Human Reproduction, Vol. 18, No. 5, 903-907,
May 2003
© 2003 European Society of Human Reproduction and Embryology
Stimulated intra-uterine insemination is not a natural choice for the treatment of unexplained subfertility
Should the guidelines be changed?
Reproductive Medicine, Bioscience Centre, International Centre for Life, Times Square, Newcastle-upon-Tyne, UK. e-mail: jane.stewart{at}nuth.northy.nhs.uk
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Abstract |
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 Top Abstract IntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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The Royal College of Obstetricians and Gynaecologists Guidelines for the management of infertility in secondary care (1998) states that stimulated intrauterine insemination (IUI) has Grade A evidence to confirm its effective use in unexplained infertility. This paper challenges that assertion after closer assessment of the papers upon which it was based. With the current appraisal of the Guidelines as part of the ‘scope’ of the assessment of infertility management by the National Institute of Clinical Excellence it is important that the guidelines are indeed critically reviewed prior to their updated publication. With the emphasis on minimizing the risk of multiple pregnancies, a formal trial of stimulated IUI is called for in order to justify its continued use in this setting. Strict attention to limiting the number of follicles treated in verified unexplained subfertility is necessary to validate such a trial.
Key words: intrauterine insemination/ovarian stimulation /unexplained subfertility
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Introduction |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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Stimulated intra-uterine insemination (IUI) has been used for a number of years as a treatment for subfertility. Regimes vary between centres and indeed between clinicians, but in essence involve artificial induction of ovulation combined with appropriately timed delivery of sperm into the uterine cavity. This technique has been used to treat a range of causes of subfertility from ovulatory to male factor problems, and including so-called ‘unexplained subfertility’.
Unexplained subfertility may reasonably be defined as the failure to conceive in the face of normal baseline investigations (tubal patency, semen analysis and ovulation) with regular intercourse over a period of three years (Hull, 1985
). Candidate sites for potential causes include oocyte quality, sperm function, sperm and oocyte interactions, tubal function and environment, endometrium, early embryo development and function, embryo-endometrial interactions, implantation and many others besides. Thus a diagnosis of unexplained subfertility may include one or a combination of factors. A group of couples with this diagnosis is therefore liable to be extremely heterogeneous with regard to their reproductive potential both with or without treatment.
Cumulative conception rates reveal that after 3 years of trying for a pregnancy, a couple can expect about 3% chance of conceiving without treatment (Hull, 1985) per menstrual cycle. A clinical pregnancy rate of over 20% can be achieved with IVF in these couples (HFEA Annual Report, 2000), which is thus an appropriate treatment for the condition. IVF however involves huge investments of time and emotion and not least, in many cases, significant financial input or a long wait. Whilst there are some diagnostic benefits to performing IVF, an effective ‘intermediate’ step would be of great benefit. Is stimulated IUI such a step?
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A suitable option? |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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Requiring similar drug regimes to IVF, stimulated IUI is unlicensed in the UK. In the best hands it is closely monitored by means of transvaginal ultrasound scans and estrogen concentration estimations on a regular basis. The purpose of close monitoring is to allow the control of the number of follicles reaching maturity prior to induction of ovulation and insemination. Despite this care, cycles can be complicated by excess follicular development and the complication of ovarian hyperstimulation syndrome (OHSS) is a risk. In addition, multiple pregnancy rates remain high. Injudicious or liberal use of this treatment may result in unacceptable multiple pregnancy rates including higher order multiples (Gleicher et al., 2000
). What are the gains to a couple of undergoing stimulated IUI for unexplained subfertility? The process of stimulated IUI potentially ‘bypasses’ several influences on fertility. These include minor sperm abnormalities, since the preparation of sperm for IUI may result in the delivery of a higher concentration of normal motile sperm into the female tract, and since sperm–mucus interactions are avoided in the cervix an advantage may also be conferred from this. Timing of sperm delivery features in the success of stimulated IUI although it is likely that in a couple having regular intercourse, timing alone is not a significant factor in their failure to conceive. There may, in addition, be an advantage to some women in the effects of the artificial regime on the endometrium and its function. The greatest positive factor however is likely to be the induction of multifolliculogenesis. Other advantages of stimulated IUI to take into account are the psychological benefit of ‘something being done’ during a waiting period as well as the ‘low tech’ approach and the cheaper per cycle cost to self-funded patients.
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The RCOG Guidelines |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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In the Guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG, 1998
), Recommendation 50 states that..."Ovarian stimulation with intrauterine insemination is an effective treatment for couples with unexplained infertility". It is given Grade A for evidence base meaning "based on randomized controlled trials". This guideline has caused some controversy in units where such treatment is not traditionally offered, preference being given to treatment with IVF or gamete intrafallopian transfer (GIFT) directly. Is there now any justification for not offering stimulated IUI as a treatment for unexplained subfertility? The weight of a Grade A recommendation makes it difficult to avoid.
The RCOG assessment is based on a meta-analysis presented by Hughes (1997) that included 22 studies considered relevant to the questions raised. Hughes’ questions were: (i) Is FSH plus IUI more effective than FSH plus timed intercourse in the treatment of persistent unexplained infertility? (ii) What are the independent effects of FSH, IUI, clomiphene citrate, male factor and endometriosis on fecundability in persistent infertility? Do these questions in fact address the use of stimulated IUI as a treatment for unexplained subfertility compared with no treatment? The value of meta-analysis comes from asking specific questions, acquiring the most appropriate data to answer those questions and not drawing conclusions apart from answering the original questions. Hughes has reviewed the papers used for his meta-analysis in a table in his paper (omitting one [Evans et al., 1991]). The RCOG guidelines cite no additional papers. The following data (Table I) presents some slightly different aspects of the papers considered.
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A closer look |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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The meta-analysis has apparently successfully answered Hughes’ two questions with regard to the use of IUI in conjunction with FSH using the data derived from these studies. It confirms the advantage of stimulated IUI over ovarian stimulation alone and Hughes also states that by logistic regression he is able to infer that FSH and IUI..."both significantly improve fecundity"..., but adds that..."high quality studies are required to estimate confidently the true effects of IUI and FSH treatment". About one quarter of the papers used in the meta-analysis do not include couples with ‘unexplained subfertility’ and less than a third make use of untreated controls. In fact only one included study (Zikopoulos et al., 1993
) directly addresses the question of stimulated IUI in unexplained subfertility versus no treatment. In addition there are several definitions of unexplained subfertility in use and in particular the number of follicles treated and the cancellation criteria for treatment cycles and their rates are in general not reported. This heterogeneity in the studies is discussed by Hughes but with this in mind the limitations of the conclusions need to be taken into account. Indeed Hughes states that "one of the key findings of the review is that further studies of FSH/IUI versus no treatment are urgently needed". With these reservations it is difficult to justify the Grade A weighting placed on the data by the RCOG. |
Multifolliculogenesis |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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Although there are studies showing that increasing the follicle numbers treated affects the pregnancy rate (Tomlinson et al., 1996
; Chang et al., 1998), there is evidence not included in Hughes’ review, that controlling follicular numbers removes the advantage of stimulated IUI over IUI alone (Murdoch et al., 1991). It is possible therefore that the effect of stimulated IUI on unexplained subfertility is primarily a result of ovarian stimulation and multifolliculogenesis. This brings into question the concerns about multiple pregnancies since this is clearly a complication of multifolliculogenesis.
It has been estimated that the multiple pregnancy rate associated with ovarian stimulation treatment is responsible for the majority of higher order births (Levene et al., 1992). Ovulation induction treatment was responsible for around 40% of triplet and higher order births in the USA in both 1996 and 1997 (Morbidity and Mortality Weekly Report, 2000). The delivery rates however, do not take into account fetal reduction procedures and pregnancy complications including miscarriage which will represent further multiple pregnancies. In addition, as unlicensed treatment in the UK, full data with regard to numbers of treatments being performed, follicle numbers treated and outcomes are not readily available. What is of great importance is that authors reporting ovarian stimulation success, rarely report the maximum numbers of follicles treated and the criteria for cycle cancellation. There is no useful estimate of the risks run to achieve those successes.
Papers examining the treatment of unexplained subfertility with stimulated IUI compared with normal controls are few. Only one other, not represented by Hughes, was identified via Medline (Aboulghar et al., 1993). This paper is however seriously flawed as there was no matching or randomization of control couples who were living away from the treatment centre, mostly abroad. Thus they were a selected group who could not be relied upon to represent appropriate untreated controls. From Hughes’ list only three fulfilled the three conditions. Both Deaton et al. (1990) and Martinez et al. (1990) however used only clomiphene citrate stimulated cycles and their papers therefore do not fully inform this debate. The study reported by Zikopoulos et al. (1993) represents the best attempt to date to assess the question of the use of stimulated IUI in unexplained subfertility. They were able to show in a complex type of cross-over trial, that the cycle fecundity for stimulated IUI or ovarian stimulation with timed intercourse of 0.11 was a significant increase over that achieved (0.02) with timed intercourse in natural cycles (P < 0.01). The direct comparison of stimulated IUI versus timed intercourse is not given but a cycle fecundity of 0.1 for stimulated IUI alone is quoted. They did however report a multiple pregnancy rate of 36% including one set of triplets. A total of 7% of treatment cycles were cancelled for excessive follicular response. Notably however, this was only done when more than four large follicles were seen on scan and the mean number of follicles treated were 3.8 in conception cycles and 3.4 in non-conception cycles (P < 0.05) showing that, although not materializing in the results thus far, the risk of large multiple pregnancy was present for almost every individual treated and that follicle numbers do relate to pregnancy rates. There were nine live births from 17 conceptions.
In 1998, the same year as the RCOG Guidelines were published, Guzick et al. (1998) reported in Fertility and Sterility for the American Society for Reproductive Medicine Practice Committee, their evaluation of the data collected from publications between 1985 and 1995 relating to stimulated IUI in unexplained subfertility. They concluded that..."the dearth of randomized controlled trials in this area precluded the writing of guidelines that were strictly evidence based." although they did support the use of stimulated IUI cycles. No discussion was made of the multiple pregnancy rates and relative costs that these may accrue.
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A rational answer? |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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So is ovarian stimulation a rational answer to unexplained subfertility? That depends on the acceptance of the risk of multiple pregnancy and an assessment of cost effectiveness. Philips et al. (2000
) address this in part showing stimulated IUI to be more cost effective than IVF per pregnancy. The modelling used assumes four cycles of treatment with a clinical pregnancy rate of 20% per cycle. Only treatment costs are evaluated however, there is no account taken of the cost of management of the complicated pregnancy and perinatal period associated with multiple pregnancy, nor the potential long term costs to the health service of caring for children with long term problems associated with multiple birth. These costs will be incurred by families whose treatment was self-funded as well as by those receiving NHS-funded treatment. Treatment involving multiple follicles increases the pregnancy rate and therefore apparent cost effectiveness of treatment, with a price of multiple pregnancy and potentially lower take home baby rates per pregnancy achieved, whilst reducing the number of follicles treated is liable to increase the number of cancelled cycles and reduce the pregnancy rate. To evaluate this fully many factors have to be taken into account including cost (not just of treatment but potentially complex antenatal and neonatal care), other risks e.g. OHSS, the emotional and financial wellbeing of the couples and the potential physical and emotional wellbeing of the child/children. In contrast, IVF has the advantages of providing diagnostic information in some cases, of a proven record of success and a limit to the multiple pregnancy rate. With the current move in the UK to two-embryo transfers in IVF many of the burdens associated with this risk are alleviated. IVF is clearly more complex and carries associated risks. The most serious potential risk in the IVF procedure is OHSS, but a successful embryo freezing programme may reduce this significantly if not in the fresh cycle then at least by potentially avoiding further stimulated cycles. The economics of treatment can be calculated but the other gains and costs have no financial label. They should take equal priority however, since the emotional stakes are so high.
It could be argued that it is irrational to persist with multifollicular treatment cycles in stimulated IUI in a climate where there is a push for two-embryo transfers and possibly eventually single embryo transfers in IVF. The use of follicle reduction in stimulated cycles provides an immediate remedy to avoid cancellation of a cycle where an excess but finite number of follicles have developed but this adds significantly to the per cycle cost effectively putting it on a par with IVF, especially if fertilization of the spare oocytes and storage of those embryos is considered.
Since the question has yet to be answered, a trial in couples with unexplained subfertility, of stimulated IUI with uni- or bi-follicular response, versus no treatment, would provide valuable data with regards cost effectiveness and rationale of the treatment. This may finally allow clear Grade A data to be given in our RCOG guidelines.
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Conclusion |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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In conclusion, a closer examination of the data used to provide ‘Grade A’ evidence for the use of stimulated IUI in unexplained subfertility shows major flaws in the conclusion drawn by the RCOG in the 1998 Guidelines. The Guidelines were due for review last year and will be considered for ratification by the National Institute of Clinical Excellence in its current appraisal of the treatment of infertility. The success of stimulated IUI is at least in part derived from treatment following multifollicular stimulation. The use of this strategy is challenged in the face of national recommendations to minimise the induction of multiple pregnancy in other areas of fertility treatment. An appropriate trial for the use of low-risk, uni- (or bi-) follicular stimulated IUI is called for.
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References |
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TopAbstractIntroductionA suitable option?The RCOG GuidelinesA closer lookMultifolliculogenesisA rational answer?ConclusionReferences |
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