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Stress-associated Epigenetic Alterations in Newborns After Fetal Surgery

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ClinicalTrials.gov Identifier: NCT04027374
Recruitment Status : Recruiting
First Posted : July 22, 2019
Last Update Posted : July 23, 2019
Sponsor:
Collaborators:
University of Zurich
Psychiatric University Hospital, Zurich
Information provided by (Responsible Party):
University Children's Hospital, Zurich

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

Condition or disease Intervention/treatment
Meningomyelocele Procedure: Fetal surgery for MMC repair

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Study Type : Observational
Estimated Enrollment : 90 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Epigenetic Alterations in Stress Regulation Genes Among Newborns After Fetal Surgery for Myelomeningocele Repair: An Exploratory Study
Actual Study Start Date : July 1, 2019
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : October 31, 2021

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
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
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.



Primary Outcome Measures :
  1. Methylation status at NRC3C1 and the FKBP5 gene [ Time Frame: Day 2 - Day 3 ]

    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.



Secondary Outcome Measures :
  1. Patient Health Questionnaire (PHQ) [ Time Frame: Week 6 and month 3 ]
    Maternal and paternal mental health will be assessed by the Patient Health Questionnaire (PHQ) bei Spitzer et al., 1999. The questionnaire consists of 9 items with a Likert Scale from 0-3. The sum score (range 0-27) will be used. Higher scores represent more mental health problems.


Other Outcome Measures:
  1. Infant Behavior Questionnaire (IBQ-Very Short Form) [ Time Frame: Month 3 ]
    Child temperament will be assessed by the mother-rated Infant Behavior Questionnaire (Rothbart, 2000). We will use the Very Short Form (IBQ-Very Short Form) that consists of 36 items with a Likert scale from 1-7. The 36 items can be assigned to three scales: surgency, negative affect, and effortful control. Scale scores will be computed according to the manual.


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.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 3 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
Criteria

Inclusion Criteria:

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.

Exclusion Criteria for all 3 groups:

  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04027374


Contacts
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Contact: Markus A Landolt, PhD +41442667396 markus.landolt@kispi.uzh.ch
Contact: Ueli Möhrlen, MD +41442667111 ueli.moehrlen@kispi.uzh.ch

Locations
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Switzerland
University Children's Hospital Zurich Recruiting
Zürich, Switzerland, 8032
Contact: Markus A Landolt, PhD    +41442667396    markus.landolt@kispi.uzh.ch   
Contact: Ueli Möhrlen, MD    +41442667111    ueli.moehrlen@kispi.uzh.ch   
Sponsors and Collaborators
University Children's Hospital, Zurich
University of Zurich
Psychiatric University Hospital, Zurich
Investigators
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Principal Investigator: 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
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Responsible Party: University Children's Hospital, Zurich
ClinicalTrials.gov Identifier: NCT04027374    
Other Study ID Numbers: BASEC 2019-00598
First Posted: July 22, 2019    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Meningomyelocele
Spina Bifida Cystica
Neural Tube Defects
Nervous System Malformations
Nervous System Diseases
Congenital Abnormalities
Spinal Dysraphism