- Email: [email protected]
Outcomes for Ectopia Cordis
ORIGINAL ARTICLES Outcomes for Ectopia Cordis Benjamin J. Smith, MD1, Jonathan N. Flyer, MD1,2, Erika M. Edwards, PhD, MPH1,3,4, Roger F. Soll, MD1,4,5, Jeffrey D. Horbar, MD1,4,5, and Scott B. Yeager, MD1,2 Objectives To utilize a large multicenter neonatal cohort to describe survival and clinical outcomes of very low birth weight (VLBW) or preterm infants with ectopia cordis.
Study design Data were prospectively collected on 2 211 262 infants (born 2000-2017) from 845 US centers. Both VLBW (401-1500 g or 22-29 weeks of gestation) and non-VLBW (>1500 g and >29 weeks) infants had diagnoses or anatomic descriptors consistent with ectopia cordis and/or pentalogy of Cantrell. The primary outcome was neonatal survival, defined as hospital discharge or initial length of stay of ³12 months. Results In total, 180 infants had ectopia cordis, 135 (76%) with findings of pentalogy of Cantrell. VLBW infants comprised 52% of the population. VLBW mortality was 96% with 79% dying within 12 hours, compared with 59% and 36%, respectively, for non-VLBW. One-third of VLBW infants received life support compared with 65% of non-VLBW. Surgery was reported for 34% of VLBW and 68% of non-VLBW infants. Congenital heart disease was reported in 8% of VLBW and 36% of non-VLBW, with conotruncal abnormalities most common. Survival exceeded 50% for infants >2500 g and >37 weeks of gestation. Conclusions Survival of VLBW infants with ectopia cordis was poor and substantially worse compared with nonVLBW, with notable discrepancies in resuscitative efforts and surgical interventions. Although gestational age and weight strongly influence current survival, more detailed information regarding the severity of cardiac and noncardiac abnormalities is required to fully determine prognosis and inform counseling. (J Pediatr 2019;-:1-6).
E
ctopia cordis is a rare congenital anomaly in which the heart is positioned either partially or completely outside the thoracic cavity. This malposition was first described by Haller in 1706,1 and in 1958 was incorporated by Cantrell into a pentad of anatomic abnormalities including omphalocele, anterior diaphragmatic hernia, diaphragmatic pericardial defects, and intracardiac defects.2 Though the etiology of ectopia cordis has yet to be fully understood, the prevailing theory is an error in ventral folding morphogenesis, leading to midline defects.1,3 The reported prevalence of ectopia cordis at live birth ranges from 5 to 8 per million,4-6 with variable and substantial mortality.4,5,7-10 To date, the published literature on ectopia cordis and pentalogy of Cantrell (POC) consists primarily of small case series and literature reviews.4,11,12 Two cohort studies examined the outcomes of 39 newborns with ectopia cordis and POC. Of these, only 3 were preterm or low birth weight.5,6 Understanding the survival and clinical outcomes of infants with ectopia cordis is essential to providing accurate and informed prenatal counseling. Given the paucity of data for this special pediatric population, we examined a cohort of both very low birth weight (VLBW) infants, defined by weights 401-1500 g or 22 to 29 weeks of gestational age at birth, and nonVLBW infants, using data from Vermont Oxford Network (VON). The primary study aim was to report survival and clinical outcomes of preterm and/or low birth weight infants born with ectopia cordis. The secondary aim was to describe the spectrum of anatomic abnormalities that may accompany ectopia cordis, including other midline defects and congenital heart disease.
Methods VON is a voluntary worldwide community dedicated to improving the quality, safety, and value of neonatal care through a coordinated program of data-driven quality improvement, education, and research. Member hospitals submit data on either VLBW infants only, or on all neonatal intensive care unit (NICU) admissions regardless of birth weight or gestational age. Data are submitted to VON using uniform definitions and systematic coding outlined in the VON Manual of From the 1Department of Pediatrics, 2Division of Pediatric Cardiology, and 3Department of Mathematics and Statistics, University of Vermont, 4Vermont Oxford Network, and 5Division of Neonatology, University of Vermont, Burlington, VT
CHD NICU POC VLBW VON
Congenital heart disease Neonatal intensive care unit Pentalogy of Cantrell Very low birth weight Vermont Oxford Network
J.H. and R.S. are employees of Vermont Oxford Network. E.E. receives salary support from Vermont Oxford Network. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.09.014
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Operations.13 This cohort study used prospectively collected data on infants born from January 1, 2000 to December 31, 2017. For this study, both the VLBW and all NICU admission databases were searched for free text descriptors of ectopia cordis, and VON systematic coding and free text descriptors indicating POC. During the study period, 845 VON member hospitals in the US submitted data on VLBW infants, and 437 of those hospitals also reported data on all NICU infants; therefore, the sample was enriched with VLBW infants. All anatomic abnormalities that were described by free text and not predefined VON code were reviewed by 2 authors. Atrial septal defect, ventricular septal defect, and coarctation of the aorta were abstracted during the review process; all other congenital anomalies were reported using VON coding.13 A summary of case inclusion criteria, case review, and infant survival is provided in Figure 1. Overall survival was defined as either hospital discharge or continued inpatient admission at 1 year of age. Length of stay was defined by number of days from admission until death, discharge, or date of first birthday. Infants transferred from nonmember hospitals were followed for mortality and length of stay until ultimate disposition. Small for gestational age was defined within categories of sex, race, and ethnicity as birth weight below the 10th percentile, using smoothed curves constructed from the US Natality Dataset.14 Life support collectively referred to resuscitative interventions, defined as any respiratory support (face mask ventilation, nasal continuous positive airway pressure,
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endotracheal intubation, surfactant therapy, and/or mechanical ventilation), chest compressions, and/or epinephrine administration.
Results From 2000 through 2017, there were 2 211 262 infants in the study population, including 725 134 VLBW. Ectopia cordis was reported in 180 infants born in 135 hospitals, of whom 94 were VLBW. Eight infants were born at nonmember facilities and transferred to a member hospital. Among VLBW infants with ectopia cordis, 62 infants (66%) died in the delivery room without receiving life support, and 32 infants (34%) received life support (Figure 1). Twenty (21%) of these VLBW infants were alive at 12 hours, and 15 (16%) past the third day. Only 4 VLBW infants (4%) met survival criteria: 3 were discharged, and 1 was still in the hospital at 1 year. Among 86 non-VLBW infants with ectopia cordis, 26 (30%) died in the delivery room without receiving life support, 56 (65%) received life support, and 4 (5%) did not require life support. Of those 60 infants, 55 (64%) survived ³12 hours and 47 (55%) past the third day. Overall, 35 (41%) non-VLBW infants met survival criteria: 32 (43%) were discharged and 3 were still hospitalized at 1 year. Mortality for VLBW infants was 96%, including 79% within the initial 12 hours, compared with 59% and 36%, respectively, for non-VLBW infants. Patient characteristics for VLBW and non-VLBW infants are summarized in Table I. The VLBW mean gestational
Figure 1. Study consort diagram. Consort diagram of the case inclusion process. VON databases were screened for appropriate ectopia cordis and POC criteria between the years 2000-2017 with 180 cases identified. *Life support was collectively defined as any combination of respiratory support, chest compressions, and/or epinephrine. †Four additional non-VLBW infants did not require life support, and survived. 2
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Table I. Patient characteristics (n = 180) Patient Characteristics Maternal Race/ethnicity Black non-Hispanic White non-Hispanic Hispanic Other Vaginal delivery Prenatal care Infants with ectopia cordis Gestational age, wk, mean (SD) Birth weight, g, mean (SD) Small for gestational age Female Life support‡ Apgar at 1 min £3 Apgar at 5 min £3 Anomalies Ectopia cordis§ Ectopia cordis with congenital diaphragmatic hernia, omphalocele, and/or another anomaly POC Born at reporting hospital Length of stay (median, IQR)
VLBW* (n = 94)
Non-VLBW† (n = 86)
24 (26%) 45 (49%) 16 (17%) 7 (8%) 45 (48%) 91 (97%)
13 (15%) 53 (62%) 15 (18%) 4 (5%) 29 (34%) 84 (98%)
28 (4) 953 (352) 42 (46) 47 (51) 32 (34) 81 (89) 67 (75)
36 (3) 2678 (631) 23 (27) 52 (49) 56 (65) 33 (39) 25 (30)
9 (10) 21 (22)
7 (8) 5 (5)
64 (68) 92 (98) 1 (0)
75 (87) 67 (78) 9 (70)
Values are absolute patient numbers (n) and percent (%). *VLBW: 401-1500 g or 22-29 completed weeks of gestational age. †Non-VLBW: >1500 g and >29 weeks of gestational age. ‡Life support was collectively defined as any combination of respiratory support, chest compressions, and/or epinephrine. §Infants with solitary finding reported.
age was 28 weeks and mean birth weight 953 g, compared with 36 weeks and 2678 g for non-VLBW. Prenatal care was reported for nearly all VLBW (97%) and non-VLBW (98%) infants; 38% of VLBW and 66% of non-VLBW infants <34 weeks of gestation received antenatal steroids. Nearly one-half of the VLBW (48%) were delivered vaginally, compared with 34% of non-VLBW infants. The majority of VLBW (75%) infants had Apgar scores of £3 at 5 minutes of life, compared with 30% of non-VLBW infants. One-third of VLBW (34%) infants received life support, compared with 65% of non-VLBW infants. Of infants who survived greater than 3 days, surgical interventions were reported in 5 of 15 (33%) VLBW and 32 of 47 (68%) non-VLBW infants. Survival in relation to birth weight and gestational age is summarized in Figure 2. Overall survival was 4% for infants with birth weight <1500g, 6% for 1500-2000 g, 39% for 2000-2500 g, 50% for 2501-3000 g, and 58% for infants greater than 3000 g (Figure 2, A). Overall survival was 6% for infants <31 weeks of gestation, 13% for infants 3136 weeks, and 59% for infants greater than 37 weeks (Figure 2, B). Survival among small for gestational age infants was 12%, compared with 28% if appropriate size for age (Figure 2, C). Survival did not improve or show a trend over the 17-year data collection period. Congenital abnormalities consistent with POC were reported in 68% of VLBW and 87% of non-VLBW infants who survived at least 3 days; 22% of VLBW and 5% of non-VLBW infants were documented as having omphalocele Outcomes for Ectopia Cordis
or diaphragmatic hernia without additional abnormalities. Congenital heart disease (CHD) was reported in 7% of VLBW and 36% non-VLBW infants; tetralogy of Fallot and double outlet right ventricle were the most common for both populations (Table II). Of the 180 infants, 38 (21%) had at least 1 cardiac abnormality, with 27 (15%) having an isolated abnormality, 9 (5%) having 2, and 2 (1.1%) having 3. Eight of the 11 infants with multiple cardiac abnormalities survived.
Discussion Congenital abnormalities consistent with POC (omphalocele, anterior diaphragmatic hernia, diaphragmatic pericardium defects, and intracardiac defects in addition to ectopia cordis) were reported in 77% of all infants (68% of VLBW and 87% of non-VLBW), which is consistent with previous studies.5 An additional 22% of VLBW and 5% of non-VLBW infants with ectopia cordis were documented as having an omphalocele or diaphragmatic hernia without further findings of POC. CHD was reported in 7% of VLBW and 36% non-VLBW. Conotruncal abnormalities, including tetralogy of Fallot and double outlet right ventricle, were the most common in both populations, which is consistent with previously published literature.5 The majority of reported CHD (27 of 38 defects), occurred in isolation. Previous studies report the occurrence of CHD among VLBW infants being 3-4 times higher than that of the general population.15 We did not find this within our cohort; however, associated cardiac malformations were likely to be underreported, especially among infants who died in the delivery room without diagnostic imaging. The gestational age at which ectopia cordis can be diagnosed by fetal ultrasound varies but has been reported as early as 10 weeks and likely depends on the extent of the malformation.16 Severe forms of ectopia cordis, which have the poorest prognosis, should be the most apparent on prenatal ultrasound and available to guide counseling. Information regarding prenatal diagnosis, family counseling, and/or postnatal resuscitation directives are not collected by VON databases; thus, it is unclear what, if any, prenatal counseling was offered, and if plans for limited resuscitation were in place prior to delivery. Two prenatal surrogates that suggest limited postnatal interventions were pursued in the VLBW group include a lower cesarean delivery rate and less frequent antenatal steroid therapy. Only 52% of VLBW infants were delivered via cesarean delivery, compared with a national average of 71.8%.17 Antenatal steroid use among VLBW infants was 38%, compared with a national average of 76%.17 The cesarean delivery rate was 66% among the non-VLBW group. Despite advances in technology and surgical technique, correction of severe ectopia cordis remains challenging because of potential anatomic distortion caused by repositioning the heart into the thoracic cavity. Depending on the extent of exteriorization and cardiac malposition, surgery may require multiple stages, with initial intervention to 3
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Figure 2. Infant survival by birth weight, gestational age, and size for gestation. (n = 176)*. A, Total infant survival across birth weight. B, Gestational age. C, Size for gestational age. Infants are considered small for gestational age if theeir birth weight is <10th percentile for gestation. *Four infants did not have birth weight reported. 4
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Table II. Reported CHD* (n = 180) CHD Tetralogy of Fallot DORV ASD VSD Transposition Pulmonary atresia Single ventricle HLHS Coarctation of aorta Cor triatriatum Truncus arteriosus Tricuspid atresia Interrupted aortic arch
VLBW†, n (%)
Non-VLBW‡, n (%)
5 (5.3) 1 (1.1) 1 (1.1) 1 (1.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 0 (0) 0 (0) 0 (0)
15 (17.4) 9 (10.5) 2 (2.3) 2 (2.3) 3 (3.5) 3 (3.5) 2 (2.3) 2 (2.3) 1 (1.2) 0 (0) 1 (1.2) 1 (1.2) 1 (1.2)
ASD, atrial septal defect; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; VSD, ventricular septal defect. Values are absolute patient numbers (n) and percent (%). *Infants may have more than 1 anomaly. †VLBW: 401-1500 g or 22-29 completed weeks of gestational age. ‡Non-VLBW: >1500 g and >29 weeks of gestational age.
provide coverage of the heart with skin flaps, grafts, or prosthetic materials.8 Even small defects that could be repaired with skin closure may alter ventricular filling pressure and affect cardiac output. Within our cohort, 33% VLBW and 68% non-VLBW infants (all surviving greater than 3 days) underwent surgery, though there are very limited data regarding type of operation or disease severity. A recent multicenter experience of prenatal ectopia cordis diagnosis reported no documented survival with complete ectopia cordis; in that study 2 infants underwent surgery and both died because of hemodynamic compromise shortly after attempted chest closure.5 Although 1 survivor of complete ectopia cordis and significant CHD has been reported, the authors noted that chest closure was completed with a skin flap and did not involve extensive mobilization of the heart.4 Prior literature has reported major surgery in VLBW infants (defined as requiring anesthesia, but excluding congenital heart disease) to have significantly higher adjusted odds of death or early neurodevelopmental impairment.18 Therefore, the need for any surgery may have influenced clinical care decisions, both in center-specific outcome counseling and technical capability. Mortality among low birth weight and preterm infants undergoing cardiac surgery is significantly worse compared with full term/appropriate weight infants.19-21 One study reported a mortality of 21% for infants born with critical CHD <37 weeks of gestation, compared with 7% between 37 and 38 weeks, and 3% for infants between 39 and 40 weeks.19 Cardiothoracic surgery is further complicated for infants who have additional malformations, such as in POC, with significant increase in mortality.19,21 Cheng et al suggest that maturity, as opposed to birth weight, may be a more important predictor of cardiac surgery outcomes, speculating that immaturity of multiple organ systems, underdevelopment of arterioles in the pulmonary vascular bed, and increased risk for infection may affect patient morbidity.19 Within our cohort, infant mortality improved with both increased age and birth weight, suggesting that maturity Outcomes for Ectopia Cordis
and size both affect outcomes. Small for gestational age infants experienced higher mortality. Unfortunately, additional information regarding surgical timing and the severity of cardiac and noncardiac abnormalities was not collected, so their effect on prognosis cannot be independently analyzed. Even after initial stabilization and corrective surgery, patients with ectopia cordis face considerable long-term morbidity and mortality. Prior longitudinal studies report compromised cardiac function (secondary to extrinsic compression and congestive heart failure), chronic lung disease (secondary to pulmonary hypoplasia and pulmonary hypertension), and high rates of developmental delay in infants with ectopia cordis/POC who survived into childhood.5,12 VON databases collects data up to 1 year of life. As such, there are no data on the long-term outcomes of the patients in this study. Ectopia cordis occurs on a wide spectrum with anatomic variation, ranging from a pulsatile heart directly beneath the skin to complete cardiac exteriorization. Based on the location of the heart, previous studies have categorized malformations as cervical, thoracic, thoracoabdominal, or abdominal.1 As expected, the prognosis of ectopia cordis appears dependent on the type and extent of the exteriorization and cardiac malposition, with previous reports detailing better outcomes for infants with abdominal or thoracoabdominal malformations.5,12 In this study, it is likely that patients with better outcomes had more limited thoracoabdominal defects, as opposed to complete ectopia cordis. This study used a large national multicenter database and was subject to incomplete reporting, although VON has policies that encourage reporting of all eligible infants.13 Although standardization was attempted through the use of systematic coding within VON databases, clinically important diagnostic ambiguity remained. In addition, neither comprehensive surgical data nor long-term outcomes were collected. Consequently, generalization and counseling based on these data should be applied cautiously. Further investigation may explore the severity of cardiac and noncardiac anatomic abnormalities, accuracy of prenatal diagnostic methods, and appropriate delivery room resuscitation management, which may improve prognosis and better inform counseling. n Submitted for publication Jun 13, 2019; last revision received Aug 15, 2019; accepted Sep 10, 2019. Reprint requests: Scott B. Yeager, MD, Division of Pediatric Cardiology, University of Vermont Medical Center, 111 Colchester Ave, Patrick 581, Burlington, VT 05401. E-mail: [email protected]
References 1. Engum SA. Embryology, sternal clefts, ectopia cordis, and Cantrell’s pentalogy. Semin Pediatr Surg 2008;17:154-60. 2. Cantrell JR, Haller JA, Ravitch MM. A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surg Gynecol Obstet 1958;107:602-14. 3. Gabriel A, Donnelly J, Kuc A, Good D, Doros G, Matusz P, et al. Ectopia cordis: a rare congenital anomaly. Clin Anat 2014;27:1193-9. 4. Hornberger LK, Colan SD, Lock JE, Wessel DL, Mayer JE Jr. Outcome of patients with ectopia cordis and significant intracardiac defects. Circulation 1996;94:II32-7. 5
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5. Escobar-Diaz MC, Sunderji S, Tworetzky W, Moon-Grady AJ. The fetus with ectopia cordis: experience and expectations from two centers. Pediatr Cardiol 2017;38:531-8. 6. Balderrabano-Saucedo N, Vizcaino-Alarcon A, Sandoval-Serrano E, Segura-Stanford B, Arevalo-Salas LA, de la Cruz LR, et al. Pentalogy of Cantrell: forty-two years of experience in the Hospital Infantil de Mexico Federico Gomez. World J Pediatr Congenit Heart Surg 2011;2:211-8. 7. Humpl T, Huggan P, Hornberger LK, McCrindle BW. Presentation and outcomes of ectopia cordis. Can J Cardiol 1999;15:1353-7. 8. Morales JM, Patel SG, Duff JA, Villareal RL, Simpson JW. Ectopia cordis and other midline defects. Ann Thorac Surg 2000;70:111-4. 9. Falkensammer CB, Ayres NA, Altman CA, Ge S, Bezold LI, Eidem BW, et al. Fetal cardiac malposition: incidence and outcome of associated cardiac and extracardiac malformations. Am J Perinatol 2008;25:277-81. 10. de Rubens Figueroa J, Sosa Cruz EF, Diaz Garcia L, Carrasco Daza D. [Cardiac malformations in patients with pentalogy of Cantrell and ectopia cordis]. Rev Esp Cardiol 2011;64:615-8. 11. Mallula KK, Sosnowski C, Awad S. Spectrum of Cantrell’s pentalogy: case series from a single tertiary care center and review of the literature. Pediatr Cardiol 2013;34:1703-10. 12. Pius S, Abubakar Ibrahim H, Bello M, Bashir Tahir M. Complete ectopia cordis: a case report and literature review. Case Rep Pediatr 2017;2017: 1858621. 13. Vermont Oxford Network Manual of Operations. Release 21.0. Burlington, VT: Vermont Oxford Network; 2016.
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14. National Center for Health Statistics. Natality public-use tape and CDROM. Hyattsville, MD: National Center for Health Statistics, Annual Products. 2007 and 2008 15. Archer JM, Yeager SB, Kenny MJ, Soll RF, Horbar JD. Distribution of and mortality from serious congenital heart disease in very low birth weight infants. Pediatrics 2011;127:293-9. 16. Sepulveda W, Wong AE, Simonetti L, Gomez E, Dezerega V, Gutierrez J. Ectopia cordis in a first-trimester sonographic screening program for aneuploidy. J Ultrasound Med 2013;32:865-71. 17. Soll RF, Edwards EM, Badger GJ, Kenny MJ, Morrow KA, Buzas JS, et al. Obstetric and neonatal care practices for infants 501 to 1500 g from 2000 to 2009. Pediatrics 2013;132:222-8. 18. Morriss FH Jr, Saha S, Bell EF, Colaizy TT, Stoll BJ, Hintz SR, et al. Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA Pediatr 2014;168:746-54. 19. Cheng HH, Almodovar MC, Laussen PC, Wypij D, Polito A, Brown DW, et al. Outcomes and risk factors for mortality in premature neonates with critical congenital heart disease. Pediatr Cardiol 2011;32:1139-46. 20. Costello JM, Pasquali SK, Jacobs JP, He X, Hill KD, Cooper DS, et al. Gestational age at birth and outcomes after neonatal cardiac surgery: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. Circulation 2014;129:2511-7. 21. Curzon CL, Milford-Beland S, Li JS, O’Brien SM, Jacobs JP, Jacobs ML, et al. Cardiac surgery in infants with low birth weight is associated with increased mortality: analysis of the Society of Thoracic Surgeons Congenital Heart Database. J Thorac Cardiovasc Surg 2008;135:546-51.
Smith et al
Study design Data were prospectively collected on 2 211 262 infants (born 2000-2017) from 845 US centers. Both VLBW (401-1500 g or 22-29 weeks of gestation) and non-VLBW (>1500 g and >29 weeks) infants had diagnoses or anatomic descriptors consistent with ectopia cordis and/or pentalogy of Cantrell. The primary outcome was neonatal survival, defined as hospital discharge or initial length of stay of ³12 months. Results In total, 180 infants had ectopia cordis, 135 (76%) with findings of pentalogy of Cantrell. VLBW infants comprised 52% of the population. VLBW mortality was 96% with 79% dying within 12 hours, compared with 59% and 36%, respectively, for non-VLBW. One-third of VLBW infants received life support compared with 65% of non-VLBW. Surgery was reported for 34% of VLBW and 68% of non-VLBW infants. Congenital heart disease was reported in 8% of VLBW and 36% of non-VLBW, with conotruncal abnormalities most common. Survival exceeded 50% for infants >2500 g and >37 weeks of gestation. Conclusions Survival of VLBW infants with ectopia cordis was poor and substantially worse compared with nonVLBW, with notable discrepancies in resuscitative efforts and surgical interventions. Although gestational age and weight strongly influence current survival, more detailed information regarding the severity of cardiac and noncardiac abnormalities is required to fully determine prognosis and inform counseling. (J Pediatr 2019;-:1-6).
E
ctopia cordis is a rare congenital anomaly in which the heart is positioned either partially or completely outside the thoracic cavity. This malposition was first described by Haller in 1706,1 and in 1958 was incorporated by Cantrell into a pentad of anatomic abnormalities including omphalocele, anterior diaphragmatic hernia, diaphragmatic pericardial defects, and intracardiac defects.2 Though the etiology of ectopia cordis has yet to be fully understood, the prevailing theory is an error in ventral folding morphogenesis, leading to midline defects.1,3 The reported prevalence of ectopia cordis at live birth ranges from 5 to 8 per million,4-6 with variable and substantial mortality.4,5,7-10 To date, the published literature on ectopia cordis and pentalogy of Cantrell (POC) consists primarily of small case series and literature reviews.4,11,12 Two cohort studies examined the outcomes of 39 newborns with ectopia cordis and POC. Of these, only 3 were preterm or low birth weight.5,6 Understanding the survival and clinical outcomes of infants with ectopia cordis is essential to providing accurate and informed prenatal counseling. Given the paucity of data for this special pediatric population, we examined a cohort of both very low birth weight (VLBW) infants, defined by weights 401-1500 g or 22 to 29 weeks of gestational age at birth, and nonVLBW infants, using data from Vermont Oxford Network (VON). The primary study aim was to report survival and clinical outcomes of preterm and/or low birth weight infants born with ectopia cordis. The secondary aim was to describe the spectrum of anatomic abnormalities that may accompany ectopia cordis, including other midline defects and congenital heart disease.
Methods VON is a voluntary worldwide community dedicated to improving the quality, safety, and value of neonatal care through a coordinated program of data-driven quality improvement, education, and research. Member hospitals submit data on either VLBW infants only, or on all neonatal intensive care unit (NICU) admissions regardless of birth weight or gestational age. Data are submitted to VON using uniform definitions and systematic coding outlined in the VON Manual of From the 1Department of Pediatrics, 2Division of Pediatric Cardiology, and 3Department of Mathematics and Statistics, University of Vermont, 4Vermont Oxford Network, and 5Division of Neonatology, University of Vermont, Burlington, VT
CHD NICU POC VLBW VON
Congenital heart disease Neonatal intensive care unit Pentalogy of Cantrell Very low birth weight Vermont Oxford Network
J.H. and R.S. are employees of Vermont Oxford Network. E.E. receives salary support from Vermont Oxford Network. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.09.014
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Operations.13 This cohort study used prospectively collected data on infants born from January 1, 2000 to December 31, 2017. For this study, both the VLBW and all NICU admission databases were searched for free text descriptors of ectopia cordis, and VON systematic coding and free text descriptors indicating POC. During the study period, 845 VON member hospitals in the US submitted data on VLBW infants, and 437 of those hospitals also reported data on all NICU infants; therefore, the sample was enriched with VLBW infants. All anatomic abnormalities that were described by free text and not predefined VON code were reviewed by 2 authors. Atrial septal defect, ventricular septal defect, and coarctation of the aorta were abstracted during the review process; all other congenital anomalies were reported using VON coding.13 A summary of case inclusion criteria, case review, and infant survival is provided in Figure 1. Overall survival was defined as either hospital discharge or continued inpatient admission at 1 year of age. Length of stay was defined by number of days from admission until death, discharge, or date of first birthday. Infants transferred from nonmember hospitals were followed for mortality and length of stay until ultimate disposition. Small for gestational age was defined within categories of sex, race, and ethnicity as birth weight below the 10th percentile, using smoothed curves constructed from the US Natality Dataset.14 Life support collectively referred to resuscitative interventions, defined as any respiratory support (face mask ventilation, nasal continuous positive airway pressure,
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endotracheal intubation, surfactant therapy, and/or mechanical ventilation), chest compressions, and/or epinephrine administration.
Results From 2000 through 2017, there were 2 211 262 infants in the study population, including 725 134 VLBW. Ectopia cordis was reported in 180 infants born in 135 hospitals, of whom 94 were VLBW. Eight infants were born at nonmember facilities and transferred to a member hospital. Among VLBW infants with ectopia cordis, 62 infants (66%) died in the delivery room without receiving life support, and 32 infants (34%) received life support (Figure 1). Twenty (21%) of these VLBW infants were alive at 12 hours, and 15 (16%) past the third day. Only 4 VLBW infants (4%) met survival criteria: 3 were discharged, and 1 was still in the hospital at 1 year. Among 86 non-VLBW infants with ectopia cordis, 26 (30%) died in the delivery room without receiving life support, 56 (65%) received life support, and 4 (5%) did not require life support. Of those 60 infants, 55 (64%) survived ³12 hours and 47 (55%) past the third day. Overall, 35 (41%) non-VLBW infants met survival criteria: 32 (43%) were discharged and 3 were still hospitalized at 1 year. Mortality for VLBW infants was 96%, including 79% within the initial 12 hours, compared with 59% and 36%, respectively, for non-VLBW infants. Patient characteristics for VLBW and non-VLBW infants are summarized in Table I. The VLBW mean gestational
Figure 1. Study consort diagram. Consort diagram of the case inclusion process. VON databases were screened for appropriate ectopia cordis and POC criteria between the years 2000-2017 with 180 cases identified. *Life support was collectively defined as any combination of respiratory support, chest compressions, and/or epinephrine. †Four additional non-VLBW infants did not require life support, and survived. 2
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Table I. Patient characteristics (n = 180) Patient Characteristics Maternal Race/ethnicity Black non-Hispanic White non-Hispanic Hispanic Other Vaginal delivery Prenatal care Infants with ectopia cordis Gestational age, wk, mean (SD) Birth weight, g, mean (SD) Small for gestational age Female Life support‡ Apgar at 1 min £3 Apgar at 5 min £3 Anomalies Ectopia cordis§ Ectopia cordis with congenital diaphragmatic hernia, omphalocele, and/or another anomaly POC Born at reporting hospital Length of stay (median, IQR)
VLBW* (n = 94)
Non-VLBW† (n = 86)
24 (26%) 45 (49%) 16 (17%) 7 (8%) 45 (48%) 91 (97%)
13 (15%) 53 (62%) 15 (18%) 4 (5%) 29 (34%) 84 (98%)
28 (4) 953 (352) 42 (46) 47 (51) 32 (34) 81 (89) 67 (75)
36 (3) 2678 (631) 23 (27) 52 (49) 56 (65) 33 (39) 25 (30)
9 (10) 21 (22)
7 (8) 5 (5)
64 (68) 92 (98) 1 (0)
75 (87) 67 (78) 9 (70)
Values are absolute patient numbers (n) and percent (%). *VLBW: 401-1500 g or 22-29 completed weeks of gestational age. †Non-VLBW: >1500 g and >29 weeks of gestational age. ‡Life support was collectively defined as any combination of respiratory support, chest compressions, and/or epinephrine. §Infants with solitary finding reported.
age was 28 weeks and mean birth weight 953 g, compared with 36 weeks and 2678 g for non-VLBW. Prenatal care was reported for nearly all VLBW (97%) and non-VLBW (98%) infants; 38% of VLBW and 66% of non-VLBW infants <34 weeks of gestation received antenatal steroids. Nearly one-half of the VLBW (48%) were delivered vaginally, compared with 34% of non-VLBW infants. The majority of VLBW (75%) infants had Apgar scores of £3 at 5 minutes of life, compared with 30% of non-VLBW infants. One-third of VLBW (34%) infants received life support, compared with 65% of non-VLBW infants. Of infants who survived greater than 3 days, surgical interventions were reported in 5 of 15 (33%) VLBW and 32 of 47 (68%) non-VLBW infants. Survival in relation to birth weight and gestational age is summarized in Figure 2. Overall survival was 4% for infants with birth weight <1500g, 6% for 1500-2000 g, 39% for 2000-2500 g, 50% for 2501-3000 g, and 58% for infants greater than 3000 g (Figure 2, A). Overall survival was 6% for infants <31 weeks of gestation, 13% for infants 3136 weeks, and 59% for infants greater than 37 weeks (Figure 2, B). Survival among small for gestational age infants was 12%, compared with 28% if appropriate size for age (Figure 2, C). Survival did not improve or show a trend over the 17-year data collection period. Congenital abnormalities consistent with POC were reported in 68% of VLBW and 87% of non-VLBW infants who survived at least 3 days; 22% of VLBW and 5% of non-VLBW infants were documented as having omphalocele Outcomes for Ectopia Cordis
or diaphragmatic hernia without additional abnormalities. Congenital heart disease (CHD) was reported in 7% of VLBW and 36% non-VLBW infants; tetralogy of Fallot and double outlet right ventricle were the most common for both populations (Table II). Of the 180 infants, 38 (21%) had at least 1 cardiac abnormality, with 27 (15%) having an isolated abnormality, 9 (5%) having 2, and 2 (1.1%) having 3. Eight of the 11 infants with multiple cardiac abnormalities survived.
Discussion Congenital abnormalities consistent with POC (omphalocele, anterior diaphragmatic hernia, diaphragmatic pericardium defects, and intracardiac defects in addition to ectopia cordis) were reported in 77% of all infants (68% of VLBW and 87% of non-VLBW), which is consistent with previous studies.5 An additional 22% of VLBW and 5% of non-VLBW infants with ectopia cordis were documented as having an omphalocele or diaphragmatic hernia without further findings of POC. CHD was reported in 7% of VLBW and 36% non-VLBW. Conotruncal abnormalities, including tetralogy of Fallot and double outlet right ventricle, were the most common in both populations, which is consistent with previously published literature.5 The majority of reported CHD (27 of 38 defects), occurred in isolation. Previous studies report the occurrence of CHD among VLBW infants being 3-4 times higher than that of the general population.15 We did not find this within our cohort; however, associated cardiac malformations were likely to be underreported, especially among infants who died in the delivery room without diagnostic imaging. The gestational age at which ectopia cordis can be diagnosed by fetal ultrasound varies but has been reported as early as 10 weeks and likely depends on the extent of the malformation.16 Severe forms of ectopia cordis, which have the poorest prognosis, should be the most apparent on prenatal ultrasound and available to guide counseling. Information regarding prenatal diagnosis, family counseling, and/or postnatal resuscitation directives are not collected by VON databases; thus, it is unclear what, if any, prenatal counseling was offered, and if plans for limited resuscitation were in place prior to delivery. Two prenatal surrogates that suggest limited postnatal interventions were pursued in the VLBW group include a lower cesarean delivery rate and less frequent antenatal steroid therapy. Only 52% of VLBW infants were delivered via cesarean delivery, compared with a national average of 71.8%.17 Antenatal steroid use among VLBW infants was 38%, compared with a national average of 76%.17 The cesarean delivery rate was 66% among the non-VLBW group. Despite advances in technology and surgical technique, correction of severe ectopia cordis remains challenging because of potential anatomic distortion caused by repositioning the heart into the thoracic cavity. Depending on the extent of exteriorization and cardiac malposition, surgery may require multiple stages, with initial intervention to 3
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Figure 2. Infant survival by birth weight, gestational age, and size for gestation. (n = 176)*. A, Total infant survival across birth weight. B, Gestational age. C, Size for gestational age. Infants are considered small for gestational age if theeir birth weight is <10th percentile for gestation. *Four infants did not have birth weight reported. 4
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Table II. Reported CHD* (n = 180) CHD Tetralogy of Fallot DORV ASD VSD Transposition Pulmonary atresia Single ventricle HLHS Coarctation of aorta Cor triatriatum Truncus arteriosus Tricuspid atresia Interrupted aortic arch
VLBW†, n (%)
Non-VLBW‡, n (%)
5 (5.3) 1 (1.1) 1 (1.1) 1 (1.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1) 0 (0) 0 (0) 0 (0)
15 (17.4) 9 (10.5) 2 (2.3) 2 (2.3) 3 (3.5) 3 (3.5) 2 (2.3) 2 (2.3) 1 (1.2) 0 (0) 1 (1.2) 1 (1.2) 1 (1.2)
ASD, atrial septal defect; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; VSD, ventricular septal defect. Values are absolute patient numbers (n) and percent (%). *Infants may have more than 1 anomaly. †VLBW: 401-1500 g or 22-29 completed weeks of gestational age. ‡Non-VLBW: >1500 g and >29 weeks of gestational age.
provide coverage of the heart with skin flaps, grafts, or prosthetic materials.8 Even small defects that could be repaired with skin closure may alter ventricular filling pressure and affect cardiac output. Within our cohort, 33% VLBW and 68% non-VLBW infants (all surviving greater than 3 days) underwent surgery, though there are very limited data regarding type of operation or disease severity. A recent multicenter experience of prenatal ectopia cordis diagnosis reported no documented survival with complete ectopia cordis; in that study 2 infants underwent surgery and both died because of hemodynamic compromise shortly after attempted chest closure.5 Although 1 survivor of complete ectopia cordis and significant CHD has been reported, the authors noted that chest closure was completed with a skin flap and did not involve extensive mobilization of the heart.4 Prior literature has reported major surgery in VLBW infants (defined as requiring anesthesia, but excluding congenital heart disease) to have significantly higher adjusted odds of death or early neurodevelopmental impairment.18 Therefore, the need for any surgery may have influenced clinical care decisions, both in center-specific outcome counseling and technical capability. Mortality among low birth weight and preterm infants undergoing cardiac surgery is significantly worse compared with full term/appropriate weight infants.19-21 One study reported a mortality of 21% for infants born with critical CHD <37 weeks of gestation, compared with 7% between 37 and 38 weeks, and 3% for infants between 39 and 40 weeks.19 Cardiothoracic surgery is further complicated for infants who have additional malformations, such as in POC, with significant increase in mortality.19,21 Cheng et al suggest that maturity, as opposed to birth weight, may be a more important predictor of cardiac surgery outcomes, speculating that immaturity of multiple organ systems, underdevelopment of arterioles in the pulmonary vascular bed, and increased risk for infection may affect patient morbidity.19 Within our cohort, infant mortality improved with both increased age and birth weight, suggesting that maturity Outcomes for Ectopia Cordis
and size both affect outcomes. Small for gestational age infants experienced higher mortality. Unfortunately, additional information regarding surgical timing and the severity of cardiac and noncardiac abnormalities was not collected, so their effect on prognosis cannot be independently analyzed. Even after initial stabilization and corrective surgery, patients with ectopia cordis face considerable long-term morbidity and mortality. Prior longitudinal studies report compromised cardiac function (secondary to extrinsic compression and congestive heart failure), chronic lung disease (secondary to pulmonary hypoplasia and pulmonary hypertension), and high rates of developmental delay in infants with ectopia cordis/POC who survived into childhood.5,12 VON databases collects data up to 1 year of life. As such, there are no data on the long-term outcomes of the patients in this study. Ectopia cordis occurs on a wide spectrum with anatomic variation, ranging from a pulsatile heart directly beneath the skin to complete cardiac exteriorization. Based on the location of the heart, previous studies have categorized malformations as cervical, thoracic, thoracoabdominal, or abdominal.1 As expected, the prognosis of ectopia cordis appears dependent on the type and extent of the exteriorization and cardiac malposition, with previous reports detailing better outcomes for infants with abdominal or thoracoabdominal malformations.5,12 In this study, it is likely that patients with better outcomes had more limited thoracoabdominal defects, as opposed to complete ectopia cordis. This study used a large national multicenter database and was subject to incomplete reporting, although VON has policies that encourage reporting of all eligible infants.13 Although standardization was attempted through the use of systematic coding within VON databases, clinically important diagnostic ambiguity remained. In addition, neither comprehensive surgical data nor long-term outcomes were collected. Consequently, generalization and counseling based on these data should be applied cautiously. Further investigation may explore the severity of cardiac and noncardiac anatomic abnormalities, accuracy of prenatal diagnostic methods, and appropriate delivery room resuscitation management, which may improve prognosis and better inform counseling. n Submitted for publication Jun 13, 2019; last revision received Aug 15, 2019; accepted Sep 10, 2019. Reprint requests: Scott B. Yeager, MD, Division of Pediatric Cardiology, University of Vermont Medical Center, 111 Colchester Ave, Patrick 581, Burlington, VT 05401. E-mail: [email protected]
References 1. Engum SA. Embryology, sternal clefts, ectopia cordis, and Cantrell’s pentalogy. Semin Pediatr Surg 2008;17:154-60. 2. Cantrell JR, Haller JA, Ravitch MM. A syndrome of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium, and heart. Surg Gynecol Obstet 1958;107:602-14. 3. Gabriel A, Donnelly J, Kuc A, Good D, Doros G, Matusz P, et al. Ectopia cordis: a rare congenital anomaly. Clin Anat 2014;27:1193-9. 4. Hornberger LK, Colan SD, Lock JE, Wessel DL, Mayer JE Jr. Outcome of patients with ectopia cordis and significant intracardiac defects. Circulation 1996;94:II32-7. 5
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5. Escobar-Diaz MC, Sunderji S, Tworetzky W, Moon-Grady AJ. The fetus with ectopia cordis: experience and expectations from two centers. Pediatr Cardiol 2017;38:531-8. 6. Balderrabano-Saucedo N, Vizcaino-Alarcon A, Sandoval-Serrano E, Segura-Stanford B, Arevalo-Salas LA, de la Cruz LR, et al. Pentalogy of Cantrell: forty-two years of experience in the Hospital Infantil de Mexico Federico Gomez. World J Pediatr Congenit Heart Surg 2011;2:211-8. 7. Humpl T, Huggan P, Hornberger LK, McCrindle BW. Presentation and outcomes of ectopia cordis. Can J Cardiol 1999;15:1353-7. 8. Morales JM, Patel SG, Duff JA, Villareal RL, Simpson JW. Ectopia cordis and other midline defects. Ann Thorac Surg 2000;70:111-4. 9. Falkensammer CB, Ayres NA, Altman CA, Ge S, Bezold LI, Eidem BW, et al. Fetal cardiac malposition: incidence and outcome of associated cardiac and extracardiac malformations. Am J Perinatol 2008;25:277-81. 10. de Rubens Figueroa J, Sosa Cruz EF, Diaz Garcia L, Carrasco Daza D. [Cardiac malformations in patients with pentalogy of Cantrell and ectopia cordis]. Rev Esp Cardiol 2011;64:615-8. 11. Mallula KK, Sosnowski C, Awad S. Spectrum of Cantrell’s pentalogy: case series from a single tertiary care center and review of the literature. Pediatr Cardiol 2013;34:1703-10. 12. Pius S, Abubakar Ibrahim H, Bello M, Bashir Tahir M. Complete ectopia cordis: a case report and literature review. Case Rep Pediatr 2017;2017: 1858621. 13. Vermont Oxford Network Manual of Operations. Release 21.0. Burlington, VT: Vermont Oxford Network; 2016.
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14. National Center for Health Statistics. Natality public-use tape and CDROM. Hyattsville, MD: National Center for Health Statistics, Annual Products. 2007 and 2008 15. Archer JM, Yeager SB, Kenny MJ, Soll RF, Horbar JD. Distribution of and mortality from serious congenital heart disease in very low birth weight infants. Pediatrics 2011;127:293-9. 16. Sepulveda W, Wong AE, Simonetti L, Gomez E, Dezerega V, Gutierrez J. Ectopia cordis in a first-trimester sonographic screening program for aneuploidy. J Ultrasound Med 2013;32:865-71. 17. Soll RF, Edwards EM, Badger GJ, Kenny MJ, Morrow KA, Buzas JS, et al. Obstetric and neonatal care practices for infants 501 to 1500 g from 2000 to 2009. Pediatrics 2013;132:222-8. 18. Morriss FH Jr, Saha S, Bell EF, Colaizy TT, Stoll BJ, Hintz SR, et al. Surgery and neurodevelopmental outcome of very low-birth-weight infants. JAMA Pediatr 2014;168:746-54. 19. Cheng HH, Almodovar MC, Laussen PC, Wypij D, Polito A, Brown DW, et al. Outcomes and risk factors for mortality in premature neonates with critical congenital heart disease. Pediatr Cardiol 2011;32:1139-46. 20. Costello JM, Pasquali SK, Jacobs JP, He X, Hill KD, Cooper DS, et al. Gestational age at birth and outcomes after neonatal cardiac surgery: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. Circulation 2014;129:2511-7. 21. Curzon CL, Milford-Beland S, Li JS, O’Brien SM, Jacobs JP, Jacobs ML, et al. Cardiac surgery in infants with low birth weight is associated with increased mortality: analysis of the Society of Thoracic Surgeons Congenital Heart Database. J Thorac Cardiovasc Surg 2008;135:546-51.
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