A Randomized Controlled Trial of Pre-retrieval Triggering Methods in in Vitro Fertilization Patients Classified as Low, Normal or High Responder

Ovarian follicular responsiveness to controlled ovarian hyperstimulation (COH) with gonadotropins is extremely variable between patients and even from cycle to cycle for the same patient. Achieving an ideal follicular response is critical to the success of assisted reproduction treatment (ART). Since the early years of ART, patients have been classified as 'poor', 'normal' or 'high' responders. Although these terms are widely used in research and in daily clinical practice, their precise definitions are not fully agreed upon. Distinguishing them has been based on various measures of ovarian reserve. The first description of a poor responder occurred in 1983, and the first international consensus criteria for poor responders (the Bologna Criteria) was published in 2011. Poor responders, in general, exhibit an inadequate response to hormonal stimulation and diminished reproductive outcome. In contrast to poor responders, high responders are characterized by an exaggerated ovarian responsiveness, accompanied by a higher risk for ovarian hyperstimulation syndrome (OHSS). In most IVF clinics, "normal responders" comprise the majority of their patients. These patients are characterized by an adequate response to gonadotropins stimulation, a relatively low risk for OHSS, and a low cancellation rate. However, even with their relatively good prognosis, it is still important to develop treatments with high efficacy, lower multiple birth rates, and a lower complication rate. In addition, ovum donors are a unique population of patients with special characteristics and challenges. Egg donation has proven to be an effective treatment option for the treatment of various forms of infertility. However, ovum donors are a young population with a significant OHSS risk. Moreover, studies regarding this population provide an ideal opportunity to determine the effects of various triggering regimens on implantation (endometrial effect) from those attributable to the oocyte cohort alone (follicular effect). In an era of evidence-based medicine and with special emphasis on reducing IVF risks (mainly OHSS and pregnancies with multiples, it is very important to find optimal and safe ovulation induction and triggering regimens for each patient population. The use of GnRH agonist (GnRHa) triggering among high responders in order to reduce or eliminate OHSS is an example of an important breakthrough in the clinical management of IVF patients. Although GnRHa triggering was shown to be as effective as human chorionic gonadotropin (hCG) at inducing oocyte maturation more than 20 years ago, its use to trigger ovulation was not possible until the introduction of GnRH antagonists for pituitary suppression. In contrast to hCG triggering, GnRHa triggering is characterized by simultaneous LH and FSH surges, similar to natural ovulation. Early results with GnRHa triggering were disappointing, as reported in several RCT"s, where higher pregnancy loss rates and lower ongoing pregnancy rates were observed. Subsequently, outcomes were dramatically improved after the adoption of adjusted regimens to enhance luteal support. A pivotal study by Engmann et al (2008) included high responder patients during their first IVF cycle and patients with a history of high response in a previous cycle. The authors reported no cases of OHSS in those patients who underwent GnRHa triggering together with intensified estrogen and progesterone supplementation, while maintaining comparable reproductive outcome to those receiving HCG triggering. Moreover, increased safety of GnRHa triggering has been reported among ovum donors in several reports. Another well designed RCT, recruited patients with OHSS risk factors (PCOS as well as oligo/amenorrhea) and further differentiated them on the triggering day into "low" vs. "high" OHSS risk according to their actual ovarian response. These researchers emphasized the fact that pre-stimulation classification as a high responder does not optimally correlate with actual response to hormonal stimulation. Therefore, there is a need to distinguish between a) pre-stimulation assessment based on clinical, laboratory and ultrasonographic parameters (such as previous OHSS, anti-müllerian hormone (AMH) and antral follicle count (AFC), respectively) and b) the actual response evaluated by the number and size of recruited follicles and serum estradiol concentration. Another prominent trend in ART in recent years has been the introduction of dual triggering, which involves a combination of GnRHa plus hCG for triggering. This regimen creates simultaneous LH and FSH surges by the GnRHa, which resembles physiologic ovulation triggering, together with sustained LH-like activity from the hCG, which stimulates the corpus luteum to excrete sufficient hormonal endometrial support. Since its introduction, dual triggering has been gaining popularity due to outstanding results in retrospective studies among both normal and high responders. Griffin et al, 2012 reported that among high responders, their dual-trigger group (GnRHa plus 1,000 IU hCG) had a significantly higher live birth rate (52.9% vs. 30.9%), implantation rate (41.9% vs. 22.1%), and clinical pregnancy rate (58.8% vs. 36.8%) as compared to GnRHa alone, without a higher risk for OHSS. A large retrospective study, which included 376 normal responders patients with 378 completed cycles, resulted in a significantly higher implantation (29.6% vs. 18.4%), clinical pregnancy (50.7% vs. 40.1%), and live-birth (41.3% vs. 30.4%) rates with an hCG (6,500 IU) together with GnRH agonist, as compared to hCG alone. Additionally, dual triggering was found as efficient method to improve final oocyte maturation among patients with a high immature oocyte rate and in patients with a low number of oocytes retrieved per number of pre-ovulatory follicles. To the best of our knowledge, there are no reports on the effect of dual triggering on IVF outcome among poor responders or OHSS occurrence in ovum donors. Moreover, in spite of the encouraging retrospective reports, prospective RCTs on dual triggering have not been reported to date. The aim of the current proposed study is to compare the efficacy of dual triggering and conventional triggering among the three IVF populations (high, normal and poor responders), as well as ovum donors. The current proposal includes three different protocols, which will be implemented in four populations in separate simultaneous RCT's:

1. Dual triggering with 1000 units hCG vs. GnRH agonist alone in high responder IVF patients and in ovum donors.
2. Dual triggering vs. 5000 units hCG in normal responders
3. Dual triggering vs. 10000 units hCG in poor responders