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Predictors of Mortality after Primary Discharge from Hospital in Patients with Esophageal Atresia
ORIGINAL ARTICLES Predictors of Mortality after Primary Discharge from Hospital in Patients with Esophageal Atresia Sharman P. Tan Tanny, MBBS, BMedSci, DCH, MSc1,2,3, Edward Fearon, MD2,3, Alisa Hawley, MN, BN, RN, RM, Neonatal Critical Care (Cert)1,2,4, Jo-Anne Brooks, RN, RM, ENB 408 Neonatal option1,2,4, Assia Comella, BMedSci1,2,5, John M. Hutson, AO, BS, MD(Monash), MD, DSC(Melb), FRACS, FAAP1,2,3, Warwick J. Teague, MBBS, DPhil Oxon, FRACS1,2,3, Anastasia Pellicano, MBBS, FRACP4, and Sebastian K. King, MBBS, PhD, FRACS1,2,3,6 Objective To describe esophageal atresia mortality rates and their associations in our cohort. Study design Patients with esophageal atresia, managed at The Royal Children’s Hospital, Melbourne (19802018), who subsequently died, were retrospectively identified from the prospective Nate Myers Oesophageal Atresia database. Data collected included patient and maternal demographics, vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects (VACTERL) associations, mortality risk factors, and preoperative, operative, and postoperative findings. Mortality before discharge was defined as death during the initial admission. Results A total of 88 of the 650 patients (13.5%) died during the study period; mortality before discharge occurred in 66 of the 88 (75.0%); mortality after discharge occurred in 22 of the 88 (25.0%). Common causes of mortality before discharge were palliation for respiratory anomalies (15/66 [22.7%]), associated syndromes (11/66 [16.7%]), and neurologic anomalies (10/66 [15.2%]). The most common syndrome leading to palliation was trisomy 18 (7/66 [10.6%]). Causes of mortality after discharge had available documentation for 17 of 22 patients (77.3%). Common causes were respiratory compromise (6/17 [35.3%]), sudden unexplained deaths (6/17 [35.3%]), and Fanconi anemia (2/17 [11.8%]). Of the patients discharged from hospital, 22 of 584 (3.8%) subsequently died. There was no statistical difference in VACTERL association between mortality before discharge (31/61 [50.8%]) and mortality after discharge (11/20 [55.0%]), nor in incidence of twins between mortality before discharge (8/56 [14.3%]) and mortality after discharge (2/18 [11.1%]). Conclusions We identified predictors of mortality in patients with esophageal atresia in a large prospective cohort. Parents of children with esophageal atresia must be counselled appropriately as to the likelihood of death after discharge from hospital. (J Pediatr 2020;-:1-6).
T
he first long-term survival of patients with esophageal atresia was described in 1939.1 The current overall survival rate for esophageal atresia is reported to be 83%-95%.2-5 Mortality may be further classified into mortality before discharge (deaths that occurred during the patient’s initial admission) and mortality after discharge (deaths that occurred after the initial admission). Risk factors for mortality before discharge, including cardiac anomalies, have been well-described in the literature.6-13 Waterston et al established survival categories derived from a combination of factors, including low birth weight, preoperative pneumonia, and congenital anomalies, which corresponded with varying risks of death.14 Subsequently, Spitz et al stratified at-risk groups according to birth weight and the presence of major congenital heart disease.15 The Spitz classification is commonly used to guide clinicians in parental counselling. However, more recently, advances in neonatal care have resulted in improvements in survival rates, especially for low birthweight and premature babies.16
TEF VACTERL
Tracheoesophageal fistula Vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects
From the 1Department of Pediatric Surgery, The Royal Children’s Hospital; 2F. Douglas Stephens Surgical Research Group, Murdoch Children’s Research Institute; 3 Department of Pediatrics, University of Melbourne; 4 Department of Neonatal Medicine, The Royal Children’s Hospital, Melbourne; 5School of Medicine, Monash University, Clayton; and the 6Department of Gastroenterology and Clinical Nutrition, The Royal Children’s Hospital, Melbourne, Victoria, Australia S.T.T. is supported by a National Health and Medical Research Council (NHMRC) Medical Research Postgraduate Scholarship (1168142) and an Australian Government Research Training Program Scholarship. Associate Professor Sebastian King’s and Associate Professor Warwick Teague’s positions as Academic Paediatric Surgeons are generously supported by The Royal Children’s Hospital Foundation. Funding for the development and maintenance of the Nate Myers Oesophageal Atresia Database is provided by the charitable efforts of the Oesophageal Atresia Research Auxiliary of The Royal Children’s Hospital, Melbourne whose assistance is gratefully acknowledged. The authors declare no conflicts of interest. Portions of this study were presented at the 5th International Conference of Esophageal Atresia, June 24-28, 2019, Rome, Italy. 0022-3476/$ - see front matter. Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.031
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Recent studies have, therefore, found no association with birth weight and mortality.3,4,17 The Spitz classification was revisited in a cohort from 1993 to 2015 and found that 50% survival was achievable in patients with esophageal atresia under 1 kg.16 However, all 3 patients less than 800 g did not survive in this group. Other risk factors for mortality before discharge described in the literature include chromosomal anomalies, and the sequelae of postoperative anastomotic leak.3,4,18,19 Risk factors for mortality in extremely low birth weight neonates have also been described in the literature in general—these include antepartum hemorrhage, multiple pregnancy, hyaline membrane disease, and breech delivery.20 However, these factors have not been investigated in the context of esophageal atresia. Late mortality has been described to be associated with chromosomal anomalies and respiratory disease, the latter including tracheomalacia, reactive airway disease, gastroesophageal reflux disease, and aspiration.3,21 However, the literature is currently limited in this aspect of mortality risk. Our study aimed to establish the risk factors for mortality in patients with esophageal atresia, with a focus on risk factors that contribute to death after the primary discharge from hospital.
Methods The prospective Nate Myers Oesophageal Atresia database includes all patients treated at The Royal Children’s Hospital, Melbourne with esophageal atresia and/or tracheoesophageal fistula (TEF) since 1948. All patients with esophageal atresia who died during their initial admission, or subsequently, from January 1980 to December 2018 were identified. Cases of mortality before January 1980 were excluded owing to the less comprehensive patient record documentation and a poorer quality of data entry. The electronic medical record (Epic Systems Corporation, Verona, Wisconsin) was crosschecked to confirm whether patients were alive or deceased. Data collected from patients’ records included demographics, preoperative findings, operative details, postoperative outcomes, and known risk factors for death. Any missing data were reported as such and excluded from the analysis. Low birth weight was defined as less than 1.5 kg, and cardiac anomalies as those requiring operative intervention or palliation.15 Prematurity was defined as less than 37 weeks of gestation. The vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects (VACTERL) association was defined as 2 or more other associations, in addition to TEF, and/or esophageal atresia.22 Mortality before discharge was defined as death during the initial admission. Mortality after discharge was defined as death after primary discharge from the hospital. The risk of bias was minimized according to the GRADE guidelines.23 Descriptive statistics for continuous variables were reported as median (range). Categorical variables were reported as percentages. Categorical data were compared 2
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with the Fisher exact test. Statistical significance was set at a P value of less than .05. Statistical analysis was performed using GraphPad Prism 7.00 for Windows (GraphPad Software, La Jolla, California). Approval from the Human Research Ethics Committee (HREC # DA 014-2014-02) was granted.
Results From January 1980 to December 2018, 650 patients with esophageal atresia with or without TEF were managed at The Royal Children’s Hospital. A total of 88 patients died, representing an overall mortality rate of 13.5%. The majority of deaths (66/88 [75.0%]) occurred during the initial admission. Characteristics of the mortality before discharge and mortality after discharge group are described in Table I, and mortality rates by time epoch are demonstrated in Table II. The most common causes of mortality before discharge was palliation for respiratory anomalies (15/66 [22.7%]), followed by associated syndromes (11/66 [16.7%]) and neurologic anomalies (10/66 [15.2%]). The most commonly associated syndrome leading to palliation was trisomy 18 (7/66 [10.6%]). Of all patients discharged from hospital, 22 of the 580 (3.8%) subsequently died. Causes of mortality after discharge had available documentation in 17 of 22 patients (77.3%). Common causes of mortality after discharge were respiratory compromise (6/17 [35.3%]), sudden deaths (6/17 [35.3%]), and Fanconi anemia (2/17 [11.8%]) (Table III). Respiratory compromise included 3 patients with aspiration related complications, 2 with tracheostomy or airways complications, and 1 with croup. In this study period, there were 21 patients requiring tracheostomies, resulting in a mortality rate of 9.5% (2/21). Sudden deaths included 5 with sudden infant death syndrome and 1 with an unexpected death at the age of 1 year and 4 months. In the Fanconi anemia-related deaths, 1 patient had secondary staphylococcal septicemia with temporoparietal hemorrhage and the other was a poor candidate for bone marrow transplant owing to existing renal impairment. In these 2 patients, 1 was associated with VACTERL (having right crossed renal ectopia and an anterior anus) and the
Table I. Characteristics of the mortality before discharge and mortality after discharge groups
Characteristics
Mortality before discharge (n = 66)
Mortality after discharge (n = 22)
P value
Age at death Age of mothers, y Prematurity Gestational age, wk Low birth weight Birth weight, g Male:female
7 d (0-165 d) 31.5 (17-43) 65.6% (42/64) 34.5 (25-42) 31.3% (20/64) 1895 (660-4100) 35:31
16 mo (3-358 mo) 25 (17-37) 55% (11/20) 36 (30-40) 5.0% (1/20) 2018 (1386-4005) 13:9
<.001 .02 .54 .22 .02 .08 .63
Values are median (range) unless otherwise specified.
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Table II. Numbers of mortality before discharge and mortality after discharge deaths by time period Groups Mortality before discharge deaths Mortality after discharge deaths Total patients Mortality rate
1980-1989
1990-1999
2000-2009
2010-2018
22
19
15
10
8
4
4
6
153 19.6%
157 14.6%
166 11.4%
174 9.2%
other was not (but had a small ventricular septal defect and a duodenal atresia). Neither had evidence of dysmorphism, and both had normal karyotype, although one was associated with a high frequency of chromosome breakage. In the remaining 3 patients with a documented cause of death, 1 died of plasmacytosis, 1 died of a traumatic brain injury, and 1 died of renal failure. The incidence of twins was not significantly different between the mortality before discharge (8/56 [14.3%]) and mortality after discharge (2/18 [11.1%]) groups. The types of esophageal atresia, according to the Gross classification, within each mortality groups are described in Table IV. Chromosomal abnormalities and syndromic association data were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 19 of 22 patients (86.4%) in the mortality after discharge group. All cases of trisomy 18 (12/60 [20.0%]) and trisomy 21 (6/60 [10.0%]) were in the mortality before discharge group. The frequency of CHARGE syndrome (coloboma, heart defects, atresia choanae) was 7 of 60 (11.7%) in the mortality before discharge group and 1 of 19 (5.3%) in the mortality after discharge group. Data pertaining to VACTERL association were available in 61 of 66 patients (92.4%) in the mortality before discharge group and 20 of 22 patients (90.9%) in the mortality after discharge group. There was no statistically significant difference in the incidence of the VACTERL association between the mortality before discharge (31/61 [50.8%]) and mortality after discharge group (11/20 [55.0%]).
Table III. Causes of death in the mortality after discharge group (n = 17) Causes of death Respiratory compromise Aspiration-related complications Tracheostomy or airways complications Croup Sudden deaths Sudden infant death syndrome Unexpected death at >1 year old Fanconi anaemia-related deaths Trauma Renal failure Plasmacytosis
n (%) 6 (35.3)
6 (35.3) 2 (11.8) 1 (5.9) 1 (5.9) 1 (5.9)
Table IV. Distribution of esophageal atresia type within the mortality before discharge and mortality after discharge groups Esophageal atresias Type A Type B Type C Type D Type E Other variant: Esophagobronchial fistula with tracheal atresia Unrecorded
Mortality before discharge (n = 66)
Mortality after discharge (n = 22)
7 (10.6) 2 (3.0) 56 (84.8) 0 (0) 0 (0) 1 (1.5)
1 (4.5) 0 (0) 18 (81.8) 0 (0) 2 (9.1) 0 (0)
0 (0)
1 (4.5)
Values are number (%).
Two patients in the mortality before discharge group had an anastomotic leak, and one in the mortality after discharge group had an anastomotic leak (P = .91). Similarly, 2 patients in the mortality before discharge group had recurrence of a fistula, compared with 1 patient in the mortality after discharge group (P = .91). Data pertaining to fundoplication were available in 61 of 66 patients (92.4%) in the mortality before discharge group and 15 of 22 patients (62.1%) in the mortality after discharge group. Fundoplication rates were lower in the mortality before discharge group (1/61 [1.6%]) compared with the mortality after discharge group (5/15, 33.3%; P < .0001). Respiratory support data were available in 59 of 66 patients (89.4%) in the mortality before discharge group and 12 of 22 patients (54.5%) in the mortality after discharge group. The need for more intensive respiratory support (high-frequency oscillating ventilation or high-frequency jet ventilation) was increased in the mortality before discharge group (22/59 [37.3%]) compared with the mortality after discharge group (1/12 [8.3%]); however, this difference was not statistically significant (P = .05). Preoperative intubation data were available in 58 of 66 patients (87.9%) in the mortality before discharge group and 15 of 22 patients (68.2%) in the mortality after discharge group. Preoperative intubation was more common in the mortality before discharge group (32/58 [55.2%]) compared with the mortality after discharge group (5/15 [33.3%]). However, this difference was not statistically significant (P = .28). Data pertaining to respiratory anomalies were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 19 of 22 patients (86.4%) in the mortality after discharge group. Respiratory anomalies were more common in the mortality after discharge group (9/19 [47.4%]) compared with the mortality before discharge group (22/60 [36.7%]). However, this difference was also not statistically significant (P = .41). Data pertaining to hyaline membrane disease were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 16 of 22 patients (24.2%) in the mortality after discharge group. The incidences of hyaline membrane disease in the mortality before discharge group (21/60 [35.0%]) and the
Predictors of Mortality after Primary Discharge from Hospital in Patients with Esophageal Atresia
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mortality after discharge group (6/16 [37.5%]) were similar (P = .86).
Discussion Patients with esophageal atresia have an overall survival rate of 83%-95%.2-5 Improvements over time relate to advances in neonatal care and surgical techniques. Therefore, there is an increasing focus toward the management of long-term morbidity for patients with esophageal atresia. However, these children are still dying frequently, and it is imperative for us to understand factors that continue to affect mortality. Our study has found that mortality after discharge from hospital affected 3.8% of patients, of which the leading causes were respiratory compromise, sudden unexplained deaths, and Fanconi anemia. In our study, we identified an overall mortality rate of 13.5%, from the 1980s to the present, with more recent rates being 9.2% since the 2010s. Similarly, the current literature describes an overall improving mortality rate with time as well, with 16% described in the 1990s, and 9% from 2010 forward.24-26 This improvement in survival largely relates to improvements in neonatal intensive care treatment. One of the risk factors for early mortality is thought to have a relationship with autonomic instability, and at our institution we are embarking on a study of these patients using Holter monitoring. Late mortality described since the 1960s until the present day, ranges from 23% to 25% of all cases of death, similar to our findings.27,28 Although the causes of mortality before discharge in our cohort were similar to those reported in the literature,6-15,29 our study adds to the currently limited understanding of mortality after discharge in patients with esophageal atresia. In a study by Choudhury et al of 240 patients, 17 late deaths were recorded (7.1%).3 The primary cause of late deaths were respiratory causes (sudden infant death syndrome, aspiration, tracheomalacia, and reactive airway disease), accounting for 59% of late deaths.3 Deaths owing to aspiration has also been attributed to be precipitated by severe symptoms of gastroesophageal reflux disease.30 The rate of sudden unexpected deaths in infants worldwide, in comparison, ranges from 0.4 to 0.6 per 1000 live births.31 This rate is much higher in the esophageal atresia population as we have found, which is not surprising, given that tracheomalacia, gastroesophageal reflux, and intrapulmonary aspiration are potential mechanisms of asphyxia in sudden infant death.32 Similarly, the rate of tracheostomy-related deaths in our cohort of patients with esophageal atresia, at 9.5%, is higher than that reported in the literature, which was up to 5.9%.33 Although respiratory compromise and sudden deaths are difficult to predict and prevent, Fanconi anemia may be tested for before symptoms appear. This screening may allow for early patient and family counselling, regular monitoring, and commencement of treatment promptly to improve quality of life and prolong lifespan. 4
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Fanconi anemia is a genetic condition that results in progressive bone marrow failure and an increased risk of acute myeloid leukemia. The disease usually becomes symptomatic between the ages of 2 and 12 years. It is, therefore, logical that its association is related to our mortality after discharge cohort and not the mortality before discharge cohort. Fanconi anemia is often associated with congenital anomalies, and been described in association with esophageal atresia/ TEF.34,35 Despite co-occurring infrequently, our results demonstrated that Fanconi anemia was a major cause of mortality after discharge among patients with esophageal atresia in our cohort. A high index of suspicion for the development of Fanconi anemia should be kept in the long-term follow-up of patients with esophageal atresia, especially those with failure to thrive and associated congenital anomalies.36,37 Early diagnosis of Fanconi anemia is important, because it allows the disease to be managed expeditiously. This knowledge also allows families to obtain genetic counselling early, which would provide information regarding the risk of recurrence in future pregnancies and facilitate testing for siblings of affected patients. In our cohort, respiratory anomalies were more common in the mortality after discharge group, although this figure did not reach statistical significance. However, it is worth noting that respiratory compromise was the most common cause of mortality after discharge in this cohort. Similarly, Choudhury et al found that respiratory anomalies, including tracheomalacia, were implicated in cases of mortality after discharge.3 A previous study of twins by Orford et al described increased mortality of twins, compared with singletons.38 However, the timing of mortality was not defined, and this study also demonstrated lower mean birth weights and gestational ages for twin infants. Twins with esophageal atresia/ TEF have also been shown to have more complex anatomy. Whalen et al reported that 37% of twins in their cohort had an esophageal anatomy other than the most common type of esophageal atresia (esophageal atresia with distal TEF).39 Twins have also been reported to have a greater incidence of multiple congenital anomalies.38,39 However, our study suggests that infants with esophageal atresia who are a twin are not significantly more likely to suffer from mortality after discharge, compared with mortality before discharge. Although we used data from our prospectively maintained database, our study was limited by its retrospective nature. Inherent in this study design is that some measures we investigated did not have complete documentation in the patient record. In relation to maternal and birth history, we had to rely on transfer documentation at our institution, having no maternity unit on site. This factor made it difficult to obtain accurate data on antepartum hemorrhage and breech delivery. In the cases of mortality after discharge, it is also possible that patients had admissions at other institutions, and we may not have received correspondence regarding these external admissions. As such, some of these details may not be available to us. However, it is worth nothing that deaths in our cohort are checked against a state-wide Tan Tanny et al
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registry, which captures all deaths occurring without our state. Post-mortem examinations were also conducted in some cases, and these are documented in the medical records. Ultimately, death in patients with esophageal atresia is a relatively rare event, and may benefit from an investigation in a multicenter setting to increase the generalizability of findings. Because the current literature on mortality after discharge is limited, our findings contribute to the current understanding of this topic. Parents of children with esophageal atresia must be counselled appropriately as to the risk of death after primary discharge from hospital. Such findings may also be used to provide a more targeted follow-up for children with esophageal atresia after primary discharge from hospital. n We thank Mr Thomas Clarnette, Mr Joseph Crameri, Dr Elizabeth McLeod, Mr Michael Nightingale, and Mr Russell Taylor, for contributing patients to this study. Submitted for publication Sep 25, 2019; last revision received Dec 2, 2019; accepted Dec 13, 2019. Reprint requests: Sharman P. Tan Tanny, MBBS, BMedSci, DCH, MSc, Department of Paediatric Surgery, The Royal Children’s Hospital, 50 Flemington Road, Melbourne VIC 3052, Australia. E-mail: sharman.tantanny@ rch.org.au
References 1. Myers NA. The history of oesophageal atresia and tracheo-oesophageal fistula–1670-1984. Prog Pediatr Surg 1986;20:106-57. 2. Engum SA, Grosfeld JL, West KW, Rescorla FJ, Scherer LR 3rd. Analysis of morbidity and mortality in 227 cases of esophageal atresia and/or tracheoesophageal fistula over two decades. Arch Surg 1995;130:502-8. discussion: 8-9. 3. Choudhury SR, Ashcraft KW, Sharp RJ, Murphy JP, Snyder CL, Sigalet DL. Survival of patients with esophageal atresia: influence of birth weight, cardiac anomaly, and late respiratory complications. J Pediatr Surg 1999;34:70-3. discussion: 4. 4. Masuya R, Kaji T, Mukai M, Nakame K, Kawano T, Machigashira S, et al. Predictive factors affecting the prognosis and late complications of 73 consecutive cases of esophageal atresia at 2 centers. Pediatr Surg Int 2018;34:1027-33. 5. Yamoto M, Nomura A, Fukumoto K, Takahashi T, Nakaya K, Sekioka A, et al. New prognostic classification and managements in infants with esophageal atresia. Pediatr Surg Int 2018;34:1019-26. 6. Greenwood RD, Rosenthal A. Cardiovascular malformations associated with tracheoesophageal fistula and esophageal atresia. Pediatrics 1976;57:87-91. 7. Healey PJ, Sawin RS, Hall DG, Schaller RT, Tapper D. Delayed primary repair of esophageal atresia with tracheoesophageal fistula: is it worth the wait? Arch Surg 1998;133:552-6. 8. Cassina M, Ruol M, Pertile R, Midrio P, Piffer S, Vicenzi V, et al. Prevalence, characteristics, and survival of children with esophageal atresia: a 32-year population-based study including 1,417,724 consecutive newborns. Birth Defect Res A Clin Mol Teratol 2016;106:542-8. 9. Hartley MJ, Smith NP, Jaffray B. Statistical modelling of survival for babies with oesophageal atresia. J Pediatr Surg 2016;51:1110-4. 10. Okamoto T, Takamizawa S, Arai H, Bitoh Y, Nakao M, Yokoi A, et al. Esophageal atresia: prognostic classification revisited. Surgery 2009;145:675-81. 11. Peters RT, Ragab H, Columb MO, Bruce J, MacKinnon RJ, Craigie RJ. Mortality and morbidity in oesophageal atresia. Pediatr Surg Int 2017;33:989-94.
12. Sinha CK, Haider N, Marri RR, Rajimwale A, Fisher R, Nour S. Modified prognostic criteria for oesophageal atresia and tracheo-oesophageal fistula. Eur J Pediatr Surg 2007;17:153-7. 13. Sulkowski JP, Cooper JN, Lopez JJ, Jadcherla Y, Cuenot A, Mattei P, et al. Morbidity and mortality in patients with esophageal atresia. Surgery 2014;156:483-91. 14. Waterston DJ, Carter RE, Aberdeen E. Oesophageal atresia: tracheooesophageal fistula. A study of survival in 218 infants. Lancet 1962;1: 819-22. 15. Spitz L, Kiely EM, Morecroft JA, Drake DP. Oesophageal atresia: at-risk groups for the 1990s. J Pediatr Surg 1994;29:723-5. 16. Hannon EJ, Billington J, Kiely EM, Pierro A, Spitz L, Cross K, et al. Oesophageal atresia is correctable and survivable in infants less than 1 kg. Pediatr Surg Int 2016;32:571-6. 17. Calisti A, Oriolo L, Nanni L, Molle P, Briganti V, D’Urzo C. Mortality and long term morbidity in esophageal atresia: the reduced impact of low birth weight and maturity on surgical outcome. J Perinat Med 2004;32:171-5. 18. Beasley SW, Allen M, Myers N. The effects of Down syndrome and other chromosomal abnormalities on survival and management in oesophageal atresia. Pediatr Surg Int 1997;12:550-1. 19. Rokitansky AM, Kolankaya VA, Seidl S, Mayr J, Bichler B, Schreiner W, et al. Recent evaluation of prognostic risk factors in esophageal atresia–a multicenter review of 223 cases. Eur J Pediatr Surg 1993;3:196-201. 20. Yu VY, Downe L, Astbury J, Bajuk B. Perinatal factors and adverse outcome in extremely low birthweight infants. Arch Dis Child 1986;61:554-8. 21. Grosfeld JL, Ballantine TV. Esophageal atresia and tracheoesophageal fistula: effect of delayed thoracotomy on survival. Surgery 1978;84: 394-402. 22. Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, et al. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A 2012;158a:3087-100. 23. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol 2011;64:407-15. 24. Zimmer J, Eaton S, Murchison LE, De Coppi P, Ure BM, Dingemann C. State of play: eight decades of surgery for esophageal atresia. European J Pediatr Surg 2019;29:39-48. 25. Oddsberg J, Lu Y, Lagergren J. Aspects of esophageal atresia in a population-based setting: incidence, mortality, and cancer risk. Pediatr Surg Int 2012;28:249-57. 26. Tonz M, Kohli S, Kaiser G. Oesophageal atresia: what has changed in the last 3 decades? Pediatr Surg Int 2004;20:768-72. 27. Brereton RJ, Zachary RB, Spitz L. Preventable death in oesophageal atresia. Arch Dis Child 1978;53:276-83. 28. Konkin DE, O’Hali WA, Webber EM, Blair GK. Outcomes in esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003;38:1726-9. 29. Li XW, Jiang YJ, Wang XQ, Yu JL, Li LQ. A scoring system to predict mortality in infants with esophageal atresia: a case-control study. Medicine 2017;96:e7755. 30. Montgomery M, Frenckner B. Esophageal atresia: mortality and complications related to gastroesophageal reflux. Eur J Pediatr Surg 1993;3:3358. 31. Taylor BJ, Garstang J, Engelberts A, Obonai T, Cote A, Freemantle J, et al. International comparison of sudden unexpected death in infancy rates using a newly proposed set of cause-of-death codes. Arch Dis Child 2015;100:1018-23. 32. Jeffery HE, Rahilly P, Read DJ. Multiple causes of asphyxia in infants at high risk for sudden infant death. Arch Dis Child 1983;58:92-100. 33. Dal’Astra AP, Quirino AV, Caixeta JA, Avelino MA. Tracheostomy in childhood: review of the literature on complications and mortality over the last three decades. Braz J Otorhinolaryngol 2017;83: 207-14. 34. de Jong EM, Felix JF, de Klein A, Tibboel D. Etiology of esophageal atresia and tracheoesophageal fistula: “mind the gap”. Curr Gastroenterol Rep 2010;12:215-22.
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35. Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD. The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry. Pediatrics 1993;91:1116-20. 36. Faivre L, Portnoi MF, Pals G, Stoppa-Lyonnet D, Le Merrer M, ThauvinRobinet C, et al. Should chromosome breakage studies be performed in patients with VACTERL association? Am J Med Genet A 2005;137: 55-8.
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37. Perel Y, Butenandt O, Carrere A, Saura R, Fayon M, Lamireau T, et al. Oesophageal atresia, VACTERL association: Fanconi’s anaemia related spectrum of anomalies. Arch Dis Child 1998;78: 375-6. 38. Orford J, Glasson M, Beasley S, Shi E, Myers N, Cass D. Oesophageal atresia in twins. Pediatr Surg Int 2000;16:541-5. 39. Whalen TV Jr, Albin DM, Woolley MM. Esophageal atresia and tracheoesophageal fistula in the twin. Anatomic variants. Ann Surg 1987;205:322-3.
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T
he first long-term survival of patients with esophageal atresia was described in 1939.1 The current overall survival rate for esophageal atresia is reported to be 83%-95%.2-5 Mortality may be further classified into mortality before discharge (deaths that occurred during the patient’s initial admission) and mortality after discharge (deaths that occurred after the initial admission). Risk factors for mortality before discharge, including cardiac anomalies, have been well-described in the literature.6-13 Waterston et al established survival categories derived from a combination of factors, including low birth weight, preoperative pneumonia, and congenital anomalies, which corresponded with varying risks of death.14 Subsequently, Spitz et al stratified at-risk groups according to birth weight and the presence of major congenital heart disease.15 The Spitz classification is commonly used to guide clinicians in parental counselling. However, more recently, advances in neonatal care have resulted in improvements in survival rates, especially for low birthweight and premature babies.16
TEF VACTERL
Tracheoesophageal fistula Vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects
From the 1Department of Pediatric Surgery, The Royal Children’s Hospital; 2F. Douglas Stephens Surgical Research Group, Murdoch Children’s Research Institute; 3 Department of Pediatrics, University of Melbourne; 4 Department of Neonatal Medicine, The Royal Children’s Hospital, Melbourne; 5School of Medicine, Monash University, Clayton; and the 6Department of Gastroenterology and Clinical Nutrition, The Royal Children’s Hospital, Melbourne, Victoria, Australia S.T.T. is supported by a National Health and Medical Research Council (NHMRC) Medical Research Postgraduate Scholarship (1168142) and an Australian Government Research Training Program Scholarship. Associate Professor Sebastian King’s and Associate Professor Warwick Teague’s positions as Academic Paediatric Surgeons are generously supported by The Royal Children’s Hospital Foundation. Funding for the development and maintenance of the Nate Myers Oesophageal Atresia Database is provided by the charitable efforts of the Oesophageal Atresia Research Auxiliary of The Royal Children’s Hospital, Melbourne whose assistance is gratefully acknowledged. The authors declare no conflicts of interest. Portions of this study were presented at the 5th International Conference of Esophageal Atresia, June 24-28, 2019, Rome, Italy. 0022-3476/$ - see front matter. Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.031
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Recent studies have, therefore, found no association with birth weight and mortality.3,4,17 The Spitz classification was revisited in a cohort from 1993 to 2015 and found that 50% survival was achievable in patients with esophageal atresia under 1 kg.16 However, all 3 patients less than 800 g did not survive in this group. Other risk factors for mortality before discharge described in the literature include chromosomal anomalies, and the sequelae of postoperative anastomotic leak.3,4,18,19 Risk factors for mortality in extremely low birth weight neonates have also been described in the literature in general—these include antepartum hemorrhage, multiple pregnancy, hyaline membrane disease, and breech delivery.20 However, these factors have not been investigated in the context of esophageal atresia. Late mortality has been described to be associated with chromosomal anomalies and respiratory disease, the latter including tracheomalacia, reactive airway disease, gastroesophageal reflux disease, and aspiration.3,21 However, the literature is currently limited in this aspect of mortality risk. Our study aimed to establish the risk factors for mortality in patients with esophageal atresia, with a focus on risk factors that contribute to death after the primary discharge from hospital.
Methods The prospective Nate Myers Oesophageal Atresia database includes all patients treated at The Royal Children’s Hospital, Melbourne with esophageal atresia and/or tracheoesophageal fistula (TEF) since 1948. All patients with esophageal atresia who died during their initial admission, or subsequently, from January 1980 to December 2018 were identified. Cases of mortality before January 1980 were excluded owing to the less comprehensive patient record documentation and a poorer quality of data entry. The electronic medical record (Epic Systems Corporation, Verona, Wisconsin) was crosschecked to confirm whether patients were alive or deceased. Data collected from patients’ records included demographics, preoperative findings, operative details, postoperative outcomes, and known risk factors for death. Any missing data were reported as such and excluded from the analysis. Low birth weight was defined as less than 1.5 kg, and cardiac anomalies as those requiring operative intervention or palliation.15 Prematurity was defined as less than 37 weeks of gestation. The vertebral anomalies, anorectal malformations, cardiovascular anomalies, tracheoesophageal fistula, renal anomalies, and limb defects (VACTERL) association was defined as 2 or more other associations, in addition to TEF, and/or esophageal atresia.22 Mortality before discharge was defined as death during the initial admission. Mortality after discharge was defined as death after primary discharge from the hospital. The risk of bias was minimized according to the GRADE guidelines.23 Descriptive statistics for continuous variables were reported as median (range). Categorical variables were reported as percentages. Categorical data were compared 2
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with the Fisher exact test. Statistical significance was set at a P value of less than .05. Statistical analysis was performed using GraphPad Prism 7.00 for Windows (GraphPad Software, La Jolla, California). Approval from the Human Research Ethics Committee (HREC # DA 014-2014-02) was granted.
Results From January 1980 to December 2018, 650 patients with esophageal atresia with or without TEF were managed at The Royal Children’s Hospital. A total of 88 patients died, representing an overall mortality rate of 13.5%. The majority of deaths (66/88 [75.0%]) occurred during the initial admission. Characteristics of the mortality before discharge and mortality after discharge group are described in Table I, and mortality rates by time epoch are demonstrated in Table II. The most common causes of mortality before discharge was palliation for respiratory anomalies (15/66 [22.7%]), followed by associated syndromes (11/66 [16.7%]) and neurologic anomalies (10/66 [15.2%]). The most commonly associated syndrome leading to palliation was trisomy 18 (7/66 [10.6%]). Of all patients discharged from hospital, 22 of the 580 (3.8%) subsequently died. Causes of mortality after discharge had available documentation in 17 of 22 patients (77.3%). Common causes of mortality after discharge were respiratory compromise (6/17 [35.3%]), sudden deaths (6/17 [35.3%]), and Fanconi anemia (2/17 [11.8%]) (Table III). Respiratory compromise included 3 patients with aspiration related complications, 2 with tracheostomy or airways complications, and 1 with croup. In this study period, there were 21 patients requiring tracheostomies, resulting in a mortality rate of 9.5% (2/21). Sudden deaths included 5 with sudden infant death syndrome and 1 with an unexpected death at the age of 1 year and 4 months. In the Fanconi anemia-related deaths, 1 patient had secondary staphylococcal septicemia with temporoparietal hemorrhage and the other was a poor candidate for bone marrow transplant owing to existing renal impairment. In these 2 patients, 1 was associated with VACTERL (having right crossed renal ectopia and an anterior anus) and the
Table I. Characteristics of the mortality before discharge and mortality after discharge groups
Characteristics
Mortality before discharge (n = 66)
Mortality after discharge (n = 22)
P value
Age at death Age of mothers, y Prematurity Gestational age, wk Low birth weight Birth weight, g Male:female
7 d (0-165 d) 31.5 (17-43) 65.6% (42/64) 34.5 (25-42) 31.3% (20/64) 1895 (660-4100) 35:31
16 mo (3-358 mo) 25 (17-37) 55% (11/20) 36 (30-40) 5.0% (1/20) 2018 (1386-4005) 13:9
<.001 .02 .54 .22 .02 .08 .63
Values are median (range) unless otherwise specified.
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Table II. Numbers of mortality before discharge and mortality after discharge deaths by time period Groups Mortality before discharge deaths Mortality after discharge deaths Total patients Mortality rate
1980-1989
1990-1999
2000-2009
2010-2018
22
19
15
10
8
4
4
6
153 19.6%
157 14.6%
166 11.4%
174 9.2%
other was not (but had a small ventricular septal defect and a duodenal atresia). Neither had evidence of dysmorphism, and both had normal karyotype, although one was associated with a high frequency of chromosome breakage. In the remaining 3 patients with a documented cause of death, 1 died of plasmacytosis, 1 died of a traumatic brain injury, and 1 died of renal failure. The incidence of twins was not significantly different between the mortality before discharge (8/56 [14.3%]) and mortality after discharge (2/18 [11.1%]) groups. The types of esophageal atresia, according to the Gross classification, within each mortality groups are described in Table IV. Chromosomal abnormalities and syndromic association data were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 19 of 22 patients (86.4%) in the mortality after discharge group. All cases of trisomy 18 (12/60 [20.0%]) and trisomy 21 (6/60 [10.0%]) were in the mortality before discharge group. The frequency of CHARGE syndrome (coloboma, heart defects, atresia choanae) was 7 of 60 (11.7%) in the mortality before discharge group and 1 of 19 (5.3%) in the mortality after discharge group. Data pertaining to VACTERL association were available in 61 of 66 patients (92.4%) in the mortality before discharge group and 20 of 22 patients (90.9%) in the mortality after discharge group. There was no statistically significant difference in the incidence of the VACTERL association between the mortality before discharge (31/61 [50.8%]) and mortality after discharge group (11/20 [55.0%]).
Table III. Causes of death in the mortality after discharge group (n = 17) Causes of death Respiratory compromise Aspiration-related complications Tracheostomy or airways complications Croup Sudden deaths Sudden infant death syndrome Unexpected death at >1 year old Fanconi anaemia-related deaths Trauma Renal failure Plasmacytosis
n (%) 6 (35.3)
6 (35.3) 2 (11.8) 1 (5.9) 1 (5.9) 1 (5.9)
Table IV. Distribution of esophageal atresia type within the mortality before discharge and mortality after discharge groups Esophageal atresias Type A Type B Type C Type D Type E Other variant: Esophagobronchial fistula with tracheal atresia Unrecorded
Mortality before discharge (n = 66)
Mortality after discharge (n = 22)
7 (10.6) 2 (3.0) 56 (84.8) 0 (0) 0 (0) 1 (1.5)
1 (4.5) 0 (0) 18 (81.8) 0 (0) 2 (9.1) 0 (0)
0 (0)
1 (4.5)
Values are number (%).
Two patients in the mortality before discharge group had an anastomotic leak, and one in the mortality after discharge group had an anastomotic leak (P = .91). Similarly, 2 patients in the mortality before discharge group had recurrence of a fistula, compared with 1 patient in the mortality after discharge group (P = .91). Data pertaining to fundoplication were available in 61 of 66 patients (92.4%) in the mortality before discharge group and 15 of 22 patients (62.1%) in the mortality after discharge group. Fundoplication rates were lower in the mortality before discharge group (1/61 [1.6%]) compared with the mortality after discharge group (5/15, 33.3%; P < .0001). Respiratory support data were available in 59 of 66 patients (89.4%) in the mortality before discharge group and 12 of 22 patients (54.5%) in the mortality after discharge group. The need for more intensive respiratory support (high-frequency oscillating ventilation or high-frequency jet ventilation) was increased in the mortality before discharge group (22/59 [37.3%]) compared with the mortality after discharge group (1/12 [8.3%]); however, this difference was not statistically significant (P = .05). Preoperative intubation data were available in 58 of 66 patients (87.9%) in the mortality before discharge group and 15 of 22 patients (68.2%) in the mortality after discharge group. Preoperative intubation was more common in the mortality before discharge group (32/58 [55.2%]) compared with the mortality after discharge group (5/15 [33.3%]). However, this difference was not statistically significant (P = .28). Data pertaining to respiratory anomalies were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 19 of 22 patients (86.4%) in the mortality after discharge group. Respiratory anomalies were more common in the mortality after discharge group (9/19 [47.4%]) compared with the mortality before discharge group (22/60 [36.7%]). However, this difference was also not statistically significant (P = .41). Data pertaining to hyaline membrane disease were available in 60 of 66 patients (90.9%) in the mortality before discharge group and 16 of 22 patients (24.2%) in the mortality after discharge group. The incidences of hyaline membrane disease in the mortality before discharge group (21/60 [35.0%]) and the
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mortality after discharge group (6/16 [37.5%]) were similar (P = .86).
Discussion Patients with esophageal atresia have an overall survival rate of 83%-95%.2-5 Improvements over time relate to advances in neonatal care and surgical techniques. Therefore, there is an increasing focus toward the management of long-term morbidity for patients with esophageal atresia. However, these children are still dying frequently, and it is imperative for us to understand factors that continue to affect mortality. Our study has found that mortality after discharge from hospital affected 3.8% of patients, of which the leading causes were respiratory compromise, sudden unexplained deaths, and Fanconi anemia. In our study, we identified an overall mortality rate of 13.5%, from the 1980s to the present, with more recent rates being 9.2% since the 2010s. Similarly, the current literature describes an overall improving mortality rate with time as well, with 16% described in the 1990s, and 9% from 2010 forward.24-26 This improvement in survival largely relates to improvements in neonatal intensive care treatment. One of the risk factors for early mortality is thought to have a relationship with autonomic instability, and at our institution we are embarking on a study of these patients using Holter monitoring. Late mortality described since the 1960s until the present day, ranges from 23% to 25% of all cases of death, similar to our findings.27,28 Although the causes of mortality before discharge in our cohort were similar to those reported in the literature,6-15,29 our study adds to the currently limited understanding of mortality after discharge in patients with esophageal atresia. In a study by Choudhury et al of 240 patients, 17 late deaths were recorded (7.1%).3 The primary cause of late deaths were respiratory causes (sudden infant death syndrome, aspiration, tracheomalacia, and reactive airway disease), accounting for 59% of late deaths.3 Deaths owing to aspiration has also been attributed to be precipitated by severe symptoms of gastroesophageal reflux disease.30 The rate of sudden unexpected deaths in infants worldwide, in comparison, ranges from 0.4 to 0.6 per 1000 live births.31 This rate is much higher in the esophageal atresia population as we have found, which is not surprising, given that tracheomalacia, gastroesophageal reflux, and intrapulmonary aspiration are potential mechanisms of asphyxia in sudden infant death.32 Similarly, the rate of tracheostomy-related deaths in our cohort of patients with esophageal atresia, at 9.5%, is higher than that reported in the literature, which was up to 5.9%.33 Although respiratory compromise and sudden deaths are difficult to predict and prevent, Fanconi anemia may be tested for before symptoms appear. This screening may allow for early patient and family counselling, regular monitoring, and commencement of treatment promptly to improve quality of life and prolong lifespan. 4
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Fanconi anemia is a genetic condition that results in progressive bone marrow failure and an increased risk of acute myeloid leukemia. The disease usually becomes symptomatic between the ages of 2 and 12 years. It is, therefore, logical that its association is related to our mortality after discharge cohort and not the mortality before discharge cohort. Fanconi anemia is often associated with congenital anomalies, and been described in association with esophageal atresia/ TEF.34,35 Despite co-occurring infrequently, our results demonstrated that Fanconi anemia was a major cause of mortality after discharge among patients with esophageal atresia in our cohort. A high index of suspicion for the development of Fanconi anemia should be kept in the long-term follow-up of patients with esophageal atresia, especially those with failure to thrive and associated congenital anomalies.36,37 Early diagnosis of Fanconi anemia is important, because it allows the disease to be managed expeditiously. This knowledge also allows families to obtain genetic counselling early, which would provide information regarding the risk of recurrence in future pregnancies and facilitate testing for siblings of affected patients. In our cohort, respiratory anomalies were more common in the mortality after discharge group, although this figure did not reach statistical significance. However, it is worth noting that respiratory compromise was the most common cause of mortality after discharge in this cohort. Similarly, Choudhury et al found that respiratory anomalies, including tracheomalacia, were implicated in cases of mortality after discharge.3 A previous study of twins by Orford et al described increased mortality of twins, compared with singletons.38 However, the timing of mortality was not defined, and this study also demonstrated lower mean birth weights and gestational ages for twin infants. Twins with esophageal atresia/ TEF have also been shown to have more complex anatomy. Whalen et al reported that 37% of twins in their cohort had an esophageal anatomy other than the most common type of esophageal atresia (esophageal atresia with distal TEF).39 Twins have also been reported to have a greater incidence of multiple congenital anomalies.38,39 However, our study suggests that infants with esophageal atresia who are a twin are not significantly more likely to suffer from mortality after discharge, compared with mortality before discharge. Although we used data from our prospectively maintained database, our study was limited by its retrospective nature. Inherent in this study design is that some measures we investigated did not have complete documentation in the patient record. In relation to maternal and birth history, we had to rely on transfer documentation at our institution, having no maternity unit on site. This factor made it difficult to obtain accurate data on antepartum hemorrhage and breech delivery. In the cases of mortality after discharge, it is also possible that patients had admissions at other institutions, and we may not have received correspondence regarding these external admissions. As such, some of these details may not be available to us. However, it is worth nothing that deaths in our cohort are checked against a state-wide Tan Tanny et al
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registry, which captures all deaths occurring without our state. Post-mortem examinations were also conducted in some cases, and these are documented in the medical records. Ultimately, death in patients with esophageal atresia is a relatively rare event, and may benefit from an investigation in a multicenter setting to increase the generalizability of findings. Because the current literature on mortality after discharge is limited, our findings contribute to the current understanding of this topic. Parents of children with esophageal atresia must be counselled appropriately as to the risk of death after primary discharge from hospital. Such findings may also be used to provide a more targeted follow-up for children with esophageal atresia after primary discharge from hospital. n We thank Mr Thomas Clarnette, Mr Joseph Crameri, Dr Elizabeth McLeod, Mr Michael Nightingale, and Mr Russell Taylor, for contributing patients to this study. Submitted for publication Sep 25, 2019; last revision received Dec 2, 2019; accepted Dec 13, 2019. Reprint requests: Sharman P. Tan Tanny, MBBS, BMedSci, DCH, MSc, Department of Paediatric Surgery, The Royal Children’s Hospital, 50 Flemington Road, Melbourne VIC 3052, Australia. E-mail: sharman.tantanny@ rch.org.au
References 1. Myers NA. The history of oesophageal atresia and tracheo-oesophageal fistula–1670-1984. Prog Pediatr Surg 1986;20:106-57. 2. Engum SA, Grosfeld JL, West KW, Rescorla FJ, Scherer LR 3rd. Analysis of morbidity and mortality in 227 cases of esophageal atresia and/or tracheoesophageal fistula over two decades. Arch Surg 1995;130:502-8. discussion: 8-9. 3. Choudhury SR, Ashcraft KW, Sharp RJ, Murphy JP, Snyder CL, Sigalet DL. Survival of patients with esophageal atresia: influence of birth weight, cardiac anomaly, and late respiratory complications. J Pediatr Surg 1999;34:70-3. discussion: 4. 4. Masuya R, Kaji T, Mukai M, Nakame K, Kawano T, Machigashira S, et al. Predictive factors affecting the prognosis and late complications of 73 consecutive cases of esophageal atresia at 2 centers. Pediatr Surg Int 2018;34:1027-33. 5. Yamoto M, Nomura A, Fukumoto K, Takahashi T, Nakaya K, Sekioka A, et al. New prognostic classification and managements in infants with esophageal atresia. Pediatr Surg Int 2018;34:1019-26. 6. Greenwood RD, Rosenthal A. Cardiovascular malformations associated with tracheoesophageal fistula and esophageal atresia. Pediatrics 1976;57:87-91. 7. Healey PJ, Sawin RS, Hall DG, Schaller RT, Tapper D. Delayed primary repair of esophageal atresia with tracheoesophageal fistula: is it worth the wait? Arch Surg 1998;133:552-6. 8. Cassina M, Ruol M, Pertile R, Midrio P, Piffer S, Vicenzi V, et al. Prevalence, characteristics, and survival of children with esophageal atresia: a 32-year population-based study including 1,417,724 consecutive newborns. Birth Defect Res A Clin Mol Teratol 2016;106:542-8. 9. Hartley MJ, Smith NP, Jaffray B. Statistical modelling of survival for babies with oesophageal atresia. J Pediatr Surg 2016;51:1110-4. 10. Okamoto T, Takamizawa S, Arai H, Bitoh Y, Nakao M, Yokoi A, et al. Esophageal atresia: prognostic classification revisited. Surgery 2009;145:675-81. 11. Peters RT, Ragab H, Columb MO, Bruce J, MacKinnon RJ, Craigie RJ. Mortality and morbidity in oesophageal atresia. Pediatr Surg Int 2017;33:989-94.
12. Sinha CK, Haider N, Marri RR, Rajimwale A, Fisher R, Nour S. Modified prognostic criteria for oesophageal atresia and tracheo-oesophageal fistula. Eur J Pediatr Surg 2007;17:153-7. 13. Sulkowski JP, Cooper JN, Lopez JJ, Jadcherla Y, Cuenot A, Mattei P, et al. Morbidity and mortality in patients with esophageal atresia. Surgery 2014;156:483-91. 14. Waterston DJ, Carter RE, Aberdeen E. Oesophageal atresia: tracheooesophageal fistula. A study of survival in 218 infants. Lancet 1962;1: 819-22. 15. Spitz L, Kiely EM, Morecroft JA, Drake DP. Oesophageal atresia: at-risk groups for the 1990s. J Pediatr Surg 1994;29:723-5. 16. Hannon EJ, Billington J, Kiely EM, Pierro A, Spitz L, Cross K, et al. Oesophageal atresia is correctable and survivable in infants less than 1 kg. Pediatr Surg Int 2016;32:571-6. 17. Calisti A, Oriolo L, Nanni L, Molle P, Briganti V, D’Urzo C. Mortality and long term morbidity in esophageal atresia: the reduced impact of low birth weight and maturity on surgical outcome. J Perinat Med 2004;32:171-5. 18. Beasley SW, Allen M, Myers N. The effects of Down syndrome and other chromosomal abnormalities on survival and management in oesophageal atresia. Pediatr Surg Int 1997;12:550-1. 19. Rokitansky AM, Kolankaya VA, Seidl S, Mayr J, Bichler B, Schreiner W, et al. Recent evaluation of prognostic risk factors in esophageal atresia–a multicenter review of 223 cases. Eur J Pediatr Surg 1993;3:196-201. 20. Yu VY, Downe L, Astbury J, Bajuk B. Perinatal factors and adverse outcome in extremely low birthweight infants. Arch Dis Child 1986;61:554-8. 21. Grosfeld JL, Ballantine TV. Esophageal atresia and tracheoesophageal fistula: effect of delayed thoracotomy on survival. Surgery 1978;84: 394-402. 22. Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, et al. Clinical geneticists’ views of VACTERL/VATER association. Am J Med Genet A 2012;158a:3087-100. 23. Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence–study limitations (risk of bias). J Clin Epidemiol 2011;64:407-15. 24. Zimmer J, Eaton S, Murchison LE, De Coppi P, Ure BM, Dingemann C. State of play: eight decades of surgery for esophageal atresia. European J Pediatr Surg 2019;29:39-48. 25. Oddsberg J, Lu Y, Lagergren J. Aspects of esophageal atresia in a population-based setting: incidence, mortality, and cancer risk. Pediatr Surg Int 2012;28:249-57. 26. Tonz M, Kohli S, Kaiser G. Oesophageal atresia: what has changed in the last 3 decades? Pediatr Surg Int 2004;20:768-72. 27. Brereton RJ, Zachary RB, Spitz L. Preventable death in oesophageal atresia. Arch Dis Child 1978;53:276-83. 28. Konkin DE, O’Hali WA, Webber EM, Blair GK. Outcomes in esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2003;38:1726-9. 29. Li XW, Jiang YJ, Wang XQ, Yu JL, Li LQ. A scoring system to predict mortality in infants with esophageal atresia: a case-control study. Medicine 2017;96:e7755. 30. Montgomery M, Frenckner B. Esophageal atresia: mortality and complications related to gastroesophageal reflux. Eur J Pediatr Surg 1993;3:3358. 31. Taylor BJ, Garstang J, Engelberts A, Obonai T, Cote A, Freemantle J, et al. International comparison of sudden unexpected death in infancy rates using a newly proposed set of cause-of-death codes. Arch Dis Child 2015;100:1018-23. 32. Jeffery HE, Rahilly P, Read DJ. Multiple causes of asphyxia in infants at high risk for sudden infant death. Arch Dis Child 1983;58:92-100. 33. Dal’Astra AP, Quirino AV, Caixeta JA, Avelino MA. Tracheostomy in childhood: review of the literature on complications and mortality over the last three decades. Braz J Otorhinolaryngol 2017;83: 207-14. 34. de Jong EM, Felix JF, de Klein A, Tibboel D. Etiology of esophageal atresia and tracheoesophageal fistula: “mind the gap”. Curr Gastroenterol Rep 2010;12:215-22.
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35. Giampietro PF, Adler-Brecher B, Verlander PC, Pavlakis SG, Davis JG, Auerbach AD. The need for more accurate and timely diagnosis in Fanconi anemia: a report from the International Fanconi Anemia Registry. Pediatrics 1993;91:1116-20. 36. Faivre L, Portnoi MF, Pals G, Stoppa-Lyonnet D, Le Merrer M, ThauvinRobinet C, et al. Should chromosome breakage studies be performed in patients with VACTERL association? Am J Med Genet A 2005;137: 55-8.
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37. Perel Y, Butenandt O, Carrere A, Saura R, Fayon M, Lamireau T, et al. Oesophageal atresia, VACTERL association: Fanconi’s anaemia related spectrum of anomalies. Arch Dis Child 1998;78: 375-6. 38. Orford J, Glasson M, Beasley S, Shi E, Myers N, Cass D. Oesophageal atresia in twins. Pediatr Surg Int 2000;16:541-5. 39. Whalen TV Jr, Albin DM, Woolley MM. Esophageal atresia and tracheoesophageal fistula in the twin. Anatomic variants. Ann Surg 1987;205:322-3.
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