A Study of the Effects of a Novel Ovarian Stimulation Regimen on Embryo Aneuploidy Rates in In Vitro Fertilization (IVF)

NCT00866008 | Terminated Phase 4

• 3 other identifiers: MOSTrialCCMO: NL18499.000.07(a)METC: 07/172
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

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. 1.Conventional regimen with a daily dose of 225 IU recombinant FSH and GnRH agonist long protocol co-treatment
2. 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.

Conditions

In Vitro Fertilization

Keywords

IVF; In vitro implantation; Preimplantation genetic screening; Aneuploidy

Outcome Measures

Primary Outcomes (1)

• Proportion of chromosomally abnormal and mosaic day 3 embryos per patient based on PGS analysis.

  2 years

Secondary Outcomes (1)

• Number of oocytes retrieved.

  2 years

Study Arms (2)

1

EXPERIMENTAL

Conventional regimen with a daily dose of 225 IU recombinant FSH and GnRH agonist long protocol co-treatment.

Drug: Ovarian stimulation

2

EXPERIMENTAL

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.

Drug: Ovarian stimulation

Interventions

Ovarian stimulation DRUG

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.

Also known as: Follitropine (Puregon), Ganirelix (Orgalutran), Triptoreline (Decapeptyl)

1; 2

Eligibility Criteria

• Age: 18 Years - 37 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Bart CJM Fauser: lead

Study Sites (1)

University Medical Center Utrecht

Utrecht, Utrecht, Netherlands

Location

Related Publications (1)

• 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. doi: 10.1093/humrep/del484. Epub 2007 Jan 4.

  PMID: 17204525 BACKGROUND

MeSH Terms

Conditions

Aneuploidy

Interventions

Ovulation Induction; follitropin beta; ganirelix; Triptorelin Pamoate

Condition Hierarchy (Ancestors)

Chromosome Aberrations; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Reproductive Techniques, Assisted; Reproductive Techniques; Therapeutics; Investigative Techniques; Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins

Study Officials

• Nick S Macklon, Prof, PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: March 19, 2009
• First Posted: March 20, 2009
• Study Start: October 1, 2008
• Primary Completion: January 1, 2011
• Study Completion: January 1, 2011
• Last Updated: July 22, 2013

Record last verified: 2013-07

Locations

NL (1)