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IUGR AND LONG TERM CV FUNCTION

Eduard Gratacós

www.fetalmedicinebarcelona.org

martes 18 de junio de 13

http://www.fetalmedicinebarcelona.org



1. Fetal growth and cardiovascular function

2. IUGR and cardiac programming

3. Clinical implications




GROWTH RESTRICTION AND THE FETAL HEART

Adaptive responseProgressive failure

Permanent Epigenetic changes

CLINICAL MONITORING

CARDIAC PROGRAMMING


IUGRtarget organ in hypoxic centralization

GROWTH RESTRICTION AND THE FETAL HEART

Adaptive responseProgressive failure

Permanent Epigenetic changes

CLINICAL MONITORING

CARDIAC PROGRAMMING



Cardiac function

Cardiac dysfunction: early event & progression

termAGA

IUGR-s1 s2 s3

0

1

2

3

4

*

*

*

M

od-M

PI (

z-sc

ores

)

0

50

100

150

200

250

300

350

400

*

*

*BN

P (p

g/m

L)termAGA

IUGR-s1 s2 s3pretermAGA

Myocardial Performance Index Cord blood BNP

Data are mean(SEM). *P<0.01 compared to AGA. Doppler parameters in Z-scores

Girsen et al UOG 2007Crispi et al. AJOG 2008





CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR

0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

-30 -25 -20 -15 -10 -5 0Days before delivery

Z-scores

DVAoITEI





CARDIOVASCULAR DYSFUNCTION IS A COMMON FEATURE OF IUGR

Cruz-‐Mar(nez, 2010

0

0,5

1,0

1,5

2,0

2,5

3,0

3,5

-30 -25 -20 -15 -10 -5 0Days before delivery

Z-scores

DVAoITEI





CARDIOVASCULAR DYSFUNCTION IN LATE-ONSET IUGR

50

CONTROL

SGA

0

10

20

30

40

Tiss

ue D

oppl

er E

’ > 9

0th

cent

ile (%

)

*

LEFT RIGHT

0

5

10

15

20

25

30

DV AoI MPI

Freq

uenc

y of

abn

orm

ality

(%

)

ControlsSGA

*

*





CARDIOVASCULAR DYSFUNCTION IN LATE-ONSET IUGR

50

CONTROL

SGA

0

10

20

30

40

Tiss

ue D

oppl

er E

’ > 9

0th

cent

ile (%

)

*

LEFT RIGHT

Comas 2011

0

5

10

15

20

25

30

DV AoI MPI

Freq

uenc

y of

abn

orm

ality

(%

)

ControlsSGA

*

*

Crus-‐Mar(nez 2009




1986 Barker (MRC Unit, Southampton, UK):

Coronary heart disease mortality rates

Cardiovascular risk factors


Low birth weight

Cardiovascular risk factors

Barker Lancet 1989, Barker BMJ 1993, Osmond BMJ 1993, Barker BMJ 1995, Fall BMJ 1995, Stein Lancet 1996, Leon BMJ 1998, Forsen BMJ 1999, Eriksson BMJ 2001, Osmond Stroke 2007

cardiovascular mortality

coronary heart diseasehypertension

stroketype 2 diabetes

obesity

FETAL GROWTH RESTRICTION: 6-7% NEWBORNS



“The Barker hypothesis”

Fetal programming:Coronary heart disease originates through responses to under nutrition during fetal life, which permanently change the body's structure, physiology and metabolism




Fetal growth restriction

Epigenetic changes in metabolic regulation

Normalization of diet (or overnutrition)

Insulin resistance

Obesity/Diabetes/

Hypertension

Cardiovascular disease

CLASSIC HYPOTHESIS



Epigenetic changes in metabolic regulation

Normalization of diet (or overnutrition)

Insulin resistance

Obesity/Diabetes/

Hypertension



Epigenetic changes in cardiac regulation

Persistence of abnormal cardiac function

Lack of ability to further adaptation


CLASSIC HYPOTHESIS ALTERNATIVE/COMPLEMENTARY HYPOTHESIS


Animal data: restriction of oxygen leads to dilated and less-efficient hearts

Chicken embryo model

Effects of hypoxia on the embryonic heart

Tintu et al. Plos One 2009


Evidence of the impact of IUGR in postnatal cardiac function

Maria

Height 106 cm (normal)Weight 21 kg (normal)

Carlota

Height 104 cm (p3)Weight 16 kg (p9)


Maria (N)

Normal cardiac function

E/A mitralE = 91 cm/s

76 ms

Tissue Doppler:Myocardial velocities (septal annulusl)

E’ = 15 cm/s

S’ = 10 cm/s

E/E’ = 6


Maria (N)

Normal heart


Maria (N)

Normal heart

Carlota (IUGR)

Globular heart


www.fetalmedicinebarcelona.org/ Crispi et al. Circulation 2010

Cardiac remodelling in IUGR

Cardiac shape

Systolic function

Diastolic function




control IUGR

Crispi 2010

Impact of prenatal severity on cardiovascular programming in late-IUGR


control IUGR

Crispi 2010


Fetuses EFW<p10 evaluated at 5 years

Classified by CPR, p3 and UtA Doppler:• All normal: SGA• Any abnormal: late-IUGR


control IUGR

Crispi 2012

Crispi 2010


Fetuses EFW<p10 evaluated at 5 years

Classified by CPR, p3 and UtA Doppler:• All normal: SGA• Any abnormal: late-IUGR


PREDIMED NEJM 2013

ADULTHOOD

Effect of dietary interventions on CV disease



CAPS Pediatrics 2012

CHILDHOOD

Effect of dietary interventions on CV disease

Childhood Asthma Prevention Study




To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA

Factors associated to cIMT

Characteristics Adjusted coef. (n=88)Adjusted coef. (n=88)Characteristics

Coef. (95%CI) P value

IUGR 0.0264(0.0170; 0.0358) <0.001

Gestational age at delivery

-0.0024(-0.0036;-0.0011) <0.001

Female sex -0.0003(-0.0096;0.0090) 0.95

Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02

BMI at follow up 0.0035(0.0013;0.0057) 0.01

direct effect





To evaluate the effect of postnatal diet on cardiovascular remodelling in SGA

Factors associated to cIMT

Characteristics Adjusted coef. (n=88)Adjusted coef. (n=88)Characteristics

Coef. (95%CI) P value

IUGR 0.0264(0.0170; 0.0358) <0.001

Gestational age at delivery

-0.0024(-0.0036;-0.0011) <0.001

Female sex -0.0003(-0.0096;0.0090) 0.95

Formula/Mix feeding 0.0110(0.0020;0.0200) 0.02

BMI at follow up 0.0035(0.0013;0.0057) 0.01

direct effect

% polyunsaturated fats

AGA

SGA/IUGR

cIMT




Fetal CV score versus perinatal prognostic factors to predict postnatal hypertension and increased intima-media thickness in IUGR

ABNORMAL CV OUTCOME:

DBP >95th centile

Aortic IMT >95th centile


IUGR: EFW / birthweight <p10.


IUGRn=100

Conventional Doppler

Fetal Echocardiography


DBP >95th centile



IUGR: EFW / birthweight <p10.


IUGRn=100

Conventional Doppler

Fetal Echocardiography


DBP >95th centile


Logistic Regression


DBP >95th centile + aIMT>95th centile

YES26%

NO74%

CV Risk in IUGR children at 6 months

n=100


Prediction of hypertension and increased vascular thickness at 6 months of age in fetuses with IUGR

CV score: DR 90% - FPR 25% (PPV 38%, NPV 98%)

Cruz, 2013



Conclusions





Conclusions• Cardiac dysfunction/adaptation is a

constitutional feature of IUGR

• Cardiac dysfunction in fetal life induces permanent CV programming and remodelling resulting in child conditions demonstrated to increase susceptibility to cardiovascular disease later in life

• This opens new public health opportunities for the prevention of cardiovascular disease from early life, and new research lines exploring early intervention.




iugr and long term cv function - medicinafetalbarcelona · iugr and long term cv function eduard...

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