Moscow 2011 25minchildrens.memorialhermann.org/uploadedFiles/_Library...Delivery < 34 wks:25% •...
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20-3-2012 1 Prenatal management of the fetus with isolated Congenital Diaphragmatic Hernia Jan Deprest Center for Fetal Medicine Department Woman and Child, Division Woman University Hospitals Leuven Leuven, Belgium On behalf of the FETO consortium A number of instruments and devices are used of label The presenter has no financial interests to disclose Prenatal Diagnosis of CDH Diaphragm hypoechogenic line between lungs – viscera Screening programmes should pick up CDH Raises the question of prognosis 13 wk 21 wk 27 wk Contact: [email protected] Outline Outline Prenatal Prediction Prenatal Prediction Experimental Fetal Therapy Experimental Fetal Therapy Clinical Fetal Therapy Clinical Fetal Therapy Results Results TOTAL trial TOTAL trial Issues & Questions Issues & Questions Contact: [email protected] Outline Isolated Congenital Diaphragmatic Hernia • Prenatal diagnosis & prediction of outcome of i‐CDH • Planimetric methods • Volumetric methods • Vascular assessment • Prenatal therapy • Rationale and experimental basis • Current clinical technique • Results • Currently investigated within randomized trial
Transcript of Moscow 2011 25minchildrens.memorialhermann.org/uploadedFiles/_Library...Delivery < 34 wks:25% •...
20-3-2012
1
Prenatal management of the fetuswith isolated Congenital Diaphragmatic Hernia
Jan DeprestCenter for Fetal MedicineDepartment Woman and Child, Division Woman
University Hospitals LeuvenLeuven, Belgium
On behalf of the FETO consortium
A number of instruments and devices are used of labelThe presenter has no financial interests to disclose
Prenatal Diagnosis of CDH
Diaphragm
hypoechogenic line between lungs – viscera
Screening programmes should pick up CDH
Raises the question of prognosis
13 wk 21 wk
27 wk
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OutlineOutline Prenatal PredictionPrenatal PredictionExperimental
Fetal Therapy
Experimental
Fetal Therapy
Clinical
Fetal Therapy
Clinical
Fetal TherapyResultsResults TOTAL trialTOTAL trial
Issues &
Questions
Issues &
Questions
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Outline
Isolated Congenital DiaphragmaticHernia
• Prenatal diagnosis & prediction of outcome of i‐CDH• Planimetric methods• Volumetric methods• Vascular assessment
• Prenatal therapy• Rationale and experimental basis• Current clinical technique• Results
• Currently investigated within randomized trial
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Congenital Diaphragmatic Hernia
Increasingly being picked up in screening programmes
Few in utero problems
Postnatal:
correctable defect
ventilatory insufficiency
pulmonary hypertension
long term morbidity
Overall outcome
associated: 85% mortality
isolated: 30% mortality
Deprest et al, Sem Fet Neonat Med 2009
Reduced number of airwaysAbnormal compliance
CDH
normal
Reduced and
abnormal vessels
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Survival and hidden mortality
Isolated CDH n TOP rate survival till discharge
Gallot 2007 314 7% 63%
Steege 2003 185 n.a. 70 %
Schaible 2006 244* ‐ 70%
Hedrick 2007 89 n.a. 66%
Datin‐Dorrière 08 99 20% 63%
Mettauer 09 147 postnatal series 77%
Grushka 2009 121 postnatal series 81%
* In utero referral in third trimester, ECMO policy of 50%; case load 35 cases/year** isolated only, courtesy G Ryan & D Bohn , University of Toronto, Canada (May 2010)
Mt Sinai (2000‐2009)** 86 15% 65%
Sick Kids (2002‐2009) ** 45 Postnatal series 85%
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Fetal Therapy
Experimental
Fetal Therapy
Clinical
Fetal Therapy
Clinical
Fetal TherapyResultsResults TOTAL trialTOTAL trial
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Issues &
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Liver position
Liver herniationAntenatal CDH registry 2006
Mullasery UOG 2010Mayer Prenat Diagn 2011
Survival: 74% → 45%
Prediction prognosis
Lung to Head Ratio (LHR)Metkus 1996
Antenatal CDH registry 2006‐8Knox 2010Alfarai 2011
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Metkus et al, 1996
Jani et al, 2006
Peralta 2005
Lung to head ratio
• LHR increases with gestation(Peralta, 2005)
• Different methods of which the tracing method is most accurate (Jani, 2006)
• Using correct nomogram, expressed as a percentage what is expected in normal fetus, provides gestational ageindependent size estimation
Observed/expected LHR
OBSERVED Fetal Lung Area
(fetus at risk for lung hypoplasia)
EXPECTED Fetal Lung Area
(matched normal fetus)
matched fetus
based on
gestational age
area measured
0.5
area predicted
2.0
O/E = 25%
Methodology and discussion in Claus et al, Fet Diagn Ther 2010
Right lung
18 22 26 30 34 38
Gestation (wks)
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Lung area to head
circumference
ratio
18 22 26 30 34 38
Gestation (wks)
0
10
20
30
40
50
60
70
80
90
Observed / Expected LHR (%)
O/E LHR discounts effect of gestational age
Fetuses with left CDH (n=329)
100
Peralta et al 2005Jani et al 2007
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Fetal Therapy
Experimental
Fetal Therapy
Clinical
Fetal Therapy
Clinical
Fetal TherapyResultsResults TOTAL trialTOTAL trial
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Issues &
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< 15 15‐25 26‐35 36‐45O/E LHR (%)
0
10
20
30
40
50
60
70
80
90
100
Survivalrate (%)
46 and higher
extreme
liver in abdomen (“down”)liver in thorax (“up”)
severe moderate mild
Current algorithm
Antenatal Registry – Jani et al, UOG 2008
(n=329 LCDH) ‐Deprest J et al, Sem Neonat Fetl Med, 2008.
1% 14% 45% 40%
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Clinical
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Isolated CDH eiter expectantly managed (n=100)
Jani et al UOG 2009
≤25 26‐45 >45
Patch rate (%)
0
10
20
30
40
50
60
70
80
90
100
O/E LHR (%)
0
10
20
30
40
50
60
Conventional ventilation
days
≤25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
Enteral feeding
days
<25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
NICU**
days
<25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
70
80
90
≤25 26‐45 >45
O/E LHR (%)
Oxygen O2 at 28d (%)
100
Early neonatal morbidity indicators
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O/E LHR and CDH
• Normative data for calculation expected LHR ‐Peralta et al, UOG 2005
– Calculation formula based on the raw data – Deprest et al, Fet Diagn Ther 2010
– available as calculator on www.totaltrial.eu
• Antenatal registry CDH:– Prediction of mortality : Jani et al, UOG 2006 (LHR), 2007 (O/E LHR)
– Accuracy versus GA: Jani et al, UOG 2008
– Prediction of morbidity: Jani et al, UOG 2009
– Validation with pathology: Jani et al, UOG 2011 (on line)
• Learning curve: Cruz‐Martinez et al, UOG 2010
• Recent meta‐analysis: Knox et al, J Mat Fet Med 2010
• Assessment methods reviewed in Claus et al, Fet Diagn Ther 2011
2 versus 3 dimensional
Cross section at the 4 chamber view
Of ONE lung
volumetric measurement
of two lungs and of liver herniation
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≤ 25 26‐35 36‐45 > 45
Observed to expected total FLV (%)
0
10
20
30
40
50
60
70
80
90
Survivalrate (%)
Liver up
Cannie et al UOG 2008
20% survival rate
~ 33%
Multicenter studies prediction on volumetry
Cannie et al UOG 2008 – n = 40 – 35 LCDH
0 10 20 30 40 50
LiTR (%)
0
10
20
30
40
50
60
70
80
o/e TFLV (%)
Liver to thorax ratio (LiTR)OR survival: 0.87 (0.79‐0.95) (p=0.003)
o/e Total Fetal Lung Volume (TFLV)OR: 1.16 (1.04‐1.30) (p=0.09)
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False positive rate (%)
Sensitivity
(%)
1007550250
100
75
50
25
0
2D‐USMRI
MRI may be better than 2D LHR in predicting outcomeIsolated CDH born alive >30 wks, paired observations (n=76
Cannie et al UOG 2008
O/E LHR rather than volumetry ?
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Prenatal prediction: lung vasculature
Measurements of– Pulmonary artery diameters
(Sokol et al.AJOG;2006)
– Flow velocity waveforms(Laudy 1997; Sivan 2000; Fuke 2003, Moreno UOG 2008)
– Resistance within (Rizzo, UOG 1996; Mitchell, UOG 1998; Chaoui, UOG 1999)
– Power Doppler imaging(Mahieu‐Caputo, 2004, Ruano 2004‐6)
– Fractional moving blood volume (Hernandez‐Andrade, UOG 04; Moreno, UOG 2010; Cruz –Martinez , UOG 2010)
– Hyperoxygenation test(Broth 2002, Doné UOG 2010)
Proximal branch intrapulmonary artery
Fractional Moving Blood Volume (FMBV)
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Clinical
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Clinical
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Lung growth is triggered by tracheal occlusion
Flake et al, 20000
Congenital
High
Airway
Obstruction
Anatomical repair → Tracheal Occlusion
Jost 1948 , Carmel 1960, Di Fiore & Wilson 1994
Luks & Deprest, Leuven 1995‐1996
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Fetal Tracheal Occlusion
normal surfactant
85 % ↓ periphericmuscularization
Tracheal Occlusion In utero reversal TO
prevention of egress of produced lung fluidmechanotransduction induces lung growth
Temporary Fetal Tracheal Occlusion
improves postnatal pulmonary function
Abnormal differentiation ( Lipsett 1998); ↓AE2 ( De Paepe 1998); ↓ surfactant ( O’Toole 1996)
Flageole H, et al: J Ped Surg 1997Evrard V, et al, Ann Surg 1997Roubliova X, et al. J Ped Surg, 2004Roubliova X, et al, Am J Obstet Gynecol, 2004Davey et al, Ped Research 2003
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Clinical Experience
Prenatal Diagnosis 2010
University Hospitals Leuven
Jan DeprestKarel AllegaertToni Lerut
King’s College Hospital London
Kypros NicolaidesAnne GreenoughMark Davenport
Hospital Clinic Barcelona
Eduardo GratacosAna Martin Ancel
Monsterrat Castanon
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Experimental
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Clinical instruments
• Fetoscope 1.3 mm• Off label use
• deported eye piece
• pixels: 17,000
• 11540AA (K Storz, Germany)
• Sheath (3.0 mm)+ forceps
+ needle
• catheter and balloon• Baltacci catheter & Goldbal2
Balt (20*7 mm, France)• Off label use
Deprest et al, J Ped Surg 2011 Testing prior to use
Gynecol Surg 2010
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Lessons learned from FETO experience
lung <25% & liver in thorax
Isolated lesion
Ideal protocol
Balloon in at 26‐28 weeks
Reversal at 34 weeks
Clinical Procedure (n=210 by 2008)
• 3.3 mm; loco(‐regional)
• 10 min
• pancuronium 0.2 mg/kg
• fentanyl 10 µg/kg
Deprest et al, 2005; FETO Consortium, UOG 2009
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0
10
20
30
40
50
60
70
26‐27 28‐29 30‐31 32‐33 > 34
Gestation at delivery (wks)
% Median 35 wks
Median GA
@ birth: 35.3 wks
(26‐41 wks)
Related to GA @ FETOGA @ PPROM
PPROM ≤3 wks: 16.7%Dependent on operation time
Conservative management
~25%
Gestational age at delivery
Need for urgent balloon retrieval
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Retrieval of balloon
Ideally in utero at 34 weeks
Enhances lung maturation
Allows vaginal delivery
Allows transfer to referring unit
Earlier than planned:
As late as possible
just prior to delivery
or at the time of earlier delivery
Tracheoscopy
or puncture
7%
Exit
21%
Fetoscopy
50%
Ultrasound
Guided
19%
% in a consecutive series of 210 cases – FETO consortium UOG 2009Removal balloon >24 h prior to delivery increases survival (p<0.001; Done SMFM 2011)
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Emergency postnatal extraction(ideally on placental support)
Cause of neonatal death in ~5%in unprepared/inexperienced hands
(1/5 of unscheduled postnatal extractions)
(nearly always) AVOIDABLE1. Patient must be near experienced hands
2. Make emergency removal easier
Prototype bronchoscopewith fiber endoscope& extraction forceps
FP7 programme – www.eurostec.eu
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FETO experience
FETO consortium, UOG 2009
Left sided 175 49.1%
Isolated 158 49.4%
+ cardicac 6 50%
+ CCAM 7 57.1%
+ pleural effusion 2 50%
+ del chromosome 8 missed on karyotype 2 0%
Right sided 34 35.3%
Isolated 29 35.3%
+ CCAM 1 0%
+ pleural effusion 4 25%
Bilateral 1 0%
Type n (%) survival
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Results FETO
< 15 15‐25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
70
80
90
100
Survivalrate (%)
Right (contralateral) lung O/E LHR vs survival
FETO Consortium, UOG 2009n=210 – 175 LCDH – 158 iLCDH
PPROM ~ 20% < 34 wks• most common complication• operation time dependent
Delivery < 34 wks: 25%• urgent need for balloon removal
Gestational age: 35.3 wks median
Survival rate:<20% → 50% for L‐CDH0% → 35% for R‐CDH
Survival is related to• lung size (LHR)• gestation at delivery (p<0.001)• balloon removal >24 hrs (p<001)Peralta, AJOG 2007 – Jani, UOG 2009 – Done 2012
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Isolated left CDH – FETO experience
0
10
20
30
40
50
60
70
80
<29 wks 30‐31 wks 32‐33 wks 34 wks +
% of population % survival
Survival below 32 wks ~ controlsSurvival beyond 32 wks is ~ 60%
Same at 32‐33 as 34 wks +
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Isolated CDH eiter expectantly managed (n=100) or FETO (n=90)
Done et al 2012 (UOG, in press)
≤25 26‐45 >45
Patch rate (%)
0
10
20
30
40
50
60
70
80
90
100
O/E LHR (%)
0
10
20
30
40
50
60
Conventional ventilation
days
≤25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
Enteral feeding
days
<25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
NICU**
days
<25 26‐45 >45
O/E LHR (%)
0
10
20
30
40
50
60
70
80
90
≤25 26‐45 >45
O/E LHR (%)
Oxygen O2 at 28d (%)
100
FETO decreases morbidity
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www.TOTAL trial.eu
Tracheal
Occlusion
To
Accelerate
Lunggrowth
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< 15 15‐25 26‐35 36‐45
O/E LHR (%)
0
10
20
30
40
50
60
70
80
90
100
Survivalrate (%)
46 and higher
extreme
liver in abdomen (“down”)liver in thorax (“up”)
severe moderate mild
2 randomized trials
From : Sem Neonat Fetl Med, 2008.
FETO [27 – 29+6 wks]
vs. expectant
Outcome measure:
Survival
Kicked off Leuven: Q2/2011
Barcelona
Paris, London
FETO [30‐31+6 wks]
vs. expectant
Outcome measure:
Survival w/o BPD
Started: 10/2008
48 inclusions
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isolated left CDH – normal karyotype
SEVERE (<25%, liver up or down)MODERATE (26‐35%, any liver& 36‐45%, up)
measurement
standardized postnatal therapy
counseling and consentweb randomization 1:1
FETO 27‐29+6w
unplug≤34+6 w
expectant management
REFERING CENTER
FETO 30 ‐ 32+6w
Flow of patient
FETO CENTER
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Clinical
Fetal TherapyResultsResults TOTAL trialTOTAL trial
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Issues &
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www.totaltrial.eu
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Trachea
Breysem et al, 2010 (Radiology)
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Trachea
• In follow up progressive relative decrease(Breysem et al, Radiol 2010)
• Iatrogenic damage at the time of problematicremoval (McHugh et al & Deprest et al, Pediatr Radiol 2010)
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Conclusion
• Prenatal diagnosis of CDH and assessment of prognosis is feasible– Functional prediction must be improved
• Fetal Endoluminal Tracheal Occlusion
– minimally invasive intervention with limited maternal side effects
– might improve prognosis
– associated with PPROM & preterm labour
– must be evaluated in a properly designed trial
– long term follow up is being gathetered at this stage
• Identification of those not salvageable by FETO– Smallest lungs: alternatives?
– Individual profiling : “personalized medicine” based on –omics profile
