14 10 Austria Iugr

UPDATE ON DIAGNOSIS AND
MANAGEMENT OF

FETAL GROWTH RESTRICTION
Eduard Gratacós
BCNatal – Barcelona Center of Maternal-Fetal and Neonatal Medicine!

Hospital Clínic and Hospital Sant Joan de Déu!
Universitat de Barcelona
www.fetalmedicinebarcelona.org/
1. Identify small fetus!
2. FGR vs. SGA !
3. Early vs. Late !
4. Parameters for fetal follow-up!
5. Stage-based management protocol
www.medicinafetalbarcelona.org/
Detect SGA fetuses
1st: Accurate dating

!
2nd: Accurate measuring
!
n=3450 (spontaneous deliveries)
US Da&ng
!
<14.0 w: CRL (Robinson)
!
14-‐24 w: BPD (Mul)
!
>24 w: HC±LFL (Snijders)
GA at delivery
1.Robinson HP. Br J OBtstet Gynaecol 1975;82:702-‐710.

2.Mul T. Ultrasound Obstet Gynecol 1996; 8: 397–402.
3. Hadlock FP. Radiology. 1984 Feb;150(2):535-‐40.
!
US Da&ng
Detect SGA fetuses
1st: Accurate dating

!
2nd: Accurate measuring
Neonatal and Fetal GA-adjusted “normal”
weight in the same population
IMPROVING DETECTION: THE DEFINITION OF “RESTRICTION”!
Birthweight inverse relation with perinatal outcome AND brain-cardiac remodelling
C H
A R
S E
RE
www.medicinafetalbarcelona.org/ Mula 2013, Lobmaier 2013

2. FGR vs. SGA !
3. Early vs. Late!
Return
Exclude primary fetal defect
Exclude extrinsic cause
ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!

Perinatal and Long-term Outcomes
Poor perinatal outcome + IUFD! Perinatal outcome normal - No IUFD!

(Doppler) Signs of adaptation NO signs of adaptation
IUGR
SGA

Placental insufficiency Unknown (constitutional + others)
FGR vs. SGA: DIFFERENT MANAGEMENT
The discovery of UA and hemodynamics of IUGR
Constitutionally small Placental insufficiency Extrinsic cause
Primary fetal
defect
SGA FGR
N cases
UA Doppler +!
(EARLY-ONSET)
UA Doppler N!
(LATE-ONSET)
N cases
Savchev 2013
20 25 30 35 40
FGR = abnormal UA Doppler
BEING SMALL EARLY IN PREGNANCY IS A PROBLEM!
PROBLEM #1: MORTALITY
cCTG-‐STV<3 ms
Pathological
CGT
60%
DVa (rev)
19%
Yes No
<26 26-28 >28
Perinatal >90% 30-‐40% <10%

Mortality
Baschat 2003
Hecher 2003
Grivell 2009
www.medicinafetalbarcelona.org/ Cruz-‐Lemini 2012
Early-onset IUGR!
PROBLEM #2: (NEUROLOGICAL) MORBIDITY
Brain US anomalies in 30w IUGR
Controls IUGR ant AoI IUGR REV AoI
60
45
(%)
30
15
<29 29-32 >32.0
Neurological >90% 30-‐40% <10%

Morbidity
Fouron 2004
Del Rio 2008
Cruz-‐Mar&nez 2012
BEING SMALL LATE IS ALSO A PROBLEM
Significant increase in the risk of

SGA
adverse perinatal outcome!
Hershkovitz et al. Ultrasound Obstet Gynecol 2000 !
Severi et al. Ultrasound Obstet Gynecol 2002!
Figueras et al . Eur J Obstet Gynecol Reprod Biol 2008
Significant increase in the risk of

<p95 adverse neurodevelopment!
e
Eixarch et al. Ultrasound Obstet Gynecol 2008 !
Severi et al. Ultrasound Obstet Gynecol 2002!
Figueras et al . Eur J Obstet Gynecol Reprod Biol 2008
SGA = constitutionally small?

SGA: proportion of perinatal adverse
outcomes in 376 consecutive cases
Figueras 2011
50%
45%
40%
IMPACT OF NON-DETECTED IUGR ON
30%
LATE FETAL MORTALITY! 30%
25%
Barcelona!
20%
2005-2010
10%
0%
FGR Unknown Others
Classification of stillbirth by relevant condition at birth (ReCoDe):

population-based cohort study
Gardosi et al. BMJ 2005 and 2013
!
IUGR as relevant condition identified in 43-60%
!
Overall stillbirth rate (/ 1000 births) 4.2, but only 2.4 in non-SGA
pregnancies, increasing to
9.7 with antenatally detected IUGR and 19.8 in not detected IUGR.
Neurobehavioral performance of term
SGA newborns
* * * N=120
* * SGA vs !
100 AGA
* p <0.05!
Adjusted for GA, maternal age,
socioeconomic status and smoking
*
120
100
* ** **
80
Bayley Score
60
40
Satchev, 2012!
20 Geva 2008!
Figueras 2008!
Eixarch 2010
cognitive language motor socio-emotional adaptive
behavior
Cardiovascular programming in !
SGA / late-IUGR
control IUGR Fetuses EFW<p10 evaluated at 5 years!
!
Classified by CPR, p3 and UtA Doppler:!
• All normal: SGA!
• Any abnormal: late-IUGR
Crispi 2010
www.medicinafetalbarcelona.org/ Crispi 2012

r e
o
ym
FGR = abnormal
a UA Doppler? n
o t
n
N cases
UA Doppler +!
(EARLY-ONSET)
UA Doppler N!
(LATE-ONSET)
N cases
Savchev 2013
20 25 30 35 40
Prognostic criteria of “poor outcome”-SGA!
CS for distress and/or neonatal acidosis
UtA CPR
<p5 EFW CENTILE <3
>p95
N=509 SGA + 509 controls
www.medicinafetalbarcelona.org/ Figueras 2012

Late-onset intrauterine growth restriction vs. small-for-gestational age!
(submitted)
40% of late-SGA with 11 % risk (14% of all adverse outcomes)
SGA
Late-IUGR
60% of late-SGA with 40% risk (86% of all adverse outcomes)
Figueras 2012
www.medicinafetalbarcelona.org/docencia
FGR = EFW <p10 + any of
UtA CPR
<p5 EFW CENTILE <3
>p95
www.medicinafetalbarcelona.org/ Figueras 2012

Distribution of cases when IUGR = abnormal UA Doppler
Savchev 2013
Distribution of cases when IUGR = abnormal CPR or UtA or EFW<p3
Savchev 2013
Exclude primary fetal defect
Exclude extrinsic cause
ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!

Perinatal and Long-term Outcomes
Poor perinatal outcome + IUFD! Perinatal outcome normal - No IUFD!

(Doppler) Signs of adaptation NO signs of adaptation
IUGR
SGA

Placental insufficiency Unknown (constitutional + others)
FGR vs. SGA: DIFFERENT MANAGEMENT
2. FGR vs. SGA !
3. Early vs. Late!
Return
EARLY-ONSET LATE-ONSET
4-8 %
PREECLAMPSIA
1%
PREECLAMPSIA + IUGR
1%
IUGR
4-8 %
35 40
20 25 30
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
6 %
SGA?
3
IUGR
0
20 25 30 35 40
32w @diagnosis
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.
FETAL DETERIORATION IN PLACENTAL INSUFFICIENCY
PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!

DEATH
Increment placental
impedance
UTERINE A. >p95
CPR <p5 UMBILICAL A. >p95
Centralization
!
MIDDLE CEREBRAL A. <p5 Ao ISTHMUS >p95
cardiac ischemia
Diastolic failure
growth DUCTUS VENOSUS >p95 and a-
cCTG: reduced short-term CTG ABNORMAL

variability
Systolic cardiac
failure
FETAL DETERIORATION IN PLACENTAL INSUFFICIENCY !
EARLY VS LATE IUGR (>34s)
PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!

DEATH
Increment placental minimal tolerance to hypoxia
impedance
UTERINE A. >p95 Placental injury <30%
CPR <p5 UMBILICAL A. >p95
Centralization
MIDDLE CEREBRAL A. <p5 Ao ISTHMUS >p95
cardiac ischemia !
Diastolic failure
growth DUCTUS VENOSUS >p95 and a-
CTG / BPP ABNORMAL
mild hypoxia
no cardiovascular adaptation Systolic cardiac
failure
signs perinatal
adaptation/ outcome
severity %
3
yes poorer
IUGR
CLINICAL PROBLEMS
3
SGA?
no normal 0
# 1: DIAGNOSIS!
20 detection
25<50% 30 35 40
# 2: POOR PERINATAL OUTCOME (∼50%)!

• A “Late-IUGR subset” with poorer perinatal • 5-7% newborns!
outcome can be identified • detection < 50%!
• > 40% late pregnancy IUFD!
# 3: LONG TERM OUTCOME (∼50%)!
• Neurological, cardiovascular and
Fetal programming!
metabolic impact!
!
No means to select high risk groups • diagnosis SGA vs. Late-IUGR
IUGR= low CPR or high UtA or EFW<p3 or low PlGF
6 %
SGA?
3
IUGR
0
20 25 30 35 40
32w @diagnosis
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.
2. FGR vs. SGA !
3. Early vs. Late!
4. Parameters for fetal follow up!
Return
S D
umbilical artery
normal and anormal
hemodynamics
Placental status
<30%
Cardiac pump
normal function
placenta + cardiac ischemia
Cardiac pump
abnormal function
middle cerebral artery
normal and abnormal
hemodynamics
Normal oxygenation
[normal waveform]
[mild vasodilation]
[marked vasodilation]
hypoxia
30 % venous return

REFLECTS DIASTOLIC PRESSURE IN
RIGHT (AND LEFT) HEART
ductus venosus
normal and abnormal
hemodynamics
S D
A
Venous vessel: pulsation due to retrograde

pressure
S D A
ductus venosus
normal and abnormal
hemodynamics
compliance right
chambers: effect sobre P
on venous return
no
Myocardial
ischemia
P
compliance
P
Early-onset IUGR!
PROBLEM #1: MORTALITY
cCTG-‐STV<3 ms
Pathological
CGT
60%
BPP!
IUFD 23% in BPP=6 and 11% in BPP=8!
Poor correlation with DVa(rev)!
DVa (rev) Cochrane: poor contribution to prediction
19%
Baschat 2007, Kafur 2008, Lalor 2010, Crispi 2009
Yes No
<26 26-28 >28
Perinatal >90% 30-‐40% <10%

Mortality
Baschat 2003
Hecher 2003
Grivell 2009
www.medicinafetalbarcelona.org/ Cruz-‐Lemini 2012
Early-onset IUGR!
PROBLEM #2: (NEUROLOGICAL) MORBIDITY
Brain US anomalies in 30w IUGR
Controls Controls
IUGR antegrade AoI IUGR DV<5 z-score
IUGR retrograde AoI IUGR DV>5 z-score
60
*
*
45
(%)
30
15
<29 29-32 >32.0
Perinatal >90% 30-‐40% <10%

Mortality
Fouron 2004
Del Rio 2008
Cruz-‐Mar&nez 2012
2. FGR vs. SGA !
3. Early vs. Late!
4. Parameters for fetal follow up!
Return
IUGR = abnormal CPR or UtA or EFW<p3
Savchev 2013
RATIONALE FOR A STAGE-BASED APPROACH TO THE
MANAGEMENT OF FGR
PLACENTAL DISEASE HYPOXIA ACIDOSIS SERIOUS INJURY DEATH
Diagnostic/chronic markers! Prognostic/Acute markers!

Early and Late IUGR Early IUGR
Increment placental
impedance
cardiac
Diastoli
Centralization
cCTG: reduced STV
Systolic cardiac
Stage fetal
deterioration I II III IV failure
Risks of
prematurity LOW MODERATE HIGH
Red Line LATE IUGR Red Line EARLY IUGR
Protocol IUGR 
First step: UtA + CPR + EFW = SGA or IUGR
!
CPR! Ut A ! MCA!
I low EFW (<p3) or mild placental
resistance / redistribution! <p5 >p95 <p5
!
!
III Severe placental resistance / AEDV AoI >p95
redistribution!
!
! DV >p95 REDV
III Severe hemodynamic adaptation
- Low suspicion acidosis!
!
!
IV High suspicion of acidosis - ! DV ! CGT decelerations of
(a rev) reduced short-term
High risk of death variability
IUGR!
Management protocol according to severity stages
Stage IV III II I
DV>p95 EFW<p3
DV(a-‐) (a) AEDV
Criteria REDV (b) AoI>95 CPR<p5
cCTG abn.
UtA>p95
CTG dec.
MCA<p5
Delivery Any &me 30 34 37
Follow-‐up Hours/Daily 1-‐2 d 2/w 1/w
Mode CS CS CS or LI LI
<26w 26-28 28-30 30-34 34-37
Mort. >90% 50% <10%

Morb. >90% 50%
Stage 1
Delivery
The main goal in FGR is identification!
!
Small fetus (EFW<p10) must be divided in:!

FGR (placenta, poor perinatal and long-term outcome) !
SGA (we don’t know, perinatal outcome N, poor long term)!
!
Early and late-onset FGR (GA 32s) represent two
distinct phenotypes of the same disease!
!
Clinically, a single stage-based protocol allows

optimizing decisions in all cases

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UPDATE ON DIAGNOSIS AND

BCNatal – Barcelona Center of Maternal-Fetal and Neonatal Medicine!

2. FGR vs. SGA !

3. Early vs. Late !

4. Parameters for fetal follow-up!

5. Stage-based management protocol

1st: Accurate dating

1.Robinson HP. Br J OBtstet Gynaecol 1975;82:702-­‐710.

1st: Accurate dating

www.medicinafetalbarcelona.org/ Mula 2013, Lobmaier 2013

2. FGR vs. SGA !

3. Early vs. Late!

4. Stage-based management protocol

Exclude extrinsic cause

ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!

Poor perinatal outcome + IUFD! Perinatal outcome normal - No IUFD!

FGR vs. SGA: DIFFERENT MANAGEMENT

FGR = abnormal UA Doppler

<26 26-28 >28

Perinatal >90% 30-­‐40% <10%

<29 29-32 >32.0

Neurological >90% 30-­‐40% <10%

Significant increase in the risk of

Significant increase in the risk of

SGA = constitutionally small?

Classification of stillbirth by relevant condition at birth (ReCoDe):

www.medicinafetalbarcelona.org/ Crispi 2012

N=509 SGA + 509 controls

www.medicinafetalbarcelona.org/ Figueras 2012

40% of late-SGA with 11 % risk (14% of all adverse outcomes)

60% of late-SGA with 40% risk (86% of all adverse outcomes)

www.medicinafetalbarcelona.org/ Figueras 2012

Exclude extrinsic cause

ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!

Poor perinatal outcome + IUFD! Perinatal outcome normal - No IUFD!

FGR vs. SGA: DIFFERENT MANAGEMENT

2. FGR vs. SGA !

3. Early vs. Late!

4. Stage-based management protocol

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

PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS

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

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

PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!

CPR <p5 UMBILICAL A. >p95

growth DUCTUS VENOSUS >p95 and a-

cCTG: reduced short-term CTG ABNORMAL

PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!

UTERINE A. >p95 Placental injury <30%

CPR <p5 UMBILICAL A. >p95

MIDDLE CEREBRAL A. <p5 Ao ISTHMUS >p95

growth DUCTUS VENOSUS >p95 and a-

CTG / BPP ABNORMAL

# 2: POOR PERINATAL OUTCOME (∼50%)!

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

PROBLEM: MANAGEMENT PROBLEM: DIAGNOSIS

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

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

2. FGR vs. SGA !

3. Early vs. Late!

4. Parameters for fetal follow up!

4. Stage-based management protocol

placenta + cardiac ischemia

1.Robinson HP. Br J OBtstet Gynaecol 1975;82:702-‐710.

Perinatal >90% 30-‐40% <10%

Neurological >90% 30-‐40% <10%

Perinatal >90% 30-‐40% <10%

Perinatal >90% 30-‐40% <10%

Follow-‐up Hours/Daily 1-‐2 d 2/w 1/w