programación fetal evidencias actuales y papel de la “nutrición” fetal

www.medicinafetalbarcelona.org/

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!

www.medicinafetalbarcelona.org

http://www.medicinafetal


Neonatal and Fetal GA-adjusted “normal” weight in the same population


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


Reorganización cerebral

Remodelado Cardiovascular

Programación Metabolica

Restricción crecimiento fetal!Adaptación = Epigenetica = “Programación” permanente


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


Fetal programming

Brain reorganiza0on (+/-‐ injury)

exposure


Neuroimage 2012 PLoS One 2012

IUGR = reduced connectivity


normal IUGR


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


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


1986 Barker (MRC Unit, Southampton, UK): Coronary heart disease mortality rates


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


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)


Fetus Young OldChild Mature

IMPACT OF ENVIRONMENT

BIOLOGIC PROGRAMMING AND AGE

OPPORTUNITY FOR CORRECTION


Fetus Child

Problem evident

WINDOW OF OPPORTUNITY

Programming / Organ remodelling

BIRT

H

IDENTIFICATION OF THE PROBLEM: UNDERNUTRITION,

NOT WEIGHT

INDIVIDUAL BIOMARKERS

INTERVENTION


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

programación fetal evidencias actuales y papel de la “nutrición” fetal

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