In Vitro Fertilization Clinical Trial
Official title:
The Impact of the Heterogeneity of the Recruited Cohort of Follicles During Ovarian Hyperstimulation for IVF on Aneuploidy Rates of Generated Embryos.
Background:
By limiting the number of embryos transferred to the uterus to only a single embryo, the
risk of multiple gestation can be reduced. In order to improve the effectiveness of single
embryo transfer, the ability to select the embryo with the highest potential to develop into
a healthy child is of vital importance. While embryos rated as high quality by standardized
morphological assessment are associated with higher implantation and pregnancy rates, it is
still not possible to predict with certainty which embryo will implant and has the highest
potential to develop into a healthy child. An increasing body of evidence indicates that the
incidence of chromosomal abnormalities in embryos is extremely high and good embryo
morphology does not necessarily exclude an abnormal chromosomal constitution. Since
aneuploidies are considered the main cause of embryonic wastage and loss, this phenomenon
may be primarily responsible for the relatively poor pregnancy rates reported after IVF.
The introduction of fluorescent in-situ hybridization (FISH) techniques for preimplantation
genetic diagnosis has enabled screening of embryos for chromosomal aneuploidies before
transfer. Preimplantation genetic screening (PGS) would be of special interest for couples
that are thought to have a higher risk of developing chromosomally abnormal embryos, with
the aim of improving their chances for an ongoing pregnancy after IVF. PGS is applied
clinically in numerous IVF laboratories throughout the world, and high rates of chromosomal
abnormalities have been reported in IVF derived embryos. However, a recent meta-analysis has
shown that PGS is yet to have a significant impact on IVF outcomes. This may partly be
explained by the fact that most aneuploidies observed at this stage originate during the
first mitotic divisions of early preimplantation development, resulting in chromosomally
mosaic embryos. If a chromosomally mosaic embryo is biopsied, this cell may not be
representative for the remaining embryo.
The investigators' group recently completed the first prospectively designed, randomized
trial, comparing embryo aneuploidy rates following two ovarian hyperstimulation regimes in a
group of 111 IVF patients. Milder stimulation was associated with a reduction in the number
of oocytes retrieved and embryos generated. However, the proportion of chromosomally normal
embryos was significantly increased. These results showed for the first time a direct
correlation between the ovarian stimulation protocol and the incidence of chromosome
abnormalities in the embryo. The observation that mild stimulation in some patients still
resulted in a high oocyte yield and concurring higher proportions of abnormal embryos,
underscores the need for further development of minimal stimulation approaches.
Primary Objective:
To determine whether the administration of hCG during the late follicular phase, instead of
continuing with a fixed dose FSH, results in a more homogeneous cohort of growing follicles
and the development of only the most competent oocytes, leading to lower aneuploidy rates in
resulting embryos.
Study design:
Prospectively randomized, clinical study in 110 women undergoing IVF treatment
Intervention:
Randomization to one of two ovarian stimulation protocols:
1. Conventional regimen with a daily dose of 225 IU recombinant FSH and GnRH agonist long
protocol co-treatment
2. Mild ovarian stimulation regimen using the endogenous FSH production by starting
treatment on day 5 of the menstrual cycle with 150 IU / d recFSH with GnRH antagonist
co treatment starting on day 6. As soon as two follicles reach 12 mm, treatment is
continued with 200 IU / d rec hCG.
In both arms, oocyte pick up, insemination and embryo culture will be performed according to
standard procedures. On day 3, all suitable embryos will be biopsied and one or two
blastomeres removed, depending on the number of cells within the embryo.
FISH analysis will be performed for 10 chromosomes (1, 7, 13, 15, 16, 18, 21, 22, X and Y).
Only chromosomally normal embryos will be transferred and cryopreserved. Embryos diagnosed
as aneuploid or mosaic will be investigated for their implantation and developmental
potential, by transferring them to an in vitro implantation model. After an extended culture
period, implantation behaviour will be assessed and the entire embryo is reanalysed to
detect the proportion of chromosomally abnormal cells. The implantation behaviour will be
correlated to the type of abnormality and the chromosome(s) involved.
Primary outcome parameters:
Ovarian response, as assessed by the number of oocytes obtained and the proportion of
chromosomally abnormal embryos per patient.
Secondary outcome parameters:
Number of oocytes retrieved, fertilization rates and proportion of morphologically high
quality embryos on day 3.
Serum estradiol, LH, progesterone, androgen and hCG levels on cycle day 3 and day of hCG.
Status | Terminated |
Enrollment | 34 |
Est. completion date | January 2011 |
Est. primary completion date | January 2011 |
Accepts healthy volunteers | Accepts Healthy Volunteers |
Gender | Female |
Age group | 18 Years to 37 Years |
Eligibility |
Inclusion Criteria: - Female age = 37 years - BMI 18-29 kg/m2 - Regular cycle (25-35 days) - Standard indication for IVF - No major uterine abnormalities - Written informed consent Exclusion Criteria: - Indication for IVF male factor with a total motile sperm count < 20x106 - ICSI or andrological indication - Known abnormal (male or female) karyotype - Oocyte donation - One previous IVF treatment not resulting in embryo transfer - History of recurrent abortion - Medical contra indication for pregnancy or IVF treatment - Relevant systemic disease - Active substance abuse |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Netherlands | University Medical Center Utrecht | Utrecht |
Lead Sponsor | Collaborator |
---|---|
Bart CJM Fauser |
Netherlands,
Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, Macklon NS, Fauser BC. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007 Apr;22(4):980-8. Epub 2007 Jan 4. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Proportion of chromosomally abnormal and mosaic day 3 embryos per patient based on PGS analysis. | 2 years | No | |
Secondary | Number of oocytes retrieved. | 2 years | No |
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