Key messages
• In women with predicted normal response (meaning their ovaries are expected to respond in an average way to stimulation medication), short protocols using gonadotropin-releasing hormone (GnRH) antagonists likely result in similar live birth or ongoing pregnancy rates to long protocols using GnRH agonists, and short antagonist protocols likely reduce the risk of ovarian hyperstimulation syndrome (OHSS, a condition where the ovaries over-respond to fertility medications and become swollen and painful, and in severe cases can cause serious illness) compared to long GnRH agonist protocols.
• Ovarian stimulation without pituitary suppression may reduce the live birth rate or ongoing pregnancy rate compared with short GnRH antagonist protocols and with GnRH agonist flare protocols.
• In women with predicted high response (meaning their ovaries are expected to produce many eggs in response to stimulation, which increases the risk of complications such as OHSS), using human menopausal gonadotropin (hMG) in short GnRH antagonist protocols may reduce OHSS risk compared to recombinant follicle-stimulating hormone (rFSH).
What is IVF?
Some people with infertility require IVF to conceive. IVF involves several steps, including: controlled ovarian stimulation (COS), where women receive medication to help the ovaries produce multiple eggs in one cycle; egg collection, which involves retrieving eggs from the ovaries; fertilisation, where scientists mix eggs and sperm outside the body to create embryos; and embryo transfer, where an embryo is placed inside the womb.
COS is a critical step. It typically involves hormone injections (called gonadotropins) to stimulate the growth of eggs within the ovaries. To prevent natural ovulation during this process, medications are also used to suppress the hormones that trigger egg release (pituitary suppression). These treatments are combined in specific ways, called protocols.
The choice of protocol depends on individual factors like age, body weight and ovarian reserve (the number of eggs in the ovaries). Different protocols may affect the chances of pregnancy, the risk of complications like ovarian hyperstimulation syndrome (OHSS) and the number of eggs collected. However, it is not yet clear which protocols are the most effective and safe.
What did we want to find out?
We wanted to find out if any COS protocol was better than the others, and whether any of these protocols were associated with unwanted effects.
What did we do?
We searched for studies that compared different COS protocols. We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included 338 studies investigating 15 direct comparisons between different COS protocols in 59,086 women. Of these, 226 studies included only women with predicted normal response, 31 included only women with predicted high response and 81 included only women with predicted low response.
Live birth
Pituitary suppression methods
For women with predicted normal response, short protocols using GnRH antagonists likely result in similar live birth or ongoing pregnancy rates to long protocols using GnRH agonists. The evidence suggests that if the chance of live birth following treatment with long agonist protocols is assumed to be 28%, the live birth rate with short antagonist protocols would be between 24% and 30%. For the remaining participants (low- and high-responding women), we were not confident in the evidence.
Remaining evidence
The remaining analyses did not confidently identify a difference in live birth or ongoing pregnancy between any included interventions.
Ovarian hyperstimulation syndrome
Pituitary suppression methods
For women with predicted normal response, short GnRH antagonist protocols likely reduce the risk of OHSS compared to long GnRH agonist protocols. The evidence suggests that if the chance of OHSS following treatment with long GnRH agonist is assumed to be 25%, the OHSS rate with short GnRH antagonist protocols would be between 20% and 25%. For the remaining participants (low- and high-responding women), we were not confident in the evidence.
Short GnRH antagonist protocols
For women with predicted high response, using human menopausal gonadotropin (hMG) in short GnRH antagonist protocols may reduce OHSS risk compared to recombinant FSH (rFSH). The evidence suggests that if the chance of OHSS following treatment with rFSH is assumed to be 21%, the OHSS rate with hMG would be between 6% and 14%. For the remaining participants (normal- and low-responding women), we were not confident in the evidence.
Remaining evidence
The remaining analyses did not confidently identify a difference in OHSS between any included interventions.
What are the limitations of the evidence?
We have little confidence in most of the evidence because there was a limited number of studies for some protocols, some studies were not well-designed and results were inconsistent across studies, so we were unable to be certain about the effects.
How up-to-date is the evidence?
The evidence is current to June 2024.
Read the full abstract
Controlled ovarian stimulation (COS) is an essential step in most assisted conception cycles. Different treatment combinations (termed protocols) exist in COS, yet there is no consensus on their relative effectiveness and safety.
Objectives
We aimed to assess the relative effectiveness and safety of COS protocols in clinical practice.
Search strategy
We followed standard Cochrane methodology to conduct extensive electronic searches to 11 June 2024.
Selection criteria
We included randomised controlled trials (RCTs) comparing at least two COS protocols using any form of pituitary suppression (gonadotrophin-releasing hormone (GnRH) agonists, antagonists or progestogens) and human menopausal gonadotropin (hMG), urinary or recombinant follicle-stimulating hormone (u/rFSH), with or without luteinising hormone (LH) and/or oral medications (e.g. clomifene or letrozole), for ovarian stimulation. The primary outcomes were the rates of live birth or ongoing pregnancy (LBR or OPR) and ovarian hyperstimulation syndrome (OHSS) per participant after one stimulation cycle. The secondary outcomes were the rates of clinical pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and cycle cancellation per participant, and the number of oocytes, cleavage-stage embryos, blastocyst-stage embryos and cryopreserved embryos per participant.
Data collection and analysis
Two review authors independently selected studies and extracted data. We conducted pairwise and network meta-analyses (NMA) according to participants’ predicted response to COS (normal/unselected, high or low). For each outcome and subgroup of women, we grouped treatment protocols into the following different networks: all pituitary suppression methods; all long GnRH agonist protocols; all short GnRH antagonist protocols; all GnRH agonist flare protocols; all protocols using progestogens for pituitary suppression; and all protocols using ovarian stimulation in the absence of pituitary suppression. Using the Cochrane RoB 1 tool, we restricted our primary analyses to RCTs at low risk of 'selection' and 'other' biases. We presented effect estimates as risk ratios (RR) for dichotomous outcomes, or mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI). We used Review Manager and Stata 18 for the meta-analyses.
Main results
We included 338 studies investigating a total of 15 pairwise comparisons between different COS protocols in 59,086 women. Of these, 226 trials included only women with predicted normal response or whose predicted response was unstated, 31 trials included only women with predicted high response and 81 trials included only women with predicted low response.
Primary outcome (effectiveness) - LBR or OPR per woman randomised
Pituitary suppression methods
In women with predicted normal response, short antagonist protocols probably result in little to no difference in LBR or OPR versus long agonist protocols (RR 0.95, 95% CI 0.84 to 1.07; 8 studies, 2817 women; I2 = 0%; moderate-certainty evidence). Network evidence also suggested that ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols (RR 0.71, 95% CI 0.57 to 0.90; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.52, 95% CI 0.36 to 0.75; low-certainty evidence).
Primary outcome (safety) - OHSS per woman randomised
Pituitary suppression methods
In women with predicted normal response, short GnRH antagonist protocols may reduce OHSS compared with long GnRH agonist protocols (RR 0.88, 95% CI 0.78 to 0.99; 7 studies, 2650 women; I2 = 0%; low-certainty evidence).
Short GnRH antagonist protocols
In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH (RR 0.45, 95% CI 0.3 to 0.68; 1 study, 619 women; low-certainty evidence).
Secondary outcomes
Clinical pregnancy
Pituitary suppression methods
In women with predicted normal response, network evidence suggested that ovarian stimulation without pituitary suppression lowers the clinical pregnancy rate compared with short GnRH antagonist protocols (RR 0.76, 95% CI 0.61 to 0.93; low-certainty evidence) and with GnRH agonist flare protocols (RR 0.60, 95% CI 0.44 to 0.82; low-certainty evidence).
Cancellation
Short GnRH antagonist protocols
In women with predicted high response undergoing short GnRH antagonist protocols, hMG may increase cancellation compared with rFSH (RR 5.98, 95% CI 1.78 to 20.10; 1 study, 619 women; low-certainty evidence).
For the remaining networks and participant subgroups (normal- and low-responding women), the evidence did not confidently identify differences between COS protocols and is not reported in the abstract.
Oocyte number
Pituitary suppression methods
In women with predicted normal response, short GnRH antagonist protocols (MD -0.75, 95% CI -1.49 to -0.02; 17 studies, 4062 women; I2 = 94%; low-certainty evidence), GnRH agonist flare protocols (MD -3.30, 95% CI -4.87 to -1.73; 1 study, 240 women; I2 = 96%; low-certainty evidence) and protocols without pituitary suppression (MD -5.80, 95% CI -11.24 to -0.36; 2 studies, 714 women; low-certainty evidence) may lower the oocyte number compared with long GnRH agonist protocols, respectively.
In women with predicted low response, short GnRH antagonist protocols may reduce the oocyte number versus long agonist protocols (MD -1.25, 95% CI -2.01 to -0.50; low-certainty evidence).
Long GnRH agonist protocols
In women with predicted normal response receiving long GnRH agonist protocols, combining rFSH and rLH reduces the oocyte number compared with rFSH alone (MD -0.81, 95% CI -1.33 to -0.28; 6 trials, 1289 women; I2 = 0%; high-certainty evidence).
Remaining evidence
For the remaining networks, patient subgroups and secondary outcomes, the evidence did not confidently identify differences between COS protocols.
Authors' conclusions
Short GnRH antagonist protocols may reduce OHSS rates in women with predicted normal response without compromising LBR or OPR. Ovarian stimulation without pituitary suppression may reduce the LBR or OPR compared with short GnRH antagonist protocols and with GnRH agonist flare protocols. In women with predicted high response receiving short GnRH antagonist protocols, hMG may reduce OHSS compared with rFSH. We were unable to meta-analyse results from 169 trials due to serious risk of selection or other biases, a lack of outcome data, or because of data reported in an unsuitable format for meta-analysis (e.g. per cycle); this led to underpowered analyses for several outcomes and pairwise comparisons. Future trials should focus on evaluating the effect of different COS protocols upon cumulative live birth rates, accounting for all embryo transfers (fresh and/or frozen) after a single stimulation cycle per participant.
