Fetal Surgery for Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) affects approximately 1 in 2000 newborns. Although great strides have been made in the management of CDH, significant morbidity and mortality persist.

The current mainstay of treatment of CDH involves stabilization and respiratory support at birth, followed by closure of the diaphragmatic defect, which returns the abdominal organs to the abdominal cavity and makes room in the chest for the hypoplastic lung to grow. Whereas some specialized centers report a survival rate of close to 90% with this management, pooled results from more than 50 centers worldwide indicate the overall survival rate to be 71% with this standard postnatal therapy (CDH Study Group, September 2015).

Specific morbidities in survivors include neurodevelopmental, nutritional, sensorineural hearing, and pulmonary function deficiencies, all of which are most likely attributable to the severity of lung hypoplasia and pulmonary hypertension that accompany CDH. ^{[1, 2, 3]} The severe consequences of this congenital anomaly have led investigators to pursue methods of correcting CDH or its main consequence, lung hypoplasia, prior to birth; this allows more normal postnatal function.

Fetal surgery for CDH was originally proposed to involve open fetal surgery and repair of the diaphragmatic defect, similar to postnatal surgical care, in mid-gestation. Indeed, today, there are a handful of survivors of open fetal CDH repair. ^[4]

However, as advances were made in neonatal care, the postnatal survival rate among patients undergoing standard care (without fetal intervention) improved. In addition, pioneers in this endeavor found that the fetuses who could benefit most from fetal repair were also those who were most likely to die of the procedure.

The main challenge for these fetuses was that the liver was herniated into the chest, and when the liver was reduced back into the abdomen during open fetal repair, the blood flow through the umbilical vein and inferior vena cava became occluded, resulting in death of the fetus. ^[5] Fetuses without liver herniation typically had sufficient lung development to ensure a relatively good outcome with standard postnatal care.

As investigators struggled with this challenge, two main phenomena resulted in the evolution of the current paradigm of fetal intervention for CDH, as follows:

• Advent of minimally invasive surgical procedures ^[6]
• Recognition of a condition called congenital high airway obstruction syndrome (CHAOS), in which fetuses whose airways were occluded either by a tumor or an atresia developed oversized lungs

In the 1990s, the development and implementation of minimally invasive surgical techniques advanced at a rapid pace. The manufacture of small telescopes and various new surgical instruments allowed for further innovations. Simultaneously, irritation of the uterus and the threat of preterm labor were identified as major hurdles in fetal interventions.

Reasoning that minimal manipulation of the uterus would help reduce the risk of preterm labor, the technique of fetoscopic tracheal occlusion to promote lung growth was conceived. Initial studies demonstrated that manipulation of mechanical forces involved in lung development, namely the lung fluid production that distends the airways, could be applicable in the treatment of CDH. ^{[7, 8, 9]}

Additional laboratory investigations, mainly using the fetal lamb model of CDH, confirmed the feasibility and effectiveness of the tracheal occlusion procedure, leading to the first human interventions. ^{[10, 11, 12, 13, 14, 15]} Initially, a surgical clip was placed on the trachea through a neck incision. Although this technique effectively occluded the trachea, scarring and the development of tracheal stenosis were identified as significant adverse effects. Ultimately, fetal bronchoscopy with tracheal balloon occlusion emerged as an appropriate solution. (See the image below.)

Schematic of fetal tracheal balloon occlusion, using a catheter-based detachable balloon that is placed through the side channel of the fetoscope.

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Once the technique was refined, a National Institutes of Health (NIH)-sponsored randomized controlled trial of fetal tracheal occlusion versus standard postnatal care for severe CDH was conducted. ^[16] Although this trial did not demonstrate a survival advantage with tracheal occlusion, it was notable that the group who underwent tracheal occlusion was born significantly earlier than the control group. In addition, despite this prematurity, lung function in infancy was demonstrated to be possibly slightly improved in comparison with the control group. ^[17]

These findings have led to worldwide enthusiasm for the fetal balloon tracheal occlusion technique. ^{[18, 19, 20, 21]} It is important to note, however, that this enthusiasm partly results from an inability to otherwise improve the overall survival for CDH over the past two decades, as well as the significant comorbidities among survivors of severe CDH. ^[2] Strictly speaking, fetal tracheal occlusion for CDH remains an investigational therapy for which the long-term benefits have yet to be proved in well-controlled studies. ^{[22, 23]}

Identification of fetuses with CDH who may benefit from fetal tracheal occlusion has been a major challenge. Once the diagnosis of CDH is confirmed by an experienced radiologist by means of either ultrasonography (US) or magnetic resonance imaging (MRI), a careful evaluation must be conducted for any other major anomalies, such as cardiac defects or chromosomal abnormalities. In addition, any maternal operative risk factors, such as any significant underlying medical conditions, must be considered.

If all of these contraindications are excluded, further consideration is given to fetal intervention. The main prenatal determinants currently used in assessing the severity of isolated CDH are as follows:

• Lung-to-head ratio (LHR)
• Presence or absence of liver herniation

The LHR is a measurement that can be made with US or MRI and quantifies the relative size of the lungs. ^{[24, 25]} An LHR of 1.0 or less signifies severe lung hypoplasia due to the CDH.

Liver herniation is determined by using the same imaging modalities; at the University of California, San Francisco (UCSF), the presence of liver herniation is required for consideration of the fetal tracheal occlusion procedure. Evidence indicates that the amount of liver herniation into the chest may be a better predictor of disease severity than simple presence or absence of liver herniation. ^[26]

A complete listing of inclusion and exclusion criteria for fetal intervention for CDH is outlined below and in Contraindications.

The following are inclusion criteria for fetal surgery for CDH:

• Confirmed diagnosis of CDH
• Normal fetal echocardiography result
• Normal karyotype
• Liver is herniated into the left hemithorax
• LHR ≤1.0, calculated between 24 and 26 weeks' gestation
• Fetus is 26-28 weeks' gestation
• Singleton pregnancy
• Maternal age ≥18 years
• Meets psychosocial criteria as determined by social worker screening
• Preauthorization from a third-party payor for fetal intervention OR the ability to self-pay for study treatment

The following are exclusion criteria for fetal surgery for CDH:

• Failure to meet all inclusion criteria
• Other congenital anomalies detected on US
• Presence of a contraindication for abdominal surgery or general anesthesia
• Preterm labor, preeclampsia, or uterine anomaly (eg, a large fibroid tumor)
• Family is unable or refuses to stay near medical center for the duration of the tracheal occlusion period and for the duration of the pregnancy as medically necessary

After the original randomized controlled trial of fetal endoscopic tracheal occlusion performed at UCSF, ^[16] other groups demonstrated an early survival benefit. ^{[27, 28, 23]} These studies were limited by the complex nature of the postnatal management of patients with CDH and numerous variables that are difficult to control, but overall, the therapy remains promising for severely affected fetuses. Long-term functional outcomes following fetal tracheal occlusion for CDH have yet to be reported.

The most significant potential complications, specifically quantified in the four studies previously mentioned, include the following:

• Maternal death (0%)
• Fetal demise (0-2%)
• Preterm premature rupture of membranes (35-100%)
• Preterm delivery (50-73%)

The average gestational age at delivery was 31 weeks in the UCSF series and 35 weeks in the subsequent series. A systematic review and meta-analysis by Júnior et al corroborated these data. ^[29]

Tracheomegaly and tracheobronchomegaly have also been reported with a fairly high incidence. ^{[30, 31]} For most of these patients, there are minimal symptoms, such as a barking cough, though patients who require further airway procedures have been reported. ^{[32, 33]}