update on diagnosis and management of fetal growth restriction

Eduard Gratacós

www.fetalmedicinebarcelona.org/

UPDATE ON DIAGNOSIS AND MANAGEMENT OF

FETAL GROWTH RESTRICTION

BCNatal – Barcelona Center of Maternal-Fetal and Neonatal Medicine!Hospital Clínic and Hospital Sant Joan de Déu, Universitat de Barcelona!


http://www.fetalmedicinebarcelona.org



Placental insufficiency = high risk of IUFD and fetal/neonatal acidosis!Fetal Smallness = higher risk of placental insufficiency

Risk of placental insufficiency

10

50

Feta

l wei

ght

cent

ile

“Small fetuses”

Placental “respiratory” !smallness = risk distress + IUFD

Non-“respiratory” smallness != no distress/IUFD risk



1. Identify small fetus!

2. Identify placental insufficiency (FGR vs. SGA)!

3. Determine timing of delivery



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


Mula 2013, Lobmaier 2013www.fetalmedicinebarcelona.org/

IMPROVING DETECTION: THE DEFINITION OF “RESTRICTION”!Birthweight inverse relation with perinatal outcome AND brain-cardiac remodelling

RESE

ARCH








SGA Unknown (constitutional + others)

IUGR Placental insufficiency

ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!Perinatal and Long-term Outcomes

Exclude extrinsic cause

Exclude primary fetal defect

Poor perinatal outcome + IUFD!(Doppler) Signs of adaptation

Perinatal outcome normal - No IUFD!NO signs of adaptation

FGR vs. SGA: DIFFERENT MANAGEMENT



Constitutionally small Placental insufficiency Extrinsic cause

Primary fetal defect

SGA FGR

The discovery of UA and hemodynamics of IUGR

FGR = abnormal UA Doppler

20 30 4025 35

0

N cases

N cases

UA Doppler +!(EARLY-ONSET)

UA Doppler N!(LATE-ONSET)

Savchev 2013



FGR = abnormal UA Doppler?

20 30 4025 35

0

N cases

N cases

UA Doppler +!(EARLY-ONSET)

UA Doppler N!(LATE-ONSET)

Savchev 2013

not a

nymore


Risk of CS for distress and/or neonatal acidosis!

N=509 SGA + 509 controls


UtA >p95

CPR <p5

EFW CENTILE <3

%

Prognostic criteria for poor outcome among small fetuses with normal UA Doppler

Figueras 2012



UtA >p95

CPR <p5 EFW CENTILE <3

Figueras 2012

FGR = EFW <p10 + any of



Distribution of cases when IUGR = abnormal UA Doppler

Savchev 2013



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

Savchev 2013



SGA Unknown (constitutional + others)

IUGR Placental insufficiency

ISOLATED FETAL SMALLNESS = POORER PROGNOSIS!Perinatal and Long-term Outcomes

Exclude extrinsic cause

Exclude primary fetal defect

Poor perinatal outcome + IUFD!(Doppler) Signs of adaptation

Perinatal outcome normal - No IUFD!NO signs of adaptation

FGR vs. SGA: DIFFERENT MANAGEMENT








IUGR = abnormal CPR or UtA or EFW<p3

Savchev 2013


Early-severe High risk IUFD preterm



Management = when should we deliver?

Savchev 2013

Late-mild Low risk IUFD (high at term)


deliver when risks are:


RATIONALE FOR AN INTEGRATED STAGE-BASED APPROACH TO THE MANAGEMENT OF FGR

PLACENTAL DISEASE HYPOXIA ACIDOSIS SERIOUS INJURY DEATH

cardiac ischemiaDiastolic failure

Systolic cardiac failure

Centralization

Increment placental impedance

cCTG: reduced STV

Diagnostic/chronic markers!DIFFERENCE !FGR VS SGA

Prognostic/Acute markers!INDICATION ABOUT THE SHORT-TERM RISK!

OF IUFD/BRAIN INJURY

IVIIIIIIStage fetal deterioration

HIGHMILDMINIMALRisks of prematurity



Protocol IUGRFirst step: UtA + CPR + EFW = SGA or IUGR

CPR!<p5

Ut A !>p95

MCA!<p5

DV !(a rev)

CGT decelerations of reduced short-term

variability

REDV DV >p95

!I low EFW (<p3) or mild placental

resistance / redistribution!!!

II Severe placental resistance / redistribution!

!!

III Severe hemodynamic adaptation - Low suspicion acidosis!

!!

IV High suspicion of acidosis - !High risk of death

AEDV AoI >p95


VERY HIGH HIGH MODERATE

Mort. >90% 50% <10% Morb. >90% 50%


<26w 26-28 28-30 30-34 34-37

IUGR!Management protocol according to severity stages

Deliver at Any 7me

Risk of IUFD/brain injury

DV(a-‐), cCTG, CTG dec

Stage IV

Mode CS

Follow-‐up Hours/Daily

30

DV>p95, REDV

III

CS

1-‐2 d

34

AEDV, AoI>95

II

CS or LI

2/w

37

EFW<p3, CPR <p5, UtA>95

I

LI

1/w

LOW





Delivery

Stage 1



First goal:!Identify of small fetus (EFW<p10) and classify as FGR

vs SGA according to CPR, UtA and EFW<3.!!

Second goal: !Decide timing of delivery and followup scheme: use a

stage-based integrated protocol.



Early vs. Late onset IUGR

Return


20 30 4025 35


EARLY-ONSET LATE-ONSET

PREECLAMPSIA

IUGR

PREECLAMPSIA + IUGR

1 %

1 %

4-8 %

4-8 %



IUGR

SGA?

20 30 4025 35

0

3

6 %

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

EARLY IUGR (1-2%) LATE IUGR (5-6%)

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



FETAL DETERIORATION IN PLACENTAL INSUFFICIENCY

PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!DEATH

cardiac ischemia!Diastolic failure


Centralization


growth

MIDDLE CEREBRAL A. <p5

CPR <p5

DUCTUS VENOSUS >p95 and a-

CTG ABNORMAL

UTERINE A. >p95

cCTG: reduced short-term variability

Ao ISTHMUS >p95

UMBILICAL A. >p95



FETAL DETERIORATION IN PLACENTAL INSUFFICIENCY !EARLY VS LATE IUGR (>34s)

PLACENTAL DISEASE COMPENSATED HYPOXIA DECOMPENSATED HYPOXIA SERIOUS INJURY!DEATH

cardiac ischemia!Diastolic failure


growth

UMBILICAL A. >p95

DUCTUS VENOSUS >p95 and a-

CTG / BPP ABNORMAL

Placental injury <30%

mild hypoxia no cardiovascular adaptation

minimal tolerance to hypoxia

MIDDLE CEREBRAL A. <p5

CPR <p5

UTERINE A. >p95

Ao ISTHMUS >p95

Centralization




IUGR

SGA?

20 30 4025 35

0

3

6 %

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

EARLY IUGR (1-2%) LATE IUGR (5-6%)

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



Parameters for fetal follow up in IUGR

Return



umbilical artery normal and anormal hemodynamics

DS

Cardiac pump normal function

Cardiac pump abnormal function

Placental status

<30%

placenta + cardiac ischemia


middle cerebral artery normal and abnormal hemodynamics

[marked vasodilation]

[normal waveform]

[mild vasodilation]

Normal oxygenation

hypoxia


IPUA=p80

Cerebroplacental ratio is more sensitive than UA or MCA alone

CPR <p5

IPMCA=p20

=+



30 % venous return

REFLECTS DIASTOLIC PRESSURE IN RIGHT (AND LEFT) HEART


ductus venosus normal and abnormal hemodynamics

Venous vessel: pulsation due to retrograde pressure

S DA

ductus venosus normal and abnormal hemodynamics

compliance right chambers: effect sobre

on venous return

DS A

P

P

P

P

Myocardial ischemia

compliance

no


When and how to deliver

Return


Early-severe High risk IUFD preterm



Management = when should we deliver?

Savchev 2013

Late-mild Low risk IUFD (high at term)

Stage II to IV PROTOCOL

Stage I >37w


Perinatal >90% 30-‐40% <10% Mortality


<26 26-28 29-30

Baschat 2003 Hecher 2003 Grivell 2009 Cruz-‐Lemini 2012

Early-onset IUGR!PROBLEM #1: MORTALITY

DVa (rev)

Yes No

60%

19%

cCTG-‐STV<3 ms

Pathological CGT

BPP!IUFD 23% in BPP=6 and 11% in BPP=8!

Poor correlation with DVa(rev)!Cochrane: poor contribution to prediction

Baschat 2007, Kafur 2008, Lalor 2010,

31-34

Stage IIStage IIIStage IV


Neurological >90% 30-‐40% <10% Morbidity


<29 29-32 >32.0

Fouron 2004 Del Rio 2008 Cruz-‐Mar7nez 2012

Early-onset IUGR!PROBLEM #2: (NEUROLOGICAL) MORBIDITY

(%)

0

15

30

45

60

Controls IUGR ant AoI IUGR REV AoI

Neonatal brain US anomalies in 30-34w IUGR


37-38 w (+/- check lung maturity)!

Do not use prostaglandins (Foley/Balloon)!

Select high risk cases (MCA Doppler)


Late-onset IUGR !PROBLEM #1: WHEN AND HOW TO DELIVER



Cesarean section for fetal distress after labor induction in term SGA according to MCA Doppler

(N=202)

Cruz et al, 2010

(OVERALL RISK OF CS AFTER INDUCTION 80 %)

0"

10"

20"

30"

40"

50"

60"

70"

Cesarean"sec1on"for"distress"

Neonatal"acidosis"

AGA"

SGA"normal"MCA"

SGA"abnormal"MCA"


JAMA Pediatrics 2013


≥

RISK RESPIRATORY MORBIDITY


Bonet, UOG 2014


• N=144!• Singleton

pregnancies !• 29.0 - 38.6 w !• Axial thoracic

sectionNeonatal Respiratory Morbidity (*):!• Respiratory Distress

Syndrome!• Transient tachypnea of

newborn

(*) RDS: Respiratory symptoms (eg, g r u n7ng , fl a r i n g , t a c hypnea , retrac7ons), O2 requirement + chest Rx + NICU admission TT: chest Rx impression + clinical diagnosis by clinician in charge. JAMA 2010

Patient�&�Provider�Informationwww.quantusFLM.com

Sabino�Arana�38�1Ͳ108028�Barcelona,�SpainCIF:�BͲ65084675

PATIENT NAME: CLINIC NAME:

PATIENT ID: REFERRING/ORDERING CLINICIAN:

QUANTUSFLM�ID: REPORT�DATE:�(dd/mm/yyyy)

Name�Surname

NHC12345678

btechͲ123

Complete�Center�Name

Clinician�Name�Surname

01/01/2000

Sample�Information

GESTATIONAL�AGE:

US�ACQUISITION�DATE:(dd/mm/yyyy)

REQUEST�DATE:(dd/mm/yyyy hh:mm)

##�weeks #�days

01/01/2000

01/01/2000�00:00

Test�Result��NEONATAL�RESPIRATORY�MORBIDITY

QUANTUSFLM�ID:

RESULT:

Theoretical risk for ##�weeks of�gestation:

quantusFLM risk:

RECOMMENDATION:(dd/mm/yyyy)

AUTHORIZED�SIGNER/S:

Technical�Responsible:Elisenda Bonet�i�Carné,�MSc

Imatge Firma

CLINICAL�DATA�Ͳ SPECIFICATIONSAccuracy 87%�(95%�CI:82Ͳ90%)

Sensitivity 91%�(95%�CI:77Ͳ98%)

Specificity 86%�(95%�CI:82Ͳ90%)

Positive Predictive Value 47%�(95%�CI:35Ͳ59%)

Negative Predictive Value 98%�(95%�CI:96Ͳ99%)

TEST DESCRIPTIONquantusFLM™ offers an automatic assessment of neonatal respiratory morbidity risk using an ultrasoundimage of the lateral axial transverse section of the fetal thorax at the level of the 4Ͳchamber section of thefetal heart. quantusFLM™ is based on quantitative ultrasound texture analysis to extract information fromultrasound images and a classifier which uses the extracted information to assess the risk. Test resultdepends on the delineation of the fetal lung and incorporated the gestational age. Neonatal respiratorymorbidity is defined as respiratory distress syndrome or transient tachypnea of the newborn.Test has been validated in singleton pregnancies from 28.0 to 39.0 weeks of gestation. Test are neitherintended nor validated for use in pregnancies with fetal structural abnormalities, chromosomalabnormalities, multiple pregnancies or maternal BMI>35. This result should not be considered as a finalindication but as additional information to be considered in evaluation of the patient.

quantusFLM Test�is�intended�for�clinical�use�and�should�not�be�regarded�as�investigational�or�for�research.�Present�result�has�been�obtained�using�quantusFLM X.X.�Under�the�previous�of�Law�15/1999�normative,�we�inform�you�that�your�data�will�be�included�in�a�data�base�owned�by�TransmuralBiotech,�S.L.�for�its�clinical�treatment.�You�may�exercise�the�rights�of�access,�rectification,�cancellation�and�opposition�contacting�us�at�[email protected].

REFERENCE:�Quantitative ultrasound texture analysis of�fetal�lung to�predict neonatal�respiratory morbidity.�UOG�(2014)

NonͲInvasive Assessment of�therisk of�Neonatal�Respiratory morbidity

Graphic�Test�Result NEONATAL�RESPIRATORY�MORBIDITY�RISK

HIGH LOWRISK RISK

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

Theoretical Risk*

quantusFLM Risk

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

LOW�RISK

##.#�%

##.#�%

Review results with patient

btechͲ123



Performance of Quantus FLM and comparison with currently used lab

8quantusFLM® ha sido validado mediante 144 muestras ciegas.



Late IUGR with MCA<p5 Planned delivery at 37.0 weeks

LOW RISK =1.5%

Deliver

HIGH RISK =25%

Wait and follow-up until 37.6-38.0

PERSONALIZED: FETAL LUNG MATURITY

RISK RESPIRATORY MORBIDITY

BASELINE GA-ADJUSTED = 4%



Early and late-onset determines different severity, fetal response and natural history!

!

Doppler is the main tool for follow-up and timing of delivery in stage II to IV!

!

Stage I: challenge is to determine best timing and mode of delivery!

Return


Perinatal >90% 30-‐40% <10% Mortality


<26 26-28 >28

Baschat 2003 Hecher 2003 Grivell 2009 Cruz-‐Lemini 2012

BEING SMALL EARLY IN PREGNANCY IS A PROBLEM!PROBLEM #1: MORTALITY

DVa (rev)

Yes No

60%

19%

cCTG-‐STV<3 ms

Pathological CGT


Neurological >90% 30-‐40% <10% Morbidity


<29 29-32 >32.0

Fouron 2004 Del Rio 2008 Cruz-‐Mar7nez 2012

Early-onset IUGR!PROBLEM #2: (NEUROLOGICAL) MORBIDITY

(%)

0

15

30

45

60

Controls IUGR ant AoI IUGR REV AoI

Neonatal brain US anomalies in 30-34w IUGR



Significant increase in the risk of 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

e<p95

SGA

SGA = constitutionally small?

Significant increase in the risk of adverse neurodevelopment!

Eixarch et al. Ultrasound Obstet Gynecol 2008!Severi et al. Ultrasound Obstet Gynecol 2002!Figueras et al . Eur J Obstet Gynecol Reprod Biol 2008

BEING SMALL LATE IS ALSO A PROBLEM



%

Figueras 2011

SGA: proportion of perinatal adverse outcomes in 376 consecutive cases



IMPACT OF NON-DETECTED IUGR ON LATE FETAL MORTALITY!Barcelona!2005-2010

0%

10%

20%

30%

40%

50%

FGR Unknown Others

25%30%

45%

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

* **

**

* p <0.05!Adjusted for GA, maternal age, socioeconomic status and smoking

Satchev, 2012!Geva 2008!

Figueras 2008!Eixarch 2010

N=120 SGA vs !

100 AGA

* * *

Bay

ley

Sco

re

20

40

60

80

100

120

cognitive language motor socio-emotional adaptivebehavior

* * *



control IUGR

Crispi 2012

Crispi 2010

Cardiovascular programming in !SGA / late-IUGRFetuses EFW<p10 evaluated at 5 years!!Classified by CPR, p3 and UtA Doppler:!

•All normal: SGA!•Any abnormal: late-IUGR


Documents

update on diagnosis and management of fetal growth restriction