Download - 14-01-PRBB-FetalProgramming-2.pdf
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Fetal Programming
Impact of prenatal events on the brain and the heart
!Eduard Gratacos
Barcelona Center Maternal-Fetal and Neonatal Medicine
Hospitals Clinic and Sant Joan de Deu - University of Barcelona
www.medicinafetalbarcelona.org
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Guillem was born at Maternitat (Hospital Clnic) with a diagnosis of mild fetal growth restriction. You even offered us to participate in a study of brain MRI.!!Now he is almost 4 and he is suffering:!-Language disorders!-Motor delay!-Maturational delay!-Irritable mood with intolerance to frustration!!Do you think these problems were caused by the problem of fetal growth restriction? Do you think this might cause further problems?!!We remain awaiting your news,
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Neonatal and Fetal GA-adjusted normal weight in the same population
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Brain reorganization Cardiovascular remodellingMetabolic
programming
Fetal growth restriction !(and other disorders associated with disease or abnormal environment)!
Adaptation = Epigenetics = Permanent programming
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Dichorionic Twins. Born 34 weeks!Twin 1: 1950 g (p45)!Twin 2: 1200 g (p1). Normal Doppler
Satchev, 2012!Figueras 2006-2011!Baschat 2009, 2011!
Vohr 2004!Geva 2002-2011
* * *
Bayle
y Sc
ore
20
40
60
80
100
120
cognitive language motor socio-emot adaptivebehavior
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Fetal programming
Brain reorganiza0on (+/- injury)
exposure
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Neurocognitive disorders/Learning disabilities!Overall 10%!
Estimated 2/3 of prenatal origin
Attention Deficit Hyperactivity Disorder!
2-5%
Non-specific disorders!5-8%
Autism Spectrum Disorder!0.5-1%
Fetal growth restriction
Prematurity Exposure Infection
Genetics
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NEW THERAPIES
NEW IMAGING !BIOMARKERS
IMPROVING NEURODEVELOPMENTAL DISORDERS OF FETAL ORIGIN!
NOVEL RESEARCH LINES
IMPROVING DETECTION
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VIRTUAL MULTI-SCALE DISEASE MODELLING!INTEGRATED SYSTEMS-MEDICINE/BIOLOGY APPROACH TO BRAIN REMODELLING
IMAGING BIOMARKERS FOR CLINICAL PRACTICE
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Technology
Medicine
Basic science
Multidisciplinary approach
birth
FETAL MEDICINE
IMAGE
PEDIATRIC SPECIALTIES
NEONATOLOGY LAB
BASIC RESEARCHBIOENGINEERING RESEARCH
NURSERY
NEUROPSYCHOLOGY
Supradisciplinary approach: !combined expertise for a single objective
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MICROSTRUCTURE!METABOLISM
CONNECTIVITY
CORTICAL DEVELOPMENT
EFFECTS OF IUGR ON THE !FETAL BRAIN
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Normal acoustic signature
WMD acoustic signature
Normal WMD
WM
D S
core
Ultrasound texture analysis (feature extraction + machine
learning)
J Ultrasound Med 2011 Fetal Diagn Ther 2012 Am J Obstet Gynecol 2012
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www.medicinafetalbarcelona.org
NAA
Myo Ino
Cho
MRS:MAGNETIC,RESONANCE,SPECTROSCOPY,
NEURO&METABOLOME,PROJECT,
Metabolites and neural function-maturation: -N-acetyl-aspartate (NAA): Neuronal marker. -Choline (Cho): Myelination and cell membrane turnover -Creatine (Cre): Cellular energy -Myo-Inositol (Myo-Ino): Glial marker. Osmoregulation
Sanz 2010
NEURO-METABOLOME PROJECT
Van Vliet, PLoS 2012
MRS validation of best candidates
Experimental and Clinical MR-Spectroscopy
Cell culture and experimental tissue markers
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Neuroimage 2012 PLoS One 2012
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Infants with IUGR show reduced connectivity
Background: Children with aEenFon-decit disorders have impaired corFco-striato-thalamic connecFvity.
Cortico-striato-thalamic right ipsilateral connectivity in infants with with fetal growth restriction.
normal
IUGR
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Brain reorganization Cardiovascular remodellingMetabolic
programming
Fetal growth restriction !(and other disorders associated with disease or abnormal environment)!
Adaptation = Epigenetics = Permanent programming
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1986 Barker (MRC Unit, Southampton, UK): Coronary heart disease mortality rates
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postnatal persistance of cardiovascular
remodeling
Barker BMJ 1986, Barker BMJ 1995 , Hecher CirculaAon 1995, Crispi AJOG 2008, Crispi CirculaAon 2010, Cruz FDT 2011, Crispi AJOG 2012
fetal cardiac dysfunction
cardiovascular disease in adulthood
INTRAUTERINE GROWTH
RESTRICTION hypertension coronary disease
stroke obesity
diabetes
FETAL CARDIOVASCULAR PROGRAMMING
Text
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Crispi CirculaAon 2010
Normal growth IUGR
BP 90/65
cIMT = 0.386 mm
BP 115/80
cIMT = 0.434 mm
IMPACT OF FETAL GROWTH ON CARDIOVASCULAR REMODELLING
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Shorter sarcomere length !Torre 2011, Iruretagoyena 2013
CONTROL FGR
7
7.2
7.4
7.6
7.8
8
8.2
8.4
8.6x 10-7
Sarco
meric
intra
distan
ce of
A-ba
nds
Sarco
mere
length
Sarco
mere
length
B C
CONTROL FGR
7
7.2
7.4
7.6
7.8
8
8.2
8.4
8.6x 10-7
Sarco
meric
intra
distan
ce of
A-ba
nds
Sarco
mere
length
Sarco
mere
length
B C
Fetal growth and molecular/ultrastructural remodelling
Titin isoforms:! N2BA compliant! N2B stiffer
Protein expression and isoforms !Torre 2011, Tintu 2010
Up#regula*on-Down#regula*on-
Gene set analysis (FatiScan)
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control ART
Valenzuela-Alcaraz CirculaAon 2013 Data are median+SEM. *P
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Molecular, gene and computer modeling
Epidemiology + Clin/Gene Prediction Kits + Intervention trials
Experimental models
REVERTING CARDIOVASCULAR REMODELING
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Brain reorganization Cardiovascular remodellingMetabolic
programming
Fetal growth restriction !(and other disorders associated with disease or abnormal environment)!
Adaptation = Epigenetics = Permanent programming
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Fetus Young OldChild Mature
IMPACT OF ENVIRONMENT
BIOLOGIC PROGRAMMING AND AGE
OPPORTUNITY FOR CORRECTION
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Guillem was born at Maternitat (Hospital Clnic) with a diagnosis of mild fetal growth restriction. You even offered us to participate in a study of brain MRI.!!Now he is almost 4 and he is suffering:!-Language disorders!-Motor delay!-Maturational delay!-Irritable mood with intolerance to frustration!!Do you think these problems were caused by the problem of fetal growth restriction? Do you think this might cause further problems?!!We remain awaiting your news,
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Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Brain organiza0on
BIRT
H
IDENTIFICATION OF RISK
INDIVIDUAL BIOMARKERS
INTERVENTION
4P medicine! Predictive! Preventive! Personalized! Participatory
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Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Func0onal / structural organ remodeling
BIRT
HIDENTIFICATION OF RISK
INDIVIDUAL
BIOMARKERS
INTERVENTION
fetal composite CV score for the prediction of postnatal
hypertension
!sensitivity 90%, specificity 77%
% polyunsaturated fats
AGA
IUGRcIMT
Cruz-Lemini FMF 2013, Skilton Pediatric 2012, Rodriguez 2013
4P medicine! Predictive! Preventive! Personalized! Participatory
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Fetal Programming
Impact of prenatal events on the brain and the heart
!Eduard Gratacos
Barcelona Center Maternal-Fetal and Neonatal Medicine
Hospitals Clinic and Sant Joan de Deu - University of Barcelona
www.medicinafetalbarcelona.org