UOG Journal Club: February 2016 GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials W. P. Martins, R. A. Ferriani, P. A. Navarro and C. O. Nastri Volume 47, Issue 2, Date: February, Pages 144–151 Journal Club slides prepared by Dr Joel Naftalin (UOG Editor for Trainees)

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Background Assisted reproductive techniques (ART) frequently involve controlled ovarian stimulation (COS) to improve efficacy of the treatment. COS promote development of multiple follicles and, ultimately, formation of multiple embryos. COS can result in very high steroid levels that inhibit pituitary secretion of LH and shorten the luteal phase. This is called premature luteolysis and it is thought to reduce pregnancy rates. Pharmacological support in the form of estradiol, progesterone and hCG are all used to optimize low progesterone levels in this situation. Recently, GnRH agonists have been introduced for luteal-phase support.

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Background GnRH agonists are thought to work by increasing LH production throughout the luteal phase thereby preventing premature luteolysis. It has also been suggested that GnRH agonists might work through a direct effect on embryo development and the endometrium. While there are are a growing number of published studies assessing the efficacy of GnRH agonist during the luteal phase, there is little data reporting safety outcomes.

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Objective To identify, evaluate and summarize the available evidence from randomized controlled trials (RCTs) regarding effectiveness and safety of administering a GnRH agonist during the luteal phase in women undergoing ART

Methods – eligibility criteria GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Methods – eligibility criteria The protocol of this review was registered at the international prospective register of systematic reviews (PROSPERO): CRD42014014895 For study inclusion, the intervention was addition of GnRH agonist during luteal phase compared with standard luteal-phase support and no other relevant difference between intervention and control groups. Parallel group and cross-over RCTs were considered. Pseudorandomized studies or studies randomizing embryos or oocytes rather than women or couples were not included. Studies including women undergoing ART were eligible for inclusion; those on intrauterine insemination or timed intercourse were not included.

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Results

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Results

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Results

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Results

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Conclusion Despite the relatively large number of studies and participants included in the systematic review and meta-analysis, there remain uncertainties about the estimate of the effect and its precision The results of individual studies were inconsistent which translates into substantial heterogeneity and a large confidence interval No data regarding fetal safety was identified The authors believe that further studies are required before this intervention can be included into clinical practice

Strengths Limitations GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Strengths Strict eligibility criteria were adopted with the aim of obtaining a more meaningful conclusion. Despite these stricter criteria, four new RCTs were identified allowing the inclusion of 1251 women Limitations The authors conclude that further studies are needed. Given that a number of studies were awaiting completion, might they have reached a clearer conclusion by performing the analysis at a later date? Should adverse perinatal outcomes and congenital malformations be included as secondary outcomes in the analysis if there was no data about them in any of the trials?

GnRH agonist during luteal phase in women undergoing assisted reproductive techniques: systematic review and meta-analysis of randomized controlled trials Martins et al., UOG 2016 Discussion points Can individual units justify including GnRH agonist in their protocols for luteal-phase support in light of this analysis? How would they do so? Is it ethical to charge patients for treatments of uncertain efficacy? How do we counsel women/couples about the lack of safety data? How much safety data about drugs and treatments do we require before we can consider giving them to fertility/pregnant patients? What would be the best way to ascertain if GnRH agonists were associated with adverse perinatal outcomes and congenital malformations?