Association of Inhibitors of Gastric Acid Secretion and Higher Incidence of Necrotizing Enterocolitis in Preterm Very Low-Birth-Weight Infants

Abstract

Background Inhibitors of gastric acid (IGA) are used for upper gastrointestinal bleeding or gastroesophageal reflux in preterm infants. The resultant increase in gastric pH may enhance the growth of pathogens and increase the risk of necrotizing enterocolitis (NEC). Our systematic review examined the association between IGA and NEC in preterm infants.

Methods Standard methodology of systematic reviews was followed. PubMed, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched in August 2012.

Results One case–control and one prospective cohort study (n = 11,346), both evaluating H2-blockers as IGA, were included. Meta-analysis showed a significant association between NEC and IGA (odds ratio [OR]: 1.78, 95% confidence interval [CI]: 1.4, 2.27, p < 0.00001). The prospective cohort study found higher incidence of infection (sepsis, pneumonia, urinary tract infection) with IGA (37.4% versus 9.8%, OR: 5.5, 95% CI: 2.9 to 10.4, p < 0.001).

Conclusions Exposure to H2 receptor antagonists may be associated with increased risk of NEC and infections in preterm infants.

Keywords

gastric acid - inhibitors - necrotizing enterocolitis - preterm - very low birth weight

• References

• 1 Obladen M. Necrotizing enterocolitis—150 years of fruitless search for the cause. Neonatology 2009; 96: 203-210
• 2 Grave GD, Nelson SA, Walker WA , et al. New therapies and preventive approaches for necrotizing enterocolitis: report of a research planning workshop. Pediatr Res 2007; 62: 510-514
• 3 Thompson AM, Bizzarro MJ. Necrotizing enterocolitis in newborns: pathogenesis, prevention and management. Drugs 2008; 68: 1227-1238
• 4 Henry MC, Moss RL. Necrotizing enterocolitis. Annu Rev Med 2009; 60: 111-124
• 5 Lemons JA, Bauer CR, Oh W , et al; NICHD Neonatal Research Network. Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. Pediatrics 2001; 107: E1
• 6 Guner YS, Chokshi N, Petrosyan M, Upperman JS, Ford HR, Grikscheit TC. Necrotizing enterocolitis—bench to bedside: novel and emerging strategies. Semin Pediatr Surg 2008; 17: 255-265
• 7 Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants. Pediatrics 2002; 109: 423-428
• 8 Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 2003; 6: 6-23
• 9 Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011; 364: 255-264
• 10 Stoll BJ. Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994; 21: 205-218
• 11 Malcolm WF, Cotten CM. Metoclopramide, H2 blockers, and proton pump inhibitors: pharmacotherapy for gastroesophageal reflux in neonates. Clin Perinatol 2012; 39: 99-109
• 12 Stroup DF, Berlin JA, Morton SC , et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008-2012
• 13 Lin HJ, Shi LP, Luo F, Bao Y, Ma XL. [Value of radiographic assessment scale in necrotizing enterocolitis]. Zhongguo Dang Dai Er Ke Za Zhi 2012; 14: 97-100
• 14 Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603-605
• 15 Higgins JPT, Deeks JJ (editors). Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S, (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org
• 16 Sterne Jonathan AC, Sutton AJ, Ioannidis JP , et al. Recommendations for examining and interpreting funnel plot asymmetry in meta analyses of randomised controlled trials. BMJ 2011; 342: d4002
• 17 Terrin G, Passariello A, De Curtis M , et al. Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 2012; 129: e40-e45
• 18 Guillet R, Stoll BJ, Cotten CM , et al; National Institute of Child Health and Human Development Neonatal Research Network. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117: e137-e142
• 19 Gantz M, Roy J, Guillet R. Analyzing retrospective data with time-varying exposure: a cautionary tale of H2 blockers in ELBW neonates. Am J Perinatol 2008; 25: 93-100
• 20 Ward RM, Tammara B, Sullivan SE , et al. Single-dose, multiple-dose, and population pharmacokinetics of pantoprazole in neonates and preterm infants with a clinical diagnosis of gastroesophageal reflux disease (GERD). Eur J Clin Pharmacol 2010; 66: 555-561
• 21 Omari TI, Haslam RR, Lundborg P, Davidson GP. Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux. J Pediatr Gastroenterol Nutr 2007; 44: 41-44
• 22 Omari T, Lundborg P, Sandström M , et al. Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease. J Pediatr 2009; 155: 222-228
• 23 Kierkus J, Furmaga-Jablonska W, Sullivan JE , et al. Pharmacodynamics and safety of pantoprazole in neonates, preterm infants, and infants aged 1 through 11 months with a clinical diagnosis of gastroesophageal reflux disease. Dig Dis Sci 2011; 56: 425-434
• 24 Wheatley E, Kennedy KA. Cross-over trial of treatment for bradycardia attributed to gastroesophageal reflux in preterm infants. J Pediatr 2009; 155: 516-521
• 25 Kelly EJ, Chatfield SL, Brownlee KG , et al. The effect of intravenous ranitidine on the intragastric pH of preterm infants receiving dexamethasone. Arch Dis Child 1993; 69 (1 Spec No) 37-39
• 26 Khalaf MN, Porat R, Brodsky NL, Bhandari V. Clinical correlations in infants in the neonatal intensive care unit with varying severity of gastroesophageal reflux. J Pediatr Gastroenterol Nutr 2001; 32: 45-49
• 27 Kuusela AL, Ruuska T, Karikoski R , et al. A randomized, controlled study of prophylactic ranitidine in preventing stress-induced gastric mucosal lesions in neonatal intensive care unit patients. Crit Care Med 1997; 25: 346-351
• 28 Lazzaroni M, Petrillo M, Tornaghi R , et al. Upper GI bleeding in healthy full-term infants: a case-control study. Am J Gastroenterol 2002; 97: 89-94
• 29 Sarna MS, Saili A, Dutta AK, Sharma D. Stress associated gastric bleeding in newborn—role of ranitidine. Indian Pediatr 1991; 28: 1305-1308
• 30 Pulsifer-Anderson E, Guillet R. National Institutes of Health recommends the routine use of H2 blockers in preterm infants be carefully evaluated. Neonatal Netw 2006; 25: 223-224
• 31 Tryba M. Role of acid suppressants in intensive care medicine. Best Pract Res Clin Gastroenterol 2001; 15: 447-461
• 32 Kuusela AL, Mäki M, Ruuska T, Laippala P. Stress-induced gastric findings in critically ill newborn infants: frequency and risk factors. Intensive Care Med 2000; 26: 1501-1506
• 33 Mäki M, Ruuska T, Kuusela AL, Karikoski-Leo R, Ikonen RS. High prevalence of asymptomatic esophageal and gastric lesions in preterm infants in intensive care. Crit Care Med 1993; 21: 1863-1867
• 34 Cotten CM, Malcolm WF. Ranitidine use is associated with increased morbidity and mortality in very low birthweight infants. Evid Based Med 2012; (Jun) 26
• 35 Dai D, Walker WA. Role of bacterial colonization in neonatal necrotizing enterocolitis and its prevention. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi 1998; 39: 357-365
• 36 Lichtman SM. Bacterial translocation in humans. J Pediatr Gastroenterol Nutr 2001; 33: 1-10
• 37 Ciftci I, Ozdemir M, Aktan M, Aslan K. Bacterial translocation and intestinal injury in experimental necrotizing enterocolitis model. Bratisl Lek Listy 2012; 113: 206-210
• 38 Giannella RA, Broitman SA, Zamcheck N. Gastric acid barrier to ingested microorganisms in man: studies in vivo and in vitro. Gut 1972; 13: 251-256
• 39 Kelly EJ, Chatfield SL, Brownlee KG , et al. The effect of intravenous ranitidine on the intragastric pH of preterm infants receiving dexamethasone. Arch Dis Child 1993; 69 (1 Spec No) 37-39
• 40 Carrion V, Egan EA. Prevention of neonatal necrotizing enterocolitis. J Pediatr Gastroenterol Nutr 1990; 11: 317-323
• 41 Başaran UN, Celayir S, Eray N, Oztürk R, Senyüz OF. The effect of an H2-receptor antagonist on small-bowel colonization and bacterial translocation in newborn rats. Pediatr Surg Int 1998; 13: 118-120
• 42 Karikoski R, Ruuska T. [Stress-related gastric mucosal lesions in neonatal intensive care patients—an unrecognized problem]. Duodecim 1998; 114: 313 , 315–316
• 43 Cothran DS, Borowitz SM, Sutphen JL, Dudley SM, Donowitz LG. Alteration of normal gastric flora in neonates receiving ranitidine. J Perinatol 1997; 17: 383-388
• 44 Beck-Sague CM, Azimi P, Fonseca SN , et al. Bloodstream infections in neonatal intensive care unit patients: results of a multicenter study. Pediatr Infect Dis J 1994; 13: 1110-1116
• 45 Kelly EJ, Newell SJ, Brownlee KG, Primrose JN, Dear PR. Gastric acid secretion in preterm infants. Early Hum Dev 1993; 35: 215-220
• 46 Choung RS, Ruff KC, Malhotra A , et al. Clinical predictors of small intestinal bacterial overgrowth by duodenal aspirate culture. Aliment Pharmacol Ther 2011; 33: 1059-1067
• 47 Lewis SJ, Franco S, Young G, O'Keefe SJ. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther 1996; 10: 557-561
• 48 Wang K, Lin HJ, Perng CL , et al. The effect of H2-receptor antagonist and proton pump inhibitor on microbial proliferation in the stomach. Hepatogastroenterology 2004; 51: 1540-1543
• 49 Sanaka M, Yamamoto T, Kuyama Y. Effects of proton pump inhibitors on gastric emptying: a systematic review. Dig Dis Sci 2010; 55: 2431-2440
• 50 Parkman HP, Urbain JL, Knight LC , et al. Effect of gastric acid suppressants on human gastric motility. Gut 1998; 42: 243-250
• 51 Goddard AF, Spiller RC. The effect of omeprazole on gastric juice viscosity, pH and bacterial counts. Aliment Pharmacol Ther 1996; 10: 105-109
• 52 Miano TA, Reichert MG, Houle TT, MacGregor DA, Kincaid EH, Bowton DL. Nosocomial pneumonia risk and stress ulcer prophylaxis: a comparison of pantoprazole vs ranitidine in cardiothoracic surgery patients. Chest 2009; 136: 440-447
• 53 Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b-245. Gut 1992; 33: 617-621
• 54 Agastya G, West BC, Callahan JM. Omeprazole inhibits phagocytosis and acidification of phagolysosomes of normal human neutrophils in vitro. Immunopharmacol Immunotoxicol 2000; 22: 357-372
• 55 Yoshida N, Yoshikawa T, Tanaka Y , et al. A new mechanism for anti-inflammatory actions of proton pump inhibitors—inhibitory effects on neutrophil-endothelial cell interactions. Aliment Pharmacol Ther 2000; 14 (Suppl. 01) 74-81
• 56 Biçakçi U, Tander B, Aritürk E , et al. Effects of omeprazole and gentamicin on the biochemical and histopathological alterations of the hypoxia/ reoxygenation induced intestinal injury in newborn rats. Pediatr Surg Int 2005; 21: 800-805
• 57 Cadir FO, Bicakci U, Tander B , et al. Protective effects of vitamin E and omeprazole on the hypoxia/reoxygenation induced intestinal injury in newborn rats. Pediatr Surg Int 2008; 24: 809-813
• 58 Shivanna B, Jiang W, Wang L, Couroucli XI, Moorthy B. Omeprazole attenuates hyperoxic lung injury in mice via aryl hydrocarbon receptor activation and is associated with increased expression of cytochrome P4501A enzymes. J Pharmacol Exp Ther 2011; 339: 106-114
• 59 Shivanna B, Chu C, Welty SE , et al. Omeprazole attenuates hyperoxic injury in H441 cells via the aryl hydrocarbon receptor. Free Radic Biol Med 2011; 51: 1910-1917