Fetal Therapy

1. INTRODUCTION

• Definition: Interventions (medical, surgical, or gene-based) administered to the fetus in-utero to correct or ameliorate congenital abnormalities and improve postnatal outcomes.
• Paradigm Shift: Moves away from "termination vs. waiting" to viewing the "Fetus as a Patient".
• Goal: To prevent fetal death or halt the progression of disease that would otherwise result in irreversible organ damage or severe disability.

2. PREREQUISITES FOR FETAL THERAPY (Eurofetus Criteria)

Before undertaking any intervention, the following must be met:

1. Accurate Diagnosis: Confirmed by Level II USG, MRI, or Karyotype/Microarray.
2. Natural History: The condition must have a known poor prognosis if left untreated.
3. Absence of Other Lethal Anomalies: Fetus should not have co-existing lethal genetic defects.
4. Evidence: Proven benefit of the procedure in animal models or clinical trials.
5. Maternal Safety: Maternal risk must be minimal and acceptable.
6. Consent: Informed consent regarding risks to mother and fetus (and future pregnancies).

3. CLASSIFICATION OF FETAL THERAPY

Therapy is broadly classified based on invasiveness:

1. Medical (Transplacental): Drugs given to mother $\to$ Placenta $\to$ Fetus.
2. Minimally Invasive (Percutaneous/Fetoscopic): Needle or endoscope guided by ultrasound.
3. Open Fetal Surgery: Maternal hysterotomy to expose the fetus.
4. Ex-Utero Intrapartum Treatment (EXIT): Procedures during delivery while on placental support.

4. MEDICAL FETAL THERAPY (Pharmacologic)

Non-invasive and most commonly used.

A. Fetal Lung Maturation (Standard of Care)

• Indication: Risk of preterm delivery (24–34 weeks) due to PPROM, preeclampsia, or threatened labor.
• Agents: Betamethasone (12mg x 2) or Dexamethasone (6mg x 4).
• Mechanism: Accelerates surfactant production, reduces RDS, IVH, NEC, and neonatal mortality.
• Benefit: Improves neurodevelopmental outcomes.

B. Fetal Arrhythmias

• Supraventricular Tachycardia (SVT):
  • First Line: Digoxin (Transplacental).
  • Second Line: Flecainide or Sotalol (if hydrops develops, as Digoxin transfer reduces in hydrops).
• Congenital Heart Block (Immune):
  • Cause: Maternal Anti-Ro/La antibodies (SLE/Sjogren's).
  • Therapy: Dexamethasone (to reduce inflammation) + $\beta$-mimetics (Salbutamol) to increase heart rate.

C. Endocrine & Metabolic Disorders

• Congenital Adrenal Hyperplasia (CAH):
  • Drug: Dexamethasone started <7 weeks gestation (before genital differentiation).
  • Goal: Suppress fetal ACTH to prevent virilization of female fetus.
• Fetal Hypothyroidism (Goiter):
  • Drug: Intra-amniotic Thyroxine injection.
  • Goal: Reduce goiter size to prevent polyhydramnios and airway obstruction.

D. Infectious Disease

• Toxoplasmosis: Spiramycin (to prevent transmission) or Pyrimethamine/Sulfadiazine (if fetus infected).
• CMV: High-dose Valacyclovir (reducing viral load and hearing loss).

5. MINIMALLY INVASIVE SURGICAL THERAPY

Performed under Ultrasound or Fetoscopic guidance.

A. Ultrasound-Guided Needle Procedures

1. Intrauterine Transfusion (IUT):
   • Indication: Fetal Anemia (Rh Isoimmunization, Parvovirus B19).
   • Technique: Cordocentesis (Umbilical vein puncture). Transfusion of O-negative packed cells.
2. Shunt Placements (Catheters):
   • Vesico-Amniotic Shunt: For Lower Urinary Tract Obstruction (LUTO/PUV) to restore amniotic fluid and prevent pulmonary hypoplasia. (Trial: PLUTO - showed survival benefit but renal function often remains poor).
   • Thoraco-Amniotic Shunt: For massive pleural effusion/chylothorax causing hydrops.
3. Radiofrequency Ablation (RFA):
   • Used in monochorionic twins for selective feticide of an acardiac twin (TRAP sequence).

B. Fetoscopic Surgery (Video-Endoscopic)

1. Twin-Twin Transfusion Syndrome (TTTS):
   • Pathology: Unbalanced AV anastomoses in MC twins.
   • Procedure: Fetoscopic Laser Photocoagulation of placental vessels (Solomon technique).
   • Outcome: Standard of care for Stage II-IV TTTS; superior to amnioreduction.
2. Congenital Diaphragmatic Hernia (CDH):
   • Problem: Pulmonary hypoplasia due to bowel herniation.
   • Procedure: FETO (Fetoscopic Endoluminal Tracheal Occlusion).
   • Mechanism: A balloon is placed in the fetal trachea (26-28 weeks) $\to$ Lung fluid accumulates $\to$ Lungs expand ("Stretch to grow"). Balloon removed at 34 weeks.
   • Evidence: TOTAL Trial showed survival benefit in severe cases.
3. Amniotic Band Syndrome:
   • Fetoscopic lysis of constricting bands to prevent limb amputation.

6. OPEN FETAL SURGERY

Involves maternal laparotomy and hysterotomy. Highest risk to mother (uterine rupture).

Myelomeningocele (MMC) Repair

• Rationale: The "Two-Hit Hypothesis" (Primary neural tube failure + Secondary chemical trauma from amniotic fluid).
• Procedure: Closure of the defect at 23–25 weeks.
• Evidence: MOMS Trial (Management of Myelomeningocele Study).
  • Benefits: Reduced need for VP shunts (40% vs 82%), improved motor function (doubled likelihood of walking).
  • Risks: Preterm labor, uterine dehiscence, placental abruption.
• Current Status: Standard option for eligible candidates.

7. EXIT PROCEDURE (Ex Utero Intrapartum Treatment)

• Concept: A specialized delivery, not just a C-section.
• Indication: Major airway obstruction (Cervical Teratoma, Lymphangioma, CHAOS).
• Steps:
  1. Deep maternal anesthesia (uterine relaxation).
  2. Fetus partially delivered (head/shoulders).
  3. Placental circulation maintained (fetal oxygenation continues).
  4. Airway secured (Intubation/Tracheostomy).
  5. Cord clamped only after airway is secure.

8. FUTURE DIRECTIONS: GENE & STEM CELL THERAPY

• In-Utero Stem Cell Transplantation (IUSCT):
  • Rationale: Fetal immune tolerance allows engraftment without rejection.
  • Potential: Osteogenesis Imperfecta, Thalassemia, Sickle Cell.
• Gene Editing (CRISPR-Cas9):
  • Experimental correction of monogenic disorders (e.g., Surfactant Protein B deficiency, SMA) in animal models.

9. COMPLICATIONS & ETHICS