidelines should be established in each individual centre. It should be noted that in a prospective study (Tur et al., 2005), the regimen of gonadotrophin administration was the chronic low-dose step-up regimen where the starting dose of recombinant or highly purified FSH was 75 IU/day for most women (>85%) (37.5 IU/day in previous high responders and 150 IU/day for those women aged ≥40 years or for previous poor responders). The effectiveness and safety of low-dose administration of FSH in WHO group II anovulatory infertile women are well established (Balasch et al., 1996; White et al., 1996; Homburg and Howles, 1999), but evaluation of this therapeutic option for treatment of patients with non-ovulatory disorders, including unexplained infertility, has been limited (Balasch et al., 1994; Hughes et al., 1998; Sengoku et al., 1999). As stressed by the ESHRE Capri Workshop Group (2000), prevention is the most important means of decreasing multiple gestation rates, and multiple gestation rates in ovulation induction and ovulation induction cycles can be reduced by using lower dosage gonadotrophin regimens. Thus, large-scale studies investigating the clinical efficacy of lowdose FSH administration combined with IUI for unexplained infertility are warranted. Notably, a very recent large observational study (Papageorgiou et al., 2004) including 3219 IUI cycles (334, or 10%, of them resulting in pregnancies) in 1256 patients receiving minimal ovarian stimulation with recombinant FSH (50 or 75 IU daily from day 4 to 7 and then the dose was adjusted according to oestradiol concentrations in order to achieve a maximum of two follicles >15 mm in diameter on the day of HCG injection) has shown that minimal recombinant FSH stimulation in IUI cycles may reduce the rates of twins (<10% of all pregnancies) and high order multiples (<0.5% of all viable pregnancies) while maintaining acceptable pregnancy rates. Prospective randomized studies comparing IUI with minimal ovarian stimulation and IUI with more aggressive stimulation are needed in order to confirm these results.
Acknowledgements This work was supported in part by grants from the Instituto de Salud Carlos III (RCMN C03/08), and the Comissionat per a Universitat i Recerca-Generalitat de Catalunya (2001SGR 00372).
References Aboulghar MA, Mansour RT, Serour GI et al. 2001 Controlled ovarian hyperstimulation and intrauterine insemination for
treatment of unexplained infertility should be limited to a maximum of three trials. Fertility and Sterility 75, 88–91. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG 2003 Diagnosis and management of unexplained infertility: an update. Archives of Gynecology and Obstetrics 267, 177–188. Balasch J, Ballescá JL, Pimentel C et al. 1994 Late low-dose pure follicle stimulating hormone for ovarian stimulation in intrauterine insemination cycles. Human Reproduction 9, 1863–1866. Balasch J, Tur R, Peinado JA 1996 The safety and effectiveness of stepwise and low-dose administration of follicle stimulating hormone in WHO group II anovulatory infertile women: evidence from a large multicenter study in Spain. Journal of Assisted Reproduction and Genetics 13, 551–556. Chalmers TC, Smith H Jr, Blackburn B et al. 1981 A method for assessing the quality of a randomized control trial. Controlled Clinical Trials 2, 31–49. Cohlen BJ 1998 Intrauterine insemination and controlled ovarian hyperstimulation. In: Templeton A, Cooke I, O’Brien PMS (eds) Evidence-Based Fertility Treatment. RCOG Press, London, pp. 205–216. Cohlen BJ, te Velde ER, van Kooij RJ 1995 Is there still a place for intra-uterine insemination as a treatment for male subfertility? International Journal of Andrology 18 (suppl. 2), 72–75. Cohlen BJ, te Velde ER, van Kooij RJ et al. 1998 Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study. Human Reproduction 13, 1553–1558. Cohlen BJ, Hughes E, te Velde ER 2004a Intra-uterine insemination for unexplained infertility (protocol for a Cochrane Review). In: The Cochrane Library, Issue 3. Wiley, Chichester. Cohlen BJ, Vandekerckhove P, te Velde ER, Habbema JDF 2004b Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men (Cochrane Review). In: The Cochrane Library, Issue 3. Wiley, Chichester. Collins JA 1990 Ovulation induction in the treatment of unexplained infertility. Seminars in Reproductive Endocrinology 8, 165–173. Collins JA 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. Current best evidence for the advanced treatment of unexplained subfertility. Human Reproduction 18, 907–912. Collins JA, Wrixon W, Janes LB, Wilson EH 1983 Treatmentindependent pregnancy among infertile couples. New England Journal of Medicine 309, 1201–1206. Collins JA, Burrows EA, Willan AR 1995 The prognosis for live birth among untreated infertile couples. Fertility and Sterility 64, 22–28. Corchia C, Mastroiacovo P, Lanni R et al. 1996 What proportion of multiple births are due to ovulation induction? A register-based study in Italy. American Journal of Public Health 86, 851–854. Costello MF 2004 Systematic review of the treatment of ovulatory infertility with clomiphene citrate and intrauterine insemination. Australian and New Zealand Journal of Obstetrics and Gynaecology 44, 93–102. Crosignani PG, Walters DE, Soliani A 1991 The ESHRE multicentre trial on the treatment of unexplained infertility: a preliminary report. Human Reproduction 6, 953–958. Curole DN, Dickey RP, Taylor SN et al. 1989 Pregnancies in cancelled gamete intrafallopian transfer cycles. Fertility and Sterility 51, 363–364. Derom C, Derom R, Vlietinck R et al. 1993 Iatrogenic multiple pregnancies in East Flanders, Belgium. Fertility and Sterility 60, 493–496. Dickey RP, Taylor SN, Lu PY, Sartor BM et al. 2001 Relationship of follicle numbers and estradiol levels to multiple implantation of 3606 intrauterine insemination cycles. Fertility and Sterility 75, 69–78. Dunphy BC, Li TC, Macleod JC et al. 1990 The interaction of parameters of male and female fertility in couples with previously unexplained infertility. Fertility and Sterility 54, 824–827. ESHRE Capri Workshop Group 1996 Guidelines to the prevalence,
671
Article - Unexplained infertility - J Balasch
672
diagnosis, treatment and management of infertility, 1996. Human Reproduction 11, 1775–1807. ESHRE Capri Workshop Group 2000 Multiple gestation pregnancy. Human Reproduction 15, 1856–1864. Evans MI, Littman L, St Louis L et al. 1995 Evolving patterns of iatrogenic multifetal pregnancy generation: implications for aggressiveness of infertility treatments. American Journal of Obstetrics and Gynecology 172, 1750–1755. Evers JLH 2002 Female subfertility. Lancet 360, 151–159. Gleicher N, Karande V 2001 Forget about ovulation induction! Proceed directly to IVF. In: Ben-Rafael Z, Shoham Z, Frydman R (eds) Proceedings of the 2nd World Congress on Controversies in Obstetrics and Gynecology. Monduzzi Editore, Bologna, pp. 211–215. Gleicher N, Oleske DM, Tur-Kaspa I et al. 2000 Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. New England Journal of Medicine 343, 2–7. Goverde AJ, McDonnell J, Vermeiden JPW et al. 2000 Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 355, 13–18. Guzick DS, Sullivan MW, Adamson GD et al. 1998 Efficacy of treatment for unexplained infertility. Fertility and Sterility 70, 207–213. Guzick DS, Carson SA, Coutifaris C et al. for the National Cooperative Reproductive Medicine Network 1999 Efficacy of ovulation induction and intrauterine insemination in the treatment of infertility. New England Journal of Medicine 340, 177–183. Haney AF, Hughes CL, Whitesides DB, Dodson WC 1987 Treatment-independent, treatment-associated and pregnancies after additional therapy in a program of in vitro fertilization and embryo transfer. Fertility and Sterility 47, 634–638. Homburg R 2003 The case for initial treatment with intrauterine insemination as opposed to in vitro fertilization for idiopathic infertility. Human Fertility (Cambridge) 6, 122–124. Homburg R, Howles CM 1999 Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Human Reproduction Update 5, 493–499. Homburg R, Insler V 2002 Ovulation induction in perspective. Human Reproduction Update 8, 449–462. Hughes EG 1997 The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Human Reproduction 12, 1865–1872. Hughes EG 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. ‘Effective treatment’ or ‘not a natural choice’? Human Reproduction 18, 912–914. Hughes EG, Collins JA, Gunby J 1998 A randomized controlled trial of three low-dose gonadotrophin protocols for unexplained infertility. Human Reproduction 13, 1527–1531. Hughes EG, Collins J, Vandekerckhove P 2001 Clomiphene citrate for unexplained subfertility in women (Cochrane Review I). The Cochrane Library, Issue 2. Update Software, Oxford. Hull MGR 1992 Infertility treatment: relative effectiveness of conventional and assisted conception methods. Human Reproduction 7, 785–796. Hull MGR, Glazener CMA, Kelly NJ et al. 1985 Population study of causes, treatment, and outcome of infertility. British Medical Journal 291, 1693–1697. Jones HW 2003 Multiple births: how are we doing? Fertility and Sterility 79, 17–21. Levene MI, Wild J, Steer P 1992 Higher multiple births and the modern management of infertility in Britain. British Journal of Obstetrics and Gynaecology 99, 607–613. Matorras R, Díaz T, Corcostegui B et al. 2002 Ovarian stimulation in intrauterine insemination with donor sperm: a randomized study comparing clomiphene citrate in fixed protocol versus highly purified urinary FSH. Human Reproduction 17, 2107–2111. Nan PM, Cohlen BJ, te Velde ER et al. 1994 Intra-uterine insemination or timed intercourse after ovarian stimulation for
male subfertility? A controlled study. Human Reproduction 9, 2022–2026. National Collaborating Centre for Women’s and Children’s Health 2004 Fertility: Assessment and Treatment for People with Fertility Problems. Intrauterine insemination. Commissioned by the National Institute for Clinical Excellence. RCOG Press, London, pp. 75–80. Ombelet W 2003 Semen quality and intrauterine insemination. Reproductive BioMedicine Online 7, 485–492. Papageorgiou TC, Guibert J, Savale M et al. 2004 Low dose recombinant FSH treatment may reduce multiple gestations caused by controlled ovarian hyperstimulation and intrauterine insemination. British Journal of Obstetrics and Gynaecology 111, 1277–1282. Sengoku K, Tamate K, Takaoka Y et al. 1999 The clinical efficacy of low-dose step-up follicle stimulating hormone administration for treatment of unexplained infertility. Human Reproduction 14, 349–353. Stewart JA 2003 Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility. Should the guidelines be changed? Human Reproduction 18, 903–907. te Velde ER, Cohlen BJ 1999 The management of infertility. New England Journal of Medicine 340, 224–226. Tur R, Barri PN, Coroleu B et al. 2001 Risk factors for high-order multiple implantation after ovarian stimulation with gonadotrophins: evidence from a large series of 1878 consecutive pregnancies in a single centre. Human Reproduction 16, 2124–2129. Tur R, Barri PN, Coroleu B et al. 2005 The use of a prediction model for high-order multiple implantation after ovarian stimulation with gonadotropins. Fertility and Sterility 2005, in press. White DM, Polson DW, Kiddy D et al. 1996 Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. Journal of Clinical Endocrinology and Metabolism 81, 3821–3824. Wilcox LS, Kiely JL, Melvin CL, Martin MC 1996 Assisted reproductive technologies: estimates of their contribution to multiple births and newborn hospital days in the United States. Fertility and Sterility 65, 361–366. Zeyneloglu HB, Arici A, Olive DL, Duleba AJ 1998 Comparison of intrauterine insemination with timed intercourse in superovulated cycles with gonadotropins: a meta-analysis. Fertility and Sterility 69, 486–491.
Received 24 September 2004; refereed 15 October 2004; accepted 21 October 2004.