Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction

Gonadotropin-releasing hormone agonists (GnRHa) are commonly used in assisted reproduction technology (ART) cycles to prevent a luteinising hormone (LH) surge during controlled ovarian hyperstimulation (COH) prior to planned oocyte retrieval, thus optimising the chances of live birth. We compared the benefits and risks of the different GnRHa protocols used.

To evaluate the effectiveness and safety of different GnRHa protocols used as adjuncts to COH in women undergoing ART.

We searched the following databases in December 2022: the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and registries of ongoing trials. We also searched the reference lists of relevant articles and contacted experts in the field for any additional trials.

We included randomised controlled trials (RCTs) comparing any two protocols of GnRHa, or variations of the protocol in terms of different doses or duration, used in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles in subfertile women.

We used standard methodological procedures recommended by Cochrane. Our primary outcome measures were number of live births or ongoing pregnancies and incidence of ovarian hyperstimulation syndrome (OHSS) per woman/couple randomised. Our secondary outcome measures included number of clinical pregnancies, pregnancy losses, number of oocytes retrieved, amount of gonadotropins used, and cost and acceptability of the treatment protocols.

We included 40 RCTs (4148 women). The trials evaluated 10 different comparisons between protocols. The evidence is current to December 2022. Only half of the studies reported the primary outcome of live birth or ongoing pregnancy rates. We restricted the primary analysis of live birth and ongoing pregnancy to trials with low risk of selection and reporting bias. Nineteen studies compared long and short protocols. The primary analysis restricted to trials with low risk of bias included five studies reporting on live birth or ongoing pregnancy rates. Results showed little or no difference when the long protocol was compared with a short protocol (odds ratio (OR) 1.45, 95% confidence interval (CI) 0.83 to 2.52; I² = 0%; 5 studies, 381 women; low-certainty evidence). For the same comparison, there was evidence that the long protocol may improve clinical pregnancy rates when compared to the short protocol (OR 1.56, 95% CI 1.01 to 2.40; I² = 23%; 8 studies, 552 women; low-certainty evidence). No study in this comparison reported on OHSS. We are uncertain if there is a difference between groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort (OR 1.78, 95% CI 0.72 to 4.36; 1 study, 150 women; very low-certainty evidence); long luteal versus long follicular phase (OR 1.89, 95% CI 0.87 to 4.10; 1 study, 223 women; very low-certainty evidence); GnRHa reduced-dose versus GnRHa same-dose continued in the long protocol (OR 1.59, 95% CI 0.66 to 3.87; 1 study, 96 women; very low-certainty evidence); GnRHa administration for two versus three weeks before stimulation (OR 0.88, 95% CI 0.37 to 2.05; 1 study, 85 women; very low-certainty evidence); GnRHa continued versus discontinued after human chorionic gonadotropin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; 1 study, 181 women; very low-certainty evidence); and 500 µg dose versus 80 µg dose in the short protocol (OR 0.31, 95% CI 0.10 to 0.98; 1 study, 200 women; very low-certainty evidence). Clinical pregnancy rates may improve with a 100 µg dose compared to a 25 µg dose in the short protocol (OR 2.30, 95% CI 1.06 to 5.00; 2 studies, 133 women; low-certainty evidence). Only four of the 40 included studies reported adverse events. We are uncertain of any difference in OHSS rate in the GnRHa reduced-dose versus GnRHa same-dose regimen in the long protocol (OR 0.47, 95% CI 0.04 to 5.35; 1 study, 96 women; very low-certainty evidence) or when administration of GnRHa lasted for two versus three weeks before stimulation (OR 0.93, 95% CI 0.06 to 15.37; 1 study, 85 women; very low-certainty evidence). Regarding miscarriage rates, we are uncertain of any difference when the GnRHa long protocol was administered for two versus three weeks before stimulation (OR 0.93, 95% CI 0.18 to 4.87; 1 study, 85 women; very low-certainty evidence) and when a 500 µg dose was compared with an 80 µg dose in the short protocol (OR 3.15, 95% CI 0.32 to 31.05; 1 study, 131 women; very low-certainty evidence). No studies reported on cost-effectiveness or acceptability of the different treatment protocols. The certainty of the evidence ranged from low to very low. The main limitations were failure to report live birth or ongoing pregnancy rates, poor reporting of methods in the primary studies, imprecise findings due to lack of data, and insufficient data regarding adverse events. Only eight of the 40 included studies were conducted within the last 10 years.

When comparing long and short GnRHa protocols, we found little or no difference in live birth and ongoing pregnancy rates, but there was evidence that the long protocol may improve clinical pregnancy rates overall. We were uncertain of any difference in OHSS and miscarriage rates for all comparisons, which were reported by only two studies each. There was insufficient evidence to draw any conclusions regarding other adverse effects or the cost-effectiveness and acceptability of the different treatment protocols.