The editors and current author would like to thank and acknowledge the significant contribution of the previous author of this chapter from the 2004 first edition Dr. Rodney B. Boychuk. This current third edition chapter is a revision and update of the original author’s work.
A male infant is born to a 23 year old G1P0 mother with no prenatal care at 39 weeks gestation (based on last menstrual period) via NSVD (normal spontaneous vaginal delivery). Following delivery, the baby cries immediately; however, at 1 minute of age, he has an APGAR score of 5 with severe cyanosis and an HR less than 100. The neonatal resuscitation team is called to the delivery room. On arrival, the resuscitation team notes that the respiratory effort is poor so bag-mask ventilation is initiated; however the abdomen is scaphoid, there are no breath sounds on the left, and heart tones are louder on the right. A diaphragmatic hernia is immediately suspected and the patient is intubated. Color and heart rate improve. An orogastric (OG) tube is inserted to decompress the stomach. The patient is brought to the NICU where a chest x-ray confirms a left sided diaphragmatic hernia with bowel in the left hemithorax.
Congenital diaphragmatic hernia (CDH) is rare, occurring in approximately 1 in 2500 to 5000 births with a slight predilection for males (1-4). Advances in obstetric screening have facilitated in utero diagnosis of CDH in 50% to 60% of patients. Antepartum diagnosis not only allows for potential prenatal interventions, but also, the development of management plans and transfers of infants to care to facilities that are better equipped for patients with higher acuity. Despite improvements in perinatal management, this condition is still associated with a 30% to 50% mortality rate (5). Most of these deaths occur within the first year of life. Infants surviving this perinatal period are still at increased risk of morbidity, thus requiring an interdisciplinary team.
CDH is characterized by a structural defect in the diaphragm that may range from a small opening to complete absence of the diaphragm. The most common anomaly is the defective fusion in between the transverse septum and pleuroperitoneal membranes (1,6). In any case, the primary culprit for patient morbidity and mortality is the accompanying pulmonary hypoplasia.
Embryologically, the diaphragm forms during the sixth week of gestation with the fusion of four structures: the pleuroperitoneal membranes, the dorsal mesentery of the esophagus, the transverse septum, and the body wall. This formation, which becomes the diaphragm, then separates the intrathoracic cavity from the intra-abdominal contents.
The exact embryological defect that results in CDH is still debated. It was initially thought that CDH was caused by the failure of fusion by the four aforementioned structures, as seen in rat models with defects in the primordial diaphragm (i.e., the pleuroperitoneal fold). This aberrant development results in a persistent pleuroperitoneal canal, allowing the intra-abdominal viscera to herniate into the chest cavity, and subsequently impeding adequate lung growth. The other major hypothesis proposes that pulmonary hypoplasia precedes the formation of the diaphragmatic hernia. Research using rat models found that an alteration in lung bud development also affected the post hepatic mesenchymal plate, which is a structure that normally influences diaphragmatic development (1,6).
Genetics, environmental exposures, and nutritional deficiencies have also been implicated in the pathogenesis of CDH. Possible mechanisms include disturbances in the vitamin A pathway, low retinol and retinol-binding protein levels, nitrogen exposure, and mutations in WT1 and COUP-THII genes (1,6).
Regardless of etiology, the herniation of abdominal viscera into the thoracic cavity is associated with a corresponding lack of pulmonary development that is more significant on the side of the defect. The most common type of CDH is the Bochdalek hernia (80% to 90%), a defect in the posterolateral aspect of the diaphragm. The next most prevalent type is the Morgagni hernia (6%), which is located in the anterior or retrosternal aspect of the diaphragm. Rarely, CDH may be central. 80% to 85% of CDH defects are on the left, while <5% are bilateral (1,7,8).
This reduced pulmonary development is characterized by the underdevelopment of the pulmonary vessels and decreased branching of the distal respiratory tree and alveoli. The diminished pulmonary vasculature leads to decreased perfusion, while the attenuated respiratory branching and alveoli formation result in restricted ventilation, oxygenation, and gas exchange. 70% of patients developing pulmonary hypertension within the first week of life (5). These all manifest in neonatal respiratory distress with severity corresponding to the degree of hypoplasia. Despite the high prevalence of pulmonary hypertension by one week of life, the pulmonary hypertension resolves in most infants between weeks 1 and 3 of life. The presence of severe pulmonary hypertension at 2 weeks of life has a strong association with morbidity and mortality (4).
Despite major advancements in the field of ultrasonography, 20% to 40% of CDH cases are not detected antenatally (8). CDH is typically an incidental finding on routine ultrasound (US) and may be detected as early as the first trimester; however, earlier diagnosis is associated with poor prognosis (8). Antenatal US findings include polyhydramnios, chest mass, fluid-filled stomach in the thoracic cavity, or in severe cases, hydrops fetalis. The inappropriate position of the stomach and esophageal compression impair swallowing, which may result in polyhydramnios. The primary objective of early, antenatal diagnosis of CDH is determining the severity of the defect. This can be done by assessing the lung area to head circumference ratio (LHR), identifying the position of the liver, and estimating fetal lung volume. These measurements also may aid in assessing prognosis.
If CDH is not diagnosed antenatally, these neonates may present as a neonatal emergency in the delivery room. The primary sign associated with CDH is respiratory distress. Depending on the severity of pulmonary hypoplasia and pulmonary hypertension, infants with CDH may present up to 48 hours after birth. Infants in respiratory distress caused by CDH typically do not respond to the usual measures of neonatal resuscitation and may even worsen with bag-mask ventilation (BMV). In addition, physical examination reveals diminished or absent breath sounds in the affected side with increased heart sounds on the contralateral side, tachypnea, and scaphoid abdomen. As the stomach and bowel fill with gas (exacerbated by BMV), cardiopulmonary functions are further compromised, leading to progressive hypoxia and respiratory acidosis. The neonate exhibits escalating respiratory distress, cyanosis, and ultimately bradycardia.
A chest radiograph confirms the diagnosis. On x-ray, the air-filled stomach or bowel is seen occupying the affected hemithorax with resultant displacement of the mediastinum and heart to the contralateral side. Of note, CDH has been misdiagnosed as a tension pneumothorax, with acute respiratory distress temporarily relieved by needle decompression. This x-ray finding of a hyperlucent hemithorax due to intrathoracic gastric dilatation alone is an unusual presentation of CDH in the neonatal period. Careful examination of the abdomen on x-ray is crucial, since the absence of the stomach bubble in the left upper quadrant of the abdomen is an important radiologic clue to make the diagnosis. Identification of a naso- or orogastric tube in the thorax assists in the confirmation of the diagnosis. Further imaging, including echocardiography, may be required in patients with inconclusive findings or severe cardiac anomalies (5).
Most cases of CDH (60%) have an isolated diaphragmatic defect, with associated pulmonary hypoplasia and/or persistent pulmonary hypertension of newborn (PPHN) with resulting cardiac dysfunction. However, 40% of CDH cases can be associated with other congenital anomalies. These include gastrointestinal, cardiac, or genitourinary abnormalities, in addition to, chromosomal aneuploidy (e.g., trisomies 13, 18, 21, and Turner syndrome). Thus, genetic analysis in conjunction with antenatal US findings may assist prenatal planning and counseling, including early pregnancy termination (20% to 50% of cases), possible in utero intervention, and preparation for birth at a perinatal center (3).
The differential diagnosis of CDH may be split into prenatal and postnatal diagnoses. On antenatal US, structural defects in the diaphragm with or without corresponding pulmonary hypoplasia can represent any of the following differential diagnoses (3,9): congenital diaphragmatic eventration, bronchogenic cysts, congenital pulmonary airway malformation (cystic adenomatoid malformation), pulmonary sequestration, pulmonary agenesis. Postnatal respiratory distress is associated with congenital/neonatal disorders, including: neonatal respiratory distress syndrome, transient tachypnea of the newborn (TTN), meconium aspiration syndrome, other causes of pulmonary hypoplasia (Potter sequence with renal hypoplasia, oligohydramnios).
The infant born with CDH remains one of the most complex patients to manage. Although the structural defect in the diaphragm can be surgically corrected in the postnatal period, little can be done for the existing pulmonary hypoplasia. Pulmonary hypoplasia and pulmonary hypertension with the resulting persistent hypoxemia remain the leading cause of death in CDH (10). Current research is focused on the perinatal period and how best to intervene both surgically and medically with the ultimate goal of limiting the degree of pulmonary hypertension or treating it as soon as possible. Over the last decade, there has been a significant improvement in the understanding of the pathophysiology of CDH and its management with the development of many new treatment options that were not previously available (5).
The management of CDH focuses on several key strategies: gentle ventilation with permissive hypercapnia, hemodynamic monitoring, attenuation of pulmonary hypertension, and eventual surgery once the patient is stabilized. The European Congenital Diaphragmatic Hernia (CDH EURO) Consortium most recently produced an updated version of their CDH management guidelines in 2015. They recommend routine intubation of all patients with CDH at birth when the prenatal diagnosis is known. BVM ventilation is to be avoided since this results in gastric expansion (11,12).
During the stabilization period, it is recommended to perform an echocardiographic assessment within the first 4 to 12 hours to assess the patient’s cardiac anatomy and biventricular systolic and diastolic functions. Echocardiography is also used to evaluate for pulmonary hypertension and to identify associated major congenital heart disease. It is paramount to avoid aggressive fluid resuscitation in these patients since it can exacerbate their symptoms. Echocardiography also aids in the decision of medication adjuncts that may be used in the management of pulmonary hypertension (12,13). Although inhaled nitric oxide (iNO) is commonly considered for pulmonary hypertension, it has not been found to improve survival or reduce the need for ECMO in patients with CDH and may even be detrimental to patients with left ventricular (LV) dysfunction (6,11). Therefore, iNO may be considered if there are no signs of LV dysfunction; however, it should be promptly discontinued if there is no clinical improvement. Similarly, prostaglandin E1 may be used to maintain the ductus arteriosus patency in severely hypoxic patients, but only in the absence of right ventricular failure. In the setting of ventricular dysfunction, milrinone (phosphodiesterase 3 inhibitor) has both inotropic and lusitropic (myocardial relaxation during diastole) effects on the heart in addition to being a pulmonary vasodilator. This reduces pulmonary vascular resistance and may assist in managing pulmonary hypertension. Other pulmonary vasodilators such as sildenafil (phosphodiesterase 5 inhibitor), bosentan (endothelin receptor antagonist), and epoprostenol (prostaglandin I2 analog) have an important role in long term pulmonary vessel stabilization; however, there is little evidence of their effectiveness in the acute stabilization period. There are some reports of sildenafil augmenting pulmonary vessel development when given antenatally, but its efficacy is still being explored in ongoing studies (11).
Nonetheless, for patients in critical respiratory distress with progressive hypoxemia secondary to severe pulmonary hypertension, the 2015 CDH EURO Consortium recommends considering IV sildenafil for symptomatic relief. If intubation is indicated, premedication with sedatives is recommended to reduce stress (12).
If there is high suspicion for CDH but it has not been confirmed, it is safer to intubate than bag-mask ventilate the infant, as BMV can result in overexpansion of the stomach or bowel in the thoracic cavity and lead to further respiratory distress. A naso- or orogastric tube should be placed to decompress the stomach, which can result in considerable clinical improvement.
Although there are no recent guidelines in the US, both the European and Canadian guidelines emphasize the importance of stabilizing the neonate by ensuring adequate oxygenation and perfusion, while simultaneously minimizing high pulmonary pressures. This is primarily achieved by intubation. Importantly, ventilation should be gentle, to minimize the complications of volutrauma and barotrauma. Key principles for gentle ventilation include limiting the peak inspiratory pressures (PIP) to <25 cm H2O; aiming for a preductal saturation between 80% to 90% and postductal saturation >70%; and targeting a PaCO2 of 50 to 70 mmHg with permissive hypercapnia to a pH of 7.2. These strategies reduce the risk of lung injury, requirement for extracorporeal membrane oxygenation (ECMO), and overall mortality. If higher PIP is needed, utilizing high-frequency oscillatory ventilation (HFOV) or ECMO may be used as rescue therapies (13).
If the patient cannot be stabilized with conventional mechanical ventilation or HFOV, ECMO or extracorporeal life support (ECLS) provides an alternative treatment option for these patients. ECLS involves the cannulation of the infant’s vessels with a cardiopulmonary bypass pump that circulates the infant’s blood through artificial gas-exchange membranes and then returns the oxygenated blood to the infant. CDH is the most common cause of neonatal respiratory distress that requires ECMO/ECLS. There are no strict criteria for the utilization of ECMO, but common indications include failure of conventional medical and ventilatory management with persistent hypoxemia, persistent oxygenation index (OI) >40 (OI = mean airway pressure X FiO2× 100 / PaO2), or symptomatic left ventricular dysfunction. Several antenatal US findings have been associated with the increased need for ECLS postnatally: observed to expected LHR <25%, liver herniation >20%, and observed to expected total fetal lung volume <25%. Relative contraindications to ECMO include infants born at 32 weeks of gestation or less and/or weighing less than 1,700 to 2,000 grams, as these patients’ vessels may be too small to cannulate (14). In addition, infants with concomitant major congenital heart disease or genetic abnormalities/syndromes may also be considered contraindications for ECLS.
ECMO is not without risks. The bronchial and pulmonary vascular hypoplasia seen in CDH both aggravate the risk of ventilator-induced lung injury, which can still occur during ECLS. The aforementioned ventilation strategies to reduce volutrauma, barotrauma, and atelectrauma are still relevant in the use of ECMO. In addition, the duration of ECMO should also be considered, since prolonged ECMO treatment is correlated with reduced survival rates after 2 weeks (15).
Recent studies have demonstrated that tracheal obstruction stimulates fetal lung growth which has opened the doors for new treatment options for severe CDH. An exciting clinical trial completed in 2021 found significant benefit when performing Fetoscopic Endoluminal Tracheal Occlusion (FETO) on patients with severe left sided CDH and pulmonary hypoplasia at less than 29 weeks 6 days of gestation. FETO works by inserting an inflatable balloon into the fetus’s trachea at 28 weeks, at the beginning of rapid lung maturation, and removing it several weeks later at gestational week 34. The balloon is inflated after insertion into the trachea to keep it in place, similar to a foley balloon. This procedure can be performed with the mother under local anesthesia and has low maternal risk. Compared to expectant management, patients who received FETO had increased rates of both survival to discharge and survival up to 6 months of age. Unfortunately, the study also found that FETO increased the risk of preterm, prelabor rupture of membranes (PPROM), and preterm delivery. Of note, this treatment has only been studied in singleton pregnancies with maternal age greater than 18 years, CDH without other major structural or chromosomal abnormalities, and an observed to expected LHR of <25% (7).
The optimal timing of post delivery surgical management is still under debate, but most clinicians wait until 24 to 48 hours after improvement or stabilization of the patient’s pulmonary hypertension. For patients receiving ECMO with a severe CDH phenotype, earlier surgical repair of the structural defects contributing to hypoxia may be more beneficial than waiting for the ability to wean completely from ECLS (16,17). Clinicians must evaluate the advantage of clinical stability prior to surgery, the likelihood of being able to wean the patient off ECMO, and the complications of delaying surgical repair.
The surgical repair of CDH depends on the severity of the defect and stability of the patient (17). Typically, a subcostal approach is used for adequate visualization to safely reduce the herniated contents into the abdomen. If the abdominal cavity is not large enough to house the herniated contents, a Silastic (silicone) patch may be used for temporary abdominal closure. Ideally, the CDH should be closed with a primary repair of the diaphragmatic tissue. If the defect is deemed too large, a Gore-Tex (polytetrafluoroethylene) patch is typically used to augment the repair. Of note, children with patch repairs have increased rates of CDH recurrence as the child grows, since the patch itself does not expand (10).
Minimally invasive (laparoscopic and thoracoscopic) techniques have been reported in relatively stable infants, but there are no studies comparing these approaches to the conventional abdominal approach.
Advances in therapeutic modalities and the increased availability of ECMO have significantly improved survival rates for patients with CDH, with survival rates up to 70% to 90% in non-ECMO infants and up to 56% in infants who underwent ECMO (6,17). These survival rates, however, underestimate the mortality secondary to termination or stillbirth due to severe CDH.
Several scoring systems have been developed to predict disease severity using objective measurements taken in the postnatal period. The Brindle CDH mortality risk model uses birth weight (<1500g), Apgar score at 5 minutes (<7 or missing), degree of pulmonary hypertension on echocardiography, presence of a major cardiac anomaly, and identification of chromosomal abnormalities to calculate a risk assessment (18). Other predictors associated with poor prognosis include severe pulmonary hypoplasia, other major structural anomalies, symptom onset within 24 hours of birth, and need for ECMO (6). In a retrospective study conducted in 2016, patients that did not require ECLS only had a mortality of 1.1% compared to 44% in the group requiring ECLS. If patients on ECLS survive to CDH repair, overall survival is 65% (16). Overall, studies have found that delaying surgical repair to allow for respiratory stabilization produces a more favorable survival rate (16).
The most effective way to predict morbidity and mortality is the degree of the structural defect, using the observed to expected LHR, as a proxy measurement. If the observed to expected LHR is <25%, patients are classified as having severe lung hypoplasia with survival rates <25%. The observed to expected LHR can also be used in predicting the associated complications, such as, the need for extended ventilation, use of supplemental oxygen, and prolonged time on enteral tube feeding (6,18).
Infants surviving the perinatal period are at increased risk of long-term complications of the cardiopulmonary, gastrointestinal, neurologic, and skeletal systems. Chronic respiratory conditions are the most common morbidity sustained by long-term survivors, with the overall incidence of 33% to 52% among patients with CDH (3). Patients with severe pulmonary hypertension requiring ECMO and/or patch repair are at the highest risk of chronic pulmonary complications.
Patients with patch repairs are at the highest risk of recurrent diaphragmatic hernias. Gastroesophageal reflux disease (GERD) is also a common complication among children with CDH, especially when the defect includes the esophageal hiatus. If the intestines were involved in the CDH, intestinal obstruction, volvulus, and adhesions have all been reported complications. Most CDH cases are known as true defects between the abdominal and thoracic cavities, but about 20% of CDH cases have a non-muscular pleuroperitoneal sac covering the abdominal organ contents known as a hernia sac type CDH. These hernia sacs are associated with increased survival and less severe pulmonary hypertension. Interestingly, even patients with liver herniation, which normally predicts a higher mortality rate, have a survival of 93% when there is also presence of a hernia sac (19).
The risk of neurocognitive deficits is significant in children who survive with CDH. Many perinatal interventions increase this risk further, with patients who have undergone ECLS having the highest incidence of neurological complications, including neurodevelopmental delay and sensorineural abnormalities (2).
In summary, advancements in both the early diagnosis and treatment of CDH have made a remarkable difference in long-term survival of patients with CDH. Despite this, CDH remains a difficult condition to manage with high rates of mortality and morbidity. If not diagnosed via antenatal ultrasound, these patients may present in the delivery room in respiratory distress that does not respond to initial standard resuscitation measures. The key elements of management are gentle ventilation with permissive hypercapnia, early treatment of pulmonary hypertension, and clinical stability prior to definitive surgical repair. Ongoing research is focused on improving strategies during this perinatal stabilization period and therapeutic modalities to facilitate pulmonary development in utero.
Questions
1. The earliest way to diagnose a congenital diaphragmatic hernia is by:
a. physical examination
b. history
c. fetal ultrasound
d. fetal CT scan
2. Which of the following confirms the diagnosis of congenital diaphragmatic hernia?
a. neonatal respiratory distress with signs of hypoxia within 24 hours of delivery
b. chest x-ray showing bowel loops and NG tube in the thoracic cavity
c. acute respiratory distress relieved by needle aspiration
d. echocardiography revealing pulmonary hypertension
3. Which of the following fetal imaging findings is most likely associated with the poorest prognosis?
a. Visualization of a hernia sac on imaging
b. Total fetal lung volume of 45% on MRI
c. Observed to expected total fetal lung volume of 45% on ultrasound
d. Lung area to head circumference ratio (LHR) of 45% on ultrasound
4. Treatment of congenital diaphragmatic hernia includes:
a. immediate surgical repair
b. reducing herniated contents back into the abdominal cavity while still in the delivery room
c. provide immediate optimal resuscitation and stabilization prior to surgical repair
d. always closing the defect with primary repair of the native diaphragmatic tissue
5. Which of the following statements are true regarding congenital diaphragmatic hernias?
a. Patients who received ECMO have a survival rate of about 50%.
b. The surgeon does not need to worry about long-term medical problems since they are typically resolved prior to surgical repair.
c. There are essentially no medical problems after surgical repair.
d. The long-term outcome of survivors reveals no significant chronic pulmonary problems.
Neonatal x-rays with several congenital diaphragmatic hernias: www.hawaii.edu/medicine/pediatrics/neoxray/neoxray.html
References
1. Ameis D, Khoshgoo N, Keijzer R. Abnormal lung development in congenital diaphragmatic hernia. Sem Pediatr Surg. 2017;26(3):123-128. doi:10.1053/j.sempedsurg.2017.04.011
2. Danzer E, Hoffman C, D’Agostino JA, et al. Short-Term Neurodevelopmental Outcome in Congenital Diaphragmatic Hernia: The Impact of Extracorporeal Membrane Oxygenation and Timing of Repair. Pediatr Crit Care Med. 2018;19(1):64-74. doi:10.1097/PCC.0000000000001406
3. Harting MT, Holinger LE, Lally KP. Chapter 24. Congenital Diaphragmatic Hernia and Eventration. In: Holcomb GW, Murphy JP, St. Peter SD, Gatti JM (eds). Holcomb and Ashcraft’s Pediatric Surgery, 7th edition, 2020. Elsevier, Philadelphia, pp: 377-402.
4. Lusk LA, Wai KC, Moon-Grady AJ, Steurer MA, Keller RL. Persistence of Pulmonary Hypertension by Echocardiography Predicts Short-Term Outcomes in Congenital Diaphragmatic Hernia. J Pediatr. 2015;166(2):251-256.
5. Horn-Oudshoorn EJJ, Knol R, Pas ABT, et al. Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts. Arch Dis Child Fetal Neonatal Ed. 2020;105(4):449-454. doi:10.1136/archdischild-2019-318606
6. Chandrasekharan PK, Rawat M, Madappa R, Rothstein DH, Lakshminrusimha S. Congenital Diaphragmatic hernia – a review. Matern Health Neonatol Perinatol. 2017;3(1):6. doi:10.1186/s40748-017-0045-1
7. Deprest JA, Nicolaides KH, Benachi A, et al. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. New Engl J Med. 2021;385(2):107-118. doi:10.1056/NEJMoa2027030
8. Mieghem T, Russo FM, Engels A, et al. Congenital Diaphragmatic Hernia. In: Copel JA (ed). Obstetric Imaging: Fetal Diagnosis and Care, 2nd edition. Elsevier, Philadelphia, pp: 124-129.
9. Lopez MA. Congenital Diaphragmatic Hernia. In: Buicko J, Lopez MA. Lopez-Viego M (eds). Handbook of Pediatric Surgery, 2019. Wolters Kluwer, Philadelphia, pp:340-350.
10. Russo FM, Benachi A, Van Mieghem T, et al. Antenatal sildenafil administration to prevent pulmonary hypertension in congenital diaphragmatic hernia (SToP-PH): study protocol for a phase I/IIb placenta transfer and safety study. Trials. 2018;19(1):524. doi:10.1186/s13063-018-2897-8
11. Williams E, Greenough A. Respiratory Support of Infants With Congenital Diaphragmatic Hernia. Front Pediatr. 2021;9:1-8. Accessed April 17, 2022. https://www.frontiersin.org/article/10.3389/fp 21ed.2021.808317
12. Snoek KG, Reiss IKM, Greenough A, et al. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. doi:10.1159/000444210
13. Deeney S, Howley LW, Hodges M, et al. Impact of Objective Echocardiographic Criteria for Timing of Congenital Diaphragmatic Hernia Repair. J Pediatr. 2018;192:99-104.e4. doi:10.1016/j.jpeds.2017.09.004
14. Guner Y, Jancelewicz T, Di Nardo M, et al. Management of Congenital Diaphragmatic Hernia Treated With Extracorporeal Life Support: Interim Guidelines Consensus Statement From the Extracorporeal Life Support Organization. ASAIO J. 2021;67(2):113-120. doi:10.1097/MAT.0000000000001338
15. Kays DW, Talbert JL, Islam S, Larson SD, Taylor JA, Perkins J. Improved Survival in Left Liver-Up Congenital Diaphragmatic Hernia by Early Repair Before Extracorporeal Membrane Oxygenation: Optimization of Patient Selection by Multivariate Risk Modeling. J Am Coll Surg. 2016;222(4):459-470. doi:10.1016/j.jamcollsurg.2015.12.059
16. Golden J, Jones N, Zagory J, Castle S, Bliss D. Outcomes of congenital diaphragmatic hernia repair on extracorporeal life support. Pediatr Surg Int. 2017;33(2):125-131. doi:10.1007/s00383-016-4002-2
17. Harting MT, Hollinger L, Tsao K, et al. Aggressive Surgical Management of Congenital Diaphragmatic Hernia: Worth the Effort?: A Multicenter, Prospective, Cohort Study. Ann Surg. 2018;267(5):977-982. doi:10.1097/SLA.0000000000002144
18. Cochius-den Otter SCM, Erdem Ö, van Rosmalen J, et al. Validation of a Prediction Rule for Mortality in Congenital Diaphragmatic Hernia. Pediatrics. 2020;145(4):e20192379. doi:10.1542/peds.2019-2379
19. Raitio A, Salim A, Losty PD. Congenital diaphragmatic hernia—does the presence of a hernia sac improve outcome? A systematic review of published studies. Eur J Pediatr. 2021;180(2):333-337. doi:10.1007/s00431-020-03779-1
Answers to questions
1.c, 2.b, 3.d, 4.c, 5.a