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ISRN Gastroenterology
Volume 2012 (2012), Article ID 628317, 9 pages
http://dx.doi.org/10.5402/2012/628317
Review Article

What Really Causes Necrotising Enterocolitis?

General Medicine, King’s College Hospital, London SE5 9RS, UK

Received 11 October 2012; Accepted 19 November 2012

Academic Editors: A. Nakajima and W. Vogel

Copyright © 2012 Thomas Peter Fox and Charles Godavitarne. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background. One of the most serious gastrointestinal disorders occurring in neonates is necrotising enterocolitis (NEC). It is recognised as the most common intra-abdominal emergency and is the leading cause of short bowel syndrome. With extremely high mortality and morbidity, this enigmatic disease remains a challenge for neonatologists around the world as its definite aetiology has yet to be determined. As current medical knowledge stands, there is no single well-defined cause of NEC. Instead, there are nearly 20 risk factors that are proposed to increase the likelihood of developing NEC. Aims and Objectives. The aim of this project was to conduct a comprehensive literature review around the 20 or so well-documented and less well-documented risk factors for necrotising enterocolitis. Materials and Methods. Searches of the Medline, Embase, and Science direct databases were conducted using the words “necrotising enterocolitis + the risk factor in question” for example, “necrotising enterocolitis + dehydration.” Search results were ordered by relevance with bias given to more recent publications. Conclusion. This literature review has demonstrated the complexity of necrotising enterocolitis and emphasised the likely multifactorial aetiology. Further research is needed to investigate the extent to which each risk factor is implicated in necrotising enterocolitis.

1. Background

One of the most serious disorders and the single most serious gastrointestinal disorder occurring in neonates is necrotising enterocolitis [13]. This enigmatic disease remains a challenge for neonatologists around the world as its definite aetiology has yet to be determined. It is recognised as the most common intra-abdominal emergency effecting neonates and it is the leading cause of short bowel syndrome [4, 5]. Necrotising enterocolitis is characterised by the bowel wall necrosis of variable thickness, which leads to perforation in up to one-third of cases [6].

The condition was first described by Paltauf in 1888 but the term “necrotising enterocolitis” was used for the first time by Schmid and Quaiser in 1953 [7, 8]. Since then, there has been a tremendous increase in the incidence of NEC. This has been attributed largely to two factors. The first is the increase in the number of premature births by Caesarean section for therapeutic reasons resulting in the delivery of premature babies. The second reason is due to the advancement in technology of neonatal care, for example, intensive care units and surfactant therapy have enabled most premature babies to overcome a number of previously fatal conditions and survive, making them highly susceptible to developing NEC [9, 10].

2. Epidemiology

The incidence of NEC varies not only from country to country but also among different NICUs in the same country. Research by the National Institute of Child Health and Human Development observed variations from 4 to 20% in the prevalence of NEC at centres across northern America, suggesting that iatrogenic factors may play a large role. These have yet to be identified [11, 12]. The incidence in the population as a whole is estimated to be between one to three cases per 1000 live births. However, NEC occurs in 2–5% of very low birth weight infants (VLBW) and in 1–8% of neonatal intensive care unit admissions (NICU) [13]. A survey carried out in 1994 by the British Paediatric Surveillance Unit reported 300 new cases of NEC in the UK in one year with an overall death rate of 22% [14]. Median gestation was 29 weeks and 65% of babies weighed under 1500 g. However, 12% of babies that developed NEC were born at term [1517].

3. Pathology

NEC can arise in any area of the GI tract; however, the most common sites are the terminal ileum, caecum, and ascending colon [18]. Pneumatosis intestinalis (the presence of submucosal and subserosal gas within the bowel wall) is the most characteristic appearance of the gut radiologically and on laparotomy. The gas is mainly nitrogen and hydrogen formed by gas producing bacteria in the GI tract [19]. Histologically, the earliest signs of NEC are necrosis of the mucosa with microthrombus formation, leading to oedema, patchy ulceration and haemorrhage [20].

Important elements in modulating the damage that results from NEC are the inflammatory cytokines interleukin 1, 3, 6, tumour necrosis factor (TNF), and platelet activating factor (PAF). Indeed, these markers can be used to predict the severity of the disease [21]. PAF is a proinflammatory cytokine and has been shown to be of a particular importance [22]. Stool levels of PAF rise sharply with the onset of NEC and the administration of PAF to rats in a hypoxic atmosphere has shown to induce NEC [23]. Furthermore, PAF antagonists reduce the incidence and severity of NEC in rats [24]. This may also explain why enteral feeding is a risk factor for NEC; as stool concentrations of PAF increase, enteral feeding is commenced [25].

4. Aetiology

Many potential risk factors have been explored in relation to the aetiology of NEC; however, the definite aetiology still eludes modern medical research. It is possible that no individual factor is sufficient to precipitate NEC. Risk factors identified so far are shown in Table 1, [26].

tab1
Table 1: From Roberton’s Textbook of Neonatology. Risk factors for necrotising enterocolitis.

5. Literature Review

At present there is no single, well-defined cause of necrotising enterocolitis. Instead, we have nearly 20 risk factors that are proposed to increase the likelihood of developing NEC [26]. In this literature review, the various risk factors that are thought to be most significant will be discussed as well as certain parameters that may change with the onset of NEC.

6. Birth Weight and Prematurity

Low birth weight and prematurity have been identified as among the most important risk factors for NEC [2730]. NEC occurs in up to 5% of VLBW infants and the median gestation is around 29 weeks [31]. 65% of cases had a birth weight under 1500 g and only 12% of cases are born at term. Indeed, preterm infants born under 30 weeks who develop NEC usually have no other risk factors [32].

7. Gender

Carter and Holditch-Davis published a study in 2008 involving 134 preterm infants which concluded that there was no relationship between gender and NEC [33]. Ballot et al. conducted a study of 474 preterm infants in Johannesburg and were able to determine minor discrepancies between gender incidence of NEC (OR 3.21; 95% CI 1.6–6.3) [34]. However, most research has concluded that no differences are noted in the incidence of NEC according to gender [35]. Therefore gender is not thought to be a risk factor for NEC.

8. Neonatal Hypoxia

Recurrent apnoea, respiratory distress, assisted ventilation, and umbilical artery catheterisation are all known to contribute to hypoxic events in the first few weeks of life [26]. Palmer and Thomas conducted a study in 1987 which identified all of the above as risk factors for VLBW infants [36]. An adverse intrauterine environment can lead to chronic foetal hypoxia and IUGR. This can result in a diversion of cardiac output away from the gut which could precipitate necrotising enterocolitis [37].

In the term infant with NEC, risk factors for gut hypoxia are invariably present. NEC may follow severe generalised hypoxia, maternal cocaine use, or exchange transfusion [38]. An early study by Goldberg and Thomas into 5 infants born at term who developed NEC in 5–7 days found that they had all suffered from severe hypoxia during birth [39].

The use of hyperbaric oxygen therapy trialled in rat models has been shown to significantly reduce the severity of NEC [40]. However, further research is required before this can progress to human trials.

9. Maternal Milk versus Formula Milk

Breast milk protects against NEC [41]. In a study by Lucas and Cole involving 926 preterm infants, the exclusively formula fed group had a 6–10-fold increase in the rates of NEC than those fed with breast milk alone and 3 times the rates of those fed on a mixture of breast milk and formula. In the same study, delayed enteral feeding was also associated with a decreased incidence of NEC [42]. A systematic review conducted in 2003 also found a 3-fold increase in the likelihood of developing NEC if the infant is solely fed on formula [43]. When the general health of the infant is considered, breast milk also appears to be far superior [26]. There are significant benefits to infant host defence; sensory-neural development, gastrointestinal maturation, and some aspects of nutritional status are observed when premature infants are fed with their mothers’ own milk. A reduction in infection-related morbidity in human milk-fed premature infants has been reported in nearly a dozen descriptive, as well as some RCTs in the past 25 years [44].

Trophic feeding is defined as the use of minimal enteral feeds (continuous drip of less than 1 mL/hour) with parenteral nutrition. This has been shown to lower the incidence of feeding intolerance, shorten the duration of time to regain birth weight, and decrease the incidence of NEC [45, 46]. Little is gained nutritionally from trophic feeding; however, some degree of nutrient exposure is essential even to the immature gut to prevent intestinal mucosal atrophy [47]. A recent trial by Berseth and Bisquera investigating the benefits of trophic feeding over standard milk advancement had to be stopped because babies receiving the standard regimen had a higher rate of NEC (10% versus 1.4%) [48]. Henderson et al. suggested that the duration of trophic feeding and the rate of the advancement of feed volumes are key modifiable risk factors for NEC in preterm infants [49].

Manipulating the chemical composition of formula milk, by reducing protein content, adding prebiotics, growth factors, or secretory IgA, can modulate an intestinal development. This has been suggested to reduce the differential responses between breast-fed and formula-fed neonates [50].

Mothers of preterm infants produce milk that has a higher protein content, higher caloric density, and higher calcium and sodium content than milk from mothers who deliver at term [51]. This matches (to a certain extent) the increased needs of the premature infant. This has led to the development of specialised preterm infant formulae.

When infants on the NICU do not show adequate growth and weight gain there are a number of things that can be considered: firstly, increasing the volume of feeds. When the volume cannot be advanced any further there are two options: use donor hind milk or add commercial fortifiers. There have been a number of reports of infants developing NEC following the addition of commercial fortifiers [52, 53].

A key component of feeds that may be a modifiable risk factor for NEC is osmolarity [54]. There is a concern that additives to maternal milk may alter the osmolarity and hence remove the protective effect against NEC [55]. A number of studies have found that human milk and formula milk interact to induce a rapid increase in osmolarity higher than that which would be expected from composition alone. This rise could be explained by the amylase activity of human milk, inducing the hydrolysis of the dextrin content of formula milk, leading to small osmotically active molecules of oligosaccharides. Routine additives can significantly increase the osmolarity of EBM to levels that exceed current guidelines for premature infant feeding. The high osmolarity of fortified human milk should therefore be considered in the nutritional management of preterm infants [56, 57].

10. Blood Results

Anaemia is associated with an increased risk of developing NEC [26]. Blau et al. also found that neonatal transfusion of packed red blood cells could be a trigger for NEC [58]. A further study in December 2010 by Josephson et al. concluded that PRBC transfusions were merely a marker of disease severity and that there was no correlation with NEC [59]. Such conflicting views, published within weeks, of each other highlight the need for a further research in this area.

Polycythaemia was first suggested as a risk factor for NEC in 1975 [60] although initial studies failed to confirm this suggestion [61]. A review of 36 premature infants born over a period of 5 years dismissed polycythaemia as a risk factor in the development of NEC [62]. However more recently, many studies have identified increased incidences of polycythaemia in groups of infants that develop NEC compared to a control group [6366]. The aetiology of neonatal polycythaemia is related either to intrauterine hypoxia, or secondary to fetal transfusion. There is a linear relationship between hematocrit and viscosity until 65% after which it is exponential. It is the increased viscosity of blood that is responsible for reduced mesenteric perfusion [67, 68]. As viscosity increases so does the tendency to form microthrombi which can further impede mesenteric perfusion. At present, polycythaemia is widely regarded as a significant risk factor and current guidelines recommend the prompt diagnosis and management to avoid adverse outcomes [69].

Platelets are an acute phase reactant, and thrombocytosis can represent physiologic stress to an infant. However, acute NEC is more commonly associated with thrombocytopenia (<100,000/μL) [70]. The evidence behind thrombocytosis directly causing NEC is scanty; however, it stands to reason that a thrombogenic state could reduce mesenteric blood flow [71].

80–90% of cases of NEC are associated with thrombocytopenia to some degree [72]. Kenton et al. conducted a study on 91 infants and found that severe thrombocytopenia is a valuable prognostic indicator of mortality associated with NEC and may influence management options. Thrombocytopenia may become more profound in severe cases that become complicated with consumption coagulopathy [73]. This report suggested that prospective studies of infants with early and severe thrombocytopenia may help determine the optimal timing of laparotomy in infants with NEC. Ververidis et al. concluded that a platelet count of less than or a sudden fall in platelets was a poor prognostic indicator [74]. It therefore seems that while thrombocytosis is a risk factor because it induces a thrombogenic state that may impede mesenteric blood flow, thrombocytopenia is perhaps more useful as a prognostic indicator.

11. Dehydration/Electrolyte Disturbances

Dehydration is a risk factor for NEC [75]. When severe, it increases the viscosity of blood. Increased viscosity has been shown to decrease mesenteric perfusion and hence may precipitate NEC. There are numerous case studies demonstrating this phenomenon [76, 77]. Interestingly, hyperhydration has also been shown to increase the risk of NEC in a Cochrane review [78]. The conclusions to this review were that the careful restriction of water intake is required so that physiological needs are met without allowing significant dehydration.

12. Acute Phase Proteins

C-Reactive Protein (CRP) is one of the acute phase reactants which has been proven to be a useful marker of inflammation, not only in the gastrointestinal system but also systemically [79]. CRP is usually elevated in NEC [26]. It has not been found useful in predicting the onset of NEC as the rise in CRP appears to lag behind the clinical onset [80]. This study showed that CRP has increasing sensitivity but remains a nonspecific marker of NEC [81]. Many studies have analysed the serial changes in CRP before and after the diagnosis of NEC and it is thought that it may be more useful in predicting outcome and determining severity [82]. A retrospective analysis of data ranging from January 2001 to July 2006 on preterm (gestation < 32 weeks) neonates with definite NEC found that serial changes in CRP may predict the progression to surgery as well as death [83].

There are many other neonatal conditions which are associated with an elevated CRP: septicaemia, meningitis, urinary tract infection, pneumonia, meconium aspiration syndrome, or presumptive infection [84, 85].

The usefulness of CRP in diagnosing NEC seems to be in conjunction with radiographic changes, classically pneumatosis intestinalis. CRP is also useful in discriminating BeII’s stage II NEC from the benign form of pneumatosis intestinalis, NEC suspect, or spuriously suggestive GI conditions [86].

13. Liver Function Tests

Liver function tests (LFTs) incorporate albumin, alanine transaminase, aspartate transaminase, alkaline phosphatise, and total bilirubin. They allow physicians to gain information about the functional state of a patient’s liver. Unsurprisingly, they often become deranged following the onset of NEC, but there is little evidence regarding their value in contributing to a diagnosis [87]. Unfortunately, many premature infants may already have abnormal LFTs because of parenteral feeding regimens; the link between PN and deranged liver enzymes is well established [8891]. This could limit their usefulness in the diagnosis and monitoring of NEC.

14. The Use of Stool Inflammatory Markers inDiagnosing Necrotising Enterocolitis

Faecal calprotectin (FC) is a cytosolic component of neutrophils and is a useful marker for the exacerbation of inflammatory bowel disease. It is measured by a noninvasive biochemical test and is widely used to differentiate between functional bowel problems and inflammatory bowel disease. Thuijls et al. conducted a study in 2010 of 14 confirmed cases of NEC and concluded that faecal calprotectin is a potential diagnostic marker for NEC in neonates [92]. Its value in allowing early diagnosis of NEC has been alluded to by further trials [93, 94]. FC has been shown to be elevated in neonates with NEC but what remains unknown is its value in predicting the onset of NEC. Does the rise in FC precede clinical symptoms and other biochemical tests? Research involving larger cohorts is necessary to certify its true value and is an area of further interest to the author.

15. Umbilical Catheterisation

There are conflicting reports of the extent to which umbilical catheterisation is potentially a risk factor for developing necrotising enterocolitis. Inherently it is extremely difficult to assess because of the challenges of isolating it as a variable. Early research showed an impairment in mesenteric blood flow was, associated with an umbilical catheter insertion [95]. Roberton’s Textbook of Neonatology clearly states that it is a risk factor as do other sources [96]. However, other studies have shown the opposite to be true. Guthrie et al. studied 15072 neonates and found lower rates of NEC in those who had received an UAC at birth [97]. This conveys a potential protective effect of the catheters. However, a Cochrane review found that UAC was not a contributing factor in the aetiology of NEC [98]. With such conflicting research, the jury is clearly still “out” on the true risks of an umbilical catheterisation.

16. Clinical Risk Indicator in Babies

The Clinical Risk Index for Babies (CRIBs) score is a well-validated risk-adjustment instrument widely used in neonatal intensive care. Its appropriateness with contemporary data has been questioned so in 2003, a revised CRIB II score was developed [99]. This new scoring system was found to be a good predictive instrument for mortality in preterm infants by a large validation study in 2010 [100].

17. Congenital Disease (PDA)

The evidence behind a congenital persistent patent ductus arteriosis (PDA) as a cause for NEC is well established and has been confirmed by several prospective studies [101103]. The left-to-right shunt that occurs in PDA results in the decreased velocity of mesenteric blood flow [104]. The intestinal mucosa has high metabolic activity and requires about 80% of total intestinal blood flow. When this is decreased, it becomes more susceptible to the disruption of its immune barrier functions [105].

18. Antibiotics

The immature immune system of preterm neonates puts them at the higher risk of neonatal sepsis. Benzylpenicillin and Gentamicin are given to most preterm babies because of the increased risk of sepsis. A recent retrospective cohort study involving 5693 premature babies found that the prolonged use (greater than 5 days) of antibiotic therapy was associated with and increased the risk of NEC [106]. The use of antibiotics for 5 days or less in premature infants was thoroughly assessed in a large RCT and no increase in the incidence of NEC was found between the control group and the study group [107].

19. Indomethacin

Exposure to indomethacin can occur prenatally as a tocolytic agent or postnatally to affect the closure of a PDA [108, 109]. The efficacy of this treatment has been demonstrated in several prospective trials [110, 111]. Perinatal exposure has been documented as a risk factor for intestinal injury in VLBW infants [112114]. However, other studies have not been able to support these claims [115, 116]. With increasing usage, reports emerged the linking indomethacin use to isolated intestinal perforation (IIP) and necrotising enterocolitis [117119]. However, most of these were retrospective studies and did not carefully differentiate between IIP and NEC. Furthermore, one of these studies failed to eliminate PDA as a confounding variable, a well-documented risk factor for NEC [120]. In contrast, a thorough prospective analysis over 12 years into the exact effect of perinatal indomethacin use found a positive association with IIP but a negative association with NEC using multivariate logistic regression analysis (exposed: 14.6% unexposed: 9.9%) [121]. These findings were independent of maternal milk feeding and have been supported by subsequent research [122]. It appears therefore that the protective benefits of indomethacin for NEC have potentially been masked by confounders such as IIP and PDA.

20. Dexamethasone

Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. The most likely underlying pathogenesis involves persistent inflammation in the lungs. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects [123]. Early studies appeared to show a link between dexamethasone use and NEC, one reporting a 7.4% increase in the group exposed to steroids [124]. Increased frequency of sepsis and neonatal infections was also seen in this group. Despite this finding, many other studies have reported an overall decrease in perinatal mortality in the group treated with steroids [125]. More recently, the topic of steroid use perinatally has been the focus of an extensive Cochrane review. It demonstrated that steroids are effective both prenatally and/or postnatally in promoting lung maturation, and that they were not found to be associated with increased incidence of NEC [126, 127].

Other identified risk factors that are not possible to discuss within the confines of this report include maternal cocaine use, variations in blood glucose levels, sepsis, IgA supplementation, and the stool cultures of pathogenic micro-organisms [128, 129].

21. Conclusions

This paper highlights just one of the many challenges involved in neonatal intensive care. Necrotising enterocolitis has proven itself as an immensely enigmatic and morbid disease, the aetiology of which is tied up in a minefield of medical literature, much of it conflicting in its findings. This paper has demonstrated the paramount importance nutrition in the first few weeks of life and what a fine balance needs to be struck between malnourishment and high risk aggressive feeding.

There still remain many potential risk factors for NEC; however, the extent to which these risk factors are important in the aetiology of NEC continues to elude medical research. It seems that no individual factor alone is sufficient to precipitate NEC pointing to a multifactorial aetiology. However, with the management of premature neonates being aggressively monitored and standardised, possibilities or a more intrinsic nutrient-gene interaction arises, which we have yet to understand. By understanding this in the future, we might be able to develop targeted therapies for individuals who are most susceptible to NEC.

Abbreviations

NEC:Necrotising enterocolitis
EBM: Expressed breast milk
DEBM: Donor expressed breast milk
RACH: Royal Alexandra children’s hospital
RSCH: Royal Sussex County hospital
TPN: Total parenteral nutrition
EN: Enteral nutrition
RDS: Respiratory distress syndrome
CLD: Chronic lung disease
PDA: Patent ductus arteriosus
IVH: Intraventricular haemorrhage
BPD: Bronchopulmonary dysplasia
GOR: Gastro-oesophageal reflux
PTX: Pneumothorax
FC: Faecal calprotectin
IIP:Isolated intestinal perforation.

Disclosure

The authors confirm that the submitted work is all their own work and is in their own words. They confirm that the sources (books, journals, websites, etc.) they have referred to and from which they have quoted are listed in the citations submitted with this piece of work.

References

  1. J. L. Grosfeld, “Jejumoilial atresia and stenosis,” in Paediatric Surgery, p. 838, Chicago, Ill, USA, 4th edition, 1986.
  2. L. W. Martin and J. T. Zerella, “Jejunoilial atresia: a proposed classification,” Journal of Pediatric Surgery, vol. 11, p. 1149, 1967.
  3. N. McIntosh, P. Helms, S. Rosalind, and S. Logan, Textbook of Paediatrics, Churchill Livingston, London, UK, 7th edition, 2008.
  4. P. W. Wales and E. R. Christison-Lagay, “Short bowel syndrome: epidemiology and etiology,” Seminars in Pediatric Surgery, vol. 19, no. 1, pp. 3–9, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. B. P. Modi, M. Langer, Y. A. Ching et al., “Improved survival in a multidisciplinary short bowel syndrome program,” Journal of Pediatric Surgery, vol. 43, no. 1, pp. 20–24, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. D. A. Kafetzis, C. Skevaki, and C. Costalos, “Neonatal necrotizing enterocolitis: an overview,” Current Opinion in Infectious Diseases, vol. 16, no. 4, pp. 349–355, 2003. View at Scopus
  7. A. Paltauf, “Die spontane dickdarmruptur der neugebornen,” Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin, vol. 111, no. 3, pp. 461–474, 1888. View at Publisher · View at Google Scholar · View at Scopus
  8. O. Schmid and K. Quaiser, “Uer eine besondere schwere verlaufende Form von Enteritis beim saugling,” Oesterr Z Kinderh, vol. 8, p. 114, 1953.
  9. A. M. Kosloske, “Epidemiology of necrotizing enterocolitis,” Acta Paediatrica, Supplement, vol. 83, no. 396, pp. 2–7, 1994. View at Scopus
  10. R. C. Holman, B. J. Stoll, M. J. Clarke, and R. I. Glass, “The epidemiology of necrotizing enterocolitis infant mortality in the United States,” American Journal of Public Health, vol. 87, no. 12, pp. 2026–2031, 1997. View at Scopus
  11. R. D. Uauy, A. A. Fanaroff, S. B. Korones, E. A. Phillips, J. B. Philips, and L. L. Wright, “Necrotizing entercolitis in very low birth weight infants: biodemographic and clinical correlates,” Journal of Pediatrics, vol. 119, no. 4, pp. 630–638, 1991. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Rennie, Roberton’s Textbook of Neonatology, Elsevier, Beijing, China, 4th edition, 2005.
  13. A. M. Kosloske, “Epidemiology of necrotising enterocolitis,” Acta Paediatrica, vol. 83, no. s396, pp. 2–7, 1994. View at Publisher · View at Google Scholar
  14. A. Lucas and R. Abbott, “British paediatric surveillance unit,” Annual Report, Royal College of Paediatrics and Child Health, 1997, http://bpsu.inopsu.com/publications/reports/nnec.html.
  15. P. J. Beeby and H. Jeffery, “Risk factors for necrotising enterocolitis: the influence of gestational age,” Archives of Disease in Childhood, vol. 67, no. 4, pp. 432–435, 1992. View at Scopus
  16. D. A. Clark and M. Miller, “What causes NEC and how can it be prevented? Current topics,” in Neonatology 1, pp. 160–176, Saunders, London, UK, 1996.
  17. R. M. Kliegman, W. A. Walker, and R. H. Yolken, “Necrotizing enterocolitis: research agenda for a disease of unknown etiology and pathogenesis,” Pediatric Research, vol. 34, no. 6, pp. 701–708, 1993. View at Scopus
  18. T. V. Santulli, J. N. Schullinger, and W. C. Heird, “Acute necrotizing enterocolitis in infancy: a review of 64 cases,” Pediatrics, vol. 55, no. 3, pp. 376–387, 1975. View at Scopus
  19. R. Engel, N. Virnig, C. Hunt, and M. Levitt, “Origin of mural gas in NEC,” Paediatric Research, vol. 7, p. 292, 1975.
  20. G. B. Hopkins, V. E. Gould, J. K. Stevenson, and T. K. Oliver Jr., “Necrotizing enterocolitis in premature infants. A clinical and pathologic evaluation of autopsy material,” American Journal of Diseases of Children, vol. 120, no. 3, pp. 229–232, 1970.
  21. J. A. Morecroft, L. Spitz, P. A. Hamilton, and S. J. K. Holmes, “Plasma interleukin-6 and tumour necrosis factor levels as predictors of disease severity and outcome in necrotizing enterocolitis,” Journal of Pediatric Surgery, vol. 29, no. 6, pp. 798–800, 1994. View at Publisher · View at Google Scholar · View at Scopus
  22. A. K. Ewer, “Role of platelet-activating factor in the pathophysiology of necrotizing enterocolitis,” Acta Paediatrica. Supplement, vol. 91, no. 437, pp. 2–5, 2002.
  23. W. MacKendrick, N. Hill, W. Hsueh, and M. Caplan, “Increase in plasma platelet-activating factor levels in enterally fed preterm infants,” Biology of the Neonate, vol. 64, no. 2-3, pp. 89–95, 1993. View at Scopus
  24. M. S. Caplan, E. Hedlund, L. Adler, M. Lickerman, and W. Hsueh, “The platelet-activating factor receptor antogonist WEB 2170 prevents neonatal necrotizing enterocolitis in rats,” Journal of Pediatric Gastroenterology and Nutrition, vol. 24, no. 3, pp. 296–301, 1997. View at Publisher · View at Google Scholar · View at Scopus
  25. M. D. Amer, E. Hedlund, J. Rochester, and M. S. Caplan, “Platelet-activating factor concentration in the stool of human newborns: effects of enteral feeding and neonatal necrotizing enterocolitis,” Biology of the Neonate, vol. 85, no. 3, pp. 159–166, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. J. Rennie, Roberton’s Textbook of Neonatology, Elsevier, Beijing, China, 4th edition, 2005.
  27. I. R. Holzman and D. R. Brown, “Necrotizing enterocolitis: a complication of prematurity,” Seminars in Perinatology, vol. 10, no. 3, pp. 208–216, 1986. View at Scopus
  28. D. A. Clark and M. J. S. Miller, “What causes neonatal necrotising enterocolitis and how can it be prevented? Current topics,” in Neonatology 1, pp. 160–176, WB Saunders, London, UK, 1996.
  29. V. Y. H. Yu, R. Joseph, and B. Bajuk, “Perinatal risk factors for necrotizing enterocolitis,” Archives of Disease in Childhood, vol. 59, no. 5, pp. 430–434, 1984. View at Scopus
  30. A. Bajraktarevic, A. D. Djulepa, H. Boloban et al., “Low birth weight is the most important risk factor for developing necrotizing enterocolitis in Bosnia,” Early Human Development, vol. 86, p. S71, 2010.
  31. P. J. Beeby and H. Jeffery, “Risk factors for necrotising enterocolitis: the influence of gestational age,” Archives of Disease in Childhood, vol. 67, no. 4, pp. 432–435, 1992. View at Scopus
  32. J. Rennie, Roberton’s Textbook of Neonatology, Elsevier, Beijing, China, 4th edition, 2005.
  33. B. M. Carter and D. Holditch-Davis, “Risk factors for necrotizing enterocolitis in preterm infants: how race, gender, and health status contribute,” Advances in Neonatal Care, vol. 8, no. 5, pp. 285–290, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. D. E. Ballot, T. F. Chirwa, and P. A. Cooper, “Determinants of survival in very low birth weight neonates in a public sector hospital in Johannesburg,” BMC Pediatrics, vol. 10, article no. 30, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. A. R. Llanos, M. E. Moss, M. C. Pinzòn, T. Dye, R. A. Sinkin, and J. W. Kendig, “Epidemiology of neonatal necrotising enterocolitis: a population-based study,” Paediatric and Perinatal Epidemiology, vol. 16, no. 4, pp. 342–349, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. S. R. Palmer, S. J. Thomas, R. W. I. Cooke, et al., “Birthweight-specific risk factors for necrotising enterocolitis,” Journal of Epidemiology and Community Health, vol. 41, no. 3, pp. 210–214, 1987. View at Scopus
  37. G. A. Hackett, S. Campbell, H. Gamsu, T. Cohen-Overbeek, and J. M. Pearce, “Doppler studies in the growth retarded fetus and prediction of neonatal necrotising enterocolitis, haemorrhage, and neonatal morbidity,” British Medical Journal, vol. 294, no. 6563, pp. 13–16, 1987. View at Scopus
  38. P. J. Beeby and H. Jeffery, “Risk factors for necrotising enterocolitis: the influence of gestational age,” Archives of Disease in Childhood, vol. 67, no. 4, pp. 432–435, 1992. View at Scopus
  39. R. N. Goldberg, D. W. Thomas, and F. R. Sinatra, “Necrotizing enterocolitis in the asphyxiated full-term infant,” American Journal of Perinatology, vol. 1, no. 1, pp. 40–42, 1983. View at Scopus
  40. A. Guven, G. Gundogdu, B. Uysal et al., “Hyperbaric oxygen therapy reduces the severity of necrotizing enterocolitis in a neonatal rat model,” Journal of Pediatric Surgery, vol. 44, no. 3, pp. 534–540, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. S. Sullivan, R. J. Schanler, J. H. Kim et al., “An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products,” Journal of Pediatrics, vol. 156, no. 4, pp. 562.e1–567.e1, 2010. View at Publisher · View at Google Scholar · View at Scopus
  42. A. Lucas and T. J. Cole, “Breast milk and neonatal necrotising enterocolitis,” The Lancet, vol. 336, no. 8730-8731, pp. 1519–1523, 1990. View at Scopus
  43. W. McGuire and M. Y. Anthony, “Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 88, no. 1, pp. F11–F14, 2003. View at Scopus
  44. R. J. Schanler, “Outcomes of human milk-fed premature infants,” Seminars in Perinatology, vol. 35, no. 1, pp. 29–33, 2011. View at Publisher · View at Google Scholar · View at Scopus
  45. R. J. McClure, “Trophic feeding of the preterm infant,” Acta Paediatrica. Supplement, vol. 90, no. 436, pp. 19–21, 2001. View at Scopus
  46. R. J. McClure and S. J. Newell, “Randomised controlled study of clinical outcome following trophic feeding,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 82, no. 1, pp. F29–F33, 2000. View at Scopus
  47. M. G. MacDonald, M. D. Kullet, and M. M. Seshia, Avery’s Neonatology. Pathophysiology and Management of the Newborn, Williams and Wilkins, Philadelphia, Pa, USA, 6th edition, 2005.
  48. C. L. Berseth, J. A. Bisquera, and V. U. Paje, “Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants,” Pediatrics, vol. 111, no. 3, pp. 529–534, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. G. Henderson, S. Craig, P. Brocklehurst, and W. McGuire, “Enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre case-control study,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 94, no. 2, pp. F120–F123, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. I. Le Hurou-Luron, S. Blat, and G. Boudry, “Breast- v. formula-feeding: impacts on the digestive tract and immediate and long-term health effects,” Nutrition Research Reviews, vol. 23, no. 1, pp. 23–36, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. S. J. Gross, R. J. David, L. Bauman, and R. M. Tomarelli, “Nutritional composition of milk produced by mothers delivering preterm,” Journal of Pediatrics, vol. 96, no. 4, pp. 641–644, 1980. View at Scopus
  52. J. van Acker, F. de Smet, G. Muyldermans, A. Bougatef, A. Naessens, and S. Lauwers, “Outbreak of necrotizing enterocolitis associated with Enterobacter sakazakii in powdered milk formula,” Journal of Clinical Microbiology, vol. 39, no. 1, pp. 293–297, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. E. Weir, “Powdered infant formula and fatal infection with Enterobacter sakazakii,” Canadian Medical Association Journal, vol. 166, no. 12, p. 1570, 2002. View at Scopus
  54. A. Fernández Polo, M. J. Cabañas Poy, S. Clemente Bautista, M. Oliveras Arenas, F. Castillo Salinas, and E. Hidalgo Albert, “Osmolality of oral liquid dosage forms to be administered to newborns in a hospital,” Farmacia Hospitalaria, vol. 31, no. 5, pp. 311–314, 2007. View at Publisher · View at Google Scholar · View at Scopus
  55. C. Bruns, “Hyperosmolarity—a cause of necrotising enterocolitis? Osmolarity of therapeutic additives in premature infant feeding,” Krankenhauspharmazie, vol. 27, no. 2, pp. 63–69, 2006. View at Scopus
  56. M. de Curtis, M. Candusso, C. Pieltain, and J. Rigo, “Effect of fortification on the osmolality of human milk,” Archives of Disease in Childhood: Fetal and Neonatal Edition, vol. 81, no. 2, pp. F141–F143, 1999. View at Scopus
  57. L. Srinivasan, R. Bokiniec, C. King, G. Weaver, and A. D. Edwards, “Increased osmolality of breast milk with therapeutic additives,” Archives of Disease in Childhood: Fetal and Neonatal Edition, p. 89, 2004.
  58. J. Blau, J. M. Calo, D. Dozor, M. Sutton, G. Alpan, and E. F. La Gamma, “Transfusion-related acute gut injury: necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion,” Journal of Pediatrics, vol. 158, no. 3, pp. 403–409, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. C. D. Josephson, A. Wesolowski, G. Bao et al., “Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants?” Journal of Pediatrics, vol. 157, no. 6, pp. 972.e3–978.e3, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. R. D. Leake, B. Thanopoulos, and R. Nieberg, “Hyperviscosity syndrome associated with necrotizing enterocolitis,” American Journal of Diseases of Children, vol. 129, no. 10, pp. 1192–1194, 1975. View at Scopus
  61. T. Gunn and E. Outerbridge, “Polycythemia as a cause of necrotizing enterocolitis,” Canadian Medical Association Journal, vol. 117, no. 5, p. 438, 1977. View at Scopus
  62. Z. Ali, “A review of 36 babies with necrotizing enterocolitis,” Journal of Tropical Pediatrics, vol. 35, no. 6, pp. 274–276, 1989. View at Scopus
  63. D. K. Lambert, R. D. Christensen, E. Henry et al., “Necrotizing enterocolitis in term neonates: data from a multihospital health-care system,” Journal of Perinatology, vol. 27, no. 7, pp. 437–443, 2007. View at Publisher · View at Google Scholar · View at Scopus
  64. N. A. Buch, S. M. Ahmad, S. W. Ali, and H. M. Hassan, “An epidemiological study of neonatal necrotizing enterocolitis,” Saudi Medical Journal, vol. 22, no. 3, pp. 231–237, 2001. View at Scopus
  65. T. E. Wiswell, C. F. Robertson, T. A. Jones, and D. J. Tuttle, “Necrotizing enterocolitis in full-term infants. A case-control study,” American Journal of Diseases of Children, vol. 142, no. 5, pp. 532–535, 1988. View at Scopus
  66. A. J. Clarke and J. R. Sibert, “Hypernatraemic dehydration and necrotizing enterocolitis,” Postgraduate Medical Journal, vol. 61, no. 711, pp. 65–66, 1985. View at Scopus
  67. S. P. Dunn, K. R. Gross, L. R. Scherer, S. Moenning, A. Desanto, and J. L. Grosfeld, “The effect of polycythemia and hyperviscosity on bowel ischemia,” Journal of Pediatric Surgery, vol. 20, no. 4, pp. 324–327, 1985. View at Scopus
  68. M. H. LeBlanc, C. D'Cruz, and K. Pate, “Necrotizing enterocolitis can be caused by polycythemic hyperviscosity in the newborn dog,” Journal of Pediatrics, vol. 105, no. 5, pp. 804–809, 1984. View at Scopus
  69. WHO, “Polycythemia in the Newborn,” AIIMS- NICU protocols, 2007, http://www.newbornwhocc.org/.
  70. S. C. Springer, “Necrotizing Enterocolitis: Differential Diagnoses & Workup,” 2011, http://emedicine.medscape.com/article/977956-diagnosis.
  71. Y. Bayraktar and O. Harmanci, “Etiology and consequences of thrombosis in abdominal vessels,” World Journal of Gastroenterology, vol. 12, no. 8, pp. 1165–1174, 2006. View at Scopus
  72. R. F. Burrows and J. G. Kelton, “Perinatal thrombocytopenia,” Clinics in Perinatology, vol. 22, no. 3, pp. 779–801, 1995. View at Scopus
  73. A. B. Kenton, D. O'Donovan, D. L. Cass et al., “Severe thrombocytopenia predicts outcome in neonates with necrotizing enterocolitis,” Journal of Perinatology, vol. 25, no. 1, pp. 14–20, 2005. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Ververidis, E. M. Kiely, L. Spitz, D. P. Drake, S. Eaton, and A. Pierro, “The clinical significance of thrombocytopenia in neonates with necrotizing enterocolitis,” Journal of Pediatric Surgery, vol. 36, no. 5, pp. 799–803, 2001. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Saxena, M. Kannan, and V. P. Choudhry, “Neonatal thrombosis,” Indian Journal of Pediatrics, vol. 70, no. 11, pp. 903–907, 2003. View at Scopus
  76. A. J. Clarke and J. R. Sibert, “Hypernatraemic dehydration and necrotizing enterocolitis,” Postgraduate Medical Journal, vol. 61, no. 711, pp. 65–66, 1985. View at Scopus
  77. S. Oddie, S. Richmond, and M. Coulthard, “Hypernatraemic dehydration and breast feeding: a population study,” Archives of Disease in Childhood, vol. 85, no. 4, pp. 318–320, 2001. View at Publisher · View at Google Scholar · View at Scopus
  78. E. F. Bell and M. J. Acarregui, “Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD000503, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. D. Isaacs, J. North, D. Lindsell, and A. R. Wilkinson, “Serum acute phase reactants in necrotizing enterocolitis,” Acta Paediatrica Scandinavica, vol. 76, no. 6, pp. 923–927, 1987. View at Scopus
  80. M. Hällström, A. M. Koivisto, M. Janas, and O. Tammela, “Laboratory parameters predictive of developing necrotizing enterocolitis in infants born before 33 weeks of gestation,” Journal of Pediatric Surgery, vol. 41, no. 4, pp. 792–798, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. N. Evennett, N. Alexander, M. Petrov, A. Pierro, and S. Eaton, “A systematic review of serologic tests in the diagnosis of necrotizing enterocolitis,” Journal of Pediatric Surgery, vol. 44, no. 11, pp. 2192–2201, 2009. View at Publisher · View at Google Scholar · View at Scopus
  82. P. H. Schober and J. Nassiri, “Risk factors and severity indices in necrotizing enterocolitis,” Acta Paediatrica. Supplement, vol. 83, no. 396, pp. 49–52, 1994. View at Scopus
  83. R. Srinivasjois, E. Nathan, D. Doherty, and S. Patole, “Prediction of progression of definite necrotising enterocolitis to need for surgery or death in preterm neonates,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 23, no. 7, pp. 695–700, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. M. Pourcyrous, H. S. Bada, S. B. Korones, V. Baselski, and S. P. Wong, “Significance of serial C-reactive protein responses in neonatal infection and other disorders,” Pediatrics, vol. 92, no. 3, pp. 431–435, 1993. View at Scopus
  85. M. Pourcyrous, H. S. Bada, S. B. Korones, F. F. Barrett, W. Jennings, and T. Lockey, “Acute phase reactants in neonatal bacterial infection,” Journal of Perinatology, vol. 11, no. 4, pp. 319–325, 1991. View at Scopus
  86. M. Pourcyrous, S. B. Korones, W. Yang, T. F. Boulden, and H. S. Bada, “C-reactive protein in the diagnosis, management, and prognosis of neonatal necrotizing enterocolitis,” Pediatrics, vol. 116, no. 5, pp. 1064–1069, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. R. N. Goldberg, D. W. Thomas, and F. R. Sinatra, “Necrotizing enterocolitis in the asphyxiated full-term infant,” American Journal of Perinatology, vol. 1, no. 1, pp. 40–42, 1983. View at Scopus
  88. B. Stoll, D. A. Horst, L. Cui et al., “Chronic parenteral nutrition induces hepatic inflammation, steatosis, and insulin resistance in neonatal pigs,” Journal of Nutrition, vol. 140, no. 12, pp. 2193–2200, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. P. J. Javid, S. Collier, D. Richardson et al., “The role of enteral nutrition in the reversal of parenteral nutrition-associated liver dysfunction in infants,” Journal of Pediatric Surgery, vol. 40, no. 6, pp. 1015–1018, 2005. View at Publisher · View at Google Scholar · View at Scopus
  90. P. J. Clarke, M. J. Ball, and M. G. W. Kettlewell, “Liver function tests in patients receiving parenteral nutrition,” Journal of Parenteral and Enteral Nutrition, vol. 15, no. 1, pp. 54–59, 1991. View at Scopus
  91. D. A. K. Watters, S. Chamroonkul, and C. D. M. Griffith, “Changes in liver function tests associated with parenteral nutrition,” Journal of the Royal College of Surgeons of Edinburgh, vol. 29, no. 6, pp. 339–344, 1984. View at Scopus
  92. G. Thuijls, J. P. M. Derikx, K. van Wijck et al., “Non-invasive markers for early diagnosis and determination of the severity of necrotizing enterocolitis,” Annals of Surgery, vol. 251, no. 6, pp. 1174–1180, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Carroll, A. Corfield, R. Spicer, and P. Cairns, “Faecal calprotectin concentrations and diagnosis of necrotising enterocolitis,” The Lancet, vol. 361, no. 9354, pp. 310–311, 2003. View at Publisher · View at Google Scholar · View at Scopus
  94. Q. Yang, P. B. Smith, R. N. Goldberg, and C. M. Cotten, “Dynamic change of fecal calprotectin in very low birth weight infants during the first month of life,” Neonatology, vol. 94, no. 4, pp. 267–271, 2008. View at Publisher · View at Google Scholar · View at Scopus
  95. T. Rand, M. Weninger, C. Kohlhauser et al., “Effects of umbilical arterial catheterization on mesenteric hemodynamics,” Pediatric Radiology, vol. 26, no. 7, pp. 435–438, 1996. View at Publisher · View at Google Scholar · View at Scopus
  96. A. Gentili, V. Landuzzi, L. Pasini, A. Pigna, A. Cacciari, and A. S. Corticelli, “Risk factors and protective factors in a population a risk for newborn necrotizing enterocolitis,” La Pediatria Medica e Chirurgica, vol. 18, no. 5, pp. 487–492, 1996. View at Scopus
  97. S. O. Guthrie, P. V. Gordon, V. Thomas, J. A. Thorp, J. Peabody, and R. H. Clark, “Necrotizing enterocolitis among neonates in the United States,” Journal of Perinatology, vol. 23, no. 4, pp. 278–285, 2003. View at Publisher · View at Google Scholar · View at Scopus
  98. N. S. Kabra, M. Kumar, and S. S. Shah, “Multiple versus single lumen umbilical venous catheters for newborn infants,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD004498, 2005. View at Scopus
  99. G. Parry, J. Tucker, and W. Tarnow-Mordi, “CRIB II: an update of the clinical risk index for babies score,” The Lancet, vol. 361, no. 9371, pp. 1789–1791, 2003. View at Publisher · View at Google Scholar · View at Scopus
  100. P. K. Rastogi, V. Sreenivas, and N. Kumar, “Validation of CRIB II for prediction of mortality in premature babies,” Indian Pediatrics, vol. 47, no. 2, pp. 145–147, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. J. Madan, J. Fiascone, V. Balasubramanian, J. Griffith, and J. I. Hagadorn, “Predictors of ductal closure and intestinal complications in very low birth weight infants treated with indomethacin,” Neonatology, vol. 94, no. 1, pp. 45–51, 2008. View at Publisher · View at Google Scholar · View at Scopus
  102. S. E. G. Hamrick and G. Hansmann, “Patent ductus arteriosus of the preterm infant,” Pediatrics, vol. 125, no. 5, pp. 1020–1030, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. R. L. Meyers, G. Alpan, E. Lin, and R. I. Clyman, “Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption,” Pediatric Research, vol. 29, no. 6, pp. 569–574, 1991. View at Scopus
  104. D. O'Donovan, A. Baetiong, K. Adams et al., “Necrotizing enterocolitis and gastrointestinal complications after indomethacin therapy and surgical ligation in premature infants with patent ductus arteriosus,” Journal of Perinatology, vol. 23, no. 4, pp. 286–290, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. P. T. Nowicki, C. E. Miller, and R. C. Edwards, “Effects of hypoxia and ischemia on autoregulation in postnatal intestine,” American Journal of Physiology, vol. 261, no. 1, pp. G152–G157, 1991. View at Scopus
  106. C. Michael Cotten, S. Taylor, B. Stoll et al., “Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of necrotizing enterocolitis and death for extremely low birth weight infants,” Pediatrics, vol. 123, no. 1, pp. 58–66, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. A. Tagare, S. Kadam, U. Vaidya, and A. Pandit, “Routine antibiotic use in preterm neonates: a randomised controlled trial,” The Journal of Hospital Infection, vol. 74, no. 4, pp. 332–336, 2010. View at Scopus
  108. J. Madan, J. Fiascone, V. Balasubramanian, J. Griffith, and J. I. Hagadorn, “Predictors of ductal closure and intestinal complications in very low birth weight infants treated with indomethacin,” Neonatology, vol. 94, no. 1, pp. 45–51, 2008. View at Publisher · View at Google Scholar · View at Scopus
  109. G. A. Macones, S. J. Marder, B. Clothier, and D. M. Stamilio, “The controversy surrounding indomethacin for tocolysis,” American Journal of Obstetrics and Gynecology, vol. 184, no. 3, pp. 264–272, 2001. View at Publisher · View at Google Scholar · View at Scopus
  110. W. J. Morales and H. Madhav, “Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study,” American Journal of Obstetrics and Gynecology, vol. 169, no. 1, pp. 97–102, 1993. View at Scopus
  111. T. Kurki, M. Eronen, R. A. Lumme, and O. Ylikorkala, “A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor,” Obstetrics and Gynecology, vol. 78, no. 6, pp. 1093–1097, 1991. View at Scopus
  112. S. Abbasi, J. S. Gerdes, H. M. Sehdev, S. S. Samimi, and J. Ludmir, “Neonatal outcome after exposure to indomethacin in utero: a retrospective case cohort study,” American Journal of Obstetrics and Gynecology, vol. 189, no. 3, pp. 782–785, 2003. View at Publisher · View at Google Scholar · View at Scopus
  113. S. B. Amin, R. A. Sinkin, and J. C. Glantz, “Metaanalysis of the effect of antenatal indomethacin on neonatal outcomes,” American Journal of Obstetrics and Gynecology, vol. 197, no. 5, pp. 486.e1–486.e10, 2007. View at Publisher · View at Google Scholar · View at Scopus
  114. A. M. Fujii, E. Brown, M. Mirochnick, S. O'Brien, and G. Kaufman, “Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus,” Journal of Perinatology, vol. 22, no. 7, pp. 535–540, 2002. View at Publisher · View at Google Scholar · View at Scopus
  115. S. T. Vermillion and R. B. Newman, “Recent indomethacin tocolysis is not associated with neonatal complications in preterm infants,” American Journal of Obstetrics and Gynecology, vol. 181, no. 5, pp. 1083–1086, 1999. View at Publisher · View at Google Scholar · View at Scopus
  116. B. V. Parilla, W. A. Grobman W., R. B. Holtzman, H. A. Thomas, and S. L. Dooley, “Indomethacin tocolysis and risk of necrotizing enterocolitis,” Obstetrics and Gynecology, vol. 96, no. 1, pp. 120–123, 2000. View at Publisher · View at Google Scholar · View at Scopus
  117. N. A. Shorter, J. Y. Liu, D. P. Mooney, and B. J. Harmon, “Indomethacin-associated bowel perforations: a study of possible risk factors,” Journal of Pediatric Surgery, vol. 34, no. 3, pp. 442–444, 1999. View at Scopus
  118. Y. Kawase, T. Ishii, H. Arai, and N. Uga, “Gastrointestinal perforation in very low-birthweight infants,” Pediatrics International, vol. 48, no. 6, pp. 599–603, 2006. View at Publisher · View at Google Scholar · View at Scopus
  119. J. L. Grosfeld, M. Chaet, F. Molinari et al., “Increased risk of necrotizing enterocolitis in premature infants with patent ductus arteriosus treated with indomethacin,” Annals of Surgery, vol. 224, no. 3, pp. 350–357, 1996. View at Publisher · View at Google Scholar · View at Scopus
  120. M. E. Norton, J. Merrill, B. A. B. Cooper, J. A. Kuller, and R. I. Clyman, “Neonatal complications after the administration of indomethacin for preterm labor,” New England Journal of Medicine, vol. 329, no. 22, pp. 1602–1607, 1993. View at Publisher · View at Google Scholar · View at Scopus
  121. R. Sharma, M. L. Hudak, J. J. Tepas 3rd et al., “Prenatal or postnatal indomethacin exposure and neonatal gut injury associated with isolated intestinal perforation and necrotizing enterocolitis,” Journal of Perinatology, vol. 30, no. 12, pp. 786–793, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. P. C. Tsao, S. J. Chen, C. F. Yang et al., “Comparison of intravenous and enteral indomethacin administration for closure of patent ductus arteriosus in extremely-low-birth-weight infants,” Journal of the Chinese Medical Association, vol. 73, no. 1, pp. 15–20, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. H. L. Halliday, R. A. Ehrenkranz, and L. W. Doyle, “Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD001146, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. D. E. da Costa, P. A. K. Nair, and S. M. Al Khusaiby, “Effects of antenatal steroids on the complications of prematurity in an era of surfactant replacement therapy in Oman,” Journal of Tropical Pediatrics, vol. 46, no. 6, pp. 375–377, 2000. View at Publisher · View at Google Scholar · View at Scopus
  125. R. C. Pattinson, J. D. Makin, M. Funk et al., “The use of dexamethasone in women with preterm premature rupture of membranes—a multicentre, double-blind, placebo-controlled, randomised trial,” South African Medical Journal, vol. 89, no. 8, pp. 865–870, 1999. View at Scopus
  126. D. Roberts and S. Dalziel, “Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth,” Cochrane Database of Systematic Reviews, vol. 3, Article ID CD004454, 2006. View at Scopus
  127. H. L. Halliday, R. A. Ehrenkranz, and L. W. Doyle, “Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD001145, 2009. View at Scopus
  128. G. Deshpande, S. Rao, and S. Patole, “Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: a systematic review of randomised controlled trials,” The Lancet, vol. 369, no. 9573, pp. 1614–1620, 2007. View at Publisher · View at Google Scholar · View at Scopus
  129. C. Czyrko, C. A. Del Pin, J. A. O'Neill Jr., G. J. Peckham, and A. J. Ross 3rd, “Maternal cocaine abuse and necrotizing enterocolitis: outcome and survival,” Journal of Pediatric Surgery, vol. 26, no. 4, pp. 414–421, 1991. View at Publisher · View at Google Scholar · View at Scopus