Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial

Human Reproduction, vol. 37, pp. 2808–2816

Abstract

STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births? SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births. WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain. STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM. LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants. WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS. STUDY FUNDING/COMPETING INTEREST(S): The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest. TRIAL REGISTRATION NUMBER: Dutch Trial register NL5455 (NTR5599). TRIAL REGISTRATION DATE: 18 December 2015. DATE OF FIRST PATIENT’S ENROLMENT: 26 January 2017.

Authors 18

1. Monique H. Mochtar

   Amsterdam UMC Location University of Amsterdam · Amsterdam Reproduction Development

   Affiliation as printed

   Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

   Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

2. Dagmar E. Besselink

   Radboud University Nijmegen · Radboud University Medical Center

   Affiliation as printed

   Department of Obstetrics & Gynaecology, Radboud University Medical Centre , Nijmegen, The Netherlands

3. H Betjes

   Flevoziekenhuis

   Affiliation as printed

   Department Obstetrics and Gynaecology, Flevo Hospital , Almere, The Netherlands

4. Jan Peter de Bruin

   Jeroen Bosch Ziekenhuis

   Affiliation as printed

   Department of Gynaecology & Obstetrics, Jeroen Bosch Hospital , Den Bosch, The Netherlands

5. Astrid EP Cantineau

   University Medical Center Groningen · University of Groningen

   Affiliation as printed

   Department of Obstetrics and Gynaecology, University of Groningen, University Medical Centre Groningen , Groningen, The Netherlands

6. Eva R. Groenewoud

   Noordwest Ziekenhuisgroep

   Affiliation as printed

   Department of Obstetrics, Gynaecology & Reproductive Medicine, Noordwest Ziekenhuisgroep , Den Helder, The Netherlands

7. Angelo B. Hooker

   Zaans Medisch Centrum

   Affiliation as printed

   Department of Obstetrics and Gynaecology, Zaans Medical Center , Zaandam, The Netherlands

8. Cornelis Bavo Lambalk

   Amsterdam Reproduction Development · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Department of Reproductive Medicine, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

9. Janet Kwee

   OLVG

   Affiliation as printed

   Department of Obstetrics and Gynaecology, OLVG West , Amsterdam, The Netherlands

10. Eugenie M. Kaaijk

    OLVG

    Affiliation as printed

    Department of Obstetrics and Gynaecology, OLVG Oost , Amsterdam, The Netherlands

11. Leoni A. Louwé Aachen Department of Gynaecology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Gynaecology, Leiden University Medical Center , Leiden, The Netherlands

12. J W M Maas

    Maastricht University Medical Centre · Maastricht University

    Affiliation as printed

    Department of Obstetrics and Gynaecology MUMC+ and Grow-school of Oncology and Reproduction, Maastricht University , Maastricht, The Netherlands

13. Ben W. Mol

    University of Aberdeen · Monash University

    Affiliation as printed

    Aberdeen Centre for Women’s Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen , Aberdeen, UK

    Department of Obstetrics and Gynaecology, Monash University , Clayton, VIC, Australia

14. Minouche M. E. van Rumste

    Catharina Ziekenhuis

    Affiliation as printed

    Department of Gynaecology, Catharina Hospital , Eindhoven, The Netherlands

15. Maaike A. F. Traas

    Gelre Hospitals

    Affiliation as printed

    Department of Gynaecology, Gelre Hospital , Apeldoorn, The Netherlands

16. Mariëtte Goddijn

    Amsterdam UMC Location University of Amsterdam · Amsterdam Reproduction Development

    Affiliation as printed

    Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

    Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

17. Madelon van Wely

    Amsterdam UMC Location University of Amsterdam · Amsterdam Reproduction Development

    Affiliation as printed

    Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

    Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

18. Femke Mol corresponding

    Amsterdam UMC Location University of Amsterdam · Amsterdam Reproduction Development

    Affiliation as printed

    Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands

    Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam Reproduction and Development Research Institute , Amsterdam, The Netherlands