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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

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!
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.  

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!

US  Da&ng

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Detect SGA fetuses

1st: Accurate dating


!
2nd: Accurate measuring

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

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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


1. Identify small fetus!

2. FGR vs. SGA !

3. Early vs. Late!

4. Stage-based management protocol

Return
www.medicinafetalbarcelona.org/
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

www.medicinafetalbarcelona.org/
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

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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
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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?


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SGA: proportion of perinatal adverse
outcomes in 376 consecutive cases

Figueras 2011
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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.

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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
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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

www.fetalmedicinebarcelona.org/
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
www.medicinafetalbarcelona.org/
Distribution of cases when IUGR = abnormal CPR or UtA or EFW<p3

Savchev 2013
www.medicinafetalbarcelona.org/
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

www.medicinafetalbarcelona.org/
1. Identify small fetus!

2. FGR vs. SGA !

3. Early vs. Late!

4. Stage-based management protocol

Return
www.medicinafetalbarcelona.org/
EARLY-ONSET LATE-ONSET

4-8 %
PREECLAMPSIA

1%

PREECLAMPSIA + IUGR

1%

IUGR
4-8 %

35 40
20 25 30

www.medicinafetalbarcelona.org/
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.

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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

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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

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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

www.medicinafetalbarcelona.org/
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.

www.fetalmedicinebarcelona.org/
1. Identify small fetus!

2. FGR vs. SGA !

3. Early vs. Late!

4. Parameters for fetal follow up!

4. Stage-based management protocol

Return
www.medicinafetalbarcelona.org/
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
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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
www.medicinafetalbarcelona.org/
1. Identify small fetus!

2. FGR vs. SGA !

3. Early vs. Late!

4. Parameters for fetal follow up!

5. Stage-based management protocol

Return
www.medicinafetalbarcelona.org/
IUGR = abnormal CPR or UtA or EFW<p3

Savchev 2013
www.medicinafetalbarcelona.org/
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

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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

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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%

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Stage 1
Delivery

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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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