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NIHR Signal Two ways to reduce ovarian overstimulation during fertility treatment compared

Published on 26 July 2016

doi: 10.3310/signal-000273

This Cochrane review finds that the risk of over-stimulating the ovaries with gonadotrophin-releasing hormone (GnRH) antagonists is between 6% and 9% compared to about 11% with GnRH agonists. Both treatments resulted in similar live birth rates of around 29% for women undergoing fertility treatment.

GnRH agonists replace the body’s natural hormone cycle to provide a steady rise in levels of the hormones that trigger egg-release, preventing hormonal surges that may cause the treatment to fail. GnRH antagonists are increasingly being used in the UK but work in a different way. They block the natural hormones at a key point in the treatment cycle to prevent hormone surge.

The findings reinforce 2013 NICE guidelines to choose a GnRH antagonist if the woman is at risk of ovarian hyper-stimulation. Cost-effectiveness was not assessed and this would need to be factored into decision-making if considering their wider use.

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Why was this study needed?

In 2013, nearly 50,000 women in the UK who had difficulties conceiving a baby naturally received “assistive reproductive technology” commonly known as fertility treatment, with 2.2% of all babies born in the UK conceived this way.

Some form of fertility treatment use drugs and artificial hormones to stimulate the woman’s body to produce eggs, which are collected and fertilised externally in the laboratory, then re-implanted into the woman. The two most commonly used forms of fertility treatment are in vitro fertilisation – where the egg is mixed with multiple sperm – and intra-cytoplasmic sperm injection – where a single sperm is injected directly into the egg to fertilise it.

Prior to egg collection, the process has to be carefully managed to ensure that the body’s hormones are perfectly balanced and maximise the chances of success.

Ovarian hyperstimulation syndrome is a potentially serious complication of hormone treatment for infertility. It can cause nausea, vomiting, dehydration and, rarely, death.

This review compared two methods of controlling the action of the hormone gonadotrophin to see which method would result in the largest number of live births and the lowest rate of adverse effects.

What did this study do?

This systematic review identified 73 randomised controlled trials including a total of 12,212 women undergoing fertility treatment. Studies compared the effectiveness of either GnRH agonists or GnRH antagonists. Where possible, studies were pooled in meta-analysis to compare their effects on the rate of live births and the adverse effect of over-stimulating the ovaries.

The included studies for the main outcomes were judged as moderate quality partly because the risk of bias was unclear from the study reports. Some studies had a risk of bias because of the way that patients were allocated to the treatment group.

What did it find?

  • There was no difference in the rate of live births following either GnRH antagonist or GnRH agonists (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85 to 1.23; meta-analysis of 12 studies). The live birth rate was about 29% with a GnRH agonist and 25 to 33% after a GnRH antagonist.
  • GnRH antagonists significantly reduced the risk of ovarian hyperstimulation syndrome compared to GnRH agonists (OR 0.61, 95% CI 0.51 to 0.72; 36 studies), with a rate of about 6-9% with an antagonist compared with 11% with an agonist.
  • Fewer cycles were cancelled due to the risk of ovarian hyperstimulation syndrome in the GnRH antagonist group (OR 0.47, 95% CI 0.32 to 0.69; 19 studies). However, more cycles were also cancelled in this group due to poor ovarian response (OR 1.32, 95% CI 1.06 to 1.65; 25 studies).
  • There was no difference between GnRH antagonist and GnRH agonists in the number of on-going pregnancies (lasting beyond 12 weeks) or the rate of miscarriages.

What does current guidance say on this issue?

NICE 2013 guidelines recommend using a long course of GnRH agonists in women who are at a low risk of ovarian hyperstimulation syndrome. Women with an increased risk should be offered GnRH antagonists.

What are the implications?

This review indicates that GnRH antagonists are just as likely as GnRH agonists to result in live birth, and may be safer in terms of reducing the risk of over-stimulating the ovaries.

This is a large body of evidence, and the findings reinforce NICE recommendations that women at increased risk of ovarian hyperstimulation syndrome should be prescribed antagonists.

This review did not include an economic evaluation, so it is unclear whether there is any difference in the cost-effectiveness of either treatment.

Citation and Funding

Al-Inany HG, Youssef MA, Ayeleke RO,et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016;4:CD001750.

No funding information was provided for this study.

Bibliography

HFEA. Fertility treatment in 2013: trends and figures. London: Human Fertilisation & Embryology Authority; 2014.

HFEA. IVF - What is in vitro fertilisation (IVF) and how does it work? London: Human Fertilisation & Embryology Authority; updated 2014.

HFEA. What is intra-cytoplasmic sperm injection (ICSI) and how does it work? London: Human Fertilisation & Embryology Authority; updated 2015.

NICE. Fertility problems: assessment and treatment. CG156. London: National Institute for Health and Care Excellence; 2013.

RCOG. Ovarian hyperstimulation syndrome: what you need to know. London: Royal College of Obstetricians and Gynaecologists; 2007.

Why was this study needed?

In 2013, nearly 50,000 women in the UK who had difficulties conceiving a baby naturally received “assistive reproductive technology” commonly known as fertility treatment, with 2.2% of all babies born in the UK conceived this way.

Some form of fertility treatment use drugs and artificial hormones to stimulate the woman’s body to produce eggs, which are collected and fertilised externally in the laboratory, then re-implanted into the woman. The two most commonly used forms of fertility treatment are in vitro fertilisation – where the egg is mixed with multiple sperm – and intra-cytoplasmic sperm injection – where a single sperm is injected directly into the egg to fertilise it.

Prior to egg collection, the process has to be carefully managed to ensure that the body’s hormones are perfectly balanced and maximise the chances of success.

Ovarian hyperstimulation syndrome is a potentially serious complication of hormone treatment for infertility. It can cause nausea, vomiting, dehydration and, rarely, death.

This review compared two methods of controlling the action of the hormone gonadotrophin to see which method would result in the largest number of live births and the lowest rate of adverse effects.

What did this study do?

This systematic review identified 73 randomised controlled trials including a total of 12,212 women undergoing fertility treatment. Studies compared the effectiveness of either GnRH agonists or GnRH antagonists. Where possible, studies were pooled in meta-analysis to compare their effects on the rate of live births and the adverse effect of over-stimulating the ovaries.

The included studies for the main outcomes were judged as moderate quality partly because the risk of bias was unclear from the study reports. Some studies had a risk of bias because of the way that patients were allocated to the treatment group.

What did it find?

  • There was no difference in the rate of live births following either GnRH antagonist or GnRH agonists (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85 to 1.23; meta-analysis of 12 studies). The live birth rate was about 29% with a GnRH agonist and 25 to 33% after a GnRH antagonist.
  • GnRH antagonists significantly reduced the risk of ovarian hyperstimulation syndrome compared to GnRH agonists (OR 0.61, 95% CI 0.51 to 0.72; 36 studies), with a rate of about 6-9% with an antagonist compared with 11% with an agonist.
  • Fewer cycles were cancelled due to the risk of ovarian hyperstimulation syndrome in the GnRH antagonist group (OR 0.47, 95% CI 0.32 to 0.69; 19 studies). However, more cycles were also cancelled in this group due to poor ovarian response (OR 1.32, 95% CI 1.06 to 1.65; 25 studies).
  • There was no difference between GnRH antagonist and GnRH agonists in the number of on-going pregnancies (lasting beyond 12 weeks) or the rate of miscarriages.

What does current guidance say on this issue?

NICE 2013 guidelines recommend using a long course of GnRH agonists in women who are at a low risk of ovarian hyperstimulation syndrome. Women with an increased risk should be offered GnRH antagonists.

What are the implications?

This review indicates that GnRH antagonists are just as likely as GnRH agonists to result in live birth, and may be safer in terms of reducing the risk of over-stimulating the ovaries.

This is a large body of evidence, and the findings reinforce NICE recommendations that women at increased risk of ovarian hyperstimulation syndrome should be prescribed antagonists.

This review did not include an economic evaluation, so it is unclear whether there is any difference in the cost-effectiveness of either treatment.

Citation and Funding

Al-Inany HG, Youssef MA, Ayeleke RO,et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2016;4:CD001750.

No funding information was provided for this study.

Bibliography

HFEA. Fertility treatment in 2013: trends and figures. London: Human Fertilisation & Embryology Authority; 2014.

HFEA. IVF - What is in vitro fertilisation (IVF) and how does it work? London: Human Fertilisation & Embryology Authority; updated 2014.

HFEA. What is intra-cytoplasmic sperm injection (ICSI) and how does it work? London: Human Fertilisation & Embryology Authority; updated 2015.

NICE. Fertility problems: assessment and treatment. CG156. London: National Institute for Health and Care Excellence; 2013.

RCOG. Ovarian hyperstimulation syndrome: what you need to know. London: Royal College of Obstetricians and Gynaecologists; 2007.

Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

Published on 29 April 2016

Al-Inany, H. G.,Youssef, M. A.,Ayeleke, R. O.,Brown, J.,Lam, W. S.,Broekmans, F. J.

Cochrane Database Syst Rev Volume 4 , 2016

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 I(2) 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 birthThere was no conclusive 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, I(2)= 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%.OHSSGnRH 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, I(2) = 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 effectsThere was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.04, 95% CI 0.82 to 1.30; 33 RCTs, n = 7022, I(2) = 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, I(2) = 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, I(2) = 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.

When the ovaries are stimulated to produce eggs for collection, there is a risk of a surge of lutenising hormone that results in the egg being released before it was the optimal size and prevents the collection of multiple eggs, meaning that the assistive reproductive technology cycle fails.

This lutenising hormone surge can be controlled using artificial gonadotrophin-releasing hormone (GnRH) agonists which occupy the receptors of natural gonadatrophin and lead to a more controlled rate of hormone rise throughout the process. However, GnRH agonists have been associated with ovarian hyperstimulation syndrome which can be dangerous as it leads to fluid build-up in the abdomen and can lead to blood clots.

GnRH antagonists may avoid this complication, by blocking the natural gonadotrophin at a key point in the process where there is an increased risk of lutenising hormone surge.

Expert commentary

GnRH antagonist control for in vitro fertilisation provides the opportunity for clinicians to provide efficacious but substantially safer treatment with a reduced risk of ovarian hyperstimulation syndrome. This review which includes 73 randomised controlled trials and 12,212 participants found that the use of GnRH antagonists as compared to GnRH agonists was associated with a marked reduction in ovarian hyperstimulation syndrome (OR 0.61, 95% C 0.51 to 0.72) while live birth rates were unaffected. The widespread adoption of GnRH antagonist control based on these findings has contributed to a reduction in maternal morbidity and has also enabled clinicians to explore alternative ways of triggering oocyte maturation to further improve in vitro fertilisation outcomes.

Professor Scott M Nelson, Muirhead Chair in Obstetrics & Gynaecology, University of Glasgow