Comparison between start of ovarian stimulation on cycle day 2 versus cycle day 5 with GnRH antagonist in IVF treatment: a randomized controlled trial.

Introduction: Conventional GnRH agonist ovarian stimulation protocols in
in-vitro fertilisation (IVF) aim for the development of multiple embryos to improve
selection for transfer. The introduction of GnRH antagonists has provided
the opportunity for milder stimulation protocols. These protocols aim for limited
dominant follicle selection by widening the natural FSH window through
administering exogenous FSH in the mid- to late follicular phase. Milder stimulation
protocols have the advantage of being less expensive and more patientfriendly.
Although with mild stimulation protocols the expected number of oocytes
retrieved will be lower, pregnancy rates have shown to be similar possibly
because embryo quality out favours embryo quantity. The purpose of this study
was to compare the clinical applicability of a mild stimulation (start stimulation
at cycle day 5)/fixed GnRH antagonist protocol with a regular (start stimulation
at cycle day 2)/GnRH antagonist protocol in terms of embryo quality.
Material and Methods: This trial was a bi-center, prospective, randomized
controlled clinical trial conducted between October 2008 and September 2010.
Women aged 18-39 years with a body mass index of 18-29 kg/m2, a menstrual
cycle length of 25-35 days, no major uterine or ovarian abnormalities, normal
FSH serum levels on cycle day 2 (>12 U/L), and undergoing the first IVF or
ICSI treatment cycle were eligible to enrol in the study. Randomization to one
of the two treatment groups (start of rFSH at cycle day 2 (CD 2) or cycle day
5 (CD 5)) was performed according to a computer-generated randomization
schedule, assigned via numbered sealed envelopes. All patients started with
150 IU of recFSH on CD 2 or CD 5 depending on the arm they were randomized
for. This dose of recFSH was fixed for the whole stimulation period. To
prevent premature LH surges, both treatment arms started with a daily injection
of GnRH antagonist on cycle day 6 up to and including the day of bolus hCG. A
single embryo was transferred at day 3 or 5 after oocyte retrieval.
Results: A total of 147 patients signed informed consent for eligibility evaluation
and participation in this trial. Finally, a total of 129 patients started stimulation
in to one of the two treatment groups. At last, 97 patients completed
the treatment and underwent a single embryo transfer. Demographics of the
intention-to-treat population as well as relevant fertility characteristics, and
ultrasound findings were comparable in the two groups.
The total cancellation per started cycle in the CD2 group was 13.8% (9
of 65 patients) and 34.9% (22 of 63 patients) in the CD5 group (p = 0.21).
There was a higher cancellation due to monofollicular growth in the CD5 group
(9.5%) compared to the CD2 group (1.5%) (p = 0.17). Cancellation because
of hyperresponse was the same in the CD2 group and the CD5 group (1.5%)
(p = 0.17). The percentage of patients without an ET due to total fertilization
failure or no good quality embryo to transfer in the CD2 group and the CD5
group was 4.6% versus 1.6%, respectively (p = 0.08).
The proportion of morphological top embryos, was 51.1% in the CD2 group
and 41.2% in the CD5 group (p = 0.15). The ongoing pregnancy rate per started
cycle was 28% in the CD2 group and 16% in the CD5 group (p = 0.096).
Conclusions: The late start of ovarian stimulation by rFSH in an antagonist
cycle seems not to be more effective in creating a mild response with high
quality embryo's, compared to early, standard start of the rFSH and may even
produce poorer outcomes in terms of ongoing pregnancies. Further studies
should focus on individualised dosing based on ovarian response testing prior
to initiating stimulation with rFSH.