Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

Gonadotrophin‐releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo‐oestrogenic side‐effects, flare‐up, or long down‐regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple‐dose fixed (0.25 mg daily from day six to seven of stimulation), multiple‐dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single‐dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011.

Objectives

To evaluate the effectiveness and safety of gonadotrophin‐releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles.

Search methods

We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). We contacted the authors of eligible studies for missing or unpublished data. The evidence is current to 28 April 2015.

Selection criteria

Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different GnRH agonist versus GnRH antagonist protocols in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Data collection and analysis

Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary review outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Other adverse effects (miscarriage and cycle cancellation) were secondary outcomes. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I2 statistic. We assessed the overall quality of the evidence for each comparison using GRADE methods.

Main results

We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long‐course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods.

Live birth

There was no evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I2= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%.

OHSS

GnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I2 = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%.

Other adverse effects

There was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.03, 95% CI 0.82 to 1.29; 34 RCTs, n = 7082, I2 = 0%, moderate quality evidence).

With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I2 = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I2 = 68%; moderate quality evidence).

Authors' conclusions

There is moderate quality evidence that the use of GnRH antagonist compared with long‐course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth.

Author(s)

Hesham G Al‐Inany, Mohamed A Youssef, Reuben Olugbenga Ayeleke, Julie Brown, Wai Sun Lam, Frank J Broekmans

Abstract

Plain language summary

Gonadotrophin‐releasing hormone antagonists versus GnRH agonist in subfertile couples undergoing assisted reproductive technology

Review question

This updated Cochrane review evaluated the efficacy and safety of GnRH antagonists compared to the more widely‐used GnRH agonists (long‐course protocol).

Background:

Gonadotrophin‐releasing hormone (GnRH) agonist is commonly used to prevent cycle cancellation secondary to a premature luteinizing hormone (LH) surge, and thereby increase the chance of live birth in women undergoing assisted reproductive technology (ART), while reducing the risk of complications such as ovarian hyperstimulation syndrome (OHSS). Gonadotrophin‐releasing hormone (GnRH) antagonists are now being seriously considered as a potential means of achieving better treatment outcomes because the protocol is more flexible and antagonists may reduce OHSS more effectively than agonists. However, there is the need to evaluate the benefits as well as the safety of these GnRH antagonist regimens in comparison with the existing GnRH agonist regimens.

Study characteristics

We found 73 randomised controlled trials comparing GnRH antagonist with GnRH agonist in a total of 12,212 women undergoing ART. The evidence is current to May 2015

Key results

There was no evidence of a difference between the groups in live birth rates (i.e. rates at conclusion of a course of treatment). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%. However, the OHSS rates were much higher after GnRH agonist. The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%.

Quality of the evidence

The evidence was of moderate quality for both live birth and OHSS. The main limitations of the evidence were the possibility of publication bias for live birth (with small studies likely to report favourable outcomes for GnRH antagonist) and poor reporting of study methods for OHSS.

Author(s)

Hesham G Al‐Inany, Mohamed A Youssef, Reuben Olugbenga Ayeleke, Julie Brown, Wai Sun Lam, Frank J Broekmans

Reviewer's Conclusions

Authors' conclusions

Implications for practice

The GnRH antagonist protocol is a short and simple protocol with evidence suggesting a comparable live birth rate and a substantial reduction in the incidence of ovarian hyperstimulation syndrome when compared to GnRH agonist long protocol in women undergoing ART.

Implications for research

In view of the shortcomings noted in the included studies, especially with regard to the methods of reporting of trial procedures, more properly designed studies in accordance with the CONSORT statement are need to further evaluate the effectiveness and safety of the GnRH antagonist protocol (Schulz 2010). For example, it would be desirable to have trials with low risk of bias with primary outcomes of live birth and OHSS. In addition, further studies are needed to assess this treatment regimen in poor and high responders. We attempted to subgroup treatment regimens by the ovulation triggering agent but no data were available for a proper analysis, as the majority of the included studies either used hCG or did not specify their triggering agents. This is a potential area to be explored by future research. It is also important to understand why pregnancy outcomes have become progressively more favourable with the use of GnRH antagonists. One possible explanation for this could be a decrease in LH instability. This area should be further investigated. Although not a focus of the current update, the potential effects of OCP pretreatment should be further investigated.

Patient satisfaction surveys should also be undertaken to evaluate their impression about GnRH antagonist treatment regimens.

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