Original Paper Neonatology 2014;105:74–78 DOI: 10.1159/000356033
Received: August 26, 2013 Accepted after revision: September 23, 2013 Published online: November 26, 2013
Necrotizing Enterocolitis in Small-for-Gestational-Age Neonates: A Matched Case-Control Study Isabelle M.C. Ree Vivianne E.H.J. Smits-Wintjens Esther G.J. Rijntjes-Jacobs Iris C.M. Pelsma Sylke J. Steggerda Frans J. Walther Enrico Lopriore Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Key Words Small for gestational age · Necrotizing enterocolitis · Patent ductus arteriosus
risk of development of NEC is more than twofold increased in SGA neonates compared to AGA neonates. We found no association between the severity of SGA and NEC. © 2013 S. Karger AG, Basel
Abstract Background: Small for gestational age (SGA) neonates are at increased risk of mortality and morbidity, including necrotizing enterocolitis (NEC), but detailed information on the incidence and risk factors of NEC in SGA neonates is lacking. Objective: This study aims to estimate the incidence of NEC in a large cohort of SGA neonates, compared to appropriate for gestational age (AGA) neonates. Methods: We included all SGA neonates without congenital malformations admitted to our neonatal nursery between 2004 and 2013. Neonates in the SGA group were matched for gestational age with a control group of AGA neonates admitted during the same study period. We recorded the occurrence of NEC and studied the association with SGA and other potential risk factors. Results: A total of 475 SGA neonates were matched for gestational age at birth to 475 control AGA neonates. The incidence of NEC in the SGA group was 3.2% (15/475) versus 1.3% (6/475) in the AGA group (OR 2.55, 95% CI 0.98–6.63, p = 0.047). The incidence of NEC in the subgroups with mild, moderate and severe SGA was 2.3% (5/215), 4.7% (5/1.07) and 3.2% (5/153), respectively (p = 0.531). Conclusions: The
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0074$39.50/0 E-Mail [email protected] www.karger.com/neo
Introduction
Small for gestational age (SGA) is defined as a birth weight (BW) 110 mm Hg. Respiratory distress syndrome was recorded when both intubation and surfactant administration were required. The diagnosis of NEC was made in the presence of clinical and radio-
NEC in SGA Neonates
logic features according to Bell’s criteria [21]. Only neonates classified as having definite NEC (Bell stages II and III) were included, with stage II being confirmed by radiological pneumatosis intestinalis and stage III requiring surgery for abdominal perforation. We verified in each NEC case that the diagnosis was in accordance with Bell’s criteria. The primary outcome of the study was the occurrence of NEC. Secondary outcomes were neonatal morbidity and mortality associated with SGA and NEC. Outcome was compared between the SGA and AGA group. Informed consent and ethical approval is not needed for this type of study in the Netherlands. Statistical Analysis We calculated that group sizes of at least 442 infants were required to demonstrate a 3% difference in NEC (5 vs. 2%) with 0.05 significance and a power of 80% by one-tailed analysis. Results of categorical variables were compared between the SGA and AGA neonates using the χ2 test; Student’s t test was used for continuous variables. The following variables are known to have a potential association with NEC and were studied in a univariate logistic regression model: SGA, maternal hypertension, gestational age at birth of ≤32 weeks, patent ductus arteriosus, respiratory distress syndrome, and polycythemia. Variables that showed a significant difference between SGA and AGA neonates in the univariate analysis were included in a multivariate logistic regression model to adjust for potential confounding. Results are presented as odds ratios (OR) with 95% confidence intervals (95% CI). p < 0.05 was regarded as statistically significant. Statistical analysis was performed using IBM SPSS Statistics 20.0 (Chicago, Ill., USA).
Results
A total of 475 SGA neonates fulfilled our eligibility criteria and were included in the study. They were matched with a control group of 475 AGA neonates. In the group of SGA neonates, 153 (32%) were classified as severe SGA, 107 (23%) were moderate SGA, and 215 (45%) mild SGA. Baseline characteristics of the cohort are presented in table 1. Maternal hypertension occurred more often in the group of SGA neonates and SGA neonates were more likely to be born through cesarean delivery. Maternal diabetes occurred more often in the AGA group. The overall incidence of NEC was 2.2% (21/950). The incidence of NEC in the SGA group was 3.2% (15/475) versus 1.3% (6/475) in the AGA group (OR 2.55, 95% CI 0.98–6.63, p = 0.047). The incidence of NEC in the subgroups with mild, moderate and severe SGA was 2.3% (5/215), 4.7% (5/107) and 3.2% (5/153), respectively (p = 0.531). The distribution of NEC in our study population is shown in figure 1. The median age at onset of NEC in the SGA group and AGA group was 13.1 (interquartile range 7.75–30.75) and Neonatology 2014;105:74–78 DOI: 10.1159/000356033
75
Total n = 950 (100%)
SGA n = 475 (50%)
BW p < 2.3 n = 153 (16.1%)
Fig. 1. Flowchart NEC in the matched SGA and AGA groups.
NEC n=5 (3.2%)
No NEC n = 148 (96.7%)
AGA n = 475 (50%)
BW p 5–10 n = 215 (22.6%)
BW p 2.3–5 n = 107 (11.3%)
NEC n=5 (4.7%)
No NEC n = 102 (95.3%)
NEC n=5 (2.3%)
No NEC n = 210 (97.7%)
NEC n=6 (1.3%)
No NEC n = 469 (98.7%)
Table 1. Baseline characteristics in the matched SGA and AGA groups
Female, n (%) Cesarean delivery, n (%) Twins, n (%) Maternal hypertension, n (%) Maternal diabetes, n (%) Gestational age at birth, weeks (mean ± SD) Birth weight, g (mean ± SD)
16.3 (interquartile range 5.00–19.00) days postpartum, respectively (p = 0.507). Surgical intervention for NEC ≥grade III was equally distributed between the SGA and AGA group, 0.8% (4/475) versus 0.6% (3/475), respectively (p = 0.704). SGA neonates were more prone to sepsis (OR 2.02, 95% CI 1.40–2.90, p = 0.000). In addition, neonatal mortality occurred more often in the SGA group, than in the AGA group (OR 2.15, 95% CI 1.00– 4.62, p = 0.045) (table 2). In our study population, three risk factors were found to be significantly associated with increased risk for NEC: SGA (OR 2.55, 95% CI 0.98–6.63, p = 0.049), patent ductus arteriosus (OR 5.61, 95% CI 2.20–14.31, p = 0.000) and respiratory distress syndrome (OR 3.47, 95% CI 1.41–8.52, p = 0.004). We also found more hypotension (OR 5.03, 95% CI 1.98–12.81, p = 0.000), sepsis (OR 6.31, 95% CI 2.63–15.13, p = 0.000) and a higher mortality (OR 76
Neonatology 2014;105:74–78 DOI: 10.1159/000356033
SGA (n = 475)
AGA (n = 475)
p value
222 (47) 302 (64) 146 (31) 173 (36) 9 (2) 33.3 ± 4.1 1,476 ± 674
216 (46) 181 (38) 159 (33) 100 (21) 25 (5) 33.3 ± 4.1 2,254 ± 977
0.696 0.000 0.378 0.000 0.010 0.937 0.000
5.17, 95% CI 1.44–18.55, p = 0.005) among the NEC cases. Risk factors associated with NEC by univariate analysis were entered in a multivariable logistic regression model to measure the independent association with NEC (table 3). On multivariate analysis, only the presence of patent ductus arteriosus (OR 4.36, 95% CI 1.24–15.41, p = 0.022) showed an independent association with NEC.
Discussion
In this study, we evaluated the impact of being born either SGA or AGA on the development of NEC. In our analyses, SGA was associated with increased risk of NEC and an increased mortality. Our results are obtained from a large study population and in line with previous studies, demonstrate a higher incidence of NEC in preterm SGA Ree/Smits-Wintjens/Rijntjes-Jacobs/ Pelsma/Steggerda/Walther/Lopriore
Table 2. Mortality and morbidity in the matched SGA and AGA groups
Necrotizing enterocolitis Grade II Grade III Patent ductus arteriosus Respiratory distress syndrome Polycythemia (venous Ht >70%) Hypotension Sepsis Mortality
SGA (n = 475)
AGA (n = 475)
OR (95% CI)
p value
15 (3.2) 11 (2.3) 4 (0.8) 50 (10.5) 71 (14.9) 26 (5.5) 52 (10.9) 96 (20.2) 21 (4.4)
6 (1.3) 3 (0.6) 3 (0.6) 33 (6.9) 77 (16.2) 23 (4.8) 39 (8.2) 53 (11.2) 10 (2.1)
2.55 (0.98 – 6.63) 3.73 (1.03 – 13.46) 1.34 (0.30 – 6.00) 1.57 (0.99 – 2.49) 0.91 (0.64 – 1.29) 1.14 (0.64 – 2.02) 1.37 (0.89 – 2.13) 2.02 (1.40 – 2.90) 2.15 (1.00 – 4.62)
0.047 0.031 0.704 0.052 0.591 0.385 0.152 0.000 0.045
Data are presented as n (%) unless stated otherwise.
Table 3. Risk factors for NEC in the matched SGA and AGA groups
SGA Maternal hypertension Gestational age ≤32 weeks Patent ductus arteriosus Respiratory distress syndrome Polycythemia (venous Ht >70%)
NEC (n = 21)
No NEC (n = 929)
Univariate OR (95% CI)
p value
Multivariate OR (95% CI)
p value
15 (71.4) 6 (28.6) 11 (52.4) 7 (33.3) 8 (38.1) 1 (4.8)
460 (49.5) 267 (28.7) 413 (44.5) 76 (8.2) 140 (15.1) 48 (5.2)
2.55 (0.98 – 6.63) 0.99 (0.38 – 2.57) 1.37 (0.58 – 3.27) 5.61 (2.20 – 14.31) 3.47 (1.41 – 8.52) 0.92 (0.12 – 6.98)
0.049 0.985 0.463 0.000 0.004 0.930
2.53 (0.95 – 6.76) 1.62 (0.57 – 4.58) 1.59 (0.50 – 5.05) 4.36 (1.24 – 15.41) 2.61 (0.77 – 8.85) 0.88 (0.11 – 7.00)
0.065 0.366 0.432 0.022 0.124 0.910
Data are presented as n (%) unless stated otherwise.
neonates [4, 18], or tending towards such a correlation [14, 15]. However, we could not confirm a relationship between severity of SGA and the occurrence of NEC. This study provides supportive information on a large, recent sample of neonates with SGA, matched to AGA controls, and includes all gestational ages. We did not differentiate between intrauterine growth restriction (IUGR) and SGA, as the adverse outcomes of IUGR and a postnatal diagnosis of SGA generally correlate well. IUGR is defined as patients with an antenatal diagnosis of growth restriction or retardation. Antenatal diagnosis of IUGR also tends to suffer from a high level of unreliability [4]. In addition, no distinction was made between the different causes of growth restriction, other than by recording maternal hypertension and excluding neonates with major congenital anomalies. The pathogenesis of NEC in SGA neonates is not clear. Several hypotheses have been postulated focusing mostly on the link between hypoxic-ischemic injury to the gastro-
intestinal tract, physiological immaturity of the gastrointestinal tract and alterations in the normal microbiological flora of the intestines [9, 22]. Fetal hypoxia and growth restriction are often the result of adverse intrauterine circumstances, which may initiate the ‘diving reflex’, whereby cardiac output is shunted away from the intestines in favor of the brain and heart. This process in combination with reperfusion may result in hypoxic-ischemic injury to the intestines, which contributes to the onset of NEC [9, 23]. In addition, immaturity of the gastrointestinal tract is likely to be a contributing factor to the development of NEC, as all our NEC cases were born preterm. In immature intestinal tissue, tight junctions are not yet properly formed, peristalsis is impaired and the mucus coat is underdeveloped. The immature intestinal barrier of preterm neonates creates an intestinal environment susceptible to NEC [24]. As shown in this study, it is complicated to separate the influence of an individual risk factor on the development of NEC, as many factors are involved and show a high
NEC in SGA Neonates
Neonatology 2014;105:74–78 DOI: 10.1159/000356033
77
level of interaction. On multivariate analysis, only the presence of a patent ductus arteriosus shows an independent effect on the occurrence of NEC, while SGA tends towards such an association, but lacks statistical significance. SGA contributes to fetal hypoxia and immaturity of the gastrointestinal tract. The presence of a patent ductus arteriosus alters the fetal blood flow, causing a reduction in mesenteric blood flow, which results in hypoperfusion, mucosal hypoxia, ischemia, and ulceration, allowing bacterial invasion to occur [25, 26]. The data in this study should be interpreted with care due to the retrospective study design. We could not con-
firm the role of other known risk factors such as polycythemia and respiratory distress syndrome, but this might be due to the small number of NEC cases. Our study was not powered to detect these associations. In conclusion, we found that SGA neonates are at increased risk of NEC compared to AGA neonates. It is important to take this risk into account in the care of SGA neonates. Nevertheless, the pathogenesis of NEC is still poorly understood and this study confirms the complexity of separating the effect of various potential risk factors.
References 1 ACOG Practice Bulletin: Intrauterine growth restriction, No. 12, January 2000. Int J Gynecol Obstet 2001;72:85–96. 2 Beckerath von AK, Kollmann M, Rotky-Fast C, Karpf E, Lang U, Klaritsch P: Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol 2013;208:130.e1–e6. 3 Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A: Morbidity and mortality among very low birthweight neonates with intrauterine growth restriction. Am J Obstet Gynecol 2000;182:198–206. 4 Garite TJ, Clark R, Thorp JA: Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 2004;191:481–487. 5 Mandruzzato G, Antsaklis A, Botet F, Chervenak FA, Figueras F, Grunebaum A, Puerto B, Skupski D, Stanojevic M: Intrauterine restriction. J Perinat Med 2008;36:277–281. 6 Pike K, Pillow JJ, Lucas JS: Long-term respiratory consequences of intrauterine growth restriction. Semin Fetal Neonatal Med 2012;17: 92–98. 7 Resnik R: Intrauterine growth restriction. Obstet Gynecol 2002;99:490–496. 8 Kosloske AM: Epidemiology of necrotizing enterocolitis. Acta Paediatr 1994;83:2–7. 9 Lin PW, Stoll BJ: Necrotising enterocolitis. Lancet 2006;368:1271–1283. 10 Fitzgibbons SC, Ching Y, Yu D, Carpenter J, Kenny M, Weldon C, Lillehei C, Valim C, Horbar JD, Jaksic T: Mortality of necrotizing enterocolitis expressed by birth weight categories. J Pediatr Surg 2009;44:1072–1076.
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11 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. 12 Llanos AR, Moss ME, Pinzòn MC, Dye T, Sinkin RA, Kendig JW: Epidemiology of neonatal necrotizing enterocolitis: a populationbased study. Paediatr Perinat Epidemiol 2002; 16:342–349. 13 Uauy RD, Fanaroff AA, Korones SB, Phillips EA, Philips JB, Wright LL: Necrotizing enterocolitis in very low birth weight infants: biodemographic and clinical correlates. J Pediatr 1991;119:630–638. 14 Bardin C, Zelkowitz P, Papageorgiou A: Outcome of small-for-gestational age infants born before 27 weeks of gestation. Pediatrics 1997;100:E4. 15 Dogra S, Mukhopadhyay K, Narang A: Feed intolerance and necrotizing enterocolitis in preterm small-for-gestational age neonates with normal umbilical artery Doppler flow. J Trop Pediatr 2012;58:513–516. 16 Giapros V, Drougia A, Krallis N, Theocharis P, Andronikou S: Morbidity and mortality patterns in small-for-gestational age infants born preterm. J Matern Fetal Neonatal Med 2012;25:153–157. 17 Regev RH, Lusky A, Dolfin T, Litmanovitz I, Arnon S, Reichman B: Excess mortality and morbidity among small-for-gestational age premature infants: a population-based study. J Pediatr 2003;143:186–191. 18 Westby Wold SH, Sommerfelt K, Reigstad H, Rønnestad A, Medbø S, Farstad T, Kaaresen PI, Støen R, Leversen KT, Irgens LM, Markestad T: Neonatal mortality and morbidity in extremely preterm small for gestational age infants: a population-based study. Arch Dis Child Fetal Neonatal Ed 2009;94:F363–F367.
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19 Kloosterman GJ: Intrauterine growth and intrauterine growth curves. Ned Tijdschr Verloskd Gynaecol 1969;69:349–365. 20 Khoury MF, Erickson JD, Cordero JF, McCarthy BJ: Congenital malformations and intrauterine growth retardation: a population study. Pediatrics 1988;82:83–90. 21 Bell MJ: Neonatal necrotizing enterocolitis. N Engl J Med 1978;298:281–282. 22 Thompson AL, Bizarro MJ: Necrotizing enterocolitis in newborns. Pathogenesis, prevention and management. Drugs 2008; 68: 1227–1238. 23 Hackett GA, Campbell S, Gamsu H, CohenOverbeek T, Pearce JM: Doppler studies in the growth-retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity. BMJ 1987; 294:13–16. 24 Anand RJ, Leaphart CL, Mollen KP, Hackam DJ: The role of the intestinal barrier in the pathogenesis of necrotizing enterocolitis. Shock 2007;27:124–133. 25 Dollberg S, Lusky A, Reichman B: Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population-based study. J Pediatr Gastroenterol Nutr 2005;40:184–188. 26 Grosfeld JL, Chaet M, Molinari F, Engle W, Engum SA, West KW, Rescoria FJ, Scherer LR: Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin. Ann Surg 1996;224:350–357.
Ree/Smits-Wintjens/Rijntjes-Jacobs/ Pelsma/Steggerda/Walther/Lopriore
Copyright: S. Karger AG, Basel 2013. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Received: August 26, 2013 Accepted after revision: September 23, 2013 Published online: November 26, 2013
Necrotizing Enterocolitis in Small-for-Gestational-Age Neonates: A Matched Case-Control Study Isabelle M.C. Ree Vivianne E.H.J. Smits-Wintjens Esther G.J. Rijntjes-Jacobs Iris C.M. Pelsma Sylke J. Steggerda Frans J. Walther Enrico Lopriore Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Key Words Small for gestational age · Necrotizing enterocolitis · Patent ductus arteriosus
risk of development of NEC is more than twofold increased in SGA neonates compared to AGA neonates. We found no association between the severity of SGA and NEC. © 2013 S. Karger AG, Basel
Abstract Background: Small for gestational age (SGA) neonates are at increased risk of mortality and morbidity, including necrotizing enterocolitis (NEC), but detailed information on the incidence and risk factors of NEC in SGA neonates is lacking. Objective: This study aims to estimate the incidence of NEC in a large cohort of SGA neonates, compared to appropriate for gestational age (AGA) neonates. Methods: We included all SGA neonates without congenital malformations admitted to our neonatal nursery between 2004 and 2013. Neonates in the SGA group were matched for gestational age with a control group of AGA neonates admitted during the same study period. We recorded the occurrence of NEC and studied the association with SGA and other potential risk factors. Results: A total of 475 SGA neonates were matched for gestational age at birth to 475 control AGA neonates. The incidence of NEC in the SGA group was 3.2% (15/475) versus 1.3% (6/475) in the AGA group (OR 2.55, 95% CI 0.98–6.63, p = 0.047). The incidence of NEC in the subgroups with mild, moderate and severe SGA was 2.3% (5/215), 4.7% (5/1.07) and 3.2% (5/153), respectively (p = 0.531). Conclusions: The
© 2013 S. Karger AG, Basel 1661–7800/14/1051–0074$39.50/0 E-Mail [email protected] www.karger.com/neo
Introduction
Small for gestational age (SGA) is defined as a birth weight (BW) 110 mm Hg. Respiratory distress syndrome was recorded when both intubation and surfactant administration were required. The diagnosis of NEC was made in the presence of clinical and radio-
NEC in SGA Neonates
logic features according to Bell’s criteria [21]. Only neonates classified as having definite NEC (Bell stages II and III) were included, with stage II being confirmed by radiological pneumatosis intestinalis and stage III requiring surgery for abdominal perforation. We verified in each NEC case that the diagnosis was in accordance with Bell’s criteria. The primary outcome of the study was the occurrence of NEC. Secondary outcomes were neonatal morbidity and mortality associated with SGA and NEC. Outcome was compared between the SGA and AGA group. Informed consent and ethical approval is not needed for this type of study in the Netherlands. Statistical Analysis We calculated that group sizes of at least 442 infants were required to demonstrate a 3% difference in NEC (5 vs. 2%) with 0.05 significance and a power of 80% by one-tailed analysis. Results of categorical variables were compared between the SGA and AGA neonates using the χ2 test; Student’s t test was used for continuous variables. The following variables are known to have a potential association with NEC and were studied in a univariate logistic regression model: SGA, maternal hypertension, gestational age at birth of ≤32 weeks, patent ductus arteriosus, respiratory distress syndrome, and polycythemia. Variables that showed a significant difference between SGA and AGA neonates in the univariate analysis were included in a multivariate logistic regression model to adjust for potential confounding. Results are presented as odds ratios (OR) with 95% confidence intervals (95% CI). p < 0.05 was regarded as statistically significant. Statistical analysis was performed using IBM SPSS Statistics 20.0 (Chicago, Ill., USA).
Results
A total of 475 SGA neonates fulfilled our eligibility criteria and were included in the study. They were matched with a control group of 475 AGA neonates. In the group of SGA neonates, 153 (32%) were classified as severe SGA, 107 (23%) were moderate SGA, and 215 (45%) mild SGA. Baseline characteristics of the cohort are presented in table 1. Maternal hypertension occurred more often in the group of SGA neonates and SGA neonates were more likely to be born through cesarean delivery. Maternal diabetes occurred more often in the AGA group. The overall incidence of NEC was 2.2% (21/950). The incidence of NEC in the SGA group was 3.2% (15/475) versus 1.3% (6/475) in the AGA group (OR 2.55, 95% CI 0.98–6.63, p = 0.047). The incidence of NEC in the subgroups with mild, moderate and severe SGA was 2.3% (5/215), 4.7% (5/107) and 3.2% (5/153), respectively (p = 0.531). The distribution of NEC in our study population is shown in figure 1. The median age at onset of NEC in the SGA group and AGA group was 13.1 (interquartile range 7.75–30.75) and Neonatology 2014;105:74–78 DOI: 10.1159/000356033
75
Total n = 950 (100%)
SGA n = 475 (50%)
BW p < 2.3 n = 153 (16.1%)
Fig. 1. Flowchart NEC in the matched SGA and AGA groups.
NEC n=5 (3.2%)
No NEC n = 148 (96.7%)
AGA n = 475 (50%)
BW p 5–10 n = 215 (22.6%)
BW p 2.3–5 n = 107 (11.3%)
NEC n=5 (4.7%)
No NEC n = 102 (95.3%)
NEC n=5 (2.3%)
No NEC n = 210 (97.7%)
NEC n=6 (1.3%)
No NEC n = 469 (98.7%)
Table 1. Baseline characteristics in the matched SGA and AGA groups
Female, n (%) Cesarean delivery, n (%) Twins, n (%) Maternal hypertension, n (%) Maternal diabetes, n (%) Gestational age at birth, weeks (mean ± SD) Birth weight, g (mean ± SD)
16.3 (interquartile range 5.00–19.00) days postpartum, respectively (p = 0.507). Surgical intervention for NEC ≥grade III was equally distributed between the SGA and AGA group, 0.8% (4/475) versus 0.6% (3/475), respectively (p = 0.704). SGA neonates were more prone to sepsis (OR 2.02, 95% CI 1.40–2.90, p = 0.000). In addition, neonatal mortality occurred more often in the SGA group, than in the AGA group (OR 2.15, 95% CI 1.00– 4.62, p = 0.045) (table 2). In our study population, three risk factors were found to be significantly associated with increased risk for NEC: SGA (OR 2.55, 95% CI 0.98–6.63, p = 0.049), patent ductus arteriosus (OR 5.61, 95% CI 2.20–14.31, p = 0.000) and respiratory distress syndrome (OR 3.47, 95% CI 1.41–8.52, p = 0.004). We also found more hypotension (OR 5.03, 95% CI 1.98–12.81, p = 0.000), sepsis (OR 6.31, 95% CI 2.63–15.13, p = 0.000) and a higher mortality (OR 76
Neonatology 2014;105:74–78 DOI: 10.1159/000356033
SGA (n = 475)
AGA (n = 475)
p value
222 (47) 302 (64) 146 (31) 173 (36) 9 (2) 33.3 ± 4.1 1,476 ± 674
216 (46) 181 (38) 159 (33) 100 (21) 25 (5) 33.3 ± 4.1 2,254 ± 977
0.696 0.000 0.378 0.000 0.010 0.937 0.000
5.17, 95% CI 1.44–18.55, p = 0.005) among the NEC cases. Risk factors associated with NEC by univariate analysis were entered in a multivariable logistic regression model to measure the independent association with NEC (table 3). On multivariate analysis, only the presence of patent ductus arteriosus (OR 4.36, 95% CI 1.24–15.41, p = 0.022) showed an independent association with NEC.
Discussion
In this study, we evaluated the impact of being born either SGA or AGA on the development of NEC. In our analyses, SGA was associated with increased risk of NEC and an increased mortality. Our results are obtained from a large study population and in line with previous studies, demonstrate a higher incidence of NEC in preterm SGA Ree/Smits-Wintjens/Rijntjes-Jacobs/ Pelsma/Steggerda/Walther/Lopriore
Table 2. Mortality and morbidity in the matched SGA and AGA groups
Necrotizing enterocolitis Grade II Grade III Patent ductus arteriosus Respiratory distress syndrome Polycythemia (venous Ht >70%) Hypotension Sepsis Mortality
SGA (n = 475)
AGA (n = 475)
OR (95% CI)
p value
15 (3.2) 11 (2.3) 4 (0.8) 50 (10.5) 71 (14.9) 26 (5.5) 52 (10.9) 96 (20.2) 21 (4.4)
6 (1.3) 3 (0.6) 3 (0.6) 33 (6.9) 77 (16.2) 23 (4.8) 39 (8.2) 53 (11.2) 10 (2.1)
2.55 (0.98 – 6.63) 3.73 (1.03 – 13.46) 1.34 (0.30 – 6.00) 1.57 (0.99 – 2.49) 0.91 (0.64 – 1.29) 1.14 (0.64 – 2.02) 1.37 (0.89 – 2.13) 2.02 (1.40 – 2.90) 2.15 (1.00 – 4.62)
0.047 0.031 0.704 0.052 0.591 0.385 0.152 0.000 0.045
Data are presented as n (%) unless stated otherwise.
Table 3. Risk factors for NEC in the matched SGA and AGA groups
SGA Maternal hypertension Gestational age ≤32 weeks Patent ductus arteriosus Respiratory distress syndrome Polycythemia (venous Ht >70%)
NEC (n = 21)
No NEC (n = 929)
Univariate OR (95% CI)
p value
Multivariate OR (95% CI)
p value
15 (71.4) 6 (28.6) 11 (52.4) 7 (33.3) 8 (38.1) 1 (4.8)
460 (49.5) 267 (28.7) 413 (44.5) 76 (8.2) 140 (15.1) 48 (5.2)
2.55 (0.98 – 6.63) 0.99 (0.38 – 2.57) 1.37 (0.58 – 3.27) 5.61 (2.20 – 14.31) 3.47 (1.41 – 8.52) 0.92 (0.12 – 6.98)
0.049 0.985 0.463 0.000 0.004 0.930
2.53 (0.95 – 6.76) 1.62 (0.57 – 4.58) 1.59 (0.50 – 5.05) 4.36 (1.24 – 15.41) 2.61 (0.77 – 8.85) 0.88 (0.11 – 7.00)
0.065 0.366 0.432 0.022 0.124 0.910
Data are presented as n (%) unless stated otherwise.
neonates [4, 18], or tending towards such a correlation [14, 15]. However, we could not confirm a relationship between severity of SGA and the occurrence of NEC. This study provides supportive information on a large, recent sample of neonates with SGA, matched to AGA controls, and includes all gestational ages. We did not differentiate between intrauterine growth restriction (IUGR) and SGA, as the adverse outcomes of IUGR and a postnatal diagnosis of SGA generally correlate well. IUGR is defined as patients with an antenatal diagnosis of growth restriction or retardation. Antenatal diagnosis of IUGR also tends to suffer from a high level of unreliability [4]. In addition, no distinction was made between the different causes of growth restriction, other than by recording maternal hypertension and excluding neonates with major congenital anomalies. The pathogenesis of NEC in SGA neonates is not clear. Several hypotheses have been postulated focusing mostly on the link between hypoxic-ischemic injury to the gastro-
intestinal tract, physiological immaturity of the gastrointestinal tract and alterations in the normal microbiological flora of the intestines [9, 22]. Fetal hypoxia and growth restriction are often the result of adverse intrauterine circumstances, which may initiate the ‘diving reflex’, whereby cardiac output is shunted away from the intestines in favor of the brain and heart. This process in combination with reperfusion may result in hypoxic-ischemic injury to the intestines, which contributes to the onset of NEC [9, 23]. In addition, immaturity of the gastrointestinal tract is likely to be a contributing factor to the development of NEC, as all our NEC cases were born preterm. In immature intestinal tissue, tight junctions are not yet properly formed, peristalsis is impaired and the mucus coat is underdeveloped. The immature intestinal barrier of preterm neonates creates an intestinal environment susceptible to NEC [24]. As shown in this study, it is complicated to separate the influence of an individual risk factor on the development of NEC, as many factors are involved and show a high
NEC in SGA Neonates
Neonatology 2014;105:74–78 DOI: 10.1159/000356033
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level of interaction. On multivariate analysis, only the presence of a patent ductus arteriosus shows an independent effect on the occurrence of NEC, while SGA tends towards such an association, but lacks statistical significance. SGA contributes to fetal hypoxia and immaturity of the gastrointestinal tract. The presence of a patent ductus arteriosus alters the fetal blood flow, causing a reduction in mesenteric blood flow, which results in hypoperfusion, mucosal hypoxia, ischemia, and ulceration, allowing bacterial invasion to occur [25, 26]. The data in this study should be interpreted with care due to the retrospective study design. We could not con-
firm the role of other known risk factors such as polycythemia and respiratory distress syndrome, but this might be due to the small number of NEC cases. Our study was not powered to detect these associations. In conclusion, we found that SGA neonates are at increased risk of NEC compared to AGA neonates. It is important to take this risk into account in the care of SGA neonates. Nevertheless, the pathogenesis of NEC is still poorly understood and this study confirms the complexity of separating the effect of various potential risk factors.
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