impact of (early and late) iugr on neurodevelopment impact of (early and late) iugr on...
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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
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
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
1. IUGR vs. SGA - Early vs. Late
2. Early-onset IUGR and neurodevelopment
3. Late-onset IUGR and neurodevelopment
martes 18 de junio de 13
1. IUGR vs. SGA - Early vs. Late
2. Early-onset IUGR and neurodevelopment
3. Late-onset IUGR and neurodevelopment
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
The discovery of UA and hemodynamics of IUGR
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
20 30 4025 35 Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
20 30 4025 35
0
N cases
N cases
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
20 30 4025 35
0
N cases
N cases
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
20 30 4025 35
0
N cases
N cases
UA Doppler +(EARLY-ONSET)
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal defect
SGA IUGR
The discovery of UA and hemodynamics of IUGR
IUGR = abnormal UA Doppler
20 30 4025 35
0
N cases
N cases
UA Doppler +(EARLY-ONSET)
UA Doppler N(LATE-ONSET)
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Distribution of cases when IUGR = abnormal UA Doppler
Savchev 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Distribution of cases when IUGR = abnormal CPR or UtA or EFW<p3
Savchev 2013
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS
Placental disease: high (UA+, PE high) Placental disease: low (UA-, PE low)
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS
Placental disease: high (UA+, PE high) Placental disease: low (UA-, PE low)
Hypoxia ++: systemic CV adaptation Hypoxia +/-: central CV adaptation
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS
Placental disease: high (UA+, PE high) Placental disease: low (UA-, PE low)
Hypoxia ++: systemic CV adaptation Hypoxia +/-: central CV adaptation
Tolerance to hypoxia. Natural history Low tolerance: no natural history
32w @diagnosis
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
IUGR
SGA?
20 30 4025 35
0
3
6 %
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
EARLY IUGR (1%) LATE IUGR (5-7%)
PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS
Placental disease: high (UA+, PE high) Placental disease: low (UA-, PE low)
Hypoxia ++: systemic CV adaptation Hypoxia +/-: central CV adaptation
Tolerance to hypoxia. Natural history Low tolerance: no natural history
High mortality and morbidity Low mortality but poor long outcome.
32w @diagnosis
martes 18 de junio de 13
1. IUGR vs. SGA - Early vs. Late
2. Early-onset IUGR and neurodevelopment
3. Late-onset IUGR and neurodevelopment
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
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
martes 18 de junio de 13
www.fetalmedicinebarcelona.org/
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
martes 18 de junio de 13
Perinatal >90% 30-‐40% <10%Mortality
www.fetalmedicinebarcelona.org/
<29 29-32 >32.0
Fouron 2004Del Rio 2008Cruz-‐Mar5nez 2012
Early-onset IUGRPREDICTION OF SERIOUS NEUROLOGICAL MORBIDITY
martes 18 de junio de 13
Perinatal >90% 30-‐40% <10%Mortality
www.fetalmedicinebarcelona.org/
<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
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
Early-onset IUGR: TARGETED NEUROSONOGRAPHYAbnormal findings = 16% (n=108)
Eixarch 2013
martes 18 de junio de 13
www.medicinafetalbarcelona.org/
SEVERE IUGR: TARGETED NEUROSONOGRAPHY
martes 18 de junio de 13
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)
martes 18 de junio de 13
1. IUGR vs. SGA - Early vs. Late
2. Early-onset IUGR and neurodevelopment
3. Late-onset IUGR and neurodevelopment
martes 18 de junio de 13
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exposure
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Fetal programming
Brain reorganiza5on(+/-‐ injury)
exposure
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Batalle 2012Eixarch 2012
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Batalle 2012Eixarch 2012
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Dichorionic Twins. Born 34 weeksTwin 1: 1950 g (p45)Twin 2: 1200 g (p1). Normal Doppler
martes 18 de junio de 13
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
martes 18 de junio de 13
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
Lagercrantz H. Better born too soon than too small.
Lancet 1997
martes 18 de junio de 13
Clinical implications:
Does delivery at 37 weeks improve outcomes?
Does SGA vs IUGR affect prognosis?
Prediction with biomarkers
martes 18 de junio de 13
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
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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
martes 18 de junio de 13
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
No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler)
martes 18 de junio de 13
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
No differences in relation with IUGR or SGA status (EFW<p3, CPR or UtA Doppler)
Egaña 2013
Cortical measures
martes 18 de junio de 13
Brain cortical development in patients with high risk of abnormal neurodevelopment (IUGR)
Egaña 2013
Abnormal! ! NormalA A
martes 18 de junio de 13
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
martes 18 de junio de 13
Fetus Young OldChild Mature
IMPACT OF ENVIRONMENT
BIOLOGIC PROGRAMMING AND AGEEarly and Late-Onset IUGR
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Fetus Young OldChild Mature
IMPACT OF ENVIRONMENT
BIOLOGIC PROGRAMMING AND AGEEarly and Late-Onset IUGR
OPPORTUNITY FOR CORRECTION
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Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Brain organiza5on
BIRT
H
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Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Brain organiza5on
BIRT
H
IDENTIFICATION OF RISK
INDIVIDUALBIOMARKERS
INTERVENTION
martes 18 de junio de 13
Fetus Child
Problem evident
WINDOW OF OPPORTUNITY
Brain organiza5on
BIRT
H
IDENTIFICATION OF RISK
INDIVIDUALBIOMARKERS
INTERVENTION
Intelligence
Fetal(Early)
postnatal
Genes
martes 18 de junio de 13
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
martes 18 de junio de 13