Intravenous Immunoglobulin for Preventing Infection in Preterm and-Or Low Birth Weight Infants[2]

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Intravenous immunoglobulin for preventing infection inpreterm and/or low birth weight infants (Review)

Ohlsson A, Lacy JB

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration andpublished in The Cochrane Library 2013, Issue 7

http://www.thecochranelibrary.com

Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants (Review)Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1 ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

9DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .38DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 IVIG vs placebo or no treatment, Outcome 1 Sepsis, one or more episodes. . . . . . 38

Analysis 1.2. Comparison 1 IVIG vs placebo or no treatment, Outcome 2 Any serious infection, one or more episodes. 39 Analysis 1.3. Comparison 1 IVIG vs placebo or no treatment, Outcome 3 NEC, one or more episodes. . . . . . 40 Analysis 1.4. Comparison 1 IVIG vs placebo or no treatment, Outcome 4 Mortality (all causes). . . . . . . . 41 Analysis 1.5. Comparison 1 IVIG vs placebo or no treatment, Outcome 5 Mortality (infectious). . . . . . . . 42 Analysis 1.6. Comparison 1 IVIG vs placebo or no treatment, Outcome 6 Duration of hospitalisation. . . . . . 43 Analysis 1.7. Comparison 1 IVIG vs placebo or no treatment, Outcome 7 Bronchopulmonary dysplasia. . . . . 44 Analysis 1.8. Comparison 1 IVIG vs placebo or no treatment, Outcome 8 Intraventricular haemorrhage any grade. . 44 Analysis 1.9. Comparison 1 IVIG vs placebo or no treatment, Outcome 9 Intraventricular haemorrhage grade 3 or 4. 45

45 WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .48INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Intravenous immunoglobulin for preventing infection inpreterm and/or low birth weight infants

Arne Ohlsson1, Janet B Lacy 2

1Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada. 2Scarborough, Canada

Contact address: Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Managementand Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. [email protected] .

Editorial group: Cochrane Neonatal Group.Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 7, 2013.Review content assessed as up-to-date: 29 May 2013.

Citation: Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants.Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD000361. DOI: 10.1002/14651858.CD000361.pub3.

Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

Nosocomial infections continue to be a signicant cause of morbidity and mortality among preterm and/or low birth weight (LBW)infants. Preterm infants are decient in immunoglobulin G (IgG); therefore, administration of intravenous immunoglobulin (IVIG)may have the potential of preventing or altering the course of nosocomial infections.

ObjectivesTo use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no inter-vention) to preterm (< 37 weeks postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safein preventing nosocomial infection.

Search methods

For this update, MEDLINE, EMBASE, CINAHL, The Cochrane Library , Controlled Trials, ClinicalTrials.gov and PAS Abstracts2view were searched in May 2013.

Selection criteria

We selected randomised controlled trials (RCTs) in which a group of participants to whom IVIG was given was compared with a control group that received a placebo or no intervention for preterm (< 37 weeks gestational age) and/or LBW (< 2500 g) infants.

Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in whichthe follow-up period was one week or less.

Data collection and analysis

Data collection and analysis was performed in accordance with the methods of the Cochrane Neonatal Review Group.

Main results

Nineteen studies enrolling approximately 5000 preterm and/or LBW infants met inclusion criteria. No new trials were identied inMay 2013.

1Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants (Review)Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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IVIG is frequently given to immunodecient patients who havedecreased antibody production capabilities. In immunodecientpatients, IVIG is administered to maintain adequate antibody lev-els to prevent infection and to confer passive immunity.

How the intervention might work

Maternaltransportof immunoglobulins to the fetusmainly occursafter 32 weeks gestation, and endogenous synthesisdoes notbeginuntil about 24 weeks afterbirth, so thepreterm infant is especially vulnerable to infectious sources in the neonatal intensive care unit(Baker 1990a ). Mean serum levels of IgG are 400 mg/dL in in-fants at less than 32 weeks gestational age (GA) compared with1000 mg/dL in term infants (Hobbs 1967; Stiehm 1966). Theidea of preventing nosocomial infection with IVIG is attractive,as administration of IVIG provides IgG that can bind to cell sur-face receptors,provide opsonic activity, activate complement, pro-mote antibody-dependent cytotoxicity and improve neutrophilicchemo-luminescence (Baley 1988).

Why it is important to do this review

Administration of IVIG to LBW infants has been studied exten-sively. Numerous descriptive review articles, commentaries andeditorials on the use of IVIG in neonates have been published,often by the same researchers. These papers have included sev-eral randomised controlled trials (RCTs), the authors personalexperience with IVIG and/or information about the preparationor dosing regimen of IVIG ( Weisman 1986; Bortolussi 1986a ;Bortolussi1986b; Fischer1986; Stiehm 1986; Baley 1988; Fischer1988; Gonzalez 1989; Kyllonen 1989; Stabile 1989; Noya 1989; Johnston 1990; Fischer 1990a ; Fischer 1990b; Fischer 1990c;Baker 1990a ; Baker 1990b; Bussel 1990b; Hammarstrom 1990;Kliegman 1990; Stiehm 1990; Whitelaw 1990; Berger 1991; Hill1991a ; Hill 1991b; Irani 1991; Kliegman 1991; Magny 1991a ;Rondini 1991; Haque 1992; Siber 1992; Weisman 1992; Hill1993; Weisman 1993; Weisman 1994b; Wolach 1997). Salzer(Salzer 1991) presented (in abstract form only) the results of a meta-analysis of seven studies and concluded that no signicantreduction was seen in the incidence of sepsis in the treated group.In Effective Care of the Newborn Infant, Baley and Fanaroff (Baley 1992) present overviews of RCTs that studied the admin-istration of IVIG to neonates. They reviewed seven studies of theprophylactic use of IVIG that reported an outcome of sepsis andconcluded, The preliminary data generated in trials of IVIG arepromising, but useof this treatmentmodality still needs to be con-sidered experimental and [it] should only, as yet, be used understudy conditions. Lacy and Ohlsson (Lacy 1995) included addi-tional trials and concluded that routine administration of IVIG topreterm infants to prevent infection is not recommended. Jensonand Pollock ( Jenson 1997) used slightly different inclusion crite-

ria and, like Lacy and Ohlsson (Lacy 1995), noted heterogene-ity among studies. They concluded, this heterogeneity probably belies the minimal benet, at most, of prophylactic IVIG. Theresults of a Canadian multidisciplinary consensus-building initia-tive (Consensus 1997) have been published, and the use of IVIG

for prophylaxis of neonatal nosocomial infection was consideredinappropriate. This review provides an update of our previous re-view, which was last updated with no changes in 2010 (Ohlsson2001; Ohlsson 2007) and was rst published in 1998 (Ohlsson1998).

O B J E C T I V E S

To use systematic review/meta-analytical techniques to determine whether IVIG administration (comparedwith placebo or no inter-vention) to preterm (< 37 weeks gestational age (GA) at birth)orLBW (< 2500 g birth weight) infants or both is effective/safe inpreventing nosocomial infection.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Studies in which preterm and/or LBW neonates were randomly assigned to receive IVIG or placebo or no intervention.

Types of participants

Preterm and/or LBW neonates.

Types of interventions

IVIG for the prevention of bacterial or fungal infection. Studiesthat were designed to evaluate the effects of IVIG on humoral im-mune markers were excluded, as were studies in which the follow-up period was one week or less. Studies that assessed the effective-ness of IVIG for treatment of suspected or conrmed infection were excluded.

Types of outcome measures

Primary outcomes

Sepsis, one or more episodes (clinical signs and symptomsof sepsis and positive blood culture for bacteria or fungi).



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Secondary outcomes

Any serious infection (clinical signs and symptoms inconjunction with positive cultures (bacteria or fungi) fromnormally sterile body uids (blood, cerebrospinal uid, urineobtained by catheterization or suprapubic tap) or from tissue at

autopsy). As per this denition, cases of sepsis if reportedseparately were also included in any serious infection.

Necrotizing enterocolitis (NEC) diagnosed according toBells criteria (Bell 1978). For repeated episodes of sepsis, any serious infection and NEC, only one occurrence per infant wascounted as an outcome.

Death from all causes. Death from infection (including death from NEC). Length of hospital stay. Incidence of bronchopulmonary dysplasia (BPD), dened

as an additional oxygen requirement (above room air) at 28 daysof age or a requirement for assisted ventilation for reasons otherthan apnoea of prematurity.

Incidence of intraventricular haemorrhage (IVH), any grade, classied according to Papile (Papile 1983).

Incidence of IVH, grade 3 or 4, classied according toPapile (Papile 1983).

Reports on possible side effects as described by the authors.

Search methods for identication of studies

The search strategy used to identify studies adhered to the guide-lines of the Cochrane Neonatal Review Group.

Electronic searches

MEDLINE was searched from 1966 to July 2007. EMBASE (Ex-cerpta Medica online) was searched from 1980 to July 2007. The Cochrane Library , Issue 2,2007, wassearched. Nolanguage restric-tions were applied. Ms Elizabeth Uleryk developedandapplied anextensive search strategy (available upon request) for MEDLINEand EMBASE in February 2001 and September 2003. The samestrategy was used in 2007.In December 2009, we updated the search as follows: MEDLINE(searchviaPubMed),CINAHL,EMBASEandtheCochraneCen-tral Register of Controlled Trials (CENTRAL; The Cochrane Li-brary ) were searched from 2003 to December 2009. Search term:immunoglobulin. Limits: human, newborn infant and clinicaltrial. No language restrictions were applied.Searches on May 28, 2013, were conducted by Ms Coleen M.Ovelman, Trials Search Co-ordinator, and Yolanda R. Brosseau,Managing Editor, the Cochrane Neonatal Review Group. Ab-stracts of the Pediatric Academic Societies (PAS)Annual Meetingsfrom 2000 to 2013 were searched on the same day by one of thereview authors (AO).

Searching other resources

The search was initiated by review of personal les and publishedmeta-analyses. The reference list of identied studies and subse-quently retrieved articles was scanned for additional references.

Data collection and analysis

Data collection and analysis were done in accordance with themethods of the Cochrane Neonatal Review Group.

Selection of studies

The criteria used to select studies for inclusion in this overview were:

design: RCT in which treatment with IVIG was compared with a placebo or no intervention provided to a control group;

population: inclusion of preterm (< 37 weeks gestationalage) and/or LBW (< 2500 g) infants;

intervention: administration of IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days orlonger). (Studies that were primarily designed to assess the effectsof IVIG on humoral immune markers were excluded, as werestudies in which the follow-up period was one week or less.Studies designed to assess the effectiveness of treatment withIVIG for suspected/established infection were excluded.); and

reporting: included at least one of the following outcomes:sepsis, any serious infection, death from all causes, death frominfection, length of hospital stay, IVH, NEC or BPD;anddescriptions of side effects.

The titles (and abstracts when available) in MEDLINE, EMBASEand The Cochrane Library printouts were reviewed by the two re-view authors. Any article that the review authors believed mightmeet the inclusion criterianotedabove or shouldhave its referencelist searched was retrieved. Informal attempts were made to locateunpublished studies, andattemptsweremadeto request additionalinformation from authors of published studies. Additional infor-mation was obtained on one published study (Sandberg 2000). All identied trials (excluding those that used IVIG for treatment)are listed in the tables of Included studies and Excluded studies.

Data extraction and management

Data abstraction forms were developed and were pilot-tested toverify denitions of terms. The two review authors independently abstracted information on each study, andone reviewauthor (AO)checked forany discrepancies and pooled theresults. Data abstrac-tion included whether the study involved prophylaxis or treat-ment, the number of participants enrolled, the number of partic-ipants enrolled but later excluded, the time period and geograph-ical location of the study, baseline characteristics of participants,

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inclusion/exclusion criteria, the preparation and dosing regimenof IVIG and placebo and length of follow-up.Information on outcomes and on the numbers of affected infants was abstracted. The total number of infants with sepsis (clinicalsigns andsymptomspluspositivebloodculture (bacteriaor fungi))

and any serious infection (clinical signs and symptoms in con- junction with positive cultures (bacteria or fungi) from normally sterile body uids) was abstracted, as was information on NEC,death from all causes and death from infection. Information onlength of hospital stay and on incidence of BPD and IVH wascollected. Information on probable infection was not collected, asthe denitions used by different investigators were too variable.

Assessment of risk of bias in included studies

Assessment of the quality of included studies (excluding abstracts) was performed independently by JBL and AO, using criteria de-veloped by the Cochrane Neonatal Review Group. These criteria

included blinding of randomisation, blinding of the intervention,complete follow-up and blinding of outcome measurement. Foreach criterion, three possibilities were identied: yes, cant tell andno. The assignment was notdone with the assessors blinded to au-thor, institution, journal of publication or results, as both assessors were familiar with most of the studies and with the typographicallayout of the journals and would have knowledge of these even when blinded. In addition, the results sections of articles ofteninclude methodological information. After independent evalua-tion was performed, the two assessors discussed the results of eachstudy, and any discrepancies were resolved.For the update in 2009, the following issues were evaluated andentered into the risk of bias table:

Sequence generation: Was the allocation sequenceadequately generated?;

Allocation concealment: Was allocation adequately concealed?;

Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?;

Incomplete outcome data: Were incomplete outcome data adequately addressed?;

Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?; and

Other sources of bias: Was the study apparently free of other problems that could put it at high risk of bias?

Measures of treatment effect

The statistical package (RevMan 5.2) provided by the CochraneCollaboration was used. Typical relative risk (RR) and typical risk difference (RD) with 95% condence intervals (CIs) using thexed-effect model are reported. If a statistically signicant reduc-

tion in RD was noted, the number needed to treat to benet(NNTB) or harm (NNTH) was calculated.

Assessment of heterogeneity

Statistically signicant between-study heterogeneity was reported when identied, and the test for inconsistency (I2 statistic) wasapplied when statistically signicant heterogeneity was noted (Higgins 2003). For this update, the following cut-offs were used:

75%: high heterogeneity.

Data synthesis

Meta-analysis was performed using Review Manager software(RevMan 5.2) as supplied by The Cochrane Collaboration. Forestimates of typical RR and RD, we used the Mantel-Haenszelmethod. For measured quantities, we used the inverse variancemethod. Allmeta-analyses were done usingthe xed -effect model.

Subgroup analysis and investigation of heterogeneity

Future updates will consider post hocsubgroup analyses to exploreany heterogeneity noted in the primary analysis.

R E S U L T S

Description of studies

Included StudiesDetails of the included studies are provided in the Table of In-cluded Studies.Nineteen studies, including approximately 5000 preterm and/or LBW infants, met inclusion criteria. These studies were per-formed in many countries (US, Italy, UK, Saudi Arabia, France,Thailand, Belgium, Turkey, Sweden and Austria). The amount of IVIG per dose varied from 120 mg/kg (Haque 1986) to 1 g/kg (Bussel 1990a ). The number of doses varied from a single dose( Atici 1996, Haque 1986, Christensen 1989, Ratrisawadi 1991, Weisman 1994a ) to seven doses (Stabile 1988).Different IVIG preparations were used: Gammagard (Baker1992); Sandoglobulin ( Atici 1996, Bussel 1990a , Chirico 1987,Clapp 1989, Fanaroff 1994, Tanzer 1997, Van Overmeire 1993, Weisman 1994a ); Gamimmune (Christensen 1989); Intraglobin(Conway 1990, Haque 1986, Ratrisawadi 1991); IgVena (Didato1988); Biotransfusion (Magny 1991b); unnamed product (Spady 1994; Sandberg 2000 (study supported by Baxter AG, Austria));Venogamma (Stabile 1988); Gammumine-N (Chou 1998).



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Excluded StudiesSix studies were excluded, as they included infants who were heav-ier or more mature at birth than was permitted by the inclusioncriteria(Kinney 1991, Adhikari1996); lackedinformationon out-comes (Kacet 1991; Malik 1990); lacked a randomised control

group ( Acunas 1994) or provided immunoglobulin intramuscu-larly (Monintja 1989).

Risk of bias in included studies

The assessment of individual studies is presented in theCharacteristics of included studies table.The methodological quality of the studies varied. Five studies were of high quality (Baker 1992, Christensen 1989, Clapp 1989,Fanaroff-I 1994, Weisman 1994a ) (i.e. complete follow-up, blind-ing of randomisation, intervention and outcome measurementcould be ascertained from thepublished reports). In theremaining 15 studies, elements of bias could not be excluded. The lack of a placebo in 10 studies ( Atici 1996, Chirico 1987, Conway 1990,Didato 1988, Fanaroff 1994 (phase II), Haque 1986, Ratrisawadi1991, Stabile 1988, Tanzer 1997, Van Overmeire1993) precludedblinding of the caregivers. One study (Fanaroff 1994) includedtwo phases, with phase I providing a placebo but not phase II.In several studies, blinding of randomisation was not clearly de-scribed (Chirico 1987, Magny 1991b, Ratrisawadi 1991, Stabile1988). In the study by Sandberg (Sandberg 2000), an intention-to-treat analysis was not applied. One study (Spady 1994) hasbeen published in abstract form only, and the quality thereforecould not be fully assessed. The study by Bussel (Bussel 1990a )represents an interim analysis, with data lacking from a large pro-portion of the infants randomly assigned.

Effects of interventions

Nineteen studies met inclusion criteria. These included a total of approximately5000 preterm and/or LBW infants and reported onat least one of the outcomes of interest for this systematic review.No new trial was identied in the literature search conducted inMay 2013. One additional trial was identied in July 2007 (Lelik

2004). However, this trial enrolled infants atgreater than 38weeksgestational age and with birth weight greater than 2500 g. Thestudy was therefore excluded. No new studies were identied inthe literature search conducted in September 2003.For details of results, seeDataand analyses. It should be noted that

for most outcomes, the large study by Fanaroff (Fanaroff 1994)greatly inuenced the summary statistics, with an assigned weightranging from 42.7% for the outcome of any serious infection to88.3% for the outcome of IVH grade 3 or 4.IVIGVERSUSPLACEBO OR NOTREATMENT (COMPAR-ISON 1)PRIMARY OUTCOME

Sepsis, one or more episodes (Outcome 1.1) ( Figure 1 ):

Ten studies (including 3975 infants) reported on the outcome of one or more episodes of sepsis per infant (clinical signs and symp-toms of infection and positive blood culture). Only the study by

Ratrisawadi (Ratrisawadi 1991) showed a statistically signicantreduction in sepsis (RR 0.38; 95% CI 0.19 to 0.79). When allstudies were combined, a statistically signicant (P = 0.02) reduc-tion in sepsis was noted (typical RR 0.85, 95% CI 0.74 to 0.98);typical RD -0.03, 95% CI -0.05 to 0.00; NNT 33, 95% CI 20to innity). Signicant between-study heterogeneity was observedfor this outcome for both RR and RD (P = 0.02; I2 = 54%; mod-erate for RR, 55% moderate for RD).

Any serious infection, one or more episodes (Outcome 1.2) ( Figure 2 ):

Sixteen studies (including 4986 infants) reported on one or more

episodes of any serious infection (sepsis, meningitis, urinary tractinfection). Four studies ( Atici 1996, Baker 1992, Haque 1986,Ratrisawadi 1991) showed a statistically signicant reduction inany serious infection. A statistically signicant reduction wasfound when all studies were combined (typical RR 0.82, 95% CI0.74 to 0.92; typical RD -0.04, 95% CI -0.06 to -0.02; NNTB25, 95% CI 17 to 50). Statistically signicant between-study het-erogeneity was observed for this outcome (P = 0.01 and I2 = 50%(moderate) for RR; P = 0.0006 and I2 = 62% (moderate) for RD).



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Figure 1. Forest plot of comparison: 1 IVIG versus placebo or no treatment, outcome: 1.1 Sepsis, one or more episodes.

Figure 2. Forest plot of comparison: 1 IVIG versus placebo or no treatment, outcome: 1.2 Any seriousinfection, one or more episodes.

Necrotizing enterocolitis (NEC), one or more episodes (Out-come 1.3):

Seven studies (including 4081 infants) reported on NEC (Bells

stage 2 or 3). One study (Fanaroff 1994) showed a borderlinestatistically signicant increase in NEC (RR 1.26, 95% CI 1.00to 1.59). When all studies were combined, no signicant increase was evident (typical RR 1.08, 95% CI 0.89 to 1.32; typical RD



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In only one study, the outcome of BPD was dened and data wereprovided. Several authors failed to dene the outcome of BPD,and others dened the outcome but did not provide data. In a smallstudy(n=115),Clapp(Clapp 1989) showeda trend towards

increased BPD(RR 1.53, 95%CI 0.78 to 3.01; RD 0.10, 95% CI-0.06 to0.25).In anothersmall study (n= 61),Chou(Chou 1998)found similar results (RR 1.61, 95% CI 0.42 to 6.16; RD 0.06,95%CI -0.11 to 0.23). When combined (n = 176), the typicalRR was 1.55 (95% CI 0.85 to 2.84), and the typical RD was0.09 (95% CI -0.03 to 0.20). No between-study heterogeneity was observed for this outcome for RR (P = 0.95; I2 = 0% (none))and for RD (P = 0.74; I2 = 0% (none)).Intraventricularhaemorrhage (IVH) anygrade(Outcome 1.8):

Four studies (including 3176 infants) reported on IVH (any grade). Prophylactic IVIG did not have a statistically signicanteffect on this outcome (typical RR 1.02, 95% CI 0.88 to 1.19;

typical RD 0.00, 95% CI -0.02 to 0.03). No statistically signi-cant between-study heterogeneity was observed for this outcome(RR,P=0.39;I2 = 0.9% (none);RD, P = 0.39; I2 = 0.6% (none)).Intraventricular haemorrhage (IVH) grade 3 or 4 (Outcome 1.9):

Two studies (including 3000 infants) reported on IVH grade 3 or4. The typical RR was 1.01 (95% CI 0.85 to 1.21), and thetypicalRD was 0.00 (95% CI -0.02 to 0.03). Statistically signicant be-tween-study heterogeneity was observed (RR, P = 0.09, I2 = 65%(moderate); RD, P = 0.08, I2 = 68% (moderate)). A rise in serum IgG in the treatment group was noted in all studiesthat measured serum levels of IgG.

No major adverse effects of IVIG were reported in any of thestudies.Results from excluded studies (see Characteristics of excludedstudies) were similar to those from included studies.

D I S C U S S I O N

The effectiveness of IVIG in preventing nosocomial infection inneonates has been well studied. To date, more than 5000 pretermand/or LBW neonates have been enrolled in trials from many different areas of the world. No new trial was identied for this

update conductedin May2013. Oneadditional trial wasidentiedfor the update of the review conducted in July 2007 (Lelik 2004).However, the study included infants at > 38 weeks gestation and> 2500 g birth weight. Therefore, the study was excluded.

The methodologicalqualityof the included trials varied. Five stud-ieswere of high quality, but elements of bias could not be excludedin the other studies, mainly because of the fact that the interven-tion and the assessment of outcomes were performed unblinded

to group assignment, or there was lack of complete follow-up of all randomly assigned infants. IVIG caused increased levels of IgGin serum. No major side effects were noted.

A small but statistically signicant reduction in the incidence of sepsis and of any serious infection was found. Statistically sig-nicant between-study heterogeneity was observed for these out-comes. The heterogeneity might be explained in part by variablerates of sepsis and any serious infection in the control groups; dif-ferences inpreparation,doseand/ordoseschedule for IVIG; differ-ences in causative organisms for nosocomial infection; differencesin attention to other preventive measures for nosocomial infectionand differences in other co-interventions by place and over time.Some asymmetry was noted when funnel plots were performedfor sepsis and any serious infection. For the two main outcomes

sepsis (one or more episodes) and any serious infection (one ormoreepisodes) moderate inconsistency between study results wasnoted (I2 54% and 50%, respectively).

Nostatisticallysignicant differences werenotedin mortality fromall causes, mortality from infection, NEC, BPD or IVH. Resultsfor these outcomes were centred around an RR of 1.0, with very narrow CIs indicating no trends in either direction. In none of thestudies that provided data on IVH was there any assurance thatall neonates were subjected to ascertainment of an IVH according to a preset schedule for ultrasonographic examination. A trendtowards shortened duration of hospital stay was noted with IVIGtreatment [weightedmean difference (WMD) -2.1 days, 95%CI -4.5 to 0.3 days] . The outcome of hospital stay ishighly dependenton the GA at birth of the neonate, the availability of institutionsproviding Level II care to which the neonate can be transferredand the social situation of the family.

It is possible that the IVIG preparations used in these studies didnot contain the necessary antibodies to prevent infection and thatthe use of preparations with known specic antibodies againstcommonpathogens ina specicneonatal intensivecareunit mightbe more effective ( Weisman 1994b).

The benets of 3.0% and 4.0% reduction in sepsis and in any serious infection, respectively, should be weighed against the costsand the values assigned to this outcome. No serious side effectshave been reported from IVIG to date, but unknown long-termrisks of administration of blood products and the pain associated with establishing an intravenous route for IVIG should be taken

into account.Units with high nosocomial infection rates may want to compareand adjust their infection control policies to those settings withlow rates by using benchmarking techniques. If the rates remainhigh after such measures are taken, use of IVIG might be justied.Prophylacticuse of IVIG should be based on a full economic eval-uation and a clinical decision analysis that incorporates baselinerisk for serious nosocomial infection, both clinical and economic



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outcomes following prophylactic IVIG and values attached to in-fections prevented. Such analyses have not been performed.

Although differences in inclusion criteria are seen, as well as differ-ences in the number of studies published at the time of the reviewsand thenumber of statistical analyses performed, the results of oursystematic review are close to those of three previous meta-analy-ses (Lacy 1995, Jenson 1997, Ohlsson 1998). The results of thesemeta-analyses should encourage basic scientists and clinicians topursue other avenues to enhance the immune system of pretermand/or LBW infants and to prevent nosocomial infection.

A U T H O R S C O N C L U S I O N SImplications for practice

IVIG administration results in a 3% to 4% reduction in sepsis/any serious infection but isnot associated with reductions in mortality or other morbidities (NEC, IVH, length of hospital stay). Pro-phylacticuse of IVIG is not associated with anyshort-term seriousside effects. The decision to use prophylactic IVIG will depend onthe costs and the values assigned to the clinical outcomes.

Implications for research

A full economic evaluation and a clinical decision analysis that in-corporates baseline risk for conrmed nosocomial infection, clini-cal outcomes and economic outcomes after prophylactic IVIG, as well as values attached to infections prevented, is needed.

There is no justication for conducting additional RCTs to testthe efcacy of previously studied IVIG preparations in reducing

nosocomial infection in preterm and/or LBW infants. It is possi-ble that the IVIG preparations used in published studies did notcontain the necessary antibodies to prevent infection. The use of preparations with known specic antibodies against the commonpathogens in a specic neonatal intensive care unit might be more

effective, and RCTs to test the effectiveness of such preparationsmay be justied. The results of these meta-analyses should en-courage basic scientists and clinicians to pursue other avenues toprevent nosocomial infection.

A C K N O W L E D G E M E N T S

Dr K. Thiringer provided us with additional information on thetrial by Sandberg 2000.

Ms Elizabeth Uleryk developed and executed extensive searchesof MEDLINE and EMBASE in February of 2001 and September

2003.DrRyzhakOleuassistedwith translationof the studyfrom Russianto English by Lelik (Lelik 2004).

Searches on May 28, 2013, were conducted by MsColleen M.Ovelman, Trials Search Co-ordinator, and Yolanda R. Brosseau,Managing Editor, the Cochrane Neonatal Review Group.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver NationalInstitute of Child Health and Human Development, NationalInstitutes of Health, Department of Health and Human Services,USA, under Contract No. HHSN267200603418C.

R E F E R E N C E S

References to studies included in this review

Atici 1996 {published data only} Atici A, Satar M, Karabay A, Yilimaz M. Intravenousimmunoglobulin for prophylaxis of nosocomial sepsis.Indian Journal of Pediatrics 1996;63:51721.

Baker 1992 {published data only}Baker CJ, Melish ME, Hall RT, et al.Intravenous immuneglobulin for the prevention of nosocomial infection in low-birth-weight neonates. New England Journal of Medicine

1992;327:2139.Bussel 1990a {published data only}

Bussel JB. Intravenous gammaglobulin in the prophylaxisof late sepsis in very-low-birth-weight infants: preliminary results of a randomized, double-blind, placebo-controlledtrial. Reviews of Infectious Diseases 1990;12:S45762.

Chirico 1987 {published data only}Chirico G, Rondini G, Plebani A, Chiara A, Massa M,Ugazio AG. Intravenous gammaglobulin therapy for

prophylaxis of infection in high-risk neonates. Journal of Pediatrics 1987;110 :43742.

Chou 1998 {published data only}Chou Y-H, Yau K-I T. The use of prophylactic intravenousimmunoglobulin therapy in very low birthweight infants.Chang Gung Medical Journal 1998;21:3716.

Christensen 1989 {published data only}Christensen RD, Hardman T, Thornton J, Hill HR. A randomized, double-blind, placebo-controlled investigation

of the safety of intravenous immune globulin administrationto preterm neonates. Journal of Perinatology 1989;9:12630.

Clapp 1989 {published data only}Clapp DW, Kliegman RM, Baley JE, et al.Use of intravenously administered immune globulin to preventnosocomial sepsis in low birth weight infants: report of a pilot study. Journal of Pediatrics 1989;115 :9738.

Conway 1990 {published data only}Conway SP, Ng PC, Howel D, Maclain B, Gooi HC.



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Baley 1992Baley JE, Fanaroff AA. Neonatal infections. Part 2: Specicinfectious diseases and therapies. In: Sinclair J, BrackenMB editor(s). Effective Care of the Newborn Infant . Oxford:Oxford University Press, 1992:496506.

Bell 1978Bell MJ, Ternberg JL, Feigin RD, et al.Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinicalstaging. Annals of Surgery 1978;187:17.

Berger 1991Berger M. Use of intravenously administered immuneglobulin in newborn infants: prophylaxis, treatment, both,or neither. Journal of Pediatrics 1991;118 :5579.

Bortolussi 1986a Bortolussi R, Fischer GW. Opsonic and protective activity of immunoglobulin, modied immunoglobulin, and serumagainst neonatal Escherichia coli K1 infection. Pediatric Research 1986;20:1758.

Bortolussi 1986bBortolussi R. Potential for intravenous gamma-globulin usein neonatal gram-negative infection: an overview. Pediatric Infectious Diseases 1986;5:S198200.

Bussel 1990bBussel JB. Neonatal uses of intravenous immunoglobulin. American Journal of Pediatric Hematol/Oncology 1990;12:5059.

Consensus 1997Consensus Working Group. Present and future uses of IVIG: a Canadian multidisciplinary consensus-building initiative. Canadian Journal of Allergy and Clinical Immunology 1997;2:176208.

Fischer 1986

Fischer GW, Hemming VG, Hunter KW, et al.Intravenousimmunoglobulin in the treatment of neonatal sepsis:therapeutic strategies and laboratory studies. Pediatric Infectious Disease 1986;5:S1715.

Fischer 1988FischerGW. Therapeutic usesof intravenous gammaglobulinfor pediatric infections. Pediatric Clinics of North America 1988;35:51733.

Fischer 1990a Fischer GW, Weisman LE. Therapeutic intervention of clinical sepsis with intravenous immunoglobulin, whiteblood cells and antibiotics. Scandinavian Journal of Infectious Diseases 1990;73 Suppl :1721.

Fischer 1990bFischer GW, Hemming VG, Gloser HP, Bachmyer H, vonPilar CE, Wilson SR, et al.Polyvalent group B streptococcalimmune globulin for intravenous administration: overview.Reviews of Infectious Diseases 1990;12:S48391.

Fischer 1990cFischer GW. Immunoglobulin therapy for neonatal sepsis:an overview of animal and clinical studies. Journal of Clinical Immunology 1990;10:40S6S.

Gonzalez 1989Gonzalez LA, Hill HR. The current status of intravenousgamma-globulin use in neonates. Pediatric Infectious Disease Journal 1989;8:31522.

Hammarstrom 1990Hammarstrom L, Smith CIE. The use of intravenous IgGas prophylaxis and for treatment of infections. Infection1990;18:31424.

Haque 1992Haque KH. Does the commercial type of IVIG used makea difference?. Pediatrics 1992;89:8067.

Higgins 2003Higgins JPT, Thompson SG, Deeks JJ, Altman DG.Measuring inconsistency in meta-analyses. British Medical Journal 2003;327:55760.

Hill 1993Hill HR. Intravenous immunoglobulin use in the neonate:role in prophylaxis and therapy of infection. Pediatric Infectious Disease Journal 1993;12:54959.

Hill 1991a Hill RH. Is prophylaxis of neonates with intravenousimmunoglobulin benecial. American Journal of Diseases of Children 1991;145:122930.

Hill 1991bHill HR. The role of intravenous immunoglobulin in thetreatment and prevention of neonatal bacterial infection.Seminars in Perinatology 1991;15:416.

Hobbs 1967Hobbs JR, Davis JA. Serum IgG-globulin levels andgestational age in premature babies. Lancet 1967;I:7579.

Irani 1991Irani SF, Wagle SU, Deshpande PG. Role of intravenous

immunoglobulin in prevention and treatment of neonatalinfection. Indian Pediatrics 1991;28:4439. Jenson 1997

Jenson HB, Pollock BH. Meta-analyses of the effectivenessof intravenous immune globulin for prevention andtreatment of neonatal sepsis. Pediatrics 1997;99:e2.

Johnston 1990 Johnston RB. Immunotherapy and immunoprophylaxis inthe newborn infant: the need for denitive trials. Reviews of Infectious Diseases 1990;12:S3923.

Kliegman 1990Kliegman RM, Clapp DW, Berger M. Targetedimmunoglobulin therapy for the prevention of neonatalinfections. Reviews of Infectious Diseases 1990;12:S44356.

Kliegman 1991Kliegman RM, Clapp DW. Rational principles forimmunoglobulin prophylaxis and therapy for neonatalinfections. Clinics in Perinatology 1991;18:303324.

Kyllonen 1989Kyllonen KS, Clapp W, Kliegman RM, Baley JE, ShenkerN, Fanaroff AA, et al.Dosage of intravenously administeredimmune globulin and dosing interval required to maintain



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target levels of immunoglobulin G in low birth weightinfants. Journal of Pediatrics 1989;115 :10136.

Lacy 1995Lacy JB, Ohlsson A. Administration of intravenousimmunoglobulins for prophylaxis or treatment of infectionin preterm infants: meta-analyses. Archives of Disease inChildhood 1995;72:F1515.

Magny 1991a Magny J-F. Les immunoglobulines sont-elles utiles dans letraitment des infections neonatales?. La Revue du Praticien1991;41:136870.

Noya 1989Noya FJD, Baker CJ. Intravenously administered immuneglobulin for premature infants: a time to wait. Journal of Pediatrics 1989;115 :96971.

Papile 1983Papile LA, Munsick-Bruno G, Schafer A. Relationship of cerebral intraventricular hemorrhage and early childhoodneurologic handicaps. Journal of Pediatrics 1983;103:

2737.Rondini 1991

Rondini G, Chirico G, Ugazio AG. Intravenousimmunoglobulin for prophylaxis of infection in preterminfants. Developmental Pharmacology and Therapeutics 1991;17:1449.

Salzer 1991Salzer HR, Weninger M, Pollak A, Kolmer M. Prophylacticimmunoglobulin (IG) treatment in infants less than 30

weeks gestation a meta analysis [abstract]. European Journal of Pediatrics 1991;150:604.

Siber 1992Siber GR. Immune globulin to prevent nosocomial

infections. New England Journal of Medicine 1992;327:26971.Stabile 1989

Stabile A, Sopo SM, Pastore M, Pesaresi MA. Intravenousimmune globulin doses and infection prophylaxis in very low birth weight neonates. Journal of Pediatrics 1989;114 :168.

Stiehm 1966Stiehm RE, Fudenberg HH. Serum levels of immuneglobulins in health and disease: a survey. Pediatrics 1966;37:71527.

Stiehm 1986Stiehm ER. Intravenous immunoglobulins in neonates andinfants: an overview. Pediatric Infectious Disease 1986;5:

S2179.Stiehm 1990

Stiehm ER. Role of immunoglobulin therapy in neonatalinfections: where we stand today. Reviews of Infectious Diseases 1990;12:S43942.

Stoll 1996Stoll BJ, Gordon T, Korones SB, et al.Late-onset sepsis invery low birth weight neonates: a report from the National

Institute of Child Health and Human DevelopmentNeonatal Research Network. Journal of Pediatrics 1996;129:6371.

Weisman 1986 Weisman LE, Fischer GW, Hemming VG, Peck CC.Pharmacokinetics of intravenous immunoglobulin(Sandoglobulin) in neonates. Pediatric Infectious Disease 1986;5:S1858.

Weisman 1992 Weisman LE, Cruess DF, Fischer GW. Current status of intravenous immunoglobulin in preventing or treating neonatal bacterial infections. Clinical Reviews in Allergy 1992;10:1328.

Weisman 1993 Weisman LE, Cruess DF, Fischer GW. Standard versushyperimmune immunoglobulin in preventing or treating neonatal bacterial infections. Clinics in Perinatology 1993;20:21124.

Weisman 1994b

Weisman LE, Cruess DF, Fischer GW. Opsonicactivity of commercially available standard intravenousimmunoglobulin preparations. Pediatric Infectious Disease Journal 1994;13:11225.

Whitelaw 1990 Whitelaw A. Treatment of sepsis with IgG in very low birthweight infants. Archives of Disease in Childhood 1990;65:3478.

Wolach 1997 Wolach B. Neonatal sepsis: pathogenesis and supportivetherapy. Seminars in Perinatology 1997;21:2838.

References to other published versions of this review

Ohlsson 1998Ohlsson A, Lacy JB. Intravenous immunoglobulin forpreventing infection in preterm and/or low birth weightinfants. Cochrane Database of Systematic Reviews 1998, Issue2. [DOI: 10.1002/14651858.CD000361]


Ohlsson 2004Ohlsson A, Lacy JB. Intravenous immunoglobulin forpreventing infection in preterm and/or low birth weight

infants. Cochrane Database of Systematic Reviews 2004, Issue1. [DOI: 10.1002/14651858.CD000361.pub2]


Indicates the major publication for the study



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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Atici 1996

Methods Single-centre, randomised, controlled trial without the use of a placeboI. Blinding of randomisation cant tellII. Blinding of intervention noIII. Complete follow-up yesIV. Blinding of outcome measurement(s) no

Participants 76 infants with GA < 34 weeksSingle-centre study, Turkey May 15, 1993 June 15, 1994

Interventions 40 infants with mean GA (SD) 31.4 2.9 wk, mean BW (SD) 1623 468 g received

0.5 g/kg of IVIG (Sandoglobulin, Sandoz) within 24 hours of birth36 infants with mean GA (SD) 32.3 2.4 wk, mean BW (SD) 1684 519 g served ascontrols (no placebo was given)

Outcomes Proven infection (clinical ndings and blood and/or cerebrospinal uid culture positivefor a pathogen)Total mortality, infectious mortality, days in hospital

Notes Proven infection, mortality from any cause, infectious mortality and days in hospitalcould be ascertained from this study No adverse effects were noted

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selectionbias)

Unclear risk A block randomisation method was used.No further information was provided

Allocation concealment (selection bias) Unclear risk A block randomisation method was used.No further information was provided

Blinding (performance bias and detectionbias) All outcomes

High risk No placebo was used

Incomplete outcome data (attrition bias) All outcomes

Low risk Outcomes were reported on all infants en-rolled

Selective reporting (reporting bias) Unclear risk Theprotocol for thes tudywasnotavailableto us, and we therefore cannot tell whetherthere were any deviations



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Atici 1996 (Continued)

Other bias Low risk Appears free of other bias

Baker 1992

Methods Multicentre, randomised, double-blind, placebo-controlled trialI. Blinding of randomisation yesII. Blinding of intervention yesIII. Complete follow-up yesIV. Blinding of outcome measurement yes

Participants 588 infants with a BW of 500 to 1750 g. Age 3 to 7 daysSix centres in the US July 16, 1987 to December 12, 1988

Interventions 287 infants received 500 mg/kg of IVIG (Gammagard, Baxter Healthcare, Hyland Di-vision, Glendale, Calif) at enrolment (age 3 to 7 days), 1 week later and then every 14days until a total of ve infusions had been given or until hospital discharge, whichevercame rst297 infants received an equal volume of a sterile solution of 5% albumin and 0.9%sodium chloride

Outcomes Proven infection (clinical ndings of sepsis and at least one of the following: a positiveblood culture (bacteriaor fungi), isolation of a pathogen from a normally sterile body site(CSF, pleural, peritoneal or joint uid; bone; soft tissue or urine obtained by suprapubicor bladder catheterization) or isolationof virus from an infantwith clinical deterioration)NEC (stage II or III)IVH (grade I to IV)

BPD (denition not provided)Total days in hospitalEleven neonates were excluded from the study but were included in the intention-to-treat analysis

Notes The following outcomes could be ascertained from this study: any serious infection(bacterial + fungal), IVH, NEC, death from all causes. Total episodes for sepsis werereported. A total of 50 episodes of sepsis were reported among 287 infants in the IVIGgroup and 75 episodes of sepsis among 197 infants in the placebo group. The outcomesepsis, one or more episodes could not be ascertained from this study. Adverse reactions were noted during 10 infusions (5 in each study group, or < 1%). Mildincreases or decreases in blood pressure, heart rate or temperature that were reversed when the rate of infusion was slowed. Two infants in each group had uid overload afteran infusion and were treated with a single dose of furosemide

Risk of bias



Low risk A randomisation table was used



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Baker 1992 (Continued)

Allocation concealment (selection bias) Low risk Infants were randomly assigned by thepharmacist at thestudy site to receive either

IVIG or albumin placebo


Low risk Albumin placebo was used


Low risk Outcomes were reported for all randomly assigned infants



Bussel 1990a

Methods Randomized, double-blind, placebo-controlled trial.I. Blinding of randomisation yesII. Blinding of intervention yesIII. Complete follow-up noIV. Blinding of outcome measurement yes

Participants 240 infants with BW < 1300 g Data for 172 participants are presented in this preliminary analysis; of these, 46 wereexcluded from the statistical analysis (29 because they died during the rst 5 days of life, 4 because of protocol violations and 13 because of inadequate follow-up usually because of their return to the referring hospital. 126 infants remained)Single US centreSeptember 1984 to October 1987

Interventions 61 neonates (mean BW 977 g) received a dose of 1 g of a 6% solution of IVIG (San-doglobulin, Sandoz Pharmaceuticals, East Hanover, NJ) on 4 of the rst 5 days of life,and a fth dose was administered on day 15 or as close to that day as possible (the dosecould be given as late as day 21)65 neonates (mean BW 1043 g) received an albumin placebo at equal oncotic load atthe same times

Outcomes Sepsis (signs and symptoms compatible with sepsis and a positive blood or CSF culture)IVH diagnosed by ultrasonographic examination at 3 to 7 days of age1 neonate excluded because of severe anomalies incompatible with lifeFor additional exclusions, see Participants

Notes This is an interim analysis of a larger study, the results of which have not been reportedto dateData are available on the outcome of sepsis but not on IVH



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Bussel 1990a (Continued)

No adverse effects were reported

Risk of bias



Unclear risk A random number generator was used

Allocation concealment (selection bias) Low risk Blinding of randomisation yes


Low risk Albumin was used as placebo


High risk Data for 172 participants are presented inthis preliminary analysis; of these, 46 wereexcluded from the statistical analysis (29because they died during the rst 5 days of life, 4 because of protocol violations and13because of inadequate follow-up usually because of their return to the referring hos-pital. 126 infants remained)

Selective reporting (reporting bias) High risk Noted in incomplete outcome data sectionabove. The protocol for the study was notavailable to us, and wetherefore cannot tell whether there were any other deviations


Chirico 1987

Methods Randomised, controlled trial without the use of a placeboI. Blinding of randomisation yesII. Blinding of intervention noIII. Complete follow-up yesIV. Blinding of outcome measurement no

Participants In this study, a subgroup with BW


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Chirico 1987 (Continued)

Outcomes Criteria for diagnosis of sepsis, meningitis, arthritis, pneumonia, urinary tract infectionand surface infection included both a positive culture of blood, cerebrospinal uid, tra-

cheal aspirate, urine or pus, respectively, and the presence of clinical and non-microbi-ological laboratory features. For the diagnosis of pneumonia, the appearance of a new inltrate on a chest roentgenogram was also requiredNEC was diagnosed when typical clinical and radiological symptoms were present3 infants in the control group who died within 24 hours after birth were excluded fromthe analysis by the authors

Notes The outcomes of sepsis, any serious infection, NEC, length of hospital stay, death fromall causes and deaths from infection could be ascertained from this study. The 3 infantsin the control group who died within 3 days of life are included in our analyses as perintention to treatNo side effects were observed after IVIG administration

Risk of bias



Unclear risk No information was provided

Allocation concealment (selection bias) Low risk Sealed envelopes were used




Low risk 3 infants in the control group who died within 24 hours after birth were excludedfrom the analysis by the authors





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Chou 1998

Methods Randomised placebo-controlled trial with the use of a non identical-looking placebo(saline)I. Blinding of randomisation cant tellII. Blinding of intervention noIII. Complete follow-up yesIV. Blinding of outcome measurement(s) no

Participants 61 infants with a BW < 1500 g were enrolled. Single-centre study, Taiwan July 1993 to June 1994

Interventions 31 infants, mean BW (SD) 1210 340 g, mean GA (SD) 29.7 2.2 wk, receivedGammumine-N (Miles Inc. Cutter Biological, USA). IVIG was infused for 30 minutesto 2 hours within the rst 12 hours of birth, and every 2 weeks until the patient weighed1800 g or was discharged. The dose of IVIG was 750 to 1000 mg/kg/dose if the infantsBW was < 1000 g and 500 to 750 mg/kg/dose if the infants BW was between 1001 and1500 g.30 neonates, mean BW (SD) 1320 250 g and mean GA (SD) 30.6 1.7 wk receivedsaline infusion

Outcomes

Notes

Risk of bias




Allocation concealment (selection bias) Unclear risk Participants were randomly divided into 2groups


High risk A non identical-looking placebo (saline) was used


Low risk Complete follow-up yes





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Christensen 1989

Methods Randomised, double-blind, placebo-controlled study I. Blinding of randomisation yesII. Blinding of intervention yesIII. Complete follow-up yesIV. Blinding of outcome measurement yes

Participants 20 preterm neonates, weight < 2000 g at entry to study and < 7 days of ageSingle centre, USDates not given

Interventions 10 neonates received IVIG (Gamimmune-N, Cutter Biologicals, Berkeley, California)5% IgG in 10% maltose at 15 mL/kg BW as a single infusion10 neonates received equal volume of 0.1% albumin in 10% maltose

Outcomes Nosocomial infection (not dened)Survival

Notes This study provides information on death from infections and death from all causesNo differences in heart rate, respiratory rate, rectal temperature and urine output werenoted before, during and after infusions of IVIG or placebo (no differences betweengroups)

Risk of bias




Allocation concealment (selection bias) Low risk IVIG and placebo were dispensed from thepharmacy to study nurses in accordance with a random number sequence knownonly to the study pharmacist


Low risk Albumin was used as placebo



Selective reporting (reporting bias) Low risk The protocol for the study was not availableto us, and we therefore cannot tell whetherthere were any deviations




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Clapp 1989

Methods Randomised, double-blind, placebo-controlled trialI. Blinding of randomisation yesII. Blinding of intervention yesIII. Complete follow-up yesIV. Blinding of outcome measurement yes

Participants 115 infants with BW of 600 to 2000 g and < 48 hours of ageSingle centre, USNovember 1, 1986 to August 31, 1987

Interventions 56 neonates (GA = 30 wk; mean BW (SD) 1.3 0.7 kg) received IVIG (Sandoglobulin). Initial infusions of IVIG were 500 mg/kg for infants weighing > 1000 g at birth and700 mg/kg for infants weighing < 1000 g. If serum IgG levels were < 700 mg/dL on day 2 or 6 after transfusion in the IVIG group, an additional dose of IVIG was administeredat that time and subsequent doses were increased by 200 mg/kg. The objective was to

maintain IgG serum levels at >700 mg/dL59 neonates (GA 31 wk; mean BW (SD) 1.3 0.4 kg) received placebo (equal volumeof 6% or 10% sucrose solution). When an infant receiving IVIG required an extra dose,the paired participant in the placebo group received an additional infusion

Outcomes Sepsis (systemic clinical deterioration with a positive blood culture, cerebrospinal uidor aspirate of another normally sterile body cavity)NEC(abdominal distension withgastricretention, abdominal erythema orbloodystools, with radiographic evidenceof pneumatosisintestinalis,portal venous gas or pneumoperi-toneum and staged by the modied Bells criteria)Length of hospital stay Death from all causesDeath from infection

BPD (requiring O2 at 28 days for BPD)IVH (Papile classication)

Notes From the data presented, the outcomes of sepsis, any serious infection, NEC, BPD,IVH, length of hospital stay, death from all causes and death from infection could beascertained. Three episodes of sepsis/proven infection occurred in (an) infant(s) born at24 weeks GA and BW of 600 g. We assumed that this was only one infant and assignedonly one outcome in the meta-analysesTransient tachycardia and a decrease in blood pressure were noted in one infant whoreceived IVIG. Transient rise inalanine aminotransferase level was noted in1 infant whoreceived IVIG and in 1 who received placebo

Risk of bias






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Clapp 1989 (Continued)

Allocation concealment (selection bias) Low risk All investigators and caretakers, with theexception of clinical pharmacist, were un-

aware of the random assignment of eachinfant


Unclear risk A placebo was used, but a 6% or 12% su-crose solution was used, which may notlook identical and would taste differently should a caretaker have tried to taste a drop



Selective reporting (reporting bias) Unclear risk Theprotocol for thes tudywasnotavailableto us, and we therefore cannot tell if there were any deviations


Conway 1990

Methods Randomised controlled trial without use of a placeboI. Blinding of randomisation yesII. Blinding of intervention noIII. Complete follow-up noIV. Blinding of outcome measurement no

Participants 66 neonates of < 30 wk GA 2 centres in the UK Dates not given

Interventions 34 infants received 200 mg/kg IVIG (Intraglobin F, Biotest Pharma, FRG) within 48hoursofbirthand at3-weeklyintervalsuntildischarge from theneonatalunit. Onclinicalsuspicion of infection, neonates in the treatment group only were given a supplementary dose of IVIG 100 mg/kg. A further 100 mg/kg was given within the next 48 hours if infection was conrmed32 infants received routine intensive care

Outcomes Sepsis (blood culture proven infection)NEC (clinical ndings and pneumatosis intestinalis on abdominal X-ray or conrmedat autopsy)IVH (no denition given)BPD (no denition given)Length of stay in NICU (median and range)

Notes Outcomes of sepsis and NEC could be ascertained. We used as denominators all ran-domly assigned participants. We included in the outcome of mortality (all causes) theinfants who were withdrawn because of early death. 1 infant with 2 episodes of NEC



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Conway 1990 (Continued)

was counted as 1 outcome.Side effects were not reported

Risk of bias




Allocation concealment (selection bias) Low risk Sealed envelopes




Low risk Eleven infants 6 in the control group and5 in the treatment group were withdrawnfrom the trial because of early death fromextreme prematurity (n = 7), early return tothe referring hospital (n = 3) and electivetreatment with IVIG for severe congenitalsepticaemia (n = 1)

Selective reporting (reporting bias) Unclear risk See Incomplete outcome data addressed?Theprotocol forthe studywasnot availableto us, and we therefore cannot tell if there were any deviations


Didato 1988

Methods Randomised controlled trial without the use of a placeboI. Blinding of randomisation yesII. Blinding of intervention noIII. Complete follow-up yesIV. Blinding of outcome measurement no

Participants 80 infants with a BW of 2000 g or less

Single centre, Italy June 1985 to December 1986

Interventions 40 infants received 0.5 g/kg/wk of IVIG (IgVena, Sclavo; Siena, Italy) until theyreachedthe GA of 36 weeks and during the entire period of intensive care40 infants received no placebo or other intervention



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Didato 1988 (Continued)

Outcomes Sepsis denedas clinical manifestations, microbiological ndings (positive blood cultureor CSFculture) and non-microbiological laboratory ndings (total and differential white

blood cell count, erythrocyte sedimentation rate, C-reactive protein, platelet count, testsof haemostatic function)

Notes Anyserious infection,death f romall causesanddeath f rominfectioncouldbeascertainedin this study. As sepsis included neonates with positive CSF cultures, the results wereincluded in the any serious infection category only. Datacould not be separated betweensepsis and meningitisNo side effects or adverse reactions were observed after IVIG administration

Risk of bias



Unclear risk Randomised controlled trial without theuse of a placebo

Allocation concealment (selection bias) Low risk Randomly assigned by sealed envelopes




Low risk Outcomes were reported for all infants ran-domly assigned



Fanaroff 1994

Methods Multicentre,2-phasecontrolledt rial.Phase1 wasplacebocontrolledanddoubleblinded;phase 2 was not placebo controlledI. Blinding of randomisation yesII. Blinding of intervention yes/no*III. Complete follow-up yesIV. Blinding of outcome measurement yes/no**This study had 2 phases; in phase 1a, placebo was used, but not in phase 2

Participants 2416 infants with BW 501 to 1500 g and randomly assigned at a mean age of 44 25hours after birth8 centres in the US January 1, 1988 to March 31, 1991 (or through April, 1991)



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Fanaroff 1994 (Continued)

Selective reporting (reporting bias) Unclear risk Theprotocol for thes tudywasnotavailableto us, and we therefore cannot tell if there

were any deviations


Fanaroff-I 1994

Methods Phase 1 of Fanaroff 1994, placebo-controlled

Participants 1218 infants with BW 501 to 1500 g and randomly assigned at a mean age of 44 25hours after birth8 centres in the US January 1, 1988 to March 31, 1991 (or through April 1991)

Interventions In phase 1595 infants received IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, NJ)623 infants received placebo equal volume of 5% albumin solution in the same vehicleprepared by the manufacturer of the immune globulin. The infants received their rstdose of study drug within 24 hours of randomisation. To achieve a target levelof 700 mg of immune globulin/dL, infants weighing 501 to 1000 g were given 900 mg of immuneglobulin per kg of body weight, and infants weighing 1001 to 1500 g were given 700mg per kg. The infusions were repeated every 2 weeks until the infants weighed 1800 g, were transferred to another hospital, died or were sent home

Outcomes Sepsis (symptoms compatible with infection and a positive blood culture for bacteria orfungi obtained at least 96 hours after birth and before 120 days of life; for commensals,the diagnosis required 2 positive blood cultures obtained no more than 4 days apart)The diagnosis of meningitis required a positive culture of CSF. The diagnosis of urinary tract infection required a pure culture from urine obtained by catheterization or supra-pubic punctureProven infection (including septicaemia, meningitis or urinary tract infection) during the rst 120 days of lifeNEC (Bells modied classication)BPD (not dened)Days in hospital

Notes

Risk of bias



Unclear risk Multicentre, 2-phase controlled trial. Phase1 was placebo controlled and doubleblinded;phase2 wasnot placebocontrolled



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Haque 1986 (Continued)

Allocation concealment (selection bias) Low risk Envelopes were used







Magny 1991b

Methods Multicentre, randomised, controlled, double-blind study I. Blinding of randomisation - cant tellII. Blinding of intervention - yesIII. Complete follow-up - yesIV. Blinding of outcome measurement - yes

Participants 235 neonates of less than or equal to 32 weeks gestation, hospitalised before 25 hoursof life and having endotracheal tube and/or umbilical catheter on admission4 centres in Paris, France1987 to 1989

Interventions 120 neonates received500 mg (10 mL) of polyvalent Ig(Biotransfusion, France) on days0, 1, 2, 3, 17 and 31 of lifeIn the placebo group, 115 neonates received 10 mL of 0.2% albumin in the same fashion

Outcomes Death from infectionCertain nosocomial infection (clinical signs of infection, positive cultures (blood, urine,cerebrospinal uid, tracheal aspirate, stools, gastric aspirate), at least 2 biological signsof infection (abnormal number of leukocytes, immature leukocytes > 5%, thrombocy-topenia < 150 000/mm3, rise in brinogen levels > 4.5 g/L, rise in C-reactive proteinlevels > 20 mg/L)NEC was diagnosed when bloody stools were associated with radiological pneumatosisNeonatal infection and infection occurring within the rst 4 days of life, potentially of maternal origin, were not counted as evaluation criteria

Notes Death from infection could be ascertained in this study. The denition of nosocomialinfection did not meet our criteria for sepsis or any serious infection. The number of infants with 1 or more episodes of NEC could not be ascertained. The 46 infants for whom the protocol was broken were maintained in the statistical analysesThere were neither clinical nor biologic side effects in any of the patients after Ig infusion



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Magny 1991b (Continued)

Risk of bias



Low risk A randomisation table was prepared by thestatistician for each unit

Allocation concealment (selection bias) Low risk The investigators were blind


Low risk


Low risk In 46 infants (21 in the IVIG group; 25 inthe placebo group), irregularities occurredin the protocol (1 dose forgotten or no fol-low-upuntil45daysoflifebecauseoftrans-fer out of the unit). The data from these 46infants were maintained for statistical anal-ysis but were considered separately

Selective reporting (reporting bias) Low risk See Incomplete outcome data addressed.Theprotocol forthe studywasnot availableto us, and we therefore cannot tell if there were any other deviations


Ratrisawadi 1991

Methods Randomised controlled trial, without the use of a placebo groupI. Blinding of randomisation - cant tellII. Blinding of intervention - noIII. Complete follow-up - cant tellIV. Blinding of outcome measurement - no

Participants 68 infants with a BW of 1000 to 1500 g Single centre, Bangkok, ThailandFebruary 1988 to March 1990

Interventions 34 neonates received 250 mg/kg of IVIG (Biotest Pharma, West Germany) within 4hours of birth34 neonates received 500 mg/kg of IVIG within 4 hours of birth34 neonates received no intervention

Outcomes Sepsis (presence of clinical ndings of sepsis plus positive blood cultures)



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Ratrisawadi 1991 (Continued)

Notes The outcomes of sepsis and death from all causes could be ascertained in this study No adverse effects were observed during the period of study

Risk of bias



Unclear risk Randomised, controlled trial, without theuse of a placebo group

Allocation concealment (selection bias) Unclear risk Blinding of randomisation - cant tell

Blinding (performance bias and detectionbias)

All outcomes



Unclear risk Infants (number not stated) who expired within 24 hours of life or requiredblood ex-change transfusion were excluded from thestudy. In spite of these exclusions, thenum-ber of participants in each group is identi-cal (n = 34)

Selective reporting (reporting bias) Unclear risk See above. The protocol for the study wasnotavailable to us,and we therefore cannottell if there were any other deviations


Sandberg 2000

Methods Randomised double-blind placebo controlled trialI. Blinding of randomisation - yesII. Blinding of intervention - yesIII. Complete follow-up - noIV. Blinding of outcome measurement(s) - yes

Participants 105 infants were randomly assigned into the study. 24 infants (12 in each group) wereexcluded because of initial serum IgG level > 4 g/L, violation of the study protocol,

withdrawal of consent or intrauterine infection

Interventions 40 infants, mean GA (SD) 27.5 2.2 wk and mean BW (SD) 1.06 0.39 kg, received1 g/kg (20 mL/kg) of IVIG (Baxter) on study day 0 (< 48 hours of age) and on days 3,7, 14 and 21. 41 infants, mean GA (SD) 27.7 2.5 wk, mean BW (SD) 1.13 0.38 kg,received an equal volume of placebo (human albumin 5%)



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Sandberg 2000 (Continued)

Outcomes Sepsis (symptoms and positive blood culture)Days on ventilator

Total mortality from any cause. Infectious mortality

Notes Outcomes of sepsis, death from all causes and death from infection could be ascertainedfrom this study

Risk of bias



Low risk According to Dr Klara Thiringer, randomi-sation was achieved by a computer-gener-ated list for each of the 4 centres, and in-fantswere allocated by the use of sealed en-velopes

Allocation concealment (selection bias) Low risk Infants were allocated by the use of sealedenvelopes


Low risk


Low risk 105 infants were randomly assigned intothe study. 24 infants (12 in each group) were excluded because of initial serum IgG

level > 4 g/L, violation of the study proto-col, withdrawal of consent or intrauterineinfection



Spady 1994

Methods Randomised, double-blind trialPublished in abstract form only - full quality assessment not possible

Participants 111 VLBW infants

Interventions 54 infants were given 300 mg/kg of IVIG (name of product not given) as 5% solution,once between 24 and 72 hours of age and again 72 hours later57 infants were given the same volumes as 5% dextrose



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Spady 1994 (Continued)

Outcomes The outcome of sepsis was not dened in this abstract, but according to the authors,sepsis occurred in 17 infants in the IVIG group and in 15 in the control group

Hospital stay

Notes Lengthofhospital staycouldbeascertainedfromthisstudy,which ispublished inabstractform only Respiratory rate increased in the IVIG groupafter the rst infusion. No other side effectsoccurred

Risk of bias



Unclear risk Published in abstract form only - full qual-ity assessment not possible

Allocation concealment (selection bias) Unclear risk See above


Unclear risk See above


Unclear risk See above

Selective reporting (reporting bias) Unclear risk See above

Other bias Unclear risk See above

Stabile 1988

Methods Single-centre, randomised, controlled trial without the use of a placebo groupI Blinding of randomisation - cant tellII Blinding of intervention - noIII Complete follow-up - noIV Blinding of outcome measurement - no

Participants 94 neonates, GA 34 weeks gestation or BW 1500 g Single centre, Rome, Italy May 1984 to June 1986

Interventions 0.5 g/kg IVIG (Venogamma Polivalente, Ismunit, Pomezia, Italy) on the 1st, 2nd, 3rd,7th, 14th, 21st and28th days of life (treatment group)or no intervention(controlgroup)

Outcomes SepsiswasdenedasclinicalsignsofsystemicinfectionandpositivebloodorCSFculturefor a pathogen14 neonates were excluded from the analysis. 6 neonates in the treatment group wereexcluded: 3 underwent exchange transfusion, 2 died from severe respiratory distress



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Stabile 1988 (Continued)

syndrome and 1 had suspected prenatal infection. 8 control neonates were excluded: 2underwent exchange transfusion, 3 died of severe respiratory distress syndrome, 1 diedof respiratory distress syndrome and IVH and 2 had suspected prenatal infection

Notes Sepsis, any serious infection, death from all causes and death from infection could beascertained from this study. Infants who died and were excluded by the authors areincluded in our analysis..nonewborn infant showedany localorgeneral reactioneitherduring orafter infusions.Three infants showed a temporary increase in IgE from 10-18 to 28-38 IU/mL withoutconcurrent side effects

Risk of bias


Random sequence generation (selectionbias) Unclear risk No information was provided

Allocation concealment (selection bias) Unclear risk Infants were randomly assigned




High risk Complete follow-up - no14 neonates were excluded from the analy-si

Documents

Intravenous Immunoglobulin for Preventing Infection in Preterm and-Or Low Birth Weight Infants[2]