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

  • Review
  • Intervention

Authors

  • Arne Ohlsson,

    Corresponding author
    1. University of Toronto, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, Toronto, Ontario, Canada
    • Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada. aohlsson@mtsinai.on.ca.

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  • Janet B Lacy

    1. Scarborough, Ontario, Canada
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Abstract

Background

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

Objectives

To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' postmenstrual age (PMA) at birth) or LBW (< 2500 g birth weight) infants or both is effective/safe in 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 which the 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 identified in May 2013.

When all studies were combined, a significant reduction in sepsis was noted (typical risk ratio (RR) 0.85, 95% confidence interval (CI) 0.74 to 0.98; typical risk difference (RD) -0.03, 95% CI 0.00 to -0.05; number needed to treat for an additional beneficial outcome (NNTB) 33, 95% CI 20 to infinity), and moderate between-study heterogeneity was reported (I2 54% for RR, 55% for RD). A significant reduction of one or more episodes was found for any serious infection when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.02 to -0.06; NNTB 25, 95% CI 17 to 50), and moderate between-study heterogeneity was observed (I2 50% for RR, 62% for RD). No statistically significant differences in mortality from all causes were noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01), and no heterogeneity for RR (I2 = 21%) or low heterogeneity for RD was documented (I2 = 28%). No statistically significant difference was seen in mortality from infection; in incidence of necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD) or intraventricular haemorrhage (IVH) or in length of hospital stay. No major adverse effects of IVIG were reported in any of these studies.

Authors' 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 clinically important outcomes, including mortality. 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. There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infections in preterm and/or LBW infants.

摘要

背景

靜脈注射免疫球蛋白對預防早產兒/低體重新生兒感染症之成效

院內感染至今仍是導致早產兒/低體重新生兒併發症與死亡之主要原因,母體的免疫球蛋白自懷孕32週始傳給胎兒,新生兒則要到出生數月後才開始製造免疫球蛋白。靜脈注射免疫球蛋白 (intravenous immunoglobulin) 的作用機轉主要是提供G型免疫球蛋白 (immunoglobulin G) 與細胞表面受器結合,產生調理作用、活化補體系統、促進抗體依賴型細胞毒殺反應,並且促進嗜中性球的化學發光 (chemo luminescence) ,故有潛力用來避免或改變院內感染的病程。

目標

探討在早產兒 (出生週數小於37週) /低體重新生兒 (出生體重小於2500克) 身上使用靜脈注射免疫球蛋白,以預防院內感染之成效與安全性 (與給予安慰劑或未給予治療作比較) 。

搜尋策略

我們搜尋了MEDLINE、EMBASE、及Cochrane Library Databases等資料庫 (2007年7月) ,使用關鍵字如下:免疫球蛋白和隨機分組 (random allocation) 或對照實驗 (controlled trials) 或隨機對照實驗 (randomized controlled trials;RCTs) 。搜尋亦包括隨機對照實驗的參考資料和個人檔案,並未限制論文使用的語言。

選擇標準

選擇論文的標準如下:1) 研究設計:比較實驗組 (施打靜脈注射免疫球蛋白) 與對照組 (施打安慰劑或未予處置) 的隨機對照實驗;2) 研究對象:出生週數小於37週之早產兒/出生體重小於2500克之低體重新生兒;3) 處置:施打靜脈注射免疫球蛋白,以預防住院期間 (大於等於八天) 的細菌/黴菌感染[若研究是探討靜脈注射免疫球蛋白對體液免疫力 (humoral immune) 標記之影響,而追蹤時間少於一週者將被排除];4) 至少包含下列實驗結果達一項以上:敗血症、任何嚴重感染、各種原因造成的死亡、感染導致的死亡、住院天數、腦室內出血 (intraventricular hemorrhage;IVH) 、壞死性腸炎 (necrotizing enterocolitis;NEC) 、肺支氣管發育不良 (bronchopulmonary dysplasia;BPD) 。

資料收集與分析

各研究中的結果由兩位作者獨立審查,再由另一位研究者評估其間差異並作結論。結果以相對風險 (relative risk;RR) 和風險差 (risk difference;RD) 以及95% 信賴區間 (confidence intervals;CI) 表示,當風險差達顯著水準時,會再計算number needed to treat (NNT) 。所有符合搜尋標準的論文皆納入分析,若發現各論文之間的差異達顯著標準,便進行不一致性測驗 (I平方值) 。

主要結論

在二十篇依照搜尋策略選出的論文中,有一篇2007年7月的研究針對週數大於38週;出生體重大於2500克的新生兒,因此不納入統計。剩下的十九篇共納入約5000名早產兒/低體重新生兒,內容至少包含本評論欲探討之結果一項以上。匯集各篇研究資料發現敗血症的發生率有顯著降低 (p值為0.02) ,相對風險[0.85 (95% 信賴區間0.74, 0.98)];風險差[−0.03 (95% 信賴區間0.00, −0.05)];需要被治療的病人數目 (NNT, Number Needed to Treat) 為33。各篇研究間的異質性已達顯著差異 (p值為0.02) ;I平方值為54% 。另外罹患一次或多次嚴重感染的發生率也有顯著降低,[相對風險0.82 (95% 信賴區間0.74, 0.92) ;風險差 −0.04 (95% 信賴區間 −0.02, −0.06,) ;需要被治療的病人數目25 (95% 信賴區間17, 50)]。同樣的各篇研究間的異質性亦達顯著差異 (p值為0.0006) ;I平方值為50% 。至於各種原因造成的死亡率、感染導致的死亡、壞死性腸炎、肺支氣管發育不良、腦室內出血的發生率以及住院天數都沒有顯著差異。這些研究中皆未報告有靜脈注射免疫球蛋白導致的重大不良反應。

作者結論

使用靜脈注射免疫球蛋白可降低嚴重感染的發生達3% ,但無法降低壞死性腸炎、腦室內出血的發生或減少住院天數,對於降低死亡率也沒有顯著效果。就臨床觀點而言,這種治療的重要性並不大。預防性使用靜脈注射免疫球蛋白並未導致任何短期嚴重的副作用,至於使用與否端看其費用和療效孰輕孰重,進一步以隨機對照實驗研究其對降低早產兒/低體重新生兒院內感染的效益似乎無甚需要,本文鼓勵研究者及臨床醫師追求其他預防院內感染之措施。

翻譯人

本摘要由馬偕醫院宋季純翻譯。

此翻譯計畫由臺灣國家衛生研究院 (National Health Research Institutes, Taiwan) 統籌。

總結

嬰兒在胎內或出生後 (尤其在加護病房) 都有被感染的風險,可能導致重大疾病或死亡,母體的免疫球蛋白 (血液中負責抵抗感染的物質) 在懷胎32週後開始會進入胎兒體內,至於胎兒本身的免疫球蛋白則從出生後數個月開始製造,因此理論上感染導致的傷害可以用靜脈施予的免疫球蛋白來預防,目前約有5000名新生兒曾接受此治療並對其效果進行評估,發現使用靜脈注射免疫球蛋白僅降低3% 的血液感染及4% 的各式嚴重感染,對於其他重大併發症或住院天數並無顯著改善,最重要的是此療法不能降低死亡率。目前並未發現有任何短期重大的副作用。以臨床觀點而言,院內感染風險僅降低3 – 4% 而死亡率無法降低,顯示靜脈注射免疫球蛋白的重要性不大。

Résumé scientifique

Immunoglobuline intraveineuse pour prévenir les infections chez les nouveau-nés prématurés et/ou de faible poids de naissance

Contexte

Les infections nosocomiales demeurent une importante cause de morbidité et de mortalité chez les nouveau-nés prématurés et/ou de faible poids de naissance. Les nouveau-nés prématurés souffrent d'une carence en IgG, et l'administration d'immunoglobuline intraveineuse (IGIV) pourrait potentiellement prévenir ou modifier le cours des infections nosocomiales.

Objectifs

Évaluer l'efficacité/innocuité de l'administration d'IGIV chez des nourrissons prématurés et/ou de faible poids de naissance dans la prévention des infections nosocomiales.

Stratégie de recherche documentaire

Pour cette mise à jour, nous avons consulté MEDLINE, EMBASE, CINAHL et la Bibliothèque Cochrane jusqu'en décembre 2009.

Critères de sélection

Nous avons sélectionné les essais contrôlés randomisés (ECR) comparant l'administration d'IGIV à un placebo ou à une absence d'intervention chez des nouveau-nés prématurés (< 37 semaines d'âge gestationnel) et/ou de FPN (< 2 500 g). Les études principalement conçues pour évaluer les effets de l'IGIV sur les marqueurs de l'immunité humorale ont été exclues, de même que les études présentant une période de suivi inférieure ou égale à une semaine.

Recueil et analyse des données

La collecte et l'analyse des données ont été effectuées selon les méthodes du groupe de revue Cochrane sur la néonatologie.

Résultats principaux

Dix-neuf études recrutant environ 5 000 nouveau-nés prématurés et/ou de FPN remplissaient les critères d'inclusion.

Lorsque toutes les études étaient combinées, on observait une réduction statistiquement significative de la sepsie (RR typique de 0,85, IC à 95 %, entre 0,74 et 0,98 ; DR typique de -0,03, IC à 95 %, entre 0,00 et -0,05). Il existait une hétérogénéité statistiquement significative entre les études (I2 de 54 %). Une réduction statistiquement significative de n'importe quelle infection grave (un ou plusieurs épisodes) était observée lorsque toutes les études étaient combinées (RR typique de 0,82, IC à 95 %, entre 0,74 et 0,92 ; DR typique de -0,04, IC à 95 %, entre -0,02 et -0,06). Il existait une hétérogénéité statistiquement significative entre les études (I2 de 50 %). Aucune différence statistiquement significative n'était observée concernant la mortalité toutes causes confondues, la mortalité pour cause d'infection, l'incidence de l'ECN, de la DBP et de l'HIV, ou la durée de séjour à l'hôpital. Aucun effet indésirable grave associé à l'IGIV n'était signalé dans aucune des études.

Conclusions des auteurs

L'administration d'IGIV entraîne une réduction de 3 % de la sepsie et de 4 % d'un ou plusieurs épisodes de n'importe quelle infection grave, mais n'est associée à aucune autre réduction de critères de jugement cliniquement importants, notamment la mortalité. L'administration prophylactique d'IGIV n'est associée à aucun effet secondaire grave à court terme.

La décision d'utiliser de l'IGIV prophylactique doit être prise sur la base des coûts et de la valeur accordée aux résultats cliniques. La réalisation d'autres ECR examinant l'efficacité de préparations d'IGIV déjà étudiées pour réduire les infections nosocomiales chez les nourrissons prématurés et/ou de FPN n'est pas justifiée.

Plain language summary

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

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 immunoglobulin (substance in the blood that can fight infection) from the mother to the fetus mainly occurs after 32 weeks' gestation, and infants do not begin to produce immunoglobulin until several months after birth. Theoretically, the adverse effects of infection could be reduced by the preventive administration of intravenous immunoglobulin. To date, approximately 5000 infants have been enrolled in studies conducted to evaluate the effects of prophylactic use of intravenous immunoglobulin on neonatal outcomes. Intravenous administration of immunoglobulin results in a 3% reduction in blood-borne infection and a 4% reduction in serious infection. Intravenous administration of immunoglobulin is not associated with reductions in other important neonatal outcomes or in length of hospital stay. Most important, 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% to 4% reduction in nosocomial infection without a reduction in mortality or other important clinical outcomes is of marginal importance.

Résumé simplifié

Immunoglobuline intraveineuse pour prévenir les infections chez les nouveau-nés prématurés et/ou de faible poids de naissance

Les nourrissons peuvent contracter des infections in utero ou à l'hôpital après la naissance, en particulier s'ils doivent être placés en soins intensifs. Ces infections peuvent entraîner une maladie grave ou le décès du nouveau-né. Le transport des immunoglobulines (substances présentes dans le sang qui permettent de combattre les infections) de la mère au fœtus se produit principalement à partir de 32 semaines de gestation, et les nourrissons ne commencent à produire des immunoglobulines que plusieurs mois après la naissance. Théoriquement, l'administration préventive d'immunoglobuline intraveineuse pourrait permettre de limiter les effets indésirables des infections. À ce jour, environ 5 000 nourrissons ont été recrutés dans des études évaluant les effets de l'administration prophylactique d'immunoglobulines intraveineuses sur les résultats des nouveau-nés. L'administration intraveineuse d'immunoglobulines entraîne une réduction de 3 % des infections transmissibles par le sang et de 4 % de n'importe quelle infection grave. L'administration intraveineuse d'immunoglobulines n'entraîne pas de réduction d'autres résultats néonataux importants ou de la durée du séjour à l'hôpital. Qui plus est, l'administration intraveineuse d'immunoglobulines ne présente pas d'effet important sur la mortalité. L'administration prophylactique d'IGIV n'est associée à aucun effet secondaire grave à court terme. D'un point de vue clinique, une réduction de 3-4 % des infections nosocomiales sans réduction de la mortalité ou d'autres résultats cliniques importants présente une signification marginale.

Notes de traduction

Traduit par: French Cochrane Centre 1st February, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Background

Description of the condition

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 been reported in a cohort of 6911 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).

Description of the intervention

Intravenous immunoglobulin (IVIG) contains pooled immunoglobulin G (IgG) extracted from the plasma of more than 1000 blood donors. 

IVIG is frequently given to immunodeficient patients who have decreased antibody production capabilities. In immunodeficient patients, IVIG is administered to maintain adequate antibody levels to prevent infection and to confer passive immunity.

How the intervention might work

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). Mean serum levels of IgG are 400 mg/dL in infants at less than 32 weeks' gestational age (GA) compared with 1000 mg/dL in term infants (Hobbs 1967; Stiehm 1966). The idea of preventing nosocomial infection with 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).

Why it is important to do this review

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 randomised 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 no significant reduction 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 administration of IVIG to neonates. They reviewed seven studies of the prophylactic use of IVIG that reported an outcome of sepsis and concluded, "The preliminary data generated in trials of IVIG are promising, but use of this treatment modality still needs to be considered experimental and [it] should only, as yet, be used under study conditions." Lacy and Ohlsson (Lacy 1995) included additional trials and concluded that routine administration of IVIG to preterm infants to prevent infection is not recommended. Jenson and Pollock (Jenson 1997) used slightly different inclusion criteria and, like Lacy and Ohlsson (Lacy 1995), noted heterogeneity among studies. They concluded, "this heterogeneity probably belies the minimal benefit, at most, of prophylactic IVIG". The results of a Canadian multidisciplinary consensus-building initiative (Consensus 1997) have been published, and the use of IVIG for prophylaxis of neonatal nosocomial infection was considered inappropriate. This review provides an update of our previous review, which was last updated with no changes in 2010 (Ohlsson 2001; Ohlsson 2007) and was first published in 1998 (Ohlsson 1998).

Objectives

To use systematic review/meta-analytical techniques to determine whether IVIG administration (compared with placebo or no intervention) to preterm (< 37 weeks' gestational age (GA) at birth)or LBW (< 2500 g birth weight) infants or both is effective/safe in preventing nosocomial infection.

Methods

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. Studies that were designed to evaluate the effects 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 outcomes
  • Sepsis, one or more episodes (clinical signs and symptoms of sepsis and positive blood culture for bacteria or fungi).

Secondary outcomes
  • Any serious infection (clinical signs and symptoms in conjunction with positive cultures (bacteria or fungi) from normally sterile body fluids (blood, cerebrospinal 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.

  • 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.

  • Death from all causes.

  • Death from infection (including death from NEC).

  • Length of hospital stay.

  • Incidence of bronchopulmonary dysplasia (BPD), defined as an additional oxygen requirement (above room air) at 28 days of age or a requirement for assisted ventilation for reasons other than apnoea of prematurity.

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

  • Incidence of IVH, grade 3 or 4, classified according to Papile (Papile 1983).

  • Reports on possible side effects as described by the authors.

Search methods for identification of studies

The search strategy used to identify studies adhered to the guidelines of the Cochrane Neonatal Review Group.

Electronic searches

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.

In December 2009, we updated the search as follows: MEDLINE (search via PubMed), CINAHL, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library) were searched from 2003 to December 2009. Search term: immunoglobulin. Limits: human, newborn infant and clinical trial. 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. Abstracts of the Pediatric Academic Societies (PAS) Annual Meetings from 2000 to 2013 were searched on the same day by one of the review authors (AO).

Searching other resources

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.

Data collection and analysis

Data collection and analysis were done in accordance with the methods 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' gestational age) and/or LBW (< 2500 g) infants;

  • intervention: administration of IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days or longer). (Studies that were primarily designed to assess the effects 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.); and

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

The titles (and abstracts when available) in MEDLINE, EMBASE and The Cochrane Library printouts were reviewed by the two review authors. Any article that the review authors believed might meet the inclusion criteria noted above or 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. Additional information was obtained on one published study (Sandberg 2000).

All identified 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 to verify definitions of terms. The two review authors independently abstracted information on each study, and one review author (AO) checked for any discrepancies and pooled the results. Data abstraction included whether the study involved prophylaxis or treatment, the number of participants enrolled, the number of participants enrolled but later excluded, the time period and geographical location of the study, baseline characteristics of participants, inclusion/exclusion criteria, the preparation and dosing regimen of 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 (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 death from infection. Information on length of hospital stay and on incidence of BPD and IVH was collected. Information on probable infection was not collected, as the definitions 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 developed by the Cochrane Neonatal Review Group. These criteria included blinding of randomisation, blinding of the intervention, complete follow-up and blinding of outcome measurement. For each criterion, three possibilities were identified: yes, can't tell and 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 with 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 independent evaluation was performed, the two assessors discussed the results of each study, and any discrepancies were resolved. 

For the update in 2009, the following issues were evaluated and entered into the risk of bias table:

  • Sequence generation: Was the allocation sequence adequately 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 Cochrane Collaboration was used. Typical relative risk (RR) and typical risk difference (RD) with 95% confidence intervals (CIs) using the fixed-effect model are reported. If a statistically significant reduction in RD was noted, the number needed to treat to benefit (NNTB) or harm (NNTH) was calculated.

Assessment of heterogeneity

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

  • <25%: no heterogeneity;

  • 25% to 49%: low heterogeneity;

  • 50% to 74%: moderate heterogeneity; and

  • > 75%: high heterogeneity.

Data synthesis

Meta-analysis was performed using Review Manager software (RevMan 5.2) as supplied by The Cochrane Collaboration. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed -effect model.

Subgroup analysis and investigation of heterogeneity

Future updates will consider post hoc subgroup analyses to explore any heterogeneity noted in the primary analysis.

Results

Description of studies

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

Nineteen studies, including approximately 5000 preterm and/or LBW infants, met inclusion criteria. These studies were performed 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 (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 who were heavier or more mature at birth than was permitted by the inclusion criteria (Kinney 1991, Adhikari 1996); lacked information on outcomes (Kacet 1991; Malik 1990); lacked a randomised control group (Acunas 1994) or provided immunoglobulin intramuscularly (Monintja 1989).

Risk of bias in included studies

The assessment of individual studies is presented in the Characteristics 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, blinding of randomisation, 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 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, with phase I providing a placebo but not phase II. In several studies, blinding of randomisation 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 therefore could not be fully assessed. The study by Bussel (Bussel 1990a) represents an interim analysis, with data lacking from a large proportion of the infants randomly assigned.

Effects of interventions

Nineteen studies met inclusion criteria. These included a total of approximately 5000 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review. No new trial was identified in the literature search conducted in May 2013. One additional trial was identified in July 2007 (Lelik 2004). However, this trial enrolled infants at greater than 38 weeks' gestational age and with birth weight greater than 2500 g. The study was therefore excluded. No new studies were identified in the literature search conducted in September 2003.

For details of results, see Data and analyses. It should be noted that for most outcomes, the large study by Fanaroff (Fanaroff 1994) greatly influenced the summary statistics, with an assigned weight ranging from 42.7% for the outcome of any serious infection to 88.3% for the outcome of IVH grade 3 or 4.

IVIG VERSUS PLACEBO OR NO TREATMENT (COMPARISON 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 symptoms of infection and positive blood culture). Only the study by Ratrisawadi (Ratrisawadi 1991) showed a statistically significant reduction in sepsis (RR 0.38; 95% CI 0.19 to 0.79). When all studies were combined, a statistically significant (P = 0.02) reduction 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 20 to infinity). Significant between-study heterogeneity was observed for this outcome for both RR and RD (P = 0.02; I2 = 54%; moderate 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 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 found when all studies were combined (typical RR 0.82, 95% CI 0.74 to 0.92; typical RD -0.04, 95% CI -0.06 to -0.02; NNTB 25, 95% CI 17 to 50). Statistically significant between-study heterogeneity was observed for this outcome (P = 0.01 and I2 = 50% (moderate) for RR; P = 0.0006 and I2 = 62% (moderate) for RD).

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 serious infection, one or more episodes.

Necrotizing enterocolitis (NEC), one or more episodes (Outcome 1.3):

Seven studies (including 4081 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 to 1.59). When all studies were combined, no significant increase was evident (typical RR 1.08, 95% CI 0.89 to 1.32; typical RD 0.01, 95% CI -0.01 to 0.02). No statistically significant between-study heterogeneity was observed for this outcome for RR (P = 0.14; I2 = 38% (low)), but it was observed for RD (P = 0.05, I2 = 52% (moderate)).

Mortality (all causes) (Outcome 1.4) ( Figure 3 ):

Fifteen studies (including 4125 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, no statistically significant reduction was noted (typical RR 0.89, 95% CI 0.75 to 1.05; typical RD -0.01, 95% CI -0.03 to 0.01). No statistically significant between-study heterogeneity was observed for this outcome for RR (P = 0.22; I2 = 21% (none)) and for RD (P = 0.15; I2 = 28% (low)).

Figure 3.

Forest plot of comparison: 1 IVIG versus placebo or no treatment, outcome: 1.4 Mortality (all causes).

Mortality (infectious) (Outcome 1.5):

Ten studies (including 1690 infants) reported on mortality from infection. 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 to 1.22; typical RD -0.01, 95% CI -0.03 to 0.01). No statistically significant between-study heterogeneity was observed for this outcome for RR (P = 0.11; I2 = 40% (low)) and for RD (P = 0.08; I2 = 42% (low)).

Duration of hospitalisation (Outcome 1.6):

None of eight studies (including 3562 infants) reported a significant reduction in length of hospital stay after IVIG prophylaxis. The overall typical weighted mean difference was -2.1 days (95% CI -4.5 to 0.3). No statistically significant between-study heterogeneity was observed (P = 0.67 and I2 = 0% (none) for both RR and RD).

Bronchopulmonary dysplasia (BPD) (Outcome 1.7):

In only one study, the outcome of BPD was defined and data were provided. Several authors failed to define the outcome of BPD, and others defined the outcome but did not provide data. In a small study (n = 115), Clapp (Clapp 1989) showed a trend towards increased BPD (RR 1.53, 95% CI 0.78 to 3.01; RD 0.10, 95% CI -0.06 to 0.25). In another small 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 typical RR was 1.55 (95% CI 0.85 to 2.84), and the typical RD was 0.09 (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)).

Intraventricular haemorrhage (IVH) any grade (Outcome 1.8):

Four studies (including 3176 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 to 1.19; typical RD 0.00, 95% CI -0.02 to 0.03). No statistically significant 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 or 4. The typical RR was 1.01 (95% CI 0.85 to 1.21), and the typical RD was 0.00 (95% CI -0.02 to 0.03). Statistically significant between-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 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 Characteristics of excluded studies) were similar to those from included studies.

Discussion

The effectiveness of IVIG in preventing nosocomial infection in neonates has been well studied. To date, more than 5000 preterm and/or LBW neonates have been enrolled in trials from many different areas of the world. No new trial was identified for this update conducted in May 2013. One additional trial was identified for 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 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 because of 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 randomly assigned infants. IVIG caused increased levels of IgG in serum. No major side effects were noted.

A small but statistically significant reduction in the incidence of sepsis and of any serious infection was found. Statistically significant between-study heterogeneity was observed for these outcomes. The heterogeneity might be explained in part 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 study results was noted (I2 54% and 50%, respectively).

No statistically significant differences were noted in mortality from all causes, mortality from infection, NEC, BPD or IVH. Results for these outcomes were centred around an 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 any assurance that all neonates were subjected to ascertainment of an IVH according to a preset schedule for ultrasonographic examination. A trend towards shortened duration of hospital stay was noted with IVIG treatment [weighted mean difference (WMD) -2.1 days, 95% CI -4.5 to 0.3 days] . The outcome of hospital stay is highly dependent on the GA at birth of the neonate, the 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 3.0% and 4.0% reduction in sepsis and in any serious infection, respectively, should be weighed against the costs and the values assigned to this outcome. No serious side effects have been reported from IVIG to date, but unknown long-term risks 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 compare and adjust their infection control policies to those settings with low rates by using benchmarking techniques. If the rates remain high after such measures are taken, use of IVIG might be justified. Prophylactic use of IVIG should be based on a full economic evaluation and a clinical decision analysis that incorporates baseline risk for serious nosocomial infection, both clinical and economic outcomes following prophylactic IVIG and values attached to infections prevented. Such analyses have not been performed.

Although differences in inclusion criteria are seen, as well as differences in the number of studies published at the time of the reviews and the number of statistical analyses performed, 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 infection.

Authors' conclusions

Implications for practice

IVIG administration results in a 3% to 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 after prophylactic IVIG, as well as values attached to infections prevented, is needed.

There is no justification for conducting additional RCTs to test the efficacy of previously studied IVIG preparations in reducing nosocomial infection 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 infection.

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 translation of the study from Russian to 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 National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C. 

Data and analyses

Download statistical data

Comparison 1. IVIG vs placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Sepsis, one or more episodes103975Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.74, 0.98]
2 Any serious infection, one or more episodes164986Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.74, 0.92]
3 NEC, one or more episodes74081Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.89, 1.32]
4 Mortality (all causes)154125Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.75, 1.05]
5 Mortality (infectious)101690Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.56, 1.22]
6 Duration of hospitalisation83562Mean Difference (IV, Fixed, 95% CI)-2.12 [-4.54, 0.30]
7 Bronchopulmonary dysplasia2176Risk Ratio (M-H, Fixed, 95% CI)1.55 [0.85, 2.84]
8 Intraventricular haemorrhage any grade43176Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.88, 1.19]
9 Intraventricular haemorrhage grade 3 or 423000Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.85, 1.21]
Analysis 1.1.

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

Analysis 1.2.

Comparison 1 IVIG vs placebo or no treatment, Outcome 2 Any serious infection, one or more episodes.

Analysis 1.3.

Comparison 1 IVIG vs placebo or no treatment, Outcome 3 NEC, one or more episodes.

Analysis 1.4.

Comparison 1 IVIG vs placebo or no treatment, Outcome 4 Mortality (all causes).

Analysis 1.5.

Comparison 1 IVIG vs placebo or no treatment, Outcome 5 Mortality (infectious).

Analysis 1.6.

Comparison 1 IVIG vs placebo or no treatment, Outcome 6 Duration of hospitalisation.

Analysis 1.7.

Comparison 1 IVIG vs placebo or no treatment, Outcome 7 Bronchopulmonary dysplasia.

Analysis 1.8.

Comparison 1 IVIG vs placebo or no treatment, Outcome 8 Intraventricular haemorrhage any grade.

Analysis 1.9.

Comparison 1 IVIG vs placebo or no treatment, Outcome 9 Intraventricular haemorrhage grade 3 or 4.

What's new

DateEventDescription
28 May 2013New search has been performed

Review updated in May, 2013.

No new trials identified.

Conclusions not changed.

28 May 2013New citation required but conclusions have not changedUpdated search: May, 2013.

History

Protocol first published: Issue 2, 1998
Review first published: Issue 2, 1998

DateEventDescription
7 April 2010Amended

Review updated Issue 4, 2010.

Risk of Bias tables completed for this amended version.

25 February 2010New search has been performed

This updates the existing review "Intravenous immunoglobulin for preventing infection in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews (Ohlsson 2007).

Updated search found no new trials.

No changes to conclusions.

3 July 2008AmendedConverted to new review format.
23 July 2007New search has been performedThis 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 center studies from Turkey, one single center study from Taiwan and one multi-center study conducted in four centers 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.
20 October 2003New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Arne Ohlsson:

Literature search and identification of trials for inclusion.
Evaluation of methodological quality of included trials.
Abstraction of data.
Verification and entry of data into RevMan.
Writing of review text.

Janet Lacy:

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

Both reviewers contributed to this update in 2013.

Arne Ohlsson (AO) wrote the original review and updated the review in 2003 and 2007.

The February 2010 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton and Roger Soll). The 2010 update was reviewed and approved by AO.

Declarations of interest

None

Sources of support

Internal sources

  • Department of Paediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

Differences between protocol and review

None

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Atici 1996

MethodsSingle-centre, randomised, controlled trial without the use of a placebo
I. Blinding of randomisation-can't tell
II. Blinding of intervention-no
III. Complete follow-up-yes
IV. Blinding of outcome measurement(s)-no
Participants76 infants with GA < 34 weeks
Single-centre study, Turkey
May 15, 1993-June 15, 1994
Interventions40 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 with mean GA (SD) 32.3 ± 2.4 wk, mean BW (SD) 1684 ± 519 g served as controls (no placebo was given)
OutcomesProven infection (clinical findings and blood and/or cerebrospinal fluid culture positive for a pathogen)
Total mortality, infectious mortality, days in hospital
NotesProven infection, mortality from any cause, infectious mortality and days in hospital could be ascertained from this study
No adverse effects were noted
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskA block randomisation method was used. No further information was provided
Allocation concealment (selection bias)Unclear riskA block randomisation method was used. No further information was provided
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported on all infants enrolled
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Baker 1992

MethodsMulticentre, randomised, double-blind, placebo-controlled trial
I. Blinding of randomisation-yes
II. Blinding of intervention-yes
III. Complete follow-up-yes
IV. Blinding of outcome measurement-yes
Participants588 infants with a BW of 500 to 1750 g. Age 3 to 7 days
Six centres in the US
July 16, 1987 to December 12, 1988
Interventions287 infants received 500 mg/kg of IVIG (Gammagard, Baxter Healthcare, Hyland Division, Glendale, Calif) at enrolment (age 3 to 7 days), 1 week 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
OutcomesProven infection (clinical findings of sepsis and at least one of the following: a positive blood culture (bacteria or fungi), 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 isolation of virus from an infant with clinical deterioration)
NEC (stage II or III)
IVH (grade I to 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
NotesThe following outcomes could be ascertained from this study: any serious infection (bacterial + fungal), IVH, NEC, death from all causes. Total episodes for sepsis were reported. A total of 50 episodes of sepsis were reported 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA randomisation table was used
Allocation concealment (selection bias)Low riskInfants were randomly assigned by the pharmacist at the study site to receive either IVIG or albumin placebo
Blinding (performance bias and detection bias)
All outcomes
Low riskAlbumin placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported for all randomly assigned infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Bussel 1990a

MethodsRandomized, double-blind, placebo-controlled trial.
I. Blinding of randomisation-yes
II. Blinding of intervention-yes
III. Complete follow-up-no
IV. Blinding of outcome measurement-yes
Participants240 infants with BW < 1300 g
Data for 172 participants 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 US centre
September 1984 to October 1987
Interventions61 neonates (mean BW 977 g) received a dose of 1 g of a 6% solution of IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, NJ) 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
OutcomesSepsis (signs and symptoms compatible with sepsis and a positive blood or CSF culture)
IVH diagnosed by ultrasonographic examination at 3 to 7 days of age
1 neonate excluded because of severe anomalies incompatible with life
For additional exclusions, see "Participants"
NotesThis 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskA random number generator was used
Allocation concealment (selection bias)Low riskBlinding of randomisation-yes
Blinding (performance bias and detection bias)
All outcomes
Low riskAlbumin was used as placebo
Incomplete outcome data (attrition bias)
All outcomes
High riskData for 172 participants 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)
Selective reporting (reporting bias)High riskNoted in incomplete outcome data section above. The protocol for the study was not available to us, and we therefore cannot tell whether there were any other deviations
Other biasLow riskAppears free of other bias

Chirico 1987

MethodsRandomised, controlled trial without the use of a placebo
I. Blinding of randomisation-yes
II. Blinding of intervention-no
III. Complete follow-up-yes
IV. Blinding of outcome measurement-no
ParticipantsIn this study, a subgroup with BW </= 1500 g (n = 86) of the total population of 133 infants (BW range 550 to 3340 g; GA range 24 to 40 wk) fulfilled the inclusion criteria for this systematic review
Single centre, Italy
Dates not given
Interventions43 infants received 0.5 g/kg of IVIG (Sandoglobulin) weekly for 1 month
43 infants received no placebo or other intervention
OutcomesCriteria 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 radiological symptoms were present
3 infants in the control group who died within 24 hours after birth were excluded from the analysis by the authors
NotesThe outcomes of sepsis, any serious infection, NEC, length of hospital stay, death from all causes and deaths from infection 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Low riskSealed envelopes were used
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low risk3 infants in the control group who died within 24 hours after birth were excluded from the analysis by the authors
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Chou 1998

MethodsRandomised placebo-controlled trial with the use of a non-identical-looking placebo (saline)
I. Blinding of randomisation-can't tell
II. Blinding of intervention-no
III. Complete follow-up-yes
IV. Blinding of outcome measurement(s)-no
Participants61 infants with a BW < 1500 g were enrolled. Single-centre study, Taiwan
July 1993 to June 1994
Interventions31 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 weeks until the patient weighed 1800 g or was discharged. The dose of IVIG was 750 to 1000 mg/kg/dose if the infant's BW was < 1000 g and 500 to 750 mg/kg/dose if the infant's BW was between 1001 and 1500 g.
30 neonates, mean BW (SD) 1320 ± 250 g and mean GA (SD) 30.6 ± 1.7 wk received saline infusion
Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Unclear riskParticipants were randomly divided into 2 groups
Blinding (performance bias and detection bias)
All outcomes
High riskA non-identical-looking placebo (saline) was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up-yes
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Christensen 1989

MethodsRandomised, double-blind, placebo-controlled study
I. Blinding of randomisation-yes
II. Blinding of intervention-yes
III. Complete follow-up-yes
IV. Blinding of outcome measurement-yes
Participants20 preterm neonates, weight < 2000 g at entry to study and < 7 days of age
Single centre, US
Dates not given
Interventions10 neonates received IVIG (Gamimmune-N, Cutter Biologicals, Berkeley, California) 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
OutcomesNosocomial infection (not defined)
Survival
NotesThis study provides information on death from infections and death from all causes
No differences in heart rate, respiratory rate, rectal temperature and urine output were noted before, during and after infusions of IVIG or placebo (no differences between groups)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Low riskIVIG and placebo were dispensed from the pharmacy to study nurses in accordance with a random number sequence known only to the study pharmacist
Blinding (performance bias and detection bias)
All outcomes
Low riskAlbumin was used as placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported for all randomly assigned infants
Selective reporting (reporting bias)Low riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Clapp 1989

MethodsRandomised, double-blind, placebo-controlled trial
I. Blinding of randomisation-yes
II. Blinding of intervention-yes
III. Complete follow-up-yes
IV. Blinding of outcome measurement-yes
Participants115 infants with BW of 600 to 2000 g and < 48 hours of age
Single centre, US
November 1, 1986 to August 31, 1987
Interventions56 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 participant in the placebo group received an additional infusion
OutcomesSepsis (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
Death from all causes
Death from infection
BPD (requiring O2 at 28 days for BPD)
IVH (Papile classification)
NotesFrom 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 be ascertained. Three episodes of sepsis/proven 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 were noted in one infant who received IVIG. Transient rise in alanine aminotransferase level was noted in 1 infant who received IVIG and in 1 who received placebo
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Low riskAll investigators and caretakers, with the exception of clinical pharmacist, were unaware of the random assignment of each infant
Blinding (performance bias and detection bias)
All outcomes
Unclear riskA placebo was used, but a 6% or 12% sucrose solution was used, which may not look identical and would taste differently should a caretaker have tried to taste a drop
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported for all randomly assigned infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Conway 1990

MethodsRandomised controlled trial without use of a placebo
I. Blinding of randomisation-yes
II. Blinding of intervention-no
III. Complete follow-up-no
IV. Blinding of outcome measurement-no
Participants66 neonates of < 30 wk GA
2 centres in the UK
Dates not given
Interventions34 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
OutcomesSepsis (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)
NotesOutcomes of sepsis and NEC could be ascertained. We used as denominators all randomly assigned participants. We included in the outcome of mortality (all causes) the infants who were withdrawn because of early death. 1 infant with 2 episodes of NEC was counted as 1 outcome.
Side effects were not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskEleven infants-6 in the control group and 5 in the treatment group-were withdrawn from the trial because of 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)
Selective reporting (reporting bias)Unclear riskSee "Incomplete outcome data addressed?" The protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Didato 1988

MethodsRandomised controlled trial without the use of a placebo
I. Blinding of randomisation-yes
II. Blinding of intervention-no
III. Complete follow-up-yes
IV. Blinding of outcome measurement-no
Participants80 infants with a BW of 2000 g or less
Single centre, Italy
June 1985 to December 1986
Interventions40 infants received 0.5 g/kg/wk of IVIG (IgVena, Sclavo; Siena, Italy) until they reached the GA of 36 weeks and during the entire period of intensive care
40 infants received no placebo or other intervention
OutcomesSepsis defined as clinical manifestations, microbiological findings (positive blood culture or CSF culture) and non-microbiological laboratory findings (total and differential white blood cell count, erythrocyte sedimentation rate, C-reactive protein, platelet count, tests of haemostatic function)
NotesAny serious infection, death from all causes and death 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 after IVIG administration
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised controlled trial without the use of a placebo
Allocation concealment (selection bias)Low riskRandomly assigned by sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported for all infants randomly assigned
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Fanaroff 1994

MethodsMulticentre, 2-phase controlled trial. Phase 1 was placebo controlled and double blinded; phase 2 was not placebo controlled
I. Blinding of randomisation-yes
II. Blinding of intervention-yes/no*
III. Complete follow-up-yes
IV. Blinding of outcome measurement-yes/no*
*This study had 2 phases; in phase 1a, placebo was used, but not in phase 2
Participants2416 infants with BW 501 to 1500 g and randomly assigned at a mean age of 44 ± 25 hours after birth
8 centres in the US
January 1, 1988 to March 31, 1991 (or through April, 1991)
InterventionsIn phase 1
595 infants received IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, NJ)
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 randomisation. 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 2 weeks until the infants weighed 1800 g, were transferred to another hospital, died or were sent home
In phase 2
609 infants received IVIG as per above (phase 1)
589 received no intervention
OutcomesSepsis (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 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 suprapubic puncture
Proven 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
NotesThe 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAn unbiased coin design was used
Allocation concealment (selection bias)Low riskAll lots of IVIG and placebo were marked and recorded by code
Blinding (performance bias and detection bias)
All outcomes
Low riskYes/No; this study had 2 phases; in phase 1a, placebo was used, but not in phase 2
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all randomly assigned infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Fanaroff-I 1994

MethodsPhase 1 of Fanaroff 1994, placebo-controlled
Participants1218 infants with BW 501 to 1500 g and randomly assigned at a mean age of 44 ± 25 hours after birth
8 centres in the US
January 1, 1988 to March 31, 1991 (or through April 1991)
InterventionsIn phase 1
595 infants received IVIG (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, NJ)
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 randomisation. 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 2 weeks until the infants weighed 1800 g, were transferred to another hospital, died or were sent home
OutcomesSepsis (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 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 suprapubic puncture
Proven 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
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMulticentre, 2-phase controlled trial. Phase 1 was placebo controlled and double blinded; phase 2 was not placebo controlled
Allocation concealment (selection bias)Low riskAn unbiased coin design was used
Blinding (performance bias and detection bias)
All outcomes
Low riskAll lots of IVIG and placebo were marked and recorded by code. A placebo was used in phase 1
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes reported for all randomly assigned infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Haque 1986

MethodsRandomised controlled trial, without the use of a placebo
I. Blinding of randomisation-yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement - no
Participants150 neonates of 28 to 37 weeks GA and less than 4 hours of age
Single centre, Saudi Arabia
Dates not given
Interventions50 neonates received IVIG (Intraglobulin, Biotest Pharma, West Germany) 120 mg/kg within 2 to 4 hours of birth
50 neonates received IVIG (Intraglobulin) 120 mg/kg on days 1 and 8 of life
50 neonates received no intervention
OutcomesSepsis was defined as presence of clinical features and a positive culture of blood or cerebrospinal fluid
NotesSepsis, 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.
Mean age at onset of infection was 46.3 hours (range 8 to 76 hours), suggesting that some infants had infection acquired in utero and were infected at the time of enrolment
No adverse effect of therapy was noted during the study and at 6-month follow-up
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Low riskEnvelopes were used
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes were reported for all randomly assigned infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Magny 1991b

MethodsMulticentre, randomised, controlled, double-blind study
I. Blinding of randomisation - can't tell
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement - yes
Participants235 neonates of less than or equal to 32 weeks' gestation, hospitalised before 25 hours of life and having endotracheal tube and/or umbilical catheter on admission
4 centres in Paris, France
1987 to 1989
Interventions120 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
OutcomesDeath from infection
Certain nosocomial infection (clinical signs of infection, positive cultures (blood, urine, cerebrospinal fluid, tracheal aspirate, stools, gastric aspirate), at least 2 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 radiological pneumatosis
Neonatal infection and infection occurring within the first 4 days of life, potentially of maternal origin, were not counted as evaluation criteria
NotesDeath 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 1 or more episodes of NEC could not be ascertained. The 46 infants for whom 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"
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA randomisation table was prepared by the statistician for each unit
Allocation concealment (selection bias)Low riskThe investigators were "blind"
Blinding (performance bias and detection bias)
All outcomes
Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low riskIn 46 infants (21 in the IVIG group; 25 in the placebo group), irregularities occurred in the protocol (1 dose forgotten or no follow-up until 45 days of life because of transfer out of the unit). The data from these 46 infants were maintained for statistical analysis but were considered separately
Selective reporting (reporting bias)Low riskSee "Incomplete outcome data addressed". The protocol for the study was not available to us, and we therefore cannot tell if there were any other deviations
Other biasLow riskAppears free of other bias

Ratrisawadi 1991

MethodsRandomised controlled trial, without the use of a placebo group
I. Blinding of randomisation - can't tell
II. Blinding of intervention - no
III. Complete follow-up - can't tell
IV. Blinding of outcome measurement - no
Participants68 infants with a BW of 1000 to 1500 g
Single centre, Bangkok, Thailand
February 1988 to March 1990
Interventions34 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
OutcomesSepsis (presence of clinical findings of sepsis plus positive blood cultures)
NotesThe 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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised, controlled trial, without the use of a placebo group
Allocation concealment (selection bias)Unclear riskBlinding of randomisation - can't tell
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInfants (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 participants in each group is identical (n = 34)
Selective reporting (reporting bias)Unclear riskSee above. The protocol for the study was not available to us, and we therefore cannot tell if there were any other deviations
Other biasLow riskAppears free of other bias

Sandberg 2000

MethodsRandomised double-blind placebo controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - no
IV. Blinding of outcome measurement(s) - yes
Participants105 infants were randomly assigned 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
Interventions40 infants, mean GA (SD) 27.5 ± 2.2 wk and mean BW (SD) 1.06 ± 0.39 kg, received 1 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%)
OutcomesSepsis (symptoms and positive blood culture)
Days on ventilator
Total mortality from any cause. Infectious mortality
NotesOutcomes of sepsis, death from all causes and death from infection could be ascertained from this study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAccording to Dr Klara Thiringer, randomisation was achieved by a computer-generated list for each of the 4 centres, and infants were allocated by the use of sealed envelopes
Allocation concealment (selection bias)Low riskInfants were allocated by the use of sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk105 infants were randomly assigned 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
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Spady 1994

MethodsRandomised, double-blind trial
Published in abstract form only - full quality assessment not possible
Participants111 VLBW infants
Interventions54 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 later
57 infants were given the same volumes as 5% dextrose
OutcomesThe 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
NotesLength of hospital stay could be ascertained from this study, which is published in abstract form only
Respiratory rate increased in the IVIG group after the first infusion. No other side effects occurred
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskPublished in abstract form only - full quality assessment not possible
Allocation concealment (selection bias)Unclear riskSee above
Blinding (performance bias and detection bias)
All outcomes
Unclear riskSee above
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskSee above
Selective reporting (reporting bias)Unclear riskSee above
Other biasUnclear riskSee above

Stabile 1988

MethodsSingle-centre, randomised, controlled trial without the use of a placebo group
I Blinding of randomisation - can't tell
II Blinding of intervention - no
III Complete follow-up - no
IV Blinding of outcome measurement - no
Participants94 neonates, GA ≤ 34 weeks' gestation or BW ≤ 1500 g
Single centre, Rome, Italy
May 1984 to June 1986
Interventions0.5 g/kg IVIG (Venogamma Polivalente, Ismunit, Pomezia, Italy) on the 1st, 2nd, 3rd, 7th, 14th, 21st and 28th days of life (treatment group) or no intervention (control group)
OutcomesSepsis 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 1 had suspected prenatal infection. 8 control neonates were excluded: 2 underwent exchange transfusion, 3 died of severe respiratory distress syndrome, 1 died of respiratory distress syndrome and IVH and 2 had suspected prenatal infection
NotesSepsis, any serious infection, death from all causes and death from infection could be ascertained from this study. Infants who 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".
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information was provided
Allocation concealment (selection bias)Unclear riskInfants were randomly assigned
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
High risk

Complete follow-up - no

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

Selective reporting (reporting bias)High riskNo; see comments above. The protocol for the study was not available to us, and we therefore cannot tell whether there were any other deviations
Other biasLow riskAppears free of other bias

Tanzer 1997

MethodsSingle-centre, quasi-randomised trial without the use of a placebo
I. Blinding of randomisation - no
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measure(s) - no
Participants80 preterm neonates. Single centre, Turkey. Dates for the study period not provided
Interventions40 infants with mean (SE) GA of 36.18 (0.17) weeks and mean (SE) BW of 1.85 (0.07) kg were given 500 mg/kg of IVIG (Sandoglobulin R) if they were weighing more than 1500 g and 700 mg/kg if they were weighing < 1500 g at birth on days 1, 2 and 8 of life
40 infants with mean (SE) GA of 35.58 (0.19) weeks and mean (SE) BW of 1.67 (0.07) kg got no placebo
OutcomesBlood 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
NotesSepsis, death from all causes could be ascertained from this study. No adverse effects were noted. The outcome of days in hospital was reported only for the control group. Treatment with IVIG resulted in a statistically significant increase in serum IgG concentrations.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskInfants were divided into two groups on the basis of order of admission
Allocation concealment (selection bias)High riskAllocation was known based on order of admission
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcomes wee reported on all enrolled infants
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell whether there were any deviations
Other biasLow riskAppears free of other bias

Van Overmeire 1993

MethodsRandomised controlled trial without the use of a placebo group
I. Blinding of randomisation - yes
II. Blinding of intervention - no
III. Complete follow-up - yes
IV. Blinding of outcome measurement - no
Participants116 neonates of < 32 wk GA and < 1500 g BW.
Single centre, Antwerp, Belgium
Dates not given
Interventions56 neonates received 500 mg IVIG (Sandoglobulin) in 10 mL of saline over a period of 30 minutes within the first 12 hours of life. This infusion was repeated every 24 hours until the 7th day of life, then was administered weekly for another 3 weeks. 60 neonates received no placebo or other intervention
OutcomesThe 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
NotesAny 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskAllocation was by means of envelopes
Blinding (performance bias and detection bias)
All outcomes
High riskNo placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskComplete follow-up - yes
Selective reporting (reporting bias)Unclear riskThe protocol for the study was not available to us, and we therefore cannot tell if there were any deviations
Other biasLow riskAppears free of other bias

Weisman 1994a

  1. a

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

MethodsMulticentre, randomised, double-blind, placebo-controlled trial
I. Blinding of randomisation - yes
II. Blinding of intervention - yes
III. Complete follow-up - yes
IV. Blinding of outcome measurement - yes
Participants753 neonates with a BW of 500 to 2000 g, GA ≤ 34 wk, postnatal age ≤ 12 h
9 centres in the US
June 1985 to April 1989
Interventions372 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
OutcomesAll 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 2 positive cultures were required
Infection was defined as clinical signs and symptoms and isolation of a causative organism from 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 the need for continued oxygen or ventilatory support at 28 days of age for reasons other than apnoea and a chest radiograph or histopathological criteria compatible with the diagnosis. IVH was graded on a scale of 1 to 4 according to Papile. Bell's classification of stage II or greater was used to define NEC
NotesSepsis, 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
IVIG-treated infants had a 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
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk 
Blinding (performance bias and detection bias)
All outcomes
Low risk 
Incomplete outcome data (attrition bias)
All outcomes
Low risk 
Other biasLow risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Acunas 1994This is an RCT comparing the effects of fresh frozen plasma or gamma globulin on humoral immunity in neonatal sepsis. This study did not meet the inclusion criteria, as a randomised untreated control group was not included. A non-randomised concurrent group of infants without suspicion of infection and matched for age, birth weight and gestational age served as a control group
Adhikari 1996This 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. Mean weight in the IVIG group was 2702 g, and in the placebo group 2679 g; thus, most neonates did not fulfill the entry criterion of 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 1991The authors do not provide enough information regarding definitions of outcomes for inclusion in this systematic review
Kinney 1991This is a double-blind RCT designed to determine whether IVIG administration modifies the incidence of infection 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. Thus, this study did 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 2004This is a randomised controlled trial, but the infants enrolled were > 38 weeks' gestation and weighed > 2500 g; therefore the study population did not fulfill our inclusion criteria
Malik 1990This 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 1989Immunoglobulin was given intramuscularly. It is unclear whether this is an RCT. Sepsis was not clearly defined

Ancillary