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

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.

Value of estrogen pretreatment in patients with diminished ovarian reserve and elevated FSH on a line antagonist regimen: a retrospective controlled study

“…Pretreatment with estrogen, progestin, or OC can eliminate the corpus luteum, suppress endogenous FSH, restore serum FSH to normal levels, and restore the sensitivity of FSH receptors [ 14 ]. Miyoshi et al suggested that estrogen can upregulate FSH and LH receptors on granulosa cells to increase their sensitivity to Gn and synergize with FSH to promote follicular growth and proliferation of granulosa cells [ 15 ]. Meta-analysis showed that OC combined with GnRH antagonist treatment decreased the rates of ongoing pregnancy, however there was also no evidence of a difference in live birth or clinical pregnancy rates between women who were pretreated with and without estrogen [ 16 , 17 ].…”

Optimal timing of GnRH antagonist initiation in IVF-ET: a retrospective cohort study on advanced maternal age women

“…The latest review by Venetis et al. included more studies and reported that fixed GnRH-ant protocol resulted in a higher ongoing pregnancy rate ( 3 , 10 ). However, reproductive characteristics vary greatly among different populations, while very few studies exist analyzing the optimal timing of GnRH-ant initiation for specific subpopulations.…”

“…Al-Inany et al reported no significant difference between the two protocols, but also emphasized the trend of higher pregnancy rate of fixed GnRH-ant protocol. The latest review by Venetis et al included more studies and reported that fixed GnRH-ant protocol resulted in a higher ongoing pregnancy rate (3,10). However, reproductive characteristics vary greatly among different populations, while very few studies exist analyzing the optimal timing of GnRH-ant initiation for specific subpopulations.…”

“…All included women received GnRH-ant protocol for ovarian stimulation, and the initiation time of GnRH-ant is based on standard operating procedure (SOP) in our center: (1) Fixed GnRH-ant protocol: GnRH-ant was initiated at day 6 of stimulation; (2) Flexible protocol: GnRH-ant was initiated when the largest ovarian follicle has reached a diameter of 12 to 14 mm. The definition of GnRH-ant protocol in accordance with most of the previous studies ( 10 ). The study follow-up period was two years from the day of oocyte retrieval.…”

“…In a recent systematic review, different GnRH-ant initiation protocols were compared, and a fixed protocol was found to be significantly superior to a flexible protocol in terms of ongoing pregnancy rates ( 10 ). Study populations in the included studies were heterogeneous, and further high-quality studies need to be conducted with more homogeneous cohorts to confirm the findings.…”