Journal of Perinatology (2015), 1–6 © 2015 Nature America, Inc. All rights reserved 0743-8346/15 www.nature.com/jp
ORIGINAL ARTICLE
Intestinal perforation in very preterm neonates: risk factors and outcomes J Shah1, N Singhal2, O da Silva3, N Rouvinez-Bouali4, M Seshia5, SK Lee1,6 and PS Shah1,6 on behalf of the Canadian Neonatal Network7 OBJECTIVE: To compare neonatal outcomes of preterm infants (born at o32 weeks’ gestation) with focal/spontaneous intestinal perforation (SIP), necrotizing enterocolitis (NEC)-related perforation, NEC without perforation or no NEC/perforation. STUDY DESIGN: Retrospective cohort study of 17 426 infants admitted to Canadian neonatal intensive care units during 2010 to 2013. The primary outcome was a composite of mortality or morbidity (bronchopulmonary dysplasia, severe retinopathy, periventricular leukomalacia or nosocomial infection). Association of intestinal perforation with neonatal outcome was evaluated using multivariate logistic regression. RESULT: SIP was present in 178 (1.0%) infants, NEC-related perforation in 246 (1.4%) and NEC without perforation in 538 (3.1%). Any intestinal perforation was associated with higher odds of the composite outcome (adjusted odds ratio (AOR): 8.21, 95% confidence interval (95% CI) 6.26 to 10.8); however, the odds were significantly lower for focal/SIP compared with NEC-related perforation (AOR: 0.29, 95% CI 0.17 to 0.51). CONCLUSION: Of the two types of intestinal perforation, NEC-related perforation was associated with the highest risk of an adverse neonatal outcome. Journal of Perinatology advance online publication, 30 April 2015; doi:10.1038/jp.2015.41
INTRODUCTION Intestinal perforation in neonates, especially preterm infants, is an uncommon yet well-recognized entity.1,2 There are two major types of intestinal perforation, necrotizing enterocolitis (NEC)related and focal or spontaneous intestinal perforation (SIP). Although they affect the same organ and are commonly seen in extremely low birth weight and low gestational age infants, the two types of perforation are separate and distinct clinical and pathological entities.2,3 Perforation associated with NEC has been classified as stage 3 NEC with classic preceding signs of abdominal distension, intestinal ischemia and with or without pneumatosis intestinalis. Focal/SIP occurs in relatively younger and lower birth weight infants and usually happens at around 7 days of postnatal age, which is earlier in the postnatal period than in classic NEC.1,2,4–6 Histologically NEC is associated with coagulative necrosis involving a large area of intestine, whereas focal/SIP is associated with hemorrhagic necrosis involving a small focal lesion.6 Clinical characteristics associated with focal/SIP include bluish discoloration and gasless abdomen in the absence of pneumatosis.4,6 Focal/SIP is perceived to occur secondary to immaturity, postnatal exposure to dexamethasone1,7–10 or indomethacin,1,2,6,7,9–12 hypotension (reflected by need for inotropes),1,4 leukocytosis,4 candidiasis,3,4,9 staphylococcus epidermidis infection,3,9,13 placement of an umbilical arterial catheter2 or the presence of patent ductus arteriosus.1 Neonatal mortality has been reported to be higher in infants with SIP and NEC-related perforation than in those without
perforation.14 Mortality has also been reported to be lower among infants with SIP compared with those with surgical NEC;2,15 however, reports of other neonatal morbidities are scant and most studies are of small sample size. It is perceived that infants with SIP are in better condition at the time of diagnosis compared with those with NEC-related perforation and are likely to recover well without significant neonatal impact; however, data are lacking in this regard. Our objective was to compare mortality and neonatal morbidities among very preterm infants born at o32 weeks’ gestation who had focal/SIP, NEC-related perforation or NEC without perforation and infants without NEC or focal/SIP using a population-based data set. STUDY DESIGN AND METHODS Study design This retrospective cohort study included preterm infants of o32 weeks’ gestation admitted between 1 January 2010 and 31 December 2013 to neonatal intensive care units (NICUs) participating in the Canadian Neonatal Network. Study population comprised of 490% of all neonates of o32 weeks’ gestation admitted to NICUs in Canada. Infants with a major congenital anomaly (defined as life-threatening anomaly or one that untreated could affect physical and/or neurodevelopmental outcomes) and infants who were moribund on admission (for whom either no resuscitation was offered or palliative care at birth was
1 Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 2Department of Pediatrics, Foothills Hospital, University of Calgary, Calgary, AB, Canada; 3Department of Pediatrics, London Health Sciences Center, University of Western Ontario, London, ON, Canada; 4Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa University, Ottawa, ON, Canada; 5Department of Pediatrics, Winnipeg Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada and 6MaternalInfant Care Research Centre, Mount Sinai Hospital, Toronto, ON, Canada. Correspondence: Dr PS Shah, Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Room 19-231F, Toronto, ON M5G 1X5, Canada. E-mail: [email protected] 7 See Appendix. Received 30 December 2014; revised 3 March 2015; accepted 23 March 2015
Intestinal perforation in very preterm neonates J Shah et al
2 planned) were excluded. Eligible infants were divided into four groups according to their diagnosis: (1) Focal/SIP; (2) NEC-related perforation; (3) NEC but no perforation; and (4) no NEC or SIP. Diagnosis of NEC was based on modified Bell’s staging of stages 2 and 3.16 Focal/SIP was diagnosed according to local practices based on lack of clinical features of NEC, radiological finding of perforation, absence of radiological features of intestinal ischemia (fixed dilated bowel loops, pneumatosis intestinalis and so on) and/or intra-operative surgical report and/or histopathology where perforation was located in the ileum and on the antimesentric border. Data were collected by local sites regarding reason for perforation; however, details of diagnostic criteria were not collected in the data set. Outcomes Our primary outcome was a composite of mortality or any of the following major morbidities: (1) bronchopulmonary dysplasia defined as the need for oxygen at 36 weeks postmenstrual age17 or at discharge or transfer; (2) periventricular leukomalacia (PVL) diagnosed using neuroimaging after 21 days of age; (3) severe retinopathy of prematurity defined as 4stage 2 retinopathy according to the International Classification18 or surgery for retinopathy; and (4) nosocomial infection defined as clinical signs of sepsis and a positive bacterial culture from blood or cerebrospinal fluid. Our secondary outcomes included the individual components of the composite outcome. Definitions Gestational age was defined as the best estimate based on date of in vitro fertilization, early ultrasound, last menstrual period, obstetric estimate or pediatric estimate, in that hierarchical order. Severity of illness at admission was defined using the Score of Neonatal Acute Physiology II (SNAPII) score.19 Prophylactic indomethacin was defined as use of indomethacin within the first 24 h of birth for the purpose of preventing intraventricular hemorrhage. Small for gestational age was defined as birth weight o10th centile for gestational age and sex. Therapeutic indomethacin was defined as use of indomethacin for the purpose of treatment of a symptomatic patent ductus arteriosus. Data collection and ethics Trained abstractors collected data from patient charts throughout each infant’s NICU stay according to a standard protocol. Data were entered electronically into a data-entry program with built-in error-checking.20 Data on maternal and infant characteristics, predisposing factors and neonatal outcomes were then retrieved from the network database for analysis. Ethics approval was granted at each site by either the local Research Ethics Board or through an institutional quality improvement process for data collection and benchmarking. The study was approved by the executive committee of the Canadian Neonatal Network. Statistical analyses Maternal and infant characteristics were compared between the four groups individually and between combinations of the groups (for example, all perforations vs NEC without perforation and all perforations vs no NEC, no perforations) using Student’s t-test or the Mann–Whitney test for continuous outcomes and the chisquare test for categorical outcomes, as appropriate. Predictors of special interest were use of prophylactic indomethacin, receipt of antenatal steroid, postnatal use of hydrocortisone in the first week after birth, use of inotropes in the first week after birth, small-forgestational-age status and SNAPII score. Multivariate logistic regression models were applied to identify the impact of the covariates on the primary and secondary outcomes. A P-value of o0.05 was considered significant. Journal of Perinatology (2015), 1 – 6
RESULTS Out of the 17 426 eligible infants, 178 (1.0%) developed focal/SIP, 246 (1.4%) developed NEC-related perforation, 538 (3.1%) developed NEC without perforation and the remaining 16 464 (94.5%) had neither NEC nor focal/SIP (Figure 1). Of the infants with focal/ SIP, 122 (69%) received surgical management (27 deaths). Of the infants with NEC-related perforation, 113 received surgery (45 deaths), 33 had drain followed by surgery (18 deaths), 36 had only drain (27 deaths) and for 64 data regarding surgery or drain were not recorded owing to transfers (34 deaths). Of the infants with NEC without perforation, 106 received surgery (33 deaths), 9 had drain for ascites followed by surgery (4 deaths), 16 had only drain for ascites (7 deaths) and 407 did not receive surgery (57 deaths). Table 1 reports the maternal and infant characteristics of the study population. There were no significant differences between the characteristics of the infants with focal/SIP and those with NEC-related perforation. However, compared with infants without perforation, those with perforation of either cause had higher SNAPII scores and lower Apgar scores, were of younger gestation and had lower birth weights. A higher number of infants with perforations also received therapeutic indomethacin, hydrocortisone in the first week of birth and inotropes in the first week. The rate of patent ductus arteriosus was also higher in infants with perforations. Table 2 includes univariate comparisons of the composite and secondary outcome rates. The rate of the composite outcome was significantly lower among infants with focal/SIP compared with those with NEC-related perforation, which was mostly due to the low mortality rate among infants with focal/SIP. The rates of the composite outcome and the majority of other outcomes were significantly higher in infants with perforation compared with those with NEC without perforation and the control (no NEC, no perforation) group. Table 3 reports the results of multivariate analyses after adjustment for confounders and risk factors. After adjustment, the reduced odds of the composite outcome due to lower mortality remained in infants with focal/SIP compared with those with NEC-related perforation. There was no difference in the primary or any secondary outcomes between infants with focal/ SIP and those with NEC (with perforation and without perforation combined). With the exception of PVL, there were significantly higher odds of the composite and individual secondary outcomes among patients who had focal/SIP compared with infants without perforation or NEC. There were also higher odds of the composite outcome, mortality and bronchopulmonary dysplasia among infants with perforation (focal/SIP or NEC related) compared with neonates with NEC without perforation. There were higher odds of both the composite outcome and all secondary outcomes among infants with perforation (focal/SIP or NEC related) compared with those without NEC or perforation. Planned subgroup analyses of infants born at o 28 weeks’ gestation (n = 4857) revealed that focal/SIP occurred in 2.3%, NECrelated perforation in 3.4% and NEC in 6.1%. Results of multivariate analyses indicated similar results to those for the entire cohort as described above. DISCUSSION In this large population-based cohort of very preterm infants, we identified that rate of focal/SIP in preterm infants born at o32 weeks’ gestation is 1% and NEC-related perforation is 1.4%. The rate of a composite outcome of mortality or neonatal morbidity was significantly lower for focal/SIP compared with NEC-related perforation, which was mainly related to lower mortality prior to discharge. Focal/SIP was associated with twofold to fourfold higher odds of the composite outcome, mortality, © 2015 Nature America, Inc.
Intestinal perforation in very preterm neonates J Shah et al
3 bronchopulmonary dysplasia, severe retinopathy of prematurity and nosocomial infection compared with infants without NEC or perforation. Any intestinal perforation was associated with
eightfold higher odds of a composite outcome of mortality or major morbidity compared with infants without NEC or perforation after adjusting for risk factors and confounders.
Figure 1. Flow chart of the neonates included in the study. NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; SIP, spontaneous intestinal perforation.
Table 1.
Maternal and infant characteristics of the study population
Characteristics
Focal/SIP (A), n = 178
NEC with perforation (B), n = 246
NEC, no perforation (C), n = 538
P-valuesa
No NEC, no perforation (D), n = 16 464
A vs B A vs B+C A vs D A+B vs C A+B vs D Maternal age, mean (s.d.) Illicit drugs, n (%) Smoking, n (%) Hypertension, n (%) Diabetes, n (%) Chorioamnionitis, n (%) Antenatal steroid, n (%) Antibiotics during labor, n (%) Cesarean birth, n (%) Apgar score o 7 at 5 min, n (%) SNAPII score 420, n (%) Gestational age (weeks), mean (s.d.) Birth weight (g), mean (s.d.) Small for gestational age, n (%) Male, n (%) Outborn, n (%) Prophylactic indomethacin, n (%) Therapeutic indomethacin or ibuprofen, n (%) Inotropes in first 7 days, n (%) Hydrocortisone in first 7 days, n (%) Patent ductus arteriosus, n (%) Grade 3/4 intraventricular hemorrhage, n (%)
30.7 5 34 25 19 33 139 116 108 80 71 26.9 991 22 105 43 18 63
(5.9) (2.8) (19.1) (14.7) (11.7) (25.2) (83.7) (72.1) (60.7) (46.5) (40.6) (2.8) (392) (12.4) (59.0) (24.2) (10.1) (35.4)
30.6 11 34 28 23 52 205 177 127 97 99 26.6 983 24 143 47 29 91
(6.6) (4.5) (13.8) (11.7) (10.0) (28.6) (86.1) (76.0) (51.8) (39.8) (40.2) (2.6) (379) (9.8) (58.1) (19.1) (11.8) (37.0)
30.5 31 85 86 63 94 465 356 326 185 141 27.5 1110 57 320 98 35 170
(5.9) (5.8) (15.8) (16.5) (12.4) (24.2) (89.6) (70.6) (60.7) (34.9) (26.3) (2.4) (429) (10.6) (59.7) (18.2) (6.5) (31.6)
30.9 742 2323 3026 1802 2210 13943 10772 9695 4156 2385 29.1 1348 1571 8929 2571 417 2495
(5.9) (4.5) (14.1) (19.0) (11.4) (18.6) (87.1) (69.4) (59.1) (25.6) (14.7) (2.5) (452) (9.6) (54.3) (15.6) (2.5) (15.2)
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
NS NS NS NS NS NS NS NS NS 0.01 0.01 NS 0.02 NS NS NS NS NS
NS NS NS NS NS 0.05 NS NS NS o0.01 o0.01 o0.01 o0.01 NS NS o0.01 o0.01 o0.01
NS NS NS NS NS NS 0.04 NS NS 0.02 o0.01 o0.01 o0.01 NS NS NS 0.01 NS
NS NS NS o0.01 NS o0.01 NS 0.03 NS o0.01 o0.01 o0.01 o0.01 NS NS o0.01 o0.01 o0.01
59 13 112 45
(33.2) (7.3) (62.9) (27.4)
71 10 134 55
(28.9) (4.1) (55.8) (23.7)
90 11 267 67
(16.7) (2.0) (49.6) (13.0)
1457 260 4316 987
(8.9) (1.6) (26.5) (7.4)
NS NS NS NS
o0.01 o0.01 0.01 o0.01
o0.01 o0.01 o0.01 o0.01
o0.01 o0.01 o0.01 o0.01
o0.01 o0.01 o0.01 o0.01
Abbeviations: NEC, necrotizing enterocolitis; NS, non significant; SIP, spontaneous intestinal perforation; SNAPII, Score of Neonatal Acute Physiology, version II. a Significance tested using Student’s t-test and Pearson chi-square test for continuous and categorical variables, respectively.
© 2015 Nature America, Inc.
Journal of Perinatology (2015), 1 – 6
Intestinal perforation in very preterm neonates J Shah et al
4 Table 2.
Univariate comparison of outcomes
Outcomes, n (%)
Focal/SIP (A), n = 178
NEC with perforation (B), n = 246
NEC, no perforation (C), n = 538
P-valuesa
No NEC, no perforation (D), n = 16 464
A vs B A vs B+C A vs D A+B vs C A+B vs D Primary outcome Mortality or major morbidity Secondary outcomes Mortality Bronchopulmonary dysplasia Periventricular leukomalacia Severe retinopathy of prematurity Nosocomial infection
128 (71.9) 44 64 13 24
(24.7) (45.4) (7.9) (25.8)
66 (37.1)
214 (87.0)
351 (65.2)
4571 (27.8)
o 0.01
NS
o0.01 o 0.01
o0.01
124 72 27 25
101 161 29 64
902 2424 372 464
o 0.01 NS NS NS
NS NS NS NS
o0.01 o 0.01 o0.01 o 0.01 o0.01 0.01 o0.01 0.10
o0.01 o0.01 o0.01 o0.01
NS
NS
o0.01
o0.01
(50.4) (53.7) (11.6) (22.5)
112 (45.5)
(18.8) (35.2) (5.7) (18.2)
209 (38.9)
(5.5) (15.8) (2.8) (7.2)
1782 (10.8)
NS
a
Abbreviations: NEC, necrotizing enterocolitis; NS, not significant; SIP, spontaneous intestinal perforation. Significance tested using Student’s t-test.
Table 3.
Multivariate analyses of outcomes Adjusted odds ratios (95% CI)a
Outcomes Focal/SIP vs NEC with perforation
Focal/SIP vs NEC (with and without perforation)
SIP vs no NEC, no perforation
All perforation vs NEC without perforation
All perforation vs no NEC, no perforation
Primary outcome Mortality or major morbidity
0.29 (0.17, 0.51)b
0.72 (0.48, 1.09)
4.23 (2.88, 6.20)b
1.78 (1.28, 2.47)b
8.21 (6.26, 10.8)b
Secondary outcomes Mortality Bronchopulmonary dysplasia Periventricular leukomalacia Severe retinopathy of prematurity Nosocomial infections
0.29 0.68 0.59 1.11 0.72
0.68 1.12 0.84 1.26 0.81
2.78 2.84 1.62 3.14 3.54
(0.18, (0.41, (0.28, (0.55, (0.48,
0.46)b 1.15) 1.24) 2.25) 1.08)
(0.45, (0.74, (0.42, (0.72, (0.57,
1.02) 1.69) 1.66) 2.19) 1.16)
(1.80, (1.93, (0.85, (1.88, (2.54,
4.28)b 4.20)b 3.07) 5.26)b 4.94)b
2.47 1.61 1.56 1.19 1.06
(1.82, (1.16, (0.93, (0.76, (0.81,
3.38)b 2.24)b 2.63) 1.86) 1.40)
8.29 3.59 2.48 2.92 4.45
(6.41, (2.73, (1.71, (2.03, (3.59,
10.7)b 4.71)b 3.59)b 4.18)b 5.50)b
Abbreviations: CI, confidence interval; NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation. aAll models adjusted by use of prophylactic indomethacin, use of antenatal steroids, use of inotropes in the first week after birth, small for gestational age status and severity of illness on admission (SNAPII (Score of Neonatal Acute Physiology, version II) score 420). bIndicates Po0.05.
Distinguishing between focal/SIP and NEC-related perforation is important for prognosis and counselling. Our findings of lower mortality in focal/SIP compared with NECrelated perforation are consistent with previous reports. In recent analyses of data from the Vermont Oxford Network, Fisher et al.15 reported a 1.1% incidence of focal/SIP and a 2.3% incidence of NEC-related perforation. The study also reported a nearly twofold mortality rate in NEC-related perforation compared with focal/SIP, similar to our findings and those of others.2 This may be due to lower inflammatory load21 following focal/SIP as compared with NEC-related perforation and the relatively stable hemodynamic condition of patients with focal/SIP. Similar to several reports in the literature, we were also able to demonstrate previously reported associations of focal/SIP with lower gestational age,1,4–6 lower birth weight,1,4,5 younger postnatal age,1,4–6 exposure to indomethacin,1,2,6,7 exposure to postnatal steroids,1,7,8,22 hypotension requiring inotropes4 in the first week after birth and staphylococcal3,9,13 and Candidial sepsis.3,9 As far as indomethacin is concerned, early use23 or use to prevent intraventricular hemorrhage has been shown to be associated with focal SIP in some studies15,24 but not in others.12 Sharma et al.24 reported that therapeutic indomethacin had a protective effect on NEC, whereas Wadhwan et al.12 reported that Journal of Perinatology (2015), 1 – 6
it was associated with focal/SIP. We did not identify any difference in therapeutic indomethacin use between those who had focal/SIP vs those who had NEC-related perforation. However, no maternal factors such as age, hypertension, chorioamnionitis and antenatal steroid use25 or neonatal factors such as gender9,25 and smallfor-gestational status were significantly different in our cohort, which is discordant with some previous reports. In an observational study1,26 at 16 tertiary centers in the United States, it was identified that among infants with perforation 50% underwent laparotomy and the remaining underwent surgery. In our study, 70% of those who had focal/SIP underwent surgery, which could be due to the fact that focal/SIP has been recognized as a local disease for which primary repair is likely to be the treatment of choice27 if a patient is otherwise stable. Recently, Mehrar et al.28 reported a significantly higher rate of brain lesions in patients with intestinal perforation compared with those without perforation, indicating the likelihood of neurodevelopmental impairment. We identified no significant difference between focal/SIP group and NEC (perforation and all) with reference to cystic PVL. Our findings are different than those of Attridge et al.29 The difference could be due to us including all forms of PVL, whereas Attridge et al.29 included only cystic PVL, or it could just be a matter of small sample size as the incidence of © 2015 Nature America, Inc.
Intestinal perforation in very preterm neonates J Shah et al
5 cystic PVL is very low in current era. However, studies of neurodevelopmental outcomes following focal/SIP have been conflicting. Although Wadhwan et al.12 reported that focal/SIP was associated with an increased risk of poor neurodevelopmental outcomes, Shah et al.14 reported that there was no difference in long-term neurodevelopmental outcomes among extremely low birth weight neonates with medical NEC, surgical NEC and focal/ SIP. Unfortunately, long-term neurodevelopmental data were not available in this cohort. However, we observed twofold to threefold increase in rates of PVL in neonates with NEC or perforation compared with those who did not have NEC nor perforation. In animal models, the risk factors for focal/SIP identified above have been shown to demonstrate a cumulative effect.30 The signaling pathways for nitric oxide synthase, epidermal growth factor and insulin-like growth factor are affected, which results in altered trophism of the ileum, thinning of intestinal submucosa and hyperplasia of mucosa. Reduction in nitric oxide synthase leads to disturbed intestinal motility and makes the distal intestine vulnerable to perforation.30 In typical cases of focal/SIP, there is focal necrosis of the muscularis externa3,24,31 without any evidence of ischemia or coagulative necrosis.6,30 Tatekawa et al.32 reported thinning of intestinal musculature near the site of focal perforations, further supporting alteration of trophism. In a histological examination, Lai et al.27 also reported that in patients with focal/SIP the thickness of the muscularis propria was attenuated at the site of perforation, whereas the remaining intestine was normal. These findings suggest that focal/SIP is a disease of focal alteration and, unless associated with a widespread inflammatory response, will result in lower mortality compared with NEC-related perforations. The strengths of our study include the use of a populationbased cohort, detailed and meticulous data collection, data regarding availability of risk factors for intestinal perforation and a large sample size that allowed us to conduct adjusted analyses. However, we must acknowledge the limitations. We did not collect data on the method of confirmation of a diagnosis of focal/ SIP vs NEC-related perforation. However, 70% of our patients in the perforation group underwent a laparotomy, where confirmatory evidence was obtained. The remaining cases were diagnosed based on the clinical evaluation of the medical team. We did not have details regarding the clinical status of infants when a perforation was diagnosed, which may have had a significant role in the subsequent development of morbidities and mortality. Our data indicated that severity of illness at admission was significantly higher for both infants with focal/SIP and those with NECrelated perforation. As such, we adjusted our analyses for severity of illness at admission. We were not able to collect data on neurodevelopmental outcomes in these neonates, which would have been very useful information for counselling parents at the time of perforation. Finally, we adjusted for many risk factors and confounders; however, the issue of residual confounding remains. CONCLUSIONS Intestinal perforation, both focal/SIP and NEC-related, is associated with higher odds of neonatal mortality and morbidities compared with patients without perforation or NEC; however, there were lower odds of mortality in infants with focal/SIP compared with those with NEC-related perforation. Many of the common neonatal morbidities were higher among infants with perforation, suggesting the possible release of inflammatory markers even following focal perforation. Future studies should investigate the impact of perforation on neurodevelopmental outcomes during childhood. In addition, predicting which infants are at high risk of intestinal perforation should be a further avenue for research, as © 2015 Nature America, Inc.
prevention of perforation would be important to prevent adverse outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS We thank the staff of the Canadian Neonatal Network Coordinating Centre for their hard work, Mr Junmin Yang for statistical support and Dr Ruth Warre for providing editorial support during preparation of the manuscript. Although no funding was received specifically for this study, the Canadian Neonatal Network (CNN) received organizational support from the CNN Coordinating Centre, which is based at the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital, Toronto, Ontario, Canada. MiCare is supported by funding from the Canadian Institutes of Health Research and Mount Sinai Hospital, Toronto.
REFERENCES 1 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006; 26: 93–99. 2 Buchheit JQ, Stewart DL. Clinical comparison of localized intestinal perforation and necrotizing enterocolitis in neonates. Pediatrics 1994; 93: 32–36. 3 Novack CM, Waffarn F, Sills JH, Pousti TJ, Warden MJ, Cunningham MD. Focal intestinal perforation in the extremely-low-birth-weight infant. J Perinatol 1994; 14: 450–453. 4 Adderson EE, Pappin A, Pavia AT. Spontaneous intestinal perforation in premature infants: a distinct clinical entity associated with systemic candidiasis. J Pediatr Surg 1998; 33: 1463–1467. 5 Okuyama H, Kubota A, Oue T, Kuroda S, Ikegami R, Kamiyama M. A comparison of the clinical presentation and outcome of focal intestinal perforation and necrotizing enterocolitis in very-low-birth-weight neonates. Pediatr Surg Int 2002; 18: 704–706. 6 Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 2002; 195: 796–803. 7 Attridge JT, Clark R, Gordon PV. New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation. J Perinatol 2006; 26: 667–670. 8 Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999; 19: 573–577. 9 Holland AJ, Shun A, Martin HC, Cooke-Yarborough C, Holland J. Small bowel perforation in the premature neonate: congenital or acquired? Pediatr Surg Int 2003; 19: 489–494. 10 Paquette L, Friedlich P, Ramanathan R, Seri I. Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous intestinal perforation in very low birth weight neonates. J Perinatol 2006; 26: 486–492. 11 Alpan G, Eyal F, Vinograd I, Udassin R, Amir G, Mogle P et al. Localized intestinal perforations after enteral administration of indomethacin in premature infants. J Pediatr 1985; 106: 277–281. 12 Wadhawan R, Oh W, Vohr BR, Saha S, Das A, Bell EF et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age. Arch Dis Child Fetal Neonatal Ed 2013; 98: F127–F132. 13 Meyer CL, Payne NR, Roback SA. Spontaneous, isolated intestinal perforations in neonates with birth weight less than 1,000 g not associated with necrotizing enterocolitis. J Pediatr Surg 1991; 26: 714–717. 14 Shah TA, Meinzen-Derr J, Gratton T, Steichen J, Donovan EF, Yolton K et al. Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation. J Perinatol 2012; 32: 552–558. 15 Fisher JG, Jones BA, Gutierrez IM, Hull MA, Kang KH, Kenny M et al. Mortality associated with laparotomy-confirmed neonatal spontaneous intestinal perforation: A prospective 5-year multicenter analysis. J Pediatr Surg 2014; 49: 1215–1219. 16 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179–201. 17 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82: 527–532.
Journal of Perinatology (2015), 1 – 6
Intestinal perforation in very preterm neonates J Shah et al
6 18 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005; 123: 991–999. 19 Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA. Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care. Pediatrics 1993; 91: 617–623. 20 Canadian Neonatal Network. Canadian Neonatal Network Abstractor's Manual. v 2.1.2, 1–94, 2014. Canadian Neonatal Network. Toronto, Canada. Available from http://www.canadianneonatalnetwork.org/portal/CNNHome/Publications.aspx (last accessed: 26 September 2014). 21 Bhatia AM, Stoll BJ, Cismowski MJ, Hamrick SE. Cytokine levels in the preterm infant with neonatal intestinal injury. Am J Perinatol 2014; 31: 489–496. 22 De Laet MH, Dassonville M, Johansson A, Lerminiaux C, Seghers V, Van den Eijnden S et al. Small-bowel perforation in very low birth weight neonates treated with high-dose dexamethasone. Eur J Pediatr Surg 2000; 10: 323–327. 23 Shorter NA, Liu JY, Mooney DP, Harmon BJ. Indomethacin-associated bowel perforations: a study of possible risk factors. J Pediatr Surg 1999; 34: 442–444. 24 Sharma R, Hudak ML, Tepas JJ III, Wludyka PS, Teng RJ, Hastings LK et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 2010; 30: 786–793. 25 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006; 26: 185–188.
26 Blakely ML, Lally KP, McDonald S, Brown RL, Barnhart DC, Ricketts RR et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005; 241: 984–989. 27 Lai S, Yu W, Wallace L, Sigalet D. Intestinal muscularis propria increases in thickness with corrected gestational age and is focally attenuated in patients with isolated intestinal perforations. J Pediatr Surg 2014; 49: 114–119. 28 Merhar SL, Ramos Y, Meinzen-Derr J, Kline-Fath BM. Brain magnetic resonance imaging in infants with surgical necrotizing enterocolitis or spontaneous intestinal perforation versus medical necrotizing enterocolitis. J Pediatr 2014; 164: 410–412. 29 Attridge JT, Zanelli SA, Gurka MJ, Kaufman DA. Randomized controlled trials need stratification by types of acquired neonatal intestinal diseases. e-J Neonatol Res 2011; 1(2): 59–64. 30 Gordon PV. Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res 2009; 65: 138–144. 31 Mintz AC, Applebaum H. Focal gastrointestinal perforations not associated with necrotizing enterocolitis in very low birth weight neonates. J Pediatr Surg 1993; 28: 857–860. 32 Tatekawa Y, Muraji T, Imai Y, Nishijima E, Tsugawa C. The mechanism of focal intestinal perforations in neonates with low birth weight. Pediatr Surg Int 1999; 15: 549–552.
APPENDIX Site investigators for the Canadian Neonatal Network Prakesh S Shah (Director, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario; Adele Harrison, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, British Columbia Children’s Hospital, Vancouver, British Columbia; Zenon Cieslak, Royal Columbian Hospital, New Westminster, British Columbia; Todd Sorokan, Surrey Memorial Hospital, Surrey, British Columbia; Wendy Yee, Foothills Medical Centre, Calgary, Alberta; Khalid Aziz, Royal Alexandra Hospital, Edmonton, Alberta; Zarin Kalapesi, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Ruben Alvaro, St Boniface General Hospital, Winnipeg, Manitoba; Sandesh Shivananda, Hamilton Health Sciences Centre, Hamilton, Ontario; Orlando Da Silva, London Health Sciences Centre, London, Ontario; Chuks Nwaesei, Windsor Regional Hospital, Windsor, Ontario; Kyong-Soon Lee, Hospital for Sick Children, Toronto, Ontario; Prakesh Shah, Mount Sinai Hospital, Toronto, Ontario; Michael
Dunn, Sunnybrook Health Sciences Centre, Toronto, Ontario; Nicole Rouvinez-Bouali, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; Kimberly Dow, Kingston General Hospital, Kingston, Ontario; Ermelinda Pelausa, Jewish General Hospital, Montréal, Québec; Keith Barrington, Hôpital Sainte-Justine, Montréal, Québec; Christine Drolet, Centre Hospitalier Universitaire de Québec, Sainte Foy, Patricia Riley, Montréal Children’s Hospital, Montréal, Québec; Daniel Faucher, Royal Victoria Hospital, Montréal, Québec; Valerie Bertelle, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Rody Canning, Moncton Hospital, Moncton, New Brunswick; Barbara Bulleid, Dr Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah and Luis Monterrosa, Saint John Regional Hospital, Saint John, New Brunswick; Akhil Deshpandey, Janeway Children’s Health and Rehabilitation Centre, St John’s, Newfoundland; Jehier Afifi, IWK Health Centre, Halifax, Nova Scotia; Andrzej Kajetanowicz, Cape Breton Regional Hospital, Sydney, Nova Scotia; Shoo K Lee (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.
Journal of Perinatology (2015), 1 – 6
© 2015 Nature America, Inc.
ORIGINAL ARTICLE
Intestinal perforation in very preterm neonates: risk factors and outcomes J Shah1, N Singhal2, O da Silva3, N Rouvinez-Bouali4, M Seshia5, SK Lee1,6 and PS Shah1,6 on behalf of the Canadian Neonatal Network7 OBJECTIVE: To compare neonatal outcomes of preterm infants (born at o32 weeks’ gestation) with focal/spontaneous intestinal perforation (SIP), necrotizing enterocolitis (NEC)-related perforation, NEC without perforation or no NEC/perforation. STUDY DESIGN: Retrospective cohort study of 17 426 infants admitted to Canadian neonatal intensive care units during 2010 to 2013. The primary outcome was a composite of mortality or morbidity (bronchopulmonary dysplasia, severe retinopathy, periventricular leukomalacia or nosocomial infection). Association of intestinal perforation with neonatal outcome was evaluated using multivariate logistic regression. RESULT: SIP was present in 178 (1.0%) infants, NEC-related perforation in 246 (1.4%) and NEC without perforation in 538 (3.1%). Any intestinal perforation was associated with higher odds of the composite outcome (adjusted odds ratio (AOR): 8.21, 95% confidence interval (95% CI) 6.26 to 10.8); however, the odds were significantly lower for focal/SIP compared with NEC-related perforation (AOR: 0.29, 95% CI 0.17 to 0.51). CONCLUSION: Of the two types of intestinal perforation, NEC-related perforation was associated with the highest risk of an adverse neonatal outcome. Journal of Perinatology advance online publication, 30 April 2015; doi:10.1038/jp.2015.41
INTRODUCTION Intestinal perforation in neonates, especially preterm infants, is an uncommon yet well-recognized entity.1,2 There are two major types of intestinal perforation, necrotizing enterocolitis (NEC)related and focal or spontaneous intestinal perforation (SIP). Although they affect the same organ and are commonly seen in extremely low birth weight and low gestational age infants, the two types of perforation are separate and distinct clinical and pathological entities.2,3 Perforation associated with NEC has been classified as stage 3 NEC with classic preceding signs of abdominal distension, intestinal ischemia and with or without pneumatosis intestinalis. Focal/SIP occurs in relatively younger and lower birth weight infants and usually happens at around 7 days of postnatal age, which is earlier in the postnatal period than in classic NEC.1,2,4–6 Histologically NEC is associated with coagulative necrosis involving a large area of intestine, whereas focal/SIP is associated with hemorrhagic necrosis involving a small focal lesion.6 Clinical characteristics associated with focal/SIP include bluish discoloration and gasless abdomen in the absence of pneumatosis.4,6 Focal/SIP is perceived to occur secondary to immaturity, postnatal exposure to dexamethasone1,7–10 or indomethacin,1,2,6,7,9–12 hypotension (reflected by need for inotropes),1,4 leukocytosis,4 candidiasis,3,4,9 staphylococcus epidermidis infection,3,9,13 placement of an umbilical arterial catheter2 or the presence of patent ductus arteriosus.1 Neonatal mortality has been reported to be higher in infants with SIP and NEC-related perforation than in those without
perforation.14 Mortality has also been reported to be lower among infants with SIP compared with those with surgical NEC;2,15 however, reports of other neonatal morbidities are scant and most studies are of small sample size. It is perceived that infants with SIP are in better condition at the time of diagnosis compared with those with NEC-related perforation and are likely to recover well without significant neonatal impact; however, data are lacking in this regard. Our objective was to compare mortality and neonatal morbidities among very preterm infants born at o32 weeks’ gestation who had focal/SIP, NEC-related perforation or NEC without perforation and infants without NEC or focal/SIP using a population-based data set. STUDY DESIGN AND METHODS Study design This retrospective cohort study included preterm infants of o32 weeks’ gestation admitted between 1 January 2010 and 31 December 2013 to neonatal intensive care units (NICUs) participating in the Canadian Neonatal Network. Study population comprised of 490% of all neonates of o32 weeks’ gestation admitted to NICUs in Canada. Infants with a major congenital anomaly (defined as life-threatening anomaly or one that untreated could affect physical and/or neurodevelopmental outcomes) and infants who were moribund on admission (for whom either no resuscitation was offered or palliative care at birth was
1 Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 2Department of Pediatrics, Foothills Hospital, University of Calgary, Calgary, AB, Canada; 3Department of Pediatrics, London Health Sciences Center, University of Western Ontario, London, ON, Canada; 4Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa University, Ottawa, ON, Canada; 5Department of Pediatrics, Winnipeg Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada and 6MaternalInfant Care Research Centre, Mount Sinai Hospital, Toronto, ON, Canada. Correspondence: Dr PS Shah, Department of Pediatrics, Mount Sinai Hospital, University of Toronto, Room 19-231F, Toronto, ON M5G 1X5, Canada. E-mail: [email protected] 7 See Appendix. Received 30 December 2014; revised 3 March 2015; accepted 23 March 2015
Intestinal perforation in very preterm neonates J Shah et al
2 planned) were excluded. Eligible infants were divided into four groups according to their diagnosis: (1) Focal/SIP; (2) NEC-related perforation; (3) NEC but no perforation; and (4) no NEC or SIP. Diagnosis of NEC was based on modified Bell’s staging of stages 2 and 3.16 Focal/SIP was diagnosed according to local practices based on lack of clinical features of NEC, radiological finding of perforation, absence of radiological features of intestinal ischemia (fixed dilated bowel loops, pneumatosis intestinalis and so on) and/or intra-operative surgical report and/or histopathology where perforation was located in the ileum and on the antimesentric border. Data were collected by local sites regarding reason for perforation; however, details of diagnostic criteria were not collected in the data set. Outcomes Our primary outcome was a composite of mortality or any of the following major morbidities: (1) bronchopulmonary dysplasia defined as the need for oxygen at 36 weeks postmenstrual age17 or at discharge or transfer; (2) periventricular leukomalacia (PVL) diagnosed using neuroimaging after 21 days of age; (3) severe retinopathy of prematurity defined as 4stage 2 retinopathy according to the International Classification18 or surgery for retinopathy; and (4) nosocomial infection defined as clinical signs of sepsis and a positive bacterial culture from blood or cerebrospinal fluid. Our secondary outcomes included the individual components of the composite outcome. Definitions Gestational age was defined as the best estimate based on date of in vitro fertilization, early ultrasound, last menstrual period, obstetric estimate or pediatric estimate, in that hierarchical order. Severity of illness at admission was defined using the Score of Neonatal Acute Physiology II (SNAPII) score.19 Prophylactic indomethacin was defined as use of indomethacin within the first 24 h of birth for the purpose of preventing intraventricular hemorrhage. Small for gestational age was defined as birth weight o10th centile for gestational age and sex. Therapeutic indomethacin was defined as use of indomethacin for the purpose of treatment of a symptomatic patent ductus arteriosus. Data collection and ethics Trained abstractors collected data from patient charts throughout each infant’s NICU stay according to a standard protocol. Data were entered electronically into a data-entry program with built-in error-checking.20 Data on maternal and infant characteristics, predisposing factors and neonatal outcomes were then retrieved from the network database for analysis. Ethics approval was granted at each site by either the local Research Ethics Board or through an institutional quality improvement process for data collection and benchmarking. The study was approved by the executive committee of the Canadian Neonatal Network. Statistical analyses Maternal and infant characteristics were compared between the four groups individually and between combinations of the groups (for example, all perforations vs NEC without perforation and all perforations vs no NEC, no perforations) using Student’s t-test or the Mann–Whitney test for continuous outcomes and the chisquare test for categorical outcomes, as appropriate. Predictors of special interest were use of prophylactic indomethacin, receipt of antenatal steroid, postnatal use of hydrocortisone in the first week after birth, use of inotropes in the first week after birth, small-forgestational-age status and SNAPII score. Multivariate logistic regression models were applied to identify the impact of the covariates on the primary and secondary outcomes. A P-value of o0.05 was considered significant. Journal of Perinatology (2015), 1 – 6
RESULTS Out of the 17 426 eligible infants, 178 (1.0%) developed focal/SIP, 246 (1.4%) developed NEC-related perforation, 538 (3.1%) developed NEC without perforation and the remaining 16 464 (94.5%) had neither NEC nor focal/SIP (Figure 1). Of the infants with focal/ SIP, 122 (69%) received surgical management (27 deaths). Of the infants with NEC-related perforation, 113 received surgery (45 deaths), 33 had drain followed by surgery (18 deaths), 36 had only drain (27 deaths) and for 64 data regarding surgery or drain were not recorded owing to transfers (34 deaths). Of the infants with NEC without perforation, 106 received surgery (33 deaths), 9 had drain for ascites followed by surgery (4 deaths), 16 had only drain for ascites (7 deaths) and 407 did not receive surgery (57 deaths). Table 1 reports the maternal and infant characteristics of the study population. There were no significant differences between the characteristics of the infants with focal/SIP and those with NEC-related perforation. However, compared with infants without perforation, those with perforation of either cause had higher SNAPII scores and lower Apgar scores, were of younger gestation and had lower birth weights. A higher number of infants with perforations also received therapeutic indomethacin, hydrocortisone in the first week of birth and inotropes in the first week. The rate of patent ductus arteriosus was also higher in infants with perforations. Table 2 includes univariate comparisons of the composite and secondary outcome rates. The rate of the composite outcome was significantly lower among infants with focal/SIP compared with those with NEC-related perforation, which was mostly due to the low mortality rate among infants with focal/SIP. The rates of the composite outcome and the majority of other outcomes were significantly higher in infants with perforation compared with those with NEC without perforation and the control (no NEC, no perforation) group. Table 3 reports the results of multivariate analyses after adjustment for confounders and risk factors. After adjustment, the reduced odds of the composite outcome due to lower mortality remained in infants with focal/SIP compared with those with NEC-related perforation. There was no difference in the primary or any secondary outcomes between infants with focal/ SIP and those with NEC (with perforation and without perforation combined). With the exception of PVL, there were significantly higher odds of the composite and individual secondary outcomes among patients who had focal/SIP compared with infants without perforation or NEC. There were also higher odds of the composite outcome, mortality and bronchopulmonary dysplasia among infants with perforation (focal/SIP or NEC related) compared with neonates with NEC without perforation. There were higher odds of both the composite outcome and all secondary outcomes among infants with perforation (focal/SIP or NEC related) compared with those without NEC or perforation. Planned subgroup analyses of infants born at o 28 weeks’ gestation (n = 4857) revealed that focal/SIP occurred in 2.3%, NECrelated perforation in 3.4% and NEC in 6.1%. Results of multivariate analyses indicated similar results to those for the entire cohort as described above. DISCUSSION In this large population-based cohort of very preterm infants, we identified that rate of focal/SIP in preterm infants born at o32 weeks’ gestation is 1% and NEC-related perforation is 1.4%. The rate of a composite outcome of mortality or neonatal morbidity was significantly lower for focal/SIP compared with NEC-related perforation, which was mainly related to lower mortality prior to discharge. Focal/SIP was associated with twofold to fourfold higher odds of the composite outcome, mortality, © 2015 Nature America, Inc.
Intestinal perforation in very preterm neonates J Shah et al
3 bronchopulmonary dysplasia, severe retinopathy of prematurity and nosocomial infection compared with infants without NEC or perforation. Any intestinal perforation was associated with
eightfold higher odds of a composite outcome of mortality or major morbidity compared with infants without NEC or perforation after adjusting for risk factors and confounders.
Figure 1. Flow chart of the neonates included in the study. NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; SIP, spontaneous intestinal perforation.
Table 1.
Maternal and infant characteristics of the study population
Characteristics
Focal/SIP (A), n = 178
NEC with perforation (B), n = 246
NEC, no perforation (C), n = 538
P-valuesa
No NEC, no perforation (D), n = 16 464
A vs B A vs B+C A vs D A+B vs C A+B vs D Maternal age, mean (s.d.) Illicit drugs, n (%) Smoking, n (%) Hypertension, n (%) Diabetes, n (%) Chorioamnionitis, n (%) Antenatal steroid, n (%) Antibiotics during labor, n (%) Cesarean birth, n (%) Apgar score o 7 at 5 min, n (%) SNAPII score 420, n (%) Gestational age (weeks), mean (s.d.) Birth weight (g), mean (s.d.) Small for gestational age, n (%) Male, n (%) Outborn, n (%) Prophylactic indomethacin, n (%) Therapeutic indomethacin or ibuprofen, n (%) Inotropes in first 7 days, n (%) Hydrocortisone in first 7 days, n (%) Patent ductus arteriosus, n (%) Grade 3/4 intraventricular hemorrhage, n (%)
30.7 5 34 25 19 33 139 116 108 80 71 26.9 991 22 105 43 18 63
(5.9) (2.8) (19.1) (14.7) (11.7) (25.2) (83.7) (72.1) (60.7) (46.5) (40.6) (2.8) (392) (12.4) (59.0) (24.2) (10.1) (35.4)
30.6 11 34 28 23 52 205 177 127 97 99 26.6 983 24 143 47 29 91
(6.6) (4.5) (13.8) (11.7) (10.0) (28.6) (86.1) (76.0) (51.8) (39.8) (40.2) (2.6) (379) (9.8) (58.1) (19.1) (11.8) (37.0)
30.5 31 85 86 63 94 465 356 326 185 141 27.5 1110 57 320 98 35 170
(5.9) (5.8) (15.8) (16.5) (12.4) (24.2) (89.6) (70.6) (60.7) (34.9) (26.3) (2.4) (429) (10.6) (59.7) (18.2) (6.5) (31.6)
30.9 742 2323 3026 1802 2210 13943 10772 9695 4156 2385 29.1 1348 1571 8929 2571 417 2495
(5.9) (4.5) (14.1) (19.0) (11.4) (18.6) (87.1) (69.4) (59.1) (25.6) (14.7) (2.5) (452) (9.6) (54.3) (15.6) (2.5) (15.2)
NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS
NS NS NS NS NS NS NS NS NS 0.01 0.01 NS 0.02 NS NS NS NS NS
NS NS NS NS NS 0.05 NS NS NS o0.01 o0.01 o0.01 o0.01 NS NS o0.01 o0.01 o0.01
NS NS NS NS NS NS 0.04 NS NS 0.02 o0.01 o0.01 o0.01 NS NS NS 0.01 NS
NS NS NS o0.01 NS o0.01 NS 0.03 NS o0.01 o0.01 o0.01 o0.01 NS NS o0.01 o0.01 o0.01
59 13 112 45
(33.2) (7.3) (62.9) (27.4)
71 10 134 55
(28.9) (4.1) (55.8) (23.7)
90 11 267 67
(16.7) (2.0) (49.6) (13.0)
1457 260 4316 987
(8.9) (1.6) (26.5) (7.4)
NS NS NS NS
o0.01 o0.01 0.01 o0.01
o0.01 o0.01 o0.01 o0.01
o0.01 o0.01 o0.01 o0.01
o0.01 o0.01 o0.01 o0.01
Abbeviations: NEC, necrotizing enterocolitis; NS, non significant; SIP, spontaneous intestinal perforation; SNAPII, Score of Neonatal Acute Physiology, version II. a Significance tested using Student’s t-test and Pearson chi-square test for continuous and categorical variables, respectively.
© 2015 Nature America, Inc.
Journal of Perinatology (2015), 1 – 6
Intestinal perforation in very preterm neonates J Shah et al
4 Table 2.
Univariate comparison of outcomes
Outcomes, n (%)
Focal/SIP (A), n = 178
NEC with perforation (B), n = 246
NEC, no perforation (C), n = 538
P-valuesa
No NEC, no perforation (D), n = 16 464
A vs B A vs B+C A vs D A+B vs C A+B vs D Primary outcome Mortality or major morbidity Secondary outcomes Mortality Bronchopulmonary dysplasia Periventricular leukomalacia Severe retinopathy of prematurity Nosocomial infection
128 (71.9) 44 64 13 24
(24.7) (45.4) (7.9) (25.8)
66 (37.1)
214 (87.0)
351 (65.2)
4571 (27.8)
o 0.01
NS
o0.01 o 0.01
o0.01
124 72 27 25
101 161 29 64
902 2424 372 464
o 0.01 NS NS NS
NS NS NS NS
o0.01 o 0.01 o0.01 o 0.01 o0.01 0.01 o0.01 0.10
o0.01 o0.01 o0.01 o0.01
NS
NS
o0.01
o0.01
(50.4) (53.7) (11.6) (22.5)
112 (45.5)
(18.8) (35.2) (5.7) (18.2)
209 (38.9)
(5.5) (15.8) (2.8) (7.2)
1782 (10.8)
NS
a
Abbreviations: NEC, necrotizing enterocolitis; NS, not significant; SIP, spontaneous intestinal perforation. Significance tested using Student’s t-test.
Table 3.
Multivariate analyses of outcomes Adjusted odds ratios (95% CI)a
Outcomes Focal/SIP vs NEC with perforation
Focal/SIP vs NEC (with and without perforation)
SIP vs no NEC, no perforation
All perforation vs NEC without perforation
All perforation vs no NEC, no perforation
Primary outcome Mortality or major morbidity
0.29 (0.17, 0.51)b
0.72 (0.48, 1.09)
4.23 (2.88, 6.20)b
1.78 (1.28, 2.47)b
8.21 (6.26, 10.8)b
Secondary outcomes Mortality Bronchopulmonary dysplasia Periventricular leukomalacia Severe retinopathy of prematurity Nosocomial infections
0.29 0.68 0.59 1.11 0.72
0.68 1.12 0.84 1.26 0.81
2.78 2.84 1.62 3.14 3.54
(0.18, (0.41, (0.28, (0.55, (0.48,
0.46)b 1.15) 1.24) 2.25) 1.08)
(0.45, (0.74, (0.42, (0.72, (0.57,
1.02) 1.69) 1.66) 2.19) 1.16)
(1.80, (1.93, (0.85, (1.88, (2.54,
4.28)b 4.20)b 3.07) 5.26)b 4.94)b
2.47 1.61 1.56 1.19 1.06
(1.82, (1.16, (0.93, (0.76, (0.81,
3.38)b 2.24)b 2.63) 1.86) 1.40)
8.29 3.59 2.48 2.92 4.45
(6.41, (2.73, (1.71, (2.03, (3.59,
10.7)b 4.71)b 3.59)b 4.18)b 5.50)b
Abbreviations: CI, confidence interval; NEC, necrotizing enterocolitis; SIP, spontaneous intestinal perforation. aAll models adjusted by use of prophylactic indomethacin, use of antenatal steroids, use of inotropes in the first week after birth, small for gestational age status and severity of illness on admission (SNAPII (Score of Neonatal Acute Physiology, version II) score 420). bIndicates Po0.05.
Distinguishing between focal/SIP and NEC-related perforation is important for prognosis and counselling. Our findings of lower mortality in focal/SIP compared with NECrelated perforation are consistent with previous reports. In recent analyses of data from the Vermont Oxford Network, Fisher et al.15 reported a 1.1% incidence of focal/SIP and a 2.3% incidence of NEC-related perforation. The study also reported a nearly twofold mortality rate in NEC-related perforation compared with focal/SIP, similar to our findings and those of others.2 This may be due to lower inflammatory load21 following focal/SIP as compared with NEC-related perforation and the relatively stable hemodynamic condition of patients with focal/SIP. Similar to several reports in the literature, we were also able to demonstrate previously reported associations of focal/SIP with lower gestational age,1,4–6 lower birth weight,1,4,5 younger postnatal age,1,4–6 exposure to indomethacin,1,2,6,7 exposure to postnatal steroids,1,7,8,22 hypotension requiring inotropes4 in the first week after birth and staphylococcal3,9,13 and Candidial sepsis.3,9 As far as indomethacin is concerned, early use23 or use to prevent intraventricular hemorrhage has been shown to be associated with focal SIP in some studies15,24 but not in others.12 Sharma et al.24 reported that therapeutic indomethacin had a protective effect on NEC, whereas Wadhwan et al.12 reported that Journal of Perinatology (2015), 1 – 6
it was associated with focal/SIP. We did not identify any difference in therapeutic indomethacin use between those who had focal/SIP vs those who had NEC-related perforation. However, no maternal factors such as age, hypertension, chorioamnionitis and antenatal steroid use25 or neonatal factors such as gender9,25 and smallfor-gestational status were significantly different in our cohort, which is discordant with some previous reports. In an observational study1,26 at 16 tertiary centers in the United States, it was identified that among infants with perforation 50% underwent laparotomy and the remaining underwent surgery. In our study, 70% of those who had focal/SIP underwent surgery, which could be due to the fact that focal/SIP has been recognized as a local disease for which primary repair is likely to be the treatment of choice27 if a patient is otherwise stable. Recently, Mehrar et al.28 reported a significantly higher rate of brain lesions in patients with intestinal perforation compared with those without perforation, indicating the likelihood of neurodevelopmental impairment. We identified no significant difference between focal/SIP group and NEC (perforation and all) with reference to cystic PVL. Our findings are different than those of Attridge et al.29 The difference could be due to us including all forms of PVL, whereas Attridge et al.29 included only cystic PVL, or it could just be a matter of small sample size as the incidence of © 2015 Nature America, Inc.
Intestinal perforation in very preterm neonates J Shah et al
5 cystic PVL is very low in current era. However, studies of neurodevelopmental outcomes following focal/SIP have been conflicting. Although Wadhwan et al.12 reported that focal/SIP was associated with an increased risk of poor neurodevelopmental outcomes, Shah et al.14 reported that there was no difference in long-term neurodevelopmental outcomes among extremely low birth weight neonates with medical NEC, surgical NEC and focal/ SIP. Unfortunately, long-term neurodevelopmental data were not available in this cohort. However, we observed twofold to threefold increase in rates of PVL in neonates with NEC or perforation compared with those who did not have NEC nor perforation. In animal models, the risk factors for focal/SIP identified above have been shown to demonstrate a cumulative effect.30 The signaling pathways for nitric oxide synthase, epidermal growth factor and insulin-like growth factor are affected, which results in altered trophism of the ileum, thinning of intestinal submucosa and hyperplasia of mucosa. Reduction in nitric oxide synthase leads to disturbed intestinal motility and makes the distal intestine vulnerable to perforation.30 In typical cases of focal/SIP, there is focal necrosis of the muscularis externa3,24,31 without any evidence of ischemia or coagulative necrosis.6,30 Tatekawa et al.32 reported thinning of intestinal musculature near the site of focal perforations, further supporting alteration of trophism. In a histological examination, Lai et al.27 also reported that in patients with focal/SIP the thickness of the muscularis propria was attenuated at the site of perforation, whereas the remaining intestine was normal. These findings suggest that focal/SIP is a disease of focal alteration and, unless associated with a widespread inflammatory response, will result in lower mortality compared with NEC-related perforations. The strengths of our study include the use of a populationbased cohort, detailed and meticulous data collection, data regarding availability of risk factors for intestinal perforation and a large sample size that allowed us to conduct adjusted analyses. However, we must acknowledge the limitations. We did not collect data on the method of confirmation of a diagnosis of focal/ SIP vs NEC-related perforation. However, 70% of our patients in the perforation group underwent a laparotomy, where confirmatory evidence was obtained. The remaining cases were diagnosed based on the clinical evaluation of the medical team. We did not have details regarding the clinical status of infants when a perforation was diagnosed, which may have had a significant role in the subsequent development of morbidities and mortality. Our data indicated that severity of illness at admission was significantly higher for both infants with focal/SIP and those with NECrelated perforation. As such, we adjusted our analyses for severity of illness at admission. We were not able to collect data on neurodevelopmental outcomes in these neonates, which would have been very useful information for counselling parents at the time of perforation. Finally, we adjusted for many risk factors and confounders; however, the issue of residual confounding remains. CONCLUSIONS Intestinal perforation, both focal/SIP and NEC-related, is associated with higher odds of neonatal mortality and morbidities compared with patients without perforation or NEC; however, there were lower odds of mortality in infants with focal/SIP compared with those with NEC-related perforation. Many of the common neonatal morbidities were higher among infants with perforation, suggesting the possible release of inflammatory markers even following focal perforation. Future studies should investigate the impact of perforation on neurodevelopmental outcomes during childhood. In addition, predicting which infants are at high risk of intestinal perforation should be a further avenue for research, as © 2015 Nature America, Inc.
prevention of perforation would be important to prevent adverse outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGMENTS We thank the staff of the Canadian Neonatal Network Coordinating Centre for their hard work, Mr Junmin Yang for statistical support and Dr Ruth Warre for providing editorial support during preparation of the manuscript. Although no funding was received specifically for this study, the Canadian Neonatal Network (CNN) received organizational support from the CNN Coordinating Centre, which is based at the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital, Toronto, Ontario, Canada. MiCare is supported by funding from the Canadian Institutes of Health Research and Mount Sinai Hospital, Toronto.
REFERENCES 1 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure. J Perinatol 2006; 26: 93–99. 2 Buchheit JQ, Stewart DL. Clinical comparison of localized intestinal perforation and necrotizing enterocolitis in neonates. Pediatrics 1994; 93: 32–36. 3 Novack CM, Waffarn F, Sills JH, Pousti TJ, Warden MJ, Cunningham MD. Focal intestinal perforation in the extremely-low-birth-weight infant. J Perinatol 1994; 14: 450–453. 4 Adderson EE, Pappin A, Pavia AT. Spontaneous intestinal perforation in premature infants: a distinct clinical entity associated with systemic candidiasis. J Pediatr Surg 1998; 33: 1463–1467. 5 Okuyama H, Kubota A, Oue T, Kuroda S, Ikegami R, Kamiyama M. A comparison of the clinical presentation and outcome of focal intestinal perforation and necrotizing enterocolitis in very-low-birth-weight neonates. Pediatr Surg Int 2002; 18: 704–706. 6 Pumberger W, Mayr M, Kohlhauser C, Weninger M. Spontaneous localized intestinal perforation in very-low-birth-weight infants: a distinct clinical entity different from necrotizing enterocolitis. J Am Coll Surg 2002; 195: 796–803. 7 Attridge JT, Clark R, Gordon PV. New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation. J Perinatol 2006; 26: 667–670. 8 Gordon P, Rutledge J, Sawin R, Thomas S, Woodrum D. Early postnatal dexamethasone increases the risk of focal small bowel perforation in extremely low birth weight infants. J Perinatol 1999; 19: 573–577. 9 Holland AJ, Shun A, Martin HC, Cooke-Yarborough C, Holland J. Small bowel perforation in the premature neonate: congenital or acquired? Pediatr Surg Int 2003; 19: 489–494. 10 Paquette L, Friedlich P, Ramanathan R, Seri I. Concurrent use of indomethacin and dexamethasone increases the risk of spontaneous intestinal perforation in very low birth weight neonates. J Perinatol 2006; 26: 486–492. 11 Alpan G, Eyal F, Vinograd I, Udassin R, Amir G, Mogle P et al. Localized intestinal perforations after enteral administration of indomethacin in premature infants. J Pediatr 1985; 106: 277–281. 12 Wadhawan R, Oh W, Vohr BR, Saha S, Das A, Bell EF et al. Spontaneous intestinal perforation in extremely low birth weight infants: association with indometacin therapy and effects on neurodevelopmental outcomes at 18-22 months corrected age. Arch Dis Child Fetal Neonatal Ed 2013; 98: F127–F132. 13 Meyer CL, Payne NR, Roback SA. Spontaneous, isolated intestinal perforations in neonates with birth weight less than 1,000 g not associated with necrotizing enterocolitis. J Pediatr Surg 1991; 26: 714–717. 14 Shah TA, Meinzen-Derr J, Gratton T, Steichen J, Donovan EF, Yolton K et al. Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation. J Perinatol 2012; 32: 552–558. 15 Fisher JG, Jones BA, Gutierrez IM, Hull MA, Kang KH, Kenny M et al. Mortality associated with laparotomy-confirmed neonatal spontaneous intestinal perforation: A prospective 5-year multicenter analysis. J Pediatr Surg 2014; 49: 1215–1219. 16 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986; 33: 179–201. 17 Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82: 527–532.
Journal of Perinatology (2015), 1 – 6
Intestinal perforation in very preterm neonates J Shah et al
6 18 International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005; 123: 991–999. 19 Richardson DK, Gray JE, McCormick MC, Workman K, Goldmann DA. Score for Neonatal Acute Physiology: a physiologic severity index for neonatal intensive care. Pediatrics 1993; 91: 617–623. 20 Canadian Neonatal Network. Canadian Neonatal Network Abstractor's Manual. v 2.1.2, 1–94, 2014. Canadian Neonatal Network. Toronto, Canada. Available from http://www.canadianneonatalnetwork.org/portal/CNNHome/Publications.aspx (last accessed: 26 September 2014). 21 Bhatia AM, Stoll BJ, Cismowski MJ, Hamrick SE. Cytokine levels in the preterm infant with neonatal intestinal injury. Am J Perinatol 2014; 31: 489–496. 22 De Laet MH, Dassonville M, Johansson A, Lerminiaux C, Seghers V, Van den Eijnden S et al. Small-bowel perforation in very low birth weight neonates treated with high-dose dexamethasone. Eur J Pediatr Surg 2000; 10: 323–327. 23 Shorter NA, Liu JY, Mooney DP, Harmon BJ. Indomethacin-associated bowel perforations: a study of possible risk factors. J Pediatr Surg 1999; 34: 442–444. 24 Sharma R, Hudak ML, Tepas JJ III, Wludyka PS, Teng RJ, Hastings LK et al. Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis. J Perinatol 2010; 30: 786–793. 25 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations. J Perinatol 2006; 26: 185–188.
26 Blakely ML, Lally KP, McDonald S, Brown RL, Barnhart DC, Ricketts RR et al. Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation: a prospective cohort study by the NICHD Neonatal Research Network. Ann Surg 2005; 241: 984–989. 27 Lai S, Yu W, Wallace L, Sigalet D. Intestinal muscularis propria increases in thickness with corrected gestational age and is focally attenuated in patients with isolated intestinal perforations. J Pediatr Surg 2014; 49: 114–119. 28 Merhar SL, Ramos Y, Meinzen-Derr J, Kline-Fath BM. Brain magnetic resonance imaging in infants with surgical necrotizing enterocolitis or spontaneous intestinal perforation versus medical necrotizing enterocolitis. J Pediatr 2014; 164: 410–412. 29 Attridge JT, Zanelli SA, Gurka MJ, Kaufman DA. Randomized controlled trials need stratification by types of acquired neonatal intestinal diseases. e-J Neonatol Res 2011; 1(2): 59–64. 30 Gordon PV. Understanding intestinal vulnerability to perforation in the extremely low birth weight infant. Pediatr Res 2009; 65: 138–144. 31 Mintz AC, Applebaum H. Focal gastrointestinal perforations not associated with necrotizing enterocolitis in very low birth weight neonates. J Pediatr Surg 1993; 28: 857–860. 32 Tatekawa Y, Muraji T, Imai Y, Nishijima E, Tsugawa C. The mechanism of focal intestinal perforations in neonates with low birth weight. Pediatr Surg Int 1999; 15: 549–552.
APPENDIX Site investigators for the Canadian Neonatal Network Prakesh S Shah (Director, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario; Adele Harrison, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, British Columbia Children’s Hospital, Vancouver, British Columbia; Zenon Cieslak, Royal Columbian Hospital, New Westminster, British Columbia; Todd Sorokan, Surrey Memorial Hospital, Surrey, British Columbia; Wendy Yee, Foothills Medical Centre, Calgary, Alberta; Khalid Aziz, Royal Alexandra Hospital, Edmonton, Alberta; Zarin Kalapesi, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Ruben Alvaro, St Boniface General Hospital, Winnipeg, Manitoba; Sandesh Shivananda, Hamilton Health Sciences Centre, Hamilton, Ontario; Orlando Da Silva, London Health Sciences Centre, London, Ontario; Chuks Nwaesei, Windsor Regional Hospital, Windsor, Ontario; Kyong-Soon Lee, Hospital for Sick Children, Toronto, Ontario; Prakesh Shah, Mount Sinai Hospital, Toronto, Ontario; Michael
Dunn, Sunnybrook Health Sciences Centre, Toronto, Ontario; Nicole Rouvinez-Bouali, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; Kimberly Dow, Kingston General Hospital, Kingston, Ontario; Ermelinda Pelausa, Jewish General Hospital, Montréal, Québec; Keith Barrington, Hôpital Sainte-Justine, Montréal, Québec; Christine Drolet, Centre Hospitalier Universitaire de Québec, Sainte Foy, Patricia Riley, Montréal Children’s Hospital, Montréal, Québec; Daniel Faucher, Royal Victoria Hospital, Montréal, Québec; Valerie Bertelle, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Rody Canning, Moncton Hospital, Moncton, New Brunswick; Barbara Bulleid, Dr Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah and Luis Monterrosa, Saint John Regional Hospital, Saint John, New Brunswick; Akhil Deshpandey, Janeway Children’s Health and Rehabilitation Centre, St John’s, Newfoundland; Jehier Afifi, IWK Health Centre, Halifax, Nova Scotia; Andrzej Kajetanowicz, Cape Breton Regional Hospital, Sydney, Nova Scotia; Shoo K Lee (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.
Journal of Perinatology (2015), 1 – 6
© 2015 Nature America, Inc.
