Infertility Clinical Trial
Official title:
Clinical Use of the Perifollicular Vascularity Assessment in in-Vitro Fertilization Cycles: a Pilot Study
On February 2004, a law (n. 40/2004) regulating assisted reproduction techniques (ARTs) was
approved in Italy. This law aimed to regulate the treatment of infertility in Italy,
contains several restrictions, such as the prohibition to fertilize more than three oocytes
and the obligation to transfer simultaneously all embryos obtained. Several evidences showed
that the outcome of the in-vitro fertilization (IVF) techniques is strongly correlated with
quality of transferred embryos (choosing the right embryos). Furthermore, this prerequisite
is actually illegal in Italy, and an optimal oocyte selection can be considered as the only
one crucial factor in the determining the outcome of the IVF cycle (choosing the right
oocytes). Experimental data have demonstrated that perifollicular blood flow assessment is a
good marker of oocyte competence, embryo viability, implantation potential, and subsequent
pregnancy rate.
The purpose of this study will be to evaluate in a clinical setting whether the assessment
of the perifollicular vascularity is a feasible and useful procedure for the selection of
oocytes with the best developmental potential in IVF programs when only a limited number of
oocytes can be fertilized.
One hundred fourteen women with tubal factor or unexplained infertility undergoing IVF
programs in our department will be enrolled in a wild protocol. Successively, the enrolled
patients will be divided into two different sub-protocols evaluating the role of the
perifollicular vascularity in good- and poor-prognosis patients. The diagnosis will be
established by hysterosalpingography and/or laparoscopic dye test and with partner’s semen
analysis.
All patients will be randomly allocated in two independent groups (experimental and control
groups) using a computer-software, and the random allocation sequence will be concealed in
closed and dark envelope until the interventions will be assigned.
In the experimental group alone, a power Doppler assessment of perifollicular vascularity
will be performed the day of oocyte retrieval (36 h after hCG injection). The vascularity of
each ovulatory follicle will be successively studied using an advanced image analysis
software and its extension will be graded using a well validated grading system. The
periovulatory follicles will be categorized in high-grade (grades 3-4) and low-grade (grades
1-2).
After patient’ sedation with IV propofol, oocytes will be retrieved using a 17 G
double-lumen aspiration needle with a low pressure and individually cultured marking the
test-tube and, successively, the culture plate with a code corresponding to perifollicular
vascularity degree. The retrieved oocytes will be washed and the mature oocytes, determined
by the presence of a first polar body (metaphase II; MII oocytes), will be classified by an
experienced biologist initially blinded to previous perifollicular vascularization. In
particular, MII oocytes will be graded into three groups according to the number of
anomalies: grade I, oocytes without any anomaly; grade II, oocytes with one anomaly; and
grade III, oocytes with at least two anomalies.
The three oocytes with the highest grade will be considered “the best” oocytes to fertilize
in the control group, whereas in the experimental group they will be selected integrating
morphological and ultrasonographic criteria. In particular, the embryologist will use the
ultrasonographic criteria to choice within oocytes with similar morphologic degree.
In both groups, three MII oocytes will be inseminated at 4 h after recovery with 10000-20000
motile sperm and placed in the CO2 incubator at a temperature of 37°C in 5% CO2 in air, and
the fertilization will be evaluated 18 h later and confirmed by the presence of two
pronuclei and two polar bodies. The fertilized oocytes will be classified with a well
standardized scoring system for zygotes and cultured for a total of 48 h from oocytes IVF.
Before transfer, the cleavage embryos will be again graded according to the embryo
morphology and the relative proportion of anucleate fragments present in the zona pellucida.
All embryos, with exclusion of those arrested (not cleaved after 24 h from IVF), will be
replaced in each patient without ultrasonographic guidance using ultrasoft Frydman catheter.
The luteal phase will be supported by 100 mg natural progesterone daily administrated. A
serum β-hCG assessment will be performed on 15th day after embryos transfer.
For each cycle, the serum estradiol levels and the number of dominant follicles on the day
of hCG administration, the duration of ovarian stimulation, and the units of r-FSH
administered will be recorded. The concordance between the ultrasonographic grading score
and the oocyte degree will be also evaluated in each case.
Cancelled cycles (cases of absence of follicular response after 35 days of treatment or a
serum E2 value >2500 pg/ml), fertilization (percentage of fertilized oocytes / total
oocytes), implantation (percentage of intra-uterine gestational sacs / total transferred
embryos), clinical (percentage of rising β-hCG with sonographic evidence of intrauterine
gestational sac and fetal cardiac activity at 7 weeks of pregnancy / total non-cancelled
cycles) and ongoing (percentage of vital pregnancies confirmed by ultrasonography at 12
weeks of gestational age / total non-cancelled cycles) pregnancies rates will be evaluated
in each patients. The number of multiple pregnancies and ovarian hyperstimulation syndromes
(OHSS) will be also recorded in both groups.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic
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