Cochrane Clinical Answers - Fulltext - How do GnRH antagonists compare with GnRH agonists for improving outcomes in couples undergoing assisted reproductive technology?

Question:How do GnRH antagonists compare with GnRH agonists for improving outcomes in couples undergoing assisted reproductive technology?

Clinical Answer:

GnRH antagonists are as effective as GnRH agonists for achieving live birth and reduce the risk of ovarian hyperstimulation.

In couples undergoing controlled ovarian hyperstimulation as part of an IVF or ICSI program, there is moderate-quality evidence showing similar live birth rates, ongoing pregnancy rates or miscarriage rates when women received GnRH antagonist compared with long-course GnRH agonist. However, fewer women receiving GnRH antagonist experienced ovarian hyperstimulation compared with GnRH agonist (on average 73 compared with 114 per 1000 women). Clinical pregnancy rates were lower with GnRH antagonist, but in women undergoing minimal ovarian stimulation, rates were higher with GnRH antagonist than with long-course GnRH agonist. Cycle cancellation rates were higher with GnRH antagonist compared with GnRH agonist when cancellation was due to poor ovarian response but rates were lower when due to high risk of ovarian hyperstimulation.

Full outcome data is detailed below:

1.GnRH antagonist versus long-course GnRH agonist

  • Population, Intervention, Comparator

    Population:

    Subfertile couples undergoing controlled ovarian hyperstimulation as part of an IVF or ICSI program. Most trials used hCG trigger or did not state which trigger was used; one of the included trials used a combination of both hCG and GnRH agonist as trigger agents

    Intervention:

    GnRH antagonist: single, long-acting administration (4 trials); fixed, daily administration (GnRH antagonist begun on day six of FSH treatment regardless of follicle size; 14 trials) or flexible daily administration (GnRH antagonist was administered according to the lead follicle size and not the cycle date, nor the day of FSH administration; most trials). Cetrorelix was administered in 44 trials, ganirelix in 19 trials, both drugs in 3 trials and this was unclear in 7 trials

    Comparator:

    Long-course GnRH agonist (no further details provided)

  • OUTCOME 1.1: Live birth rate per woman randomized

    Quality of the evidence:

    The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

    Narrative result:

    11 RCTs with 2243 participants found no statistically significant difference between groups. Subgroup analysis in women undergoing minimal stimulation IVF or analysis grouped by trigger (hCG trigger or unknown trigger) found similar results to the main analysis.

    Relative effect or mean difference:

    There was no statistically significant difference between groups (OR 1.02, 95% CI 0.85 to 1.23).

    Forest plot from Cochrane Review

    Absolute effect:

    276 per 1000 women (95% CI 241 to 315) with GnRH antagonist compared with 275 per 1000 women with GnRH agonist.

    Reference:
    Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
    • OUTCOME 1.2: Ovarian hyperstimulation syndrome (OHSS) per woman randomized

      Quality of the evidence:

      The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

      Narrative result:

      36 RCTs with 7944 participants found that fewer women receiving GnRH antagonist experienced ovarian hyperstimulation compared with GnRH agonist. Subgroup analysis in women with moderate or severe OHSS found similar result to the main analysis.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of GnRH antagonist (OR 0.61, 95% CI 0.51 to 0.72).

      Forest plot from Cochrane Review

      Absolute effect:

      73 per 1000 women (95% CI 62 to 85) with GnRH antagonist compared with 114 per 1000 women with GnRH agonist.

      Reference:
      Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
      • OUTCOME 1.3: Ongoing pregnancy rate per woman randomized

        Quality of the evidence:

        The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

        Narrative result:

        36 RCTs with 8251 participants found no statistically significant difference between groups. Subgroup analysis in women undergoing minimal stimulation IVF or analysis grouped by trigger (hCG trigger, mixed trigger or unknown trigger) found similar results to the main analysis.

        Relative effect or mean difference:

        There was no statistically significant difference between groups (OR 0.92, 95% CI 0.83 to 1.01).

        Forest plot from Cochrane Review

        Absolute effect:

        276 per 1000 women (95% CI 256 to 295) with GnRH antagonist compared with 293 per 1000 women with GnRH agonist.

        Reference:
        Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
        • OUTCOME 1.4: Clinical pregnancy rate per woman randomized

          Quality of the evidence:

          The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

          Narrative result:

          53 RCTs with 9899 participants found that clinical pregnancy rate was lower among women receiving GnRH antagonist compared with GnRH agonist. Subgroup analysis in women undergoing minimal ovarian stimulation found different results. Click below for full details.

          Relative effect or mean difference:

          There was a statistically significant difference between groups, in favor of GnRH agonist (OR 0.91, 95% CI 0.83 to 1.00).

          Forest plot from Cochrane Review

          Absolute effect:

          283 per 1000 women (95% CI 267 to 303) with GnRH antagonist compared with 303 per 1000 women with GnRH agonist.

          Reference:
          Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
          • Subgroup analysis 1.4.1: Clinical pregnancy rate per woman randomized – [subgroup: minimal stimulation]
            Risk of bias of studies:

            The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 2/6 (33%) of the studies failed to report adequate allocation concealment and random sequence generation processes, none reported adequate blinding of participants/carers/outcome assessors and 2/6 (33%) had high or unclear numbers of withdrawals.

            Narrative result:

            Six RCTs with 1102 participants found that clinical pregnancy rate was higher among women receiving GnRH antagonist compared with GnRH agonist. Minimal ovarian stimulation was not defined.

            Relative effect or mean difference:

            There was a statistically significant difference between groups, in favor of GnRH antagonist (OR 1.50, 95% CI 1.15 to 1.96).

            Forest plot from Cochrane Review

            Absolute effect:

            300 per 1000 women (95% CI 247 to 358) with GnRH antagonist compared with 222 per 1000 women with GnRH agonist.

            Reference:
            Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
        • OUTCOME 1.5: Miscarriage rate per woman randomized

          Quality of the evidence:

          The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

          Narrative result:

          33 RCTs with 7022 participants found no statistically significant difference between groups.

          Relative effect or mean difference:

          There was no statistically significant difference between groups (OR 1.03, 95% CI 0.82 to 1.29).

          Forest plot from Cochrane Review

          Absolute effect:

          49 per 1000 women (95% CI 40 to 61) with GnRH antagonist compared with 48 per 1000 women with GnRH agonist.

          Reference:
          Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
          • OUTCOME 1.6: Cycle cancellation rate per woman randomized

            Narrative result:

            This outcome was reported separately by reason of cancellation: due to high risk of OHSS or due to poor ovarian response. Cycle cancellation rates were higher with GnRH antagonist compared with GnRH agonist when due to poor ovarian response, but rates were lower when due to high risk of OHSS. Click below for full details.

            Reference:
            Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
            • Subgroup analysis 1.6.1: Cycle cancellation rate per woman randomized - [subgroup: Cancellation due to high risk of OHSS]
              Risk of bias of studies:

              The reviewers did not perform a GRADE assessment of the quality of the evidence. In this analysis 8/19 (42%) of the studies failed to report adequate allocation concealment, 18/19 (95%) did not report adequate blinding of participants/carers/outcome assessors and 5/19 (26%) had high or unclear numbers of withdrawals.

              Narrative result:

              19 RCTs with 4256 participants found that cycle cancellation rate per women was lower among women on GnRH antagonist compared with GnRH agonist.

              Relative effect or mean difference:

              There was a statistically significant difference between groups, in favor of GnRH agonist (OR 0.47, 95% CI 0.32 to 0.69).

              Forest plot from Cochrane Review

              Absolute effect:

              9 per 1000 women (95% CI 6 to 13) with GnRH antagonist compared with 19 per 1000 women with GnRH agonist.

              Reference:
              Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]
            • Subgroup analysis 1.6.2: Cycle cancellation rate per woman randomized - [subgroup: Cancellation due to poor ovarian response]
              Quality of the evidence:

              The reviewers performed a GRADE assessment of the quality of evidence for this outcome at this time point and stated that the evidence was moderate quality. See Summary of findings from Cochrane review

              Narrative result:

              24 RCTs with 5170 participants found that cycle cancellation rate per women was higher among women on GnRH antagonist with GnRH agonist.

              Relative effect or mean difference:

              There was a statistically significant difference between groups, in favor of GnRH antagonist (OR 1.32, 95% CI 1.08 to 1.65).

              Forest plot from Cochrane Review

              Absolute effect:

              35 per 1000 women (95% CI 29 to 44) with GnRH antagonist compared with 26 per 1000 women with GnRH agonist.

              Reference:
              Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]

          Additional Information:

          DOI

          10.1002/cca.1314

          Publication Dates

          1. Published Online: 28 SEP 2016

          CCA derived from

          Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750. DOI: 10.1002/14651858.CD001750.pub4. [Review search date: April 2015]

          How to Cite

          How do GnRH antagonists compare with GnRH agonists for improving outcomes in couples undergoing assisted reproductive technology? Sera Tort (MD) and George Salamalekis (MD, MSc, PhD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2016. DOI: 10.1002/cca.1314.

          Further Information

          • CCA Associate editor: Sera Tort (MD), Clinical Editor, Cochrane Editorial Unit, London, UK.
          • CCA Associate editor: George Salamalekis (MD, MSc, PhD), Obstetrician Gynaecologist, National & Kapodistrian University of Athens, Chaidari, Athens, Greece.
          • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.