Hum. Reprod. Advance Access published online on February 8, 2008
Human Reproduction, doi:10.1093/humrep/den008
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Intrauterine insemination: how many cycles should we perform?
1 Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Academic Medical Centre, Room H4-213, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 2 Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 3 Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands 4 Department of Obstetrics and Gynaecology, Medical Centre Alkmaar, Alkmaar, The Netherlands 5 Department of Obstetrics and Gynaecology, Catharina Hospital, Eindhoven, The Netherlands 6 Department of Obstetrics and Gynaecology, Máxima Medical Centre, Veldhoven, The Netherlands
7 Correspondence address. Tel: +31-20-5663857; Fax: +31-20-6963489; E-mail: i.m.custers{at}amc.uva.nl
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Abstract |
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BACKGROUND: In the past 20 years, various recommendations have been made about the maximum number of intrauterine insemination (IUI) cycles that should be performed, because evidence underpinning a possible limit is lacking.
METHODS: We performed a multicentre, retrospective cohort analysis among couples treated with IUI up to nine cycles. Primary outcome measure was ongoing pregnancy rate (OPR) per cycle. Cumulative OPRs (COPR) after three, six and nine cycles of IUI were calculated using life-table analysis. Univariable and multivariable logistic regression analysis was performed to identify variables possibly affecting OPR's.
RESULTS: Overall, 3714 couples with male, cervical or unexplained subfertility underwent 15 303 cycles of IUI. In 70% of cycles, controlled ovarian hyperstimulation (COH) was used (51% clomiphene-citrate, 19% gonadotropins). Mean OPR rate was 5.6% per cycle. OPR in the seventh, eighth and ninth cycle were 5.1%, 6.7% and 4.6%, respectively. Taking censored patients into account, the calculated COPR was 18% after the third cycle, 30% after the seventh cycle and 41% after the ninth cycle. If censored patients were considered to have no chance of conception, a crude COPR of 25% after nine cycles was found. Multivariable regression analysis showed no significant impact of age, type of subfertility, diagnosis, use of hyperstimulation or cycle number on OPR after the sixth treatment cycle.
CONCLUSIONS: OPR in high-order IUI cycles are acceptable, and do not offer a rationale for cancellation before nine cycles. Using this type of very mild COH, it may be reasonable to conduct up to nine cycles.
Key words: intrauterine insemination/controlled ovarian hyperstimulation/subfertility/pregnancy rate/cumulative pregnancy rate
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Introduction |
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Intrauterine insemination (IUI) is probably the most used treatment in subfertility. Various aspects of IUI, such as semen preparation techniques, natural versus stimulated cycles and single versus double insemination, have been well studied (Duran et al., 2002
; Cantineau et al., 2003; Boomsma et al., 2004). Data on the optimum number of IUI treatment cycles, however, are inconsistent, and recommendations on the number of treatment cycles that should be offered vary strongly (Chaffkin et al., 1991; Aboulghar et al., 1993, 2001; Plosker et al., 1994; Agarwal and Buyalos, 1996; Campana et al., 1996; Berg et al., 1997; Yang et al., 1998; Nuojua-Huttunen et al., 1999; Sahakyan et al., 1999). Most authors recommend not to continue IUI after three to four cycles (Chaffkin et al., 1991; Aboulghar et al., 1993, 2001; Plosker et al., 1994; Agarwal and Buyalos, 1996; Yang et al., 1998; Nuojua-Huttunen et al., 1999; Sahakyan et al., 1999), whereas two authors advise to repeat IUI even after six or more cycles (Campana et al., 1996; Berg et al., 1997). However, most studies based their recommendations on relatively small patient populations varying from 200 to 600 couples (Chaffkin et al., 1991; Aboulghar et al., 1993, 2001; Plosker et al., 1994; Agarwal and Buyalos, 1996; Yang et al., 1998; Nuojua-Huttunen et al., 1999; Sahakyan et al., 1999). In addition, all studies were single centre studies, thus affecting the generalizability of their findings. In view of these issues, we aimed to document cumulative ongoing pregnancy rates (COPR) after three, six and up to a maximum of nine cycles in a large cohort of IUI cycles in a retrospective analysis of data from four centres. |
Materials and Methods |
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Patients
We performed a retrospective cohort study among consecutive couples treated with IUI from1986 to 2002. Data were collected from four fertility centres in The Netherlands: Medical Centre Alkmaar, Catharina Hospital Eindhoven, Onze Lieve Vrouwe Gasthuis Amsterdam and Vrije Universiteit Medical Centre Amsterdam.
All couples had been trying to conceive for at least 12 months. They had undergone a basic fertility workup that consisted of medical history, confirmation of an ovulatory cycle by ultrasound, basal body temperature and/or midluteal progesterone, semen analysis and assessment of tubal patency by laparoscopy or hysterosalpingography.
Indications for IUI were male subfertility, cervical factor subfertility and unexplained subfertility. Patency of at least one tube had to be confirmed. For detailed description of the definition of male subfertility, cervical factor subfertility and unexplained subfertility, as well as for the IUI protocol and semen preparation, we refer to a previous report on these data (Steures et al., 2004).
For all couples, maternal age, duration of subfertility, diagnosis, tubal patency, semen parameters, primary or secondary subfertility and the use and type of controlled ovarian hyperstimulation (COH) were registered.
Data analysis
The primary outcome measure was ongoing pregnancy, defined as presence of fetal cardiac activity at transvaginal ultrasonography at a gestational age beyond 12 weeks. OPR per cycle and COPRs up to the ninth cycle were calculated. On the basis of COPRs, a curve was constructed showing the time to pregnancy over multiple cycles. Univariable and multivariable logistic regression analysis was performed for variables possibly affecting the OPR. Variables considered in the analysis were female age, fertility history, diagnosis, use and type of COH and cycle number. Logistic regression analysis was done at cycle level, in data sets with cycle number one to six and cycle number seven to nine, separately. OPRs from the second until the ninth treatment cycle were also compared with the first treatment cycle with univariable logistic regression. For all variables, odds ratios, 95%- confidence intervals and P-values were calculated. A value of P < 0.05 was considered significant.
To evaluate whether patients who had a maximum of six cycles were different from patients proceeding treatment after six attempts, we analysed baseline characteristics in these two groups.
Data analysis was carried out using the Statistical Package for the Social Sciences (SPSS 11.5) (SPSS Inc., Chicago, IL, USA).
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Results |
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We included 3714 couples who had undergone 15 303 treatment cycles. Analysis was limited up to the ninth treatment cycle (15 245 cycles). Baseline characteristics of the couples are summarized in Table I. The characteristics of patients who had undergone a maximum of six attempts and patients who had more than six IUI cycles are shown in Table II. There were no major differences between the two groups.
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There were 935 ongoing pregnancies, resulting in a mean OPR of 5.6% per cycle. OPR varied between 7.4% in the first and 4.4% in the fifth cycle (Table III). The OPRs were relatively high in the first two cycles, with 7.4% and 7.0%, respectively, compared with around 5% in higher order cycles.
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The COPR after three cycles was 18%, to increase to 30% and 41% after six and nine cycles, respectively (Table III, Fig. 1). When the first cycle was considered as reference, the pregnancy rates in the third, fifth and sixth cycle were significantly lower after univariable logistic regression (Table III).
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To analyse whether OPRs were influenced by possible prognostic factors, we performed a stepwise logistic regression analysis. In treatment cycles one to six, we found female age, presence of a cervical factor and cycle number to be significant after univariable analysis and multivariable logistic regression analysis. After univariable and multivariable analysis, none of the potential predictors was statistically significant in treatment cycles seven to nine (Table IV).
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Discussion |
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In this large retrospective multicentre cohort study in couples undergoing over 15 000 IUI cycles, we report on the outcome of IUI after nine cycles.
We found that continuing IUI after six failed cycles still resulted in acceptable pregnancy rates; other prognostic factors had a limited impact on these pregnancy rates. Up to the ninth treatment cycle, we found pregnancy rates to be quite stable. Our reported results are comparable to two previous studies (Campana et al., 1996; Berg et al., 1997). The fact that our pregnancy rates are somewhat lower might be explained by the fact we reported on OPRs and the limited use of COH.
After logistic regression analysis, we found COH not to be of significant influence on pregnancy outcome. This is probably explained by the fact that in the Netherlands patients are stimulated rather mildly and mono or bifollicular cycles are quite common (Steures et al., 2007).
As the outcome of IUI is subject to chance, the quintessence of IUI is repeating the cycles. Small consecutive chances will then result in acceptable pregnancy rates.
Reasons to stop IUI are numerous: for a couple with repeated failed attempts continuing IUI can become a frustrating experience. From the perspective of the doctor repeating IUI cycles can be time-consuming and offering alternative options may seem easier than motivating patients who have lost confidence. Despite these understandable emotions, our data show that continuing treatment after several failed attempts is rewarding. Since a patient's opinion is partially dependent on the way she is counselled (Campana et al., 1996; Steures et al., 2005), it is especially important for a physician to discuss the benefits of repeating IUI cycles.
Psychology in terms of fear of failure is a well known and important factor in fertility treatment (Campana et al., 1996; Hammarberg et al., 2001; Olivius et al., 2004). This fear of failure must not be ignored when a couple is treated during some cycles. Appropriate counselling, i.e. emphasizing COPR instead of pregnancy rates per cycle, is therefore of paramount importance to help a couple to understand the principle of repeated cycles. Also, proper psychological guidance during fertility treatment may help couples continue treatment after failed attempts.
If patients drop out of an IUI programme and no correction is made in the analysis, one underestimates pregnancy rates of the IUI programme. This is only correct if all patients that were censored, i.e. dropped out of the programme, would indeed not have conceived upon continuation of the IUI. In that case, the pregnancy rates would have been around 25% instead of 41%. To see if censored patients, i.e. patients who stopped treatment before the seventh IUI cycle, were different from patients who continued treatment (i.e. patients whom had undergone seven cycles or more), we analysed patient characteristics in these two groups. Since we found no major differences, an overestimation of the pregnancy rates is rather unlikely.
Since we performed a retrospective cohort analysis, our study does not allow for cost effectiveness comparisons between IUI and IVF. Also, we had no complete record on multiple pregnancies in this cohort. On the basis of the use and type of ovarian stimulation, we estimated our multiple rate to be around 9%.
Cost-effectiveness of IVF with single embryo-transfer in a population of patients undergoing IUI is of great interest, but data on this topic are so far lacking.
On the basis of this large retrospective cohort study, we feel that couples should have the possibility to continue IUI treatment after six failed attempts, especially when couples are young (female age below 35 years) and still have a considerable time ahead in which they are able to conceive.
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Footnotes |
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Presented as an oral presentation at the 23rd Annual Meeting of the Society of Human Reproduction and Embryology, ESHRE 2007, Lyon, France. 
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Aboulghar MA, Mansour RT, Serour GI, Amin Y, Abbas AM, Salah IM. Ovarian superstimulation and intrauterine insemination for the treatment of unexplained infertility. Fertil Steril (1993) 60:303–306.[Web of Science][Medline]
Aboulghar M, Mansour R, Serour G, Abdrazek A, Amin Y, Rhodes C. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril (2001) 75:88–91.[CrossRef][Web of Science][Medline]
Agarwal SK, Buyalos RP. Clomiphene citrate with intrauterine insemination: is it effective therapy in women above the age of 35 years? Fertil Steril (1996) 65:759–763.[Web of Science][Medline]
Berg U, Brucker C, Berg FD. Effect of motile sperm count after swim-up on outcome of intrauterine insemination. Fertil Steril (1997) 67:747–750.[CrossRef][Web of Science][Medline]
Boomsma CM, Heineman MJ, Cohlen BJ, Farquhar C. Semen preparation techniques for intrauterine insemination. Cochrane Database Syst Rev (2004) CD004507.
Campana A, Sakkas D, Stalberg A, Bianchi PG, Comte I, Pache T, Walker D. Intrauterine insemination: evaluation of the results according to the woman's age, sperm quality, total sperm count per insemination and life table analysis. Hum Reprod (1996) 11:732–736.
Cantineau AE, Heineman MJ, Cohlen BJ. Single versus double intrauterine insemination in stimulated cycles for subfertile couples: a systematic review based on a Cochrane review. Hum Reprod (2003) 18:941–946.
Chaffkin LM, Nulsen JC, Luciano AA, Metzger DA. A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hMG) and intrauterine insemination (IUI) versus either hMG or IUI alone. Fertil Steril (1991) 55:252–257.[Web of Science][Medline]
Duran HE, Morshedi M, Kruger T, Oehninger S. Intrauterine insemination: a systematic review on determinants of success. Hum Reprod Update (2002) 8:373–384.
Hammarberg K, Astbury J, Baker H. Women's experience of IVF: a follow-up study. Hum Reprod (2001) 16:374–383.
Nuojua-Huttunen S, Tomas C, Bloigu R, Tuomivaara L, Martikainen H. Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome. Hum Reprod (1999) 14:698–703.
Olivius C, Friden B, Borg G, Bergh C. Psychological aspects of discontinuation of in vitro fertilization treatment. Fertil Steril (2004) 81:276.[CrossRef][Web of Science][Medline]
Plosker SM, Jacobson W, Amato P. Predicting and optimizing success in an intra-uterine insemination programme. Hum Reprod (1994) 9:2014–2021.
Sahakyan M, Harlow BL, Hornstein MD. Influence of age, diagnosis, and cycle number on pregnancy rates with gonadotropin-induced controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril (1999) 72:500–504.[CrossRef][Web of Science][Medline]
Steures P, van der Steeg JW, Mol BW, Eijkemans MJ, van der Veen F, Habbema JD, Hompes PG, Bossuyt PM, Verhoeve HR, van Kasteren YM, et al. Prediction of an ongoing pregnancy after intrauterine insemination. Fertil Steril (2004) 82:45–51.[CrossRef][Web of Science][Medline]
Steures P, Berkhout JC, Hompes PGA, van der Steeg JW, Bossuyt PMM, van der Veen F, Habbema JDF, Eijkemans MJC, Mol BWJ. Patients’ preferences in deciding between intrauterine insemination and expectant management. Hum Reprod (2005) 20:752–755.
Steures P, van der Steeg JW, Hompes PG, Bossuyt PM, Habbema JD, Eijkemans MJ, Koks CA, Boudrez P, van der Veen F, Mol BW. The additional value of ovarian hyperstimulation in intrauterine insemination for couples with an abnormal postcoital test and a poor prognosis: a randomized clinical trial. Fertil Steril (2007) 88:1618–1624.[CrossRef][Web of Science][Medline]
Yang JH, Wu MY, Chao KH, Chen SU, Ho HN, Yang YS. Controlled ovarian hyperstimulation and intrauterine insemination in subfertility. How many treatment cycles are sufficient? J Reprod Med (1998) 43:903–908.[Web of Science][Medline]
Submitted on August 29, 2007; resubmitted on December 19, 2007; accepted on January 9, 2008.
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