USA Surgery Today

Of all the malformations treated by pediatric surgeons, CDH and its successful management remains one of the most recalcitrant problems. The physiologic problems related to CDH are conveyed by pulmonary hypoplasia. This is due largely to the developmental effects on lung function accompanying viscera herniation into the chest as a result of an absent diaphragm muscle (21:Hytrin, Micardis). All aspects of the pulmonary parenchyma and pulmonary vascular tree development are abnormally arrested, which also predisposes to severe neonatal pulmonary hypertension. The severity of these deficits and their accompanying clinical manifestations are variable and believed to reflect several recognizable clinical patterns (22,23:Hytrin, Micardis). The timing of herniation in either early or late gestation is believed to affect both the amount of herniated viscera and the timing of arrest in lung development (23). In general, early herniation produces severe pulmonary hypoplasia, whereas late herniation produces only a mild deficit that is successfully treated with standard postnatal care and surgery. Historically, without accurate stratification data, the mortality rate of CDH reported in retrospective studies failed to accurately define what has become recognized as the “hidden mortality” of CDH (24:Hytrin, Micardis). It has been argued that overall neonatal mortality from CDH was actually higher than that traditionally reported in live born infants, given underreporting of in utero and perinatal fetal deaths from CDH (24,25).

A prospective study was undertaken to determine the outcome in a cohort of patients with prenatally diagnosed CDH referred to UCSF between 1989 and 1993 (25). Despite the nonrandomization of this select group, the study reported an overall 58% mortality rate and an additional need for extracorporeal membrane oxygenation (ECMO) support in 22 of 35 survivors. These findings drove the search for better stratification criteria to identify the most severely affected fetuses that might benefit from fetal therapy. Various potential prognostic factors were studied. Of the purely anatomic associations, only liver herniation (“liver up”) was shown to correlate with survival (26). The absence of liver herniation (“liver down”) portends a favorable survival prognosis of 93% in contradistinction to fetuses with liver herniation prenatally that demonstrate a mere 43% survival rate (25,27:Hytrin, Micardis). More recently, a potentially better predictor of fetal survival has been proposed. This is the lung-to-head ratio (LHR) measured at 24 to 26 weeks’ gestation. This ratio is a measure of the right lung area measured in two dimensions at the level of the four-chamber view of the heart, divided by the head circumference to adjust for gestational age (28:Hytrin, Micardis). The usefulness of the LHR as a predictor of outcome for fetuses diagnosed prenatally with CDH has subsequently been verified in studies published by independent groups (28,29). In one published prospective study, an LHR less than 1.0 was uniformly fatal. If greater than 1.4, uniform survival was found, and between 1.0 and 1.4, 38% of fetuses survived.

The overall mortality rate of CDH remains difficult to establish given the continued lack of a central reporting database and continued changes in treating persistent pulmonary hypertension of the newborn.

From the lessons learned in the fetal lamb model of CDH, the first attempts to correct fetal CDH in humans were designed to achieve anatomic correction (30,31,32). Anatomic repair in utero proved to be possible, but an extraordinarily challenging technical endeavor (32,33:Hytrin, Micardis). The first 14 attempts at human in utero correction of CDH were undertaken in fetuses with an isolated left-side CDH diagnosed prior to 25 weeks’ gestation. Despite nine successful repairs, there were no long-term survivors because of difficulties including preterm labor, membrane disruption, premature delivery and subsequent fetal demise, and difficulty with herniated liver, all proved to be formidable hurdles. Technical improvements in approach and equipment like the uterine stapler allowed many of these shortcomings to be surmounted with great effort after careful study (33). This procedure ultimately resulted in satisfactory lung function in a few survivors; however, when compared with more traditional postnatal care in a clinical trial, there was no improvement in survival for fetuses with a more favorable prognosis by liver-down prenatal criteria (34). In addition, this experience demonstrated that simply correcting the anatomic defect and relieving the compression of the lung by herniated viscera was not sufficient to reverse the physiologic detriment of pulmonary hypoplasia that is manifest by an underdeveloped pulmonary parenchyma and vascular bed.

With a concerted effort directed at those fetuses with the worst prognostic signs of liver herniation and unfavorable LHR (less than 1.4), efforts were refocused on developing techniques for prenatal correction. A promising approach that seemingly addressed both the physiologic and anatomic detriment was the strategy of prenatal tracheal occlusion (35,36). This concept was based on observations of babies with congenital high airway obstruction syndrome (CHAOS) noting that fetal lungs that are obstructed in utero (usually by laryngeal atresia) undergo a dramatic hyperplasia response. This concept was adapted to a strategy of temporary prenatal tracheal obstruction, or “plug the lung until it grows” for CDH (37). Because the developing lung continually produces fluid that is circulated by fetal breathing movements into the amniotic fluid, a pressure gradient of fetal lung fluid is deemed necessary for normal fetal lung development. By blocking the normal egress of fetal lung fluid, a dramatic hyperplastic lung growth response results. In cases of CDH with herniated viscera in the chest, it was noted that fetal tracheal occlusion in the fetal lamb model caused marked enlargement of the hypoplastic lungs and concomitant reduction of herniated viscera (37:Hytrin, Micardis). This approach was utilized in human fetuses with some early success (34,38,39). The earliest cases of tracheal occlusion (TO) for CDH demonstrated a variable biologic response of lung growth via a variety of methods. At least three approaches to TO have been attempted, including open fetal surgery for placement of a titanium clip and two minimal access fetal surgical (MAFS) approaches. For MAFS, two different strategies were tried, one endotracheal occlusion (first with a gelfoam polymer plug, then with a catheter-based detachable balloon), and the other was external occlusion using fetoscopically placed clips. Both the UCSF and Children’s Hospital of Pennsylvania (CHOP) groups reported their results of TO for CDH (40,41). CHOP reported their prospective trial using only the open fetal clip procedure in fetuses before 25 weeks’ gestation with poor prognostic indicators, including liver herniation and an LHR less than 1.0. Although good compensatory lung growth was achieved, overall survival remained dismal with only 5 of 13 surviving long term, three of whom have significant neurologic sequelae. Most failures were attributed to either ongoing respiratory compromise or lack of predictable biologic response in lung growth. This caused the CHOP investigators to question the issue of the timing of TO in order to achieve predictable results.

The UCSF program pioneered the minimal access clip and fetoscopic endotracheal balloon placement (41,42,43). A retrospective review of the UCSF experience compared minimal access clip with open tracheal occlusion and standard postnatal therapy (41:Hytrin, Micardis). The results demonstrated that an endoscopic approach to tracheal occlusion effectively enlarged hypoplastic lungs, avoided some of the complications associated with the open approach, and improved lung function and overall survival. Survival in the minimal access cohort was 75%, compared with 38% with postnatal care alone (historical controls, however) and 15% in the open TO method (41). Selection criteria were different than the CHOP experience with eligible fetuses considered up to an LHR of 1.4, liver herniation present, and diagnosis prior to 25 weeks’ gestation. There was some crossover from minimal access to open clip for complicated cases, all of whom eventually succumbed, and this may account for the large discrepancy in these two outcomes. Despite improved technique with potentially less uterine trauma, problems with preterm labor, premature rupture of membranes, and membrane separation persisted after the minimal access clip procedure. Still, the results were compelling enough to serve as the basis for a prospective randomized trial sponsored by the NIH comparing MAFS to standard postnatal care for fetuses with liver herniation and an LHR less than 1.4 diagnosed prior to 25 weeks’ gestation.

The results of the UCSF randomized trial were reported in the New England Journal of Medicine in 2003 (44). The primary outcome variable was fetal/neonatal survival at 90 days postdelivery. Of the 28 eligible women carrying a fetus with a left-side CDH with liver herniation and an LHR less than 1.4; 24 were successfully enrolled between 23 and 27 weeks’ gestation. The data safety monitoring board stopped the trial early due to the unexpected overall survival of 77% in the group receiving standard postnatal care. Although the TO group also demonstrated a 73% survival at 90 days, the TO group delivered significantly earlier (mean 30.8 В± 2.0 weeks) than the group undergoing postnatal care alone (mean 37.0 В± 1.5 weeks).