Assessing Neurodevelopment in Congenital Heart Disease. (NEUROHEART)

Abnormal Neurodevelopment Detection in Congenital Heart Disease: Predictive Methods Based on Prenatal and Postnatal Factors.

Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in 100 newborns per year. Children with CHD are a known risk population for brain injury, with neurodevelopmental alterations shown over time in up to 50% of cases. No adequate description exists of the type of neurocognitive anomalies or risk factors associated with CHD, and consequently no prognostic markers that may allow identification of high-risk cases are available.

Study Overview

• Status: Unknown
• Conditions: Congenital Heart Disease
• Intervention / Treatment: Procedure: Sonography; Device: Magnetic Resonance Imaging; Other: Bailey Test; Procedure: cord blood sample; Procedure: Surgical intervention; Procedure: Brain monitoring

Detailed Description

The main objectives of this study are: 1. to describe the neurodevelopmental outcome of patients with CHD at 24 months of age; 2. identify the subgroup with poorer outcome; and 3. evaluate the utility of fetal and postnatal diagnostic techniques for early detection of patients at risk for altered neurological outcomes.

Seven Spanish referral centers for CHD included in the research network on maternal and child health currently participating in this prospective multicentric case-control coordinated study. Fetuses with CHD (transposition of great arteries, tetralogy of Fallot, hypoplastic left heart syndrome and septal defects) will be studied from 24 weeks of gestation to 2 years of age. Diagnostic tests will be repeated throughout the study in all patients, from the fetal period to 24 months of age, and will include: fetal cerebral hemodynamic Doppler assessment, functional echocardiography, brain MRI, regional cerebral oxymetry, electroencephalography and serum neurological and cardiac biomarkers analysis. Neurodevelopmental assessment will be made at 12 months of age using the ages and stages questionnaire (ASQ) and at 24 months of age with the Bayley-III test. From this data, statistical analysis will select the most useful as predictors of damage; to be then combined and create algorithms for predicting brain damage and poor neurodevelopment. Once description has been made, we will proceed to identify amongst our results, children with the poorest neurological outcome and remark possible common prenatal and early life markers in them as well as the CHD severity they present.

While advances in early diagnosis and postnatal management have increased survival in CHD children, worrying long-term outcomes, particularly neurodevelopmental disability, have emerged as a key prognostic factor in the counseling of these pregnancies. Evidence available does not allow clinicians to assess on neurological prognosis although has opened up the possibility of finding prenatal markers of brain damage. Even though, no prospective studies have been performed until now. We present a multicentric prospective study able to recruit enough fetal CHD affected pregnancies to obtain neurological prognostic tools.

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Irene Ribera, MD; Phone Number: 3086 934893000; Email: irene.ribera@vhir.org
• Study Contact Backup: Name: Aina Ruiz, MD; Phone Number: 3086 934893000; Email: aruizrom@gmail.com

Study Locations

• Spain
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Irene Ribera, Dr; Phone Number: 3086 934893000; Email: irene.ribera@vhir.org
    • Contact: Elisa Llurba, Dr; Phone Number: 3086 934893000; Email: irene.ribera@vhir.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Single pregnancies
• Major Congenital Heart Disease
• Informed Consent Signed

Exclusion Criteria:

• Major extra-cardiac malformations
• Parental Refusal to participate
• Maternal Chronic Disease
• Multiple Pregnancies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy fetuses; Pregnant patients carrying a healthy fetus. Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging and bailey test.	Procedure: Sonography; Fetal Ultrasound exploration; Device: Magnetic Resonance Imaging; Fetal MRI for brain study; Other: Bailey Test; Neurodevelopment paediatric assessment test performed at 2 years of age.; Procedure: cord blood sample; Cord blood samples will be taken after birth in both groups.
Other: Congenital Hearth Disease; Pregnant patients carrying a fetus with a moderate-severe congenital heart disease Interventions in this group will be: cord blood sample, sonography, Magnetic Resonance Imaging, Surgical intervention, brain monitoring and bailey test.	Procedure: Sonography; Fetal Ultrasound exploration; Device: Magnetic Resonance Imaging; Fetal MRI for brain study; Other: Bailey Test; Neurodevelopment paediatric assessment test performed at 2 years of age.; Procedure: cord blood sample; Cord blood samples will be taken after birth in both groups.; Procedure: Surgical intervention; Congenital Heart Disease repair; Procedure: Brain monitoring; EEG and continuous brain oximetry before surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bailey-III test punctuation	Results in pediatric Bailey-III test scale	45 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biparietal diameter (mm)	Biparietal diameter (mm) measured with MRI	one day
Lateral sulcus depth	Lateral sulcus depth (mm) measured with MRI	one day
Cerebral insula	Insula (mm) measured with MRI	one day
Brain biometries	Calcarine sulcus depth (mm)	one day
Cerebral cingulata sulcus	Cingulata sulcus depth (mm) measured with MRI	one day
Corpus callosum	Corpus callosum (mm) measured with MRI	one day
Cerebellum	Cerebellum vermis (mm) measured with MRI	one day
Umbilical doppler	Umbilical artery pulsatility index	one day
Middle cerebral artery doppler	Middle cerebral artery pulsatility index	one day
Angiogenic PLGF (placental growth factor)	Placental growth factor in maternal serum	Two days
Angiogenic s-FLt (soluble fms-like tyrosine kinase)	Soluble fms-like tyrosine kinase factor in maternal serum	Two days

Collaborators and Investigators

• Sponsor: Hospital Universitari Vall d'Hebron Research Institute
• Collaborators: Hospital General Universitario Gregorio Marañon; Hospital Universitario 12 de Octubre; Institut Universitari Dexeus; Hospital Universitario La Paz; Hospital Sant Joan de Deu
• Investigators: Study Director: Elisa Llurba, MD, PhD, Hospital Universitari Vall d'Hebron

Publications and helpful links

General Publications

• Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900. doi: 10.1016/s0735-1097(02)01886-7.
• Bellinger DC, Jonas RA, Rappaport LA, Wypij D, Wernovsky G, Kuban KC, Barnes PD, Holmes GL, Hickey PR, Strand RD, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med. 1995 Mar 2;332(9):549-55. doi: 10.1056/NEJM199503023320901.
• Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr. 2000 Nov;137(5):638-45. doi: 10.1067/mpd.2000.109152.
• Masoller N, Martinez JM, Gomez O, Bennasar M, Crispi F, Sanz-Cortes M, Egana-Ugrinovic G, Bartrons J, Puerto B, Gratacos E. Evidence of second-trimester changes in head biometry and brain perfusion in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2014 Aug;44(2):182-7. doi: 10.1002/uog.13373. Epub 2014 Jul 8.
• Ruiz A, Cruz-Lemini M, Masoller N, Sanz-Cortes M, Ferrer Q, Ribera I, Martinez JM, Crispi F, Arevalo S, Gomez O, Perez-Hoyos S, Carreras E, Gratacos E, Llurba E. Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease. Ultrasound Obstet Gynecol. 2017 Mar;49(3):379-386. doi: 10.1002/uog.15970.
• Ribera I, Ruiz A, Sanchez O, Eixarch E, Antolin E, Gomez-Montes E, Perez-Cruz M, Cruz-Lemini M, Sanz-Cortes M, Arevalo S, Ferrer Q, Vazquez E, Vega L, Dolader P, Montoliu A, Boix H, Simoes RV, Masoller N, Sanchez-de-Toledo J, Comas M, Bartha JM, Galindo A, Martinez JM, Gomez-Roig L, Crispi F, Gomez O, Carreras E, Cabero L, Gratacos E, Llurba E. Multicenter prospective clinical study to evaluate children short-term neurodevelopmental outcome in congenital heart disease (children NEURO-HEART): study protocol. BMC Pediatr. 2019 Sep 10;19(1):326. doi: 10.1186/s12887-019-1689-y.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Anticipated): May 1, 2017
• Study Completion (Anticipated): May 1, 2018

Study Registration Dates

• First Submitted: October 31, 2016
• First Submitted That Met QC Criteria: December 14, 2016
• First Posted (Estimate): December 19, 2016

Study Record Updates

• Last Update Posted (Estimate): December 19, 2016
• Last Update Submitted That Met QC Criteria: December 14, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: LVOTO; Fallot; Great Arteries Transposition
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital
• Other Study ID Numbers: PR(AMI)317/2012

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO