pediatrics 2011 terrin peds.2011 0796

DOI: 10.1542/peds.2011-0796; originally published online December 12, 2011;Pediatrics

Salvia, Laura Lega, Francesco Messina, Roberto Paludetto and Roberto Berni CananiGianluca Terrin, Annalisa Passariello, Mario De Curtis, Francesco Manguso, Gennaro

Outcome in NewbornsRanitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal

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of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2011 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Ranitidine is Associated With Infections, NecrotizingEnterocolitis, and Fatal Outcome in Newborns

WHATS KNOWN ON THIS SUBJECT: Although still off-label fornewborns, the use of inhibitors of gastric acid secretioncontinues to increase. Acid-suppressive drugs could facilitate theonset of infections in adults and children. Evidence for efficacy isweak in newborns, particularly if preterm.

WHAT THIS STUDY ADDS: This is the first prospective studydemonstrating an association between the use of ranitidine andinfections, necrotizing enterocolitis, and fatal outcome in very lowbirth weight newborns. Caution is advocated in using ranitidine innewborns.

abstractBACKGROUND AND OBJECTIVES: Gastric acidity is a major nonimmunedefense mechanism against infections. The objective of this study wasto investigate whether ranitidine treatment in very low birth weight(VLBW) infants is associated with an increased risk of infections, nec-rotizing enterocolitis (NEC), and fatal outcome.

METHODS: Newborns with birth weight between 401 and 1500 g orgestational age between 24 and 32 weeks, consecutively observedin neonatal intensive care units, were enrolled in a multicenter pro-spective observational study. The rates of infectious diseases, NEC,and death in enrolled subjects exposed or not to ranitidine wererecorded.

RESULTS: We evaluated 274 VLBW infants: 91 had taken ranitidine and183 had not. The main clinical and demographic characteristics did notdiffer between the 2 groups. Thirty-four (37.4%) of the 91 childrenexposed to ranitidine and 18 (9.8%) of the 183 not exposed toranitidine had contracted infections (odds ratio 5.5, 95% confidenceinterval 2.910.4, P , .001). The risk of NEC was 6.6-fold higher inranitidine-treated VLBW infants (95% confidence interval 1.725.0, P =.003) than in control subjects. Mortality rate was significantly higherin newborns receiving ranitidine (9.9% vs 1.6%, P = .003).

CONCLUSIONS: Ranitidine therapy is associated with an increasedrisk of infections, NEC, and fatal outcome in VLBW infants. Cautionis advocated in the use of this drug in neonatal age. Pediatrics2012;129:16

AUTHORS: Gianluca Terrin, MD, PhD,a Annalisa Passariello,MD, PhD,b,c Mario De Curtis, MD, PhD,d FrancescoManguso, MD, PhD,e Gennaro Salvia, MD,f Laura Lega, MD,g

Francesco Messina, MD,h Roberto Paludetto, MD,b andRoberto Berni Canani, MD, PhDb,i

aDepartment of Womens Health and Territorial Medicine,University La Sapienza, Rome, Italy; bDepartment of Pediatrics,University Federico II, Naples, Italy; cNeonatology Unit, MonaldiHospital, Naples, Italy; dDepartment of Pediatrics, University LaSapienza, Rome, Italy; eGastroenterology Unit, Cardarelli Hospital,Naples, Italy; fNeonatology Unit, Fatebenefratelli Hospital, Naples,Italy; gNeonatology Unit, Meyer Pediatric Hospital, Florence, Italy;hNeonatology Unit, V. Betania Evangelic Hospital, Naples, Italy; andiEuropean Laboratory for the Investigation of Food InducedDiseases, Naples, Italy

KEY WORDSgastric acidity inhibitors, histamine-2 receptor antagonists,sepsis, pneumonia, urinary tract infections, microflora, very lowbirth weight

ABBREVIATIONSBWbirth weightCIconfidence intervalCRIBCritical Risk Index for BabiesGAgestational ageGERDgastroesophageal reflux diseaseH2Rhistamine-2 receptorIVHintraventricular hemorrhageNECnecrotizing enterocolitisORodds ratioPDApersistent ductus arteriosusUTIurinary tract infectionVLBWvery low birth weight

www.pediatrics.org/cgi/doi/10.1542/peds.2011-0796

doi:10.1542/peds.2011-0796

Accepted for publication Sep 9, 2011

Address correspondence to Roberto Berni Canani, MD, PhD,Department of Pediatrics, University of Naples Federico II, ViaPansini 5, 80131, Naples, Italy. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright 2012 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

PEDIATRICS Volume 129, Number 1, January 2012 1

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Infections are a common cause ofmorbidity and mortality in prematureinfants.1 Gastric juice is a major non-immune defense mechanism againstinfections.2 Treatment with inhibitorsof gastric acid secretion leads to in-sufficient elimination of several inges-ted pathogens.311 Many studies showthat these drugs facilitate the onset ofinfections in adults37,12 and children,as we recently demonstrated.10 Thereis evidence of an increased risk ofinfections and necrotizing enterocolitis(NEC) related to the use of histamine-2receptor (H2-R) blockers and protonpump inhibitors in neonates.1315 Thesemedications, like many others admin-istered in neonatology, have not beenapproved by the US Food and DrugAdministration for use in this popula-tion and are prescribed in an off-labelmanner because of the perceivedsafety and potential benefit demon-strated for older populations. Despitethese aspects, the use of these drugshas progressively increased.12,16 In theNICU, the most common indicationsfor the administration of inhibitors ofgastric acid secretion are prophylaxisor therapy of stress ulcers and gas-troesophageal reflux disease (GERD),1517

but their efficacy in preterm infantsis still debated.16 In this context, weconducted a safety study to determinewhether there was an increased risk ofinfectious diseases, NEC, and mortalityin preterm newborns exposed to ranit-idine treatment.

METHODS

Populations

Newborns with birth weight ranging be-tween 401 and 1500 g or gestational agebetween 24 and 32 weeks, consecutivelyobserved in 4 Italian NICUs (UniversityFederico II, Naples; Fatebenefratelli Hos-pital, Naples; Meyer Pediatric Hospital,Florence; V. Betania Evangelic Hospital,Naples), from January 2006 to June 2007,were considered eligible for the study.

Exclusion criteria were immunodefi-ciency, malformations, evidence ofinfections or NEC before enrollment,critical conditions (blood pH , 6.8, orhypoxia with persistent bradycardia forat least 1 hour), ranitidine therapy forfewer than 7 days, and hospitalizationfor fewer than 8 weeks. We evaluated 2cohorts of very low birth weight (VLBW)newborns: those exposed or not ex-posed to ranitidine treatment. Indica-tions, dosage, and duration of ranitidinetreatment were decided by the care-givers of each NICU, who were unawareof the study aims. The study protocolwas approved by the Ethics Committeeof the University of Naples Federico II.Written informed consent was obtainedfrom the parents.

Outcome Measures

The main end point of the study wasthe rate of infections in newbornsexposed or not exposed to ranitidinetreatment. Secondary outcomes wereoccurrence of NEC (Bell stage .II),mortality, and duration of hospital stay.18

Sepsis was defined by the presenceof signs suggestive of infection associ-ated with a positive blood culture,as previously described.19 Pneumoniawas defined by the presence of clinicalsigns (progressive increase in oxygenrequirement, bradycardia, and/orapnea,tachypnea, or dyspnea) associatedwith positive culture of endotrachealaspirate (when patients were intu-bated) and with pathologic signs atchest examination and radiograph.20

Urinary tract infections (UTI) was di-agnosed when a positive urine culturetogether with clinical findings, such assign of sepsis, weight loss, or growthretardationwere present.21 Diagnosis ofNEC and Bell stage were decided onthe basis of standardized clinical andradiologic criteria.22

Data Collection

Researchers not in charge of theclinical management of the subjects

enrolled, and unaware of the studyaims, prospectively collected dataregarding: gestational age (GA); birthweight (BW); Apgar score; Critical RiskIndex for Babies (CRIB) score; occur-rence of infections or NEC; antibiotictherapy; indications for and dosage ofranitidine treatment; duration of rani-tidine treatment; modality and dura-tion of mechanical ventilation; oxygentherapy; presence and duration of cen-tral vascular access; intraventricularhemorrhage (IVH); persistent ductusarteriosus (PDA); time to reach fullenteral feeding; results of microbiolog-ical, radiologic, and laboratory tests;diagnosis of stress-induced peptic dis-ease and of GERD, time to discharge, ordeath.

Feeding Protocol

Enteral feeding was started on thefirst day of life at 10 mL/kg per day,distributed in 8 to 12 feeds, usingpreterm formula in all stable infants.Maternal unfortified milk was ad-ministered when available. Aspirateresidue from the orogastric tube andabdominal circumference were mea-sured before each feed. The totalamount of gastric residue was cal-culated daily. In the absence of foodintolerance during the previous 24hours, the total amount of enteralnutrition was increased by 10 to 20mL/kg per day. Enteral nutrition wasdiscontinued in case of erythematicabdominal wall, absence of bowelsounds, or blood in the stools or inaspirates, associated with radiologicmarkers of NEC-Bell stage higher thanI.23 Parenteral nutrition was admin-istered through a central vascularaccess in all infants to maintain anadequate intake of fluids, electrolytes,and nutrients, until full enteral feeding(120 kcal/kg per day) was reached.Fluids were started at 70 to 100 mL/kgper day with increments of 10 to 20mL/kg per day until 150 to 180 mL/kgper day.

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Statistics

Weestimatedaminimumsample size of90 patients for each group to obtain apowerof thestudyof90%(type1error=0.05 with a 2-tailed test), consideringthe smallest difference in proportion ofinfectious diseases to be 20% (spe-cifically, 10% vs 30%). The Kolmogorov-Smirnov test was used to determinewhether variables were normally dis-tributed. For continuous variables,groups were compared using thet test, and the Mann-Whitney U test. Thex2 test and Fishers exact test wereused for categorical variables. For 2related dichotomous variables, theMcNemar test was used to detect dif-ferences before and after the use ofranitidine. Risks of sepsis, pneumonia,and UTI (plus 95% confidence intervals[CIs]) in patients treated with raniti-dine were estimated. We performeda multivariate analysis using binarylogistic regression analysis to evalu-ate whether GA, BW, sex, Apgar score,CRIB score, IVH, PDA, central vascularaccess, or mechanical ventilation af-fected the prescription of ranitidine.The level of significance for all statis-tical tests was 2-sided, P , .05. Sta-tistical analysis was performed bya statistician blinded to patient groupassignment, using SPSS, version 16.0for Windows (SPSS Inc., Chicago, IL).

RESULTS

A total of 309 VLBW newborns wereevaluated. Thirty-five infants were ex-cluded because of critical clinical con-ditions (10 patients), malformations (8patients), sepsis before enrollment (12patients), and length of hospitalizationfewer than 8 weeks (5 patients). Thus,we obtained data from 274 infants (120from the University of Federico II,Naples; 45 from the FatebenefratelliHospital, Naples; 23 from the MeyerPediatric Hospital, Florence; and 86from V. Betania Evangelic Hospital,Naples). Ninety-one of these infants had

received ranitidine (42 as prophylaxisof stress-induced peptic disease; 49because of suspected GERD), and 183represented the control cohort ofnewborns not exposed to ranitidine. Inall cases, the diagnosis of GERD wasmade based on clinical criteria withoutpH-metry or endoscopy.

The main demographic and clinicalcharacteristics of the 2 cohorts weresimilar (Table 1). These characteristicsdid not differ between patients re-ceiving ranitidine for prophylaxis ofstress-induced peptic disease andpatients receiving ranitidine for GERD.Multivariate binary logistic regressionanalysis (constant B 6.334) revealedthat the prescription of ranitidine byphysicians was not affected by gesta-tional age (B 20.167, odds ratio [OR]0.846, 95% CI 0.6941.031, P = .098),birth weight (B 20.001, OR 0.999, 95%CI 0.9971.001, P = .444), sex (B 0.708,OR 2.031, 95% CI 0.9724.243, P = .060),Apgar score (1 minute: B 20.147, OR0.863, 95% CI 0.6531.141, P = .301; 5minute: B 20.099, OR 0.905, 95% CI

0.4861.687, P = .754), CRIB score(B 0.008, OR 1.008, 95% CI 0.8691.169,P = .918), IVH (B 0.755, OR 2.127, 95%CI 0.6357.124, P = .221), PDA (B20.281,OR 0.755, 95% CI 0.3231.764, P = .516),central vascular access (B 0.004, OR1.004, 95% CI 0.9601.050, P = .855), ormechanical ventilation (B 20.062, OR0.940, 95% CI 0.8501.040, P = .233).

Newborns treated with ranitidine hadmore infections (OR 5.5, 95%CI 2.910.4,P , .001), namely sepsis, pneumonia,and UTI, than newborns not treatedwith ranitidine (Table 2). The pathogensresponsible for infections are listed inTable 3. The mean time to infection af-ter starting ranitidine treatment was17.9 days (95% CI 13.022.8). Amonginfants treated with ranitidine, therewas a slight but not significant in-crease in drug dosage in subjects pre-senting infections (intravenous 2.43mg/kg per day, 95% CI 1.843.03 vs 1.85mg/kg per day; 95% CI 1.552.16, P =.052; enteral route 11.44 mg/kg per day;95% CI 8.0814.80 vs 9.82 mg/kg perday; 95% CI 8.2211.42, P = .310). The

TABLE 1 Demographic and Clinical Characteristics of the Neonates Enrolled in the Study

Not Exposedto Ranitidine(n = 183)

Exposedto Ranitidine(n = 91)

P

Birth weight, g 1091 (10571124) 1083 (10311036) .812Gestational age, wk 29 (28.729.5) 29 (28.729.8) .548Male, n (%) 81 (44.3) 44 (48.4) .522Apgar score at 1 min 5.8 (5.66.1) 5.9 (5.66.3) .879Apgar score at 5 min 7.7 (7.67.9) 7.8 (7.67.9) .786CRIB score 1.3 (1.01.6) 1.7 (1.32.2) .114Persistent ductus arteriosus, n (%) 48 (26.2) 26 (28.6) .681Intraventricular hemorrhage stage III-IV, n (%) 11 (6.0) 10 (11.0) .145Central vascular access duration, d 16 (1517) 15 (1417) .967Duration of endotracheal intubation, d 4.4 (3.75.1) 4.3 (3.35.2) .853

Data expressed as mean (95% CI) when not specified.

TABLE 2 Rate of Patients Presenting Infections During the Study Period

Not exposedto Ranitidine(n = 183)

Exposedto Ranitidine(n = 91)

P

Overall infections, n (%) 18 (9.8) 34 (37.4) ,.001Sepsis, n (%) 16 (8.7) 23 (25.3) ,.001Pneumonia, n (%) 1 (0.5) 4 (4.4) .043Urinary tract infections, n (%) 1 (0.5) 7 (7.7) .002

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risk of infections was unrelated to theduration of ranitidine treatment. NECwas significantly (P = .003) more fre-quent (OR 6.6; 95% CI 1.725.0) in VLBWinfants treated with ranitidine (9.8%)than in those not exposed to ranitidine(1.6%). The risk of NEC was unrelatedto either the dosage or duration of ra-nitidine therapy. Twelve patients diedduring the study. Mortality rate was sig-nificantly higher in newborns receivingranitidine (9.9% vs 1.6%, P = .003), andhospitalization was significantly longerin those exposed to ranitidine (median52 days, interquartile range 43 vs 36days, interquartile range 22, P, .001).

DISCUSSION

With the aim of increasing informationabout the useof drugs outside the termsof their license (off-label) or of drugsthat are not specifically licensed foruse in children (unlicensed), theEuropean Parliament and the EuropeanMedicines Agency made a call for safe-ty studies on off-label and unlicensedprescription of ranitidine in newborns.Similarly, the US Food and Drug Admin-istration advocated studies on the sa-fety of off-label drugs in the pediatricage. Here we reported the results of thefirst multicenter prospective study fo-cusing on the increased morbidity (ie,infections and NEC) and mortality as-sociated with ranitidine use in VLBWnewborns.

Previousreportshavesuggestedsimilarconclusions, although all of them had

some limitations that can be consideredovercame by our study. Graham et al,14

in a retrospective study of the effectsof hand hygiene practices on hospital-acquired late-onset gram-negative sep-sis, showed that the inhibitors of gastricacid secretion entailed an increasedrisk of infection in low birth weightnewborns; however, the subjects re-ceiving inhibitors of gastric acid secre-tion were more severely ill than thosenot receiving this treatment. Differently,in our study, the prescription of raniti-dine was not influenced by the severityof the patients clinical condition, asdemonstrated by the multivariate anal-ysis. Bianconi et al24 reported an asso-ciation between ranitidine use and therisk of late-onset sepsis, but they useda retrospective design and the numberof newborns enrolled was very small.In a randomized controlled trial, Stollet al25 evaluated the relationship be-tween postnatal steroid exposure andlate-onset sepsis in VLBW infants. Theyobserved that treatment with dexa-methasone was associated with an in-creased risk of sepsis and meningitis.During the analysis of the factors pres-ent at randomization, the authors foundan increased use of H2R blocker therapyin patients developing infections. Un-fortunately, this study did not differen-tiate the effect of steroids from those ofthe H2R blocker on the risk of infections.In a prospective study, Beck-Sagueet al13 reported a fourfold increasein the risk of bloodstream infection inneonates who received H2R blockers;

however, also in this case, neonateswhodeveloped infection were more severelyill and were of lower gestational age onadmission than infants not developingthese infections. Finally, a recent studysuggested an association between NECand H2R blockers, but study design wasretrospective.15

Experimental and clinical evidence sug-gests that infections associated withthe use of inhibitors of gastric acid se-cretion can occur via diverse mecha-nisms.11,12 Gastric juice and intestinalmicroflora are 2 of the major defensefactors against invasion of the gut bymicroorganisms. In particular, the lackof normal gastric destruction of patho-gens could be considered the mostimportant aspect that predispose toinfections. The preservation of gastricacid secretion during phylogenesissupports the biological importance ofthis high-energy consuming system de-veloped to inactivate ingested micro-organisms. Gastric juice consists of HCland pepsin, which kills bacteria within15 minutes when the pH in the stomachis lower than 3.0. At a higher pH, a statedefined as hypochlorhydria, bacterialovergrowth and infections are morecommon.26 Quantitative and qualitativechanges in the composition of the in-testinal microflora are associated withthe development of sepsis and NEC.12,15

Thus, it is conceivable that hypochlo-rhydria induced by ranitidine may sig-nificantly alter the intestinal microflora,which, in turn, could contribute to theincreased susceptibility to infectionsand the abnormal immune activationobserved during NEC. The developmentof NEC could be a result of the selec-tive advantage acquired by pathogens,such as Escherichia coli and Klebsiellapneumonia, during inhibition of gastricacidity,14,9,12,15,27 as confirmed by ourmicrobiological evaluations. Further-more, the direct effect exerted by ra-nitidine on the immune system couldinfluence the risk for NEC in neonates.2830

TABLE 3 Pathogens Responsible for Infectious Episodes During the Study

Not exposedto Ranitidine

(n = 18 of 183), n (%)

Exposedto Ranitidine

(n = 34 of 91), n (%)

P

Escherichia coli 2 (11.1) 10 (29.4) ,.001Klebsiella pneumoniae 1 (5.5) 8 (23.5) .001Pseudomonas aeruginosa 1 (5.5) 6 (17.6) .006Candida albicans 5 (27.7) 3 (8.8) .794Serratia marcescens 0 (0.0) 1 (2.9) .332Staphylococcus coagulase neg. 6 (33.3) 6 (17.6) .735Group B Streptococcus 1 (5.5) 0 (0.0) .480Other pathogens 2 (11.1) 0 (0.0) .317



Activation of H2R alters the productionof inflammatory cytokines and disruptsthe Th1Th2 balance, thereby leading toinsufficient control of infections and in-flammation at the intestinal level.3133

In VLBW infants, the diagnosis of gas-tric acidrelated diseases is based onthe evaluation of nonspecific symptoms,and the empirical treatment is fre-quently the first diagnostic test.16,34 Inaddition, there is no clear evidence thatH2R blockers are beneficial in manyclinical conditions typical of neonatalage, such as apnea.15,17,35,36 The resultsof this study suggest that ranitidineshould be administered only after acareful consideration of the risk-benefitratio. In addition, in our study, weobserved an increased mortality in

newborns receiving ranitidine. Mortal-ity in this group exposed to ranitidinewas 6 times higher than in newbornsnot exposed to ranitidine treatment.This suggests that caution should beexercised regarding the administrationof ranitidine in subjects such as VLBW athigh risk of death per se. Finally, theadministration of ranitidine in VLBWinfants increases health care costs be-cause of prolonged hospital care. Inwestern countries, the median cost ofhospitalization is estimated to beabout $1250 per day for a VLBW infant.37

The difference in median duration ofhospitalization between the 2 groupsof our study was 20 days, thereby re-sulting in a reduction of about $25 000per patient.

CONCLUSIONS

Ranitidine should be administered withcare in preterm infants because of therisk of severe infectious disease, NEC,and fatal outcome. Further studies arenecessary to investigate the pathogen-esis of these effects and the possibleprophylactic measures that could betaken to prevent them.

ACKNOWLEDGMENTSThe authors acknowledge with grati-tude the commitment of the Motherand Child Health Association to the re-search efforts. The authors are gratefulto Jean Ann Gilder (Scientific Communi-cationSRL,Naples, Italy) forfinal editingof the text.

REFERENCES

1. Bizzarro MJ, Raskind C, Baltimore RS,Gallagher PG. Seventy-five years of neo-natal sepsis at Yale: 19282003. Pediat-rics. 2005;116(3):595602

2. Martinsen TC, Bergh K, Waldum HL. Gastricjuice: a barrier against infectious diseases.Basic Clin Pharmacol Toxicol. 2005;96(2):94102

3. Dial MS. Proton pump inhibitor use andenteric infections. Am J Gastroenterol.2009;104(Suppl 2):S10S16

4. Leonard J, Marshall JK, Moayyedi P. Sys-tematic review of the risk of enteric in-fection in patients taking acid suppression.Am J Gastroenterol. 2007;102(9):20472056,quiz 2057

5. Garca Rodrguez LA, Ruigmez A, Pans J.Use of acid-suppressing drugs and the riskof bacterial gastroenteritis. Clin Gastro-enterol Hepatol. 2007;5(12):14181423

6. Doorduyn Y, Van Pelt W, Siezen CLE, et al.Novel insight in the association betweensalmonellosis or campylobacteriosis andchronic illness, and the role of host ge-netics in susceptibility to these diseases.Epidemiol Infect. 2008;136(9):12251234

7. Khatami SS, Mukunda B, Ravakhah K. Coin-fection with Giardia lamblia and Clostridiumdifficile after use of ranitidine. Am J MedSci. 2004;327(2):9193

8. Cadle RM, Mansouri MD, Logan N, Kudva DR,Musher DM. Association of proton-pumpinhibitors with outcomes in Clostridium

difficile colitis. Am J Health Syst Pharm.2007;64(22):23592363

9. Doorduyn Y, Van Den Brandhof WE, VanDuynhoven YTHP, Wannet WJB, Van Pelt W.Risk factors for Salmonella Enteritidis andTyphimurium (DT104 and non-DT104) infec-tions in The Netherlands: predominant rolesfor raw eggs in Enteritidis and sandboxes inTyphimurium infections. Epidemiol Infect.2006;134(3):617626

10. Canani RB, Cirillo P, Roggero P, et al; WorkingGroup on Intestinal Infections of the ItalianSociety of Pediatric Gastroenterology, Hepa-tology and Nutrition (SIGENP). Therapy withgastric acidity inhibitors increases the riskof acute gastroenteritis and community-acquired pneumonia in children. Pediat-rics. 2006;117(5):e817e820

11. Vakil N. Acid inhibition and infections out-side the gastrointestinal tract. Am J Gas-troenterol. 2009;104(Suppl 2):S17S20

12. Canani RB, Terrin G. Gastric acidity inhib-itors and the risk of intestinal infections.Curr Opin Gastroenterol. 2010;26(1):3135

13. Beck-Sague CM, Azimi P, Fonseca SN, et al.Bloodstream infections in neonatal inten-sive care unit patients: results of a multi-center study. Pediatr Infect Dis J. 1994;13(12):11101116

14. Graham PL, III, Begg MD, Larson E, Della-Latta P, Allen A, Saiman L. Risk factors forlate onset gram-negative sepsis in low birthweight infants hospitalized in the neonatal

intensive care unit. Pediatr Infect Dis J. 2006;25(2):113117

15. Guillet R, Stoll BJ, Cotten CM, et al. Formembers of the National Institute of ChildHealth and Human Development NeonatalResearch Network. Association of H2-blocker therapy and higher incidence ofnecrotizing enterocolitis in very low birthweight infants. Pediatrics. 2006;117:137142

16. Malcolm WF, Gantz M, Martin RJ, GoldsteinRF, Goldberg RN, Cotten CM; National In-stitute of Child Health and Human De-velopment Neonatal Research Network.Use of medications for gastroesophagealreflux at discharge among extremely lowbirth weight infants. Pediatrics. 2008;121(1):2227

17. Omari TI, Haslam RR, Lundborg P, DavidsonGP. Effect of omeprazole on acid gastro-esophageal reflux and gastric acidity inpreterm infants with pathological acidreflux. J Pediatr Gastroenterol Nutr. 2007;44(1):4144

18. American Academy of Pediatrics Committeeon Fetus and Newborn. Hospital dischargeof the high-risk neonate. Pediatrics. 2008;122:119126

19. Modi N, Dor CJ, Saraswatula A, et al. Acase definition for national and interna-tional neonatal bloodstream infection sur-veillance. Arch Dis Child Fetal Neonatal Ed.2009;94(1):F8F12

ARTICLE

PEDIATRICS Volume 129, Number 1, January 2012 5 at Indonesia:AAP Sponsored on May 1, 2012pediatrics.aappublications.orgDownloaded from


20. Nissen MD. Congenital and neonatal pneu-monia. Paediatr Respir Rev. 2007;8(3):195203

21. Mori R, Lakhanpaul M, Verrier-Jones K. Di-agnosis and management of urinary tractinfection in children: summary of NICEguidance. BMJ. 2007;335(7616):395397

22. Hack M, Horbar JD, Malloy MH, Tyson JE,Wright E, Wright L. Very low birth weightoutcomes of the National Institute ofChild Health and Human DevelopmentNeonatal Network. Pediatrics. 1991;87(5):587597

23. Meinzen-Derr J, Morrow AL, Hornung RW,Donovan EF, Dietrich KN, Succop PA. Epi-demiology of necrotizing enterocolitistemporal clustering in two neonatologypractices. J Pediatr. 2009;154(5):656661

24. Bianconi S, Gudavalli M, Sutija VG, LopezAL, Barillas-Arias L, Ron N. Ranitidine andlate-onset sepsis in the neonatal intensivecare unit. J Perinat Med. 2007;35(2):147150

25. Stoll BJ, Temprosa M, Tyson JE, et al. Dexa-methasone therapy increases infection invery low birth weight infants. Pediatrics.1999;104(5). Available at: www.pediatrics.org/cgi/content/full/104/5/e63

26. Winter JW, Heading RC. The nonerosivereflux disease-gastroesophageal reflux dis-ease controversy. Curr Opin Gastroenterol.2008;24(4):509515

27. Smith A, Saiman L, Zhou J, Della-Latta P, JiaH, Graham PL III. Concordance of gastroin-testinal tract colonization and subsequentbloodstream infections with gram-negativebacilli in very low birth weight infants inthe neonatal intensive care unit. PediatrInfect Dis J. 2010;29(9):831835

28. Takagaki K, Osawa S, Horio Y, et al. Cytokineresponses of intraepithelial lymphocytesare regulated by histamine H(2) receptor.J Gastroenterol. 2009;44(4):285296

29. Xu X, Zhang D, Zhang H, et al. Neutrophilhistamine contributes to inflammation inmycoplasma pneumonia. J Exp Med. 2006;203(13):29072917

30. Sun Q, Li W, She R, et al. Evidence for a roleof mast cells in the mucosal injury inducedby Newcastle disease virus. Poult Sci. 2009;88(3):554561

31. Moharana AK, Bhattacharya SK, Mediratta PK,Sharma KK. Possible role of histamine re-ceptors in the central regulation of immune

responses. Indian J Physiol Pharmacol. 2000;44(2):153160

32. van der Pouw Kraan TC, Snijders A, BoeijeLC, et al. Histamine inhibits the productionof interleukin-12 through interaction with H2receptors. J Clin Invest. 1998;102(10):18661873

33. St Peter SD, Sharp SW, Ostlie DJ. Influenceof histamine receptor antagonists on theoutcome of perforated appicitis: analysisfrom a prospective trial. Arch Surg. 2010;145(2):143146

34. Martin RJ, Hibbs AM. Diagnosing gastro-esophageal reflux in preterm infants. Pe-diatrics. 2006;118(2):793794

35. Wheatley E, Kennedy KA. Cross-over trial oftreatment for bradycardia attributed togastroesophageal reflux in preterm infants.J Pediatr. 2009;155(4):516521

36. Clark RH, Spitzer AR. Patience is a virtuein the management of gastroesophagealreflux. J Pediatr. 2009;155(4):464465

37. Rogowski J. Using economic information ina quality improvement collaborative. Pedi-atrics. 2003;111(4 pt 2):e411e418



DOI: 10.1542/peds.2011-0796; originally published online December 12, 2011;Pediatrics

Salvia, Laura Lega, Francesco Messina, Roberto Paludetto and Roberto Berni CananiGianluca Terrin, Annalisa Passariello, Mario De Curtis, Francesco Manguso, Gennaro

Outcome in NewbornsRanitidine is Associated With Infections, Necrotizing Enterocolitis, and Fatal

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