Short GnRH antagonist protocol in ART may reduce ovarian hyperstimulation risk

A large systematic review and meta-analysis of women undergoing assisted reproduction has shown that the use of short gonadotropin-releasing hormone (GnRH) antagonist protocols, compared with long GnRH agonist protocols, during controlled ovarian stimulation (COS) may reduce the risk of ovarian hyperstimulation syndrome (OHSS) while having no major impact on live birth rates. 

“We can now say with a good level of confidence that in patients with predicted high or normal response, using long protocols is unlikely to improve their live birth rates but will probably increase their risk of OHSS,” said study author Dr Pedro Melo from the Tommy’s National Centre for Miscarriage Research, University of Birmingham, Birmingham, UK, who presented the findings at ESHRE 2022.

“Antagonist protocols are markedly shorter in duration, involve fewer injections, and have non-inferior effectiveness outcomes than those of long agonist protocols, but crucially they reduce the risk of OHSS, a major consideration in avoiding harm to patients,” he added.

Using multiple databases, Melo and co-authors identified 329 randomized controlled trials* (36,939 women included in the meta-analysis) comparing ≥2 COS protocols used in in vitro fertilization (IVF) or intracytoplasmic sperm injection and published up to November 2021. The 56 protocols included used GnRH agonists or antagonists for pituitary suppression and human menopausal gonadotropin (hMG), urinary or recombinant follicle-stimulating hormone (u/rFSH), with or without luteinizing hormone for ovarian stimulation. The most common protocols in the trials were long agonist or short antagonist with rFSH.

In women with high or normal response to COS, the use of short GnRH antagonist protocols resulted in comparable live birth rates after one stimulation cycle compared with the use of long GnRH agonist protocols (risk ratio [RR], 0.98, 95 percent confidence interval [CI], 0.85–1.13). [ESHRE 2022, abstract O-009]

However, the rate of OHSS after one stimulation cycle appeared to be lower following short GnRH antagonist vs long GnRH agonist protocols in women with normal response to COS (RR, 0.88, 95 percent CI, 0.78–0.99), with a marked reduction among women with high response rates (RR, 0.61, 95 percent CI, 0.48–0.78).

“There is this prevailing idea historically that short antagonist protocols have resulted in a lower number of live births … our data at the moment don’t support that, not for normal responding women [and with no confidence evidence] for high or low responding women,” said Melo.

Additionally, there is a probable reduction in OHSS with the short antagonist vs long agonist protocol, with up to 52- and 32-percent reductions in high and normal responding women, respectively, he continued.

In short antagonist protocols, the use of hMG vs rFSH may be protective against OHSS in high responding women, though this comes at the expense of fewer oocytes and blastocysts, he added.

The mechanism behind the reduced OHSS risk with the short GnRH antagonist protocol remains unknown, said Melo. “However, it seems likely that this results from a combination of factors, including the absence of an ovarian “flare” effect with GnRH antagonists, and the option of triggering ovulation in GnRH antagonist cycles without human chorionic gonadotropin, which is the main driver of OHSS,” he noted.

One limitation was the lack of studies assessing cumulative live birth rates which is at present the most effective outcome of IVF success, said Melo, who called for studies assessing longer term outcomes.