N A Danhof1, M van Wely1, S Repping1, C Koks2, H R Verhoeve3, J P de Bruin4, M F G Verberg5, M H A van Hooff6, B J Cohlen7, C F van Heteren8, K Fleischer9, J Gianotten10, J van Disseldorp11, J Visser12, F J M Broekmans13, B W J Mol14, F van der Veen1, M H Mochtar1. 1. Centre for Reproductive Medicine, Academic Medical Centre, Meiberg dreef 9, 1105 AZ, Amsterdam, The Netherlands. 2. Department of Obstetrics and Gynaecology, Máxima Medical Centre, Postbus 7777, 5500 MB, Veldhoven, The Netherlands. 3. Department of Obstetrics and Gynaecology, OLVG oost, Oosterpark 9, 1091 AC, Amsterdam, The Netherlands. 4. Jeroen Bosch Hospital, Department of Obstetrics and Gynecology, Postbus 90153, 5200 ME, 's-Hertogenbosch, The Netherlands. 5. Fertility Clinic Twente, Demmersweg 66, 7556 BN, Hengelo, The Netherlands. 6. Department of Obstetrics and Gynaecology, Sint Franciscus Gasthuis, Kleiweg 500, 3045 PM, Rotterdam, The Netherlands. 7. Department of Obstetrics and Gynecology, Isala Hospital, Postbus 10400, 8000 GK, Zwolle, The Netherlands. 8. Department of Obstetrics and Gynaecology, Canisius Wilhelmina Hospital, Postbus 9015, 6500 GS, Nijmegen, The Netherlands. 9. Centre for Reproductive Medicine, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. 10. Department of Obstetrics and Gynaecology, Spaarne Gasthuis, Postbus 417, 2000 AK, Haarlem, The Netherlands. 11. Department of Obstetrics and Gynaecology, St. Antonius hospital Nieuwegein, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands. 12. Department of Obstetrics and Gynaecology Amphia, Postbus 90157, 4800 RL, Breda, The Netherlands. 13. Centre for Reproductive Medicine, University Medical Centre Utrecht, Postbus 85500, 3508 GA, Utrecht, The Netherlands. 14. Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton VIC 3168, Australia.
Abstract
STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IUFSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT’S ENROLMENT: The first patient was randomized at 27 August 2013.
RCT Entities:
STUDY QUESTION: Is FSH or clomiphene citrate (CC) the most effective stimulation regimen in terms of ongoing pregnancies in couples with unexplained subfertility undergoing IUI with adherence to strict cancellation criteria as a measure to reduce the number of multiple pregnancies? SUMMARY ANSWER: In IUI with adherence to strict cancellation criteria, ovarian stimulation with FSH is not superior to CC in terms of the cumulative ongoing pregnancy rate, and yields a similar, low multiple pregnancy rate. WHAT IS ALREADY KNOWN: FSH has been shown to result in higher pregnancy rates compared to CC, but at the cost of high multiple pregnancy rates. To reduce the risk of multiple pregnancy, new ovarian stimulation regimens have been suggested, these include strict cancellation criteria to limit the number of dominant follicles per cycle i.e. withholding insemination when more than three dominant follicles develop. With such a strategy, it is unclear whether the ovarian stimulation should be done with FSH or with CC. STUDY DESIGN, SIZE, DURATION: We performed an open-label multicenter randomized superiority controlled trial in the Netherlands (NTR 4057). PARTICIPANTS/MATERIALS, SETTING, METHODS: We randomized couples diagnosed with unexplained subfertility and scheduled for a maximum of four cycles of IUI with ovarian stimulation with 75 IU FSH or 100 mg CC. Cycles were cancelled when more then three dominant follicles developed. The primary outcome was cumulative ongoing pregnancy rate. Multiple pregnancy was a secondary outcome. We analysed the data on intention to treat basis. We calculated relative risks and absolute risk difference with 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Between July 2013 and March 2016, we allocated 369 women to ovarian stimulation with FSH and 369 women to ovarian stimulation with CC. A total of 113 women (31%) had an ongoing pregnancy following ovarian stimulation with FSH and 97 women (26%) had an ongoing pregnancy following ovarian stimulation with CC (RR = 1.16, 95% CI: 0.93-1.47, ARD = 0.04, 95% CI: -0.02 to 0.11). Five women (1.4%) had a multiple pregnancy following ovarian stimulation with FSH and eight women (2.2%) had a multiple pregnancy following ovarian stimulation with CC (RR = 0.63, 95% CI: 0.21-1.89, ARD = -0.01, 95% CI: -0.03 to 0.01). LIMITATIONS, REASONS FOR CAUTION: We were not able to blind this study due to the nature of the interventions. We consider it unlikely that this has introduced performance bias, since pregnancy outcomes are objective outcome measures. WIDER IMPLICATIONS OF THE FINDINGS: We revealed that adherence to strict cancellation criteria is a successful solution to reduce the number of multiple pregnancies in IUI. To decide whether ovarian stimulation with FSH or with CC should be the regimen of choice, costs and patients' preferences should be taken into account. STUDY FUNDING/COMPETING INTEREST(S): This trial received funding from the Dutch Organization for Health Research and Development (ZonMw). Prof. Dr B.W.J. Mol is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for Merck, ObsEva and Guerbet. The other authors declare that they have no competing interests. TRIAL REGISTRATION NUMBER: Nederlands Trial Register NTR4057. TRIAL REGISTRATION DATE: 1 July 2013. DATE OF FIRST PATIENT’S ENROLMENT: The first patient was randomized at 27 August 2013.
Authors: J A Wessel; F Mol; N A Danhof; A J Bensdorp; R I Tjon-Kon Fat; F J M Broekmans; A Hoek; B W J Mol; M H Mochtar; M van Wely Journal: Hum Reprod Date: 2021-02-18 Impact factor: 6.918
Authors: Gulam Bahadur; Roy Homburg; Judith E Bosmans; Judith A F Huirne; Peter Hinstridge; Kanna Jayaprakasan; Paul Racich; Rakib Alam; Ioannis Karapanos; Afeeza Illahibuccus; Ansam Al-Habib; Eric Jauniaux Journal: BMJ Open Date: 2020-03-16 Impact factor: 2.692