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 provides room in the chest for the hypoplastic lung to develop. Whereas some specialized centers have reported a survival rate of close to 90% with this management, pooled results from more than 50 centers worldwide have indicated 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 pulmonary 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 midgestation. 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 fetal death.[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 lung overexpansion

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.)

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 fetoscopic endoluminal (or fetal endoscopic) tracheal occlusion (FETO) technique.[18, 19, 20, 21] It is important to note, however, that this enthusiasm has partly resulted from an inability to otherwise improve the overall survival for CDH over the preceding decades, as well as the significant comorbidities among survivors of severe CDH.[2] Strictly speaking, FETO for CDH remains an investigational therapy for which the long-term benefits have yet to be proved in well-controlled studies.[22, 23]

In 2021, the Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trial was published in the New England Journal of Medicine.[24] In this randomized controlled trial, which focused primarily on the results in 80 patients treated for severe left CDH with either FETO (n = 40) or expectant management (n = 40) across 10 European centers, the authors concluded that FETO improved overall survival to discharge. The rate of survival to discharge was 40% in the FETO group, compared with 15% in the no-FETO group.  

This study has been the subject of two main criticisms. The first concerns the low utilization of extracorporeal membrane oxygenation (ECMO), which has been shown to improve survival in neonates with CDH, in both groups. ECMO utilization was far less in the TOTAL trial (17%) than in the United States (30%).[25, 26]  The second criticism concerns the reported survival rates. The survival rate for severe CDH in the United States is approximately 50%, which is higher than those reported for both the FETO group and the no-FETO group in the TOTAL trial.[27]

As of October 2023, the North American Fetal Therapy Network (NAFTNET) is in the process of analyzing US and Canadian outcomes with FETO, but the findings have yet to be published. Thus, the use of FETO for severe CDH remains in equipoise.

Identifying fetuses with CDH who may benefit from FETO 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 (eg, significant underlying medical conditions) must be considered.

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

• Lung-to-head ratio (LHR)
• Observed-to-expected LHR (O:E LHR)
• Presence or absence of liver herniation
• Percent predicted lung volume (PPLV)
• Total lung volume (TLV)

The LHR and O:E LHR are measurements that can be made with US or MRI and are used to quantify the relative sizes of the lungs.[28, 29] An LHR of 1.0 or less signifies severe lung hypoplasia due to the CDH. More recently, fetal MRI has been used to calculate lung volumes in the form of PPLV and TLV, which correlate with respiratory morbidity.[30, 31, 32]

Inclusion criteria for the TOTAL trial included the following[24] :

• Maternal age 18 years or greater
• Singleton pregnancy
• Gestational age at evaluation less than 29 weeks 6 days
• Left-side CDH
• No other major structural or chromosomal defects
• Severe pulmonary hypoplasia (O/E LHR < 25%)

Currently, most centers offer FETO for severe (O/E LHR <  25%) left-side CDH. For moderate CDH and severe right-side CDH. FETO generally is not offered.[33]  

The following were exclusion criteria for the TOTAL trial[24] :

• Failure to meet all inclusion criteria
• Maternal conditions that might make fetal surgery challenging
• Technical limitations that would preclude fetal surgery (eg, those imposed by severe maternal obesity or uterine fibroids)
• Elevated risk of preterm birth (cervical length < 15 mm, müllerian anomalies, or placenta previa)
• Psychological and socioeconomic concerns

Fetal positioning is critical for successful balloon deployment. External fetal manipulation may be required to line up the fetal mouth with the entry site for the fetoscope. Before initiation of FETO, an intramuscular fetal cocktail containing a paralytic, a narcotic, and atropine is administered percutaneously. Under US guidance, a 3.3-mm cannula with an inner pyramidal trochar is introduced into the amniotic cavity. A 1.3-mm fiberoptic endoscope is introduced, as well as a delivery catheter to inflate and deploy an inflatable 0.8 mL balloon (Goldbal2). The balloon should be depolyed about 1 cm above the carina.  

There are multiple ways of deflating the balloon in utero. The author prefers a percutaneous approach using US guidance through the fetal back. Additional options include repeat fetoscopy with balloon puncture; as a last resort, an ex-utero intrapartum treatment (EXIT) procedure may be required, in which the fetus is maintained on placental circulation after the head is delivered via an open hysterotomy. The balloon is then deflated with the help of a rigid bronchoscope, and the fetus is delivered.  

After the original randomized controlled trial of FETO performed at UCSF,[16] other groups demonstrated an early survival benefit.[34, 35, 23] These studies were limited by the complex nature of the postnatal management of patients with CDH and by numerous variables that were difficult to control. Long-term functional outcomes following FETO for CDH have yet to be reported.

The TOTAL trial was the first study that robustly demonstrated a survival benefit to FETO for severe left-side CDH.[24] The authors concluded that FETO resulted in improved survival to discharge. Specifically, 40% of infants in the FETO group survived to discharge, compared with 15% in the expectant management group. Despite criticisms citing the low utilization of ECMO, this was a well-designed randomized controlled trial that has shifted the attitute around FETO. 

The most significant potential complications, specifically quantified in the 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.[36]

Tracheomegaly and tracheobronchomegaly have also been reported with a fairly high incidence.[37, 38] For most of these patients, there are minimal symptoms, such as a barking cough, though patients who require further airway procedures have been reported.[39, 40]

The risks, benefits, and potential complications are thoroughly reviewed with the patient.

Appropriate consultations are made with the pediatric surgeon, perinatologist, neonatologist, anesthesiologist, and social worker.

The patient is admitted to the obstetrical unit, and a baseline physical assessment is performed, including fetal heart rate and uterine contraction monitoring. The latest antenatal sonogram is reviewed, and indications for surgery are confirmed.

Preoperative laboratory tests include a complete blood count (CBC), blood type and screen, and urinalysis. Activity is ad libitum, and bedrest exercises are reviewed.

A 1.3-mm fetoscope within a 3.0-mm sheath (Karl Storz, Tuttlingen, Germany) and a detachable balloon occlusion system (BALTACCI-BDPE, Balt, Montmorency, France) are often used to placed the tracheal balloon under direct visualization.

The patient is kept on nil per os (NPO) status for 8 hours before surgery. Immediately before surgery, indomethacin for tocolysis may be administered, and perioperative antibiotics are given. Breakthrough contractions may be treated with intravenous (IV) magnesium sulfate. 

Depending on the surgeon's choice, anesthesia can range from local to locoregional to general.

After the procedure, the patient is readmitted to the obstetrical unit for monitoring.

Daily ultrasonography (US) and fetal echocardiography (if indicated) are performed. After the procedure on the day of surgery, the patient's diet is advanced as tolerated, and she remains in bed with lateral positioning. Owing to potential pulmonary edema, fluids are restricted to 3 L/day if the patient is treated with magnesium sulfate. Incentive spirometry and continuous pulse oximetry are instituted.

Fetal heart rate and uterine contractions are monitored until discontinued by the fetal treatment team. Tocolysis is achieved with indomethacin, magnesium sulfate, or nifedipine, as dictated by the fetal treatment team. On postoperative day 1, the patient is allowed to ambulate, and a CBC is performed.

The patient is discharged when she is ambulatory, is tolerant of a diet, is spontaneously voiding, has good pain control with oral medications, is afebrile with normal vital signs and reassuring physical examination findings, and has a normal fetal heart rate and minimal uterine contractions. Oral tocolysis is continued as needed.

Serial measurements of sonographic lung volume and O/E LHR should begin 24-48 hours following surgery and continue throughout pregnancy by US evaluation until balloon removal.

After appropriate counseling has been completed; the risks, benefits, and potential complications have been thoroughly reviewed; and it has been established that the family wishes to proceed, preparations are made for the fetoscopic endoluminal (or fetal endoscopic) tracheal occlusion (FETO) procedure.

The technique was originally described by Harrison et al[15] and subsequently outlined in detail by Deprest et al.[41] Briefly, after appropriate anesthesia is achieved, the uterine and fetal anatomy are carefully surveyed by means of ultrasonography (US). The placenta is avoided, and a laparoscopic trocar (usually a disposable central venous introducer sheath) is inserted by means of the Seldinger technique.

The fetoscope is introduced and maneuvered into the oropharynx, through the glottis, and into the trachea. The detachable balloon catheter is passed through the side-channel of the fetoscope, the balloon is inflated and detached, and then the fetoscope is withdrawn. Appropriate positioning of the balloon in the trachea is confirmed by means of US. (See the video and image below).

Since the development of the fetal tracheal occlusion technique, reversal of the occlusion has been recognized as an important part of the therapy, both to avoid the necessity of an ex-utero intrapartum treatment (EXIT) procedure[42, 43]  for delivery and to allow the lungs to recover from the distention forces that result in lung growth.[44]  Reversal is achieved through repeat fetoscopy and balloon removal 4-6 weeks after the initial procedure.

Some groups have advocated percutaneous aspiration of the balloon to deflate it, with the aim of avoiding a repeat fetoscopy. This is accomplished under US guidance. The clinician percutaneously traverses the posterior aspect of the fetus's neck with a spinal needle to aspirate the 8-mm balloon. Avoiding the lateral neck is critical to keep from injuring the carotid artery and jugular veins. This procedure is technically challenging but provides an alternative to a repeat fetoscopic procedure, which may increase the risk of premature delivery. In the future, more sophisticated tracheal occlusion devices may allow for more physiologic lung growth and development.[45]