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

Ohlsson A, Lacy JB

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 22/08/2007
Date of last substantive update: 20/10/2003
Date of last minor update: 23/07/2007
Date next stage expected 30/07/2009
Protocol first published: Issue 2, 1998
Review first published: Issue 2, 1998

Contact reviewer

Dr Arne Ohlsson
Director Evidence Based Neonatal Care and Outcomes Research
Department of Paediatrics
Mount Sinai Hospital
600 University Avenue
Toronto
Ontario CANADA
M5G 1X5
Telephone 1: +1 416 586 8379
Telephone 2: +1 416 341 0444
Facsimile: +1 416 586 8745
E-mail: aohlsson@mtsinai.on.ca

Contribution of reviewers

Arne Ohlsson

Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Verifying and entering data into RevMan
Writing text of review

Janet Lacy

Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Writing text of review

Both reviewers contributed to this update

Internal sources of support

Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, CANADA

External sources of support

None

What's new

This is an update of the review "Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants" published in The Cochrane Library, Issue 1, 2004 (Ohlsson 2004).

One potential new trial was identified for this update conducted in July 2007. However, the infants randomized were more than 38 weeks gestation or weighed more than 2,500 g and therefore the study did not meet the inclusion criteria of preterm or low birth weight infants.

Trials using species specific immunoglobulins (such as for staphylococcus aureus or epidermidis) were not included as they are reviewed separately by others within the Cochrane Collaboration.

There have been two previous updates of this review (2001, 2003).

In our 2001 update of this review, we identified 4 additional studies (2 single centre studies from Turkey, one single centre study from Taiwan and one multi-centre study conducted in four centres in Sweden and Austria). These studies reported on a total of 298 infants. We are aware of one additional unpublished study that enrolled 40 infants in Estonia. To our knowledge, this study has not been published. We were not able to identify any additional studies in our literature search in September 2003.

In the 2001 update of this review, secondary analyses according to study quality were abolished as we found it exceedingly difficult to ascertain whether caregivers/researchers were blinded to the randomization process and/or the intervention or not.

In 2001, the addition to our previous systematic review of outcomes from 298 randomized infants did not overturn the main results from our previous review first published in 1998. IVIG administration results in a 3-4% reduction in sepsis and any serious infection but is not associated with reductions in mortality or other important morbidities. There is no need for further trials of currently available IVIG preparations to reduce the incidence of nosocomial infections.

As we noted statistically significant heterogeneity for the two main outcomes of interest in this review (sepsis and any serious infection), we added the newly introduced "inconsistency test" (I squared). For both outcomes (sepsis and any serious infection), there was moderate "inconsistency" of 54% and 50% respectively.

Dates

Date review re-formatted: 09/10/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 23/07/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Infants may acquire infections while in the womb or in the hospital after birth, especially if they require intensive care. Such infections may cause serious illness or death. Transport of immunoglobulins (substances in the blood that can fight infections) from the mother to the fetus mainly occurs after 32 weeks gestation and infants do not begin to produce immunoglobulins until several months after birth. Theoretically, the adverse effects of infections could be reduced by the preventive administration of intravenous immunoglobulin. To date, approximately 5,000 infants have been enrolled in studies to evaluate the effect of prophylactic use of intravenous immunoglobulins on neonatal outcomes. Intravenous administration of immunoglobulins results in a 3% reduction in blood born infections and a 4% reduction in any serious infection. Intravenous administration of immunoglobulins is not associated with reductions in other important neonatal outcomes or length of hospital stay. Most importantly, intravenous immunoglobulin administration does not have any important effect on mortality. Prophylactic use of IVIG is not associated with any short term serious side effects. From a clinical perspective, a 3 - 4% reduction in nosocomial infections without a reduction in mortality or other important clinical outcomes is of marginal importance.

Abstract

Background

Nosocomial infections continue to be a significant cause of morbidity and mortality among preterm and/or low birth weight infants. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence. Intravenous immunoglobulin thus has the potential of preventing or altering the course of nosocomial infections.

Objectives

To assess the effectiveness/safety of intravenous immunoglobulin (IVIG) administration (compared to placebo or no intervention) to preterm (< 37 weeks gestational age at birth) and/or low birth weight (LBW) (< 2500 g BW) infants in preventing nosocomial infections.

Search strategy

MEDLINE, EMBASE, and The Cochrane Library Databases were searched in July 2007 using the keywords: immunoglobulin and infant-newborn and random allocation or controlled trial or randomized controlled trial (RCT). The reference lists of identified RCTs and personal files were searched. No language restrictions were applied.

Selection criteria

The criteria used to select studies for inclusion in this overview were:
1) Design: RCTs in which administration of IVIG was compared to a control group that received a placebo or no intervention.
2) Population: preterm (< 37 weeks gestational age) and/or LBW (<2500 g) infants.
3) Intervention: IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days or longer). (Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded as were studies in which the follow-up period was one week or less).
4) At least one of the following outcomes was reported: sepsis, any serious infection, death from all causes, death from infection, length of hospital stay, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD).

Data collection & analysis

Two review authors independently abstracted information for each outcome reported in each study, and one researcher (AO) checked for any discrepancies and pooled the results.

Relative Risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effects model are reported. When a statistically significant RD was found the number needed to treat (NNT) was also calculated with 95% CIs. The results include all included studies in which the outcome of interest was reported. Statistically significant between study heterogeneity was reported. The results of the inconsistency test (I squared) are also reported when statistically significant heterogeneity was found.

Main results

One potential new trial was identified in July 2007 (Lelik 2004). However, this trial enrolled infants > 38 weeks gestation and > 2,500 g birth weight and was, therefore, excluded. Nineteen studies met inclusion criteria. These included approximately 5,000 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review.

When all studies were combined there was a statistically significant reduction (p = 0.02) in sepsis, typical RR [0.85 (95% CI 0.74, 0.98)] and typical RD [-0.03 (95% CI 0.00, -0.05)], NNT 33. There was statistically significant between-study heterogeneity (p = 0.02); I squared 54%. A statistically significant reduction was found for any serious infection, one or more episodes, when all studies were combined [typical RR 0.82 (95% CI 0.74, 0.92); typical RD -0.04 (95% CI -0.02, -0.06,); NNT 25 (95% CI, 17, 50)]. There was statistically significant between-study heterogeneity (p = 0.0006); I squared 50%. There were no statistically significant differences for mortality from all causes, mortality from infection, incidence of NEC, BPD and IVH or length of hospital stay. No major adverse effects of IVIG were reported in any of the studies.

Reviewers' conclusions

IVIG administration results in a 3% reduction in sepsis and a 4% reduction in one or more episodes of any serious infection, but is not associated with reductions in other important outcomes: NEC, IVH, or length of hospital stay. Most importantly, IVIG administration does not have any significant effect on mortality from any cause or from infections. Prophylactic use of IVIG is not associated with any short-term serious side effects. From a clinical perspective a 3 - 4% reduction in nosocomial infections without a reduction in mortality or other important clinical outcomes is of marginal importance.

The decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes. There is no justification for further RCTs testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or LBW infants. The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections.

Background

Although survival has improved for preterm and/or low birth weight (LBW) infants, nosocomial infection continues to be a significant cause of morbidity and mortality in this population. A 25% incidence of late onset infection has recently been reported in a cohort of 6,911 very LBW infants who were admitted to 12 US centres and who survived beyond three days (Stoll 1996). Neonates in whom late-onset sepsis developed were significantly more likely to die than those who were not infected (17% vs. 7%; p < 0.0001) (Stoll 1996).

Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until about 24 weeks after birth, so the preterm infant is especially vulnerable to infectious sources in the Neonatal Intensive Care Unit (Baker 1990a). The mean serum levels of IgG are 400 mg/dl in infants less than 32 weeks gestational age (GA) compared to 1000 mg/dl in term infants (Hobbs 1967; Stiehm 1966). The idea of preventing nosocomial infection with intravenous immunoglobulin (IVIG) is attractive as administration of IVIG provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence (Baley 1988).

The administration of IVIG to LBW infants has been studied extensively. Numerous descriptive review articles, commentaries and editorials on the use of IVIG in neonates have been published, often by the same researchers. These papers have included several randomized controlled trials (RCTs), the authors' personal experience with IVIG and/or information about the preparation or dosing regimen of IVIG (Weisman 1986; Bortolussi 1986a; Bortolussi 1986b; Fischer 1986; Stiehm 1986; Baley 1988; Fischer 1988; 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; Hill 1991a; Hill 1991b; Irani 1991; Kliegman 1991; Magny 1991a; Rondini 1991; Haque 1992; Siber 1992; Weisman 1992; Hill 1993; 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 there was no significant reduction in the incidence of sepsis in the treated group. In "Effective Care of the Newborn Infant", Baley & Fanaroff (Baley 1992) presented overviews of RCTs that studied the administration of IVIG to neonates. They reviewed seven studies of the prophylactic use of IVIG that reported an outcome of sepsis. They concluded that "The preliminary data generated in trials of IVIG are promising, but use of this treatment modality still needs to be considered experimental and should only, as yet, be used under study conditions." Lacy & Ohlsson (Lacy 1995) included additional trials and concluded that routine administration of IVIG to preterm infants to prevent infection is not recommended. Jenson & Pollock (Jenson 1997) used slightly different inclusion criteria and, like Lacy & Ohlsson (Lacy 1995), noted heterogeneity among studies. They concluded that "this heterogeneity probably belies the minimal benefit, at most, of prophylactic IVIG...". The results of a Canadian multidisciplinary consensus-building initiative (Consensus 1997), has been published and the use of IVIG for prophylaxis of neonatal nosocomial infection was considered to be inappropriate. This review provides an update of our previously updated review (Ohlsson 2001) first published in 1998 (Ohlsson 1998).

Objectives

To use systematic review/meta-analytic techniques to determine if IVIG administration (compared to placebo or no intervention) to preterm [< 37 weeks gestational age (GA) at birth)] and/or LBW (< 2500 g birth weight) infants is effective/safe in preventing nosocomial infections.

Criteria for considering studies for this review

Types of studies

Studies in which preterm and/or LBW neonates were randomized to receive IVIG or either a placebo or no intervention.

Types of participants

Preterm and/or LBW neonates.

Types of interventions

IVIG for the prevention of bacterial or fungal infection. Studies that were designed to evaluate the effect of IVIG on humoral immune markers were excluded as were studies in which the follow-up period was one week or less. Studies that assessed the effectiveness of IVIG for treatment of suspected or confirmed infection were excluded.

Types of outcome measures

PRIMARY OUTCOME:

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

SECONDARY OUTCOMES:

1. Any serious infection [clinical signs and symptoms in conjunction with positive cultures (bacteria or fungi) from normally sterile body fluids (blood, cerebro-spinal fluid, urine obtained by catheterization or suprapubic tap, or from tissue at autopsy)]. As per this definition, cases of sepsis if reported separately were also included in any serious infection.
2. Necrotizing enterocolitis (NEC) diagnosed according to Bell's criteria (Bell 1978). For repeated episodes of sepsis, any serious infection and NEC, only one occurrence per infant was counted as an outcome.
3. Death from all causes.
4. Deaths from infection (including death from NEC).
5. Length of hospital stay.
6. Incidence of bronchopulmonary dysplasia (BPD) defined as additional oxygen requirement (above room air) at 28 days of age or requiring assisted ventilation for reasons other than apnea of prematurity.
7. Incidence of intraventricular haemorrhage (IVH), any grade, classified according to Papile (Papile 1983).
8. Incidence of IVH, grade 3 or 4, classified according to Papile (Papile 1983)
9. Reports on possible side effects as described by the authors.

Search strategy for identification of studies

The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group.
The search was initiated by review of personal files and published meta-analyses. The reference list of identified studies and subsequently retrieved articles was scanned for additional references. MEDLINE was searched from 1966 to July, 2007. EMBASE (Excerpta Medica online) was searched from 1980 to July 2007. The Cochrane Library, Issue 2, 2007 was searched. No language restrictions were applied. Ms Elizabeth Uleryk developed and applied an extensive search strategy (available upon request) for MEDLINE and EMBASE in February 2001 and September 2003. The same strategy was used in 2007.

Methods of the review

The criteria used to select studies for inclusion in this overview were:
1) Design: RCT in which treatment with IVIG was compared to a control group that received a placebo or no intervention.
2) Population: preterm (< 37 weeks gestational age) and/or LBW (< 2500 g) infants.
3) Intervention: IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days or more). (Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded, as were studies in which the follow-up period was one week or less. Studies designed to assess the effectiveness of treatment with IVIG for suspected/established infection were excluded).
4) At least one of the following outcomes was reported: sepsis, any serious infection, death from all causes, death from infection, length of hospital stay, IVH, NEC, or BPD. Reports on side-effects.

The titles (and abstracts when available) in the MEDLINE, EMBASE, and Cochrane Library printouts were reviewed by the two authors. Any article that either review author felt might meet the inclusion criteria noted above or that either felt should have its reference list searched was retrieved. Informal attempts were made to locate unpublished studies and attempts were made to request additional information from authors of published studies. Information was obtained on one published study and one unpublished study (Sandberg 2000, Metsvaht 2001).

All identified trials (excluding those that used IVIG for treatment) are listed in the Table of Included Studies or in the Table of Excluded Studies.

Assessment of Quality of Studies:
An assessment of the quality of the included studies (excluding abstracts) was performed independently by JBL and AO using the criteria developed by the Cochrane Neonatal Review Group. These criteria include: I) Blinding of randomization, II) Blinding of intervention, III) Complete follow-up, IV) Blinding of outcome measurement. For each criterion there were three possibilities: yes, can't tell or no. The assignment was not done with the assessors blinded to author, institution, journal of publication or results, as both assessors were familiar with most of the studies and the typographical layout of the journals, and would have knowledge of these even when blinded. In addition the results sections of articles often include methodological information. After the independent evaluation, the two assessors discussed the results for each study and any discrepancies were resolved.

Data Abstraction:
Data abstraction forms were developed and pilot tested to verify definitions of terms. The two review authors independently abstracted information on each study and one (AO) checked for any discrepancies and pooled the results. Data abstraction included: whether the study involved prophylaxis or treatment, number of patients enrolled, number of patients enrolled but later excluded, the time period and geographical location of the study, baseline characteristics of patients, inclusion/exclusion criteria, preparation and dosing regime of IVIG and placebo, length of follow-up.

Information on outcomes and the numbers of affected infants was abstracted. The total number of infants with sepsis [clinical signs and symptoms plus positive blood culture (bacteria or fungi)] and any serious infection [clinical signs and symptoms in conjunction with positive cultures (bacteria or fungi) from normally sterile body fluids] was abstracted as was information on NEC, death from all causes, and deaths from infection. Information on length of hospital stay, incidence of BPD and IVH was collected. Information on probable infection was not collected as the definitions used by the different investigators were too variable.

Statistical Analysis:
The statistical package (RevMan 4.2) provided by the Cochrane Collaboration was used. Relative risk (RR) and Risk Difference (RD) with 95% CI's using the fixed effects model are reported. If there was a statistically significant reduction in the RD the number needed to treat (NNT) was calculated. Statistically significant between study heterogeneity was reported when identified and the test for inconsistency (I² statistic) was applied when statistically significant heterogeneity was noted.

Description of studies

Included Studies:
Details of the included studies are provided in the Table of Included Studies.

Nineteen studies including approximately 5,000 preterm and/or LBW infants met inclusion criteria. These studies were performed in many countries (U.S., Italy, U. K., Saudi Arabia, France, Thailand, Belgium, Turkey, Sweden and Austria). The amount of IVIG per dose varied from 120 mg/kg (Haque 1986) to 1g/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 (Baker 1992); 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 (Didato 1988); Biotransfusion (Magny 1991b); unnamed product (Spady 1994; Sandberg 2000 - study supported by Baxter AG, Austria); Venogamma (Stabile 1988); Gammumine-N (Chou 1998).

Excluded Studies:
Six studies were excluded as they included infants that were heavier or more mature at birth than the inclusion criteria allowed for (Kinney 1991, Adhikari 1996); lacked information on outcomes (Kacet 1991; Malik 1990); lacked a randomized control group (Acunas 1994) or immunoglobulin was given intra-muscularly (Monintja 1989).

Methodological quality of included studies

The assessment of individual studies are presented in the Table "Characteristics of Included Studies".
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, blinding of randomization, intervention and outcome measurement could be ascertained from the published reports. In the remaining 15 studies elements of bias could not be excluded. The lack of a placebo in 10 of the studies (Atici 1996, Chirico 1987, Conway 1990, Didato 1988, Fanaroff 1994 - phase II, Haque 1986, Ratrisawadi 1991, Stabile 1988, Tanzer 1997, Van Overmeire 1993) precluded blinding of the caregivers. One study (Fanaroff 1994) included two phases; phase I including a placebo but not phase II. In several studies blinding of randomization was not clearly described (Chirico 1987, Magny 1991b, Ratrisawadi 1991, Stabile 1988). In the study by Sandberg (Sandberg 2000), an intention to treat analysis was not applied. One study (Spady 1994) has been published in abstract form only and the quality could therefore not be fully assessed. The study by Bussel (Bussel 1990a) represents an interim analysis with data lacking from a large proportion of the infants randomized.

Results

One additional trial was identified in July 2007 (Lelik 2004). However, this trial enrolled infants greater than 38 weeks gestational age and greater than 2,500 g birth weight. The study was therefore excluded. No new studies were identified in the literature search conducted in September 2003. Nineteen studies met inclusion criteria. These included a total of approximately 5,000 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review. For details of results, see Tables of Analyses. It should be noted that for most outcomes, the large study by Fanaroff (1994) greatly influenced the summary statistics with an assigned weight ranging from 42.7 % for the outcome of any serious infection to 76.1% for the outcome of IVH grade 3 or 4.

PRIMARY OUTCOME:

IVIG VS. PLACEBO OR NO TREATMENT (Comparison 01):

Sepsis, one or more episodes (Outcome 01.01):

Ten studies (including 3,975 infants) reported on the outcome of one or more episodes of sepsis per infant (clinical signs and symptoms of infection and positive blood culture). Only the study by Ratrisawadi (1991) showed a statistically significant reduction in sepsis (RR 0.38; 95% CI 0.19, 0.79). When all studies were combined there was a statistically significant (p = 0.02) reduction in sepsis [typical RR 0.85 (95% CI 0.74, 0.98); typical RD [-0.03 (95% CI -0.05, 0.00); NNT 33]. There was significant between-study heterogeneity for this outcome for both RR and RD (p = 0.02; I² = 54%).

Any serious infection, one or more episodes (Outcome 01.02):

Sixteen studies (including 4,986 infants) reported on one or more episodes of any serious infection (sepsis, meningitis, urinary tract infection). Four studies (Atici 1996, Baker 1992, Haque 1986, Ratrisawadi 1991) showed a statistically significant reduction in any serious infection. A statistically significant reduction was also found when all studies were combined [typical RR 0.82 (95% CI 0.74, 0.92); typical RD -0.04 (95% CI -0.06, -0.02); NNT 25 (95% CI 17, 50)]. There was statistically significant between-study heterogeneity for this outcome (p = 0.01 and I² = 50% for RR; p = 0.0006 and I² = 62% for RD).

Necrotizing enterocolitis (NEC), one or more episodes (Outcome 01.03):

Seven studies (including 4,081 infants) reported on NEC (Bell's stage 2 or 3). One study (Fanaroff 1994) showed a borderline statistically significant increase in NEC (RR 1.26; 95% CI 1.00, 1.59). When all studies were combined there was no significant increase [typical RR 1.08 (95% CI 0.89, 1.32); typical RD 0.01 (95% CI -0.01, 0.02)]. There was no statistically significant between-study heterogeneity for this outcome for RR (p = 0.14; I² = 38%), but for RD (p = 0.05, I² = 52%).

Mortality (all causes) (Outcome 01.04):

Fifteen studies (including 4,125 infants) reported on mortality from all causes. Two studies (Chirico 1987, Tanzer 1997) showed a statistically significant reduction in this outcome When all studies were combined, there was no statistically significant reduction [typical RR 0.89 (95% CI 0.75, 1.05); typical RD -0.01 (95% CI -0.03, 0.01)]. There was no statistically significant between-study heterogeneity for this outcome for RR (p = 0.22; I² = 21%) and for RD (p = 0.15; I2 = 28%).

Mortality (infectious) (Outcome 01.05):

Ten studies (including 1,690 infants) reported on mortality from infections. One study (Atici 1996) showed a statistically significant reduction in this outcome. The overall analysis showed no significant impact of IVIG prophylaxis on this outcome [typical RR 0.83 (95% CI 0.56, 1.22); typical RD -0.01 (95% CI -0.03, 0.01)]. There was no statistically significant between-study heterogeneity for this outcome for RR (p = 0.11; I² = 40%) and for RD (p = 0.08; I² = 42%).

Duration of hospitalization (Outcome 01.06):

None of eight studies (including 3,562 infants) reported a significant reduction in length of hospital stay following IVIG prophylaxis. The overall typical weighted mean difference was -2.1 days (95% CI -4.5, 0.3). There was no statistically significant between-study heterogeneity (p = 0.67 and I²= 0% for both RR and RD).

Bronchopulmonary dysplasia (BPD) (Outcome 01.07):

In only one study was both the outcome of BPD defined and data provided. Several authors failed to define the outcome of BPD and others defined the outcome but did not provide data. In a small study, Clapp (Clapp 1989) showed a trend towards increase in BPD [RR 1.53 (95% CI 0.78,3.01); RD 0.10 (95% CI -0.06, 0.25)]. In another small study, Chou (Chou 1998) found similar results [RR 1.61 (95% CI 0.42, 6.16); RD 0.06 (95%CI -0.11, 0.23)]. When combined the typical RR was 1.55 (95% CI 0.85, 2.84) and the typical RD was 0.09 (95% CI -0.03, 0.20). There was no between-study heterogeneity for this outcome for RR (p = 0.95; I² = 0%) and for RD (p = 0.74; I² = 0%).

Intraventricular hemorrhage (IVH) any grade (Outcome 01.08):

Four studies (including 3,176 infants) reported on IVH (any grade). Prophylactic IVIG did not have a statistically significant effect on this outcome [typical RR 1.02 (95% CI 0.88, 1.19); typical RD 0.00 (95% CI -0.02, 0.03)]. There was no statistically significant between-study heterogeneity for this outcome [RR (p = 0.39; I² = 0.9%); RD (p = 0.39; I² = 0.6%)].

Intraventricular hemorrhage (IVH) grade 3 or 4 (Outcome 01.09):

Two studies (including 3,000 infants) reported on IVH grade 3 or 4. The typical RR was 1.01 (95% CI 0.85, 1.21) and the typical RD was 0.00 (95% CI -0.02, 0.03). There was statistically significant between-study heterogeneity [RR (p = 0.09; I² = 65 %; RD (p = 0.08; I² = 68%)].

A rise in serum IgG in the treatment group was noted in all studies that measured serum levels of IgG.

No major adverse effects of IVIG were reported in any of the studies.

Results from excluded studies (See Table of Excluded Studies) were similar to those from included studies.

Discussion

One additional trial was identified for this update of the review conducted in July 2007 (Lelik 2004). However, the study included infants > 38 weeks gestation and > 2,500 g birth weight. Therefore, the study was excluded. The effectiveness of IVIG to prevent nosocomial infections in neonates has been well studied. To date over 5,000 preterm and/or LBW neonates have been enrolled in trials from many different areas of the world. The methodological quality of the included trials varied. Five studies were of high quality, but elements of bias could not be excluded in the other studies, mainly due to the fact that the intervention and the assessment of outcomes were performed unblinded to group assignment or there was lack of complete follow-up of all randomized infants. IVIG resulted in increased levels of IgG in serum. There were no major side effects noted.

A small but statistically significant reduction in the incidence of sepsis and of any serious infection was found. There was statistically significant between-study heterogeneity for these outcomes. The heterogeneity might in part be explained by: variable rates of sepsis and any serious infection in the control groups; differences in preparation, dose and/or dose schedule for IVIG; differences in causative organisms for nosocomial infection; differences in attention to other preventive measures for nosocomial infection and differences in other co-interventions by place and over time. Some asymmetry was noted when funnel plots were performed for sepsis and any serious infection. For the two main outcomes, sepsis (one or more episodes) and any serious infection (one or more episodes), moderate inconsistency between the study results were noted (I² 54% and 50% respectively).

There were no statistically significant differences for mortality from all causes, mortality from infection, NEC, BPD, or IVH. The results for these outcomes were all centered around a RR of 1.0 with very narrow CIs indicating no trends in either direction. In none of the studies that provided data on IVH was there an assurance that all neonates were subjected to ascertainment of an IVH according to a preset schedule for ultrasonographic examination. There was a trend towards shortened duration of hospital stay with IVIG treatment [WMD -2.1 days (95% CI -4.5, 0.3 days)]. The outcome of hospital stay is highly dependent on the GA at birth of the neonate, availability of institutions providing Level II care to which the neonate can be transferred and the social situation of the family.

It is possible that the IVIG preparations used in these studies did not contain the necessary antibodies to prevent infection and that the use of preparations with known specific antibodies against common pathogens in a specific neonatal intensive care unit might be more effective (Weisman 1994b).

The benefits of a 3.0% and 4.0 % reduction in sepsis and any serious infection respectively should be weighed against the costs and the values assigned to this outcome. There have been no serious side-effects reported from IVIG to date, but unknown long-term risks of the 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 compare and adjust their infection control policies to those settings with low rates using bench marking techniques. If the rates remain high following such measures, the use of IVIG might be justified. The prophylactic use of IVIG should be based on a full economic evaluation and a clinical decision analysis that incorporates baseline risk for serious nosocomial infections, both clinical and economic outcomes following prophylactic IVIG, and values attached to infections prevented. Such analyses have not been performed.

Although there are differences in inclusion criteria, number of studies published at the time of the reviews, and statistical analyses, the results of our systematic review are close to those of three previous meta-analyses (Lacy 1995, Jenson 1997, Ohlsson 1998). The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to enhance the immune system of preterm and/or LBW infants and to prevent nosocomial infections.

Reviewers' conclusions

Implications for practice

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

Implications for research

A full economic evaluation and a clinical decision analysis that incorporates baseline risk for confirmed nosocomial infection, clinical outcomes and economic outcomes following prophylactic IVIG, and values attached to infections prevented is needed.

There is no justification for further RCTs testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or LBW infants. It is possible that the IVIG preparations used in published studies did not contain the necessary antibodies to prevent infection. The use of preparations with known specific antibodies against the common pathogens in a specific neonatal intensive care unit might be more effective, and RCTs to test the effectiveness of such preparations may be justified. The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections.

Acknowledgements

Dr. K. Thiringer provided us with additional information on the trial by Sandberg 2000.
Ms. Elizabeth Uleryk developed and executed extensive searches of MEDLINE and EMBASE in February of 2001 and September 2003.
Dr. Ryzhak Oleu assisted with the translation from Russian to English of the study by Lelik (Lelik 2004).

Potential conflict of interest

None

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Atici 1996	Single-centre, randomized, controlled trial without the use of a placebo. I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow-up - yes IV. Blinding of outcome measurement(s) - no	76 infants with GA < 34 wk. Single centre study, Turkey. May 15, 1993 - June 15, 1994	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 birth. 36 infants mean GA (SD) 32.3 +/-2.4 wk, mean Bw (SD) 1684 +/- 519 g served as controls (no placebo was given)	Proved infection (clinical findings and blood and/or cerebrospinal fluid culture positive for a pathogen). Total mortality, infectious mortality, days in hospital.	Proved infection, mortality from any cause, infectious mortality and days in hospital could be ascertained from this study. No adverse effects were noted.	B
Baker 1992	Multi-centre, randomized, double-blind, placebo-controlled trial. I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - yes IV. Blinding of outcome measurement - yes	588 infants with a Bw of 500 - 1750 g. Age 3 - 7 days. Six centers in the U.S. July 16, 1987 - December 12, 1988	287 infants received 500 mg/kg of IVIG (Gammagard, Baxter Healthcare, Hyland Division, Glendale, Calif.) at enrolment (age - 3 to 7 days), 1 wk later, and then every 14 days until a total of five infusions had been given or until hospital discharge, whichever came first. 297 infants received an equal volume of a sterile solution of 5 % albumin and 0.9 % sodium chloride.	Proved infection [clinical findings of sepsis and at least one of the following: a positive blood culture (bacteria or fungi), the isolation of a pathogen from a normally sterile body site (CSF, pleural, peritoneal, or joint fluid; bone; soft-tissue; or urine obtained by suprapubic or bladder catheterization), or the isolation of virus from an infant with clinical deterioration]. NEC (stage II or III) IVH (grade I - IV) BPD (definition not provided) Total days in hospital Eleven neonates were excluded from the study but were included in the intention-to-treat analysis.	The following outcomes could be ascertained from this study: any serious infection (bacterial + fungal), IVH, NEC, deaths from all causes. Total episodes for sepsis were reported. There were 50 episodes of sepsis among 287 infants in the IVIG group and 75 episodes of sepsis among 197 infants in the placebo group. The outcome "sepsis, 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%). Mild increases 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 fluid overload after an infusion and were treated with a single dose of furosemide.	A
Bussel 1990a	Randomized, double-blind, placebo-controlled trial. I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - no IV. Blinding of outcome measurement - yes	240 infants with Bw < 1300 g. Data for 172 patients are presented in this preliminary analysis; of these 46 were excluded from the statistical analysis (29 because they died during the first 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 U.S. center. September 1984 - October 1987.	61 neonates (mean Bw, 977 g) received a dose of 1 g of a 6% solution of IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, N.J.) on 4 of the first 5 days of life, and a fifth dose was administered on day 15 or as close to that day as possible (the dose could be given as late as day 21). 65 neonates (mean Bw, 1043 g) received an albumin placebo at equal oncotic load at the same times.	Sepsis (signs and symptoms compatible with sepsis and a positive blood or CSF culture) IVH diagnosed by ultrasonographic examination at 3-7 days of age. 1 neonate excluded because of severe anomalies incompatible with life. For additional exclusions see "Participants".	This is an interim analysis of a larger study, the results of which have not been reported to date. Data are available on the outcome of sepsis but not on IVH No adverse effects were reported	A
Chirico 1987	Randomized, controlled trial without the use of a placebo I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete follow up - yes IV. Blinding of outcome measurement - no	In this study a subgroup with a BW</= 1500 g (n = 86) of the total population of 133 infants (BW range 550 - 3340 g; GA range 24 - 40 wk) fulfilled the inclusion criteria for this systematic review. Single center, Italy. Dates not given.	43 infants received 0.5 g/kg of IVIG (Sandoglobulin) weekly for 1 month. 43 infants received no placebo or other intervention.	Criteria for diagnosis of sepsis, meningitis, arthritis, pneumonia, urinary tract infection, and surface infection included both a positive culture of blood, cerebrospinal fluid, tracheal aspirate, urine or pus, respectively, and the presence of clinical and non microbiological laboratory features. For the diagnosis of pneumonia, the appearance of a new infiltrate on a chest roentgenogram was also required. NEC was diagnosed when typical clinical and radiologic symptoms were present. 3 infants in the control group who died within 24 hours after birth were excluded from the analysis by the authors.	The outcomes of sepsis, any serious infection, NEC, length of hospital stay, death from all causes and deaths from infections could be ascertained from this study. The 3 infants in the control group who died within 3 days of life are included in our analyses as per intention to treat. No side effects were observed after IVIG administration.	A
Chou 1998	Randomized placebo controlled trial with the use of a non-identical looking placebo (saline). I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow up - yes IV. Blinding of outcome measurement(s) - no	61 infants with a Bw < 1500 g were enrolled. Single centre study, Taiwan. July 1993 - June 1994	31 infants, mean Bw (SD) 1210 +/- 340 g, mean GA (SD) 29.7 +/- 2.2 wk received Gammumine-N (Miles Inc. Cutter Biological, USA). IVIG was infused for 30 minutes to 2 hours within the first 12 hours of birth, and every 2 wk until the patient weighed 1800 g or was discharged. The dose of IVIG was 750-1000 mg/kg/dose if the infant's Bw was < 1000 g and 500-750 mg/kg/dose if the infant's Bw was between 1001-1500 g. 30 neonates, mean Bw (SD) 1320 +/- 250 g and mean GA (SD) 30.6 +/- 1.7 wk received saline infusion	Proved infection was defined as bacteremia (positive blood culture or CSF culture) with clinical deterioration or haemodynamic change. Blood samples for serum IgG levels were collected prior to the first dose of IVIG and on days 1, 7, 14, 21, 28, 35, 42, 49, and 56 after birth.	Any serious infection, total mortality, IVH, NEC, BPD, days in hospital and serum IgG levels were reported.	B
Christensen 1989	Randomized, double-blind, placebo-controlled study I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - yes IV. Blinding of outcome measurement - yes	20 preterm neonates, weight < 2000 g at entry to study and < 7 days of age. Single center, U.S. Dates not given.	10 neonates received IVIG (Gamimmune-N, Cutter Biologicals, Berkeley, Calif.) 5% IgG in 10% maltose at 15 ml/kg BW as a single infusion. 10 neonates received equal volume of 0.1% albumin in 10% maltose.	Nosocomial infection (not defined) Survival	This study provides information on deaths from infections and deaths from all causes. There were no differences in heart rate, respiratory rate, rectal temperature, and urine output before, during and after the infusions of IVIG or placebo (no differences between the groups)	A
Clapp 1989	Randomized, double-blind, placebo-controlled trial I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - yes IV. Blinding of outcome measurement - yes	115 infants with Bw of 600 to 2000 g and < 48 hours of age. Single center, U.S. November 1, 1986 - August 31, 1987.	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 and 700 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 administered at that time and subsequent doses were increased by 200 mg/kg. The objective was to maintain IgG serum levels at >700 mg/dl. 59 neonates (GA 31 wk; mean Bw (SD) 1.3 +/- 0.4 kg) received placebo (equal volume of 6% or 10% sucrose solution). When an infant receiving IVIG required an extra dose, the paired patient in the placebo group also received an additional infusion.	Sepsis (systemic clinical deterioration with a positive blood culture, cerebrospinal fluid, or aspirate of another normally sterile body cavity). NEC (abdominal distension with gastric retention, abdominal erythema, or bloody stools, with radiographic evidence of pneumatosis intestinalis, portal venous gas, or pneumoperitoneum and staged by the modified Bell's criteria) Length of hospital stay. Deaths from all causes. Deaths from infection. BPD (requiring O2 at 28 days for BPD) IVH (Papile classification)	From the data presented the outcomes of sepsis, any serious infection, NEC, BPD, IVH, length of hospital stay, deaths from all causes and deaths from infection could be ascertained. Three episodes of sepsis/proved infection occurred in (an) infant(s) born at 24 weeks GA and BW of 600 g. We assumed that this was only one infant and assigned only one outcome in the meta-analyses. Transient tachycardia and a decrease in blood pressure was noted in one infant who received IVIG. Transient rise in the alanine aminotransferase level was noted in one infant who received IVIG and one who received placebo.	A
Conway 1990	Randomized controlled trial without the use of a placebo I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete follow up - no IV. Blinding of outcome measurement - no	66 neonates of < 30 wk GA. 2 centers in the U.K. Dates not given.	34 infants received 200 mg/kg IVIG (Intraglobin F, Biotest Pharma, FRG) within 48 hours of birth and at 3-weekly intervals until discharge from the neonatal unit. On clinical suspicion 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 confirmed. 32 infants received routine intensive care.	Sepsis (blood-culture-proven infection). NEC (clinical findings and pneumatosis intestinalis on abdominal X-ray, or confirmed at autopsy). IVH (no definition given) BPD (no definition given) Length of stay in NICU (median and range) Eleven infants, 6 in the control group and 5 in the treatment group, were withdrawn from the trial due to early death from extreme prematurity (n=7), early return to the referring hospital (n=3), and elective treatment with IVIG for severe congenital septicaemia (n=1).	The outcomes of sepsis and NEC could by ascertained. We used as denominators all randomized patients. We included the infants that were withdrawn because of early death in the outcome of mortality (all causes). One infant with two episodes of NEC was counted as one outcome. Side effects were not reported	A
Didato 1988	Randomized controlled trial without the use of a placebo I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete follow up - yes IV. Blinding of outcome measurement - no	80 infants with a Bw of 2000 g or less. Single center, Italy. June 1985 - December 1986.	40 infants received 0.5 g/kg/week of IVIG (IgVena, Sclavo; Siena, Italy) until they reached the GA of 36 wk and during the entire period of intensive care. 40 infants received no placebo or other intervention	Sepsis defined as clinical manifestations, microbiologic findings (positive blood culture or CSF culture) and non microbiologic laboratory findings (total and differential white blood cell count, erythrocyte sedimentation rate, C-reactive protein, platelet count, tests of haemostatic function).	Any serious infection, deaths from all causes and deaths from infection could be ascertained in this study. As sepsis included neonates with positive CSF cultures the results were included in the any serious infection category only. Data could not be separated between sepsis and meningitis. No side effects or adverse reactions were observed following IVIG administration.	A
Fanaroff 1994	Multicentre, two-phase controlled trial. Phase I was placebo controlled and double-blinded; phase II was not placebo controlled. I. Blinding of randomization - yes II. Blinding of intervention - yes/no* III. Complete follow up - yes IV. Blinding of outcome measurement - yes/no* * This study had two phases; in phase 1a placebo was used but not in phase 2.	2,416 infants with Bw 501-1500 g and randomized at a mean age of 44 +/- 25 hours after birth. 8 centers in the U.S. January 1, 1988 - March 31, 1991 (or through April, 1991).	In phase I 595 infants received IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, N.J.) 623 infants received placebo - equal volume of 5 % albumin solution in the same vehicle prepared by the manufacturer of the immune globulin. The infants received their first dose of study drug within 24 hours of randomization. To achieve a target level of 700 mg of immune globulin/dl, infants weighing 501 to 1000 g were given 900 mg of immune globulin per kg of body weight and infants weighing 1001 to 1500 g were given 700 mg per kg. The infusions were repeated every two weeks until the infants weighed 1800 g, were transferred to another hospital, died or were sent home. In phase II 609 infants received IVIG as per above (Phase I) 589 received no intervention	Sepsis (symptoms compatible with infection and a positive blood culture for bacteria or fungi obtained at least 96 hours after birth and before 120 days of life; for commensals the diagnosis required two 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 suprapubic puncture. Proved infection (including septicaemia, meningitis, or urinary tract infection) during the first 120 days of life. NEC (Bell's modified classification) BPD (Not defined) Days in hospital	The following outcomes could be ascertained from this study; sepsis, any serious infection, NEC, death from all causes, death from infection, days in hospital. The infusions were discontinued in < 1% of infants (10 in the IVIG group and 11 in the placebo group) because of tachycardia or acute changes in blood pressure.	A
Fanaroff-I 1994	Phase I of Fanaroff 1994, placebo-controlled					A
Haque 1986	Randomized controlled trial, without the use of a placebo I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete follow up - yes IV. Blinding of outcome measurement - no	150 neonates of 28 to 37 wk GA and less than 4 hours of age. Single center, Saudi Arabia. Dates not given.	50 neonates received IVIG (Intraglobulin, Biotest Pharma, West Germany) 120 mg/kg within 2-4 hours of birth 50 neonates received IVIG (Intraglobulin) 120 mg/kg on day 1 and 8 of life 50 neonates received no intervention	Sepsis was defined as presence of clinical features and a positive culture of blood or cerebrospinal fluid.	Sepsis, any serious infection, death from all causes and death from infection could be ascertained in this study. One infant developed pneumonia in the control group. The mean age at onset of infection was 46.3 hrs (range 8 to 76 hrs), suggesting that some infants had infection acquired in utero and were infected at the time of enrolment. No adverse effect of the therapy was noted during the study and at 6-month follow-up.	A
Magny 1991b	Multicentre, randomized controlled, double-blind study. I. Blinding of randomization - can't tell II. Blinding of intervention - yes III. Complete follow up - yes IV. Blinding of outcome measurement - yes	235 neonates of less than or equal to 32 wk gestation, hospitalised before 25 hours of life and having endotracheal tube and/or umbilical catheter on admission. 4 centers in Paris, France. 1987 - 1989.	120 neonates received 500 mg (10 ml) of polyvalent Ig (Biotransfusion, France) on days 0, 1, 2, 3, 17, and 31 of life. In the placebo group 115 neonates received 10 ml of 0.2% albumin in the same fashion.	Deaths from infection Certain nosocomial infection [clinical signs of infection, positive cultures (blood, urine, cerebrospinal fluid, tracheal aspirate, stools, gastric aspirate), at least two biological signs of infection (abnormal number of leukocytes, immature leukocytes > 5%, thrombocytopenia < 150 000/mm3, rise in fibrinogen levels > 4.5 g/L, rise in C-reactive protein levels > 20 mg/L.] NEC was diagnosed when bloody stools were associated with radiologic pneumatosis. Neonatal infection and infection occurring within the first 4 days of life, potentially of maternal origin were not counted as evaluation criteria. In 46 infants (21 in the IVIG; 25 in the placebo group) irregularities occurred in the protocol (one dose forgotten or no follow-up until 45 days of life because of transfer out of the unit).	Deaths from infection could be ascertained in this study. The definition of nosocomial infection did not meet our criteria for sepsis or any serious infection. The number of infants with one or more episodes of NEC could not be ascertained. The 46 infants in which the protocol was broken were maintained in the statistical analyses. "There were neither clinical nor biologic side effects in any of the patients after Ig infusion".	B
Ratrisawadi 1991	Randomized controlled trial, without the use of a placebo group I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete followup - can't tell IV. Blinding of outcome measurement - no	68 infants with a Bw of 1000 - 1500 g. Single center, Bangkok, Thailand. February 1988 - March 1990.	34 neonates received 250 mg/kg of IVIG (Biotest Pharma, West Germany) within 4 hours of birth 34 neonates received 500 mg/kg of IVIG within 4 hours of birth 34 neonates received no intervention	Sepsis (presence of clinical findings of sepsis plus positive blood cultures). Infants (number not stated) who expired within 24 hours of life or required blood exchange transfusion were excluded from the study. In spite of these exclusions the number of patients in each group is identical (n= 34).	The outcomes of sepsis and deaths from all causes could be ascertained in this study. "No adverse effects were observed during the period of study".	B
Sandberg 2000	Randomized double-blind placebo controlled trial. I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete follow up - no IV. Blinding of outcome measurement(s) - yes.	105 infants were randomized into the study. 24 infants (12 in each group) were excluded because of initial serum IgG level > 4 g/L, violation of the study protocol, withdrawal of consent, or intrauterine infection.	40 infants mean GA (SD) 27.5 +/- 2.2 wk and mean Bw (SD) 1.06 +/- 0.39 kg received 1g/kg (20 ml/kg) of IVIG (Baxter) on study day 0 (< 48 hours of age), day 3, 7, 14, 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%).	Sepsis (symptoms and positive blood culture). Days on ventilator. Total mortality from any cause. Infectious mortality.	The outcomes of sepsis, deaths from all causes, and deaths from infections could be ascertained from this study. According to Dr. Klara Thiringer randomization was by a computer-generated list for each of the four centres, and infants were allocated by the use of sealed envelopes.	A
Spady 1994	Randomized double-blind trial Published in abstract form only - full quality assessment not possible	111 very LBW infants	54 infants were given 300 mg/kg of IVIG (name of product not given) as 5% solution, once betwen 24-72 hours of age and again 72 hours later. 57 infants were given the same volumes as 5% dextrose	The outcome of sepsis was not defined 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.	The length of hospital stay could be ascertained from this study published in abstract form only. Respiratory rate increased in the IVIG group following the first infusion. No other side effects occurred.	D
Stabile 1988	Single centre, randomized controlled trial without the use of a placebo group. I Blinding of randomization - can't tell II Blinding of intervention - no III Complete followup - no IV Blinding of outcome measurement - no	94 neonates, GA </= 34 wk gestation, or Bw </= 1500 g. Single center, Rome, Italy. May 1984 - June 1986.	0.5 g/kg IVIG (Venogamma Polivalente, Ismunit, Pomezia, Italy) on the 1st, 2nd, 3rd, 7th, 14th, 21st, and 28th day of life (treatment group) or no intervention (control group)	Sepsis was defined as clinical signs of systemic infection and positive blood or CSF culture for a pathogen. 14 neonates were excluded from the analysis. 6 neonates in the treatment group were excluded; 3 underwent exchange transfusion, 2 died from severe respiratory distress syndrome and one had suspected prenatal infection. 8 control neonates were excluded; 2 underwent exchange transfusion, 3 died of severe respiratory distress syndrome, one died of respiratory distress syndrome and IVH, and two had suspected prenatal infection.	Sepsis, any serious infection, deaths from all causes and deaths from infection could be ascertained from this study. Infants that died and were excluded by the authors are included in our analysis. "..no newborn infant showed any local or general reaction either during or after infusions. Three infants showed a temporary increase in IgE from 10-18 to 28-38 IU/ml without concurrent side effects".	B
Tanzer 1997	Single centre, quasi-randomized trial without the use of a placebo. I. Blinding of randomization - no. II. Blinding of intervention - no. III. Complete follow-up - yes IV. Blinding of outcome measure(s) - no.	80 preterm neonates. Single centre, Turkey. Dates for the study period not provided.	40 infants with a mean (SE) GA of 36.18 (0.17) wk, mean (SE) Bw of 1.85 (0.07) kg were given 500 mg/kg of IVIG (Sandoglobulin R) if they were weighing greater than 1500 g, and 700 mg/kg if they were weighing < 1500 at birth on days one, two and eight of life. 40 infants with a mean (SE) GA of 35.58 (0.19) wk and mean (SE) Bw of 1.67 (0.07) kg got no placebo.	Blood culture proven sepsis, mortality from any cause, sepsis related mortality, days in hospital. Serum IgG levels were measured on days 1, 2, 8 and 12.	Sepsis, deaths from all causes could be ascertained from this study. No adverse effects were noted. The outcome of days in hospital was only reported for the control group. Treatment with IVIG resulted in a statistically significant increase in the serum IgG concentrations.	C
Van Overmeire 1993	Randomized controlled trial without the use of a placebo group. I. Blinding of randomization - yes II. Blinding of intervention - no III. Complete followup - yes IV. Blinding of outcome measurement - no	116 neonates of < 32 wk GA and <1500 g Bw. Single center, Antwerp, Belgium. Dates not given.	56 neonates received 500 mg IVIG (Sandoglobulin) in 10 ml of saline over a period of 30 min within the first 12 h of life. This infusion was repeated every 24 h until the 7th day of life, then administered weekly for another 3 weeks. 60 neonates received no placebo or other intervention	The diagnosis of any serious infection was made when the clinical diagnosis, in association with suggestive laboratory data, was confirmed by a positive blood or CSF culture.	Any serious infection, hospital stay and death from all causes could be ascertained in this study. Short lasting hypotension was observed shortly after IVIG administration in one patient.	A
Weisman 1994a	Multicentre, randomized, double-blind, placebo-controlled trial I. Blinding of randomization - yes II. Blinding of intervention - yes III. Complete followup - yes IV. Blinding of outcome measurement - yes	753 neonates with a Bw of 500 to 2000 g, GA </= 34 wk, postnatal age </= 12 hours 9 centers in the U.S. June 1985 - April 1989.	372 neonates received a single intravenous infusion of 10 ml/kg of IVIG (500 mg/kg) (Sandoglobulin) 381 neonates received a single infusion of albumin 5 mg/kg	All outcomes were recorded during the first 8 weeks (56 days) of life Sepsis was defined as clinical symptoms and signs consistent with sepsis in association with isolation of a causative organism from a blood culture specimen. For the diagnosis of sepsis caused by S. epidermidis two positive cultures were required. Infection was defined as clinical signs and symptoms and isolation of a causative organism from either blood culture, CSF culture, urine culture by bladder tap or catheterization, or culture of a specimen from a normally sterile site during hospitalisation or at autopsy. BPD was defined as need for continued oxygen or ventilatory support at 28 days of age for reasons other than apnea and either a chest radiograph or histopathologic criteria compatible with the diagnosis. IVH was graded on a scale of 1-4 according to Papile. Bell's classification of stage II or greater was used to define NEC. After enrolment it was determined that 9 patients (5 received albumin and 4 IVIG) did not meet the entry criteria, and for 10 patients (5 received albumin and 5 received IVIG) the protocol was violated during the study, but all were included in the intention-to-treat analysis.	Sepsis, any serious infection, NEC, and death from infection could be ascertained from this study. Although the outcomes of IVH and BPD were well defined, figures for these outcomes were not reported by group. The IVIG-treated infants had slower heart rate during the infusion than before the infusion and higher systolic blood pressure for 2 hours after the infusion than before the infusion. Both groups tolerated the infusions similarly.	A

Abbreviations:
Bw = birth weight
g = gram
GA = gestational age
IgG = immunoglobulin
i.v. = intravenous(ly)
IVIG = intravenous immunoglobulin
kg = kilogram
LBW = low birth weight (< 2.5kg)
mg = miligram
SEM = standard error of the mean
SD = standard deviation

Characteristics of excluded studies

Study	Reason for exclusion
Acunas 1994	This is an RCT comparing the effect of fresh frozen plasma or gammaglobulin on humoral immunity in neonatal sepsis. This study did not meet the inclusion criteria as a randomized untreated control group was not included. A non-randomized concurrent group of infants without suspicion of infection and matched for age, birth weight, and gestational age served as a control group.
Adhikari 1996	This is a double-blind placebo-controlled RCT assessing the efficacy of prophylactic use of IVIG in 21 pairs of ventilated neonates weighing more than 1500 g. The mean weight in the IVIG group was 2702 g and in the placebo group 2679 g; thus most neonates did not full fill the entry criterion of a weight < 2500 g. In this study IVIG did not significantly reduce the rate of infection, the duration of ventilation or the time to clinical recovery.
Kacet 1991	The authors do not provide enough information regarding definitions of outcomes for inclusion in this systematic review.
Kinney 1991	This is a double-blind RCT designed to determine whether IVIG administration modifies the incidence of infections in high-risk neonates. 170 infants were enrolled. The study population included neonates of > 1500 g birth weight with no upper limit stated by the authors. This study did thus not meet our inclusion criteria. The authors "found no evidence that the administration of IVIG affected parameters that might be related to the occurrence of systematic or localized infectious processes".
Lelik 2004	This is a randomized controlled trial but the infants enrolled were > 38 weeks gestation and weighed > 2500 g and therefore the study population did not fulfil our inclusion criteria
Malik 1990	This study has been published in abstract form only, and the authors do not provide enough information regarding definitions of outcomes for inclusion in this systematic review.
Monintja 1989	Immunoglobulin was given intra-muscularly. It is unclear whether this is an RCT. Sepsis was not clearly defined.

References to studies

References to included studies

Atici 1996 {published data only}

Atici A, Satar M, Karabay A, Yilimaz M. Intravenous immunoglobulin for prophylaxis of nosocomial sepsis. Indian Journal of Pediatrics 1996;63:517-21.

Baker 1992 {published data only}

Baker CJ, Melish ME, Hall RT, et al. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates. New England Journal of Medicine 1992;327:213-9.

Bussel 1990a {published data only}

Bussel JB. Intravenous gammaglobulin in the prophylaxis of late sepsis in very-low-birth-weight infants: preliminary results of a randomized, double-blind, placebo-controlled trial. Reviews of Infectious Diseases 1990;12:S457-62.

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;110:437-42.

Chou 1998 {published data only}

Chou Y-H, Yau K-I T. The use of prophylactic intravenous immunoglobulin therapy in very low birthweight infants. Chang Gung Medical Journal 1998;21:371-6.

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 administration to preterm neonates. Journal of Perinatology 1989;9:126-30.

Clapp 1989 {published data only}

Clapp DW, Kliegman RM, Baley JE, et al. Use of intravenously administered immune globulin to prevent nosocomial sepsis in low birth weight infants: report of a pilot study. Journal of Pediatrics 1989;115:973-8.

Conway 1990 {published data only}

Conway SP, Ng PC, Howel D, Maclain B, Gooi HC. Prophylactic intravenous immunoglobulin in pre-term infants: a controlled trial. Vox Sanguinis 1990;59:6-11.

Didato 1988 {published data only}

Didato MA, Gioeli R, Priolisi A. The use of intravenous gamma-globulin for prevention of sepsis in pre-term infants. Helvetica Paediatrica Acta 1988;43:283-94.

Fanaroff 1994 {published data only}

Fanaroff AA, Korones SB, Wright LL, et al. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. New England Journal of Medicine 1994;330:1107-13.

Fanaroff-I 1994 {published data only}

Fanaroff-1. Phase 1 of Fanaroff 1994, placebo-controlled. 1994.

Haque 1986 {published data only}

Haque KN, Zaidi MH, Haque SK, Bahakim H, El-Hazmi M, El-Swailam M. Intravenous immunoglobulin for prevention of sepsis in preterm and low birth weight infants. Pediatric Infectious Disease 1986;5:622-5.

Magny 1991b {published data only}

Magny J-F, Bremard-Oury C, Brauit D, et al. Intravenous immunoglobulin therapy for prevention of infection in high-risk premature infants: report of a multicentre, double-blind study. Pediatrics 1991;88:437-43.

Ratrisawadi 1991 {published data only}

Ratrisawadi V, Srisuwanporn T, Puapondh Y. Intravenous immunoglobulin prophylaxis for infection in very low birth-weight infants. Journal of the Medical Association of Thailand 1991;74:14-8.

Sandberg 2000 {published data only}

Sandberg K, Fasth A, Berger A, Eibl M, Isacson K, Lisebka A, Pollak A, Tessin I, Thiringer K. Preterm infants with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G. Journal of Pediatrics 2000;137:623-8.

Spady 1994 {published data only}

Spady DW, Pabst HF, Byrnes P. Intravenous immunoglobulin (IVIG) shortens stay for low birth weight infants [abstract]. Pediatr Research 1994;35:304A.

Stabile 1988 {published data only}

Stabile A, Sopo SM, Romanelli V, Pastore M, Pesaresi MA. Intravenous immunoglobulin for prophylaxis of neonatal sepsis in premature infants. Archives of Disease in Childhood 1988;63:441-3.

Tanzer 1997 {published data only}

Tanzer F, Yazar N, Hakgudener Y, Kafali G. Intravenous immunoglobulin for sepsis prevention in preterm infants. Turkish Journal of Pediatrics 1997;39:341-5.

Van Overmeire 1993 {published data only}

Van Overmeire B, Bleyaert S, van Reempts PJ, van Acker KJ. The use of intravenously administered immunoglobulins in the prevention of severe infection in very low birth weight neonates. Biology of the Neonate 1993;64:110-5.

Weisman 1994a {published data only}

Weisman LE, Stoll BJ, Kueser TJ, et al. Intravenous immune globulin prophylaxis of late-onset sepsis in premature neonates. Journal of Pediatrics 1994;125:922-30.

References to excluded studies

Acunas 1994 {published data only}

Acunas BA, Peakman M, Liossis G, et al. Effect of fresh frozen plasma and gammaglobulin on humoral immunity in neonatal sepsis. Archives of Disease in Childhood 1994;70:F182-7.

Adhikari 1996 {published data only}

Adhikari M, Wesley AG, Fourie PB. Intravenous immunoglobulin prophylaxis in neonates on artificial ventilation. South African Medical Journal 1996;86:542-5.

Kacet 1991 {published data only}

Kacet N, Gremillet C, Zaoui C, et al. Prevention of late-onset infections in preterm infants with intravenous gamma-globulin: a randomized clinical trial [abstract ]. European Journal of Pediatrics 1991;150:604.

Kinney 1991 {published data only}

Kinney J, Mundorf L, Gleason C, et al. Efficacy and pharmacokinetics of intravenous immune globulin administration to high-risk neonates. American Journal of Diseases of Children 1991;145:1233-8.

Lelik 2004 {published data only}

Lelik MP, Efanova EA. Prevention of nosocomial infections in newborns at artificial lung ventilation. Anesteziologiia i Reanimatologiia 2004;May-June(3):41-3.

Malik 1990 {published data only}

Malik S, Giacoia GP, West K, Miller G. Intravenous immunoglobulin (IVIG) to prevent infections in infants with bronchopulmonary dysplasia (BPD) [abstract]. Pediatric Research 1990;27:273A.

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Monintja HE. Investigation on immunglobulin fortification in preventing infections in the newborn. Paediatrica Indonesiana 1989;29:91-6.

References to studies awaiting assessment

Metsvaht 2001 {unpublished data sought but not used}

Metsvaht T. A study was performed in Estonia on IgM-enriched IVIG (Pentaglobin) in the prevention of infection in neonates. The study included 20 neonates in the treatment group (IVIG) and 20 neonates (control group). The results have not been published yet.

* indicates the primary reference for the study

Other references

Additional references

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Baker CJ. New uses of intravenous immune globulin in newborn infants. Journal of Clinical Immunology 1990;10:47S-55S.

Baker 1990b

Baker CJ, Rench MA, Noya FJD, Garcia-Prats JA, and the Neonatal IVIG Study Group. Role of intravenous immunoglobulin in prevention of late-onset infection in low-birth-weight neonates. Reviews of Infectious Diseases 1990;12:S463-9.

Baley 1988

Baley JE. Neonatal sepsis: the potential for immunotherapy. Clinics in Perinatology 1988;15:755-71.

Baley 1992

Baley JE, Fanaroff AA. Neonatal infections. Part 2: Specific infectious diseases and therapies. In: Sinclair J and Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992:496-506.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7.

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Berger M. Use of intravenously administered immune globulin in newborn infants: prophylaxis, treatment, both, or neither. Journal of Pediatrics 1991;118:557-9.

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Bortolussi R, Fischer GW. Opsonic and protective activity of immunoglobulin, modified immunoglobulin, and serum against neonatal Escherichia coli K1 infection. Pediatric Research 1986;20:175-8.

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Bortolussi R. Potential for intravenous gamma-globulin use in neonatal gram-negative infection: an overview. Pediatric Infectious Diseases 1986;5:S198-200.

Bussel 1990b

Bussel JB. Neonatal uses of intravenous immunoglobulin. American Journal of Pediatric Hematol/Oncology 1990;12:505-9.

Consensus 1997

Consensus Working Group. Present and future uses of IVIG: a Canadian multidisciplinary consensus-building initiative. Canadian Journal of Allergy and Clinical Immunology 1997;2:176-208.

Fischer 1986

Fischer GW, Hemming VG, Hunter KW, et al. Intravenous immunoglobulin in the treatment of neonatal sepsis: therapeutic strategies and laboratory studies. Pediatric Infectious Disease 1986;5:S171-5.

Fischer 1988

Fischer GW. Therapeutic uses of intravenous gammaglobulin for pediatric infections. Pediatric Clinics of North America 1988;35:517-33.

Fischer 1990a

Fischer GW, Weisman LE. Therapeutic intervention of clinical sepsis with intravenous immunoglobulin, white blood cells and antibiotics. Scandinavian Journal of Infectious Diseases 1990;73 Suppl:17-21.

Fischer 1990b

Fischer GW, Hemming VG, Gloser HP, Bachmyer H, von Pilar CE, Wilson SR, Baron PA. Polyvalent group B streptococcal immune globulin for intravenous administration: overview. Reviews of Infectious Diseases 1990;12:S483-91.

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Fischer GW. Immunoglobulin therapy for neonatal sepsis: an overview of animal and clinical studies. Journal of Clinical Immunology 1990;10:40S-6S.

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Gonzalez LA, Hill HR. The current status of intravenous gamma-globulin use in neonates. Pediatric Infectious Disease Journal 1989;8:315-22.

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Hammarstrom L, Smith CIE. The use of intravenous IgG as prophylaxis and for treatment of infections. Infection 1990;18:314-24.

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Haque KH. Does the commercial type of IVIG used make a difference? Pediatrics 1992;89:806-7.

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Hill HR. Intravenous immunoglobulin use in the neonate: role in prophylaxis and therapy of infection. Pediatric Infect ious Disease Journal 1993;12:549-59.

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Hill RH. Is prophylaxis of neonates with intravenous immunoglobulin beneficial. American Journal of Diseases of Children 1991;145:1229-30.

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Hobbs JR, Davis JA. Serum IgG-globulin levels and gestational age in premature babies. Lancet 1967;I:757-9.

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Jenson HB, Pollock BH. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics 1997;99(2). URL: http://www.pediatrics. Pediatrics 1997;99:e2.

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Johnston RB. Immunotherapy and immunoprophylaxis in the newborn infant: the need for definitive trials. Reviews of Infectious Diseases 1990;12:S392-3.

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Magny J-F. Les immunoglobulines sont-elles utiles dans le traitment des infections neonatales? La Revue du Praticien 1991;41:1368-70.

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Noya FJD, Baker CJ. Intravenously administered immune globulin for premature infnats: a time to wait. Journal of Pediatrics 1989;115:969-71.

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Salzer HR, Weninger M, Pollak A, Kolmer M. Prophylactic immunoglobulin (IG) treatment in infants less than 30 weeks gestation - a metaanalysis [abstract]. European Journal of Pediatrics 1991;150:604.

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Siber GR. Immune globulin to prevent nosocomial infections. New England Journal of Medicine 1992;327:269-71.

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

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Stiehm ER. Intravenous immunoglobulins in neonates and infants: an overview. Pediatric Infectious Disease 1986;5:S217-9.

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Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. Journal of Pediatrics 1996;129:63-71.

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Weisman LE, Fischer GW, Hemming VG, Peck CC. Pharmacokinetics of intravenous immunoglobulin (Sandoglobulin) in neonates. Pediatric Infectious Disease 1986;5:S185-8.

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Weisman LE, Cruess DF, Fischer GW. Current status of intravenous immunoglobulin in preventing or treating neonatal bacterial infections. Clinical Reviews in Allergy 1992;10:13-28.

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Weisman LE, Cruess DF, Fischer GW. Standard versus hyperimmune immunoglobulin in preventing or treating neonatal bacterial infections. Clinics in Perinatology 1993;20:211-24.

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Weisman LE, Cruess DF, Fischer GW. Opsonic activity of commercially available standard intravenous immunoglobulin preparations. Pediatric Infectious Disease Journal 1994;13:1122-5.

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Whitelaw A. Treatment of sepsis with IgG in very low birthweight infants. Archives of Disease in Childhood 1990;65:347-8.

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Wolach B. Neonatal sepsis: pathogenesis and supportive therapy. Seminars in Perinatology 1997;21:28-38.

Other published versions of this review

Ohlsson 1998

Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 1998, Issue 2.

Ohlsson 2001

Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 2.

Ohlsson 2004

Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2004, Issue 1.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 IVIG vs placebo or no treatment
01 Sepsis, one or more episodes	10	3975	RR (fixed), 95% CI	0.85 [0.74, 0.98]
02 Any serious infection, one or more episodes	16	4986	RR (fixed), 95% CI	0.82 [0.74, 0.92]
03 NEC, one or more episodes	7	4081	RR (fixed), 95% CI	1.08 [0.89, 1.32]
04 Mortality (all causes)	15	4125	RR (fixed), 95% CI	0.89 [0.75, 1.05]
05 Mortality (infectious)	10	1690	RR (fixed), 95% CI	0.83 [0.56, 1.22]
06 Duration of hospitalization	8	3562	WMD (fixed), 95% CI	-2.12 [-4.54, 0.30]
07 Bronchopulmonary dysplasia	2	176	RR (fixed), 95% CI	1.55 [0.85, 2.84]
08 Intraventricular haemorrhage any grade	4	3176	RR (fixed), 95% CI	1.02 [0.88, 1.19]
09 Intraventricular haemorrhage grade 3 or 4	2	3000	RR (fixed), 95% CI	1.01 [0.85, 1.21]

01 IVIG vs placebo or no treatment

01.01 Sepsis, one or more episodes

01.02 Any serious infection, one or more episodes

01.03 NEC, one or more episodes

01.04 Mortality (all causes)

01.05 Mortality (infectious)

01.06 Duration of hospitalization

01.07 Bronchopulmonary dysplasia

01.08 Intraventricular haemorrhage any grade

01.09 Intraventricular haemorrhage grade 3 or 4

Contact details for co-reviewers

Ms Janet Lacy
1 Midcroft Drive
Scarborough
Ontario CANADA
M1S 1W9
Telephone 1: +1 416 299 5534
Facsimile: +1 416 323 7317
E-mail: jblacy@globility.com

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.