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Human Reproduction 2008

Intrauterine insemination (IUI) as a first-line treatment in developing countries and methodological aspects that might influence IUI success Willem Ombelet1,2,4, Rudi Campo1,3, Eugene Bosmans1 and Martine Nijs1 1

Genk Institute for Fertility Technologies, Department of Obstetrics and Gynaecology, Ziekenhuizen Oost-Limburg, Schiepse Bos 2, 3600 Genk, Belgium; 2Flemish Society of Obstetrics and Gynaecology, Belgium; 3Leuven Institute for Fertility and Embryology, Leuven, Belgium 4

Correspondence address. E-mail:

It is generally accepted that intrauterine insemination (IUI) should be preferred to more invasive and expensive techniques of assisted reproduction and be offered as a first-choice treatment in cases of unexplained and moderate male factor subfertility. Scientific validation of this strategy is rather difficult because literature is rather confusing and not conclusive. IUI is proven easier to perform, less invasive and less expensive than other methods of assisted reproduction. Effectivity has been documented in controlled studies under the condition that the inseminating motile count exceeds more than 1 million motile spermatozoa. Risks are minimal, provided the multiple gestation incidence can be reduced to an acceptable level and provided at least one tube is patent. Therefore, in developing countries, reflection on the implementation and use of IUI as a first-line treatment for most cases of non-tubal infertility seems mandatory. The costs are minimal, training is easy, quality control possible and severe complications are almost non-existing. In cases of unexplained infertility or combined male subfertility and ovulatory dysfunction, correction and/or ovarian stimulation with clomiphene citrate (CC) is probably the best strategy from a cost –benefit point of view unless CC-resistancy has been proven in which the use of low-dose gonadotrophins is necessary. Keywords: affordable; assisted reproduction; cost-effectiveness; developing countries; intrauterine insemination

Introduction The rationale behind intrauterine insemination (IUI) with homologous sperm is bypassing the cervical – mucus barrier and increasing the number of motile spermatozoa with a high proportion of normal forms at the site of fertilization. A few decades ago, homologous artificial insemination was only performed in cases of male subfertility and psychologic dysfunction, such as retrograde ejaculation, vaginismus, hypospadias and impotence. With the routine use of post-coital tests, other indications were added such as hostile cervical mucus and immunologic causes. This interest in IUI is undoubtedly associated with the refinement of techniques for the preparation of washed motile spermatozoa. These washing procedures are necessary to remove prostaglandins, infectious agents, antigenic proteins, non-motile spermatozoa, leucocytes and immature germ cells. This may enhance sperm quality by decreasing the formation of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo (Aitken and Clarkson, 1987). From a scientific point of view, controversy still surrounds the effectiveness of this very popular treatment procedure. 64

This may be explained by the fact that most studies are retrospective and not only vary in the comparison of the study group but also in the use or non-use of different ovarian superovulation regimen, the number of inseminations per treatment cycle, different methods of timing ovulation, different sites of insemination, various methods of sperm preparation and the well or not use of additives such as antioxidants, platelet-activating factor (PAF), etc (Fig. 1). If IUI is promoted as a first-line treatment in case of unexplained and male factor subfertility, it has to be weighed against other treatment options such as expectant management, medical and surgical treatment, IVF and ICSI. This comparison should not only involve success rates but should also include a cost– benefit analysis, an analysis of the complication rate of the different treatment options, the invasiveness of the techniques and patient compliancy. Healthcare cost consciousness has become an integral part in the attitude of policy makers worldwide. Evidence related to the cost and effectiveness of infertility treatment exists, but most studies only deal with IVF. Published data comparing cost of IVF versus IUI indicate that initiating treatment with

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IUI as a first-line treatment in developing countries

Figure 1: Diagram showing the many different variables influencing success rates in IUI programmes (AIH, artificial insemination with homologous semen).

IUI appeared to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility (Ombelet et al., 2003; Ombelet, 2005). Surprisingly and despite evidencebased arguments, data from Australia and New Zealand clearly show that almost 80% of fertility centres are convinced of the cost-effectiveness of IUI, but nearly one-third of these centres still promote IVF as a first-line treatment even with patent tubes and normal semen (Miskry and Chapman, 2002). Since IUI programmes are easy to run, this method can be extremely interesting for resource-poor countries. The techniques and methods are easy to learn, the direct and indirect costs are minimal compared with IVF/ICSI and severe complications are very rarely seen. The use of affordable and safe washing techniques and the value of natural cycle or clomiphene citrate (CC) stimulation also adds to the value of IUI in developing countries. The topics highlighted in this paper are summarized in Table I.

Effectiveness of IUI Cervical factor subfertility Bypassing the hostile cervix should increase the probability of conception. The results of a meta-analysis of randomized controlled trials comparing IUI with timed intercourse (TI) for

couples with cervical factor infertility showed a significant improved probability of conception for IUI (Cohlen, 2005). Unexplained subfertility If an infertility work-up is unable to detect a plausible explanation for couples with a history of subfertility of at least 1 year, we use the term ‘unexplained infertility’. Because a good explanation for the subfertility is lacking, the treatment is often empiric. A meta-analysis comparing IUI and TI in natural cycles showed no difference in results; therefore, IUI in natural cycles seems ineffective in case of unexplained infertility. When controlled ovarian hyperstimulation (COH) is used, IUI becomes effective compared with TI (Cohlen, 2005). There is evidence that IUI with COH increases the live birth rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles (Verhulst et al., 2006). Male factor subfertility In case of longstanding infertility caused by reduced sperm quality, expectant treatment seems to be disappointing with a spontaneous conception rate of only 2% per cycle (Collins et al., 1995). Therefore, this strategy is not applicable in clinical practice. For IUI, with or without COH, a pregnancy rate (PR) of 10– 18% per cycle has been reported (Ombelet et al., 1995, 1997a; Stone et al., 1999). A Cochrane review showed 65

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Table I. Summary of topics highlighted in this paper. † Introduction † Effectiveness of IUI Cervical factor subfertility Unexplained subfertility Male factor subfertility † Cost of ART-related services † Risks and complications of IUI versus IVF/ICSI † Couple compliancy † Treatment strategy in developing countries: a proposal † Factors influencing IUI success Natural cycle versus controlled ovarian hyperstimulation Site of insemination Exact timing of IUI Factors affecting embryo-implantation ) Endometrial thickness/polyps ) Which catheter to use ) The use of aspirin and luteal phase support Laboratory factors ) Sperm washing methods ) Addition of substances in sperm preparations ) Fallopian sperm perfusion ) The effect of the abstinence period ) Immunologic male subfertility Number of inseminations Number of IUI treatment cycles † Conclusion

that IUI is superior to TI, both in natural cycles and in cycles with COH (Cohlen et al., 2000). According to this review, IUI in natural cycles should be the treatment of choice in case of male subfertility, providing an inseminating motile count (IMC) of more than 1 million can be obtained after sperm preparation and in the absence of a triple sperm defect (according to WHO criteria). In the selection of couples to be treated with IUI, it would be interesting to establish cut-off values of semen parameters above which IUI is a real alternative for IVF/ICSI in male subfertility. According to the literature, IMC and sperm morphology are the most valuable sperm parameters to predict IUI outcome (Duran et al., 2002; Ombelet et al., 2003). There is a trend towards increasing conception rates with increasing IMC, but the cut-off value above which IUI seems to be successful, however, varies between 0.3 and 20  106. A large retrospective analysis in a selected group of patients with normal ovarian response to clomiphene (CC) stimulation showed a comparable cumulative ongoing PR after three IUI cycles for all couples, providing the IMC was more than 1 million (Ombelet et al., 1997a). Furthermore, in cases with ,1 million motile spermatozoa, IUI remains successful provided the sperm morphology score using strict criteria is 4% or more (cumulative ongoing PR of 21.9% after three IUI cycles). Acceptable PR can be achieved with IUI, even in severely oligozoospermic men (Centola, 1997). A significant improvement in PR was reported when the morphology score was more than 5% using strict criteria in a meta-analysis by Van Waart et al. (2001). A cut-off level of 0.8 million motile spermatozoa after washing was reported in a meta-analysis by van Weert et al. (2004). For total sperm motility before sperm preparation, cut-off levels vary between 30% and 50% (Ombelet et al., 1996; Dickey et al., 1999; Montanaro et al., 2001; Lee et al., 2002). 66

Cost of ART-related services In a meta-analysis, Peterson et al. (1994) showed that the PR for three cycles of gonadotrophins and IUI in a population group with unexplained infertility was superior to IVF and comparable with gamete intra-Fallopian transfer. Many other studies reported on the cost-effectiveness of IUI compared with IVF (Van Voorhis et al., 1997, 2001; Zayed et al., 1997). In a prospective randomized controlled trial, Goverde et al. (2000) concluded that three cycles of IUI offer the same likelihood of a successful pregnancy as one trial of IVF. They concluded that IUI is a more cost-effective approach, not only for unexplained subfertility, but also for moderate male factor subfertility. This important message was confirmed in another study performed in the UK (Philips et al., 2000). In this study, the authors complemented existing clinical guidelines by including cost-effectiveness of different treatment options for infertility in the UK. A series of decision-analytical models were developed to reflect current diagnostic and treatment pathways for the different causes of infertility. According to this study, stimulated IUI for unexplained and moderate male factor infertility is a cost-effective approach. In a systematic review, Garceau et al. (2002) also showed that initiating treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility. For couples with unexplained and mild male factor subfertility, Pashayan et al. (2006) showed that primary offering a full IVF cycle was less costly and more cost-effective than providing IUI followed by IVF. In their mathematical model, the assumed LBR (live birth-producing pregnancy) was only 3% for CC-stimulated IUI and 7% for gonadotrophin-stimulated IUI, although most centres worldwide have a significantly higher LBR (Ombelet et al., 2003). This might explain the opposite findings in their study.

Risks and complications of IUI versus IVF/ICSI in developing countries Transmission of life-threatening sexually transmitted diseases, infectious diseases such as HIV, HCV and Hepatitis B, constitutes particular risk in developing countries since these diseases may be highly prevalent in subfertile couples. It is estimated that nearly 40 million people worldwide are infected with HIV and prevalence among young people under age of 25 years account for approximately half of all new infections (Sauer, 2005). Most HIV patients are of reproductive age and many desire to have children. Many studies have shown that appropriate sperm processing may reduce the risk of HIV transmission through IUI and IVF/ICSI (Balet et al., 1998; Ohl et al., 2005; Manigart et al., 2006; Garrido et al., 2006; Savasi et al., 2007). Sperm washing techniques appear to be relatively safe and effective, offering HIV-serodiscordant and couples where both partners are infected an opportunity to have children, provided antiretroviral therapy and HIV monitoring are available. The challenges created by the HIV epidemic versus reproductive desires and health needs of a large HIV infected population are well described elsewhere in this monograph (Dyer et al; this monograph).

IUI as a first-line treatment in developing countries

In this context, semen decontamination through sperm processing is very important in countries with a high rate of seminal infection, since IUI and ART may become important tools, not only in the recognition of the reproductive rights of HIV-infected parents but also in the prevention of the transmission of HIV among partners and towards the fetus. The use of a novel washing method combining multiple density gradients and trypsin for removing human immunodeficiency virus-1 and hepatitis C virus from semen seems to be very promising (Loskutoff et al., 2005; Huyser et al., 2006). Ovarian hyperstimulation syndrome (OHSS) may complicate all methods of treatment in which gonadotrophins are used; however, OHSS seems to be rare after COH – IUI compared with IVF due to the fact that lower dose stimulation protocols are more often used (Dodson and Haney, 1991; Bergh and Lundkvist, 1992; Ombelet et al., 1995). The incidence of pelvic inflammatory disease after intrauterine catheterization and/or transvaginal oocyte-aspiration has been estimated to be 0.2% for IVF (Bergh and Lundkvist, 1992) and 0.01– 0.2% for IUI (Dodson and Haney, 1991; Ombelet et al., 1995). The major complication of assisted reproductive technology remains, however, the high incidence of multiple pregnancies, responsible for considerable mortality, morbidity and costs (Ombelet et al., 2005). The prediction of multiple gestation is highly uncertain, especially when gonadotrophins are used, despite careful monitoring of the cycle with ultrasonography and serum estradiol determinations. Careful monitoring remains essential and cancellation of the insemination procedure, escape IVF and follicular aspiration before IUI are reasonable options. Transvaginal ultrasound-guided aspiration of supernumerary ovarian follicles increases both the efficacy and the safety of COH – IUI with gonadotrophins (De Geyter et al., 1998; Albano et al., 2001). This method represents an alternative for conversion of overstimulated cycles to in vitro fertilization (escape IVF). Natural cycle IUI, CC

and minimal dose regimen with gonadotrophins are valuable options to prevent the unacceptable high multiple gestation rate described after ovarian hyperstimulation. Considering obstetric and perinatal outcome after IUI, to our knowledge only four papers have been published. According to Nuojua-Huttunen et al. (1999) and using the data obtained from the Finnish Medical Birth Register, IUI treatment did not increase obstetric or perinatal risks compared with matched spontaneous or IVF pregnancies. The three other studies observed a higher risk for prematurity and (very) low birth weight for IUI singletons when compared with naturally conceived singletons (Wang et al., 2002; Gaudoin et al., 2003; Ombelet et al., 2006).

Couple compliancy Since IUI is a simple and non-invasive technique, it can be performed without expensive infrastructure with a good success rate within three or four cycles, making this method of assisted reproduction very appealing for developing countries. On the other hand, we have to admit that in some areas, such as subSaharan Africa, the majority of patients suffer of tubal factor infertility. In these cases, only IVF can be proposed. Nevertheless, IUI is a safe and easy treatment with minimal risks and monitoring, at least if multiple PR can be avoided. Subsequently, a high couple compliancy is reported for IUI compared with IVF. We previously described a low dropout rate of 19.6% in a series of 1100 IUI cycles (Ombelet et al., 1996). A much higher dropout rate and long time interval between treatment cycles for IVF and ICSI have been described before (Comhaire, 1995). It is obvious that IUI must be considered as a very important first-line treatment in selected cases in developing countries. Table II gives an overview of the pros and cons of IUI compared with IVF/ICSI.

Table II. Overview of the pros and cons of IUI compared with IVF and ICSI.





† Less equipment necessary † Easy method: less complex † Less invasive: more physiological † Less expensive † Reduced psychological burden † Good couple compliancy ) low dropout rate † Low risk for OHSS, thrombo-embolism † Low to moderate MPR with NC, CC and low-dose gonadotrophin protocols † Minimal transmission of infection (IVF) † Moderate to high success-rate per cycle

† † † † †

+ success-rate per cycle + success if IMC,1 million + success if morphology,5% High MPR with gonadotrophins Risk for antisperm antibodies

† High costs (direct and indirect) † Complex stimulation protocols † * patient discomfort † Time-consuming † Invasive procedure † * risk for OHSS, thrombo-embolism † High multiple pregnancy rate † * Risk for LBW, prematurity † * Risk for genetic disorders † Lower couple compliancy ) High dropout rate

IMC, inseminating motile count; OHSS, ovarian hyperstimulation syndrome; NC, natural cycle; CC, clomiphene citrate; LBW, low birth weight (,2500 g); MPR, multiple pregnancy rate.


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Treatment strategy in developing countries: a proposal Figure 2 shows the treatment strategy used for more than 10 years at the Genk Institute for Fertility Technology. In most cases, we start with CC ovarian stimulation, although the cumulative ongoing PR is significantly lower compared with rec-FSH or (purified) urinary gonadotrophins, but with the benefit of a low multiple PR (,7%) because of intensive monitoring of the number of follicles. If more than three follicles with a mean diameter of .13 mm are present, the cycle is cancelled (Ombelet et al., 1996). Although the cumulative ongoing PR after three IUI cycles is comparable with only one IVF cycle (25%), more than 90% of our couples agree to follow our protocol being aware of the better success rate per cycle after IVF. Excellent counselling is mandatory and crucial. The strategy of using CC – IUI as a first-line treatment in most cases of non-obstructive subfertility (male and female) is of outstanding importance for developing countries.

Factors influencing IUI success The duration of subfertility, primary or secondary subfertility, endometriosis and the use or non-use of ovarian hyperstimulation are important factors influencing the success rate of IUI significantly (Crosignani and Walters, 1994; Steures et al., 2004). Other variables might be the site of insemination, the use of antioxidants, factors influencing intra-tubal environment and factors influencing embryo implantation (Iberico et al., 2004).

Figure 2: Proposed algorithm of male subfertility treatment at the Genk Institute for Fertility Technology (IMC, inseminating motile count or the number of motile spermatozoa after washing procedure; HSG, hysterosalpingography; HSCS, hystero-salpingo-contrastsonography).


Natural cycle versus controlled ovarian hyperstimulation Poor results have been described when IUI was performed in natural cycles for unexplained and cervical factor subfertility (DiMarzo et al., 1992; Ombelet et al., 1995). The rationale behind the use of ovarian hyperstimulation in artificial insemination is the increase of the number of oocytes available for fertilization and to correct subtle unpredictable ovulatory dysfunction (Arici et al., 1994). Comparing the effect of COH on PR after IUI, ovarian stimulation with gonadotrophins or rec-FSH results in a significantly higher monthly fecundability compared with CC treatment, but at the expense of a higher multiple PR (Ombelet et al., 1995, 1996). This statistical difference is not influenced by the indication for IUI. Considering the risk for multiple pregnancies and OHSS, mild COH regimen with the aim of monofollicular growth should be used. The aromatase inhibitor letrozole and CC are associated with similar PR in IUI (Al-Fozan et al., 2004). The ideal dose of letrozole remains unknown, and further studies are needed. Since letrozole is more expensive than CC, we still believe that the use of CC – IUI is the best option in developing countries, at least in the absence of bilateral tubal block and CC resistancy. Site of insemination Artificial inseminations can be done intravaginally, intracervically (ICI), pericervically using a cap, IUI, transcervical intrafallopian (IFI) or directly intraperitoneal (IPI). Most studies refer to IUI, which seems to be an easy and better way of treatment. In a donor insemination programme, Hurd et al. (1993) reported a significantly better cycle fecundity rate for IUI compared with ICI or IFI. More sperm was found in the peritoneal cavity after IUI when compared with ICI (Ripps et al., 1994). Studies comparing pregnancy outcome after IUI versus cervical cap insemination (Williams et al., 1995) and transuterotubal insemination (Oei et al., 1992) also favoured the intrauterine method. In a large randomized controlled trial, it was shown that among infertile couples, treatment with induction of superovulation and IUI is three times as likely to result in pregnancy as is intracervical insemination and twice as likely to result in pregnancy as is treatment with either superovulation and intracervical insemination or IUI alone (Guzick et al., 1999). Exact timing of IUI Exact timing is probably crucial in IUI treatment cycles. On the other hand, conflicting data are reported in the literature on which methodology is to be used. Ultrasound and hormonal monitoring with human chorionic gonadotrophin (hCG) induction probably allows the most exact timing but is relatively expensive and time-consuming. Urinary luteinizing hormone (LH) timed IUI is commonly used but has the disadvantage that the LH surge can last for up to 2 days before ovulation in some patients (Cohlen et al., 1993). A prospective, randomized cross-over study of Zreik et al. (1999) could not demonstrate an increased PR when ultrasound monitoring and hCG were used compared with urinary LH-timed inseminations. In a prospective randomized study (Lewis et al., 2006), all patients received CC and were randomized into a LH

IUI as a first-line treatment in developing countries

(urinary LH) surge group or a follicle monitoring/hCG group. Patients in the LH surge group underwent IUI on the day after a home test for the LH surge was positive, whereas those in the hCG group received hCG according to ultrasound parameters and underwent insemination 33– 40 h later. Similar results were found between groups in PR per patient or per cycle. After ovarian stimulation with CC, IUI is equally effective 24 h after a spontaneous LH surge or 36 h after administration of hCG (Vlahos et al., 2005). It seems that being aware of the importance of exact timing is essential in IUI, independent of the method being used. In developing countries, the advisable method of monitoring is probably the regimen of one or two ultrasound examinations after CC stimulation combined with hCG injection, this means prefect timing and avoidance of multiples by cancellation the cycle if three or more follicles of 14 mm or more are found. The use of gonadotrophin-releasing hormone antagonists to overcome the problem of unexpected premature LH surges is effective but too expensive to be routinely used in developing countries. Factors affecting embryo implantation Endometrial thickness/polyps A trilaminar image rather and a greater endometrial thickness provide a favourable prediction of pregnancy in IUI (Hock et al., 1997; Esmailzadeh and Faramarzi, 2007). Treatment should not be cancelled because of inadequate endometrial thickness (De Geyter et al., 2000). The use of ethinyl estradiol in clomiphene-stimulated cycles looks promising but requires confirmation (Gerli et al., 2000). If polyps are present, hysteroscopic polypectomy before IUI is an effective measure to enhance pregnancy results (Pe´rez-Medina et al., 2005). Which catheter to use In IUI programmes, most studies indicate that the catheter type does not affect the outcome after (Lavie et al., 1997; Smith et al., 2002; Fancsovits et al., 2005). On the other hand, Proctor and Boone (2007) recently showed that although the flexible catheter costs more than the rigid catheter, it is associated with a higher PR, which decreases costs of IUI treatment because fewer cycles are needed. The use of aspirin and luteal phase support There is no evidence so far that luteal support with progesterone and/or hCG affects the conception rate in IUI programmes with the exception of treatment regimen making use of GnRH analogues. Low-dose aspirin may improve uterine perfusion in women, but its value in assisted reproduction remains very controversial (Gelbaya et al., 2007; Khairy et al., 2007; Ruopp et al., 2007). Therefore, it should not be routinely recommended in assisted reproduction. Laboratory factors Sperm washing methods Preparation and washing will remove reactive oxygen species (ROS) and prostaglandines. The prostaglandines have to be removed since they will cause severe uterine cramps when a

raw semen sample is used for IUI. The preparation will concentrate morphologically more normal and motile spermatozoa, essential for good results in IUI. Most popular are the swim-up procedures, the density gradient centrifugation and the use of Sephadex columns. Conflicting data are found on the superiority of any one preparation technique in terms of fecundity (Dodson et al., 1998; Ren et al., 2004). This can be explained by the fact that almost all methods of sperm washing and preparation surpasses the low threshold number of motile spermatozoa (.1 106) needed for conception in vivo with no added benefit of additional sperm. According to a Cochrane review, there is insufficient evidence to recommend any specific preparation technique (Boomsma et al., 2007). Addition of substances in sperm preparation Whether the addition of substances such as pentoxyphylline, kallicreine, follicular fluid etc. may improve the results remains unclear and certainly unproven. On the other hand, it is important to recognize that sperm preparation methods may induce damage to spermatozoa by increasing ROS generation by spermatozoa and by removing the scavengers from the seminal plasma. More studies that investigate whether treating spermatozoa with solutions containing antioxidants during sperm preparation can improve PR with IUI in selected cases are needed. Two double-blind randomized studies evaluated the effect of PAF exposure on sperm during semen processing for IUI (Roudebush et al., 2004; Grigoriou et al., 2005). They demonstrate a significantly higher PR for the PAF-treated group in a subpopulation of couples without male factor subfertility. Until now, there is no evidence that one specific sperm washing procedure is superior to the other methods in IUI programmes, but comparative studies are urgently needed. Fallopian sperm perfusion In Fallopian tube sperm perfusion (FSP), a large volume of a sperm suspension is inseminated intrauterine with excellent results in cases of unexplained infertility (Kahn et al., 1992, 1993). A Cochrane review showed that FSP gives rise to higher PR in couples with unexplained subfertility (Cantineau et al., 2004). Results suggested the possibility of differential effectiveness of FSP depending on catheter choice. For other indications, FSP has not been proven more effective compared with IUI. The effect of the abstinence period Abstinence did not influence sperm morphology, total or grade A motility, or sperm DNA fragmentation in a prospective study described by De Jonge et al. (2004). A short (24 h) abstinence period negatively influenced chromatin quality. An abstinence interval of 3 days or less was associated with higher PR following IUI (Jurema et al., 2005). Immunologic male subfertility Most studies demonstrate a clear association between sperm surface antibodies and the fertility potential of the male (Adeghe, 1992; Acosta et al., 1994). In 1997, we published a prospective study comparing the effectiveness of the first-line IUI approach versus IVF for 69

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male immunological subfertility (Ombelet et al., 1997b). The objective of this prospective study was to compare success rates after two different treatment protocols, COH –IUI versus IVF. Both IUI and IVF yielded unexpected high PR in this selected group of patients with long-standing subfertility due to sperm surface antibodies. Since cost– benefit analysis comparing COH – IUI with IVF may favour a course of four IUI cycles, we concluded that IUI can be used as the first-line therapy in male immunological subfertility. Although most fertility centres use IVF/ICSI in case of immunological male subfertility (Lombardo et al., 2001, 2004), a well-organized prospective study is mandatory to examine the real value of IUI for this specific indication. Number of inseminations Theoretically, improved chances for conception may be expected when two consecutive inseminations are performed since ovulation of oocytes does not occur in a synchronized pattern but rather in waves of release after hCG administration (Abbasi et al., 1987). A Cochrane review, based on the results of two trials, double IUI showed no significant benefit over single IUI in the treatment of subfertile couples with partner semen (Cantineau et al., 2003). The authors admitted that there are no meaningful data to offer advice on the basis of this review. According to this report, a large randomized controlled trial of SIUI versus DIUI is mandatory. In a cross-over study, we previously showed that double insemination provided a significant better cycle fecundity after superovulation with gonadotrophins but not after ovarian stimulation with CC, but at the expense of a higher multiple PR (Ombelet et al., 1995). Number of IUI treatment cycles A significant decline in cycle fecundity after the third or fourth IUI cycle was reported in several studies (Dodson and Haney, 1991; Friedman et al., 1992; Nan et al., 1994). The remaining couples do not seem to benefit from this method of treatment when compared with other methods of assisted reproduction. Conclusion IUI is a simple, non-invasive and cheap treatment modality which can be used as a first-line treatment in most subfertility cases including male subfertility. The technical requirements necessary and the current scientific evidence on the success and complication rate provides sufficient evidence to promote IUI as a first-line treatment modality in developing countries. Especially in developing countries, the classical algorithm of diagnosis and treatment should be followed and preference should be given to those treatment modalities with the lowest complication rate, best obstetrical outcome, affordable cost and cultural acceptance. In this view, proper diagnosis and treatment of the female reproductive tract, proper semen analysis and possibility of simple ovarian stimulation and IUI should be promoted as the best first-line treatment in most cases of subfertility. IUI should be provided to all patients with at least one patent tube and an IMC after sperm preparation of more than 1.0 million. 70

In this selected group of patients, it is unwise to start with assisted reproductive techniques such as IVF and ICSI since these techniques are more invasive, more expensive and more at risk for genetic disorders and obstetric complications. Promoting IVF and ICSI to result in pregnancy ‘as quick as possible’ ignores the advantages of IUI completely.

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