A randomized controlled trial of AMH-based individualized FSH dosing in a GnRH antagonist protocol for IVF

Abstract STUDY QUESTION Does an individualized serum anti-Müllerian hormone (AMH) based FSH dosing algorithm used in a GnRH antagonist protocol increase the proportion of patients with an intended number of oocytes (5–14) retrieved compared with a standard regimen? SUMMARY ANSWER The AMH-based individualized algorithm did not increase the proportion of patients with an intended oocyte retrieval. WHAT IS KNOWN ALREADY Individualizing treatment for ovarian stimulation by serum AMH or antral follicle count can theoretically improve the ratio between benefits and risks. Current data suggest that there may be a reduced risk of ovarian hyperstimulation syndrome (OHSS), but without improved pregnancy or live birth rates. Only two randomized controlled trials (RCTs) have examined the potential of AMH-based algorithms to optimize the FSH dosing in ovarian stimulation. STUDY DESIGN, SIZE, DURATION A dual-center open-label investigator-driven RCT was conducted between January 2013 and November 2016. Eligibility was assessed in 269 women and 221 were randomized 2:1 between individualized and standard dosing groups. Women with pretreatment serum AMH > 24 pmol/L had 100 IU/day of recombinant FSH (rFSH); AMH 12–24 pmol/L had 150 IU/day of rFSH, and AMH < 12 pmol/L had maximal stimulation with corifollitropin 100 or 150 mg depending on bodyweight ±60 kg. The standard group had 150 IU/day of rFSH irrespective of pretreatment AMH. All patients followed the GnRH-antagonist protocol. The sample size calculation assumed that individualized dosing by AMH would reduce the proportion of unintended oocyte yield (outside the 5–14 range) by 50%, from 35 to 17.5%. In a 2:1 randomization this required 216 patients: 144 in the individualized and 72 patients in the standard group (80% power, 5% significance). PARTICIPANTS/MATERIALS, SETTING, METHODS All women had a presumed ovulatory normal menstrual cycle, were aged 25–38 years, weighed < 75 kg, had pretreatment AMH 4–40 pmol/L, did their first IVF or ICSI cycle and had two ovaries accessible to oocyte retrieval. Recruitment was conducted from both participating sites. Women were excluded if diagnosed with anovulatory polycystic ovary syndrome, endometriosis grade III/IV, hydrosalpings on ultrasound, recurrent miscarriages (≥3), FSH > 12 IU/L or major medical disorders. MAIN RESULTS AND THE ROLE OF CHANCE After randomization 149 women were allocated to the individualized group and 72 to the standard group. The primary outcome of women with an intended (5–14) number of oocytes retrieved was similar in the individualized (n = 105) versus the standard (n = 55) rFSH treatment group (72% [95% CI 64–79%] versus 78% [95% CI 67–86%], respectively, P = 0.68, between group standardized mean difference (SMD) −6%, 95% CI: −19–8%). In the high AMH stratum of the individualized group, significantly more women (n = 13) had an unintended low number of oocytes (<5) retrieved (38% [95% CI: 23–55%]) compared with the standard group (6% [95% CI 0.3–24%], P = 0.029, between group SMD 32%, 95% CI: 9–56%). Conversely, in the low pretreatment AMH stratum, individualized dosing using corifollitropin reduced the proportion of unintended low responders to 24% (95% CI: 12–40%) compared with 47% (95% CI: 26–69%) in the standard group, P = 0.10, between group SMD −23% (95% CI: −54–8%). OHSS was diagnosed in four women (two in each study arm), and all cases were mild. Daily luteal phase questionnaire reporting showed similar wellbeing in terms of abdominal distention, abdominal pain, dyspnea and occurrence of bleeding between groups. The cumulative live birth rate per started cycle was similar (32 and 35%) comparing the individualized with the standard group. LIMITATIONS, REASONS FOR CAUTION This study was powered for showing differences only in the distribution of oocyte retrieval when comparing individualized and standard groups, therefore additional results should be viewed with caution. In addition, there was a change of AMH assay halfway through the study period and the possibility that corifollitropin being introduced to a subgroup of the intervention has introduced confounding cannot be ruled out. WIDER IMPLICATIONS OF FINDINGS In the expected high responder AMH stratum, 100 IU/day is an insufficient rFSH dose in a high proportion of patients. Further research might explore the 125 IU/day dose for the high AMH segment. STUDY FUNDING/COMPETING INTEREST(S) None for the submitted work. ICMJE declared personal interests for two of the authors. TRIAL REGISTRATION NUMBER EUDRACT registration number: 2012-004969-40. TRIAL REGISTRATION DATE 27 November 2012. DATE OF FIRST PATIENT’S ENROLLMENT 10 January 2013.