Impact of (early and late) IUGR on neurodevelopment Impact of (early and late) IUGR on...

www.fetalmedicinebarcelona.org/

Impact of (early and late) IUGR on neurodevelopment

Eduard GratacosMaternal-Fetal Medicine Department and Research Center

Hospitals Clinic and Sant Joan de Deu - University of Barcelonawww.fetalmedicinebarcelona.org

martes 18 de junio de 13

http://www.fetalmedicinebarcelona.org


http://www.medicinafetal




















1. IUGR vs. SGA - Early vs. Late

2. Early-onset IUGR and neurodevelopment

3. Late-onset IUGR and neurodevelopment






www.medicinafetalbarcelona.org/

Savchev 2013



The discovery of UA and hemodynamics of IUGR

Savchev 2013



Constitutionally small Placental insufficiency Extrinsic cause

Primary fetal defect


IUGR = abnormal UA Doppler

Savchev 2013





SGA IUGR



Savchev 2013





SGA IUGR



20 30 4025 35 Savchev 2013





SGA IUGR



20 30 4025 35

0

N cases

N cases

Savchev 2013





SGA IUGR



20 30 4025 35

0

N cases

N cases

Savchev 2013





SGA IUGR



20 30 4025 35

0

N cases

N cases

UA Doppler +(EARLY-ONSET)

Savchev 2013





SGA IUGR



20 30 4025 35

0

N cases

N cases

UA Doppler +(EARLY-ONSET)

UA Doppler N(LATE-ONSET)

Savchev 2013



Distribution of cases when IUGR = abnormal UA Doppler

Savchev 2013



Distribution of cases when IUGR = abnormal CPR or UtA or EFW<p3

Savchev 2013



IUGR

SGA?

20 30 4025 35

0

3

6 %

IUGR= low CPR or high UtA or EFW<p3 or low PlGF





IUGR

SGA?

20 30 4025 35

0

3

6 %


32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %


EARLY IUGR (1%) LATE IUGR (5-7%)

32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %



PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS

32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %




Placental disease: high (UA+, PE high) Placental disease: low (UA-, PE low)

32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %





Hypoxia ++: systemic CV adaptation Hypoxia +/-: central CV adaptation

32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %






Tolerance to hypoxia. Natural history Low tolerance: no natural history

32w @diagnosis





IUGR

SGA?

20 30 4025 35

0

3

6 %






Tolerance to hypoxia. Natural history Low tolerance: no natural history

High mortality and morbidity Low mortality but poor long outcome.

32w @diagnosis









IUGR Controls p

n (fetuses) 90 90

GA at birth (wks) 31.2 (2.4) 31.1 (2.4) 0.73

Birthweight (g) 1078 1616 <0.001

0

7,5

15,0

22,5

30,0

(%)

BGL PVL IVH Brain abn.

***

* p<0.05

early-IUGR is associated with higher frequency of ultrasound brain lesions and abnormal neonatal neurobehaviour

0

7,5

15,0

22,5

30,0

%

Abnormal neurobehavior

Controls IUGR

Cruz et al. 2010

9

Controls IUGR





IUGR Controls p

n (fetuses) 90 90

GA at birth (wks) 31.2 (2.4) 31.1 (2.4) 0.73

Birthweight (g) 1078 1616 <0.001

0

7,5

15,0

22,5

30,0

(%)

BGL PVL IVH Brain abn.

*

***

* p<0.05

early-IUGR is associated with higher frequency of ultrasound brain lesions and abnormal neonatal neurobehaviour

0

7,5

15,0

22,5

30,0

%

Abnormal neurobehavior

Controls IUGR

*

Cruz et al. 2010

9

Controls IUGR




Perinatal >90% 30-‐40% <10%Mortality


<29 29-32 >32.0

Fouron 2004Del Rio 2008Cruz-‐Mar5nez 2012

Early-onset IUGRPREDICTION OF SERIOUS NEUROLOGICAL MORBIDITY




Perinatal >90% 30-‐40% <10%Mortality


<29 29-32 >32.0

Fouron 2004Del Rio 2008Cruz-‐Mar5nez 2012

Early-onset IUGRPREDICTION OF SERIOUS NEUROLOGICAL MORBIDITY

0

15

30

45

60

(%)

ControlsIUGR antegrade AoIIUGR retrograde AoI

ControlsIUGR DV<5 z-scoreIUGR DV>5 z-score

**

Brain US anomalies in 30w IUGR





Early-onset IUGR: TARGETED NEUROSONOGRAPHYAbnormal findings = 16% (n=108)

Eixarch 2013



SEVERE IUGR: TARGETED NEUROSONOGRAPHY


Early-onset IUGR has a strong association with poor short-term and long-term adverse neurological

outcome

Early-onset IUGR: Indication for neurosonography

If NSG normal: strongest predictor is GA<30wBest predictor aside of GA: aortic isthmus (32-37w)









exposure


Fetal programming

Brain reorganiza5on(+/-‐ injury)

exposure


Batalle 2012Eixarch 2012


Batalle 2012Eixarch 2012




Dichorionic Twins. Born 34 weeksTwin 1: 1950 g (p45)Twin 2: 1200 g (p1). Normal Doppler



Satchev, 2012Figueras 2006-2011Baschat 2009, 2011

Vohr 2004Geva 2002-2011

Marsal 00-06Visser 01-11

* * *

Bayl

ey S

core

20

40

60

80

100

120

cognitive language motor socio-emot adaptivebehavior



Satchev, 2012Figueras 2006-2011Baschat 2009, 2011

Vohr 2004Geva 2002-2011

Marsal 00-06Visser 01-11

* * *

Bayl

ey S

core

20

40

60

80

100

120

cognitive language motor socio-emot adaptivebehavior

Lagercrantz H. Better born too soon than too small.

Lancet 1997


Clinical implications:

Does delivery at 37 weeks improve outcomes?

Does SGA vs IUGR affect prognosis?

Prediction with biomarkers


www.medicinafetalbarcelona.org/docencia

292 24-‐months SGA >37 weeks

Effects on (neuro)developmental and behavioral outcome at 2 years of age Induced labor vs. expectant management in late SGA (EFW<10th cen5le)

(DIGITAT trial) AJOG 2012

13/21


Bayley’s scores at 2 years

Neurobehavioral performance of term SGA vs IUGR

* * *

Bay

ley

Sco

re

2

4

6

8

10

12

cognitive language motor socio-emotional adaptive

behavior




* * *

Bay

ley

Sco

re

2

4

6

8

10

12


behavior

No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler)




* * *

Bay

ley

Sco

re

2

4

6

8

10

12


behavior

No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler)

Egaña 2013

Cortical measures


Brain cortical development in patients with high risk of abnormal neurodevelopment (IUGR)

Egaña 2013

Abnormal! ! NormalA A


Brain cortical development in patients with high risk of abnormal neurodevelopment (IUGR)

Egaña 2013

Integrated algorithm with several brain CD measures

Composite score= e-(Y)/ (1 + e-(Y)), where Y= 6.259 + [(LID/BPD * RID/BPD * -41.264) +

(LPOD/BPD * -16.247)].

Abnormal! ! NormalA A


Fetus Young OldChild Mature

IMPACT OF ENVIRONMENT

BIOLOGIC PROGRAMMING AND AGEEarly and Late-Onset IUGR


Fetus Young OldChild Mature

IMPACT OF ENVIRONMENT

BIOLOGIC PROGRAMMING AND AGEEarly and Late-Onset IUGR

OPPORTUNITY FOR CORRECTION


Fetus Child

Problem evident

WINDOW OF OPPORTUNITY

Brain organiza5on

BIRT

H


Fetus Child

Problem evident


Brain organiza5on

BIRT

H

IDENTIFICATION OF RISK

INDIVIDUALBIOMARKERS

INTERVENTION


Fetus Child

Problem evident


Brain organiza5on

BIRT

H

IDENTIFICATION OF RISK

INDIVIDUALBIOMARKERS

INTERVENTION

Intelligence

Fetal(Early)

postnatal

Genes


Being small for gestational age has a strong association with poor long-term adverse neurological outcome

regardless of the cause

Detection of smallness is an opportunity to improve long-term health outcomes and ageing

Individualized prediction of risk will likely be possibly but not applicable as public health


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Impact of (early and late) IUGR on neurodevelopment Impact of (early and late) IUGR on...

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