Skip to main content
NCBI home page
Paediatrics & Child Health logoLink to Paediatrics & Child Health
. 2017 Nov 23;23(4):e56–e61. doi: 10.1093/pch/pxx169

Antibiotic exposure and development of necrotizing enterocolitis in very preterm neonates

Rana Esmaeilizand 1, Prakesh S Shah 2, Mary Seshia 3, Wendy Yee 4, Eugene W Yoon 2, Kimberly Dow 1,✉; Canadian Neonatal Network Investigators
PMCID: PMC6007281  PMID: 30038533

Abstract

Objective

To examine the association between the duration of antibiotic exposure and development of stage 2 or 3 necrotizing enterocolitis (NEC) in very preterm neonates.

Study Design

A retrospective case–control study was conducted from Canadian Neonatal Network data for preterm neonates born before 29 weeks’ gestation and admitted 2010 through 2013. Efforts were made to match each NEC case to two controls for gestational age, birth weight (±100 g) and sex.

Results

A total of 224 cases and 447 controls were identified. The incidence of antenatal steroid administration, the number of days nil-per-os and the number of antibiotic days prior to onset of NEC were significantly different in neonates with NEC. A multiple regression analysis revealed that the duration of antibiotic use was higher among NEC cases compared to controls (P<0.01). Empiric antibiotic treatment of 5 or more days was associated with significantly increased odds of NEC as compared with antibiotic exposure of 0 to 4 days (adjusted odds ratio: 2.02; 95% CI 1.55, 3.13).

Conclusion

Empiric antibiotic exposure for 5 or more days in preterm neonates born before 29 weeks’ gestation was associated with an increased risk of NEC.

Keywords: Antibiotic, Infant, Necrotizing enterocolitis, Premature

INTRODUCTION

Necrotizing enterocolitis (NEC) remains one of the most common causes of morbidity and mortality in neonatal intensive care units (NICUs) (1). Between 2003 and 2008, the incidence of NEC among infants less than 33 weeks’ gestation admitted to level III NICUs in Canada was 5.1% (2), which is consistent with other large network databases and single-centre studies (3,4). While the incidence in infants less than 29 weeks decreased from 10% to 8% between 2003 and 2014 in Canada, it remains significantly higher than in other countries (5,6). Meanwhile, NEC mortality rates have been reported to range from 15% to 30% (2,7).

NEC is a multifactorial disease with several risk factors including prematurity, low birth weight, formula feeding and alterations in microbial colonization of the gastrointestinal tract (1,8). In recent years, it has been proposed that the widespread use of antibiotics may contribute to aberrant gut colonization, including a reduction in the diversity of microbiota, delayed colonization with normal flora and overgrowth of pathogenic organisms (8,9). Wang et al. documented limited diversity of intestinal flora in preterm infants that may increase their vulnerability to environmental influences including antibiotic administration (8). Establishment of a normal intestinal immune system postnatally has a protective effect against systemic inflammatory states including NEC; excessive antibiotic use interferes with this process in preterm infants (10,11). Several studies have shown an association between prolonged empiric antibiotic use and NEC (12–14) As most of the evidence linking antibiotic usage and NEC has been derived from small-scale single-centre studies, the objective of our study was to examine the relationship between the duration of antibiotic exposure and onset of stage 2 or 3 NEC in a large national cohort.

METHODS

Study population

A multicentre retrospective case–control study was conducted using data from the Canadian Neonatal NetworkTM (CNN) database. The CNN maintains a national database that includes data from all tertiary-level NICU admissions across Canada. Twenty-nine of 30 sites contributed data during the study period, representing more than 95% of neonates admitted to a tertiary care NICU in the country. Data were abstracted and submitted to the coordinating centre at Mount Sinai Hospital by trained research assistants. Infants born at less than 29 weeks’ gestational age and admitted to participating units in the CNN January 2010 through December 2013 were included in the analysis. This age group was chosen as it is the population in which the incidence of NEC is highest and has been targeted for improvement as part of the Evidence-based Practice for Improving Quality (EPIQ) project (5). Infants who i) were moribund on admission, ii) had major congenital anomalies and gastrointestinal anomalies requiring surgical correction or iii) had culture proven early-onset sepsis or late-onset sepsis were excluded from the analysis. Patients who developed NEC with an available onset date formed the study cases. The date of onset was determined as the time of diagnosis and placing the baby nil per os (NPO). The infants who developed NEC before 1 week of age or after 12 weeks of postnatal age were excluded from the analysis to avoid effects of atypical cases. Approval for this study was obtained from the Executive Committee of the Canadian Neonatal Network and the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board.

Outcome

The outcome for this study was stage 2 or 3 NEC, which were defined according to the CNN abstractor’s manual using Bell’s classification (15,16). As such, NEC stage 2 or higher was defined as definite pneumatosis, portal/hepatic air or perforation diagnosed by x-ray or ultrasound, or by surgical or autopsy diagnosis. Each NEC case was matched with two controls (without NEC) randomly selected based on birth weight ± 100 g, completed week of gestation and sex using a random number generating program.

Exposure

Primary exposure in this investigation was number of days of receipt of antibiotics. Exposure was defined as one or more doses of any parenteral antibiotic during a 24-hour cycle starting at midnight. The number and percentage of days of antibiotic exposure up until the day of NEC onset was determined. Cumulative antibiotic exposure for each control was the number of days of antibiotic exposure up until the same postnatal age at which their respective matched case developed NEC. The specific type of antibiotic was not analyzed.

Variables

Several characteristics were compared between patients with and without NEC, including birth weight, gestational age, sex, Apgar score at 5 minutes, small for gestational age (SGA), antenatal steroid use (one or two doses), maternal chorioamnionitis, patent ductus arteriosus (PDA), Score for Neonatal Acute Physiology, version II (SNAP-II), inotrope use and NPO days. Study variables were defined according to the CNN Abstractors’ Manual (15). Briefly, gestational age was defined as the best estimate based on early prenatal ultrasound, obstetric examination and history, followed by paediatric estimate. If the postnatal paediatric estimate of gestation differed from the obstetric estimate by more than 2 weeks, the paediatric estimate was used. Infants were classified as being SGA if their birth weight was less than the 10th percentile (17). Early-onset sepsis and late-onset sepsis were distinguished as positive bacterial, viral or fungal culture in blood and/or cerebrospinal fluid, from birth to 2 days of age and after 2 days of age, respectively. Maternal chorioamnionitis was defined either clinically (maternal fever, uterine tenderness with or without leukocytosis) or histologically. Infants were classified as having PDA if they received pharmacological or surgical treatment for PDA closure. SNAP II is a validated scoring system of illness severity during the first 12 hours after NICU admission (15,18). NPO and inotrope days were calculated in a similar fashion to antibiotic exposure, where inotrope use was defined as days when an infant received any of dopamine, dobutamine, epinephrine, norepinephrine, milrinone or phenylephrine.

Statistical analysis

Maternal and infant characteristics were compared between cases and controls. For the variables not used as matching criteria, conditional logistic regression models were used for the comparisons of the two groups to account for the matching factors. The effect of the number of days of antibiotics usage on the occurrence of NEC was examined in conditional logistic regression model, adjusting for possible confounders. In order to account for the correlations between the twins born to the same mothers, the regression parameters in the model were estimated with the maximum partial likelihood estimates under an independent working assumption and a robust sandwich covariance matrix estimate. A P value of 0.05 was deemed significant. SAS v9.3 (Cary, NC) was used for all statistical analyses.

RESULTS

A total of 4510 infants born at less than 29 weeks’ of gestation were admitted to CNN participating units during this study. Of the 262 infants diagnosed with stage 2 or 3 NEC, 17 developed NEC before 1 week of age, and 5 after 12 weeks of age so were excluded.

For the remaining 226 cases, an attempt was made to match one case to two controls ensuring at least one control for every case. No matching controls could be identified for two cases and those two cases were excluded from the study. Only one control could be identified for one case. The remaining 223 cases were matched with two controls each, resulting in 224 cases and 447 controls. Overall, 94% (631/671) of the infants received antibiotics prior to the date of NEC onset in the case and of those, 95% (602/631) were initiated in the first 2 days. The median age of onset of NEC was 23 days (interquartile range [IQR] 13, 31).

Comparisons of maternal and infant characteristics between infants with and without NEC revealed a significantly higher usage of antenatal steroids among the NEC group (P=0.03) (Table 1). No significant differences were observed with respect to chorioamnionitis, Apgar scores, SGA, diagnosis of PDA, SNAP-II scores or inotrope use (P>0.05). There was a significantly higher number and percentage of NPO days, prior to the onset of NEC (P<0.01) in neonates who developed NEC.

Table 1.

Comparison of population characteristics between patients with and without NEC

Infants with NEC (n = 224) Matched infants without NEC (n = 447) p-value
Birth weight in g, mean (SD) 893 (238) 888 (224)
Gestation age in weeks, mean (SD) 25.9 (1.5) 25.9 (1.5)
Male sex, n (%) 120 (54%) 239 (54%)
Apgar <7 at 5 minutes, n (%) 96 (43%) 188 (43%) 0.91
Multiples, n (%) 58 (25%) 115 (26%) 0.95
C-section, n (%) 129 (58%) 257 (58%) 0.93
Small for gestational age, n (%) 15 (7%) 28 (6%)
Antenatal steroids, n (%) 199 (91%) 373 (85%) 0.03
Chorioamnionitis, n (%) 47 (28%) 97 (30%) 0.72
Patent ductus arteriosus, n (%) 138 (62%) 254 (59%) 0.35
SNAP-II score, mean (SD) 16.9 (14.2) 16.3 (14.4) 0.63
Inotrope support, n (%) 58 (26%) 119 (27%) 0.84
Age at NEC, days, median (IQR) 23 (13,31) N/A N/A
NPO days prior to day of NEC, mean (SD) 4 (5) 3 (3.0)* <0.01
Percent of NPO days prior to onset of NEC, mean (SD) 17 (19) 13 (16)* <0.01
Days of antibiotic exposure prior to onset of NEC, mean (SD) 10 (8) 7 (6)* <0.01
Percent of days of antibiotics exposure prior to onset of NEC, mean (SD) 41 (26) 34 (26) <0.01
Open in a new tab

Abbreviations: SD, standard deviation; SNAP-II, Score of Neonatal Acute Physiology, version II; NEC, necrotizing enterocolitis; NPO, nil-per-os; IQR, interquartile range *denotes days up until NEC occurred in the matched case

Following logistic regression analysis, adjusted for antenatal steroid use, BW, GA and caesearian section, the odds of developing NEC significantly increased with duration of antibiotic exposure (Figure 1). Antibiotic exposure of 5 or more days significantly increased the risk of NEC as compared with 0 to 4 days (cumulative odds ratio for antibiotic exposure ≥5 days versus <5 days: 2.02; 95% CI 1.55, 3.13). As NPO days is a variable that is potentially an intermediate of NEC, it was not adjusted for in the analysis shown in Figure 1.

Figure 1.

Figure 1.

Open in a new tab

Odds ratios (ORs) of developing NEC in relation to cumulative duration of antibiotic exposure.

DISCUSSION

In this case–control study, receipt of antibiotic therapy for 5 or more days as compared with 0 to 4 days was associated with NEC in neonates born before 29 weeks’ gestation. This small difference is in keeping with the recent work of Ting et al. who demonstrated that only a 10% increase in antibiotic use rates was associated with adverse outcomes (19). Approximately 94% of the infants in our study received antibiotics, which were started empirically in the first 2 days in 95% of these patients. A similar rate was reported in Cotten et al.’s study, where 96% of infants received a combination of two antibiotics (12). Infants diagnosed with NEC in this report were exposed to antibiotics for 41% of the days prior to disease onset, which equated to an average of 10 days of antibiotic exposure in contrast to controls who were exposed for 34% or an average of 7 days.

Our findings are in agreement with several other studies that describe an association between antibiotic duration and NEC (12–14,20,21). In a retrospective cohort analysis of low birth weight infants admitted to 19 tertiary centres between 1998 and 2001, Cotten et al. reported an increased risk of NEC or death in infants subjected to prolonged empiric antibiotic exposure for more than 5 days (adjusted odds ratio: 1.30; 95% CI: 1.10 to 1.54) (12). In this analysis, 71% of infants who had sterile cultures within the first 3 days following birth received initial antibiotic treatment with a median duration of 5 days (12). Similarly, a retrospective 2:1 case–control analysis of 124 cases from 2001 through 2008 supported the correlation of prolonged antibiotic exposure and NEC development, with the probability of NEC increasing by 20% per day of antibiotic exposure in infants without sepsis, while exposure more than 10 days was associated with a threefold increase in risk (13). These findings were comparable to those of Abdel Ghany et al. who also demonstrated that a significantly larger proportion of very low weight (VLBW) infants with NEC received initial antibiotic treatment for more than 5 days compared to those without NEC (100% versus 80%, respectively) (14). Despite these consistent findings, another group reporting on the prospective surveillance of the Polish Neonatology Network NICUs were unable to find an association between antibiotic use and NEC (22).

In our study, infants who developed NEC had a higher number of NPO days prior to the onset of NEC in comparison to the control population. This finding is in keeping with Kirtsman et al., who reported an association between NEC and NPO days (23). Cotten et al. found that the association of NEC with prolonged initial empiric antibiotic treatment was stronger for the infants who began enteral feedings on postnatal day 5 or later (12). It is possible that infants who went on to develop NEC had a greater number of NPO days as they were initially more unstable or displayed feeding intolerance. However, delaying the initiation of enteral feeds may affect the limited diversity of the intestinal flora in preterm infants, and consequently predispose them to overgrowth of pathogenic organisms that play a fundamental role in the pathogenesis of NEC.

Our data suggest that a higher proportion of neonates in the NEC group received antenatal steroids compared to neonates without NEC. In the current literature, there are mixed reports of the effect of antenatal steroids on NEC. A previous meta-analysis concluded that exposure to antenatal steroids decreased the risk of NEC (24). In contrast, Guthrie et al. identified a link between antenatal steroids and an increase in the incidence of NEC (25), which was also confirmed in two other single-centre studies (26,27). Gordon et al. proposed that steroids accelerate the growth of mucosa selectively, while causing thinning of the muscularis layer, which renders the area more vulnerable to ischemia (28). It is also possible that the association we identified could be based on chance, and given that the results are unadjusted for other characteristics, they should be interpreted with caution.

Although we reported no significant difference in the rate of PDA between the cases and controls, which is consistent with reports in the literature (2,13), others have shown that a hemodynamically significant PDA increases the risk of NEC (29,30), possibly by compromising intestinal blood flow (31,32).

The main strength of the study is that we analyzed data from a large national population cohort that uses reliable data collection methods and standard definitions of neonatal morbidities. Moreover, the case and control groups were matched with respect to gestational age, weight and sex. Although our findings are consistent with several other earlier reports, a number of limitations remain. For instance, variations exist in clinical practice both between and within centres, which are difficult to control for in a multicentre network study. Moreover, detailed information about the type of feeding and the type or number of antibiotics used was not available in the database. While an attempt was made to control for severity of illness by including baseline characteristics and the SNAP-II score in the adjustment model, there is still a possibility of residual confounding.

Despite these drawbacks, our finding that prolonged antibiotic exposure is associated with NEC in very preterm neonates highlights an important modifiable risk factor, which underscores the importance of antibiotic stewardship programs. Clinicians should administer antibiotics only when appropriate and discontinue their use whenever possible. The Canadian Paediatric Society recommended in 2007 that if laboratory results and the clinical course do not indicate bacterial infection, antibiotic therapy may be discontinued after 48 hours (33). In addition, rather than starting the majority (94%) of premature infants on routine antibiotics, as in this population, consideration could be given to observation without commencement of antibiotics in those with low risk of infection such as those born by caesarian section without rupture of membranes. More judicious use of antibiotics with narrower spectrums is also an important aspect of antibiotic stewardship programs. Further studies to review the reasons for initial empiric antibiotic treatment are warranted.

Acknowledgements

The authors would like to thank Natasha Musrap, PhD, from the MiCare research centre for editorial support in the preparation of this manuscript.

Conflicts of Interest: The authors report no conflicts of interest.

Funding/Support: Organizational support was provided by the Canadian Neonatal Network Coordinating Centre, which is based at the Maternal-Infant Care Research Centre (MiCare) at Mount Sinai Hospital in Toronto, Ontario, Canada. MiCare is supported by grant funding from the Canadian Institutes of Health Research (CIHR) (FRN87518) and in-kind support from Mount Sinai Hospital, Toronto, Ontario. PSS holds an Applied Research Chair in Reproductive and Child Health Services and Policy Research awarded by CIHR (APR-126340).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.

CNN site investigators: Prakesh S. Shah, MD, MSc (Director, Canadian Neonatal Network and site investigator), Mount Sinai Hospital, Toronto, Ontario; Adele Harrison, MD, MBChB, Victoria General Hospital, Victoria, British Columbia; Anne Synnes, MDCM, MHSC, British Columbia Children’s Hospital, Vancouver, British Columbia; Todd Sokoran, MD, Royal Columbian Hospital, New Westminster, British Columbia and Surrey Memorial Hospital, Surrey, British Columbia; Wendy Yee, MD, Foothills Medical Centre, Calgary, Alberta; Khalid Aziz, MBBS, MA, MEd, Royal Alexandra Hospital, Edmonton, Alberta; Zarin Kalapesi, MD, Regina General Hospital, Regina, Saskatchewan; Koravangattu Sankaran, MD, MBBS, Royal University Hospital, Saskatoon, Saskatchewan; Mary Seshia, MBChB, Winnipeg Health Sciences Centre, Winnipeg, Manitoba; Ruben Alvaro, MD, St. Boniface General Hospital, Winnipeg, Manitoba; Sandesh Shivananda, MBBS, MD, DM, Hamilton Health Sciences Centre, Hamilton, Ontario; Orlando Da Silva, MD, MSc, London Health Sciences Centre, London, Ontario; Chuks Nwaesei, MD, Windsor Regional Hospital, Windsor, Ontario; Kyong-Soon Lee, MD, MSc, Hospital for Sick Children, Toronto, Ontario; Michael Dunn, MD, Sunnybrook Health Sciences Centre, Toronto, Ontario; Nicole Rouvinez-Bouali, MD, Children’s Hospital of Eastern Ontario and Ottawa General Hospital, Ottawa, Ontario; Kimberly Dow, MD, Kingston General Hospital, Kingston, Ontario; Ermelinda Pelausa, MD, Jewish General Hospital, Montréal, Québec; Keith Barrington, MBChB, Hôpital Sainte-Justine, Montréal, Québec; Christine Drolet, MD, Centre Hospitalier Universitaire de Québec, Sainte Foy Québec; Patricia Riley, MD, MDCM, BSc, Montréal Children’s Hospital, Montréal, Québec and Royal Victoria Hospital, Montréal, Québec; Valerie Bertelle, MD, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec; Rody Canning, MD, Moncton Hospital, Moncton, New Brunswick; Barbara Bulleid, MD, Dr. Everett Chalmers Hospital, Fredericton, New Brunswick; Cecil Ojah, MBBS, and Luis Monterrosa, MD, Saint John Regional Hospital, Saint John, New Brunswick; Akhil Deshpandey, MD, MBBS, Janeway Children’s Health and Rehabilitation Centre, St. John’s, Newfoundland; Jehier Afifi, MB BCh, MSc, IWK Health Centre, Halifax, Nova Scotia; Andrzej Kajetanowicz, MD, Cape Breton Regional Hospital, Sydney, Nova Scotia; Shoo K. Lee, MBBS, PhD (Chairman, Canadian Neonatal Network), Mount Sinai Hospital, Toronto, Ontario.

Contributor Information

Canadian Neonatal Network Investigators:

Prakesh S Shah, Adele Harrison, Anne Synnes, Todd Sokoran, Wendy Yee, Khalid Aziz, Zarin Kalapesi, Koravangattu Sankaran, Mary Seshia, Ruben Alvaro, Sandesh Shivananda, Orlando Da Silva, Chuks Nwaesei, Kyong-Soon Lee, Michael Dunn, Nicole Rouvinez-Bouali, Kimberly Dow, Ermelinda Pelausa, Keith Barrington, Christine Drolet, Patricia Riley, Valerie Bertelle, Rody Canning, Barbara Bulleid, Cecil Ojah, Luis Monterrosa, Akhil Deshpandey, Jehier Afifi, Andrzej Kajetanowicz, and Shoo K Lee

References

  • 1. Gephart SM, McGrath JM, Effken JA, Halpern MD. Necrotizing enterocolitis risk: State of the science. Adv Neonatal Care 2012;12(2):77–87; quiz 88–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2. Yee WH, Soraisham AS, Shah VS, Aziz K, Yoon W, Lee SK; Canadian Neonatal Network Incidence and timing of presentation of necrotizing enterocolitis in preterm infants. Pediatrics 2012;129(2):e298–304. [DOI] [PubMed] [Google Scholar]
  • 3. Stoll BJ, Hansen NI, Bell EF, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Neonatal outcomes of extremely preterm infants from the nichd neonatal research network. Pediatrics 2010;126(3):443–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Horbar JD, Carpenter JH, Badger GJ, et al. Mortality and neonatal morbidity among infants 501 to 1500 grams from 2000 to 2009. Pediatrics. 2012;120:1019–1026. [DOI] [PubMed] [Google Scholar]
  • 5. Lee SK, Shah PS, Singhal N, et al. ; Canadian EPIQ Study Group Association of a quality improvement program with neonatal outcomes in extremely preterm infants: A prospective cohort study. CMAJ 2014;186(13):E485–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Isayam T, Lee SK, Mori R, et al. The Canadian Neonatal Network and the Neonatal Research Network of Japan. Pediatrics 2012;130: e957–96522966031 [Google Scholar]
  • 7. Lin PW, Stoll BJ. Necrotising enterocolitis. Lancet 2006;368(9543):1271–83. [DOI] [PubMed] [Google Scholar]
  • 8. Wang Y, Hoenig JD, Malin KJ, et al. 16s rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. Isme J 2009;3(8):944–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Claud EC, Walker WA. Hypothesis: Inappropriate colonization of the premature intestine can cause neonatal necrotizing enterocolitis. Faseb J 2001;15(8):1398–403. [DOI] [PubMed] [Google Scholar]
  • 10. Caicedo RA, Schanler RJ, Li N, Neu J. The developing intestinal ecosystem: implications for the neonate. Pediatr Res 2005;58(4):625–8. [DOI] [PubMed] [Google Scholar]
  • 11. Thanabalasuriar A, Kubes P. Neonates, antibiotics and the microbiome. Nat Med 2014;20(5):469–70. [DOI] [PubMed] [Google Scholar]
  • 12. Cotten CM, Taylor S, Stoll B, et al. ; NICHD Neonatal Research Network Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants. Pediatrics 2009;123(1):58–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Alexander VN, Northrup V, Bizzarro MJ. Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr 2011;159(3):392–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Ghany EAA, Ali AA. Empirical antibiotic treatment and the risk of necrotizing enterocolitis and death in very low birth weight neonates. Ann Saudi. Med 2012;32:521–526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. CNN Abstractor’s Manual v2.2 2015. http://www.canadianneonatalnetwork.org/portal/CNNHome/Publications.aspx. Accessed December 17, 2015.
  • 16. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187(1):1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Fenton TR, Kim JH. a systematic review and meta-analysis to revise the fenton growth chart for preterm infants. bmc Pediatr 2013;13:59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Richardson DK, Corcoran JD, Escobar GJ, Lee SK. snap-ii and snappe-ii: Simplified newborn illness severity and mortality risk scores. J Pediatr 2001;138(1):92–100. [DOI] [PubMed] [Google Scholar]
  • 19. Ting JY, Synnes A, Roberts A, et al. ; Canadian Neonatal Network Investigators. Association between antibiotic use and neonatal mortality and morbidities in very low-birth-weight infants without culture-proven sepsis or necrotizing enterocolitis. jama Pediatr 2016;170(12):1181–7. [DOI] [PubMed] [Google Scholar]
  • 20. Shah P, Nathan E, Doherty D, Patole S. Prolonged exposure to antibiotics and its associations in extremely preterm neonates–the western Australian experience. J Matern Fetal Neonatal Med 2013;26(17):1710–4. [DOI] [PubMed] [Google Scholar]
  • 21. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibler KR. Prolonged initial empirical antibiotic treatment is associated with adverse outcomes in premature infants. J Pediatr 2011;159(5):720–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Wojkowska-Mach J, Rozanska A, Borszewska-Kornacka M, et al. Necrotizing enterocolitis in preterm infants: Epidemiology and antibiotic consumption in the Polish neonatology network neonatal intensive care units in 2009. PLOS ONE. 2014;9:e92856–65. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Kirtsman M, Yoon EW, Ojah C, Cieslak Z, Lee SK, Shah PS. Nil-per-os days and necrotizing enterocolitis in extremely preterm infants. Am J Perinatol 2015;32(8):785–94. [DOI] [PubMed] [Google Scholar]
  • 24. Roberts D, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;3:CD004454. [DOI] [PubMed] [Google Scholar]
  • 25. Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003;23(4):278–85. [DOI] [PubMed] [Google Scholar]
  • 26. Kamitsuka MD, Horton MK, Williams MA. The incidence of necrotizing enterocolitis after introducing feeding schedules for infants between 1250 and 2500 grams and less than 35 weeks of gestation. Pediatrics. 2000;105(2):379–384. [DOI] [PubMed] [Google Scholar]
  • 27. Lawrence D, Brewere D, Hornung R, Mersmann M, Donovan D. Antenatal glucocorticoids use, not prenatal antibiotics, may result in increased risk of necrotizing enterocolitis in very low birth weight infants. Pediatr Res. 2001;49:Abstract 1798. [Google Scholar]
  • 28. Gordon PV, Marshall DD, Stiles AD, Price WA. The clinical, morphologic, and molecular changes in the ileum associated with early postnatal dexamethasone administration: from the baby’s bowel to the researcher’s bench. Mol Genet Metab 2001;72(2):91–103. [DOI] [PubMed] [Google Scholar]
  • 29. 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(2):184–8. [DOI] [PubMed] [Google Scholar]
  • 30. Bertino E, Giuliani F, Prandi G, Coscia A, Martano C, Fabris C. Necrotizing enterocolitis: Risk factor analysis and role of gastric residuals in very low birth weight infants. J Pediatr Gastroenterol Nutr 2009;48(4):437–42. [DOI] [PubMed] [Google Scholar]
  • 31. Murdoch EM, Sinha AK, Shanmugalingam ST, Smith GC, Kempley ST. Doppler flow velocimetry in the superior mesenteric artery on the first day of life in preterm infants and the risk of neonatal necrotizing enterocolitis. Pediatrics 2006;118(5):1999–2003. [DOI] [PubMed] [Google Scholar]
  • 32. Hermes-DeSantis ER, Clyman RI. Patent ductus arteriosus: Pathophysiology and management. j Perinatol 2006;26 (Suppl 1):S14–8; discussion S22–3. [DOI] [PubMed] [Google Scholar]
  • 33. Barrington K. Canadian Paediatric Society Fetus and Newborn Committee. Management of the infant at increased risk of sepsis. Paediatr Child Health. 2007;12(10):893–898. [PMC free article] [PubMed] [Google Scholar]

Articles from Paediatrics & Child Health are provided here courtesy of Oxford University Press

RESOURCES