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38 (2014) 92–96
Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
Congenital diaphragmatic hernia: Treatment and outcomes Andrea Badillo, MDa,n, and Cynthia Gingalewski, MDb a
Children’s National Medical Center, 111 Michigan Avenue NW, Suite W4-200, Washington, DC 20008 Randall Children’s Hospital, Portland, OR
b
article info
abstract
Keywords:
Congenital diaphragmatic hernia (CDH) is a congenital defect in the diaphragm that allows
Congenital diaphragmatic hernia
herniation of abdominal contents into the fetal chest and leads to varying degrees of
Prenatal counseling
pulmonary hypoplasia and pulmonary hypertension. Advances in prenatal diagnosis and
Postnatal treatment
the institution of standardized delivery and postnatal care protocols have led to improved
Long term outcomes
survival. Fetal endoscopic tracheal occlusion shows early promise for patients with the most severe CDH, but prospective randomized data is still required. CDH survivors have a variety of associated morbidities that require long-term follow-up and early intervention strategies for optimal care. & 2014 Elsevier Inc. All rights reserved.
Introduction
Prenatal diagnosis
Congenital diaphragmatic hernia (CDH) is one of the more common congenital anomalies with a frequency of 1/2200 live births. The defect in the diaphragm allows abdominal contents to herniate into the chest creating a mass effect that impedes lung development during a critical stage of normal lung development. The pathophysiology of CDH relates to the resultant pulmonary parenchymal and vascular hypoplasia. The hypoplastic lung is not only small but lacks the normal bronchiole branching pattern, alveolar surface area, and pulmonary vascular structure.1 Peripheral pulmonary arteries are hypermuscular, which results in increased pulmonary vascular resistance and vascular reactivity. A patient with severe CDH is highly sensitive to hypoxemia, hypotension, acidosis, and even environmental stimulation, which can precipitate pulmonary vasospasm and shunting episodes. The broad spectrum of severity in patients with CDH is dependent on the degree of pulmonary hypoplasia and pulmonary hypertension.
Over two-thirds of cases of CDH are diagnosed prenatally. The sonographic hallmark is the presence of abdominal contents within the thorax. Other more subtle findings suggestive of CDH include the presence of a pleural effusion, mediastinal shift, or abnormal position of the heart. Rightsided CDH defects (Fig. 1) are frequently missed because of the difficulty in distinguishing lung tissue from liver that has herniated into the chest. At most fetal diagnosis centers, prenatal evaluation includes high-resolution ultrasound, fetal MRI (Fig. 2), fetal echocardiography, and genetic testing. Together this information provides the foundation for comprehensive nondirective counseling for families, which includes the option for pregnancy termination. Identification of accurate prenatal predictors of CDH severity is essential to the counseling process. A number of different prenatal predictors have been proposed and refined over the years. Herniation of liver into the fetal chest is a poor prognostic factor. This is the single
n
Corresponding author. E-mail address: [email protected] (A. Badillo).
0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semperi.2013.11.005
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most reliable predictor of severity and mortality in CDH. Mortality for patients with liver herniation was 65% compared to 7% when the liver is below the diaphragm. Liver herniation was also highly predictive of the need for extracorporeal membrane oxygenation (ECMO) with 80% of patients requiring ECMO compared to 25% of those without liver herniation.2 The most utilized prenatal predictors are measures of lung volume and include the lung–head ratio (LHR), observed to expected LHR (O/E LHR), and MRI total lung volume (TLV). The LHR is the ratio of the right lung area to the head circumference calculated to minimize differences based on gestational age. In 20–26 week gestation fetuses, an LHR o0.6 was associated with 0% survival while fetuses with an LHR 41.35 had a 100% survival.3 The O/E LHR was developed in response to the observation that lung growth is 4 that of head growth in the 3rd trimester such that LHR in late gestation tends to underestimate the severity of the defect.4 The O/E LHR achieves predictive accuracy independent of gestational age by dividing the observed LHR by the normal expected LHR for gestational age.5,6 The quoted survival percentages for O/E LHR are summarized in (Table).7 Both the LHR and O/E LHR are derived from ultrasound measurements and there has been difficulty in comparing measurements from different institutions because of a lack of standardized measurement techniques and operator variability. The ability to get accurate ultrasound measurements can be further limited by the differences in maternal body habitus, position of the fetus, and the sometimes difficult distinction between lung and liver tissue. Advances in MR sequences and acquisition speed have allowed for the development of MRI fetal lung volume measurement that is operator independent and has less motion artifact. In isolated
93
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Fig. 2 – Fetal MRI of a patient with a left-sided CDH. The arrow is pointing to the bowel in the left chest. left CDH, observed to expected fetal lung volume (O/E FLV) 435% was associated with 83% survival, an O/E FLV of 25–35% had 69% survival, and O/E FLV o25% had a 13% chance of survival.8 Other groups have shown that O/E FLV also correlates with the need for ECMO.9,10 O/E FLV correlates with LHR and serves as an important adjunct in prenatal assessment and counseling.11 All of these imaging volumetric measures, however, share the same limitation in that they are structural measurements and do not offer information about the pulmonary vasculature and lung function. Until such functional predictors are identified, the prognostic information for fetuses with CDH remains incomplete.
Associated anomalies The presence of additional anomalies in babies with CDH, especially significant congenital heart disease (CHD) portends a poor outcome. While several studies have reported Table – Percentage survival for O/E LHR. O/E LHR
Fig. 1 – X-ray of a right-sided CDH patient on ECMO showing bowel in the chest and liver up.
445% 36–45% 36–45% 15–25% o15%
Liver position
Severity of hypoplasia
Percent survival
Liver down Liver up
Mild Moderate Severe Extreme
475% 30–60% 20% 0%
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survivors with CDH and CHD, this is limited to cases in which the defect is mild (LHR 41.2)12 and to cardiac defects with biventricular physiology.13 The presence of syndromes such as Fryns or chromosome abnormalities such as Trisomy 18 have been reported with some frequency and are associated with high mortality and poor outcomes.14,15 Early genetic counseling and recognition of lethal anomalies are essential to the prenatal counseling process and postnatal management planning.
Fetal intervention The mainstay of treatment for CDH remains expectant management of the pregnancy, monitoring for development of prenatal complications, and postnatal care. More recently, European investigators have used fetal endoscopic tracheal occlusion to treat severe CDH and shown increased survival in left CDH from 24% to 49% and in right CDH from 0% to 35% when compared to expectantly managed cases of CDH from their registry.5 In this procedure, a balloon is placed in the fetal trachea using an endoscopic technique. The balloon prevents fluid egress from the lung, which causes an increase in transpulmonic pressure that stimulates lung growth.16 In animal models, tracheal occlusion has shown reversal of pulmonary vascular changes induced by CDH along with lung parenchymal growth.17 However, the lung structure is not completely normal and there are reports of decreased Type II pneumocytes, decreased surfactant, and increased alveolar wall thickness that limits optimal gas exchange.18,19 Tracheal occlusion is not a new concept, but the development of a minimally invasive, endoscopic technique decreases the risk of inducing uterine irritation and preterm labor, which has been the “Achilles’ heel” of open fetal surgery in general and limited prior study of open tracheal occlusion.20 While early results of fetal endoscopic tracheal occlusion are promising, initial randomized controlled trials did not show an outcome difference, but this initial trial was limited by the small number of patients in the study, especially in the high-risk group.21 A multicenter study in Europe and North America, the TOTAL trial, at the time of this publication, was in preparation to begin recruiting patients within the year.
Delivery and postnatal management The availability and accuracy of prenatal diagnosis allows for coordinated delivery planning. Families receive comprehensive counseling about the perinatal issues related to CDH and the potential postnatal events and long-term outcomes. Fetuses with CDH should be delivered at a tertiary care center with immediate access to neonatology, pediatric surgeons, and extracorporeal membrane oxygenation (ECMO). The overall goal of the delivery plan is to reduce perinatal stress and prevent events that trigger pulmonary vasospasm and the decline that is difficult to reverse. Because of the fragile nature of CDH infants, transport is potentially hazardous and should be minimized and optimized when possible to decrease adverse events and improve overall outcome.22 Most high-volume centers opt for vaginal delivery at 38–39 weeks with a low threshold to convert to cesarean delivery for signs of fetal stress. The infant with CDH is intubated
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immediately at delivery. Bag-masking is avoided because it leads to gastrointestinal distension and compression of the lung that make ventilation more difficult. A well-functioning nasogastric tube is essential to decompress the stomach and bowel and aid with lung expansion. “Gentle ventilation strategies” are employed to reduce iatrogenic injury to hypoplastic lungs. Peak airway pressures should be limited to less than 25 cm H2O. Use of high pressures to maintain adequate gas exchange should prompt conversion to high-frequency oscillator and possible ECMO to protect the lungs from barotrauma. There have been several reports of the use of standardized protocols for postnatal CDH care and ventilator management that resulted in improved overall survival rates.23–29 All the reported standardized protocols share the use of lungprotective strategies including use of low ventilation pressures, reduced oxygen saturation goals, and permissive hypercapnia while maintaining normal acid–base balance. Blood pressure support should be given to maintain arterial mean blood pressure levels to minimize any right to left shunting. In moderate to severe CDH, surgical repair is delayed on average 1–2 weeks until the infant has been stabilized and the pulmonary vascular reactivity has decreased or resolved. Mild pulmonary hypertension and low-risk defects in CDH infants can be repaired earlier but are still delayed 24–48 h to allow for transition and to get beyond the “honeymoon period,” a period of relative stability that can be followed by onset of worsening pulmonary hypertension and respiratory difficulties.
ECMO ECMO is used to stabilize the CDH infant during the time of maximal pulmonary vascular reactivity when standard therapy fails. It is important to recognize that use of high-pressure ventilator settings to achieve oxygenation and ventilation goals is a failure of standard ventilator therapy and should prompt early use of ECMO. Proposed indications for ECMO use include inability to maintain preductal oxygen saturations 485%, peak inspiratory pressures requirements 428 cm H2O, mean airway pressure 415, pressor-resistant hypotension, inadequate oxygen delivery based on persistent metabolic acidosis or rising serum lactate level, or inability to wean from FiO2 100% in the first 48 h of life.30 Interestingly, the establishment of standardized resuscitation goals and postnatal care protocols, has been associated with decreased ECMO use in some centers25,30 and may reflect the role of clear treatment goals in reducing variability in care between care providers. ECMO use is typically restricted to infants 42 kg and gestational age 434 weeks in the absence of significant intracranial hemorrhage, chromosomal anomalies, or congenital anomalies.31 Ex Utero Intrapartum Therapy (EXIT) to ECMO has been proposed as a treatment strategy for severe CDH. However, when studied in a small series of infants with o15% predicted lung volume, there was no survival benefit in the EXIT to ECMO group compared to standard postnatal ECMO group (33% vs. 50% survival).32 CDH is the costliest non-cardiac congenital disease and ECMO use is the largest contributing factor to the economic burden of CDH, which in an environment of increasing limits in health care resources has prompted calls for the judicious use of ECMO.33 There is likely a subset of CDH babies with
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such severe pulmonary hypoplasia that disease is not survivable and for whom ECMO may be futile. Retrospective review of 62 patients requiring ECMO for CDH revealed no survivors in cases when the pre-ECMO pCO2 could not be brought down below 70.34 In such cases, discussion with families should include the possibility that disease may not be survivable and comfort care measures offered as an option. At present, however, there are no absolute predictors of lethal pulmonary hypoplasia and ECMO remains a powerful treatment modality in the preoperative stabilization of CDH babies.
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MRI.43 Almost all CDH patients have gastroesophageal reflux requiring medical treatment and some go on to require fundoplication. Oral aversion can be severe requiring gastrostomy tube feedings while intensive therapy for oral skill training takes place. Higher metabolic demands also contribute to nutritional deficiencies and poor growth with up to 56% of patients below the twenty-fifth percentile for weight.40 The AAP section on surgery has made recommendations for follow-up44 and many high-volume centers have created specialized multidisciplinary follow-up clinics to address the complex needs of this population of survivors.30
Surgical repair The dominant pathophysiology in CDH is the resultant pulmonary hypoplasia and pulmonary hypertension from herniated abdominal viscera into the chest and not the diaphragm defect itself. Recognition of this was critical to the shift from immediate to delayed timing of surgical repair.35 Surgical repair is delayed until pulmonary hypertension is significantly improved or resolved. Criteria for timing of surgical repair may include the following: absence of shunting episodes, ventilator settings FiO2 o50%, PIP o25, MAP o12 which allows for some postsurgical escalation if needed, infant off ECMO or ready to come off ECMO, normal acid–base balance, and resolution of anasarca. Surgical repair typically involves primary or patch closure of the diaphragm through an open abdominal approach. Various groups have reported success with thoracoscopic approach albeit with an increased incidence of hernia recurrence.36–38 During thoracoscopy, infant pCO2 typically rises and for patients with moderate to severe pulmonary hypertension this can precipitate pulmonary vasospasm and intraoperative instability. Furthermore, thoracoscopic closure requiring a patch is associated with substantially longer operating times than would be required to place a synthetic patch using an open technique. Given the physiologic stress associated with thoracoscopic repair of CDH, it is probably best reserved for use in cases when the diaphragm defect is small and the pulmonary hypertension mild.
Outcomes and long-term morbidity The reported survival for isolated CDH has ranged from 70% to 90% overall with survival rates decreasing to 50% when patients require ECMO. More recently, several groups have reported improved survival rates 485–96% overall and 55– 85% survival in patients requiring ECMO.23–25,27–29,39 These improved results come with the implementation of standardized treatment protocols emphasizing lung-protective ventilation strategies and well-defined criteria for going onto ECMO. The improved survival of infants with severe CDH has led to the need for improved management and follow-up of longterm morbidities. CDH survivors have a higher incidence of respiratory, neurologic, gastrointestinal, and nutritional difficulties.26,40–42 Respiratory difficulties range from asthmarelated difficulties and propensity for pulmonary infections to chronic pulmonary hypertension. CDH survivors demonstrate delays in neurocognitive and language skills42 and up to 1-month delay in structural brain development as seen on
Conclusions Advancements in prenatal diagnosis have allowed for early comprehensive prenatal counseling to educate parents about the range of severity in CDH and to prepare them for the postnatal events that can occur. Appreciation for the underlying pathophysiology of this disease and the institution of standardized treatment protocols has led to improved survival. Multidisciplinary long-term follow-up is required to address the morbidities associated with severe CDH.
refere nces
1. Kitagawa M, Hislop A, Boyden EA, Reid L. Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery, and alveolar development. Br J Surg. 1971;58 (5):342–346. 2. Hedrick HL, Danzer E, Merchant A, et al. Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia. Am J Obstet Gynecol. 2007;4(422):e1–e4. 3. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31(1):148–151 [discussion 51-2]. 4. Peralta CF, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol. 2005;26(7):718–724. 5. Jani J, Nicolaides KH, Keller RL, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol. 2007;30(1):67–71. 6. Jani JC, Peralta CF, Nicolaides KH. Lung-to-head ratio: a need to unify the technique. Ultrasound Obstet Gynecol. 2012;39(1):2–6. 7. Deprest JA, Flemmer AW, Gratacos E, Nicolaides K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2009;14(1): 8–13. 8. Victoria T, Bebbington MW, Danzer E, et al. Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia. Prenat Diagn. 2012;32(8):715–723. 9. Barnewolt CE, Kunisaki SM, Fauza DO, Nemes LP, Estroff JA, Jennings RW. Percent predicted lung volumes as measured on fetal magnetic resonance imaging: a useful biometric parameter for risk stratification in congenital diaphragmatic hernia. J Pediatr Surg. 2007;42(1):193–197. 10. Neff KW, Kilian AK, Schaible T, Schutz EM, Busing KA. Prediction of mortality and need for neonatal extracorporeal membrane oxygenation in fetuses with congenital diaphragmatic
96
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
SE
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PE
R I N A T O L O G Y
hernia: logistic regression analysis based on MRI fetal lung volume measurements. Am J Roentgenol. 2007;189(6):1307–1311. Sandaite I, Claus F, De Keyzer F, et al. Examining the relationship between the lung-to-head ratio measured on ultrasound and lung volumetry by magnetic resonance in fetuses with isolated congenital diaphragmatic hernia. Fetal Diagn Ther. 2011;29(1):80–87. Cohen MS, Rychik J, Bush DM, et al. Influence of congenital heart disease on survival in children with congenital diaphragmatic hernia. J Pediatr. 2002;141(1):25–30. Graziano JN. Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg. 2005 Jun;40(6):1045–1049 [discussion 9-50]. Neville HL, Jaksic T, Wilson JM, et al. Fryns syndrome in children with congenital diaphragmatic hernia. J Pediatr Surg. 2002;37(12):1685–1687. Bollmann R, Kalache K, Mau H, Chaoui R, Tennstedt C. Associated malformations and chromosomal defects in congenital diaphragmatic hernia. Fetal Diagn Ther. 1995;10(1): 52–59. Kitano Y, Flake AW, Quinn TM, et al. Lung growth induced by tracheal occlusion in the sheep is augmented by airway pressurization. J Pediatr Surg. 2000;35(2):216–221 [discussion 21-2]. Kanai M, Kitano Y, von Allmen D, Davies P, Adzick NS, Flake AW. Fetal tracheal occlusion in the rat model of nitrofeninduced congenital diaphragmatic hernia: tracheal occlusion reverses the arterial structural abnormality. J Pediatr Surg. 2001;36(6):839–845. O’Toole SJ, Sharma A, Karamanoukian HL, Holm B, Azizkhan RG, Glick PL. Tracheal ligation does not correct the surfactant deficiency associated with congenital diaphragmatic hernia. J Pediatr Surg. 1996;31(4):546–550. Davey MG, Hedrick HL, Bouchard S, et al. Temporary tracheal occlusion in fetal sheep with lung hypoplasia does not improve postnatal lung function. J Appl Physiol. 2003;94(3): 1054–1062. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol. 2000;183(5):1059–1066. Harrison MR, Keller RI, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal diaphragmatic hernia. N Engl J Med. 2003;349(20): 1916–1924. Nasr A, Langer JC. Influence of location of delivery on outcome in neonates with congenital diaphragmatic hernia. J Pediatr Surg. 2011;46(5):814–816. Antonoff MB, Hustead VA, Groth SS, Schmeling DJ. Protocolized management of infants with congenital diaphragmatic hernia: effect on survival. J Pediatr Surg. 2011;46(1):39–46. Garcia A, Stolar CJ. Congenital diaphragmatic hernia and protective ventilation strategies in pediatric surgery. Surg Clin North Am. 2012;92(3):659–668 [ix]. Lazar DA, Cass DL, Rodriguez MA, et al. Impact of prenatal evaluation and protocol-based perinatal management on congenital diaphragmatic hernia outcomes. J Pediatr Surg. 2011;46(5):808–813. Muratore CS, Kharasch V, Lund DP, et al. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg. 2001;36(1):133–140.
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27. Rollins MD. Recent advances in the management of congenital diaphragmatic hernia. Curr Opin Pediatr. 2012;24(3): 379–385. 28. Tracy ET, Mears SE, Smith PB, et al. Protocolized approach to the management of congenital diaphragmatic hernia: benefits of reducing variability in care. J Pediatr Surg. 2010;45 (6):1343–1348. 29. van den Hout L, Schaible T, Cohen-Overbeek TE, et al. Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol. Fetal Diagn Ther. 2011;29(1):55–63. 30. Hedrick HL, editor. Management of prenatally diagnosed congenital diaphragmatic hernia. Seminars in pediatric surgery; 2013: Elsevier. 31. Lally KP. Extracorporeal membrane oxygenation in patients with congenital diaphragmatic hernia. Semin Pediatr Surg. 1996;5(4):249–255. 32. Stoffan AP, Wilson JM, Jennings RW, Wilkins-Haug LE, Buchmiller TL. Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change outcomes for high-risk patients with congenital diaphragmatic hernia? J Pediatr Surg. 2012;47(6):1053–1057. 33. Raval MV, Wang X, Reynolds M, Fischer AC. Costs of congenital diaphragmatic hernia repair in the United Statesextracorporeal membrane oxygenation foots the bill. J Pediatr Surg. 2011;46(4):617–624. 34. Hoffman SB, Massaro AN, Gingalewski C, Short BL. Survival in congenital diaphragmatic hernia: use of predictive equations in the ECMO population. Neonatology. 2011;99(4):258–265. 35. West KW, Bengston K, Rescorla FJ, Engle WA, Grosfeld JL. Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg. 1992;216(4): 454–460 [discussion 60-2]. 36. Gander JW, Fisher JC, Gross ER, et al. Early recurrence of congenital diaphragmatic hernia is higher after thoracoscopic than open repair: a single institutional study. J Pediatr Surg. 2011;46(7):1303–1308. 37. Lansdale N, Alam S, Losty PD, Jesudason EC. Neonatal endosurgical congenital diaphragmatic hernia repair: a systematic review and meta-analysis. Ann Surg. 2010;252(1):20–26. 38. Tsao K, Lally PA, Lally KP. Minimally invasive repair of congenital diaphragmatic hernia. J Pediatr Surg. 2011;46(6):1158–1164. 39. Logan J, Rice H, Goldberg R, Cotten C. Congenital diaphragmatic hernia: a systematic review and summary of bestevidence practice strategies. J Perinatol. 2007;27(9):535–549. 40. Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2001;36(8):1171–1176. 41. Chiu PP, Sauer C, Mihailovic A, et al. The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity? J Pediatr Surg. 2006;41(5):888–892. 42. Danzer E, Gerdes M, Bernbaum J, et al. Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg. 2010;45(9):1759–1766. 43. Danzer E, Zarnow D, Gerdes M, et al. Abnormal brain development and maturation on magnetic resonance imaging in survivors of severe congenital diaphragmatic hernia. J Pediatr Surg. 2012;47(3):453–461. 44. Lally KP, Engle W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121(3): 627–632.
M I N A R S I N
P
E R I N A T O L O G Y
38 (2014) 92–96
Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
Congenital diaphragmatic hernia: Treatment and outcomes Andrea Badillo, MDa,n, and Cynthia Gingalewski, MDb a
Children’s National Medical Center, 111 Michigan Avenue NW, Suite W4-200, Washington, DC 20008 Randall Children’s Hospital, Portland, OR
b
article info
abstract
Keywords:
Congenital diaphragmatic hernia (CDH) is a congenital defect in the diaphragm that allows
Congenital diaphragmatic hernia
herniation of abdominal contents into the fetal chest and leads to varying degrees of
Prenatal counseling
pulmonary hypoplasia and pulmonary hypertension. Advances in prenatal diagnosis and
Postnatal treatment
the institution of standardized delivery and postnatal care protocols have led to improved
Long term outcomes
survival. Fetal endoscopic tracheal occlusion shows early promise for patients with the most severe CDH, but prospective randomized data is still required. CDH survivors have a variety of associated morbidities that require long-term follow-up and early intervention strategies for optimal care. & 2014 Elsevier Inc. All rights reserved.
Introduction
Prenatal diagnosis
Congenital diaphragmatic hernia (CDH) is one of the more common congenital anomalies with a frequency of 1/2200 live births. The defect in the diaphragm allows abdominal contents to herniate into the chest creating a mass effect that impedes lung development during a critical stage of normal lung development. The pathophysiology of CDH relates to the resultant pulmonary parenchymal and vascular hypoplasia. The hypoplastic lung is not only small but lacks the normal bronchiole branching pattern, alveolar surface area, and pulmonary vascular structure.1 Peripheral pulmonary arteries are hypermuscular, which results in increased pulmonary vascular resistance and vascular reactivity. A patient with severe CDH is highly sensitive to hypoxemia, hypotension, acidosis, and even environmental stimulation, which can precipitate pulmonary vasospasm and shunting episodes. The broad spectrum of severity in patients with CDH is dependent on the degree of pulmonary hypoplasia and pulmonary hypertension.
Over two-thirds of cases of CDH are diagnosed prenatally. The sonographic hallmark is the presence of abdominal contents within the thorax. Other more subtle findings suggestive of CDH include the presence of a pleural effusion, mediastinal shift, or abnormal position of the heart. Rightsided CDH defects (Fig. 1) are frequently missed because of the difficulty in distinguishing lung tissue from liver that has herniated into the chest. At most fetal diagnosis centers, prenatal evaluation includes high-resolution ultrasound, fetal MRI (Fig. 2), fetal echocardiography, and genetic testing. Together this information provides the foundation for comprehensive nondirective counseling for families, which includes the option for pregnancy termination. Identification of accurate prenatal predictors of CDH severity is essential to the counseling process. A number of different prenatal predictors have been proposed and refined over the years. Herniation of liver into the fetal chest is a poor prognostic factor. This is the single
n
Corresponding author. E-mail address: [email protected] (A. Badillo).
0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semperi.2013.11.005
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P
E R I N A T O L O G Y
most reliable predictor of severity and mortality in CDH. Mortality for patients with liver herniation was 65% compared to 7% when the liver is below the diaphragm. Liver herniation was also highly predictive of the need for extracorporeal membrane oxygenation (ECMO) with 80% of patients requiring ECMO compared to 25% of those without liver herniation.2 The most utilized prenatal predictors are measures of lung volume and include the lung–head ratio (LHR), observed to expected LHR (O/E LHR), and MRI total lung volume (TLV). The LHR is the ratio of the right lung area to the head circumference calculated to minimize differences based on gestational age. In 20–26 week gestation fetuses, an LHR o0.6 was associated with 0% survival while fetuses with an LHR 41.35 had a 100% survival.3 The O/E LHR was developed in response to the observation that lung growth is 4 that of head growth in the 3rd trimester such that LHR in late gestation tends to underestimate the severity of the defect.4 The O/E LHR achieves predictive accuracy independent of gestational age by dividing the observed LHR by the normal expected LHR for gestational age.5,6 The quoted survival percentages for O/E LHR are summarized in (Table).7 Both the LHR and O/E LHR are derived from ultrasound measurements and there has been difficulty in comparing measurements from different institutions because of a lack of standardized measurement techniques and operator variability. The ability to get accurate ultrasound measurements can be further limited by the differences in maternal body habitus, position of the fetus, and the sometimes difficult distinction between lung and liver tissue. Advances in MR sequences and acquisition speed have allowed for the development of MRI fetal lung volume measurement that is operator independent and has less motion artifact. In isolated
93
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Fig. 2 – Fetal MRI of a patient with a left-sided CDH. The arrow is pointing to the bowel in the left chest. left CDH, observed to expected fetal lung volume (O/E FLV) 435% was associated with 83% survival, an O/E FLV of 25–35% had 69% survival, and O/E FLV o25% had a 13% chance of survival.8 Other groups have shown that O/E FLV also correlates with the need for ECMO.9,10 O/E FLV correlates with LHR and serves as an important adjunct in prenatal assessment and counseling.11 All of these imaging volumetric measures, however, share the same limitation in that they are structural measurements and do not offer information about the pulmonary vasculature and lung function. Until such functional predictors are identified, the prognostic information for fetuses with CDH remains incomplete.
Associated anomalies The presence of additional anomalies in babies with CDH, especially significant congenital heart disease (CHD) portends a poor outcome. While several studies have reported Table – Percentage survival for O/E LHR. O/E LHR
Fig. 1 – X-ray of a right-sided CDH patient on ECMO showing bowel in the chest and liver up.
445% 36–45% 36–45% 15–25% o15%
Liver position
Severity of hypoplasia
Percent survival
Liver down Liver up
Mild Moderate Severe Extreme
475% 30–60% 20% 0%
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survivors with CDH and CHD, this is limited to cases in which the defect is mild (LHR 41.2)12 and to cardiac defects with biventricular physiology.13 The presence of syndromes such as Fryns or chromosome abnormalities such as Trisomy 18 have been reported with some frequency and are associated with high mortality and poor outcomes.14,15 Early genetic counseling and recognition of lethal anomalies are essential to the prenatal counseling process and postnatal management planning.
Fetal intervention The mainstay of treatment for CDH remains expectant management of the pregnancy, monitoring for development of prenatal complications, and postnatal care. More recently, European investigators have used fetal endoscopic tracheal occlusion to treat severe CDH and shown increased survival in left CDH from 24% to 49% and in right CDH from 0% to 35% when compared to expectantly managed cases of CDH from their registry.5 In this procedure, a balloon is placed in the fetal trachea using an endoscopic technique. The balloon prevents fluid egress from the lung, which causes an increase in transpulmonic pressure that stimulates lung growth.16 In animal models, tracheal occlusion has shown reversal of pulmonary vascular changes induced by CDH along with lung parenchymal growth.17 However, the lung structure is not completely normal and there are reports of decreased Type II pneumocytes, decreased surfactant, and increased alveolar wall thickness that limits optimal gas exchange.18,19 Tracheal occlusion is not a new concept, but the development of a minimally invasive, endoscopic technique decreases the risk of inducing uterine irritation and preterm labor, which has been the “Achilles’ heel” of open fetal surgery in general and limited prior study of open tracheal occlusion.20 While early results of fetal endoscopic tracheal occlusion are promising, initial randomized controlled trials did not show an outcome difference, but this initial trial was limited by the small number of patients in the study, especially in the high-risk group.21 A multicenter study in Europe and North America, the TOTAL trial, at the time of this publication, was in preparation to begin recruiting patients within the year.
Delivery and postnatal management The availability and accuracy of prenatal diagnosis allows for coordinated delivery planning. Families receive comprehensive counseling about the perinatal issues related to CDH and the potential postnatal events and long-term outcomes. Fetuses with CDH should be delivered at a tertiary care center with immediate access to neonatology, pediatric surgeons, and extracorporeal membrane oxygenation (ECMO). The overall goal of the delivery plan is to reduce perinatal stress and prevent events that trigger pulmonary vasospasm and the decline that is difficult to reverse. Because of the fragile nature of CDH infants, transport is potentially hazardous and should be minimized and optimized when possible to decrease adverse events and improve overall outcome.22 Most high-volume centers opt for vaginal delivery at 38–39 weeks with a low threshold to convert to cesarean delivery for signs of fetal stress. The infant with CDH is intubated
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immediately at delivery. Bag-masking is avoided because it leads to gastrointestinal distension and compression of the lung that make ventilation more difficult. A well-functioning nasogastric tube is essential to decompress the stomach and bowel and aid with lung expansion. “Gentle ventilation strategies” are employed to reduce iatrogenic injury to hypoplastic lungs. Peak airway pressures should be limited to less than 25 cm H2O. Use of high pressures to maintain adequate gas exchange should prompt conversion to high-frequency oscillator and possible ECMO to protect the lungs from barotrauma. There have been several reports of the use of standardized protocols for postnatal CDH care and ventilator management that resulted in improved overall survival rates.23–29 All the reported standardized protocols share the use of lungprotective strategies including use of low ventilation pressures, reduced oxygen saturation goals, and permissive hypercapnia while maintaining normal acid–base balance. Blood pressure support should be given to maintain arterial mean blood pressure levels to minimize any right to left shunting. In moderate to severe CDH, surgical repair is delayed on average 1–2 weeks until the infant has been stabilized and the pulmonary vascular reactivity has decreased or resolved. Mild pulmonary hypertension and low-risk defects in CDH infants can be repaired earlier but are still delayed 24–48 h to allow for transition and to get beyond the “honeymoon period,” a period of relative stability that can be followed by onset of worsening pulmonary hypertension and respiratory difficulties.
ECMO ECMO is used to stabilize the CDH infant during the time of maximal pulmonary vascular reactivity when standard therapy fails. It is important to recognize that use of high-pressure ventilator settings to achieve oxygenation and ventilation goals is a failure of standard ventilator therapy and should prompt early use of ECMO. Proposed indications for ECMO use include inability to maintain preductal oxygen saturations 485%, peak inspiratory pressures requirements 428 cm H2O, mean airway pressure 415, pressor-resistant hypotension, inadequate oxygen delivery based on persistent metabolic acidosis or rising serum lactate level, or inability to wean from FiO2 100% in the first 48 h of life.30 Interestingly, the establishment of standardized resuscitation goals and postnatal care protocols, has been associated with decreased ECMO use in some centers25,30 and may reflect the role of clear treatment goals in reducing variability in care between care providers. ECMO use is typically restricted to infants 42 kg and gestational age 434 weeks in the absence of significant intracranial hemorrhage, chromosomal anomalies, or congenital anomalies.31 Ex Utero Intrapartum Therapy (EXIT) to ECMO has been proposed as a treatment strategy for severe CDH. However, when studied in a small series of infants with o15% predicted lung volume, there was no survival benefit in the EXIT to ECMO group compared to standard postnatal ECMO group (33% vs. 50% survival).32 CDH is the costliest non-cardiac congenital disease and ECMO use is the largest contributing factor to the economic burden of CDH, which in an environment of increasing limits in health care resources has prompted calls for the judicious use of ECMO.33 There is likely a subset of CDH babies with
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such severe pulmonary hypoplasia that disease is not survivable and for whom ECMO may be futile. Retrospective review of 62 patients requiring ECMO for CDH revealed no survivors in cases when the pre-ECMO pCO2 could not be brought down below 70.34 In such cases, discussion with families should include the possibility that disease may not be survivable and comfort care measures offered as an option. At present, however, there are no absolute predictors of lethal pulmonary hypoplasia and ECMO remains a powerful treatment modality in the preoperative stabilization of CDH babies.
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MRI.43 Almost all CDH patients have gastroesophageal reflux requiring medical treatment and some go on to require fundoplication. Oral aversion can be severe requiring gastrostomy tube feedings while intensive therapy for oral skill training takes place. Higher metabolic demands also contribute to nutritional deficiencies and poor growth with up to 56% of patients below the twenty-fifth percentile for weight.40 The AAP section on surgery has made recommendations for follow-up44 and many high-volume centers have created specialized multidisciplinary follow-up clinics to address the complex needs of this population of survivors.30
Surgical repair The dominant pathophysiology in CDH is the resultant pulmonary hypoplasia and pulmonary hypertension from herniated abdominal viscera into the chest and not the diaphragm defect itself. Recognition of this was critical to the shift from immediate to delayed timing of surgical repair.35 Surgical repair is delayed until pulmonary hypertension is significantly improved or resolved. Criteria for timing of surgical repair may include the following: absence of shunting episodes, ventilator settings FiO2 o50%, PIP o25, MAP o12 which allows for some postsurgical escalation if needed, infant off ECMO or ready to come off ECMO, normal acid–base balance, and resolution of anasarca. Surgical repair typically involves primary or patch closure of the diaphragm through an open abdominal approach. Various groups have reported success with thoracoscopic approach albeit with an increased incidence of hernia recurrence.36–38 During thoracoscopy, infant pCO2 typically rises and for patients with moderate to severe pulmonary hypertension this can precipitate pulmonary vasospasm and intraoperative instability. Furthermore, thoracoscopic closure requiring a patch is associated with substantially longer operating times than would be required to place a synthetic patch using an open technique. Given the physiologic stress associated with thoracoscopic repair of CDH, it is probably best reserved for use in cases when the diaphragm defect is small and the pulmonary hypertension mild.
Outcomes and long-term morbidity The reported survival for isolated CDH has ranged from 70% to 90% overall with survival rates decreasing to 50% when patients require ECMO. More recently, several groups have reported improved survival rates 485–96% overall and 55– 85% survival in patients requiring ECMO.23–25,27–29,39 These improved results come with the implementation of standardized treatment protocols emphasizing lung-protective ventilation strategies and well-defined criteria for going onto ECMO. The improved survival of infants with severe CDH has led to the need for improved management and follow-up of longterm morbidities. CDH survivors have a higher incidence of respiratory, neurologic, gastrointestinal, and nutritional difficulties.26,40–42 Respiratory difficulties range from asthmarelated difficulties and propensity for pulmonary infections to chronic pulmonary hypertension. CDH survivors demonstrate delays in neurocognitive and language skills42 and up to 1-month delay in structural brain development as seen on
Conclusions Advancements in prenatal diagnosis have allowed for early comprehensive prenatal counseling to educate parents about the range of severity in CDH and to prepare them for the postnatal events that can occur. Appreciation for the underlying pathophysiology of this disease and the institution of standardized treatment protocols has led to improved survival. Multidisciplinary long-term follow-up is required to address the morbidities associated with severe CDH.
refere nces
1. Kitagawa M, Hislop A, Boyden EA, Reid L. Lung hypoplasia in congenital diaphragmatic hernia. A quantitative study of airway, artery, and alveolar development. Br J Surg. 1971;58 (5):342–346. 2. Hedrick HL, Danzer E, Merchant A, et al. Liver position and lung-to-head ratio for prediction of extracorporeal membrane oxygenation and survival in isolated left congenital diaphragmatic hernia. Am J Obstet Gynecol. 2007;4(422):e1–e4. 3. Metkus AP, Filly RA, Stringer MD, Harrison MR, Adzick NS. Sonographic predictors of survival in fetal diaphragmatic hernia. J Pediatr Surg. 1996;31(1):148–151 [discussion 51-2]. 4. Peralta CF, Cavoretto P, Csapo B, Vandecruys H, Nicolaides KH. Assessment of lung area in normal fetuses at 12-32 weeks. Ultrasound Obstet Gynecol. 2005;26(7):718–724. 5. Jani J, Nicolaides KH, Keller RL, et al. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol. 2007;30(1):67–71. 6. Jani JC, Peralta CF, Nicolaides KH. Lung-to-head ratio: a need to unify the technique. Ultrasound Obstet Gynecol. 2012;39(1):2–6. 7. Deprest JA, Flemmer AW, Gratacos E, Nicolaides K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2009;14(1): 8–13. 8. Victoria T, Bebbington MW, Danzer E, et al. Use of magnetic resonance imaging in prenatal prognosis of the fetus with isolated left congenital diaphragmatic hernia. Prenat Diagn. 2012;32(8):715–723. 9. Barnewolt CE, Kunisaki SM, Fauza DO, Nemes LP, Estroff JA, Jennings RW. Percent predicted lung volumes as measured on fetal magnetic resonance imaging: a useful biometric parameter for risk stratification in congenital diaphragmatic hernia. J Pediatr Surg. 2007;42(1):193–197. 10. Neff KW, Kilian AK, Schaible T, Schutz EM, Busing KA. Prediction of mortality and need for neonatal extracorporeal membrane oxygenation in fetuses with congenital diaphragmatic
96
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
SE
M I N A R S I N
PE
R I N A T O L O G Y
hernia: logistic regression analysis based on MRI fetal lung volume measurements. Am J Roentgenol. 2007;189(6):1307–1311. Sandaite I, Claus F, De Keyzer F, et al. Examining the relationship between the lung-to-head ratio measured on ultrasound and lung volumetry by magnetic resonance in fetuses with isolated congenital diaphragmatic hernia. Fetal Diagn Ther. 2011;29(1):80–87. Cohen MS, Rychik J, Bush DM, et al. Influence of congenital heart disease on survival in children with congenital diaphragmatic hernia. J Pediatr. 2002;141(1):25–30. Graziano JN. Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group. J Pediatr Surg. 2005 Jun;40(6):1045–1049 [discussion 9-50]. Neville HL, Jaksic T, Wilson JM, et al. Fryns syndrome in children with congenital diaphragmatic hernia. J Pediatr Surg. 2002;37(12):1685–1687. Bollmann R, Kalache K, Mau H, Chaoui R, Tennstedt C. Associated malformations and chromosomal defects in congenital diaphragmatic hernia. Fetal Diagn Ther. 1995;10(1): 52–59. Kitano Y, Flake AW, Quinn TM, et al. Lung growth induced by tracheal occlusion in the sheep is augmented by airway pressurization. J Pediatr Surg. 2000;35(2):216–221 [discussion 21-2]. Kanai M, Kitano Y, von Allmen D, Davies P, Adzick NS, Flake AW. Fetal tracheal occlusion in the rat model of nitrofeninduced congenital diaphragmatic hernia: tracheal occlusion reverses the arterial structural abnormality. J Pediatr Surg. 2001;36(6):839–845. O’Toole SJ, Sharma A, Karamanoukian HL, Holm B, Azizkhan RG, Glick PL. Tracheal ligation does not correct the surfactant deficiency associated with congenital diaphragmatic hernia. J Pediatr Surg. 1996;31(4):546–550. Davey MG, Hedrick HL, Bouchard S, et al. Temporary tracheal occlusion in fetal sheep with lung hypoplasia does not improve postnatal lung function. J Appl Physiol. 2003;94(3): 1054–1062. Flake AW, Crombleholme TM, Johnson MP, Howell LJ, Adzick NS. Treatment of severe congenital diaphragmatic hernia by fetal tracheal occlusion: clinical experience with fifteen cases. Am J Obstet Gynecol. 2000;183(5):1059–1066. Harrison MR, Keller RI, Hawgood SB, et al. A randomized trial of fetal endoscopic tracheal occlusion for severe fetal diaphragmatic hernia. N Engl J Med. 2003;349(20): 1916–1924. Nasr A, Langer JC. Influence of location of delivery on outcome in neonates with congenital diaphragmatic hernia. J Pediatr Surg. 2011;46(5):814–816. Antonoff MB, Hustead VA, Groth SS, Schmeling DJ. Protocolized management of infants with congenital diaphragmatic hernia: effect on survival. J Pediatr Surg. 2011;46(1):39–46. Garcia A, Stolar CJ. Congenital diaphragmatic hernia and protective ventilation strategies in pediatric surgery. Surg Clin North Am. 2012;92(3):659–668 [ix]. Lazar DA, Cass DL, Rodriguez MA, et al. Impact of prenatal evaluation and protocol-based perinatal management on congenital diaphragmatic hernia outcomes. J Pediatr Surg. 2011;46(5):808–813. Muratore CS, Kharasch V, Lund DP, et al. Pulmonary morbidity in 100 survivors of congenital diaphragmatic hernia monitored in a multidisciplinary clinic. J Pediatr Surg. 2001;36(1):133–140.
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27. Rollins MD. Recent advances in the management of congenital diaphragmatic hernia. Curr Opin Pediatr. 2012;24(3): 379–385. 28. Tracy ET, Mears SE, Smith PB, et al. Protocolized approach to the management of congenital diaphragmatic hernia: benefits of reducing variability in care. J Pediatr Surg. 2010;45 (6):1343–1348. 29. van den Hout L, Schaible T, Cohen-Overbeek TE, et al. Actual outcome in infants with congenital diaphragmatic hernia: the role of a standardized postnatal treatment protocol. Fetal Diagn Ther. 2011;29(1):55–63. 30. Hedrick HL, editor. Management of prenatally diagnosed congenital diaphragmatic hernia. Seminars in pediatric surgery; 2013: Elsevier. 31. Lally KP. Extracorporeal membrane oxygenation in patients with congenital diaphragmatic hernia. Semin Pediatr Surg. 1996;5(4):249–255. 32. Stoffan AP, Wilson JM, Jennings RW, Wilkins-Haug LE, Buchmiller TL. Does the ex utero intrapartum treatment to extracorporeal membrane oxygenation procedure change outcomes for high-risk patients with congenital diaphragmatic hernia? J Pediatr Surg. 2012;47(6):1053–1057. 33. Raval MV, Wang X, Reynolds M, Fischer AC. Costs of congenital diaphragmatic hernia repair in the United Statesextracorporeal membrane oxygenation foots the bill. J Pediatr Surg. 2011;46(4):617–624. 34. Hoffman SB, Massaro AN, Gingalewski C, Short BL. Survival in congenital diaphragmatic hernia: use of predictive equations in the ECMO population. Neonatology. 2011;99(4):258–265. 35. West KW, Bengston K, Rescorla FJ, Engle WA, Grosfeld JL. Delayed surgical repair and ECMO improves survival in congenital diaphragmatic hernia. Ann Surg. 1992;216(4): 454–460 [discussion 60-2]. 36. Gander JW, Fisher JC, Gross ER, et al. Early recurrence of congenital diaphragmatic hernia is higher after thoracoscopic than open repair: a single institutional study. J Pediatr Surg. 2011;46(7):1303–1308. 37. Lansdale N, Alam S, Losty PD, Jesudason EC. Neonatal endosurgical congenital diaphragmatic hernia repair: a systematic review and meta-analysis. Ann Surg. 2010;252(1):20–26. 38. Tsao K, Lally PA, Lally KP. Minimally invasive repair of congenital diaphragmatic hernia. J Pediatr Surg. 2011;46(6):1158–1164. 39. Logan J, Rice H, Goldberg R, Cotten C. Congenital diaphragmatic hernia: a systematic review and summary of bestevidence practice strategies. J Perinatol. 2007;27(9):535–549. 40. Muratore CS, Utter S, Jaksic T, Lund DP, Wilson JM. Nutritional morbidity in survivors of congenital diaphragmatic hernia. J Pediatr Surg. 2001;36(8):1171–1176. 41. Chiu PP, Sauer C, Mihailovic A, et al. The price of success in the management of congenital diaphragmatic hernia: is improved survival accompanied by an increase in long-term morbidity? J Pediatr Surg. 2006;41(5):888–892. 42. Danzer E, Gerdes M, Bernbaum J, et al. Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg. 2010;45(9):1759–1766. 43. Danzer E, Zarnow D, Gerdes M, et al. Abnormal brain development and maturation on magnetic resonance imaging in survivors of severe congenital diaphragmatic hernia. J Pediatr Surg. 2012;47(3):453–461. 44. Lally KP, Engle W. Postdischarge follow-up of infants with congenital diaphragmatic hernia. Pediatrics. 2008;121(3): 627–632.
