Pregnancy Clinical Trial
Official title:
A Randomized Controlled Trial of Pre-retrieval Triggering Methods in in Vitro Fertilization Patients Classified as Low, Normal or High Responder
Individuals undergoing In Vitro Fertilization must undergo controlled ovarian
hyperstimulation (COH) to produce enough quality eggs for fertility treatment. Ovarian
follicular responsiveness to 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). Patients have been
classified as 'poor', 'normal' or 'high' responders, which dictate the amount of
gonadotropins that they receive. It is still important to develop treatments with high
efficacy, lower multiple birth rates, and a lower complication rate for each of these groups.
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.
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 lutenizing hormone (LH) and follicle stimulating hormone (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.
Moreover, in spite of the encouraging retrospective reports, prospective randomized
controlled trials (RCT) 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).
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
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