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Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group
Journal of Pediatric Surgery (2005) 40, 1045 – 1050
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Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group Joseph N. Graziano* for the Congenital Diaphragmatic Hernia Study Group Department of Pediatrics, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109-0204, USA Index words: Congenital diaphragmatic hernia; Congenital heart disease; Congenital Diaphragmatic Hernia Study Group (CDHSG)
Abstract Background/Purpose: Patients with congenital diaphragmatic hernia (CDH) are known to have associated cardiac anomalies. Data from the Congenital Diaphragmatic Hernia Study Group has allowed better definition of the types of heart defects (HDs) and survival for these patients. Methods: Since 1995, 2636 patients were enrolled in the Congenital Diaphragmatic Hernia Study Group from 82 centers. Patients with hemodynamically significant HD, excluding patent ductus arteriosus (PDA); patent foramen ovale (PFO); and atrial septal defect (ASD), were selected. Cardiac anatomy and survival data for all patients were reviewed. Results: Two hundred eighty (10.6%) patients had significant HDs: ventricular septal defect (VSD); (42.2%), aortic arch obstruction (15%), univentricular anatomy (13.9%), tetralogy of Fallot variants (11.1%), total anomalous pulmonary venous return (3.9%), double outlet right ventricle (RV) (3.2%), pulmonary stenosis (2.5%), transposition of the great arteries (2.5%), and various other defects in 5.7%. Survival for the entire group was 67.1%; survival for patients without HD was 70.2% and for patients with HD was 41.1% ( P b .001). Patients with biventricular cardiac anatomy had a 47% survival, whereas those with univentricular anatomy had a 5% survival ( P b .001). Conclusion: Significant HD is associated with 10.6% of CDH. Survival for patients with HD is significantly lower than for patients with normal cardiac anatomy. Patients with CDH and univentricular cardiac anatomy have a poor prognosis. D 2005 Elsevier Inc. All rights reserved.
Infants with congenital diaphragmatic hernia (CDH) are well known to have other associated anomalies, with cardiac defects occurring in 10% to 35% of patients [1-4]. Presented at the 56th Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 8-10, 2004. T Corresponding author. Division of Pediatric Cardiology, University of Michigan Hospital, Women’s L1242, Box 0204, Ann Arbor, MI 48109-0204, USA. 0022-3468/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2005.03.025
Numerous studies have demonstrated a substantial reduction in survival in patients with CDH and cardiac defects [2,5-7]. The establishment of the Congenital Diaphragmatic Hernia Study Group has helped create a multicenter database for the collection of information regarding infants with CDH. This database has included information regarding the cardiac anatomy of each patient with CDH and has thus allowed for the quantification of the types of cardiac defects seen in patients with CDH from a very large number
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of patients. Furthermore, it has allowed the description of survival for this group of patients. This study sought to describe the types of heart disease associated with CDH and to report the outcome of infants with CDH and significant congenital heart defects (HDs).
1. Methods Since 1995, 82 pediatric surgical centers have participated in the collection of data for all patients with CDH treated at that center. This database includes a list of 12 common congenital HDs, with the ability to describe other more complex defects, if necessary. As of December 2003, 2636 patients were enrolled in this database. Survival data for all 2636 patients were reviewed. In addition, all patients described as having a cardiac defect were selected for further review. Details of the description of heart disease were reviewed, and patients with primary arrhythmias in the absence of structural heart disease, patients with hemodynamically insignificant defects (ie, left superior vena cava to the coronary sinus, juxtaposed atrial appendages, etc), and patients with a patent foramen ovale, atrial septal defect, or patent ductus arteriosus were excluded from the review. All remaining patients with hemodynamically significant congenital HDs were selected for review of their type of HD and clinical outcome. Because of the anonymous retrospective nature of this study, it was reviewed and approved by the institutional review board at the University of Michigan under exemption status.
2. Results Three hundred eighty-five of the 2636 (14.6%) patients were initially described by the reporting centers as having cardiac disease. Eight-two (3.1%) patients had isolated ASDs without other defects and were thus excluded from further analysis. Twenty-three (0.9%) patients had either hemodynamically insignificant anomalies (ie, interrupted inferior vena cava to the azygous vein, left superior vena cava to the coronary sinus, and bicuspid aortic valve without stenosis) or arrhythmias without structural heart disease and were also excluded. The remaining 280 (10.6%) patients thus had significant structural cardiac defects and comprised the cohort for the remaining study. The distribution of cardiac disease for all 280 patients is described in Fig. 1. Isolated VSD was the most common cardiac defect, occurring in 42.2% of patients with significant heart disease. Aortic arch obstruction was also commonly seen, occurring in 15% of patients (9.3% with isolated coarctation, 4.6% with coarctation and VSD, and interrupted aortic arch in 1.1%). Univentricular anatomy was seen in similar frequency (13.9%), the large majority of which included hypoplastic left heart syndrome (1 patient had a double inlet left ventricle/hypoplastic right ventricle).
Fig. 1 Types of cardiac defects observed in patients with CDH and congenital heart disease (n = 280).
Thus, the 3 groups of ventricular septal defect, aortic arch obstruction, and single ventricle anatomy comprised nearly three quarters of the cardiac defects seen in patients with CDH. The remaining patients had various associated defects, including tetralogy of Fallot (with and without pulmonary atresia) in 11.1%, total anomalous pulmonary venous return in 3.9%, double outlet right ventricle in 3.2%, pulmonary stenosis in 2.5%, transposition of the great arteries in 2.5%, and various other defects in 5.7%, such as atrioventricular septal defect, truncus arteriosus, and Ebstein anomaly of the tricuspid valve. Thirty-one percent of patients in the group with cardiac defects had right-sided diaphragmatic defects. This incidence of right-sided CDH was significantly higher when compared with the group without heart disease, who had a 21% incidence of right-sided CDH ( P b .001). Interestingly, this trend toward more frequent right-sided CDH was consistent for both left-sided obstructive cardiac defects such as aortic arch obstruction and hypoplastic left heart syndrome (32%, P = .01), as well as right-sided obstructive cardiac defects such as tetralogy of Fallot variants and pulmonary stenosis (34%, P = .01). Hospital survival for all study patients is described in Fig. 2. Survival for all 2636 patients with CDH was 67.1%. Patients without HDs (n = 2356) had a 70.2% survival, whereas patients with cardiac defects (n = 280) had a 41.1% survival ( P b .001). Of those patients with cardiac defects, survival varied by type of defect, as seen in Fig. 2, although survival for each of the subgroups was significantly lower than the group without heart disease, with the exception of isolated pulmonary stenosis. Of note was the extremely poor survival in patients with univentricular anatomy of 5.1% ( P b .001 as compared with patients with all other biventricular defects). Also illustrated in Fig. 2 are the reported surgical survivals for each of the congenital HDs from various cardiac surgical series [8]. Of note is the
Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis
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Fig. 2 Survival for patients with CDH, stratified by type of cardiac defect. The shaded bars at the top of the graph provide reference ranges of survival for each cardiac defect in patients without CDH [8]. *P b .001, compared with CDH without congenital heart disease. **P b .001 compared with CDH with biventricular heart disease. ***P = .03 compared with CDH with all other heart diseases. TAPVR indicates total anomalous pulmonary venous return.
significant discrepancy in survival between cardiac patients with and without CDH.
3. Discussion The association of congenital heart disease with CDH has long been described with an incidence of 10% to 35%. Our review of the largest number of CDH patients to date suggests the lower end of this spectrum of significant structural heart disease. Nonetheless, multiple population studies in the United States have estimated the incidence of congenital cardiac malformations to be between 0.3% and 0.8% of all live births [9-11], suggesting roughly a 20-fold increase in the prevalence of congenital heart disease in patients with CDH as compared with normal infants. Interestingly, in comparing the prevalence of specific HDs in CDH patients to previously published data from the Baltimore-Washington Infant Heart Study, there appears to be a trend toward more frequent left-sided obstructive defects in patients with CDH, with hypoplastic left heart syndrome being 100 times more prevalent (1.5% of all CDH vs 0.015% of all live newborns) and aortic arch obstruction being 75 times more prevalent (1.6% vs 0.021%) than the general population [9]. Furthermore, right-sided obstructive defects such as pulmonary stenosis were only 6 times more prevalent in the CDH group (0.3% vs 0.05%) than in the general population. The etiology for this discrepancy is unclear but may in part be related to the majority of diaphragmatic defects being left-sided and thus limiting
flow through the left heart via direct compression of these structures. Previous studies have demonstrated a significantly lower left ventricular mass index in patients with left-sided CDH, as compared with other neonates with pulmonary hypertension, in part supporting this speculation [12]. However, the trends toward more right-sided diaphragmatic defects in patients with left-sided obstructive defects would seem to contradict this notion. Additional data have suggested differential embryonic cell death patterns between patients with right and left diaphragmatic hernia and may thus possibly provide a cellular mechanism to the difference in cardiac pathology [13]. Nonetheless, the etiology for the increased prevalence of left-sided obstructive cardiac defect is as of yet unclear. Early reports described an extremely poor survival for patient with both diaphragmatic and cardiac defects, with some series reporting a 0% survival [2,6,7]. Our large series would suggest a survival substantially higher than these previous reports. Nonetheless, the outcome of patients with CDH seems to be significantly affected by the presence of a congenital cardiac defect more complex than a simple atrial septal defect. A major cardiovascular influence of a diaphragmatic hernia is related to the external pulmonary compression and associated pulmonary parenchymal and arterial hypoplasia on the affected side [14]. This pulmonary vascular pathology results in an elevation in pulmonary vascular resistance in the affected lung. Cohen et al [3] recently described the use of lung area/head circumference ratio as an indirect measure of the severity of pulmonary hypoplasia and found the ratio to
1048 be useful tool in stratifying the risk of mortality for CDH patients with congenital heart disease. As one might expect, patients with a low lung area/head circumference ratio had a greater risk of mortality, and the presence of heart disease had an even further negative impact on survival. The associated pulmonary vascular changes described above might be expected to have a more significant impact on patients with cardiac disease dependent on good-sized pulmonary arteries and normal pulmonary vascular resistance. In fact, the patients with the best outcome in this study were patients with ventricular septal defects and isolated pulmonary stenosis, who generally have normal-sized pulmonary arteries and normally functioning ventricles that would seem better suited to tolerate the additional burden of an increased pulmonary resistance. Patients with a known predisposition to elevated pulmonary vascular resistance, such as transposition of the great arteries and coarctation of the aorta, would thus seem more susceptible to the pulmonary changes associated with CDH [15,16]. This in fact appeared to be the trend in this study, with a higher mortality this group of patients. Finally, the patients likely to be most significantly affected by the pulmonary arterial pathology seen with CDH are those with univentricular anatomy. In the presence of a single ventricle cardiac defect, the ventricle supports both the systemic and pulmonary circulations, with the balance been these circulations being dependent on the relative resistances between these 2 circulations. Furthermore, the ultimate longterm goal in the palliation of these patients is to eliminate the bparallelQ circulation and provide a circulation in bseriesQ via cavopulmonary connections that reduce the volume overload on the single ventricle. These cavopulmonary connections provide passive pulmonary circulation and are very much dependent on low pulmonary vascular resistance and normal pulmonary arterial size and morphology to provide adequate pulmonary blood flow. As these aspects of the pulmonary circulation are most directly and negatively affected by a diaphragmatic hernia, it would be expected that the shortterm and long-term outlook for patients with univentricular anatomy and CDH would be quite poor. Our data would confirm this implication, that single ventricle physiology is poorly tolerated in patients with CDH, as there were only 2 survivors of 39 (5.1%) patients in this series. There are several limitations to this study. First, details of the cardiac anatomy were provided from numerous cardiologists from many different centers and thus may be subject to various nomenclatures and interpretations. Second, the influence of noncardiac anomalies has been described to contribute to an increase in mortality, and the presence of additional anomalies was not examined in this study group [2,3,17]. Finally, data regarding details of cardiac intervention, if any, were limited, making conclusions about the impact of these intervention on survival unclear. Despite these limitations, it is clear from these data that patients with CDH have a much higher prevalence of cardiac defects as compared with normal healthy infants,
J.N. Graziano with perhaps a trend toward more left-sided obstructive defects. Furthermore, even simple but hemodynamically significant cardiac defects have a significant negative impact on survival, with single ventricle defects having a very poor survival. Further study is needed to determine the impact of cardiac intervention on survival for these patients.
Acknowledgments The authors gratefully acknowledge the contributions of the following centers in the Congenital Diaphragmatic Hernia Study Group, for the collection of data for this study: Arnold Palmer Hospital for Women and Children, Orlando, Fla; Astrid Lindgren Children’s Hospital, Stockholm, Sweden; Boston Children’s Hospital, Boston, Mass; Cardinal Glennon Children’s Hospital, St Louis, Mo; Carolinas Medical Center, Charlotte, NC; Children’s Hospital Medical Center–Cincinnati, Cincinnati, Ohio; Children’s Hospital of Akron, Akron, Ohio; Children’s Hospital of Alabama, Birmingham, Ala; Children’s Hospital of Austin, Austin, Tex; Children’s Hospital of Buffalo, Buffalo, NY; Children’s Hospital of Illinois, Peoria, Ill; Children’s Hospital of Los Angeles, Los Angeles, Calif; Children’s Hospital of Michigan, Detroit, Mich; Children’s Hospital of Minneapolis, Minneapolis, Minn; Children’s Hospital of Oakland, Oakland, Calif; Children’s Hospital of Oklahoma, Oklahoma City, Okla; Children’s Hospital of Philadelphia, Philadelphia, Pa; Children’s Hospital of Wisconsin, Milwaukee, Wis; Children’s Mercy Hospital, Overland Park, Kan; Children’s National Medical Center, Washington, DC; Cleveland Clinic Foundation–Children’s Hospital, Cleveland, Ohio; Columbus Children’s Hospital, Columbus, Ohio; Cook Children’s Hospital, Fort Worth, Tex; DeVos Children’s Hospital, Grand Rapids, Mich; Duke University Medical Center, Durham, NC; Egelston Children’s Hospital, Atlanta, Ga; Freie Universitat Berlin, Berlin, Germany; Hasbro Children’s Hospital, Providence, RI; Hermann Children’s Hospital, Houston, Tex; Hershey Medical Center, Hershey, Pa; James Whitcomb Riley Children’s Hospital, Indianapolis, Ind; Kosair Children’s Hospital, Louisville, Ky; Legacy Emanuel Children’s Hospital, Portland, Ore; Loma Linda University Children’s Hospital, Loma Linda, Calif; Lucile Salter Packard Children’s Hospital, Palo Alto, Calif; Lutheran General Hospital, Park Ridge, Ill; Massachusetts General Hospital, Boston, Mass; Medical College of Georgia, Augusta, Ga; Medical College of Virginia, Richmond, Va; Medical University of South Carolina, Charleston, SC; Miami Valley Hospital, Dayton, Ohio; National Center for Child Health and Development, Tokyo, Japan; North Carolina Baptist Hospital, Winston-Salem, NC; Oespedale Pediatrico Bambino Gesu, Rome, Italy; Oespedale Riunite Bergamo, Bergamo, Italy; Phoenix Children’s Hospital, Phoenix, Ariz; Primary Children’s Hospital, Salt Lake City, Utah; Rainbow Babies and Children Hospital, Cleveland, Ohio; Rockford Memo-
Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis rial Children’s Hospital, Rockford, Ill; Royal Alexandra Hospital, Edmonton, Alberta, Canada; Royal Children’s Hospital, Parkville, Victoria, Australia; Royal Hospital for Sick Children, Glasgow, Scotland; Salesi Children’s Hospital, Ancona, Italy; San Diego Children’s Hospital, San Diego, Calif; Shands Children’s Hospital/University of Florida, Gainesville, Fla; Sophia Children’s Hospital, Rotterdam, Netherlands; St Christopher’s Children’s Hospital, Philadelphia, Pa; St Francis Children’s Hospital, Tulsa, Okla; St Joseph’s Hospital and Medical Center, Phoenix, Ariz; St Louis Children’s Hospital, St Louis, Mo; Strong Children’s Hospital, Rochester, NY; Sydney Children’s Hospital, Randwick, NWS, Australia; T.C. Thompson Hospital, Chattanooga, Tenn; Texas Children’s Hospital, Houston, Tex; The Hospital for Sick Children, Toronto, Ontario, Canada; Tulane University Hospital, New Orleans, La; Universitatsklinikum Mannheim gGmbH, Mannheim, Germany; University Hospital Gasthuisberg, Leuven, Belgium; University of California Los Angeles, Los Angeles, Calif; University of California San Diego, San Diego, Calif; University of Chicago, Chicago, Ill; University of Kentucky Medical Center, Lexington, Ky; University of Michigan Medical Center, Ann Arbor, Mich; University of Nebraska Medical Center, Omaha, Neb; University of New Mexico Children’s Hospital, Albuquerque, NM; University of North Carolina, Chapel Hill, NC; University of Puerto Rico Medical Center, San Juan, Puerto Rico; University of Texas Medical Branch at Galveston, Galveston, Tex; University of Virginia Health System, Charlottesville, Va; Vanderbilt Children’s Hospital, Nashville, Tenn; Wilford Hall USAF Medical Center, Lackland AFB, Tex; and Yale University Children’s Hospital, New Haven, Conn.
References [1] Greenwood RD, Rosenthal A, Nadas AS. Cardiovascular abnormalities associated with congenital diaphragmatic hernia. Pediatrics 1976; 57:92 - 7. [2] Fauza DO, Wilson JM. Congenital diaphragmatic hernia and associated anomalies: their incidence, identification, and impact on prognosis. J Pediatr Surg 1994;29:1113 - 7. [3] Cohen MS, Rychik J, Bush DM, et al. Influence of congenital heart disease on survival in children with congenital diaphragmatic hernia. J Pediatr 2002;141:25 - 30. [4] Graziano JN, Gomez CA, Hirschl RB, et al. Surgical repair of infants with congenital heart disease and congenital diaphragmatic hernia: result of combined repair [abstract]. Circulation 2000;102:II - 821. [5] Wilson JM, Fauza DO, Lund DP, et al. Antenatal diagnosis of isolated congenital diaphragmatic hernia is not an indicator of outcome. J Pediatr Surg 1994;29:815 - 9. [6] Cannon C, Dildy GA, Ward R, et al. A population-based study of congenital diaphragmatic hernia in Utah: 1988-1994. Obstet Gynecol 1996;87:959 - 63. [7] Allan LD, Irish MS, Glick PL. The fetal heart in diaphragmatic hernia. Clin Perinatol 1996;23:689 - 99. [8] Allen HD, Gutgesell HP, Clark EB, et al. Moss and Adams’ heart disease in infants, children and adolescents including the fetus and young adult. 6th ed. Philadelphia (Pa)7 Lippincott Williams & Wilkins; 2001.
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[9] Ferencz C, Neill CA. Cardiovascular malformations: prevalence at live birth. In: Freedom RM, Benson LN, Smallhorn JF, editors. Neonatal Heart Disease. New York (NY)7 Springer Verlag; 1992. p. 19 - 27. [10] Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Circulation 1971;43:323 - 32. [11] Hoffman J, Christianson R. Congenital heart disease in a cohort of 19,502 births: long term follow up. Am J Cardiol 1978;42:641 - 7. [12] Schwartz SM, Vermillion RP, Hirschl RB. Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia. J Pediatr 1994;125:447 - 51. [13] Losty PD, Vanamo K, Rintala RJ, et al. Congenital diaphragmatic hernia—does the side of the defect influence the incidence of associated malformations? J Pediatr Surg 1998;33:507 - 10. [14] Geggel RL, Murphy JD, Langleben D, et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 1985;107:457 - 64. [15] Kumar A, Taylor GP, Sandor GS, et al. Pulmonary vascular disease in neonates with transposition of the great arteries and intact ventricular septum. Br Heart J 1993;69:442 - 5. [16] Levin DL, Mills LJ, Parkey M. Morphologic development of the pulmonary vascular bed in experimental coarctation of the aorta. Circulation 1979;60:349 - 54. [17] Sweed Y, Puri P. Congenital diaphragmatic hernia: influence of associated malformations on survival. Arch Dis Child 1993;69:68 - 70.
Discussion David I. Hackam, MD, PHD, FAAP (Pittsburgh, PA): I very much enjoyed your presentation and have questions regarding the patients that were excluded. You were very careful to point out that you were focusing on hemodynamically significant defects for obvious reasons. I’m wondering if you could give us some insights as to how you defined what was bhemodynamically significant.Q Were patients excluded on the basis of echocardiographic measurements? Were patients excluded on the basis of anatomic definitions alone? Joseph N. Graziano, MD (Ann Arbor, MI): Anything other than defects that would be very common in patients with CDH, such as PFOs, ASDs, or PDAs, was considered significant. So really, it is all forms of heart disease other than those. What we called hemodynamically insignificant defects were just minor anomalies with no hemodynamic consequence. So a left superior vena cava draining to the coronary sinus, juxtaposed atrial appendages, things such as those that did not really alter the circulation at all, but were just not completely normal, those were excluded. Richard R. Ricketts, MD, FAAP (Atlanta, GA): At our center, we kind of use the wastebasket term I guess, that if they have significant heart disease, they won’t go on ECMO. Were these patients that you studied, some on ECMO, some off ECMO, and using your data, should there be some subdivision of that criteria? Maybe some of those patients should not be excluded from ECMO if they have an isolated VSD for example.
1050 Joseph N. Graziano, MD (Ann Arbor, MI): Exactly, the use of ECMO in the entire group of patients was approximately 35%. The number of patients in this cardiac subgroup on ECMO, at this time, are data that we do not yet have. I can tell you from our experience at the University of Michigan that there certainly is a much higher use of ECMO in these patients. As you see, half of the patients have VSDs or aortic arch obstruction, but the other half have significant cyanotic disease. So it’s not surprising that more of the patients require support on ECMO. I would say, I think clearly those patients with single ventricle anatomy are not good ECMO candidates, as they have very poor outcome regardless. But I do think that those patients with minor defects, such as VSDs or isolated coarctations may be candidates for ECMO. At our institution, we’ve actually looked at our experience of repairing those children, albeit a small number, but we can actually improve survival at least compared with these numbers. So I think at a center with skilled cardiac surgeons, skilled pediatric surgeons, and cardiac intensivists that we may be able to improve on some of these numbers. I think ECMO would be a reasonable option for some of these patients.
J.N. Graziano Essam Elhalaby, MD (Tanta, Egypt): I would like to know, did you try to correlate the severity of cardiac anomalies with the degree of lung hypoplasia? Joseph N. Graziano, MD (Ann Arbor, MI): That’s a good question. We were not able to do that from the data that we have at this point. There have been other studies, as you probably know, from the group at Children’s Hospital of Philadelphia that have correlated the degree of cardiac disease with the degree of pulmonary hypoplasia. But we just did not have the types of data in this series to make such conclusion. Arlet Kurkchubasche, MD, FAAP (Providence, RI): In your analysis of the data, were you able to detect any trends that correlate with right versus left-sided diaphragmatic hernia? Joseph N. Graziano, MD (Ann Arbor, MI): In the group with heart disease, there was a mildly but significantly higher incidence of right-sided CDH compared with patients without heart disease. Interestingly, this trend was true for both left-sided as well as right-sided obstructive cardiac defects.
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Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis: a report from the Congenital Diaphragmatic Hernia Study Group Joseph N. Graziano* for the Congenital Diaphragmatic Hernia Study Group Department of Pediatrics, Division of Cardiology, University of Michigan, Ann Arbor, MI 48109-0204, USA Index words: Congenital diaphragmatic hernia; Congenital heart disease; Congenital Diaphragmatic Hernia Study Group (CDHSG)
Abstract Background/Purpose: Patients with congenital diaphragmatic hernia (CDH) are known to have associated cardiac anomalies. Data from the Congenital Diaphragmatic Hernia Study Group has allowed better definition of the types of heart defects (HDs) and survival for these patients. Methods: Since 1995, 2636 patients were enrolled in the Congenital Diaphragmatic Hernia Study Group from 82 centers. Patients with hemodynamically significant HD, excluding patent ductus arteriosus (PDA); patent foramen ovale (PFO); and atrial septal defect (ASD), were selected. Cardiac anatomy and survival data for all patients were reviewed. Results: Two hundred eighty (10.6%) patients had significant HDs: ventricular septal defect (VSD); (42.2%), aortic arch obstruction (15%), univentricular anatomy (13.9%), tetralogy of Fallot variants (11.1%), total anomalous pulmonary venous return (3.9%), double outlet right ventricle (RV) (3.2%), pulmonary stenosis (2.5%), transposition of the great arteries (2.5%), and various other defects in 5.7%. Survival for the entire group was 67.1%; survival for patients without HD was 70.2% and for patients with HD was 41.1% ( P b .001). Patients with biventricular cardiac anatomy had a 47% survival, whereas those with univentricular anatomy had a 5% survival ( P b .001). Conclusion: Significant HD is associated with 10.6% of CDH. Survival for patients with HD is significantly lower than for patients with normal cardiac anatomy. Patients with CDH and univentricular cardiac anatomy have a poor prognosis. D 2005 Elsevier Inc. All rights reserved.
Infants with congenital diaphragmatic hernia (CDH) are well known to have other associated anomalies, with cardiac defects occurring in 10% to 35% of patients [1-4]. Presented at the 56th Annual Meeting of the Section on Surgery of the American Academy of Pediatrics, San Francisco, California, October 8-10, 2004. T Corresponding author. Division of Pediatric Cardiology, University of Michigan Hospital, Women’s L1242, Box 0204, Ann Arbor, MI 48109-0204, USA. 0022-3468/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2005.03.025
Numerous studies have demonstrated a substantial reduction in survival in patients with CDH and cardiac defects [2,5-7]. The establishment of the Congenital Diaphragmatic Hernia Study Group has helped create a multicenter database for the collection of information regarding infants with CDH. This database has included information regarding the cardiac anatomy of each patient with CDH and has thus allowed for the quantification of the types of cardiac defects seen in patients with CDH from a very large number
1046
J.N. Graziano
of patients. Furthermore, it has allowed the description of survival for this group of patients. This study sought to describe the types of heart disease associated with CDH and to report the outcome of infants with CDH and significant congenital heart defects (HDs).
1. Methods Since 1995, 82 pediatric surgical centers have participated in the collection of data for all patients with CDH treated at that center. This database includes a list of 12 common congenital HDs, with the ability to describe other more complex defects, if necessary. As of December 2003, 2636 patients were enrolled in this database. Survival data for all 2636 patients were reviewed. In addition, all patients described as having a cardiac defect were selected for further review. Details of the description of heart disease were reviewed, and patients with primary arrhythmias in the absence of structural heart disease, patients with hemodynamically insignificant defects (ie, left superior vena cava to the coronary sinus, juxtaposed atrial appendages, etc), and patients with a patent foramen ovale, atrial septal defect, or patent ductus arteriosus were excluded from the review. All remaining patients with hemodynamically significant congenital HDs were selected for review of their type of HD and clinical outcome. Because of the anonymous retrospective nature of this study, it was reviewed and approved by the institutional review board at the University of Michigan under exemption status.
2. Results Three hundred eighty-five of the 2636 (14.6%) patients were initially described by the reporting centers as having cardiac disease. Eight-two (3.1%) patients had isolated ASDs without other defects and were thus excluded from further analysis. Twenty-three (0.9%) patients had either hemodynamically insignificant anomalies (ie, interrupted inferior vena cava to the azygous vein, left superior vena cava to the coronary sinus, and bicuspid aortic valve without stenosis) or arrhythmias without structural heart disease and were also excluded. The remaining 280 (10.6%) patients thus had significant structural cardiac defects and comprised the cohort for the remaining study. The distribution of cardiac disease for all 280 patients is described in Fig. 1. Isolated VSD was the most common cardiac defect, occurring in 42.2% of patients with significant heart disease. Aortic arch obstruction was also commonly seen, occurring in 15% of patients (9.3% with isolated coarctation, 4.6% with coarctation and VSD, and interrupted aortic arch in 1.1%). Univentricular anatomy was seen in similar frequency (13.9%), the large majority of which included hypoplastic left heart syndrome (1 patient had a double inlet left ventricle/hypoplastic right ventricle).
Fig. 1 Types of cardiac defects observed in patients with CDH and congenital heart disease (n = 280).
Thus, the 3 groups of ventricular septal defect, aortic arch obstruction, and single ventricle anatomy comprised nearly three quarters of the cardiac defects seen in patients with CDH. The remaining patients had various associated defects, including tetralogy of Fallot (with and without pulmonary atresia) in 11.1%, total anomalous pulmonary venous return in 3.9%, double outlet right ventricle in 3.2%, pulmonary stenosis in 2.5%, transposition of the great arteries in 2.5%, and various other defects in 5.7%, such as atrioventricular septal defect, truncus arteriosus, and Ebstein anomaly of the tricuspid valve. Thirty-one percent of patients in the group with cardiac defects had right-sided diaphragmatic defects. This incidence of right-sided CDH was significantly higher when compared with the group without heart disease, who had a 21% incidence of right-sided CDH ( P b .001). Interestingly, this trend toward more frequent right-sided CDH was consistent for both left-sided obstructive cardiac defects such as aortic arch obstruction and hypoplastic left heart syndrome (32%, P = .01), as well as right-sided obstructive cardiac defects such as tetralogy of Fallot variants and pulmonary stenosis (34%, P = .01). Hospital survival for all study patients is described in Fig. 2. Survival for all 2636 patients with CDH was 67.1%. Patients without HDs (n = 2356) had a 70.2% survival, whereas patients with cardiac defects (n = 280) had a 41.1% survival ( P b .001). Of those patients with cardiac defects, survival varied by type of defect, as seen in Fig. 2, although survival for each of the subgroups was significantly lower than the group without heart disease, with the exception of isolated pulmonary stenosis. Of note was the extremely poor survival in patients with univentricular anatomy of 5.1% ( P b .001 as compared with patients with all other biventricular defects). Also illustrated in Fig. 2 are the reported surgical survivals for each of the congenital HDs from various cardiac surgical series [8]. Of note is the
Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis
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Fig. 2 Survival for patients with CDH, stratified by type of cardiac defect. The shaded bars at the top of the graph provide reference ranges of survival for each cardiac defect in patients without CDH [8]. *P b .001, compared with CDH without congenital heart disease. **P b .001 compared with CDH with biventricular heart disease. ***P = .03 compared with CDH with all other heart diseases. TAPVR indicates total anomalous pulmonary venous return.
significant discrepancy in survival between cardiac patients with and without CDH.
3. Discussion The association of congenital heart disease with CDH has long been described with an incidence of 10% to 35%. Our review of the largest number of CDH patients to date suggests the lower end of this spectrum of significant structural heart disease. Nonetheless, multiple population studies in the United States have estimated the incidence of congenital cardiac malformations to be between 0.3% and 0.8% of all live births [9-11], suggesting roughly a 20-fold increase in the prevalence of congenital heart disease in patients with CDH as compared with normal infants. Interestingly, in comparing the prevalence of specific HDs in CDH patients to previously published data from the Baltimore-Washington Infant Heart Study, there appears to be a trend toward more frequent left-sided obstructive defects in patients with CDH, with hypoplastic left heart syndrome being 100 times more prevalent (1.5% of all CDH vs 0.015% of all live newborns) and aortic arch obstruction being 75 times more prevalent (1.6% vs 0.021%) than the general population [9]. Furthermore, right-sided obstructive defects such as pulmonary stenosis were only 6 times more prevalent in the CDH group (0.3% vs 0.05%) than in the general population. The etiology for this discrepancy is unclear but may in part be related to the majority of diaphragmatic defects being left-sided and thus limiting
flow through the left heart via direct compression of these structures. Previous studies have demonstrated a significantly lower left ventricular mass index in patients with left-sided CDH, as compared with other neonates with pulmonary hypertension, in part supporting this speculation [12]. However, the trends toward more right-sided diaphragmatic defects in patients with left-sided obstructive defects would seem to contradict this notion. Additional data have suggested differential embryonic cell death patterns between patients with right and left diaphragmatic hernia and may thus possibly provide a cellular mechanism to the difference in cardiac pathology [13]. Nonetheless, the etiology for the increased prevalence of left-sided obstructive cardiac defect is as of yet unclear. Early reports described an extremely poor survival for patient with both diaphragmatic and cardiac defects, with some series reporting a 0% survival [2,6,7]. Our large series would suggest a survival substantially higher than these previous reports. Nonetheless, the outcome of patients with CDH seems to be significantly affected by the presence of a congenital cardiac defect more complex than a simple atrial septal defect. A major cardiovascular influence of a diaphragmatic hernia is related to the external pulmonary compression and associated pulmonary parenchymal and arterial hypoplasia on the affected side [14]. This pulmonary vascular pathology results in an elevation in pulmonary vascular resistance in the affected lung. Cohen et al [3] recently described the use of lung area/head circumference ratio as an indirect measure of the severity of pulmonary hypoplasia and found the ratio to
1048 be useful tool in stratifying the risk of mortality for CDH patients with congenital heart disease. As one might expect, patients with a low lung area/head circumference ratio had a greater risk of mortality, and the presence of heart disease had an even further negative impact on survival. The associated pulmonary vascular changes described above might be expected to have a more significant impact on patients with cardiac disease dependent on good-sized pulmonary arteries and normal pulmonary vascular resistance. In fact, the patients with the best outcome in this study were patients with ventricular septal defects and isolated pulmonary stenosis, who generally have normal-sized pulmonary arteries and normally functioning ventricles that would seem better suited to tolerate the additional burden of an increased pulmonary resistance. Patients with a known predisposition to elevated pulmonary vascular resistance, such as transposition of the great arteries and coarctation of the aorta, would thus seem more susceptible to the pulmonary changes associated with CDH [15,16]. This in fact appeared to be the trend in this study, with a higher mortality this group of patients. Finally, the patients likely to be most significantly affected by the pulmonary arterial pathology seen with CDH are those with univentricular anatomy. In the presence of a single ventricle cardiac defect, the ventricle supports both the systemic and pulmonary circulations, with the balance been these circulations being dependent on the relative resistances between these 2 circulations. Furthermore, the ultimate longterm goal in the palliation of these patients is to eliminate the bparallelQ circulation and provide a circulation in bseriesQ via cavopulmonary connections that reduce the volume overload on the single ventricle. These cavopulmonary connections provide passive pulmonary circulation and are very much dependent on low pulmonary vascular resistance and normal pulmonary arterial size and morphology to provide adequate pulmonary blood flow. As these aspects of the pulmonary circulation are most directly and negatively affected by a diaphragmatic hernia, it would be expected that the shortterm and long-term outlook for patients with univentricular anatomy and CDH would be quite poor. Our data would confirm this implication, that single ventricle physiology is poorly tolerated in patients with CDH, as there were only 2 survivors of 39 (5.1%) patients in this series. There are several limitations to this study. First, details of the cardiac anatomy were provided from numerous cardiologists from many different centers and thus may be subject to various nomenclatures and interpretations. Second, the influence of noncardiac anomalies has been described to contribute to an increase in mortality, and the presence of additional anomalies was not examined in this study group [2,3,17]. Finally, data regarding details of cardiac intervention, if any, were limited, making conclusions about the impact of these intervention on survival unclear. Despite these limitations, it is clear from these data that patients with CDH have a much higher prevalence of cardiac defects as compared with normal healthy infants,
J.N. Graziano with perhaps a trend toward more left-sided obstructive defects. Furthermore, even simple but hemodynamically significant cardiac defects have a significant negative impact on survival, with single ventricle defects having a very poor survival. Further study is needed to determine the impact of cardiac intervention on survival for these patients.
Acknowledgments The authors gratefully acknowledge the contributions of the following centers in the Congenital Diaphragmatic Hernia Study Group, for the collection of data for this study: Arnold Palmer Hospital for Women and Children, Orlando, Fla; Astrid Lindgren Children’s Hospital, Stockholm, Sweden; Boston Children’s Hospital, Boston, Mass; Cardinal Glennon Children’s Hospital, St Louis, Mo; Carolinas Medical Center, Charlotte, NC; Children’s Hospital Medical Center–Cincinnati, Cincinnati, Ohio; Children’s Hospital of Akron, Akron, Ohio; Children’s Hospital of Alabama, Birmingham, Ala; Children’s Hospital of Austin, Austin, Tex; Children’s Hospital of Buffalo, Buffalo, NY; Children’s Hospital of Illinois, Peoria, Ill; Children’s Hospital of Los Angeles, Los Angeles, Calif; Children’s Hospital of Michigan, Detroit, Mich; Children’s Hospital of Minneapolis, Minneapolis, Minn; Children’s Hospital of Oakland, Oakland, Calif; Children’s Hospital of Oklahoma, Oklahoma City, Okla; Children’s Hospital of Philadelphia, Philadelphia, Pa; Children’s Hospital of Wisconsin, Milwaukee, Wis; Children’s Mercy Hospital, Overland Park, Kan; Children’s National Medical Center, Washington, DC; Cleveland Clinic Foundation–Children’s Hospital, Cleveland, Ohio; Columbus Children’s Hospital, Columbus, Ohio; Cook Children’s Hospital, Fort Worth, Tex; DeVos Children’s Hospital, Grand Rapids, Mich; Duke University Medical Center, Durham, NC; Egelston Children’s Hospital, Atlanta, Ga; Freie Universitat Berlin, Berlin, Germany; Hasbro Children’s Hospital, Providence, RI; Hermann Children’s Hospital, Houston, Tex; Hershey Medical Center, Hershey, Pa; James Whitcomb Riley Children’s Hospital, Indianapolis, Ind; Kosair Children’s Hospital, Louisville, Ky; Legacy Emanuel Children’s Hospital, Portland, Ore; Loma Linda University Children’s Hospital, Loma Linda, Calif; Lucile Salter Packard Children’s Hospital, Palo Alto, Calif; Lutheran General Hospital, Park Ridge, Ill; Massachusetts General Hospital, Boston, Mass; Medical College of Georgia, Augusta, Ga; Medical College of Virginia, Richmond, Va; Medical University of South Carolina, Charleston, SC; Miami Valley Hospital, Dayton, Ohio; National Center for Child Health and Development, Tokyo, Japan; North Carolina Baptist Hospital, Winston-Salem, NC; Oespedale Pediatrico Bambino Gesu, Rome, Italy; Oespedale Riunite Bergamo, Bergamo, Italy; Phoenix Children’s Hospital, Phoenix, Ariz; Primary Children’s Hospital, Salt Lake City, Utah; Rainbow Babies and Children Hospital, Cleveland, Ohio; Rockford Memo-
Cardiac anomalies in patients with congenital diaphragmatic hernia and their prognosis rial Children’s Hospital, Rockford, Ill; Royal Alexandra Hospital, Edmonton, Alberta, Canada; Royal Children’s Hospital, Parkville, Victoria, Australia; Royal Hospital for Sick Children, Glasgow, Scotland; Salesi Children’s Hospital, Ancona, Italy; San Diego Children’s Hospital, San Diego, Calif; Shands Children’s Hospital/University of Florida, Gainesville, Fla; Sophia Children’s Hospital, Rotterdam, Netherlands; St Christopher’s Children’s Hospital, Philadelphia, Pa; St Francis Children’s Hospital, Tulsa, Okla; St Joseph’s Hospital and Medical Center, Phoenix, Ariz; St Louis Children’s Hospital, St Louis, Mo; Strong Children’s Hospital, Rochester, NY; Sydney Children’s Hospital, Randwick, NWS, Australia; T.C. Thompson Hospital, Chattanooga, Tenn; Texas Children’s Hospital, Houston, Tex; The Hospital for Sick Children, Toronto, Ontario, Canada; Tulane University Hospital, New Orleans, La; Universitatsklinikum Mannheim gGmbH, Mannheim, Germany; University Hospital Gasthuisberg, Leuven, Belgium; University of California Los Angeles, Los Angeles, Calif; University of California San Diego, San Diego, Calif; University of Chicago, Chicago, Ill; University of Kentucky Medical Center, Lexington, Ky; University of Michigan Medical Center, Ann Arbor, Mich; University of Nebraska Medical Center, Omaha, Neb; University of New Mexico Children’s Hospital, Albuquerque, NM; University of North Carolina, Chapel Hill, NC; University of Puerto Rico Medical Center, San Juan, Puerto Rico; University of Texas Medical Branch at Galveston, Galveston, Tex; University of Virginia Health System, Charlottesville, Va; Vanderbilt Children’s Hospital, Nashville, Tenn; Wilford Hall USAF Medical Center, Lackland AFB, Tex; and Yale University Children’s Hospital, New Haven, Conn.
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[9] Ferencz C, Neill CA. Cardiovascular malformations: prevalence at live birth. In: Freedom RM, Benson LN, Smallhorn JF, editors. Neonatal Heart Disease. New York (NY)7 Springer Verlag; 1992. p. 19 - 27. [10] Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Circulation 1971;43:323 - 32. [11] Hoffman J, Christianson R. Congenital heart disease in a cohort of 19,502 births: long term follow up. Am J Cardiol 1978;42:641 - 7. [12] Schwartz SM, Vermillion RP, Hirschl RB. Evaluation of left ventricular mass in children with left-sided congenital diaphragmatic hernia. J Pediatr 1994;125:447 - 51. [13] Losty PD, Vanamo K, Rintala RJ, et al. Congenital diaphragmatic hernia—does the side of the defect influence the incidence of associated malformations? J Pediatr Surg 1998;33:507 - 10. [14] Geggel RL, Murphy JD, Langleben D, et al. Congenital diaphragmatic hernia: arterial structural changes and persistent pulmonary hypertension after surgical repair. J Pediatr 1985;107:457 - 64. [15] Kumar A, Taylor GP, Sandor GS, et al. Pulmonary vascular disease in neonates with transposition of the great arteries and intact ventricular septum. Br Heart J 1993;69:442 - 5. [16] Levin DL, Mills LJ, Parkey M. Morphologic development of the pulmonary vascular bed in experimental coarctation of the aorta. Circulation 1979;60:349 - 54. [17] Sweed Y, Puri P. Congenital diaphragmatic hernia: influence of associated malformations on survival. Arch Dis Child 1993;69:68 - 70.
Discussion David I. Hackam, MD, PHD, FAAP (Pittsburgh, PA): I very much enjoyed your presentation and have questions regarding the patients that were excluded. You were very careful to point out that you were focusing on hemodynamically significant defects for obvious reasons. I’m wondering if you could give us some insights as to how you defined what was bhemodynamically significant.Q Were patients excluded on the basis of echocardiographic measurements? Were patients excluded on the basis of anatomic definitions alone? Joseph N. Graziano, MD (Ann Arbor, MI): Anything other than defects that would be very common in patients with CDH, such as PFOs, ASDs, or PDAs, was considered significant. So really, it is all forms of heart disease other than those. What we called hemodynamically insignificant defects were just minor anomalies with no hemodynamic consequence. So a left superior vena cava draining to the coronary sinus, juxtaposed atrial appendages, things such as those that did not really alter the circulation at all, but were just not completely normal, those were excluded. Richard R. Ricketts, MD, FAAP (Atlanta, GA): At our center, we kind of use the wastebasket term I guess, that if they have significant heart disease, they won’t go on ECMO. Were these patients that you studied, some on ECMO, some off ECMO, and using your data, should there be some subdivision of that criteria? Maybe some of those patients should not be excluded from ECMO if they have an isolated VSD for example.
1050 Joseph N. Graziano, MD (Ann Arbor, MI): Exactly, the use of ECMO in the entire group of patients was approximately 35%. The number of patients in this cardiac subgroup on ECMO, at this time, are data that we do not yet have. I can tell you from our experience at the University of Michigan that there certainly is a much higher use of ECMO in these patients. As you see, half of the patients have VSDs or aortic arch obstruction, but the other half have significant cyanotic disease. So it’s not surprising that more of the patients require support on ECMO. I would say, I think clearly those patients with single ventricle anatomy are not good ECMO candidates, as they have very poor outcome regardless. But I do think that those patients with minor defects, such as VSDs or isolated coarctations may be candidates for ECMO. At our institution, we’ve actually looked at our experience of repairing those children, albeit a small number, but we can actually improve survival at least compared with these numbers. So I think at a center with skilled cardiac surgeons, skilled pediatric surgeons, and cardiac intensivists that we may be able to improve on some of these numbers. I think ECMO would be a reasonable option for some of these patients.
J.N. Graziano Essam Elhalaby, MD (Tanta, Egypt): I would like to know, did you try to correlate the severity of cardiac anomalies with the degree of lung hypoplasia? Joseph N. Graziano, MD (Ann Arbor, MI): That’s a good question. We were not able to do that from the data that we have at this point. There have been other studies, as you probably know, from the group at Children’s Hospital of Philadelphia that have correlated the degree of cardiac disease with the degree of pulmonary hypoplasia. But we just did not have the types of data in this series to make such conclusion. Arlet Kurkchubasche, MD, FAAP (Providence, RI): In your analysis of the data, were you able to detect any trends that correlate with right versus left-sided diaphragmatic hernia? Joseph N. Graziano, MD (Ann Arbor, MI): In the group with heart disease, there was a mildly but significantly higher incidence of right-sided CDH compared with patients without heart disease. Interestingly, this trend was true for both left-sided as well as right-sided obstructive cardiac defects.