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. 2023 May 2;29(3):307-326.
doi: 10.1093/humupd/dmac040.

What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis

C A Venetis  1   2 , A Storr  3   4 , S J Chua  5 , B W Mol  6 , S Longobardi  7 , X Yin  8 , T D'Hooghe  9   10   11
Affiliations

What is the optimal GnRH antagonist protocol for ovarian stimulation during ART treatment? A systematic review and network meta-analysis

C A Venetis et al. Hum Reprod Update. .

Abstract

Background: Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety.

Objective and rationale: A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates.

Search methods: The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included.

Outcomes: The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates.

Wider implications: Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

Keywords: ART; GnRH antagonist; assisted reproductive technologies; cetrorelix; controlled ovarian stimulation; ganirelix; live birth; pregnancy.

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Conflict of interest statement

C.A.V. reports grants, personal fees and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees and non-financial support from Merck, Sharpe and Dohme, grants and non-financial support from Ferring, personal fees from Besins, personal fees and non-financial support from Gedeon-Richter and grants and non-financial support from Abbott. C.A.V. was supported during this work by a NHMRC Early Career Fellowship (GNT1147154). B.W.M. has received investigator grant from NHMRC (GNT1176437), personal fees from ObsEva, personal fees and research support from Merck KGaA, Darmstadt, Germany, personal fees and research support from Guerbet and personal fees from iGenomix. X.Y. is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA; a business of Merck KGaA, Darmstadt, Germany. S.L. is an employee of Merck Serono S.p.A., Rome, Italy, an affiliate of Merck KGaA, Darmstadt, Germany. T.D.H. is an employee of Merck KGaA, Darmstadt, Germany. S.J.C. and A.S. report no conflicts of interest.

Some of the data reported in this article were presented as an oral presentation at the Virtual 36th Annual Meeting of the European Society for Human Reproduction and Embryology (2020).

Figures

None
This meta-analysis showed lower ongoing pregnancy rates (OPRs) following controlled ovarian stimulation (COS) using a flexible GnRH antagonist protocol or pretreatment with an oral contraceptive pill (OCP) compared with COS using a fixed protocol or no OCP pretreatment, respectively.
Figure 1.
Figure 1.
PRISMA diagram for a systematic review and network meta-analysis to determine the optimal GnRH antagonist protocol for controlled ovarian stimulation during ART treatment. OCP, oral contraceptive pill; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RCT, randomized controlled trial.
Figure 2.
Figure 2.
Forest plots of relative risk from the pairwise meta-analyses for achievement of ongoing pregnancy in women. (A) Forest plots of RR for achievement of pregnancy in women undergoing COS using a fixed or flexible GnRH antagonist protocol. (B) Forest plots of RR for achievement of pregnancy in women undergoing COS using OCP pretreatment versus no pretreatment GnRH antagonist protocol. Weights are from random effects model. OCP, oral contraceptive pill; REML, restricted maximum likelihood method; RR, relative risk; COS, controlled ovarian stimulation.
Figure 3.
Figure 3.
Forest plots of relative risk from the network meta-analyses for pregnancy outcomes in women. (A) Forest plots of RR for achievement of live birth in women when undergoing COS using different GnRH antagonist protocols. (B) Forest plots of RR for achievement of ongoing pregnancy in women when undergoing COS using different GnRH antagonist protocols. (C) Forest plots of RR for achievement of clinical pregnancy in women when undergoing COS using different GnRH antagonist protocols. Ago, agonist; E2, oestradiol; NP, no pretreatment; OCP, oral contraceptive pill; P, progestin; RR, relative risk; COS, controlled ovarian stimulation.
Figure 4.
Figure 4.
SUCRA scores for the network meta-analyses which are used to quantify GnRH antagonist treatment ranking. The higher the value of the SUCRA, the more superior the treatment type. (A) SUCRA scores for the achievement of live birth in women undergoing COS using different GnRH antagonist protocols. (B) SUCRA scores for the achievement of ongoing pregnancy in women undergoing COS using different GnRH antagonist protocols. (C) SUCRA scores for the achievement of clinical pregnancy in women undergoing COS using different GnRH antagonist protocols. Ant, antagonist; E2, oestradiol; NP, no pretreatment; OCP, oral contraceptive pill; P, progestin; SUCRA, surface under the cumulative ranking curve (on Y-axes); COS, controlled ovarian stimulation.
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