Genomic Imprinting and Assisted Reproductive Technologies (EPIGEN)

Assessment of the Risk of Imprinting Defects in Children Born Following Assisted Reproductive Technologies (ART)

Genomic imprinting, referring to an epigenetic marking resulting in monoallelic gene expression, plays a critical role in development. Recently, various imprinting diseases were reported in animals (Large Offspring syndrome (LOS)) and humans (Beckwith-Wiedemann syndrome (BWS) and Angelman syndrome (AS)) born after ART. In all cases, an imprinting defect was involved (loss of methylation at ICR2 in BWS, at SNRPN in AS and at IGF2R DMR2 in LOS). These data suggest that ART procedures may impair the establishment or the maintenance (following fertilization) of methylation marks at maternally imprinted loci. In view of these data, the aim of this study is to determine if children born following ART exhibit an increased risk of imprinting defects. If the answer is yes, the second objective is to identify the problematic step in the ART procedure and thus to suppress or modify this step.

Study Overview

• Status: Completed
• Conditions: Pregnancy, Ovarian; Natural Pregnancy

Detailed Description

Methodology: assessment of the methylation status at 9 different imprinted loci (using Southern blot and methyl-specific quantitative PCR) in 3 groups of patients: 150 children naturally conceived, 150 children conceived after ovarian stimulation but with in vivo fertilization, and 150 children conceived after ovarian stimulation and in VITRO fertilization. These analyses will be performed on cord blood. Fragments of placental tissue will also be collected for further analyses. Patients will be selected in maternity hospitals associated with ART departments ( ANTOINE BECLERE HOSPITAL, Cochin HOSPITAL, Saint-Vincent de Paul HOSPITAL, Jean VERDIER HOSPITAL, Tenon HOSPITAL and Dijon Hospital).

This work is also a unique opportunity to establish a DNA, RNA and tissue collection allowing further investigation regarding other epigenetic modifications than DNA methylation, not only at imprinted loci, but also in other genomic regions regulated by epigenetic modifications.

• Study Type: Observational
• Enrollment (Actual): 542

Contacts and Locations

Study Locations

• France
  • Paris, France, 75012
    • Trousseau Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 26 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Women followed in a participating ART departments

Description

Inclusion Criteria:

Mother :

• Age: 26 to 40 at conception
• Single foetus pregnancy
• Signed informed consent
• Affiliation to French health benefits
• Absence of maternal pathology
• Normal foetal karyotype (if available)
• Known procedure of ovarian stimulation
• ART procedure without sperm or oocyte donation
• ART in a participating ART departments
• Delivery in a participating hospital

Father

• Age : 18 to 50 at conception
• Signed informed consent

Exclusion Criteria:

• Abnormal foetal karyotype (if available)
• Delivery before 35 weeks of amenorrhea
• Delivery in not participating hospital
• Delivery complication leading to the absence of sample collection

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
1; Pregnancy after ICSI or IVF
2; Pregnancy after ovarian stimulation
3; natural pregnancy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Assessment of the methylation status at 9 imprinted loci in cord blood collected just after birth.	At the birth

Secondary Outcome Measures

Outcome Measure	Time Frame
Assessment of other epigenetic marks (histone modifications) at imprinted loci and at non imprinted but epigenetically regulated loci.	At the birth

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Yves Le BOUC, PUPH, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• Gicquel C, El-Osta A, Le Bouc Y. Epigenetic regulation and fetal programming. Best Pract Res Clin Endocrinol Metab. 2008 Feb;22(1):1-16. doi: 10.1016/j.beem.2007.07.009.
• Rossignol S, Steunou V, Chalas C, Kerjean A, Rigolet M, Viegas-Pequignot E, Jouannet P, Le Bouc Y, Gicquel C. The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J Med Genet. 2006 Dec;43(12):902-7. doi: 10.1136/jmg.2006.042135. Epub 2006 Jul 6.
• Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y. In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am J Hum Genet. 2003 May;72(5):1338-41. doi: 10.1086/374824. No abstract available.
• Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H, Audry G, Vazquez MP, Gicquel C. Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2001 Jun;9(6):409-18. doi: 10.1038/sj.ejhg.5200649.

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: October 15, 2008
• First Submitted That Met QC Criteria: October 15, 2008
• First Posted (Estimate): October 16, 2008

Study Record Updates

• Last Update Posted (Estimate): June 18, 2015
• Last Update Submitted That Met QC Criteria: June 17, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Angelman syndrome; Reproductive techniques, assisted; Genomic imprinting; Beckwith-Wiedemann syndrome
• Additional Relevant MeSH Terms: Pregnancy Complications; Pregnancy, Ectopic; Pregnancy, Ovarian
• Other Study ID Numbers: P040440