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Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder.
Hum Reprod. 2017 Dec 01; 32(12):2506-2514.HR

Abstract

STUDY QUESTION

Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety?

SUMMARY ANSWER

Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed.

WHAT IS KNOWN ALREADY

Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response.

STUDY DESIGN SIZE, DURATION

Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders.

PARTICIPANTS/MATERIALS, SETTING, METHODS

Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective.

MAIN RESULTS AND THE ROLE OF CHANCE

We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis.

LIMITATIONS, REASONS FOR CAUTION

Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings.

WIDER IMPLICATIONS OF THE FINDINGS

In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates.

STUDY FUNDING/COMPETING INTEREST(S)

This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare.

TRIAL REGISTRATION NUMBER

Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657.

TRIAL REGISTRATION DATE

20 December 2010.

DATE OF FIRST PATIENT’S ENROLMENT

12 May 2011.

Authors+Show Affiliations

Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands.Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands.Department of Obstetrics and Gynaecology, St. Antonius Hospital, PO box 2500, 3430 EM Nieuwegein, The Netherlands.Department of Obstetrics, Gynaecology and Reproductive Medicine, Noordwest Ziekenhuisgroep, PO Box 750, 1780 AT Den Helder, The Netherlands.Department of Gynaecology, St. Franciscus Gasthuis, PO Box 10900, 3004 BA Rotterdam, The Netherlands.Fertility Clinic Reinier de Graaf group, Diaconessenhuis Voorburg, PO Box 998, 2275 CX, Voorburg, The Netherlands.Department of Obstetrics and Gynaecology, Meander Medical Centre, PO Box 1502, 3800 BM Amersfoort, The Netherlands.Centre for Reproductive Medicine, Elisabeth-TweeSteden Hospital, PO Box 90151, 5000 LC Tilburg, The Netherlands.Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis West, PO Box 9243, 1006 AE Amsterdam, The Netherlands.Department of Gynaecology, Tergooi Hospital, PO Box 1201 DA Blaricum, The Netherlands.Department of Epidemiology, University of Groningen, University Medical Centre Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.Centre for Reproductive Medicine, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands.The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, SA 5006 Adelaide, Australia. The South Australian Health and Medical Research Unit, PO Box 11060, SA 5001 Adelaide, Australia.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands.Department of Reproductive Medicine and Gynaecology, University Medical Centre Utrecht, Utrecht University, PO Box 85500, 3508 GA Utrecht, The Netherlands.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

29121269

Citation

Oudshoorn, Simone C., et al. "Individualized Versus Standard FSH Dosing in Women Starting IVF/ICSI: an RCT. Part 2: the Predicted Hyper Responder." Human Reproduction (Oxford, England), vol. 32, no. 12, 2017, pp. 2506-2514.
Oudshoorn SC, van Tilborg TC, Eijkemans MJC, et al. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder. Hum Reprod. 2017;32(12):2506-2514.
Oudshoorn, S. C., van Tilborg, T. C., Eijkemans, M. J. C., Oosterhuis, G. J. E., Friederich, J., van Hooff, M. H. A., van Santbrink, E. J. P., Brinkhuis, E. A., Smeenk, J. M. J., Kwee, J., de Koning, C. H., Groen, H., Lambalk, C. B., Mol, B. W. J., Broekmans, F. J. M., & Torrance, H. L. (2017). Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder. Human Reproduction (Oxford, England), 32(12), 2506-2514. https://doi.org/10.1093/humrep/dex319
Oudshoorn SC, et al. Individualized Versus Standard FSH Dosing in Women Starting IVF/ICSI: an RCT. Part 2: the Predicted Hyper Responder. Hum Reprod. 2017 Dec 1;32(12):2506-2514. PubMed PMID: 29121269.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder. AU - Oudshoorn,Simone C, AU - van Tilborg,Theodora C, AU - Eijkemans,Marinus J C, AU - Oosterhuis,G Jur E, AU - Friederich,Jaap, AU - van Hooff,Marcel H A, AU - van Santbrink,Evert J P, AU - Brinkhuis,Egbert A, AU - Smeenk,Jesper M J, AU - Kwee,Janet, AU - de Koning,Corry H, AU - Groen,Henk, AU - Lambalk,Cornelis B, AU - Mol,Ben Willem J, AU - Broekmans,Frank J M, AU - Torrance,Helen L, AU - ,, PY - 2017/01/27/received PY - 2017/10/12/accepted PY - 2017/11/10/pubmed PY - 2018/10/12/medline PY - 2017/11/10/entrez KW - Antral follicle count KW - FSH KW - ICSI KW - IVF KW - RCT KW - cost-effectiveness KW - hyper ovarian response KW - individualized KW - live birth KW - ovarian reserve SP - 2506 EP - 2514 JF - Human reproduction (Oxford, England) JO - Hum. Reprod. VL - 32 IS - 12 N2 - STUDY QUESTION: Does a reduced FSH dose in women with a predicted hyper response, apparent from a high antral follicle count (AFC), who are scheduled for IVF/ICSI lead to a different outcome with respect to cumulative live birth rate and safety? SUMMARY ANSWER: Although in women with a predicted hyper response (AFC > 15) undergoing IVF/ICSI a reduced FSH dose (100 IU per day) results in similar cumulative live birth rates and a lower occurrence of any grade of ovarian hyperstimulation syndrome (OHSS) as compared to a standard dose (150 IU/day), a higher first cycle cancellation rate and similar severe OHSS rate were observed. WHAT IS KNOWN ALREADY: Excessive ovarian response to controlled ovarian stimulation (COS) for IVF/ICSI may result in increased rates of cycle cancellation, the occurrence of OHSS and suboptimal live birth rates. In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can be used to predict response to COS. No consensus has been reached on whether ORT-based FSH dosing improves effectiveness and safety in women with a predicted hyper response. STUDY DESIGN SIZE, DURATION: Between May 2011 and May 2014, we performed an open-label, multicentre RCT in women with regular menstrual cycles and an AFC > 15. Women with polycystic ovary syndrome (Rotterdam criteria) were excluded. The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. Secondary outcomes included the occurrence of OHSS and cost-effectiveness. Since this RCT was embedded in a cohort study assessing over 1500 women, we expected to randomize 300 predicted hyper responders. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with an AFC > 15 were randomized to an FSH dose of 100 IU or 150 IU/day. In both groups, dose adjustment was allowed in subsequent cycles (maximum 25 IU in the reduced and 50 IU in the standard group) based on pre-specified criteria. Both effectiveness and cost-effectiveness were evaluated from an intention-to-treat perspective. MAIN RESULTS AND THE ROLE OF CHANCE: We randomized 255 women to a daily FSH dose of 100 IU and 266 women to a daily FSH dose of 150 IU. The cumulative live birth rate was 66.3% (169/255) in the reduced versus 69.5% (185/266) in the standard group (relative risk (RR) 0.95 [95%CI, 0.85-1.07], P = 0.423). The occurrence of any grade of OHSS was lower after a lower FSH dose (5.2% versus 11.8%, RR 0.44 [95%CI, 0.28-0.71], P = 0.001), but the occurrence of severe OHSS did not differ (1.3% versus 1.1%, RR 1.25 [95%CI, 0.38-4.07], P = 0.728). As dose reduction was not less expensive (€4.622 versus €4.714, delta costs/woman €92 [95%CI, -479-325]), there was no dominant strategy in the economic analysis. LIMITATIONS, REASONS FOR CAUTION: Despite our training programme, the AFC might have suffered from inter-observer variation. Although strict cancellation criteria were provided, selective cancelling in the reduced dose group (for poor response in particular) cannot be excluded as observers were not blinded for the FSH dose and small dose adjustments were allowed in subsequent cycles. However, as first cycle live birth rates did not differ from the cumulative results, the open design probably did not mask a potential benefit for the reduced dosing group. As this RCT was embedded in a larger cohort study, the power in this study was unavoidably lower than it should be. Participants had a relatively low BMI from an international perspective, which may limit generalization of the findings. WIDER IMPLICATIONS OF THE FINDINGS: In women with a predicted hyper response scheduled for IVF/ICSI, a reduced FSH dose does not affect live birth rates. A lower FSH dose did reduce the incidence of mild and moderate OHSS, but had no impact on severe OHSS. Future research into ORT-based dosing in women with a predicted hyper response should compare various safety management strategies and should be powered on a clinically relevant safety outcome while assessing non-inferiority towards live birth rates. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by The Netherlands Organization for Health Research and Development (ZonMW, Project Number 171102020). SCO, TCvT and HLT received an unrestricted research grant from Merck Serono (the Netherlands). CBL receives grants from Merck, Ferring and Guerbet. BWJM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. FJMB receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV and Merck Serono for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number: NTR2657. TRIAL REGISTRATION DATE: 20 December 2010. DATE OF FIRST PATIENT’S ENROLMENT: 12 May 2011. SN - 1460-2350 UR - https://www.unboundmedicine.com/medline/citation/29121269/Individualized_versus_standard_FSH_dosing_in_women_starting_IVF/ICSI:_an_RCT__Part_2:_The_predicted_hyper_responder_ L2 - https://academic.oup.com/humrep/article-lookup/doi/10.1093/humrep/dex319 DB - PRIME DP - Unbound Medicine ER -