Fetal Tracheal Occlusion for Congenital Diaphragmatic Hernia: Does it help?
Debnath Chatterjee, Lynne Maxwell, Kha Tran
In today’s PAAD, two guest reviewers, Debnath Chatterjee and Kha Tran, who are authorities in fetal anesthesia and surgery (DC, KT) and I (LM) will review the results from two randomized controlled studies from the Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial in left-sided CDH fetuses with moderate or severe lung hypoplasia. Before reading today’s PAAD please take a moment for reflection. There are many days that changed American history and our lives, December 7th, Nine-Eleven, and today November 22. On this day in 1963, President John F. Kennedy was assassinated and America and the world changed forever. Lynne Maxwell MD
Original Articles
Deprest JA, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, Sago H, Johnson A, Wielgoś M, Berg C, Van Calster B, Russo FM; Randomized trial of fetal surgery for severe left diaphragmatic hernia. TOTAL Trial for Severe Hypoplasia Investigators. N Engl J Med. 2021 Jul 8;385(2):107-118. Epub 2021 Jun 8. PMID: 34106556
Deprest JA, Benachi A, Gratacos E, Nicolaides KH, Berg C, Persico N, Belfort M, Gardener GJ, Ville Y, Johnson A, Morini F, Wielgoś M, Van Calster B, DeKoninck PLJ; Randomized trial of fetal surgery for moderate left diaphragmatic hernia.TOTAL Trial for Moderate Hypoplasia Investigators. N Engl J Med. 2021 Jul 8;385(2):119-129. Epub 2021 Jun 8. PMID: 34106555
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm, characterized by herniation of abdominal contents into the chest, resulting in varying degrees of pulmonary hypoplasia and pulmonary hypertension. The majority of CDH cases are left-sided posterolateral defects. Approximately 60% of CDH cases are diagnosed prenatally. Upon referral to a tertiary care center, a comprehensive prenatal evaluation is performed that includes ultrasonography, fetal MRI, fetal echocardiography, and karyotyping. Lung area/head circumference ratio (LHR) is commonly used to assess the severity of pulmonary hypoplasia and predict outcomes. To correct for gestational age, LHR is often expressed as a percentage of observed-to-expected (O/E) LHR and classified as severe (15-25%), moderate (26-35%), and mild (36-45%) with an expected survival of 20%, 55%, and 85% respectively.1 Other prenatal predictors of poor outcomes include liver herniation, associated cardiac or chromosomal anomalies, low fetal MRI lung volume measurements, and right-sided CDH.2
Despite great advances in surgical and neonatal intensive care including lung-protective ventilation strategies and ECMO, the outcomes for infants with severe diaphragmatic hernia remain poor.
In the hopes of mitigating these poor outcomes, over the last two decades fetal interventions aimed at reversing or preventing pulmonary hypoplasia in CDH have been developed and refined, and the work has gone through four phases:3
1. Open fetal surgical patch repair, which involved maternal laparotomy and hysterotomy.
2. Open fetal surgical tracheal occlusion (TO) after maternal laparotomy and hysterotomy.
3. Endoscopic fetal TO after maternal laparotomy.
4. Percutaneous fetoscopic endoluminal fetal tracheal occlusion (FETO).
Prenatal TO prevents the normal egress of lung fluid through the upper airway into the amniotic cavity, resulting in accelerated lung growth with an increase in the number of alveoli and capillary vessels.4 The third phase, which involved maternal laparotomy at 22-27 weeks gestation and delivery of the fetus via an EXIT procedure at term did not result in better survival than standard post-natal care.5 The only current fetal intervention offered for CDH is FETO, which involves percutaneous fetoscopic-assisted placement of a tracheal balloon at 27-29 weeks gestational age (GA), and removal of the balloon at 34 weeks GA (Link to NEJM video). FETO is typically performed under maternal local, or regional anesthesia. Fetal analgesia and immobilization are ensured by fetal intramuscular administration of fentanyl, muscle relaxant, and atropine. If all goes well, the mothers benefit by avoiding a laparotomy and potentially being able to deliver vaginally.
The trials were conducted across 12 FETO centers in Europe, North America, Asia, and Australia, took approximately a decade to complete and were led by the group from Leuven, Belgium. Fetoscopic tracheal occlusion was performed at 27-29 weeks GA in fetuses with severe CDH and at 30-32 weeks GA in fetuses with moderate CDH. Reversal of tracheal occlusion was performed via fetoscopy or ultrasound-guided puncture of the balloon at 34 weeks GA in both groups of fetuses. Postnatal care was standardized in both groups. The primary outcome was survival to discharge from the NICU. Secondary outcomes included operative and pregnancy complications, neonatal complications, and survival to 6 months of age.
FETO at 27-28 weeks of gestation in fetuses with severe CDH resulted in significantly higher survival to discharge from the NICU than expectant care (40% vs. 15%), and this benefit was sustained at 6 months of age. However, FETO at 30-32 weeks of gestation in fetuses with moderate CDH did not show a significant increase in survival to NICU discharge or a reduction in the need for oxygen supplementation at 6 months of age. Following FETO, the risk of preterm premature rupture of membranes was 4.5 times higher in the severe CDH cohort and 3.8 times higher in the moderate CDH cohort than the expectant group. Similarly, following FETO, the risk of preterm birth was 2.6 times higher in the severe CDH cohort and 2.9 times higher in the moderate CDH cohort than the expectant group.
In the severe CDH cohort, there were two spontaneous fetal deaths (one in each group) without an obvious cause and one neonatal death related to balloon removal. In the moderate CDH cohort, there was one neonatal death after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death from failed balloon removal. Spontaneous balloon deflation occurred eight times in the trial.
While the data from this trial shows the efficacy of FETO in fetuses with severe CDH, the authors point out that “the findings should not be generalized to centers without extensive experience in fetoscopy, FETO, and balloon removal.” All the centers in the TOTAL trial performed a minimum of 36 fetoscopies per year (for all indications) and at least 15 FETO procedures before the first participant was recruited. Fetal therapy centers in North America that participated in the TOTAL trial include Baylor College of Medicine (Houston), Children’s Memorial Hermann (Houston), and Mount Sinai (Toronto). [CD1] [LM2] Results of the TOTAL trial further advance our understanding of the efficacy and outcomes of FETO and inform perinatal counselling for families with fetuses with severe CDH, which is associated with a terrible prognosis.
References:
1. Jani J, Nicolaides KH, Keller RL, et al. Observed to expected lung area to head circumference ration in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gyneceol. 2007; 30:67-71.
2. Benachi A, Cordier AG, Cannie M, Jani J. Advances in prenatal diagnosis fo congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2014; 19: 331-37.
3. Deprest JA, Nicolaides K, Gratacos E. Fetal surgery for congenital diaphragmatic hernia is back from never gone. Fetal Diagn Ther. 2011; 29: 6-17.
4. DiFiore JW, Fauza DO, Slavin R, et al. Experimental fetal tracheal ligation reverses the structural and physiological effects of pulmonary hypoplasia in congenital diaphragmatic hernia. J Pediatr Surg. 1994; 29:248-56.
5. Harrison MR, Keller RL, Hagwood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal congenital diaphragmatic hernia. N Engl J Med. 2002: 349: 1916-24.