Journal of Perinatology (2014) 34, 319–321 & 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects J Bain1,2, DK Benjamin Jr1,2, CP Hornik1,2, DK Benjamin3, R Clark4 and PB Smith1,2 OBJECTIVE: Necrotizing enterocolitis (NEC) is associated with a significant morbidity and mortality in premature infants. We sought to identify the frequency of NEC in very-low-birth-weight infants with isolated ventricular septal defects (VSDs) or atrial septal defects (ASDs) using a large multicenter database. STUDY DESIGN: We identified a cohort of infants with birth weight o1500 g cared for in 312 neonatal intensive care units (NICUs) managed by the Pediatrix Medical Group between 1997 and 2010. We examined the association between the presence of an ASD or a VSD with development of NEC using logistic regression to control for small-for-gestational age status, antenatal steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 min and method of delivery. RESULT: Of the 98 523 infants who met inclusion criteria, 1904 (1.9%) had an ASD, 1943 (2.0%) had a VSD and 146 (0.1%) had both. The incidence of NEC was 6.2% in infants without septal defects, 9.3% in those with an ASD, 7.8% in those with a VSD, and 10.3% in infants with both an ASD and a VSD. Compared with infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone and ASD with VSD—were 1.26 (95% confidence interval 1.07 to 1.49), 1.27 (1.07 to 1.51) and 1.79 (1.03 to 3.12), respectively. CONCLUSION: The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants. Journal of Perinatology (2014) 34, 319–321; doi:10.1038/jp.2013.174; published online 16 January 2014 Keywords: necrotizing enterocolitis; atrial septal defect; ventricular septal defect
INTRODUCTION Necrotizing enterocolitis (NEC) is a common and often fatal complication of prematurity.1 Mortality associated with NEC ranges from 15 to 30%.2–6 Survivors are at increased risk of long-term morbidity, including short bowel syndrome, subsequent intestinal strictures, neurodevelopmental impairment and growth delay.7 Physiologic states associated with the development of NEC include: immature intestinal system, highly reactive intestinal immune system, altered microvascular environment including poor mesenteric blood flow and abnormal microbial colonization.8 Previous studies have identified term and near-term infants with congenital heart disease as a risk factor for developing NEC;9,10 however, they have not evaluated ventricular and atrial septal defects (VSD and ASD) in isolation, but rather in association with other congenital heart defects and in the surgical setting. VSD and ASD are the first and second most common congenital heart defects, with a prevalence in the general population of 2.6/1000 and 1.6/1000, respectively.11 These defects may result in left-to-right shunting of blood, resulting in increased pulmonary blood flow, and a subsequent decrease in systemic, and thus mesenteric blood flow. Given the high prevalence of both VSD and ASD in infants, we evaluated VSD and ASD as risk factors for NEC in premature infants using a large multicenter database.
METHODS Study population Data were obtained from an administrative database that prospectively captures information from daily progress notes generated by clinicians using a computer-assisted tool on all infants cared for by the Pediatrix Medical Group. Included in the data were diagnoses, medications, gestational age, birth weight, method of delivery, Apgar score, sex, race and occurrence of NEC. The diagnosis of a septal defect was made based on echocardiography results. We included all infants admitted within the first 28 days of life with a birth weight of o1500 g who were discharged from 312 Pediatrix Medical Group neonatal intensive care units (NICUs) in North America between 1997 and 2010. Exclusion criteria were (1) death within the first 3 days of life, (2) treatment with prostaglandins at any time before discharge, and (3) the presence of major congenital anomalies (including infants with other structural heart disease).
Definitions and statistical analysis For each infant, we identified the first episode of NEC occurring before day of life (DOL) 120, including surgically or medically treated NEC. We did not include those infants who had presumed or suspected NEC. We compared continuous and categorical variables between infants with a diagnosis of ASD, VSD, both ASD and VSD, or no cardiac septal defect. We used multivariable logistic regression models to evaluate the association between the presence of an ASD, a VSD, or both and the diagnosis of medial or surgical NEC, controlling for the following confounders present at birth: small-for-gestational age status, antenatal
1 Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA; 2Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA; 3Clemson University, Clemson, SC, USA and 4Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL, USA. Correspondence: Dr PB Smith, Department of Pediatrics, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715, USA. E-mail: [email protected] Received 1 July 2013; revised 31 October 2013; accepted 20 November 2013; published online 16 January 2014
Risk of NEC in infants with isolated ASD and VSD J Bain et al
320 steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 min and method of delivery. We controlled for potential site-specific effects using a fixed effect for site. Using a fixed effect model that is conditioned on the NICU addresses the heterogeneity of baseline risk of outcomes in each individual NICU. We used Stata 12 (College Station, TX, USA) to analyze the data, and considered Po0.05 as statistically significant.
Figure 1. Study population. ASD, atrial septal defect; DOL, day of life; NEC, necrotizing enterocolitis; VSD, ventricular septal defect.
Table 1.
RESULTS During the study period, 98 523 infants met our inclusion criteria (Figure 1). Of these, 1904/98 523 (1.9%) had an ASD, 1943/98 523 (2.0%) had a VSD, and 146/98 523 (0.1%) had both an ASD and a VSD (Table 1). For infants with septal defect, the diagnosis was made on a median DOL 7 (interquartile range 3 to 26). The incidence of NEC in infants without cardiac septal defects was 5825/94 530 (6.2%); 3966/5825 (68.1%) of those episodes were medical NEC. Infants with an ASD had an incidence of 177/1904 (9.3%), 121/177 (68.4%) of which were medical NEC. Infants with a VSD had an incidence of 152/1943 (7.8%), and 107/152 (70.4%) of those episodes were medical NEC. Finally, infants with both an ASD and a VSD had an incidence of 15/146 (10.3%), 9/15 (60.0%) of which were medical NEC. The first episode of NEC occurred on DOL 21 (interquartile range 12 to 32), DOL 24 (14 to 37), DOL 22 (14 to 34) and DOL 18 (11 to 43) for infants without septal defects, infants with an ASD, infants with a VSD, and infants with an ASD and a VSD, respectively. Among infants who developed NEC, the incidence of surgical versus medical NEC did not differ between those with and without septal defects (P ¼ 0.75); it also did not differ across patients with different types of septal defects (P ¼ 0.69). Compared with infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone and ASD with VSD—were 1.26 (95% confidence interval 1.07 to 1.49), 1.27 (1.07 to 1.51) and 1.79 (1.03 to 3.12), respectively.
DISCUSSION In our multicenter study, we observed that infants o1500 g birth weight with an ASD or a VSD were at increased risk of developing NEC as compared with infants without septal defects. To date, no
Demographics No cardiac septal defect, N ¼ 94 530 (%)
ASD, N ¼ 1904 (%)
VSD, N ¼ 1943 (%)
ASD þ VSD, N ¼ 146 (%)
Gestational age, weeks p25 26–28 29–32 33–36 X37
16 047 30 930 40 512 6721 291
Male
47 781 (51)
914 (48)
820 (42)
55 (38)
Birth weight, g o750 750–999 1000–1499
15 587 (16) 21 189 (22) 57 754 (61)
447 (23) 539 (28) 918 (48)
353 (18) 492 (25) 1098 (57)
30 (21) 36 (25) 80 (55)
SGA
22 588 (24)
413 (22)
528 (27)
55 (38)
Apgar at 5 min 0–3 4–6 7–10
3327 (4) 14 031 (15) 75 368 (81)
84 (5) 330 (18) 1446 (78)
80 (4) 329 (17) 1493 (79)
9 (6) 26 (18) 107 (75)
Race/ethnicity White Black Hispanic Other
43 994 24 243 18 257 4841
Cesarean section Antenatal steroid exposure Antenatal antibiotic exposure
67 356 (72) 68 973 (73) 38 304 (41)
(17) (33) (43) (7) (o1)
(48) (27) (20) (5)
400 826 617 52 8
904 437 371 134
(21) (43) (32) (3) (o1)
(49) (24) (20) (7)
1433 (76) 1412 (74) 776 (41)
313 698 790 135 7
997 394 386 98
(16) (36) (41) (7) (o1)
(53) (21) (21) (5.2)
1453 (75) 1426 (73) 810 (42)
26 42 61 17 0
79 25 28 6
(18) (29) (42) (12) (0)
(57) (18) (21) (4)
112 (78) 111 (76) 54 (37)
Abbreviations: ASD, atrial septal defect; SGA, small-for-gestational age; VSD, ventricular septal defect.
Journal of Perinatology (2014), 319 – 321
& 2014 Nature America, Inc.
Risk of NEC in infants with isolated ASD and VSD J Bain et al
321 study has evaluated the incidence of infants with an isolated ASD and/or VSD and the occurrence of NEC. In a previously conducted retrospective study using the National Inpatient Sample and the Kids’ Inpatient Database, infants with congenital heart disease were evaluated for the development of NEC after undergoing cardiac surgery.12 The investigators identified infants who developed NEC and who had a coexisting diagnosis of congenital heart disease. Of the 194 patients with congenital heart disease who developed NEC, 57 were diagnosed with secundum ASD, and 61 were diagnosed with a VSD in isolation. This suggests that, of all infants who underwent surgery with heart disease and developed NEC, B60% had either an ASD or a VSD.12 A study of infants with left-to-right intra-cardiac shunt, inclusive of infants with ASD, VSD, atrioventricular septal defect and persistent ductus arteriosus, demonstrated increased frequency of NEC.13 In our analysis, we excluded infants with a diagnosis of atrioventricular septal defect and those treated with prostaglandins. The association of NEC with congenital heart disease in infants has been well documented.14 The population most commonly studied consists of infants with heart lesions that would lead to lower systemic oxygen saturations including single ventricle physiology, transposition of the great arteries, truncus arteriosus and infants with a persistent ductus arteriosus.9 The development of NEC in infants with congenital heart disease can be attributed to many factors, including cardiac surgery and cardiopulmonary bypass, a baseline elevation of circulating endotoxin, and proinflammatory cytokines.14 Additional pathophysiology is also thought to contribute to the development of NEC in these infants. Previous studies have suggested that alteration in mesenteric blood flow leads to intestinal ischemia, which results in intestinal injury, thereby creating an environment that predisposes the infant to NEC.15,16 Infants with congenital heart disease also remain at risk of NEC due to conventional risk factors of bacterial overgrowth with intestinal disruption. Overall, in our population studied, the incidence of isolated ASD was 1.9% and of isolated VSD was 2.0%. These values are higher than reported by previous investigators in a meta-analysis, in which the median incidence of ASD and VSD was reported to be 0.06 and 0.28%, respectively.17 The authors included literature spanning as far back as 1955 and noted an increasing incidence of ASD and VSD in the more recent publications.17 Technological advances, specifically the advancement of echocardiography, likely account for the higher incidence reported in more recent publications. Strengths of our study include its large multicenter cohort comprising a diverse NICU population of varying size, acuity and geography. Our analysis evaluated the risk of NEC based on variables available at birth. Unmeasured confounders that vary on daily basis limit our study, including markers of acuity of illness, the presence and hemodynamic significance of a PDA, daily amount and type of enteral nutrition, and drug exposure to indocin or ibuprofen that may predispose infants to NEC. Many infants classified as not having a septal defect did not have an echocardiogram; this may have led to misclassification of these infants and ultimately biased our findings toward the null hypothesis. Ideally, to best characterize the associations between septal defects and NEC, all infants would be screened prospectively with an echocardiogram. In our analysis, the diagnosis of septal defect was a quantitative one; we did not have data on the quality of the septal defect to assess the patient-specific hemodynamics of each defect. In addition, we did not have access to radiographs or surgical operative reports to confirm the diagnosis of NEC.
& 2014 Nature America, Inc.
CONCLUSION The association of isolated ASD and VSD lesions with NEC has not been previously studied. In this large multicenter analysis, we found that infants with an ASD and/or a VSD had an increased likelihood of developing NEC as compared with infants without septal defects in our cohort group. CONFLICT OF INTEREST Dr Benjamin receives support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05 and NICHD contract HHSN275201000003I) and the non-profit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr Smith receives salary support for research from the National Institutes of Health and the US Department of Health and Human Services (NICHD 1K23HD060040-01, DHHS-1R18AE000028-01 and HHSN267200700051C); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). The other authors declare no conflict of interest.
REFERENCES 1 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364: 255–264. 2 Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003; 23: 278–285. 3 Luig M, Lui K. Epidemiology of necrotizing enterocoliti—Part I: Changing regional trends in extremely preterm infants over 14 years. J Paediatr Child Health 2005; 41: 169–173. 4 Llanos AR, Moss ME, Pinzon MC, Dye T, Sinkin RA, Kendig JW. Epidemiology of neonatal necrotising enterocolitis: a population-based study. Paediatr Perinat Epidemiol 2002; 16: 342–349. 5 Holman RC, Stoll BJ, Curns AT, Yorita KL, Steiner CA, Schonberger LB. Necrotising enterocolitis hospitalisations among neonates in the United States. Paediatr Perinat Epidemiol 2006; 20: 498–506. 6 Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006; 368: 1271–1283. 7 Henry MC, Moss RL. Neonatal necrotizing enterocolitis. Semin Pediatr Surg 2008; 17: 98–109. 8 Neu J, Mihatsch W. Recent developments in necrotizing enterocolitis. J Parenter Enteral Nutr 2012; 36(1 Suppl): 30S–35S. 9 McElhinney DB, Hedrick HL, Bush DM, Pereira GR, Stafford PW, Gaynor JW et al. Necrotizing enterocolitis in neonates with congenital heart disease: risk factors and outcomes. Pediatrics 2000; 106: 1080–1087. 10 Bolisetty S, Lui K, Oei J, Wojtulewicz J. A regional study of underlying congenital diseases in term neonates with necrotizing enterocolitis. Acta Paediatr 2000; 89: 1226–1230. 11 van der Linde D, Konings EE, Slager MA, Witsenburg M, Helbing WA, Takkenberg JJ et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58: 2241–2247. 12 Mukherjee D, Zhang Y, Chang DC, Vricella LA, Brenner JI, Abdullah F. Outcomes analysis of necrotizing enterocolitis within 11 958 neonates undergoing cardiac surgical procedures. Arch Surg 2010; 145: 389–392. 13 Cheng W, Leung MP, Tam PK. Surgical intervention in necrotizing enterocolitis in neonates with symptomatic congenital heart disease. Pediatr Surg Int 1999; 15: 492–495. 14 Giannone PJ, Luce WA, Nankervis CA, Hoffman TM, Wold LE. Necrotizing enterocolitis in neonates with congenital heart disease. Life Sci 2008; 82(7-8): 341– 347. 15 Carlo WF, Kimball TR, Michelfelder EC, Border WL. Persistent diastolic flow reversal in abdominal aortic Doppler-flow profiles is associated with an increased risk of necrotizing enterocolitis in term infants with congenital heart disease. Pediatrics 2007; 119: 330–335. 16 Murdoch EM, Sinha AK, Shanmugalingam ST, Smith GC, Kempley ST. Doppler flow velocimetry in the superior mesenteric artery on the first day of life in preterm infants and the risk of neonatal necrotizing enterocolitis. Pediatrics 2006; 118: 1999–2003. 17 Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900.
Journal of Perinatology (2014), 319 – 321
ORIGINAL ARTICLE
Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects J Bain1,2, DK Benjamin Jr1,2, CP Hornik1,2, DK Benjamin3, R Clark4 and PB Smith1,2 OBJECTIVE: Necrotizing enterocolitis (NEC) is associated with a significant morbidity and mortality in premature infants. We sought to identify the frequency of NEC in very-low-birth-weight infants with isolated ventricular septal defects (VSDs) or atrial septal defects (ASDs) using a large multicenter database. STUDY DESIGN: We identified a cohort of infants with birth weight o1500 g cared for in 312 neonatal intensive care units (NICUs) managed by the Pediatrix Medical Group between 1997 and 2010. We examined the association between the presence of an ASD or a VSD with development of NEC using logistic regression to control for small-for-gestational age status, antenatal steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 min and method of delivery. RESULT: Of the 98 523 infants who met inclusion criteria, 1904 (1.9%) had an ASD, 1943 (2.0%) had a VSD and 146 (0.1%) had both. The incidence of NEC was 6.2% in infants without septal defects, 9.3% in those with an ASD, 7.8% in those with a VSD, and 10.3% in infants with both an ASD and a VSD. Compared with infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone and ASD with VSD—were 1.26 (95% confidence interval 1.07 to 1.49), 1.27 (1.07 to 1.51) and 1.79 (1.03 to 3.12), respectively. CONCLUSION: The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants. Journal of Perinatology (2014) 34, 319–321; doi:10.1038/jp.2013.174; published online 16 January 2014 Keywords: necrotizing enterocolitis; atrial septal defect; ventricular septal defect
INTRODUCTION Necrotizing enterocolitis (NEC) is a common and often fatal complication of prematurity.1 Mortality associated with NEC ranges from 15 to 30%.2–6 Survivors are at increased risk of long-term morbidity, including short bowel syndrome, subsequent intestinal strictures, neurodevelopmental impairment and growth delay.7 Physiologic states associated with the development of NEC include: immature intestinal system, highly reactive intestinal immune system, altered microvascular environment including poor mesenteric blood flow and abnormal microbial colonization.8 Previous studies have identified term and near-term infants with congenital heart disease as a risk factor for developing NEC;9,10 however, they have not evaluated ventricular and atrial septal defects (VSD and ASD) in isolation, but rather in association with other congenital heart defects and in the surgical setting. VSD and ASD are the first and second most common congenital heart defects, with a prevalence in the general population of 2.6/1000 and 1.6/1000, respectively.11 These defects may result in left-to-right shunting of blood, resulting in increased pulmonary blood flow, and a subsequent decrease in systemic, and thus mesenteric blood flow. Given the high prevalence of both VSD and ASD in infants, we evaluated VSD and ASD as risk factors for NEC in premature infants using a large multicenter database.
METHODS Study population Data were obtained from an administrative database that prospectively captures information from daily progress notes generated by clinicians using a computer-assisted tool on all infants cared for by the Pediatrix Medical Group. Included in the data were diagnoses, medications, gestational age, birth weight, method of delivery, Apgar score, sex, race and occurrence of NEC. The diagnosis of a septal defect was made based on echocardiography results. We included all infants admitted within the first 28 days of life with a birth weight of o1500 g who were discharged from 312 Pediatrix Medical Group neonatal intensive care units (NICUs) in North America between 1997 and 2010. Exclusion criteria were (1) death within the first 3 days of life, (2) treatment with prostaglandins at any time before discharge, and (3) the presence of major congenital anomalies (including infants with other structural heart disease).
Definitions and statistical analysis For each infant, we identified the first episode of NEC occurring before day of life (DOL) 120, including surgically or medically treated NEC. We did not include those infants who had presumed or suspected NEC. We compared continuous and categorical variables between infants with a diagnosis of ASD, VSD, both ASD and VSD, or no cardiac septal defect. We used multivariable logistic regression models to evaluate the association between the presence of an ASD, a VSD, or both and the diagnosis of medial or surgical NEC, controlling for the following confounders present at birth: small-for-gestational age status, antenatal
1 Duke University Medical Center, Duke Clinical Research Institute, Durham, NC, USA; 2Department of Pediatrics, Duke University Medical Center, Duke University, Durham, NC, USA; 3Clemson University, Clemson, SC, USA and 4Pediatrix-Obstetrix Center for Research and Education, Sunrise, FL, USA. Correspondence: Dr PB Smith, Department of Pediatrics, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715, USA. E-mail: [email protected] Received 1 July 2013; revised 31 October 2013; accepted 20 November 2013; published online 16 January 2014
Risk of NEC in infants with isolated ASD and VSD J Bain et al
320 steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 min and method of delivery. We controlled for potential site-specific effects using a fixed effect for site. Using a fixed effect model that is conditioned on the NICU addresses the heterogeneity of baseline risk of outcomes in each individual NICU. We used Stata 12 (College Station, TX, USA) to analyze the data, and considered Po0.05 as statistically significant.
Figure 1. Study population. ASD, atrial septal defect; DOL, day of life; NEC, necrotizing enterocolitis; VSD, ventricular septal defect.
Table 1.
RESULTS During the study period, 98 523 infants met our inclusion criteria (Figure 1). Of these, 1904/98 523 (1.9%) had an ASD, 1943/98 523 (2.0%) had a VSD, and 146/98 523 (0.1%) had both an ASD and a VSD (Table 1). For infants with septal defect, the diagnosis was made on a median DOL 7 (interquartile range 3 to 26). The incidence of NEC in infants without cardiac septal defects was 5825/94 530 (6.2%); 3966/5825 (68.1%) of those episodes were medical NEC. Infants with an ASD had an incidence of 177/1904 (9.3%), 121/177 (68.4%) of which were medical NEC. Infants with a VSD had an incidence of 152/1943 (7.8%), and 107/152 (70.4%) of those episodes were medical NEC. Finally, infants with both an ASD and a VSD had an incidence of 15/146 (10.3%), 9/15 (60.0%) of which were medical NEC. The first episode of NEC occurred on DOL 21 (interquartile range 12 to 32), DOL 24 (14 to 37), DOL 22 (14 to 34) and DOL 18 (11 to 43) for infants without septal defects, infants with an ASD, infants with a VSD, and infants with an ASD and a VSD, respectively. Among infants who developed NEC, the incidence of surgical versus medical NEC did not differ between those with and without septal defects (P ¼ 0.75); it also did not differ across patients with different types of septal defects (P ¼ 0.69). Compared with infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone and ASD with VSD—were 1.26 (95% confidence interval 1.07 to 1.49), 1.27 (1.07 to 1.51) and 1.79 (1.03 to 3.12), respectively.
DISCUSSION In our multicenter study, we observed that infants o1500 g birth weight with an ASD or a VSD were at increased risk of developing NEC as compared with infants without septal defects. To date, no
Demographics No cardiac septal defect, N ¼ 94 530 (%)
ASD, N ¼ 1904 (%)
VSD, N ¼ 1943 (%)
ASD þ VSD, N ¼ 146 (%)
Gestational age, weeks p25 26–28 29–32 33–36 X37
16 047 30 930 40 512 6721 291
Male
47 781 (51)
914 (48)
820 (42)
55 (38)
Birth weight, g o750 750–999 1000–1499
15 587 (16) 21 189 (22) 57 754 (61)
447 (23) 539 (28) 918 (48)
353 (18) 492 (25) 1098 (57)
30 (21) 36 (25) 80 (55)
SGA
22 588 (24)
413 (22)
528 (27)
55 (38)
Apgar at 5 min 0–3 4–6 7–10
3327 (4) 14 031 (15) 75 368 (81)
84 (5) 330 (18) 1446 (78)
80 (4) 329 (17) 1493 (79)
9 (6) 26 (18) 107 (75)
Race/ethnicity White Black Hispanic Other
43 994 24 243 18 257 4841
Cesarean section Antenatal steroid exposure Antenatal antibiotic exposure
67 356 (72) 68 973 (73) 38 304 (41)
(17) (33) (43) (7) (o1)
(48) (27) (20) (5)
400 826 617 52 8
904 437 371 134
(21) (43) (32) (3) (o1)
(49) (24) (20) (7)
1433 (76) 1412 (74) 776 (41)
313 698 790 135 7
997 394 386 98
(16) (36) (41) (7) (o1)
(53) (21) (21) (5.2)
1453 (75) 1426 (73) 810 (42)
26 42 61 17 0
79 25 28 6
(18) (29) (42) (12) (0)
(57) (18) (21) (4)
112 (78) 111 (76) 54 (37)
Abbreviations: ASD, atrial septal defect; SGA, small-for-gestational age; VSD, ventricular septal defect.
Journal of Perinatology (2014), 319 – 321
& 2014 Nature America, Inc.
Risk of NEC in infants with isolated ASD and VSD J Bain et al
321 study has evaluated the incidence of infants with an isolated ASD and/or VSD and the occurrence of NEC. In a previously conducted retrospective study using the National Inpatient Sample and the Kids’ Inpatient Database, infants with congenital heart disease were evaluated for the development of NEC after undergoing cardiac surgery.12 The investigators identified infants who developed NEC and who had a coexisting diagnosis of congenital heart disease. Of the 194 patients with congenital heart disease who developed NEC, 57 were diagnosed with secundum ASD, and 61 were diagnosed with a VSD in isolation. This suggests that, of all infants who underwent surgery with heart disease and developed NEC, B60% had either an ASD or a VSD.12 A study of infants with left-to-right intra-cardiac shunt, inclusive of infants with ASD, VSD, atrioventricular septal defect and persistent ductus arteriosus, demonstrated increased frequency of NEC.13 In our analysis, we excluded infants with a diagnosis of atrioventricular septal defect and those treated with prostaglandins. The association of NEC with congenital heart disease in infants has been well documented.14 The population most commonly studied consists of infants with heart lesions that would lead to lower systemic oxygen saturations including single ventricle physiology, transposition of the great arteries, truncus arteriosus and infants with a persistent ductus arteriosus.9 The development of NEC in infants with congenital heart disease can be attributed to many factors, including cardiac surgery and cardiopulmonary bypass, a baseline elevation of circulating endotoxin, and proinflammatory cytokines.14 Additional pathophysiology is also thought to contribute to the development of NEC in these infants. Previous studies have suggested that alteration in mesenteric blood flow leads to intestinal ischemia, which results in intestinal injury, thereby creating an environment that predisposes the infant to NEC.15,16 Infants with congenital heart disease also remain at risk of NEC due to conventional risk factors of bacterial overgrowth with intestinal disruption. Overall, in our population studied, the incidence of isolated ASD was 1.9% and of isolated VSD was 2.0%. These values are higher than reported by previous investigators in a meta-analysis, in which the median incidence of ASD and VSD was reported to be 0.06 and 0.28%, respectively.17 The authors included literature spanning as far back as 1955 and noted an increasing incidence of ASD and VSD in the more recent publications.17 Technological advances, specifically the advancement of echocardiography, likely account for the higher incidence reported in more recent publications. Strengths of our study include its large multicenter cohort comprising a diverse NICU population of varying size, acuity and geography. Our analysis evaluated the risk of NEC based on variables available at birth. Unmeasured confounders that vary on daily basis limit our study, including markers of acuity of illness, the presence and hemodynamic significance of a PDA, daily amount and type of enteral nutrition, and drug exposure to indocin or ibuprofen that may predispose infants to NEC. Many infants classified as not having a septal defect did not have an echocardiogram; this may have led to misclassification of these infants and ultimately biased our findings toward the null hypothesis. Ideally, to best characterize the associations between septal defects and NEC, all infants would be screened prospectively with an echocardiogram. In our analysis, the diagnosis of septal defect was a quantitative one; we did not have data on the quality of the septal defect to assess the patient-specific hemodynamics of each defect. In addition, we did not have access to radiographs or surgical operative reports to confirm the diagnosis of NEC.
& 2014 Nature America, Inc.
CONCLUSION The association of isolated ASD and VSD lesions with NEC has not been previously studied. In this large multicenter analysis, we found that infants with an ASD and/or a VSD had an increased likelihood of developing NEC as compared with infants without septal defects in our cohort group. CONFLICT OF INTEREST Dr Benjamin receives support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05 and NICHD contract HHSN275201000003I) and the non-profit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr Smith receives salary support for research from the National Institutes of Health and the US Department of Health and Human Services (NICHD 1K23HD060040-01, DHHS-1R18AE000028-01 and HHSN267200700051C); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). The other authors declare no conflict of interest.
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