BIOL 6505 Invasive Fetal Therapy Stephen R. Carr Francois I. Luks - - PowerPoint PPT Presentation

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BIOL 6505 Invasive Fetal Therapy Stephen R. Carr Francois I. Luks - - PowerPoint PPT Presentation

Jun 21, 2023 8 likes •525 views

BIOL 6505 Invasive Fetal Therapy Stephen R. Carr Francois I. Luks Fetal Therapy Definitions: Fetal intervention Non-invasive (time, mode of delivery) Minimally invasive therapy Invasive therapy Fetal surgery EXIT

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BIOL 6505 Invasive Fetal Therapy

Stephen R. Carr Francois I. Luks

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Fetal Therapy

Definitions:

  • Fetal intervention
  • Non-invasive (time, mode of delivery)
  • Minimally invasive therapy
  • Invasive therapy
  • Fetal surgery
  • EXIT procedure
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Fetal Surgery

Problems and research:

  • Major maternal surgery (laparotomy)
  • Hysterotomy
  • Bleeding ++
  • Membrane integrity/rupture/separation
  • Intraoperative contractions
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Fetal Surgery

Problems and research:

  • Fragile fetus
  • Dehydration
  • Hypothermia (1°C per 5 min of surgery)
  • Direct fetal trauma
  • Cord manipulation
  • Complex operations!
  • Postoperative tocolysis and labor!
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Fetal Surgery

Solutions and research:

  • Back-biting hysterotomy clamps
  • Staplers
  • Absorbable staples
  • Anesthesia
  • Tocolysis
  • Halogenated gases
  • Postoperative: ideal agent?
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Fetal Surgery

Animal models:

  • Fetal rabbit
  • Basic physiologic principles
  • Fetal lamb
  • Quiescent uterus
  • Tolerant fetus
  • Long gestation (145 d)
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Fetal Surgery

Animal models:

  • Non-human primate
  • More realistic
  • Sensitive uterus
  • Last step before clinical application
  • Rhesus monkey
  • Baboon
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Fetal Surgery

Types of operations:

  • Lower urinary tract obstruction (LUTO)
  • Pulmonary hypoplasia prevention
  • Congenital diaphragmatic hernia (CDH)
  • Pulmonary hypoplasia prevention
  • Large CCAM
  • Pulmonary hypoplasia prevention
  • Avoid/reverse fetal hydrops
  • Sacrococcygeal teratoma
  • Avoid fetal hydrops and maternal ecclampsia
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Fetal Surgery

Results:

  • 100% preterm labor
  • High fetal mortality (condition-specific)
  • CDH: 14% survival
  • SCT: 0% survival
  • Vesicostomy: 75% renal failure
  • CCAM: 60% survival
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Fetal Surgery

Results:

  • Maternal complications
  • Blood transfusion

12%

  • Pulmonary edema

12-16%

  • Tocolysis

(average duration) 90.0 hours

  • ICU stay (average stay)

9.6 d

  • Mandatory subsequent C/S
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Open fetal surgery

Maternal complications:

Harrison MR, SPO 1995

Preterm labor Transfusion Amniotic fluid leak Mirror syndrome Pulmonary edema Pseudomembranous colitis Wound infection

N %

42 100 5 12 2 5 2 5 5 12 1 2 1 2

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Open fetal surgery

Results: the MOMS trial (N=78)

Adzick NS et al, 2011

Chorioamniotic separation Delivery > 36-37 wk Pulmonary edema Placental abruption Intact hysterotomy wound

N %

20 26 16 21 5 6 5 6 49 64

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Fetal Surgery

Conditions that have to be met:

  • Correct prenatal diagnosis
  • Correct differential diagnosis
  • Known natural history
  • Condition lethal if left untreated
  • No available postnatal treatment
  • Fetal operation feasible
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Fetal Surgery

So… What’s left?

  • Spina bifida
  • MOMS trial
  • Diaphragmatic hernia
  • Open repair: results worse than postnatal R/
  • Endoscopic repair: tracheal occlusion trial
  • CCAM, SCT
  • Only extreme, exceptional cases
  • Urinary tract obstruction
  • Only percutaneous, sometimes
  • TTTS, Acardiac twin
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  • Minimally invasive surgery
  • Percutaneous vs. open endoscopy vs. laparotomy
  • Local vs. regional vs. general anesthesia
  • Access and exit techniques
  • Risks:
  • Chorioamnionitis
  • Preterm labor
  • Membrane rupture/PPROM
  • Amniotic leak
  • Bleeding

Technique:

Laser Ablation for TTTS

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A V A V A V A V

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Instrument: 1 port, Mini-Endoscope

1.9 mm diameter Sheath 3 mm diameter 400 µ laser Low-flow irrigation

Laser Ablation for TTTS

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The operating room

Laser Ablation for TTTS

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0.50 0.60 0.70 0.80 0.90 1.00 30 60 90 120

Postoperative days Survival

Recipient Donor

Twin-to-twin Transfusion - Laser

Car SR et al SMFM annual meeting 2006

Do the patients survive?

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Congenital Diaphragmatic Hernia

One-Slide Background

  • Herniated viscera compress the lungs
  • Hypoplastic lungs function poorly
  • Decades ago: 80% mortality at birth
  • Prenatal repair of the hernia too invasive
  • 14% survival
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Congenital Diaphragmatic Hernia

One-Slide Background

  • Fetal tracheal occlusion makes the lungs grow
  • Works great in animal models
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Type II cell Fibroblast

STRETCH IL-6,11 PGE2 secretion Fluid excretion Cl - Cl - TG uptake and release TG incorporation

IGF, HGF, KGF, EGF, TGF-β

DNA synthesis PL synthesis SP synthesis MAP kinase cAMP PGE2 PTHrP

Late Lung Maturation

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Type II cell Fibroblast

STRETCH PGE2 secretion Fluid excretion Cl - Cl -

SPACE- OCCUPYING MASS

Late Lung Maturation

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Type II cell Fibroblast

↑STRETCH

IL-6,11 PGE2 secretion Fluid excretion Cl - Cl - TG uptake and release TG incorporation

IGF, HGF, KGF, EGF, TGF-β

DNA synthesis PL synthesis SP synthesis MAP kinase cAMP PGE2 PTHrP

TRACHEAL OCCLUSION

Late Lung Maturation

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Fetal Surgery

Diaphragmatic hernia

  • Tracheoscopy and detachable balloon
  • Prenatal surgery ‘no better’ than postnatal treatment
  • Moratorium in U.S.
  • European experience encouraging
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Tracheal balloon L lung R lung 8/3/07 9/18/07

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Fetal Tracheal Occlusion

Now what?

  • Late, temporary occlusion works
  • Rapid lung growth and proliferation
  • Investigational Device Exemption (FDA)
  • Three centers in the US:
  • Brown
  • UCSF
  • Baylor
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Spina Bifida

Outcome of fetal surgery

First report: Adzick NS et al? Bruner JP et al?

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Spina Bifida

Outcome of fetal surgery

First report: Adzick NS et al? Bruner JP et al?

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Spina Bifida

Adzick NS et al, 2011

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Spina Bifida

Adzick NS et al, 2011

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Results (%)

Fetal Control P

  • Shunt criteria met

65 92 <0.01

  • Shunt placed

40 82 <0.01

  • Hindbrain herniation

64 96 <0.01

  • Baylor Psychomotor

64.0 58.3 0.03

  • Walking unassisted

42 21 0.03

Adzick NS et al, New Engl J Med 2011

Spina Bifida: MOMS Trial

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Complications (%)

Maternal complications Fetal Control P

  • Pulmonary edema

6 0.03

  • Placental abruption

6 0.03

  • Chorioamnionitis

3 0.24

  • Preecclampsia

4 0.12

  • Blood transfusion

9 1 0.03

  • Uterine wound intact

64

Adzick NS et al, New Engl J Med 2011

Spina Bifida: MOMS Trial

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Spina Bifida

Now that the MOMS trial is over

Standard of care? What about maternal safety? What about the trial effect?

  • Future results may not match the MOMS results
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Spina Bifida

Now that the MOMS trial is over

Minimally invasive approach? (Didn’t work in 2002, but how about now?)

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Fetal Surgery Spin-off: The EXIT Procedure

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EXIT Procedure

Multidisciplinary team:

  • Obstetrical Anesthesia
  • Maternal-Fetal Medicine
  • OB OR Nurses
  • Pediatric Anesthesia
  • Pediatric Surgery
  • Pediatric ENT
  • Pediatric Radiology
  • Pediatric OR Nurses
  • Neonatologists
  • Respiratory Therapists
  • Neonatology Nurses
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Tracheostomy

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No. Gestational Age Indications mean Range Reversal of tracheal occlusion 13 31.8 29-37 Giant fetal neck mass 13 36.0 32-40 EXIT-to-ECMO 1 36 Resection of CCAM 1 38 Unilateral pulmonary agenesis 1 39 Bridge to separation for conjoined twins 1 34 CHAOS 1 31 Overall 31 34.2 29-40

The EXIT Procedure: Experience and Outcome in 31 Cases

By Sarah Bouchard, Mark P. Johnson, Alan W. Flake, Lori J. Howell, Laura B. Myers, N. Scott Adzick, and Timothy M. Crombleholme

Philadelphia, Pennsylvania

Journal of Pediatric Surgery, Vol 37, No 3 (March), 2002: pp 418-426

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The EXIT Procedure: Experience and Outcome in 31 Cases

By Sarah Bouchard, Mark P. Johnson, Alan W. Flake, Lori J. Howell, Laura B. Myers, N. Scott Adzick, and Timothy M. Crombleholme

Philadelphia, Pennsylvania

Journal of Pediatric Surgery, Vol 37, No 3 (March), 2002: pp 418-426

Table 2. Duration of Uteroplacental Gas Exchange Minutes on Uteroplacental Indications Support (range) Reversal of tracheal occlusion 26.7 ± 6.3 (18-38) Giant fetal neck mass 29.2 ± 16.4 (8-54) EXIT-to-ECMO 58 Resection of CCAM 66 Unilateral pulmonary agenesis 14 Bridge to separation conjoined twins 43 CHAOS 25 Overall 30.3 ± 14.7 (8-66)

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The Ex Utero Intrapartum Treatment Procedure: Looking Back at the EXIT

By Shinjiro Hirose, Diana L. Farmer, Hanmin Lee, Kerilyn K. Nobuhara, and Michael R. Harrison

San Francisco, California

Journal of Pediatric Surgery, Vol 39, No 3 (March), 2004: pp 375-380 Table 1. Indications and Outcome Data for EXIT Procedure Indication for EXIT CDH 45 Neck mass 5 CHAOS 2 Outcome data for EXIT procedures Survivors 27 (52%) Female:male 1:2 Gestational age at birth (wk) 31.95 ± 2.55 Birth weight (g) 1895 ± 853 Maternal blood loss (mL) 970 ± 510 Time on placental support (min) 45 ± 25 Tracheostomy-dependent (n of patients) 6