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

John Collins1

Department of Obstetrics and Gynecology, McMaster University, Hamilton and Department of Obstetrics and Gynaecology, Dalhousie University, Halifax, Canada

1 To whom correspondence should be addressed at: 400 Mader’s Cove Road, RR No.1 Mahone Bay, Nova Scotia, Canada, B0J 2E0. E-mail: collinsj{at}auracom.com


    Abstract
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
When conventional treatment of unexplained infertility has not been successful, the next choice lies between either gonadotrophin treatment with intrauterine insemination (FSH/IUI) and IVF. Cohort studies indicate that FSH/IUI is less effective while the cost per birth is higher with IVF. The relevant evidence should come from randomized controlled trials, but the results need to be recalculated for the outcome of greatest interest, a singleton live birth. Judged by this standard, FSH/IUI is statistically superior to no treatment, but the effect is small in couples with unexplained infertility. By the same standard, IVF is superior to FSH/IUI treatment, but this benefit is achieved only at considerable cost. The evidence is not robust, comprising only a few trials which involve a minute fraction of the existing patients with unexplained infertility. Current best evidence is consistent with a progression from low-tech to high-tech treatment, but it is not convincing enough to support a rigid management protocol. A large multicentre factorial trial is needed to evaluate the relative value of existing empiric treatments for unexplained infertility.

Key words: cost-effectiveness/gonadotrophins/intrauterine insemination/IVF


    Introduction
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
Because there is no apparent cause, unexplained infertility may be difficult to treat successfully. Lacking a specific treatment, little can be gained from modifying dosage or choosing different pharmaceutical preparations, and treatment plan strategies are limited. Usually treatment begins with a low tech, low cost approach, but when such treatment fails, the next treatment decision is troublesome: is it better to undertake cycles of gonadotrophin treatment with intrauterine insemination (IUI) before IVF or go directly to IVF? Valid evidence on this question is accumulating, but whether it is relevant to typical couples with unexplained infertility depends on the clinical and economic setting.


    What is the clinical setting of the question?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
Unexplained infertility is a common diagnosis, made in up to 30% of infertile couples after the conventional diagnostic assessment (Templeton and Penney, 1982Go). Negative diagnostic test results would be expected if female age were the single reason for delayed fecundity, or when a defect exists that cannot be found with currently available tests. Although diagnostic test results are normal, the prognosis for live birth is only slightly superior to that with other causes of infertility. The prognosis is worse when the duration of infertility exceeds three years and the female partner is >35 years of age (Collins et al., 1995Go). With less than two years duration of unexplained infertility the prognosis is good even without therapy, unless the female partner is >35 years of age. Treatment generally is indicated when the duration of infertility is more than three years or the female partner is >35 years of age.

Faced with the need for empiric treatment, clinicians have devised treatment plans involving clomiphene citrate (CC), IUI or both (CC/IUI). Three relevant Level I studies (randomized controlled trials; RCTs) in which 1471 women were enrolled, evaluated CC treatment (Harrison and O’Moore, 1983Go; Fisch et al., 1989Go; Glazener et al., 1990Go). One other trial involved a control group with normal fertility (Fujii et al., 1997Go). The relative likelihood of pregnancy was 1.9-fold higher with clomiphene treatment than placebo, but this significant difference has no more than marginal clinical importance. A significant relative difference might represent either an extremely small or an extremely large actual difference: a relative risk of 1.9 when the baseline risk is ten per million would have a very different clinical meaning if the baseline risk were 10%. Thus, for clinical purposes it is better to make use of the simple difference in rates between alternative treatments (risk difference or RD) and the inverse of RD, which is the number needed to treat (NNT). The NNT estimates how many times the intervention would be used before there was a single additional event with treatment compared with control. These absolute measures (RD and NNT) directly reflect the experience of patients. From the clomiphene trials, on average one additional pregnancy would occur in 40 cycles (95% CI 22–201) of CC compared with placebo treatment (The ASRM Practice Committee, 2000Go). IUI treatment is not much better: from the combined data of two RCTs of IUI treatment involving 1691 cycles, NNT was 37 cycles (95% CI 23–101) (Kirby et al., 1991Go; Guzick et al., 1999Go).

Data on the combination of CC/IUI compared with no treatment are available from one crossover RCT involving 51 women (Deaton et al., 1990). The pregnancy rates in the first phase of four cycles were 35% in the CC/IUI group and 15% in the control group. Considering all 298 cycles, the NNT for CC/IUI treatment was 16 cycles (95% CI 9–165). Thus the evidence about the effectiveness of early treatment of unexplained infertility is based on a limited number of small RCTs; at the present time that evidence suggests that sensible treatment plans should begin with three to six cycles of CC/IUI therapy because treatment with CC or IUI alone appears to be inefficient. No high quality medical care research could be found that evaluates the effectiveness of extended treatment programmes lasting more than six cycles.

Therefore, low-tech treatment of unexplained infertility is effective in only a minority of couples and many of the unsuccessful couples would then wish to consider advanced therapy involving gonadotrophin stimulation and IUI (FSH/IUI) or IVF or both. Both treatments are complex and costly, so knowing the best approach is an important objective for clinical research.


    What is the economical setting of the question?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
FSH/IUI and IVF are expensive treatments whether the source of funding is public insurance, private insurance or family income. The cost of a single IVF cycle in developed countries is 10 to 15% of the average family’s total annual income (Collins, 2002Go). Gonadotrophin drugs and cycle monitoring charges are the main cost in FSH/IUI cycles, but in IVF cycles laboratory and procedure charges add a significant further cost (Philips et al., 2000Go). The cost of an IVF cycle is approximately four times higher than the cost of a cycle of FSH/IUI treatment (van Voorhis et al., 1998Go; Philips et al., 2000Go). 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-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.

It is not surprising, then, to find Level II reports (cohort studies) indicating that FSH/IUI has a lower cost per pregnancy or live birth and that FSH/IUI is more cost-effective than IVF. In a 1997 Midwestern United States cohort study involving all diagnoses, costs per delivery were $10 282 and $37 028, respectively, for gonadotrophin/IUI cycles and ART cycles including IVF, gamete intra-Fallopian transfer (GIFT) and zygote intra-Fallopian transfer (ZIFT) (van Voorhis et al., 1998Go). In a UK modelling study published in 2000, involving four cycles of treatment, costs per pregnancy in couples with unexplained infertility were £3681 and £8770 respectively, for stimulated IUI and IVF (Philips et al., 2000Go). If there were no further input, a policy of FSH/IUI cycles prior to IVF would appear to be prudent for couples with unexplained infertility who have not conceived after a trial of low-tech treatment.


    What evidence is relevant to the question?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
If the majority of couples with unexplained infertility are faced with the question of whether to choose FSH/IUI before IVF, and the cost per birth is higher with IVF, it stands to reason that professional associations, insuring agents and the general public would favour FSH/IUI as the right course of action. It appears, however, that the evidence cited above for that position may not be an adequate basis for robust clinical recommendations, for several reasons.

First, it is important to choose the highest level of evidence about the effectiveness of FSH/IUI treatment. Several RCTs have compared gonadotrophin/IUI with various alternatives for the treatment of unexplained infertility; some of these Level I studies included a small proportion of cases with mild male infertility or treated endometriosis. Although not strictly free from diagnostic findings, the infertility in mild male and treated endometriosis cases also remains unexplained, and such couples usually are given the same treatment options as couples with no diagnostic findings (those with pure unexplained infertility). There is no good reason to believe that the effects of empiric treatments such as FSH/IUI or IVF differ because of the additional minimal diagnostic findings, considering the number and variety of unknown, undetected and unrecognized fertility defects that contribute to supposedly ‘pure’ unexplained infertility.

Second, the cost-effectiveness of clinical interventions should be based on full economic evaluations involving a randomized evaluation of FSH/IUI treatment with a parallel assessment of costs. Such studies are not common but they are the best source of information on which to make judgements about relative cost.

Third, in order to address fairly the most relevant clinical outcome, treatment effects should be established relative to live birth rather than pregnancy or other surrogate outcomes. Furthermore, a singleton live birth is the outcome of greatest interest, and consequently the effects and costs should be calculated for this expression of the success rate. Effects and costs are often expressed per delivery, however, meaning that multiple birth rates—which may differ between FSH/IUI and IVF—have to be subtracted from the overall live birth or delivery rates to estimate singleton birth rates.

Finally, in order to ensure that the observed differences are clinically as well as statistically significant, the study results should be expressed as NNT, a rendering of clinical study results which is currently as close as we are able to come to meeting the patients’ needs for digestible information (Cook and Sackett, 1995Go). Along the same lines, the analysis should be according to intention to treat: couples should be analysed within the group to which they were randomly allocated regardless of whether they made a different choice after randomization. The basis for using an intention to treat analysis is that pragmatic trials evaluate what happens in real clinical life, where discontinuation and changes in treatment plans are common events. The trial’s results will then be applicable to other clinical settings with all of their imperfections, and in particular will apply to couples at the time that they are considering whether to use a treatment, when their own future is as uncertain as that of the trial subjects at enrolment.


    Is FSH/IUI an effective treatment?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
The first relevant question concerns whether FSH/IUI treatment is more effective than having no further therapy when simpler treatment for unexplained infertility has not worked. In other words, is FSH/IUI better than no treatment?

Guzick et al. (1999Go) compared intracervical insemination (ICI) alone, IUI alone, FSH/ICI and FSH/IUI in a randomized controlled trial with a factorial design. The authors described the study as a trial of treatment for unexplained infertility, (Guzick et al., 1998Go) but some female partners had stage I or II endometriosis (if six months had elapsed after treatment) and 25% of the male partners had oligozoospermia. Also, the trial design assumes that ICI is equivalent to no treatment. In this trial, live birth rates per cycle and per couple were higher with FSH/IUI than with ICI. Table I presents results based on the intention to treat; all births during an assigned protocol of treatment, including conceptions during a cycle of rest, are included. Estimated singleton birth rates per cycle were 5.7 and 2.4% respectively, in FSH/IUI and ICI cycles.


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Table I. Calculated outcomes with FSH/IUI and ICI treatment: original data from Guzick et al (1999)
 
Although the 95% confidence intervals (CI) indicate that the differences are statistically significant, the effect of FSH/IUI per cycle is not clinically significant, given the money and time expenditure involved. The NNT is 31 cycles, implying that it would take 31 cycles of treatment before there would be one more singleton live birth with FSH/IUI than with ICI (95% CI 19–90). Of course, singleton birth rates per couple were higher than the per cycle rates: 15 and 7% during up to four cycles of treatment. The NNT per couple seems to present a more favourable view: one additional singleton live birth per 13 couples (95% CI 7–39), but that would depend on undertaking a four-cycle treatment plan. The rate of withdrawal from the study was higher in the gonadotrophin treatment groups, for several reasons, including the cost of treatment.

By statistical standards, FSH/IUI is an effective treatment for persistent unexplained infertility, judged on the outcome of singleton live births. The effect is so small, however, that it becomes clinically appreciable only in association with a protocol of four cycles. Naturally this alters the cost-effectiveness, an issue that will be dealt with momentarily.


    Is FSH/IUI treatment better than CC/IUI?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
If the impact of FSH/IUI is so small relative to no treatment, would it be better simply to suggest a repeat course of treatment with CC/IUI? Four trials have compared CC/IUI and gonadotrophin/IUI treatment, although none specifically addressed this question after previous CC/IUI treatment. The comparisons were not significant in any single trial. Only one trial was restricted to unexplained infertility (Karlstrom et al., 1993Go). The pregnancy rates were 6 (1/17) and 20% (3/15) respectively, in IUI cycles with clomiphene and gonadotrophin stimulation. The difference was not statistically significant (P = 0.27), and the numbers are too small to attempt a calculation based on live births. The lack of significance in this trial is not due simply to lack of power: the remaining trials show no consistent pattern either in mixed diagnostic groups or in male infertility, with CC superior in some comparisons and gonadotrophins in others (Balasch et al., 1994Go; Karande et al., 1996Go; Ecochard et al., 2000Go). Multiple births were not mentioned in this group of publications.

Thus, while cycles of gonadotrophin treatment with IUI are marginally superior to no treatment, FSH/IUI has not yet been proven superior to CC/IUI in couples with unexplained infertility. A trial is needed to compare extended CC/IUI treatment (say three cycles) with a similar number of FSH/IUI treatment cycles in couples with unexplained infertility who have completed an initial three cycles of CC/IUI treatment for unexplained infertility without success.


    Is IVF treatment superior to FSH/IUI?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
FSH/IUI, although significantly superior to having no further treatment, has only a small effect. Therefore would it be better to forgo FSH/IUI and go on directly to IVF treatment if low-tech treatment has not been successful? Two RCTs compared FSH/IUI and IVF treatment in couples with unexplained infertility. In the ESHRE trial, birth rates were 24.5 and 22.9% respectively, in two cycles of gonadotrophin/IUI and IVF treatment (Crosignani et al., 1992Go). The more recent Amsterdam trial compared treatment plans involving six cycles of IUI, FSH/IUI or IVF among couples with unexplained or male infertility (Goverde et al., 2000Go). One criticism of the Amsterdam trial is the low pregnancy rate per cycle with IVF, but few RCTs achieve outcomes that are as good as those in observational studies or registry collections. Also, in this RCT the IVF multiple pregnancy rate was only 21%, and some couples experienced as many as six cycles of IVF. The best evidence available suggests that delivery rates decline after the third cycle (Meldrum et al., 1998Go).

More couples withdrew from IVF cycles (42%) than FSH/IUI cycles (16%). The overall live birth rates per cycle and per couple were not significantly different with FSH/IUI or IVF. The calculated outcomes for couples with unexplained infertility are shown in Table II. Singleton live birth rates are based on the authors’ report that the multiple birth rates were 29 and 21% respectively, in FSH/IUI and IVF cycles. During an average of 3.5 years, the singleton live birth rates per cycle were 6 and 10% respectively, in the FSH/IUI and IVF groups. The singleton live birth rates per couple were 26 and 31% respectively, in the FSH/IUI and IVF groups. The clinical differences between FSH/IUI and IVF treatment of unexplained infertility were small; the NNTs were 25 cycles and 20 couples and they were not statistically significant. No trial to date appears to have been powered specifically for the comparison of IVF and FSH/IUI in unexplained infertility. Also, the reported trials involved an exceedingly small fraction of the patients worldwide undergoing treatment, so that generalizations have to be limited. Nevertheless, the best evidence available indicates that, at least in this diagnostic grouping, the difference in success rates between FSH/IUI and IVF may be quite small. Since the effects of FSH/IUI are known to be small, the true importance of the effect of IVF also may be small. In any case, there is a need for further study of the effectiveness of these advanced treatments.


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Table II. Number of patients, cycles and births among couples with unexplained infertility: data from Goverde et al. (2000)
 

    Is FSH/IUI treatment more cost-effective than IVF?
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
Three studies have evaluated the cost-effectiveness of IVF in the setting of a randomized controlled trial (Goeree et al., 1993Go; Karande et al., 1999Go; Goverde et al., 2000Go); only one, the Amsterdam trial, compared FSH/IUI and IVF (Goverde et al., 2000Go). This trial obtained actual direct costs (personnel, equipment, materials, medications and overheads) for each patient up to 12 weeks gestation and these costs were presented according to diagnostic group. The direct hospital and out-patient costs per cycle in Dutch guilders (NLG) were 931 NLG and 3350 NLG respectively, in the FSH/IUI and IVF groups. The reported cost data and calculated cost-effectiveness ratios are shown in Table III. (Note that cost-effectiveness is the same when estimated per cycle or per couple because per couple costs and effects are simply the per cycle estimates modified by the average number of cycles per couple). A better measure for comparison is the incremental cost-effectiveness (C-E) ratio. This ratio estimates the additional cost of a single additional unit of outcome, either any births or singleton births in this case. The C-E ratio is the cost difference divided by the risk difference. Since the NNT is unity divided by the risk difference, the incremental C-E ratio provides the cost of that additional unit of outcome. The incremental C-E ratios calculated from the authors’ data are shown in the last column of the table. The relatively low incremental C-E associated with singleton births per couple is due to the impact of a higher FSH/IUI multiple pregnancy rate on the smaller denominator of couples rather than cycles.


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Table III. Cost and cost-effectiveness of FSH/IUI and IVF (NLG): data from Goverde et al. (2000)
 
The small increase in effectiveness with IVF over FSH/IUI treatment is achieved only at considerable incremental cost, whether it is measured per cycle or per couple.


    Problems with the evidence
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
One obvious problem with the evidence is its scarcity. Although there are numerous possibly relevant publications, very few provide the valid evidence that is required to address these common clinical questions about the advanced treatment of unexplained infertility. Drawing general conclusions from microscopic samples is an activity that may be fraught with uncertainty.

A related problem concerns the number of patients in these studies. If 20% of the couples undergoing IVF cycles have unexplained infertility, then the studies include a minute fraction of the volume of advanced treatment for unexplained infertility. The 184 and 86 IVF cycles in the Amsterdam and ESHRE trials, for example, represent only 0.2% of the total 140 600 IVF cycles in the United States and Europe in just one year, 1998 (Nygren and Nyboe Andersen, 2001Go; Society for Assisted Reproductive Technology & American Society for Reproductive Medicine, 2002Go). Thus, so few of the patients in clinical practice are reported that one cannot determine whether the study subjects are representative.

A further problem is the lack of knowledge about prognostic factors beyond the usual surrogates for severity: duration and female partner’s age. No specific prognostic factors are known because the causes are both masked and multifactorial, so the severity of the disease cannot be graded. Variability among studies often is due to differences in the mix of severity among the subjects from study to study, but in this case there is no means of determining how that mix might affect the comparison of the effectiveness of two treatments.

Finally, an unidentifiable subset of couples with unexplained infertility may have conditions that cannot possibly respond to the effect of pre-implantation interventions. For the present, the treatment of unexplained infertility is limited to procedures that do no more than increase the probability of successful insemination. Numerous post-fertilization defects are imaginable that could contribute to this diagnostic grouping. Thus many patients and subjects of trials cannot conceive despite the use of empiric treatment. The presence of such unresponsive conditions reduces the power of RCTs to discriminate between effective and ineffective treatments.

Thus, much of the existing medical care evidence about the advanced treatment of unexplained infertility is valid, but it is not robust. Under such conditions, it is difficult for societies, associations and other authorities to formulate lasting guidelines because of the present uncertainty and the future potential for change as new data become available.


    Conclusions
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
One way or another, the clinical questions have to be addressed, no matter how uncertain the evidence may be, and whether or not there are shortcomings in the studies. The current best evidence continues to support the long-established clinical strategy based on a progression from low-tech to high-tech treatment for unexplained infertility. The most relevant evidence indicates, however, that the effects of advanced treatment with either FSH/IUI or IVF are not large, while the costs are considerable, and of course, highest for IVF.

Obviously, there is a need for more research: the important clinical questions call for a large international factorial study involving a no treatment arm as well as CC/IUI, FSH/IUI and IVF treatments. The study should have the power to address each of the six possible comparisons. While such a study might cost millions, if it is not done many more millions could be wasted on treatments that are not as effective as they now seem.

Inevitably, the results of such large definitive studies leave many unanswered important clinical questions. Observational studies and trials are needed to help sort out issues such as the optimal timing of treatment and the preferable order of treatments. Most important, however, is the need for scientific studies to elucidate some of the causes of unexplained infertility and discover specific treatments that are far more likely to be effective than the present choice of empiric remedies.


    References
 Top
 Abstract
 Introduction
 What is the clinical...
 What is the economical...
 What evidence is relevant...
 Is FSH/IUI an effective...
 Is FSH/IUI treatment better...
 Is IVF treatment superior...
 Is FSH/IUI treatment more...
 Problems with the evidence
 Conclusions
 References
 
Balasch, J., Ballesca, J.L., Pimentel, C., Creus, M., Fabregues, F. and Vanrell, J.A. (1994) Late low-dose pure follicle stimulating hormone for ovarian stimulation in intra-uterine insemination cycles. Hum. Reprod., 9, 1863–1866.[Abstract]

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Goverde, A.J., McDonnell, J., Vermeiden, J.P.W., Schats, R., Rutten, F.F.H. and Schoemaker, J. (2000) Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility. Lancet, 355, 13–18.[CrossRef][ISI][Medline]

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Guzick, D.S., Carson, S.A., Coutifaris, C., Overstreet, J.W., Factor-Litvak, P., Steinkampf, M.P., Hill, J.A., Mastroianni, L., Buster, J.E., Nakajima, S.T., Vogel, D.L. and Canfield, R. (1999) Efficacy of superovulation and intrauterine insemination in the treatment of infertility. N. Engl. J. Med., 340, 177–183.[Abstract/Free Full Text]

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Karande, V.C., Korn, A., Morris, R., Rao, R., Balin, M., Rinehart, J., Dohn, K., and Gleicher, N. (1999) Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil. Steril., 71, 468–475.[CrossRef][ISI][Medline]

Karlstrom, P.O., Bergh, T. and Lundkvist, O. (1993) A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil. Steril., 59, 554–559.[ISI][Medline]

Kirby, C.A., Flaherty, S.P., Godfrey, B.M., Warnes, G.M. and Matthews, C.D. (1991) A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse. Fertil. Steril., 56, 102–107.[ISI][Medline]

Meldrum, D.R., Silverberg, K.M., Bustillo, M. and Stokes, L. (1998) Success rate with repeated cycles of in vitro fertilization-embryo transfer. Fertil. Steril., 69, 1005–1009.[CrossRef][ISI][Medline]

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Philips, Z., Barraza-Llorens, M. and Posnett, J. (2000) Evaluation of the relative cost-effectiveness of treatments for infertility in the UK. Hum. Reprod., 15, 95–106.[Abstract/Free Full Text]

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