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Programación fetal Evidencias actuales y papel de la “nutrición” fetal
!Eduard Gratacos
BCNatal – Centre de Medicina Maternofetal i Neonatologia de Barcelona!Hospital Sant Joan de Déu i Hospital Clínic, Universitat de Barcelona!
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Neonatal and Fetal GA-adjusted “normal” weight in the same population
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UtA >p95
CPR <p5 EFW CENTILE <3
%
Prognostic criteria for “true”placental insufficiency!CS for distress and/or neonatal acidosis
N=447 SGA + 447 controls
Figueras 2012
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Reorganización cerebral
Remodelado Cardiovascular
Programación Metabolica
Restricción crecimiento fetal!Adaptación = Epigenetica = “Programación” permanente
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Gemelos bicoriales. Parto 34 semanas!Twin 1: 1950 g (p45)!Twin 2: 1200 g (p1).
Satchev, 2012!Figueras 2006-2011!Baschat 2009, 2011!
Vohr 2004!Geva 2002-2011!
Marsal 00-06!Visser 01-11
* * *
Bayl
ey S
core
20
40
60
80
100
120
cognitive languag motor socio-emot adapbeha
Lagercrantz H. Better born too soon than too small.
Lancet 1997
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Fetal programming
Brain reorganiza0on (+/-‐ injury)
exposure
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Neuroimage 2012 PLoS One 2012
IUGR = reduced connectivity
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normal IUGR
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IUGR IS ASSOCIATED WITH REDUCED DEEPER FISSURES
Case%(N=31) Control%(N=19) p*
BPD 95,33+2,95 100,64+3,23 <0,01
Left_Insular_Depth 0,30+0,06 0,27+0,02 0,021
Right_Insular_Depth 0,3+0,07 0,27+0,03 0,16
Left_Sylvian_Fiss 0,16+0,05 0,14+0,03 0,37
Right_Sylvian_Fiss 0,15+0,04 0,15+0,03 0,57
Left_PO_Fiss 0,13+0,03 0,11+0,04 0,09
Right_PO_Fiss 0,14+0,04 0,11+0,04 0,02
Left_Cing_Fiss 0,09+0,02 0,09+0,02 0,79
Right_Cing_Fiss 0,09+0,02 0,09+0,02 0,98
Left_Calc_Fiss 0,18+0,03 0,16+0,04 0,06
Right_Calc_Fiss 0,18+0,04 0,16+0,05 0,11
L/R%Insular%ratio 1,03+0,29 0,95+0,1 0,05
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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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Reorganización cerebral
Remodelado Cardiovascular
Programación Metabolica
Restricción crecimiento fetal!Adaptación = Epigenetica = “Programación” permanente
www.medicinafetalbarcelona.org/
1986 Barker (MRC Unit, Southampton, UK): Coronary heart disease mortality rates
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Fetal growth restriction !
Epigenetic changes in metabolic regulation
!Normalization of diet (or
overnutrition) !
Insulin resistance !
Obesity/Diabetes/ !
Hypertension !
Cardiovascular disease
Fetal growth restriction !
Epigenetic changes in cardiac regulation
!Persistence of abnormal cardiac
function !
Lack of ability to further adaptation
!Cardiovascular disease
CLASSIC HYPOTHESIS ALTERNATIVE/COMPLEMENTARY HYPOTHESIS
www.medicinafetalbarcelona.org/ Crispi Circula8on 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
www.medicinafetalbarcelona.org/Skilton Lancet 2007, Crispi Circula8on 2010, Crispi AJOG 2012
Cardiovascular remodeling
postnatal cardiovascular remodelling
globular heart ↓longitudinal mo0on
↓stroke volume ↑heart rate
= cardiac output
hypertension pre-‐arteriosclerosis
IMPACT OF LATE IUGR/SGA
near term SGA fetuses without signs of poor prognosis also presented CV remodeling
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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
Sarc
omer
ic int
radis
tanc
e of
A-b
ands
Sarc
omer
elen
gth
Sarc
omer
elen
gth
B C
CONTROL FGR
7
7.2
7.4
7.6
7.8
8
8.2
8.4
8.6x 10-7
Sarc
omer
ic int
radis
tanc
e of
A-b
ands
Sarc
omer
elen
gth
Sarc
omer
elen
gth
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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Fetus Young OldChild Mature
IMPACT OF ENVIRONMENT
BIOLOGIC PROGRAMMING AND AGE
OPPORTUNITY FOR CORRECTION
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Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Programming / Organ remodelling
BIRT
H
IDENTIFICATION OF THE PROBLEM: UNDERNUTRITION,
NOT WEIGHT
INDIVIDUAL BIOMARKERS
INTERVENTION
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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%
Cruz-‐Lemini FMF 2013, Skilton Pediatric 2012, Rodriguez 2013
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Reorganización cerebral
Remodelado Cardiovascular
Programación Metabolica
Restricción crecimiento fetal!Adaptación = Epigenetica = “Programación” permanente