GnRH agonist for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles: Systematic review and meta-analysis

In the last decade, GnRH antagonist has been introduced to the market to be used for pituitary desensitization in IVF/ICSI treatment cycles. GnRH antagonist shown to be an effective alternative to the standard long GnRH agonist protocols [1] . There is an ongoing debate over the optimal agent that can trigger final oocyte maturation in GnRH antagonist, leading to higher IVF success rate without increasing the risk of ovarian hyperstimulation syndrome (OHSS). Due to the specific mode of action of GnRH antagonist, quick and reversible response, GnRH agonist as a mid-cycle bolus dose varying from 0.1 up to 0.5 and HCG administration could be used to induce final oocyte maturation triggering. GnRH agonist induces endogenous LH and FSH surges which might simulate the natural mid-cycle LH surge. The serum LH and FSH levels rise after 4 and 12 h, respectively, and are elevated for 24–36 h. The amplitude of the surges is similar to those seen in the normal menstrual cycle but, in contrast to the natural cycle, the LH surge consists of two phases. These are a short ascending limb (>4 h) and a long descending limb (>20 h). Thus, final oocyte maturation trigger with GnRH agonist results in corpus luteum deficiency and a defective luteal phase (Segal and Casper, 1992) and is associated with very low ongoing pregnancy rate [2] . For this reason, several schemes of luteal support have been used to increase the chance of pregnancy [3–5] , although there is no agreement yet regarding which is the optimal one. Human chorionic gonadotropin (hCG), in addition to its well-known endocrine effect on the corpus luteum, it is the traditional final oocyte maturation trigger in GnRH agonist co-treated cycles for more than 3 decades [1] . Some studies have suggested a negative impact of HCG on endometrial [6–8] and embryo quality [9,10] . In addition, the sustained luteotrophic effect of HCG is associated with increased chances of ovarian hyperstimulation syndrome (OHSS) [11] . OHSS in its moderate and severe forms can cause significant morbidity and can be fatal in its critical stage. The incidence of severe OHSS is low and in the range of 0.5–2% of all IVF cycles [12] . Currently, there is no agreement on the optimal agent for inducing final oocyte maturation triggering in GnRH antagonist co-treated cycles yet. The purpose of our review was to evaluate and determine the efficacy and safety of both triggers in GnRH antagonist co-treated IVF/ICSI cycles.

The following electronic databases were searched: MEDLINE, EMBASE, Science Direct, Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science. National Research Register (NRR) a register of ongoing trials and the Medical Research Council’s Clinical Trials Register a search strategy were carried out based on the following terms: GnRH antagonist, final oocyte maturation triggering, HCG, GnRH agonist, AND ovarian hyperstimulation syndrome chorionic “or “OHSS “AND” IVF/ICSI/ART AND “randomized controlled trial(s)” OR “randomized controlled trial(s)”. Furthermore, we examined the reference lists of all known primary studies, review articles, citation lists of relevant publications, abstracts of major scientific meetings (e.g. ESHRE and ASRM) and included studies to identify additional relevant citations. Finally, the review authors sought ongoing and unpublished trials by contacting experts in the field. In addition, references from all identified articles were checked, and a hand search of the abstracts from the annual meetings of the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology was performed. If necessary, additional information was sought from the authors. The search was not restricted by language. The searches were conducted independently by M.Y, M.H and M. van W. Studies were selected if the target population was infertile couples undergoing GnRH antagonist co-treated – IVF/ICSI treatment cycles. The therapeutic interventions were GnRH agonist or HCG for final oocyte maturation triggering. Studies had to be of randomized design. The primary outcome measure of interest was ongoing pregnancy rate per randomized woman. Studies were selected in a two-stage process. First, the titles and abstracts from the electronic searches were scrutinized by two reviewers independently (M.Y and H.A) and full manuscripts of all citations that were likely to meet the predefined selection criteria were obtained. Secondly, final inclusion or exclusion decisions were made on examination of the full manuscripts. The selected studies were assessed for methodological quality by using the components of study design that are related to internal validity (Juni et al., 2001). Information on the adequacy of randomization, concealment and blinding was extracted. When needed the reviewers wrote the authors and tried to get hold of extra information and the raw data. From each study, outcome data were extracted in 2 × 2 tables. The outcomes we planned to assess in our analysis were ongoing pregnancy rate and OHSS incidence and number of retrieved follicles were calculated based on the number of patients randomized in all studies even if some patients were excluded or dropped out after randomization. Dichotomous outcomes were expressed as an odds ratio (OR) with 95% CI using a fixed effects model. Continuous outcomes were expressed as a mean difference (MD) with 95% CI. All statistical analyses were performed using RevMan 5.0 (Cochrane Collaboration, Oxford, UK).

The search strategy yielded 101 publications related to the topic. 82 publications were excluded as they did not fulfil the selection criteria ( Fig. 1 ). Our review and meta-analysis included all randomized controlled studies that evaluated final oocyte maturation triggering in GnRH antagonist co-treated cycles. 15 randomized controlled studies ( n  = 2259) evaluated GnRH agonist trigger in GnRH antagonist co-treated cycles ( Table 1 ). 15 studies compared HCG with GnRH agonists, 11 RCTs in fresh autologous cycles and 4 RCTs in donor recipient cycles [4,5,13–21,3,22–24] . One study evaluated the lower effective dose of HCG and 3 studies evaluated the effect of delaying or advancement of HCG administration and one study compared u HCG with rec HCG. Nine studies were randomized controlled single-centre studies [3,4,13,14,17,19,22–24] . Four studies were two-centre studies [15,18,20, and 21] . One study was a three-centre study [5] and one study was a six-centre study [16] . Ten studies performed a sample size calculation of the number of patients needed to achieve the primary outcome [4,5,15,18,20,14,17,21,22,24] . There was no sample size calculation in three studies [13,16,3] ; in two studies it was unknown [19,23] . Two studies failed to achieve the intended sample size [18,20] . Only three studies performed blinding for the assessors [22–24] . Two studies reported blinding unclearly [15,3] . Other studies reported no blinding. However, blinding of assessors would seem irrelevant given the objectivity of the outcomes. Therefore, all studies were at high risk of bias in regard to blinding. All included studies are published in peer reviewed journals as a full text. Although, there was heterogeneity between the most of the included studies as regards the inclusion and exclusion criteria, primary outcomes and luteal phase support and most of them were properly randomized using computer generated list (see Fig. 2 ). • Ongoing pregnancy rate: There was a statistically significant difference against the GnRH agonist with an OPR in fresh autologous cycles ( n  = 1024) of, OR: 0.69; 95% CI: 0.52–0.93. In oocyte-donor cycles ( n  = 342) there was no evidence of a difference (OR: 0.91; 95% CI: 0.59–1.40). • Ovarian hyperstimulation incidence (OHSS): There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous (OR: 0.06; 95% CI: 0.01–0.33 and donor cycles respectively (OR: 0.06; 95% CI: 0.01–0.27). Ongoing pregnancy rate: There was a statistically significant difference against the GnRH agonist with an OPR in fresh autologous cycles ( n  = 1024) of, OR: 0.69; 95% CI: 0.52–0.93. In oocyte-donor cycles ( n  = 342) there was no evidence of a difference (OR: 0.91; 95% CI: 0.59–1.40). Ovarian hyperstimulation incidence (OHSS): There was a statistically significant difference in favour of GnRH agonist regarding the incidence of OHSS in fresh autologous (OR: 0.06; 95% CI: 0.01–0.33 and donor cycles respectively (OR: 0.06; 95% CI: 0.01–0.27).

The authors have declared no conflict of interest .

This article does not contain any studies with human or animal subjects.

Our review has shown that HCG administration seems to be more effective trigger for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI treatment cycles than GnRH agonist. This is evidenced by the higher ongoing pregnancy rate we found in the HCG group (15 RCTs, OR: 0.75, 9R% CI: 0.59–0.96). Conversely, GnRH agonists seem to be safer than traditional HCG due to the associated low risk of OHSS (10 RCTs, OR: 0.06, 9R% CI: 0.02–0.19). However, the majority of studies evaluated GnRH agonist was conducted in normo-responder’s patients with normal risk to develop OHSS. Some investigators suggest that by administrating GnRH agonists rather than HCG, for final oocyte maturation triggering, the risk of OHSS is reduced without compromising pregnancy rates [19–21,3] . Surprisingly, out of 15 studies who evaluated GnRH agonist as a trigger, only 2 small RCTs evaluated agonists in women with PCOS at high risk to develop OHSS, meanwhile other studies included normo-responders women at a normal risk for OHSS. First study shown a nonsignificant reduction in the incidence of OHSS as the number of participants was too small and the primary outcome was inhibin A levels on the day of embryo transfer [14] . Second study, included only 66 infertile PCOS women, the incidence of OHSS was significantly reduced with comparable implantation rates, however, the study was not powered to evaluate pregnancy rate [16] . Marked luteolysis and luteal phase defect have been suggested to be the explanation of the associated lower pregnancy rate. Although, many luteal phase support modifications have been tried, in order to be as efficient trigger as HCG, such as co-administration of low dose of HCG (1500 IU) [25] or multiple doses of GnRH agonist in the luteal phase [24] or multiple injections of rec LH [23] and intense luteal phase support with high doses of progesterone plus estradiol patches [16] to overcome the insufficiency of luteal phase in GnRH agonist group, the pregnancy rate was not improved [2] . Recently, it has been suggested that GnRH agonist trigger with cryopreservation followed by later embryos transfer is more safe and effective [26] . This strategy is supported by the recently published study showing that the clinical pregnancy rate was significantly greater in the cryopreservation group than the fresh transfer group which is attributed to be due to superior endometrial receptivity in the cryopreservation group than the fresh group. These results strongly suggest impaired endometrial receptivity in fresh ET cycles after ovarian stimulation, when compared with FET cycles with artificial endometrial preparation. Impaired endometrial receptivity apparently accounted for most implantation failures in the fresh group [26] . The strengths of this review include comprehensive systematic searching for eligible studies, rigid inclusion criteria for RCTs, and data extraction and analysis by two independent investigators. Furthermore, the possibility of publication bias was minimized by including both published and unpublished studies. However, as with any review, we cannot guarantee that we found all eligible studies.

The evidence suggests that GnRH agonists as a final oocyte maturation trigger in fresh autologous cycles should not be used routinely due to its association with a significantly lower live birth rate, lower ongoing pregnancy rate and higher rate of early miscarriage. The only indication for GnRH agonist use as oocyte maturation trigger is in women who donate oocytes to recipients or in women who wish to freeze their eggs for later use in the context of fertility preservation.