Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility

‘Effective treatment’ or ‘not a natural choice’?

Edward G. Hughes

Department of Obstetrics & Gynecology, McMaster University Medical Centre, 1200 Main Street West, Room 4D14, Hamilton, ON L8N 3Z5, Canada. E-mail: hughese{at}mcmaster.ca


    Abstract
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
Helping couples to choose appropriate therapy for their unexplained subfertility demands a review of evidence for treatment benefit and harm, in the context of both patients’ and clinicians’ experience and perspective. Ovulation induction (OI) with clomiphene (CC) or gonadotrophin (FSH) and intrauterine insemination (IUI) are often chosen before resorting to IVF. The appropriateness of starting with these low and intermediate intensity treatments is supported by evidence that CC/IUI increases cycle fecundity two- to three-fold, and FSH/IUI, three- to five-fold over the baseline chance of pregnancy in this patient group. While both OI/IUI and IVF have adverse effects which deserve vigorous attention, particularly multiple pregnancy and ovarian hyperstimulation syndrome (OHSS), the balance between benefits and costs often favours OI/IUI. The cost per live birth and potential for OHSS appears lower with OI/IUI, and the proportion of multiple pregnancies similar to that seen with IVF. For these as well as physical and spiritual reasons, OI/IUI is often a natural starting point for couples, especially when female age and duration of subfertility are favourable.

Key words: clomiphene citrate/gonadotrophin/intrauterine insemination/ovarian hyperstimulation syndrome/unexplained subfertility


    Introduction
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
Good clinical decisions are founded on three essential elements: experience, perspective and evidence. Care-givers bring experience and perspective from their education and clinical practice in specific communities. Patients bring their own experience and perspectives, coloured by issues such as geography, finance, culture and spirituality. It is in this context and not in isolation, that available evidence informs decisions.

In the case of controlled ovarian stimulation (COS) and intrauterine insemination (IUI) for unexplained subfertility, what does the evidence suggest: ‘not a natural choice’ (Stewart, 2003Go), or as stated by the Royal College of Obstetricians and Gynaecologists (RCOG) guidelines, an ‘effective treatment’ (RCOG, 1998Go)?

Practice guidelines, such as those published by the RCOG, are intended to improve standards of practice by grading, summarizing, and disseminating evidence. This may be derived from rigorous and valid clinical trials, potentially biased cohort or weaker designs, or completely anecdotal reports. In interpreting conclusions, the reader needs to know from which of these sources the data arise. The categories chosen by the RCOG to give appropriate weight to summaries of evidence are as follows:

Grade A: Based on randomized controlled trials

Grade B: Based on other robust experimental or observational studies

Grade C: Based on more limited evidence but the advice relies on expert opinion and has the endorsement of respected authorities

Is this system explicit? Surely, the only ‘robust experimental studies (Grade B)’ in clinical medicine are randomized controlled trials (Grade A), creating overlap between these categories. A further concern in interpreting the guidelines is that full, referenced explanations of the evidence on which they are based are not widely disseminated. They are only available through purchase from the RCOG and may not be accessible to all care-givers, particularly outside the UK. With these caveats in mind, what do the RCOG guidelines suggest?


    Clomiphene
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
‘Current evidence suggests that the treatment of unexplained infertility with clomiphene will result in little or no benefit (Grade A). Therefore, this treatment should be used only in the context of a large randomized controlled trial (Grade C)’.

This brief statement highlights the need for access to the evidence, or at least the references, on which this recommendation is based. A recently updated Cochrane review summarized data from six randomized trials comparing clomiphene with or without IUI, to intercourse, for unexplained and endometriosis-associated subfertility (Hughes and Vandekerckhove, 2000Go). Although these small trials do not provide meaningful data on multiple pregnancy risk, they suggest a two- to three-fold increase in cycle fecundity, with a common odds ratio for pregnancy per treatment cycle of 2.5 (95% CI 1.75, 14.3). This effect-size compares favourably with that seen following FSH and IUI (Hughes, 1997Go), accepted in another RCOG guideline as an "effective treatment". The estimate for pregnancy per cycle with clomiphene versus no treatment for oligo-ovulation, is only 3.4 (95% CI 1.23, 9.48) (Hughes et al., 1997Go), but in that context, clomiphene is accepted as clinically useful (RCOG, 1998Go). Perhaps the fact that the four trials on which the latter estimate is based were all double-blind, and more rigorous than most of the studies in unexplained subfertility, explains the contrast between the two clomiphene recommendations: rejection of its use for unexplained subfertility and endorsement for oligo-ovulation.

Certainly, more valid research is justifiable for clomiphene with or without IUI, in unexplained subfertility. However, the RCOG guideline’s simple statement that current evidence suggests "little or no benefit" seems inconsistent with data for this and other treatments.


    Gonadotrophin plus IUI
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
With regard to gonadotrophin plus IUI, the guideline states..."Ovarian stimulation with intrauterine insemination is an effective treatment for couples with unexplained infertility (A)".

Grade A suggests that evidence from randomized controlled trials (RCT) forms the basis of this statement, but again, the references used are not available from the internet source. Certainly, the direct evidence supporting this assertion is limited. A single trial that compares FSH plus IUI versus timed intercourse alone for unexplained subfertility, demonstrated a five fold increase in cycle fecundity from 2 to 10% (Zikopoulos et al., 1993Go). A related trial has made the same comparison in unexplained subfertility associated with mild endometriosis. Again, cycle fecundity was increased five-fold, from 2 to 11% (odds ratio 5.6, 95% CI 1.8, 17.4) (Tummon et al., 1997Go). The comparison of FSH/IUI versus timed intercourse in natural cycles for male subfertility is also favourable. Three trials, including 605 completed cycles, suggest a five-fold increase ongoing pregnancy per completed cycle, with a common odds ratio of 5.4 (1.8,16.2) (Cohlen et al., 2002Go). Also, a multi-centre RCT comparing intracervical insemination (ICI) with IUI suggested that FSH/IUI increased the likelihood of pregnancy threefold compared with ICI and twofold compared with IUI in unmedicated cycles (Guzick et al., 1999Go).

In deciding whether or not to use ovulation augmentation and IUI for unexplained subfertility, a comparison with IVF is appropriate, in terms of risks, costs and effectiveness. While FSH/IUI may well result in a higher absolute number of multiple pregnancies than IVF, the proportional multiple rates are similar. A recent series of 1878 consecutive FSH/IUI pregnancies reported 15.6% twin and 5.7% higher order pregnancy rates (Tur et al., 2001Go). In their randomized trial, Guzick et al. reported a 21% multiple rate (Guzick et al., 1999Go) compared with recent North American IVF data (1998) reporting twin, triplet and higher order rates of 30.4, 6.2 and 0.4% respectively (The American Society for Reproductive Medicine & Society for Assisted Reproductive Technology Registry, 2002Go). Clearly, more has to be done to reduce multiple pregnancy rates for both treatments. Even with statutory limitations on the number of embryos transferred in the UK, there does not appear to be the same downward trend in multiple rates as has been reported elsewhere (Engmann et al., 2001Go; Westergaard et al., 1999Go). Also, there is significant potential for multiple pregnancies with apparently adequate monitoring of FSH/IUI cycles (Guzick et al., 1999Go). Another major adverse outcome to consider is ovarian hyperstimulation syndrome (OHSS). In the presence of risk factors, such as polycystic ovaries and young female age (D’Angelo and Amso, 2002Go), a cautious approach to gonadotrophin dosing may be taken during OI/IUI. Using a slow step-up, low-dose protocol (Sagle et al., 1991Go) decreases the incidence of OHSS while enhancing the chance of monovulation. Such conservatism is not so productive in IVF. Here, the objective is to find the middle ground between minimal and excessive stimulation. The combination of GnRH agonist and higher dose gonadotrophin, increases the incidence of OHSS, compared with FSH/IUI (Hughes et al., 1992Go).

Although the RCOG guidelines specifically state that cost effectiveness has not yet been considered, this remains an important factor in selecting treatments. A recent observational study of over 4000 cycles suggests that for women with documented tubal patency and partners with normal sperm, COS/IUI is a more cost-effective treatment than IVF (Van Voorhis et al., 2001Go). In the presence of total motile sperm counts of >10x106, the average cost per delivery with clomiphene/IUI and FSH/IUI were $7951 and $19 092 respectively, compared with $28 639 for IVF. An earlier randomized trial comparing IUI with IVF produced similar results: the cost per pregnancy, in couples with unexplained subfertility or sperm problems, was approximately three-fold higher following IVF than medicated or FSH-stimulated IUI (Goverde et al., 2000Go). This cost-effectiveness analysis did not take into account the significant burden of illness associated with multiple pregnancy. This occurred in ~30% of FSH/IUI and 20% of IVF cycles. Had these costs been included, unmedicated IUI would have been clearly more cost-effective than either of these other options.

Finally, in choosing between low and high intensity treatment, the issue of compliance is important. With ART, dropout is common—only about one-third of non-pregnant IVF couples complete three cycles (Land et al., 1997Go). Because FSH/IUI and IUI alone are more tolerable and less expensive, repeated cycles are possible, further increasing the absolute number of pregnancies associated with these treatments.


    Conclusions
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
Is a combination of ovulation augmentation and IUI an appropriate choice for unexplained subfertility? The evidence suggests that it is for some couples. Six trials of clomiphene, one of FSH, as well as several related studies of male-factor and endometriosis-associated subfertility, suggest clinically significant improvements in fecundity, when compared with intercourse in unmedicated cycles. OI/IUI is more tolerable than IVF, but shares with it risks of multiple pregnancy and OHSS.

Further randomized trials are warranted to assess the effectiveness of clomiphene, FSH and IUI for unexplained subfertility, with particular attention to these adverse outcomes, but again, this is true of IVF. There are no reported trials comparing IVF versus no treatment and only two comparing IVF with ‘conventional management’ (Jarrell et al., 1993Go; Soliman et al., 1993Go). Neither demonstrated effectiveness in women with patent Fallopian tubes (Jarrell et al., 1993Go). In studying FSH/IUI effectiveness, setting conservative limits for cycle cancellation and analysing data in sub-groups based on follicular number, will help to identify safe, effective treatment parameters. By including women who have one, two or three dominant follicles, a trial will have wider implications, particularly in countries where the standard of care currently exceeds monovular stimulation.

As stated in the introduction, the experience and perspectives of patients and care-givers are crucial in clinical decision-making—for many patients, clomiphene or FSH plus IUI may be more medically, financially and spiritually acceptable than IVF. For them, OI/IUI may indeed be a natural treatment choice.


    References
 Top
 Abstract
 Introduction
 Clomiphene
 Gonadotrophin plus IUI
 Conclusions
 References
 
Cohlen, B.J., Vandekerckhove, P., te Velde, E.R., and Habbema, J.D.F. (2002) Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for subfertility in men. Cochrane Library. 2002.

D’Angelo, A. and Amso, N. "Coasting" (withholding gonadotropins) for preventing ovarian hyperstimulation syndrome (Cochrane Review). Cochrane Library. 2002.

Engmann, L., Maconochie, N., Tan, S.L. and Bekir, J. (2001) Trends in the incidence of births and multiple births and the factors that determine the probability of multiple birth after IVF treatment. Hum. Reprod., 16, 2598–2605.[Abstract/Free Full Text]

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: a randomised trial and cost-effectiveness analysis. Lancet, 355, 13–18.[CrossRef][ISI][Medline]

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Hughes, E., Sagle, M., Fedorkow, D.M., Van de Koppel, P., Daya, S. and Collins, J. (1992) The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials. Fertil. Steril. 58, 888–896.[ISI][Medline]

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