Stress-associated Epigenetic Alterations in Newborns After Fetal Surgery

NCT04027374 | Completed

• 1 other identifier: BASEC 2019-00598
• Study Type: observational
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Open spina bifida or myelomeningocele (MMC) is a devastating congenital defect of the central nervous system for which there is no cure. The etiology of MMC remains poorly understood. Primary failure of neural tube closure at the caudal neuropore in the embryonic period results in exposure of the developing spinal cord to the uterine environment. Without protective tissue coverage, secondary destruction of the exposed neural tissue by trauma or amniotic fluid may occur throughout gestation. In order to protect the spinal cord from this secondary destruction, a fetal surgical repair can be performed between gestational weeks 20 and 26. From a psychological point of view fetal repair of MMC constitutes a highly stressful event both for the mother and the fetus. To date, however, stress of mothers and children in case of prenatal surgery for MMC repair has never been studied. It is therefore unclear, if and to what extend the procedure and its consequences are associated with stress, and if there are short- or longer-term consequences. The aims of this study are threefold:

1. 1.Do newborns after fetal surgery for MMC show epigenetic alterations in genes that are involved in stress regulation?
2. 2.With which medical and psychosocial variables are epigenetic alterations associated?
3. 3.At age 3 months, do infants after fetal surgery have a more difficult temperament compared to controls?

Conditions

Meningomyelocele

Outcome Measures

Primary Outcomes (1)

• Methylation status at NRC3C1 and the FKBP5 gene

  Saliva DNA will be isolated using prepIT.L2P following manufacturer's protocol (PT-L2P; DNA Genotek Inc.). DNA concentration, A260/A280 and A260/A230 ratios for integrity and quality will be measured using the NanoDrop spectrophotometer (ThermoFisher, Switzerland). DNA methylation specific analysis for each selected gene (NR3C1 and FKBP5) will be conducted using the EpiTect Methyl II PCR assays (Qiagen) following the manufacturer's protocol.

  Day 2 - Day 3

Secondary Outcomes (1)

• Patient Health Questionnaire (PHQ)

  Week 6 and month 3

Other Outcomes (1)

• Infant Behavior Questionnaire (IBQ-Very Short Form)

  Month 3

Study Arms (3)

Fetal surgery group

Newborns after successful fetal surgery for MMC, delivered by elective c-section at weeks 35;0 - 37;0.

Procedure: Fetal surgery for MMC repair

Glucocorticoid control group

Healthy newborns after exposure to synthetic glucocorticoids for lung maturity during pregnancy, delivered by elective c-section between 35;0 - 40;0 weeks, matched for child sex with group 1. This group is needed to control for the effects of sGC exposure.

Healthy controls

Healthy newborns, uncomplicated pregnancy, delivered at term by elective c-section between 36;0 - 39;0 weeks. Matched for child sex with group 1.

Interventions

Fetal surgery for MMC repair PROCEDURE

Fetal surgery for MMC repair

Fetal surgery group

Eligibility Criteria

• Age: 2 Days - 3 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

The study will include newborns after fetal surgery for MMC at the University Hospital Zurich and two control groups. One including healthy newborns and another including newborns after prenatal exposure to synthetic glucocorticoids (sGC) in pregnancy. Each group shall include n=30 newborns (i.e. total number of study participants: n=90). In the following paragraph you can find a detailed description of the groups as well as the inclusion and exclusion criteria for all groups.

You may qualify if:

• Group 1: Newborns after successful fetal surgery for MMC, delivered by ECS (elective c-section) at weeks 350 - 370.
• Group 2: Healthy newborns after exposure to synthetic glucocorticoids for lung maturity during pregnancy, delivered by ECS between 350 - 400 weeks, matched for child sex with group 1. This group is needed to control for the effects of sGC exposure.
• Group 3: Healthy newborns, uncomplicated pregnancy, delivered at term by ECS between 360 - 390 weeks (healthy controls). Matched for child sex with group 1.

You may not qualify if:

• Multiple pregnancies
• Apgar 5 min \<=7, or significant postpartal health problems such as respiratory distress syndrome
• ph\<7.15
• General anaesthesia for ECS
• Insufficient knowledge of German or English by the mother
• Mother exposed to traumatic stress during pregnancy (other than fetal surgery)
• Non-Caucasian origin
• Egg donation

Sponsors & Collaborators

• University Children's Hospital, Zurich: lead
• University of Zurich: collaborator
• Psychiatric University Hospital, Zurich: collaborator

Study Sites (1)

University Children's Hospital Zurich

Zurich, 8032, Switzerland

Location

Biospecimen

Retention: SAMPLES WITH DNA

DNA and RNA sample collection from the child will take place between 24 and 72 hours of life during hospitalization by trained research project staff. In order to obtain DNA and RNA, saliva will be collected using special sponge devices designed for use with infants who cannot spit independently. For DNA, 2x ORAcollect for pediatrics (OC-175; DNA Genotek Inc) will be used to collect saliva in order to obtain enough DNA sample. For RNA, 2x saliva collection devices for pediatrics (CP-190; DNA Genotek Inc) will be used to collect saliva in order to obtain enough RNA sample from the newborns.

MeSH Terms

Conditions

Meningomyelocele

Condition Hierarchy (Ancestors)

Neural Tube Defects; Nervous System Malformations; Nervous System Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Markus A Landolt, PhD

  University Children's Hospital, Zurich

  PRINCIPAL INVESTIGATOR

• Edna Gruenblatt, PhD

  University of Zurich, Department of Child and Adolescent Psychiatry

  PRINCIPAL INVESTIGATOR

• Ueli Moehrlen, MD

  University Children's Hospital, Zurich

  PRINCIPAL INVESTIGATOR

• Tilo Burckhart, MD

  University of Zurich

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2019
• First Posted: July 22, 2019
• Study Start: July 1, 2019
• Primary Completion: April 30, 2023
• Study Completion: August 31, 2023
• Last Updated: November 29, 2023

Record last verified: 2023-11

Locations

CH (1)