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Doi:10.1016/j.fertnstert.2007.01.125

The additional value of ovarian hyperstimulationin intrauterine insemination for couples withan abnormal postcoital test and a poor prognosis:a randomized clinical trial Pieternel Steures, Jan Willem van der Steeg, M.D.,Peter G. A. Hompes, M.D., PhPatrick M. M. Bossuyt, J. Dik F. Habbema, Marinus J. C. Eijkemans, M.Sc., Ph.D.,Caroline A. M. Koks, Petra Boudrez, M.D.,Fulco van der Veen, M.D., Ph.D., a Department of Obstetrics and Gynecology, Vrije Universiteit Medical Center, Amsterdam; b Center for Reproductive Medicine,Academic Medical Center, Amsterdam; c Department of Public Health, Erasmus MC, University Medical Center Rotterdam,Rotterdam; d Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam; e Department ofObstetrics and Gynecology, Ma´xima Medical Center, Veldhoven; and f Department of Obstetrics and Gynecology, Vie Curie,Venlo, the Netherlands Objective: To assess the effectiveness of controlled ovarian hyperstimulation (COH) in intrauterine insemination(IUI) for subfertile couples with an abnormal postcoital test and a poor prognosis.
Design: Randomized clinical trial.
Setting: Twenty-four fertility centers in the Netherlands.
Patient(s): Subfertile couples with a well-timed nonprogressive PCT and additional factors that reduce fertility.
Intervention(s): Couples were randomly allocated to three cycles of IUI with COH or three cycles of IUI withoutCOH.
Main Outcome Measure(s): Ongoing pregnancy within three IUI cycles.
Result(s): We randomly allocated 132 couples to IUI with COH, and 133, to IUI without COH. We observed 33pregnancies (25%) in the couples allocated to IUI with COH, of which 28 were ongoing (21%), vs. 28 pregnancies(21%) in the couples allocated to IUI without COH, of which 23 were ongoing (17%; relative risk of an ongoingpregnancy, 1.2; 95% confidence interval, 0.75 to 2.0). Two multiple pregnancies occurred in the IUI with COHgroup, and one, in the IUI without COH group.
Conclusion(s): In couples with an abnormal PCT and a poor prognosis, IUI with COH leads to pregnancy ratescomparable to those for IUI without COH. We propose to perform IUI without COH in couples with an abnormalPCT. (Fertil SterilÒ 2007;88:1618–24. Ó2007 by American Society for Reproductive Medicine.) Key Words: Intrauterine insemination, cervical factor, subfertility, postcoital test, randomized Intrauterine insemination (IUI) is a common treatment in un- trolled ovarian hyperstimulation carries the risk of multiple explained subfertile couples as well as in male subfertility pregnancies. It poses a burden to the couple and is costly be- and cervical-factor subfertility. It can be performed with or cause of the use of gonadotropins and the need for monitoring without controlled ovarian hyperstimulation (COH). Con- of follicular development and growth . These drawbacksare warranted only by a substantial gain in ongoing-preg-nancy rate from using IUI with COH compared with IUI Received July 24, 2006; revised and accepted January 22, 2007.
This randomized controlled trial is registered in the Dutch Trial Register In cases of unexplained subfertility, IUI is not effective when the couple’s spontaneous-pregnancy likelihood is Supported by grant 945-12-002 from ZonMw, the Netherlands Organiza- >30% in the next 12 months . When IUI is performed in tion for Health Research and Development, the Hague, the Netherlands.
Presented orally at the Conjoint Annual Meeting of the American Society unexplained subfertile couples, COH doubles the pregnancy for Reproductive Medicine and the Canadian Fertility and Andrology Society, ASRM/CFAS 2005, Montreal, Quebec, Canada, October15–19, 2005.
In cases of male subfertility, IUI improves pregnancy rates.
Reprint requests: Pieternel Steures, M.D., Center of Reproductive Medi- Intrauterine insemination without COH has been proven to be cine, Room H4-213, Department of Obstetrics and Gynecology, Aca- equally effective as IUI with COH and should therefore be the demic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, theNetherlands (FAX: 31-20-6963489; E-mail: first choice of treatment but couples with less severe Fertility and Sterilityâ Vol. 88, No. 6, December 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.
semen defects benefit from the addition of COH . In none taneous ongoing pregnancy in the next 12 months, resulting of the studies on IUI in male subfertility was the prognosis of Consenting eligible couples were randomly allocated to In cases of cervical-factor subfertility, IUI appears to be ef- IUI with COH or to IUI without COH for three cycles, with- fective in couples with an isolated cervical factor without ad- out a prespecified time horizon. The randomization sequence ditional factors that reduce fertility . The incremental was computer generated in balanced-block multiples of two value of COH in IUI in couples with a cervical factor has or four, stratified by center. Sealed opaque envelopes were been reported in only one retrospective study, which showed prepared by an independent individual. Clinicians in the par- a nonsignificant increase in pregnancy rate after the use of ticipating centers unsealed the first-in-order envelope after COH (odds ratio, 1.4; 95% confidence interval [CI], 0.85 to enrolling a couple. The inclusion was then confirmed by 2.2) To prevent undertreatment and overtreatment with COH, this low level of evidence needs to be confirmed or re- Cycle monitoring, detection and/or induction of ovulation, jected in a randomized clinical trial.
as well as semen preparation and insemination regimens were At present, there are no randomized clinical trials on the performed according to hospital-specific protocols. The incremental value of COH in IUI in cervical-factor subfertil- study recommended for IUI with COH the use of FSH for ity and male subfertility, taking into account the prognosis of COH. In general, a baseline transvaginal sonography was the couple. Therefore, we aimed to assess whether COH in performed on cycle day 3 to exclude ovarian cysts of size IUI is of additional value in couples with an abnormal post- >20 mm. Thereafter, the women started with daily SC injec- coital test (PCT) resulting from a cervical factor or a male tions of FSH (Gonal F; Serono Benelux BV, Den Haag, the factor and with a poor prognosis of an ongoing spontaneous Netherlands or Puregon; Organon, Oss, the Netherlands) or pregnancy because of additional factors that reduce fertility.
human menopausal gonadotropin (Menopur; Ferring, Hoofd-dorp, the Netherlands) in doses of 75 IU, until transvaginalsonography showed at least one follicle with a diameter of16 mm. Doses were adjusted in a range from 50 IU to 150 IU, depending on the ovarian response. The aim of mild ovar- The study was performed between June 1, 2002 and July 1, ian hyperstimulation was to obtain multifollicular growth.
2005 in 24 fertility centers in the Netherlands. The study Ovulation was then induced by the administration of 5,000 was approved by the local ethics committee of each partici- or 10,000 IU of hCG (Pregnyl, Organon), and women were inseminated 36 to 40 hours later. The administration ofhCG was withheld, and IUI was not performed, if there In couples who had an unfulfilled wish for a child and had were present more than three follicles with a diameter of R1 year with regular unprotected intercourse and in whom R16 mm, or five follicles with a diameter of R12 mm.
the woman had a regular cycle, a basic fertility workup wasperformed. This was done according to the guidelines of Semen samples were processed within 1 hour after ejacu- the Dutch Society of Obstetrics and Gynaecology and in lation by using a density gradient centrifugation, followed by the same way as reported in our study on the effectiveness a washing step with culture medium. The volume of semen of IUI with COH in unexplained subfertility that was inseminated varied between 0.3 mL and 0.5 mL.
After completion of the basic fertility workup, in couples In the IUI cycles without COH, ovulation detection was with an abnormal (negative) PCT, in other words, a well- performed with urine LH tests (a semi-quantitative monoclo- timed, nonprogressive PCT that was caused by a cervical fac- nal antibody–based kit; OvuQuick, Quid, San Diego, CA) tor or a male factor, the prognosis was calculated for a with a detection level of 40 IU, or by transvaginal sonogra- spontaneous ongoing pregnancy resulting in a live-born child phy. If ovulation was detected with LH tests, patients tested in the next 12 months. A spontaneous pregnancy was defined their urine samples once or twice per day, starting on an indi- as a pregnancy that occurred without treatment. The progno- vidually calculated cycle day. Women were inseminated 20 to sis was calculated according to the prediction model of 30 hours after the endogenous LH surge had been detected in Hunault et al. by using a computer program or a paper the urine sample. In case follicular growth was monitored by score list . This model incorporates the variables of fe- transvaginal sonography, hCG (Pregnyl, Organon) was ad- male age, duration of subfertility, primary or secondary sub- ministered when the dominant follicle had a diameter of fertility, referral status, and percentage of progressive motile R16 mm. Women were inseminated 36 to 40 hours thereaf- semen. Each variable is converted into a point score. The total ter. Semen was processed and inseminated in the same way as point score of each couple corresponds to a prognosis for spontaneous ongoing pregnancy. The computer model can Couples were followed until an ongoing pregnancy oc- curred. If pregnancy had not occurred, follow-up ended after the third IUI cycle or at drop out. If a pregnancy miscarried, Couples with an abnormal PCT were invited to join the follow-up continued until the next pregnancy, or the last of study if the model indicated a prognosis of %30% of a spon- The primary endpoint was ongoing pregnancy within three a number needed to treat, both with their 95% CI. We plotted IUI cycles. Ongoing pregnancy was defined as the presence Kaplan-Meier curves to visualize the time to pregnancy in the of fetal cardiac activity at transvaginal sonography at a gesta- two groups, and we compared these curves by using a log tional age of R12 weeks. Secondary endpoints were clinical pregnancies, miscarriages, ectopic pregnancies, multiple We performed additional analyses in which we evaluated pregnancies, and live birth. Clinical pregnancy was defined the pregnancy rate per IUI cycle with or without COH and ex- as the presence of a yolk sac at transvaginal sonography at pressed the treatment effect as relative risk and number a gestational age of 7 weeks. Miscarriage was defined as non- needed to treat. We compared the effectiveness of IUI with vital pregnancy, either seen at transvaginal sonography or as COH with that of IUI without COH in the subgroup of cou- a result of the loss of a visible pregnancy.
ples with a total motile sperm count (TMC) of R10 million We designed our study as a noninferiority trial. Our hy- and in the subgroup of couples with a TMC of <10 million pothesis was that IUI without COH would not be inferior to (severe male subfertility). In the IUI with COH group, we IUI with COH. If this were to be true, IUI without COH also assessed the relation between follicular growth patterns would be the preferred strategy. We considered IUI without COH not to be inferior to IUI with COH if we could excludethat the pregnancy rate without COH was R12.5% lower, us-ing a 5% significance level. A smaller difference was judged to be clinically irrelevant, because the cost and adverse ef- In total, 657 consecutive couples with an abnormal PCT and fects of COH would outweigh the slight increase in preg- a poor prognosis of a spontaneous ongoing pregnancy in the nancy rate. Assuming an 18% ongoing-pregnancy rate after next year were registered in one of the participating centers.
three cycles of IUI, 117 couples had to be enrolled in each Informed consent was obtained from 272 couples (41%), group to achieve an 80% level of power.
among whom 136 couples were randomly allocated to IUIwith COH and 136 couples to IUI without COH ().
All pregnancies occurring within the three IUI cycles were included in the analyses, as well as spontaneous pregnancies Seven randomized couples had to be excluded from the occurring before or between these IUI cycles. The treatment analyses who did not meet the inclusion criteria because effect of IUI with COH was expressed as relative risk and as they had a positive PCT, a short duration of subfertility Flowchart of trial population, with inclusion and outcome. Ong ¼ ongoing.
Steures. Value of COH in IUI for an abnormal PCT. Fertil Steril 2007.
(<12 mo), or two-sided tubal occlusion, known at the time of cies were ongoing, and one miscarried. After IUI, 26 preg- nancies (20%) occurred. Twenty-two of these pregnancieswere ongoing, 3 miscarried, and 1 was an ectopic pregnancy.
The baseline characteristics of the two groups were com- There were 2 twin pregnancies. Of the 28 ongoing pregnan- parable All women included in the study had their cies, all 26 singleton pregnancies (100%) resulted in a live tubes assessed before randomization by chlamydia antibody birth of one child; 1 twin pregnancy resulted in the live birth test (CAT), hysterosalpingography, or diagnostic laparoscopy of both children; and in the other twin pregnancy, one child (DLS). In 101 women (77%) allocated to IUI with COH and was healthy and the other one died. Eighteen couples did 107 women (80%) allocated to IUI without COH, tubal func- not complete three IUI cycles because of the burden of the tion had been assessed by hysterosalpingography or laparos- treatment, insurance problems, personal reasons, or having copy before randomization. In 8 women (7.9%) and 9 women switched earlier to IVF (13.6%). The latest IUI cycle took (8.4%), respectively, one-sided tubal occlusion was found. In the follow-up time for three IUI cycles, two and five women,respectively, underwent a hysterosalpingography or laparos- In the group allocated to IUI without COH, three women copy. In these women, both tubes were patent. Taken to- (2%) conceived spontaneously before the start of IUI. All gether, 103 women (78%) allocated to IUI with COH and three pregnancies were ongoing. One hundred and twenty 112 women (84%) allocated to IUI without COH underwent eight couples started IUI. Three women (2%) conceived a hysterosalpingography or laparoscopy, among whom 8 spontaneously between IUI cycles. These pregnancies were women (7.8%) and 9 women (8.0%), respectively, had one- all ongoing. After IUI, 22 pregnancies (17%) occurred. Sev- enteen of these pregnancies were ongoing, four miscarried, Pregnancy data are summarized in Complete fol- and one was an ectopic pregnancy. There was one twin preg- low-up was obtained for all couples. In the group allocated to nancy. Finally, of the 23 ongoing pregnancies, 21 singleton IUI with COH, three women (2%) conceived spontaneously pregnancies resulted in a live birth of one child, one singleton before the start of IUI. All pregnancies were ongoing. In pregnancy resulted in an intrauterine fetal death, and the twin 124 couples, IUI was started. Four women (3%) conceived pregnancies resulted in the live birth of both children. Ten spontaneously between IUI cycles. Three of these pregnan- couples did not complete three IUI cycles because of burden Mean duration of subfertility, y (min–max) a Data available at time of randomization in 117 and 115 women in the IUI with COH group and expectant-management b Data available at time of randomization in 64 and 65 women in the IUI with COH group and expectant-management c Data available at time of randomization in 100 and 101 women in the IUI with COH group and expectant-management d Data available at time of randomization in 72 and 66 women in the IUI with COH group and expectant-management e Data available at time of randomization in 29 and 41 women in the IUI with COH group and expectant-management Steures. Value of COH in IUI for an abnormal PCT. Fertil Steril 2007.
In the group allocated to IUI with COH, 325 IUI cycles were started, of which 43 cycles (13%) were canceled. Thepregnancy rate per started cycle was 8.0%, with an ongo- Kaplan Meier curves: time to ongoing pregnancy.
ing-pregnancy rate of 6.8% per started cycle. In 23 IUI cycles (7.1%), COH was performed with antiestrogenic medication(clomiphene citrate). In these IUI cycles, two ongoing preg- nancies occurred (8.7% per started cycle). In the group allo-cated to IUI without COH, 345 IUI cycles were started, ofwhich 34 cycles (9.9%) were canceled. The pregnancy rate per started cycle was 6.4%, with an ongoing-pregnancy rateof 4.9% per started cycle. When calculations were performed at a cycle level, the relative risk was 1.4 (95% CI, 0.74 to 2.5).
The number of cycles needed to treat for COH was 54 to achieve one additional ongoing pregnancy (95% CI, 18 toinfinity).
The pregnancies in relation to the TMC for IUI with and without COH are shown in . The effectiveness of IUI with COH in couples with a TMC of R10 million was not different from that in the total group (relative risk, 1.25;95% CI, 0.93 to 1.7). Multifollicular growth was registered Steures. Value of COH in IUI for an abnormal PCT. Fertil Steril 2007.
in 230 (82%) of the 282 inseminated cycles. Multifolliculargrowth, defined as more than one follicle with a diameter of the treatment, insurance problems, personal reasons, or of 10 mm, occurred in 62% of the inseminated cycles with having switched earlier to IVF (7.5%). The latest IUI cycle COH. In 38% of the inseminated cycles with COH, more took place within 6 months of follow-up.
than one follicle with a diameter of 15 mm was present atthe time of hCG injection. The pregnancies in relation to In total, 33 pregnancies (25%) occurred in the group allo- the follicular growth for the group allocated to IUI with cated to IUI with COH, and 28 pregnancies (21%), in the COH are shown in No clear differences in the preg- group allocated to IUI without COH ). The miscarriage nancy rates were seen between the cycles with monofollicu- rates in both groups were 15% and 18%, respectively. The number of ongoing pregnancies in the IUI with and withoutCOH groups were 28 (21%) and 23 (17%), respectively, re-sulting in a relative risk of 1.2 (95% CI, 0.75 to 2.0). The cor- responding absolute risk difference was þ4% (95% CI, –6% This is the first randomized clinical trial that evaluated the ad- to þ13%), corresponding with a number needed to treat of 26 ditional value of COH in IUI in couples with an abnormal (95% CI, 10 to infinity). The Kaplan-Meier curves showed no PCT. Our data show an almost similar effect of IUI with significant difference in the time to pregnancy in both groups and without COH in these couples. The estimates of treat- ment effect were not different in couples with a TMC of Pregnancies in relation to the TMC for IUI with and without COH.
Note: All data are n (%) unless otherwise indicated.
Steures. Value of COH in IUI for an abnormal PCT. Fertil Steril 2007.
Pregnancies after IUI with COH in relation to follicular growth.
Steures. Value of COH in IUI for an abnormal PCT. Fertil Steril 2007.
>10 million and in couples with a TMC of <10 million, but lower pregnancy rate can be explained by the prognostic pro- because the study was not powered for the additional analysis file of the couple. In the retrospective study, couples with cer- of the relation between pregnancies and the total motile vical-factor subfertility were included independently of their sperm count, this result should be interpreted with caution.
prognosis, whereas in the present study, only couples witha poor prognosis were included.
A strength of this study is that we used the prognostic pro- file of each couple, in addition to their diagnosis, as an inclu- The 4% difference in pregnancy rate that we found means sion criterion. This way, we included both couples with an that COH should not be applied in couples with an abnormal abnormal PCT and a long duration of their subfertility, as PCT. Because the 95% CI ranged from À6% to 13%, a bene- well as couples with an abnormal PCT and poor semen qual- ficial effect of COH cannot be excluded completely. How- ity or couples with an advanced maternal age. This approach ever, in clinical decision making, the risks of these two led to a selection of a more specific and homogeneous group treatment policies also should be taken into account. In from the prognostic profile. Because the treatment effect in case of multifollicular growth, which is the primary aim of subfertile couples may be dependent not only on diagnosis COH, there is a risk of multiple pregnancy, and couples are but also on prognosis, documenting the prognostic profile forced to trade off between the risks of a multiple pregnancy of the included couples makes our study results easy to inter- and cancellation of the IUI cycle, the latter obviously imply- pret and to generalize for each fertility clinic .
ing no pregnancy at all. Moreover, the risk of multiple preg-nancies cannot always be foreseen, because in IUI with COH, There are some possible limitations of this study. We erro- these pregnancies also can arise from borderline or small fol- neously included seven couples who did not meet the inclu- licles in cycles that are not canceled on the basis of existing sion criteria. These couples were distributed equally over guidelines. In contrast, IUI without COH bears no increased the two treatment policies, and therefore either inclusion or medical risk at a lower financial cost.
exclusion would not affect the results and conclusion or ourstudy. Because the aim of this trial was to assess whether ad- The PCT has been abandoned in many guidelines. How- dition of COH is effective in subfertile couples with a nega- ever, performing the PCT enables identification of couples tive PCT and at least one patent tube, we believe that with a cervical factor and avoids misclassifying these couples postrandomization exclusion is a better option than leaving as having unexplained infertility. This misdiagnosis would lead to the use of IUI with COH, which increases costs andthe risk of multiple pregnancies, without increasing chances Another limitation may be the fact that the study protocol recommended FSH for COH, but in 7.1% of IUI cycles, COHwas performed with anti-estrogenic medication (clomiphene In conclusion, IUI with COH, in couples with an abnormal citrate). However, in a Cochrane review, no significant differ- PCT and a poor prognosis, leads to pregnancy rates that are ence in live birth rates per couple after IUI with FSH and IUI comparable to those obtained by using IUI without COH. In- with anti-estrogenic medication was found Although trauterine insemination without COH should be the treatment this study had a protocol for the performance of the PCT and the treatment of IUI, the very fact that 24 centers partic-ipated in the trial may have affected the results. Nevertheless,this limitation is relative because this multicenter approach reflects the performance of the PCT and the effectiveness of 1. Fauser BCJM, Devroey P, Macklon NS. Multiple birth resulting from IUI in daily fertility practice. The ongoing-pregnancy rate ovarian stimulation for subfertility treatment. Lancet 2005;365: per started IUI cycle with or without COH of 6.8% and 2. Steures P, van der Steeg JW, Hompes PG, Habbema JD, Eijkemans MJ, 4.9%, respectively, is lower than the 10% and 13% that Broekmans FJ, et al. Intrauterine insemination with controlled ovarian were described elsewhere in a retrospective study This hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006;368:216–21.
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P. F. M. van der Heijden (Twenteborg Ziekenhuis, Almelo) 5. Cohlen BJ, Vandekerckhove P, te Velde ER, Habbema JDF. Timed inter- W. A. Scho¨ls (Meander Medisch Centrum, Amersfoort) course versus intra-uterine insemination with or without ovarian hyper- M. H. Mochtar (Academisch Medisch Centrum, Amsterdam) stimulation for subfertility in men. Cochrane Database Syst Rev H. R. Verhoeve (Onze Lieve Vrouwe Gasthuis, Amsterdam) P. G. A. Hompes (Vrij Universiteit Medisch Centrum, 6. Cohlen BJ, te Velde ER, van Kooij RJ, Looman CW, Habbema JDF. Con- trolled ovarian hyperstimulation and intrauterine insemination for treat- ing male subfertility: a controlled study. Hum Reprod 1998;13:1553–8.
L. J. van Dam (Gelre Ziekenhuis, Apeldoorn) 7. Steures P, van der Steeg JW, Hompes PGA, Bossuyt PMM, Habbema A. V. Sluijmer (Wilhelmina Ziekenhuis, Assen) JDF, Eijkemans MJC, et al. Effectiveness of intrauterine insemination R. E. Bernardus (Ziekenhuis Gooi-Noord, Blaricum) in subfertile couples with an isolated cervical factor: a randomized clin- J. P. Do¨rr (Westeinde Ziekenhuis, Den Haag) ical trial. Fertil Steril. In press.
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