The Delivery Room Resuscitation of Infants with Congenital Diaphragmatic Hernia Treated with Fetoscopic Endoluminal Tracheal Occlusion: Beyond the Balloon Free

A congenital diaphragmatic hernia (CDH) occurs when the abdominal viscera herniates through a defect in the diaphragm. CDH is a relatively common birth defect occurring in up to 1 in 2,500 live births [1, 2] with significant mortality and morbidity related to the degree of pulmonary hypoplasia, the size of the diaphragmatic defect, and the presence of any associated anomalies [2‒6]. While prenatal measures such as lung-to-head ratio (LHR), observed-to-expected lung-to-head ratio (O/E LHR), and liver position are used to predict CDH severity [7‒9], these measures are imperfect, and some variables, such as the severity of pulmonary hypertension, cannot be known until the infant is born.

The Tracheal Occlusion to Accelerate Lung Growth (TOTAL) trials for the prenatal management of severe and moderate left CDH compared survival to neonatal intensive care unit discharge in fetuses with isolated left CDH. These multicenter, prospective, randomized controlled trials found that fetoscopic endoluminal tracheal occlusion (FETO) resulted in increased fetal lung volume and increased survival [9‒11]. However, the risks of FETO include increased risk of preterm rupture of membranes and preterm delivery. In infants with severe hypoplasia treated with FETO, the median gestational age at delivery was 34.6 weeks [11].

There are limited data to guide the delivery room resuscitation of infants with CDH, and ventilatory outcomes from the delivery room are highly variable. Our experience with infants treated with FETO demonstrated that these infants have unique challenges with transition to ex utero life. This study sought to compare the delivery room resuscitation of infants with CDH treated with FETO at the Children’s Hospital of Philadelphia in comparison to severe controls, as well as to describe important lessons learned.

A retrospective single-center cohort study was conducted for maternal child dyads affected by a prenatal diagnosis of CDH at our tertiary center between January 2017 and February 2023. Data were collected and validated using the Clinical Outcomes Data Archive [12]. The study was approved by the Institutional Review Board at the Children’s Hospital of Philadelphia (IRB 21-018553). Infants treated with FETO were compared to infants who met FETO inclusion criteria during the same period but who did not proceed with FETO and who received standard of care (SOC) due to parental preference after nondirective multidisciplinary prenatal counseling. SOC infants in this study differed from infants who met FETO inclusion criteria but who were excluded due to FETO exclusion criteria including (1) maternal factors: maternal age <18 years, maternal contraindications to fetoscopic surgery, severe maternal medical conditions in pregnancy, technical limitations precluding fetoscopic surgery, short cervical length, uterine anomaly predisposing to preterm labor, placental previa, history of preterm delivery, psychological ineligibility precluding consent, and inability to remain at FETO site during time of tracheal occlusion or (2) fetal factors: intrauterine fetal death, severe intrauterine growth restriction, cardiac anomalies, genetic syndromes, lung lesions, and multiple gestations. SOC infants had no fetal intervention and were born either via cesarean or vaginal delivery according to routine obstetric indications. The trace method was preferred for the O/E LHR ultrasound measurement. If the trace method was not conducted, particularly in the earliest years of this study, the AP method was used for eligibility. Patients were considered ineligible for the treatment or control group due to inclusion and exclusion criteria specified by FDA IDE submission. The criteria for FETO enrollment changed over the study period. The initial FDA investigational device exemption (G140236) and IRB-approved study protocol were limited to patients diagnosed with isolated left CDH where the liver was intrathoracic and the O/E LHR was less than 25%. In March 2017, study enrollment was expanded to include patients with isolated left CDH who had an intrathoracic liver and an O/E LHR measured between 25% and 30%. Due to evidence of unfavorable outcomes for the moderate arm in the TOTAL trial, this latter group was removed from study protocol in May 2021. In this study, only one infant with O/E 25–30% was included with the remaining 11 infants with O/E <25%. No infants with right CDH were included throughout the entire study period. Following birth, all infants were immediately intubated and resuscitated with a standard CDH delivery room protocol.

A team of neonatologists, pediatric surgeons, maternal fetal medicine specialists, pediatric otolaryngologists, pediatric anesthesiologists, advanced practice nurses, neonatal nurses, and neonatal respiratory therapists meets regularly while a balloon is in place to perform simulations of various scenarios of balloon removal. We utilize large monitors known as Critical Knowledge screens with an example shown in Figure 1 to facilitate a shared mental model of the steps needed for these emergency situations. For deliveries with the balloon in place, neonatology, surgery, otolaryngology, and anesthesiology are all present. If a mother presents in labor with a balloon in place, the preferred mode of delivery is an ex utero intrapartum treatment (EXIT) procedure with the mother under general anesthesia. If an EXIT procedure is not possible, a modified cesarean section is performed where the infant is intubated prior to cord clamping. In either scenario, the fetus is given an intramuscular injection of fentanyl 10 μg/kilogram (kg), vecuronium 0.2 mg/kg, and atropine 20 μg/kg under ultrasound guidance prior to the procedure. Infants may experience transient hypotension secondary to maternal or fetal medications. Despite this risk of hypotension, fetal anesthesia is administered to allow for the safest and quickest mode of balloon removal as neonatal movement can limit the ability to deflate the balloon. If the mother presents in active labor, a vaginal delivery is occasionally the only option. Bronchoscopy is performed for balloon removal, ideally prior to cord clamping. A fetoscope is also available and can be used; however, the expertise of an otolaryngologist can be beneficial, particularly in cases of difficult balloon removal. In all emergency scenarios, the infant is intubated and given surfactant immediately following balloon removal. At our center, surfactant (poractant alfa) is administered at the recommended initial dose of 2.5 mL/kg. After the balloon is removed and the infant is intubated, the infant is resuscitated with positive pressure ventilation using peak inspiratory pressures of 20–25 cm H20, positive end expiratory pressure of 5 cm H20, and a ventilation rate of 40–50 breaths/minute with a respiratory function monitor in place [13]. If an infant is born within 48 h of balloon removal, surfactant is administered immediately following intubation. If there is no response, the infant may need an otolaryngology and surgical airway evaluation with bronchoscopy and possible need for reintubation or rigid suction. Venous access is established with a peripheral IV or an emergency umbilical venous catheter. If the infant responds after initial resuscitation, they are transitioned to high-frequency oscillatory ventilation (HFOV) after the endotracheal tube (ETT) is secured. Initial FiO₂ is typically 0.5 and is titrated to achieve pre-ductal oxygen saturation goals of ≥85% by 10 min after birth. Following intubation and gastric decompression, umbilical arterial and venous lines are placed, and an arterial blood gas is obtained. A chest and abdominal X-ray is obtained to confirm ETT position and adequate gastric decompression. Infants born >48 h following balloon retrieval are resuscitated following typical delivery room guidelines.

Given known risk of tracheomegaly, a microcuffed ETT is used. For infants >2.5 kg, a 3.5 mm ETT is used; for infants 2–2.5 kg, a 3.0 mm ETT is used; and for infants 1–2 kg, a 3.0 uncuffed ETT is used. For any cuffed ETTs, the ETT is lubricated. Whenever possible, a course of antenatal steroids is administered prior to balloon removal and then again if it has been more than 2 weeks since balloon removal and delivery is planned while the fetus is still less than 37 weeks gestation. This is standard practice at our center to maximize lung maturation prior to delivery.

Main outcome measures included delivery room outcomes and neonatal intensive care unit outcomes such as extracorporeal membrane oxygenation (ECMO) therapy and survival. Due to the descriptive nature of this study and expected small sample sizes in the groups, no statistical power analysis was done in the design stage. Therefore, we report a description of the summary statistics without any formal statistical analysis.

Cohort characteristics are shown in Table 1. O/E LHR was <25% for 11/12 of the FETO infants with 1 infant with O/E LHR 25–30%. Preterm premature rupture of membranes occurred in 8/12 (66.7%) FETO infants compared to only 3/35 (8.6%) SOC infants. FETO infants were more likely to be born prematurely with 8/12 (66.7%) infants born <35 weeks of gestational age compared to 3/35 (8.6%) SOC infants. There were 5 infants who required emergent balloon removal (2 EXIT and 3 tracheoscopic removal at cesarean delivery prior to cord clamping) and 7 with prenatal balloon removal (6 fetoscopic removal, 1 prenatal ultrasound-guided needle puncture). Overall, there were 6/12 (50.0%) FETO infants who delivered within 48 h of balloon removal. DR outcomes are shown in Table 2. When the balloon was still in place at the time of delivery, it was removed or deflated immediately with placement of an ETT. Surfactant was administered in 6/12 FETO (50.0%) infants compared to 2/35 (5.7%) in the SOC group who were born prematurely. Infants treated with FETO had a higher first pH and lower first carbon dioxide level. ECMO use was lower at 25.0% and survival was higher at 91.7% compared to 60.0% and 71.4% in the SOC infants, respectively. While the FETO infants were more likely to be born prematurely, all infants were >2 kg at birth, and none were too small for ECMO.

The delivery room resuscitation of infants treated with FETO is unique. We compared the delivery room resuscitation of infants treated with FETO to severe controls treated with SOC. Infants treated with FETO were more likely to be born at <35 weeks gestational age and were more likely to have an emergent delivery and resuscitation compared to those treated with expectant management.

In the original observational clinical trial of FETO, 52% of infants were born with emergent balloon removal (11 EXIT, 35 fetoscopic removal, 29 ultrasound-guided puncture, 21 postnatal tracheoscopic removal, and 13 postnatal puncture through the neck) [14]. Similarly, 42% of our balloon removals were emergent. Since the trachea is occluded with the balloon in place, retrieval must occur quickly. This often requires an EXIT procedure or modified cesarean delivery and the presence of maternal fetal medicine specialists, pediatric surgeons, otolaryngologists, neonatologists, and anesthesiologists. Generally, an EXIT procedure is preferred whenever it is deemed safe for the mother to allow for the safest mode of balloon removal and resuscitation for the infant. This risk/benefit ratio is assessed and individualized to the mother and infant. Preparation for emergent balloon removal requires an experienced multidisciplinary team, and our team has found that ongoing simulation exercises aid in communication and improve patient care. Given our experiences, we developed the pneumonic “BSSR” balloon, secretions, surfactant, and recruitment to simplify the critical steps of resuscitation of these infants and developed a Critical Knowledge screen shown in Figure 1.

FETO has been shown to promote lung growth and alveolarization, as well as changes in the molecular composition of the lung [15‒18]. In lamb models, those treated with FETO with or without balloon removal had lung growth with normalization of lung parenchymal architecture and type II cell density; however, surfactant content and composition remained abnormal [19]. While steroid and surfactant administration improve respiratory gas exchange independently, the combination results in normalization of total lung capacity [20]. Although one preclinical study of surgically created lambs found that exogenous surfactant administration at birth did not improve gas exchange [21], we have found this relative surfactant deficiency to be evident clinically, and these infants may benefit from empiric surfactant therapy. We think this discrepancy highlights the physiologic differences between preclinical models and humans and the need for future clinical studies to better characterize the transitional physiology among newborn infants with CDH. Infants treated with FETO are known to have thick, tenacious secretions and should be suctioned with the largest possible suction catheter. If infants treated with FETO are delivered with the balloon in place or within 48 h of balloon retrieval, we administer surfactant immediately following intubation to loosen any mucous plugs, as well as a second dose following stabilization. While the timing of restoration of normal surfactant levels has not been studied in humans and this practice is empirical, surfactant was noted to improve gas exchange immediately with dramatic changes in compliance and retrieval of copious tenacious secretions. Surfactant lavage, use of a meconium aspirator, and reintubation may also be necessary. Unlike traditional surfactant administration, surfactant may need to be administered to blocked airways to remove thick casts of secretions prior to ventilation as ventilation may not be possible to achieve in some cases without it.

Tracheomegaly is a known side effect of FETO, although it does not affect survival or requirement for early respiratory support [22]. However, in the setting of known risk of tracheomegaly, we intubate all infants treated with FETO >2 kg with a microcuffed ETT. The median duration of delivery room stabilization was 16 min longer in the FETO infants, which likely reflects the complex resuscitation required, sometimes in the setting of delivery via an EXIT or cesarean delivery with immediate tracheoscopic balloon removal. Cesarean rates were higher in infants treated with FETO who were all delivered via cesarean section or EXIT. This is partially due to the need for balloon removal at the time of delivery in 5 (42%) infants. This is in contrast to the SOC infants where cesarean delivery was reserved for typical obstetric indications [23]. The delivery room resuscitation of infants treated with FETO requires thoughtful preparation and an experienced multidisciplinary team. As there is a survival benefit, FETO should be offered to infants with severe isolated left CDH, but only in high-volume centers with the experience and capability of emergently removing the balloon, delivering surfactant, and managing tenacious sections and other aspects of a complex neonatal resuscitation. This requires ongoing education and simulation. We acknowledge study limitations. This was a retrospective cohort study and therefore a non-randomized sample. This study included a relatively small sample size from a single-center and thus reflects our center’s protocol and not necessarily SOC. As a single center study, outcomes may also reflect practice management differences unique to our center. Within the scope of this study, we chose to evaluate hospital-based ventilatory outcomes and acknowledge that other important outcomes such as cardiac function, pulmonary hypertension, and other complications were not evaluated. We also did not report long-term neurodevelopmental outcomes. Finally, criteria for FETO enrollment changed over the study period. From 2017 to 2021, infants with O/E LHR 25–30% met FETO inclusion criteria. While there was only 1/12 FETO infants with O/E LHR 25–30%, there were 17/35 SOC infants. Despite having a more moderate O/E LHR, SOC infants still had worse survival and higher ECMO utilization than FETO infants, and the benefits of FETO may be underestimated in this study. Strengths of this study include granular data and observations from one of the largest cohorts of infants treated with FETO in the USA. This study fills an important knowledge gap specific to this high-risk population.

The DR resuscitation of infants treated with FETO requires thoughtful preparation with an experienced multidisciplinary team. Given increased survival, FETO should be offered to infants with severe isolated left-sided CDH, but only in high-volume centers with the experience and capability of removing the balloon, emergently if needed. The neonatal clinical team must be skilled in managing the unique postnatal physiology inherent to FETO where effective interdisciplinary teamwork is essential. Empiric and immediate surfactant administration should be considered in all FETO infants to lavage thick airway secretions, particularly those delivered <48 h after balloon removal.

This study was approved by the Institutional Review Board at the Children’s Hospital of Philadelphia (IRB 21-018553). For infants treated with FETO, written informed consent was obtained from the participants’ parent/legal guardian/next of kin to participate in the study.

The authors have no conflicts of interest to declare.

This study was supported by funding from the Children’s Hospital of Philadelphia Delivery Room of the Future Frontier Program and Congenital Diaphragmatic Hernia Frontier Program.

K.T.W., N.E.R., A.M.A., and H.L.H. conceptualized and designed the study, collected and analyzed the data, drafted the initial manuscript, and reviewed and revised the manuscript. J.S.G., J.S.M., L.M., S.F., A.B., T.R., R.L.R., L.R.J., O.N., W.H.P., E.A.P., and N.S.A. assisted in designing the study, analyzing the data, and reviewing and revising the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the responding author upon reasonable request. Further inquiries can be directed to the corresponding author.