Short title: Prophylactic IVIG in neonates
Reviewer(s): Ohlsson A, Lacy JB
Date of most recent amendment: 23/12/1997
Date of most recent substantive amendment: 05/12/1997
Date next stage expected: 23/06/1998
Contact
Dr Arne Ohlsson
Staff Neonatologist
Newborn and Developmental Paediatrics
Women's College Hospital
76 Grenville Street
Toronto, ON
CANADA
M5S 1B2
Telephone1: +1 416 323 6268
Telephone2:
Facsimile: +1 416 323 6274
Email: ohlsson@ftn.net
Sources of support for the review
Women's College Hospital Foundation, CANADA
Acknowledgements
Conflict of interest
None.
To assess the effectiveness/safety of intravenous immunoglobulin (IVIG) administration (compared to placebo or no intervention) to preterm (< 37 weeks gestational age at birth) and/or low birth weight (LBW) (< 2500 g BW) infants in preventing nosocomial infections.
Medline, Embase, Cochrane Library and Reference Update Databases were searched in November 1997 using keywords: immunoglobulin and infant-newborn and random allocation or controlled trial or randomized controlled trial (RCT). The reference lists of identified RCTs, personal files and Science Citation Index were searched. No language restrictions were applied.
The criteria used to select studies for inclusion in this overview were:
1) Design: RCTs in which administration of IVIG was compared to a control group that received a placebo or no intervention.
2) Population: preterm (< 37 weeks gestational age) and/or LBW (<2500 g) infants.
3) Intervention: IVIG for the prevention of bacterial/fungal infection during initial hospital stay (8 days or longer). (Studies that were primarily designed to assess the effect of IVIG on humoral immune markers were excluded as were studies in which the follow-up period was one week or less).
4) At least one of the following outcomes was reported: sepsis, any serious infection, death from all causes, death from infection, length of hospital stay, intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD).
Two reviewers independently abstracted information for each outcome reported in each study, and one researcher (AO) checked for any discrepancies and pooled the results.
Relative risk (RR) and Risk Difference (RD) with 95% confidence intervals (CI) using the fixed effects model are reported. When a statistically significant RD was found the number needed to treat (NNT) was also calculated with 95% CIs. The results include all accepted studies in which the outcome of interest was reported. When statistically significant heterogeneity was found for an outcome, secondary (sensitivity) analyses were performed including only studies of the highest quality.
Fifteen studies met inclusion criteria. These included 5,054 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review.
When all studies were combined there was a statistically significant reduction in sepsis, one or more episodes [RR 0.83 (95% CI 0.72, 0.97); RD -0.028 (95% CI -0.006, -0.051); NNT 36 (95% CI 20, 167)]. There was significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies were combined, the results remained significant [RR 0.78 (95% CI 0.62, 0.98); RD -0.031(95% CI -0.003, -0.059); NNT 32 (95% CI 17, 333]. For this analysis there was no statistically significant between-study heterogeneity.
A statistically significant reduction was also found for any serious infection, one or more episodes, when all studies were combined [RR 0.85 (95% CI 0.75, 0.95); RD -0.032 (95% CI -0.010, -0.054,); NNT 31 (95% CI 19, 100). There was statistically significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies were combined the results remained statistically significant [RR 0.80 (95% CI 0.68, 0.94; RD -0.041 (95% CI -0.012, -0.069); NNT 24 (95% CI 15, 83)]. There was borderline statistically significant between-study heterogeneity. There were no statistically significant differences for mortality from all causes, mortality from infection, NEC, BPD, IVH or length of hospital stay. No major adverse effects of IVIG were reported in any of the studies.
IVIG administration results in a 3-4% reduction in sepsis and/or any serious infection but is not associated with reductions in other morbidities: NEC, IVH, length of hospital stay or 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 appears to be no justification for further RCTs testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or LBW infants. The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections.
Although survival has improved for preterm and/or low birth weight (LBW) infants, nosocomial infection continues to be a significant cause of morbidity and mortality in this population. A 25% incidence of late onset infection has recently been reported in a cohort of 6,911 very LBW infants who were admitted to 12 US centers and who survived beyond 3 days (Stoll 1996). Neonates in whom late-onset sepsis developed were significantly more likely to die than those who were not infected (17% vs 7%; p <0.0001) (Stoll 1996).
Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until about 24 weeks after birth, so the preterm infant is especially vulnerable to infectious sources in the Neonatal Intensive Care Unit (Baker 1990a). The mean serum levels of IgG are 400 mg/dl in infants less than 32 weeks gestational age (GA) compared to 1000 mg/dl in term infants (Hobbs 1967; Stiehm 1966). The idea of preventing nosocomial infection with intravenous immunoglobulin (IVIG) is attractive as administration of IVIG provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemoluminescence (Baley 1988).
The administration of IVIG to LBW infants has been studied extensively. Numerous descriptive review articles, commentaries and editorials on the use of IVIG in neonates have been published, often by the same researchers. These papers have included several randomized controlled trials (RCTs), the authors' personal experience with IVIG and/or information about the preparation or dosing regimen of IVIG (Weisman 1986; Bortolussi 1986a; Bortolussi 1986b; Fischer 1986; Stiehm 1986; Baley 1988; Fischer 1988; Gonzalez 1989; Kyllonen 1989; Stabile 1989; Noya 1989; Johnston 1990; Fischer 1990a; Fischer 1990b; Fischer 1990c; Baker 1990a; Baker 1990b; Bussel 1990b; Hammarstrom 1990; Kliegman 1990; Stiehm 1990; Whitelaw 1990; Berger 1991; Hill 1991a; Hill 1991b; Irani 1991; Kliegman 1991; Magny 1991a; Rondini 1991; Haque 1992; Sieber 1992; Weisman 1992; Hill 1993; Weisman 1993; Weisman 1994b; Wolach 1997). Salzer (1991) presented (in abstract form only) the results of a meta-analysis of 7 studies, and concluded that there was no significant reduction in the incidence of sepsis in the treated group. In "Effective Care of the Newborn Infant", Baley & Fanaroff (1992) presented overviews of RCTs which studied the administration of IVIG to neonates. They reviewed seven studies of the prophylactic use of IVIG which reported an outcome of sepsis. They concluded that "The preliminary data generated in trials of IVIG are promising, but use of this treatment modality still needs to be considered experimental and should only, as yet, be used under study conditions." Lacy & Ohlsson (1995) included additional trials and concluded that routine administration of IVIG to preterm infants to prevent infection is not recommended. Jenson & Pollock (1997) used slightly different inclusion criteria and, like Lacy & Ohlsson (1995), noted heterogeneity among studies. They concluded that "this heterogeneity probably belies the minimal benefit, at most, of prophylactic IVIG...". The results of a Canadian multidisciplinary consensus-building initiative (the Consensus Working Group, 1997), have recently been published and the use of IVIG for prophylaxis of neonatal nosocomial infection was considered to be inappropriate. We believe that an additional systematic review is justified as new information has become available and as none of the previous reviews has used methods identical to those recommended by the Cochrane Neonatal Review Group.
To use systematic review/meta-analytic techniques to determine if IVIG administration (compared to placebo or no intervention) to preterm (< 37 weeks gestational age (GA) at birth) and/or LBW (< 2500 g birth weight) infants is effective/safe in preventing nosocomial infections.
Types of studies
Studies in which preterm and/or LBW neonates were randomized
to receive IVIG or either a placebo or no intervention.
Types of participants
Preterm and/or LBW neonates.
Types of intervention
IVIG for the prevention of bacterial or fungal infection.
Studies that were designed to evaluate the effect of IVIG on humoral
immune markers were excluded as were studies in which the follow
up period was one week or less. Studies that assessed the effectiveness
of IVIG for treatment of suspected or confirmed infection were
excluded.
Types of outcome measures
Sepsis (clinical signs and symptoms of sepsis and positive
blood culture for bacteria or fungi). Any serious infection [clinical
signs and symptoms in conjunction with positive cultures (bacteria
or fungi) from normally sterile body fluids (blood, cerebro-spinal
fluid, urine obtained by catheterization or suprapubic tap, or
from tissue at autopsy)]. As per this definition, cases of sepsis
if reported separately were also included in any serious infection.
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. Deaths from infection (including
death from NEC). Length of hospital stay. Incidence of bronchopulmonary
dysplasia (BPD) defined as additional oxygen requirement (above
room air) at 28 days of age or requiring assisted ventilation
for reasons other than apnea of prematurity. Incidence of intraventricular
haemorrhage (IVH) classified according to Papile (Papile 1983).
Reports on possible side effects as described by the authors.
The search strategy used to identify studies was according to the guidelines of the Neonatal Cochrane Review Group.
The search was initiated by review of personal files and published meta-analyses. The reference list of identified studies and subsequently retrieved articles was scanned for additional references. MEDLINE was searched from 1966 to November 1, 1997. EMBASE (Excerpta Medica online) was searched from 1980 to November 1997. The Cochrane Library, SCISEARCH (Science Citation Index) and Reference Update were searched in November 1997. In addition the paediatric literature was hand searched to early 1997 (relevant RCTs identified by Bickle M., Tan B., Ohlsson A., and Sinclair J. in an ongoing project of hand searching the paediatric literature). No language restrictions were applied.
The criteria used to select studies for inclusion in this overview were:
1) Design: RCT in which treatment with IVIG was compared to a
control group that received a placebo or no intervention.
2) Population: preterm (< 37 weeks gestational age) and/or
LBW (<2500 g) infants.
3) Intervention: IVIG for the prevention of bacterial/fungal infection
during initial hospital stay (8 days or more). (Studies that were
primarily designed to assess the effect of IVIG on humoral immune
markers were excluded, as were studies in which the follow-up
period was one week or less. Studies designed to assess the effectiveness
of treatment with IVIG for suspected/established infection were
excluded).
4) At least one of the following outcomes was reported: sepsis,
any serious infection, death from all causes, death from infection,
length of hospital stay, IVH, NEC, or BPD. Reports on side-effects.
The titles (and abstracts when available) in the MEDLINE, EMBASE, COCHRANE LIBRARY, SCISEARCH, REFERENCE UPDATE and HAND SEARCH printouts were reviewed by the two authors. Any article that either person felt might meet the inclusion criteria noted above or that either felt should have its reference list searched were retrieved. No attempt was made to locate unpublished studies nor were attempts made to request additional information from published studies.
All identified trials (excluding those that used IVIG for treatment) are listed in the Table of Included Studies or in the Table of Excluded Studies.
Assessment of Quality of Studies
An assessment of the quality of the included studies (excluding
abstracts) was performed independently by JBL and AO using the
criteria developed by the Cochrane Neonatal Review Group. These
criteria include: I) Blinding of randomization, II) Blinding of
intervention, III) Complete follow-up, IV) Blinding of outcome
measurement. For each criterion there were three possibilities:
yes, can't tell or no. The assignment was not done with the assessors
blinded to author, institution, journal of publication or results,
as both assessors were familiar with most of the studies and the
typographical layout of the journals, and would have knowledge
of these even when blinded. In addition the results sections of
articles often include methodological information. After the independent
evaluation, the two assessors discussed the results for each study
and any discrepancies were resolved.
Data Abstraction.
Data abstraction forms were developed and pilot tested to verify
definitions of terms. The two reviewers independently abstracted
information on each study and one (AO) checked for any discrepancies
and pooled the results. Data abstraction included: whether the
study involved prophylaxis or treatment, number of patients enrolled,
number of patients enrolled but later excluded, the time period
and geographical location of the study, baseline characteristics
of patients, inclusion/exclusion criteria, preparation and dosing
regime of IVIG and placebo, length of follow-up.
Information on outcomes and the numbers of affected infants was abstracted. The total number of infants with sepsis [clinical signs and symptoms plus positive blood culture (bacteria or fungi)] and any serious infection [clinical signs and symptoms in conjunction with positive cultures (bacteria or fungi) from normally sterile body fluids] was abstracted as was information on NEC, death from all causes, and deaths from infection. Information on length of hospital stay, incidence of BPD and IVH was collected. Information on probable infection was not collected as the definitions used by the different investigators were too variable.
Statistical Analysis
The statistical package (Revman) provided by the Cochrane Collaboration
was used. Relative risk (RR) and Risk Difference (RD) with 95%
CI's using the fixed effects model are reported. If there was
a statistically significant reduction in the RD the number needed
to treat (NNT) was calculated. If heterogeneity was noted for
an outcome a sensitivity analysis was performed. In these analyses
only the studies that met all the quality criteria (blinding of
randomization, blinding of intervention, complete follow up and
blinding of outcome measurement) were included.
Details of the included studies are provided in the Table of Included Studies.
15 studies including 5,054 preterm and/or LBW infants met inclusion criteria. These studies were performed in 8 countries (U.S., Italy, U.K., Saudi Arabia, France, Thailand, Canada, Belgium). The amount of IVIG per dose varied from 120 mg/kg (Haque 1986) to 1g/kg (Bussel 1990a). The number of doses varied from a single dose (Haque 1986, Christensen 1989, Ratrisawadi 1991, Weisman 1994a) to seven doses (Stabile 1988).
Different IVIG preparations were used; Gammagard (Baker 1992); Sandoglobulin (Bussel 1990a, Chirico 1987, Clapp 1989, Fanaroff 1994, 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); Venogamma (Stabile 1988).
Six studies were excluded as they included infants that were heavier or more mature at birth than the inclusion criteria allowed for (Kinney 1991, Adhikari 1996); lacked information on outcomes (Kacet 1991; Malik 1990); lacked a randomized control group (Acunas 1994) or immunoglobulin was given intra-muscularly (Monintja 1989).
The assessment of individual studies are presented in the Table "Characteristics of Included Studies".
The methodological quality of the studies varied. Five studies were of high quality (Baker 1992, Christensen 1989, Clapp 1989, Fanaroff-I 1994, Weisman 1994a), i.e.complete follow-up, blinding of randomization, intervention and outcome measurement could be ascertained from the published reports. In the remaining 10 studies elements of bias could not be excluded. The lack of a placebo in 8 of the studies (Chirico 1987, Conway 1990, Didato 1988, Fanaroff 1994 - phase II, Haque 1986, Ratrisawadi 1991, Stabile 1988, van Overmeire 1993) precluded blinding of the caregivers. One study (Fanaroff 1994) included two phases, phase I including a placebo but not phase II. In several studies blinding of randomization was not clearly described (Chirico 1987, Magny 1991b, Ratrisawadi 1991, Stabile 1988). One study (Spady 1994) has been published in abstract form only and the quality could therefore not be fully assessed. The study by Bussel (1990a) represents an interim analysis with data lacking from a large proportion of the infants randomized.
Fifteen studies met inclusion criteria. These included 5,054 preterm and/or LBW infants and reported on at least one of the outcomes of interest for this systematic review. For details of results, see Tables of Analyses. It should be noted that for most outcomes the large study by Fanaroff (1994) greatly influenced the summary statistics with an assigned weight ranging from 47.4% for the outcome of any serious infection to 88.3% for the outcome of IVH grade 3 or 4.
a) Sepsis, one or more episodes
Eight studies (including 3,814 infants) reported on the outcome of one or more episodes of sepsis per infant (clinical signs and symptoms of infection and positive blood culture). Only the study by Ratrisawadi (1991) showed a statistically significant reduction in sepsis (RR 0.38; 95% CI 0.19, 0.79). When all studies were combined there was a statistically significant reduction in sepsis [RR 0.83 (95% CI 0.72, 0.97); RD -0.028 (95% CI -0.006, -0.051); NNT 36 (95% CI 20, 167)]. There was significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies (Clapp 1989, Fanaroff-I 1994, Weisman 1994a) (including 2,086 infants) were combined, the results remained significant [RR 0.78 (95% CI 0.62, 0.98); RD -0.031(95% CI -0.003, 0.059); NNT 32 (95% CI 17, 333]. For this analysis there was no statistically significant between-study heterogeneity.
b) Any serious infection, one or more episodes
Twelve studies (including 4,688 infants) reported on one or more episodes of any serious infection (sepsis, meningitis, urinary tract infection). Three studies (Baker 1992, Haque 1986, Ratrisawadi 1991) showed a statistically significant reduction in any serious infection. A statistically significant reduction was also found when all studies were combined [RR 0.85 (95% CI 0.75, 0.95); RD -0.032 (95% CI -0.010, -0.054,); NNT 31 (95% CI 19, 100). There was statistically significant between-study heterogeneity. When, in a sensitivity analysis, the high quality studies (including 2,670 infants) (Baker 1992, Clapp 1989, Fanaroff-I 1994, Weisman 1994a) were combined the results remained statistically significant [RR 0.80 (95% CI 0.68, 0.94; RD -0.041 (95% CI -0.012, -0.069); NNT 24 (95% CI 15, 83)]. There was borderline statistically significant between-study heterogeneity.
c) Necrotizing enterocolitis (NEC), one or more episodes
Six studies (including 4,020 infants) reported on this outcome (Bell's stage 2 or 3). One study (Fanaroff 1994) showed a borderline statistically significant increase in NEC (RR 1.26; 95% CI 1.00, 1.59). When all studies were combined there was no significant increase [RR 1.09 (95% CI 0.89, 1.33); RD 0.008 (95% CI -0.010, 0.025)]. There was statistically significant between-study heterogeneity for RD but not for RR. When the high quality studies (including 2,670 infants) (Baker 1992, Clapp 1989, Fanaroff-I 1994, Weisman 1994a) were analyzed separately the RR was 1.00 (95% CI 0.78, 1.29); the RD was 0.000 (95% CI -0.021, 0.021) and there was no statistically significant heterogeneity.
d) Mortality (all causes)
Eleven studies (including 3,827 infants) reported on mortality from all causes. One study (Chirico 1987) showed a statistically significant reduction in this outcome [RR 0.44 (95% CI 0.44 (0.20, 0.96)]. When all studies were combined there was no statistically significant reduction [RR 0.93 (95% CI 0.77, 1.12); RD -0.007 (95% CI -0.027, 0.012)]. There was no statistically significant between-study heterogeneity.
e) Mortality (infectious)
Eight studies (including 1,533 infants) reported on mortality from infections. Neither any single study nor the overall analysis showed any significant impact of IVIG prophylaxis on this outcome [RR 1.08 (95% CI 0.66, 1.75); RD 0.003 (95% CI -0.017, 0.023)]. There was no statistically significant between-study heterogeneity.
f) Duration of hospitalization
None of six studies (including 3,425 infants) reported a significant reduction in length of hospital stay following IVIG prophylaxis. The overall weighted mean difference was -2.012 days (95% CI -5.315, 1.290). There was no statistically significant between-study heterogeneity.
g) Bronchopulmonary dysplasia (BPD)
In only one study was both the outcome of BPD defined and data provided. Several authors failed to define the outcome of BPD and others defined the outcome but did not provide data. Clapp (1989) in a small study showed a trend towards increase in BPD [RR 1.53 (95% CI 0.78,3.01); RD 0.099 (95% CI -0.055, 0.254)].
h) Intraventricular haemorrhage (IVH) any grade
Three studies (including 3,115 infants) reported on this outcome. Prophylactic IVIG did not have a statistically significant effect on this outcome [RR 1.02 (95% CI 0.87, 1.18); RD 0.003 (95% CI -0.023, 0.029)]. There was no statistically significant between-study heterogeneity.
i) Intraventricular haemorrhage (IVH) grade 3 or 4
Two studies (including 3,000 infants) reported on IVH grade 3 or 4. The RR was 1.01 (95% CI 0.85, 1.21) and the RD was 0.002 (95% CI -0.022, 0.026). There was no statistically significant between-study heterogeneity.
A rise in serum IgG in the treatment group was noted in all studies that measured levels.
No major adverse effects of IVIG were reported in any of the studies.
Results from excluded studies (See Table of Excluded Studies) were similar to those from included studies.
The effectiveness of IVIG to prevent nosocomial infections in neonates has been well studied. To date over 5,000 preterm and/or LBW neonates have been enrolled in trials from many different areas of the world.
The methodological quality of the included trials varied. Five studies were of high quality but elements of bias could not be excluded in the 10 other studies mainly due to the fact that the intervention and the assessment of outcomes were performed unblinded to group assignment or there was lack of complete follow-up of all randomized infants. IVIG resulted in increased levels of IgG in serum. There were no major side effects noted.
Small but statistically significant reductions in the incidence of sepsis and any serious infection were found. There was statistically significant between-study heterogeneity for the outcomes of sepsis and any serious infection. The heterogeneity might in part be explained by: variable rates of sepsis (6% to 44%) and any serious infection (6% to 45%) 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. When, in a sensitivity analysis, only high quality studies were included, the effect size and the statistical significance for the outcomes of sepsis and any serious infection remained and the between-study heterogeneity disappeared. The between-study heterogeneity could thus to a large extent be explained by study quality. However, it should also be noted that all five high quality studies were conducted in the U.S. The baseline risk for sepsis (the most precisely defined outcome) was also similar in the three high quality studies that reported on this outcome (8.4%, 10.2% and 16.4%). The population characteristics, the general care of these infants and possible cointerventions are likely to have been similar.
There were no statistically significant differences for mortality from all causes, mortality from infection, NEC, BPD, or IVH. The results for these outcomes were all centered around a RR of 1.0 with very narrow CIs indicating no trends in either direction. In none of the studies that provided data on IVH was there an assurance that all neonates were subjected to ascertainment of an IVH according to a preset schedule for ultrasonographic examination. There was a trend towards shortened duration of hospital stay with IVIG treatment [WMD -2.0 days (95% CI -5.3, 1.3 days)]. The outcome of hospital stay is highly dependent on the GA at birth of the neonate, availability of institutions providing Level II care to which the neonate can be transferred, and the social situation of the family.
IVIG prophylaxis in LBW infants results in statistically significant reductions in sepsis and any serious infection in the high quality studies : RD for sepsis - 3.1% (95% CI -0.3%, 5.9%); RD for any serious infection - 4.1% (95% CI -1.2%, -6.9%). Based on the homogeneous high quality studies the NNT to prevent one infant from acquiring sepsis is 32 (95% CI 17, 333) and any serious infection 24 (95% CI 15, 83). As indicated by the wide CI's these are imprecise estimates in spite of the large number of infants enrolled (2,086 and 2,670 respectively). It is possible that the IVIG preparations used in these studies did not contain the necessary antibodies to prevent infection, and that the use of preparations with known specific antibodies against common pathogens in a specific neonatal intensive care unit might be more effective (Weisman 1994b).
The benefits of a 4.1% reduction in any serious infection should be weighed against the costs and the values assigned to this outcome. There have been no serious side-effects reported from IVIG to date, but unknown long-term risks of the administration of blood products and the pain associated with establishing an intravenous route for IVIG should be taken into account.
In the high quality studies, the absolute risk difference for one or more episodes of any serious infection varied from an increase of 2.2% (Weisman 1994a, baseline risk 13.6%) to a reduction of 10.6% (Baker 1992, baseline risk 35.0%). Units with high nosocomial infection rates may want to compare and adjust their infection control policies to those settings with low rates using bench marking techniques. If the rates remain high following such measures, the use of IVIG might be justified. The prophylactic use of IVIG should be based on a full economic evaluation and a clinical decision analysis that incorporates baseline risk for serious nosocomial infections, both clinical and economic outcomes following prophylactic IVIG, and values attached to infections prevented. Such analyses have not been performed.
Although there are slight differences in inclusion criteria, number of studies published at the time of the reviews, and statistical analyses, the results of our systematic review are close to those of two previous meta-analyses; [Lacy & Ohlsson (1995) and Jenson & Pollock (1997)].
The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to enhance the immune system of preterm and/or LBW infants, and to prevent nosocomial infections.
IVIG administration results in a 3-4% reduction in sepsis and/or any serious infection but is not associated with reductions in other morbidities (NEC, IVH), length of hospital stay or 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.
A full economic evaluation and a clinical decision analysis that incorporates baseline risk for confirmed nosocomial infection, both clinical and economic outcomes following prophylactic IVIG, and values attached to infections prevented are needed.
There appears to be no justification for further RCTs testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or LBW infants. It is possible that the IVIG preparations used in published studies did not contain the necessary antibodies to prevent infection. The use of preparations with known specific antibodies against the common pathogens in a specific neonatal intensive care unit might be more effective, and RCTs to test the effectiveness of such preparations may be justified. The results of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections.
Study: Baker 1992
Method: Multi-centre, randomized, double-blind, placebo-controlled
trial.
I Blinding of randomization - yes
II Blinding of intervention - yes
III Complete follow-up - yes
IV Blinding of outcome measurement - yes
Participants: 588 infants with a BW of 500 - 1750 g. Age
3 - 7 days.
Six centers in the U.S.
July 16, 1987 - December 12, 1988
Interventions: 287 infants received 500 mg/kg of IVIG (Gammagard,
Baxter Healthcare, Hyland Division, Glendale, Calif.) at enrollment
(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.
Outcomes: Proved infection [clinical findings of sepsis
and at least one of the following: a positive blood culture (bacteria
or fungi), the isolation of a pathogen from a normally sterile
body site (CSF, pleural, peritoneal, or joint fluid; bone; soft-tissue;
or urine obtained by suprapubic or bladder catheterization), or
the isolation of virus from an infant with clinical deterioration].
NEC (stage II or III)
IVH (grade I - IV)
BPD (definition not provided)
Total days in hospital
Eleven neonates were excluded from the study but were included
in the intention-to-treat analysis.
Notes: The following outcomes could be ascertained from
this study: any serious infection (bacterial + fungal), IVH, NEC,
deaths from all causes. Total episodes for sepsis were reported.
There were 50 episodes of sepsis among 287 infants in the IVIG
group and 75 episodes of sepsis among 197 infants in the placebo
group. The outcome "sepsis, one or more episodes", could
not be ascertained from this study.
Adverse reactions were noted during 10 infusions (5 in each study
group, or < 1%). Mild increases or decreases in blood pressure,
heart rate, or temperature that were reversed when the rate of
infusion was slowed. Two infants in each group had fluid overload
after an infusion and were treated with a single dose of furosemide.
Study: Bussel 1990a
Method: Randomized, double-blind, placebo-controlled trial.
I Blinding of randomization - yes
II Blinding of intervention - yes
III Complete follow-up - no
IV Blinding of outcome measurement - yes
Participants: 240 infants with birthweight < 1300 g.
Data for 172 patients are presented in this preliminary analysis;
of these 46 were excluded from the statistical analysis (29 because
they died during the first 5 days of life, 4 because of protocol
violations, and 13 because of inadequate follow-up - usually because
of their return to the referring hospital. 126 infants remained).
Single U.S. center.
September 1984 - October 1987.
Interventions: 61 neonates (mean BW, 977 g) received a
dose of 1 g of a 6% solution of IVIG (Sandoglobulin, Sandoz Pharmaceuticals,
East Hanover, N.J.) on 4 of the first 5 days of life, and a fifth
dose was administered on day 15 or as close to that day as possible
(the dose could be given as late as day 21).
65 neonates (mean BW, 1043 g) received an albumin placebo at equal
oncotic load at the same times.
Outcomes: Sepsis (signs and symptoms compatible with sepsis
and a positive blood or CSF culture)
IVH diagnosed by ultrasonographic examination at 3-7 days of age.
1 neonate excluded because of severe anomalies incompatible with
life.
For additional exclusions see "Participants".
Notes: This is an interim analysis of a larger study, the
results of which have not been reported to date.
Data are available on the outcome of sepsis but not on IVH
No adverse effects were reported
Study: Chirico 1987
Method: Randomized, controlled trial without the use of
a placebo
I Blinding of randomization - yes
II Blinding of intervention - no
III Complete follow-up - yes
IV Blinding of outcome measurement - no
Participants: In this study a subgroup with a birth weight
</= 1500 g (n = 86) of the total population of 133 infants
(BW range 550 - 3340 g; GA range 24 - 40 weeks) fulfilled the
inclusion criteria for this systematic review.
Single center, Italy.
Dates not given.
Interventions: 43 infants received 0.5 g/kg of IVIG (Sandoglobulin)
weekly for 1 month.
43 infants received no placebo or other intervention.
Outcomes: Criteria for diagnosis of sepsis, meningitis,
arthritis, pneumonia, urinary tract infection, and surface infection
included both a positive culture of blood, cerebrospinal fluid,
tracheal aspirate, urine or pus, respectively, and the presence
of clinical and nonmicrobiological laboratory features. For the
diagnosis of pneumonia, the appearance of a new infiltrate on
a chest roentgenogram was also required.
NEC was diagnosed when typical clinical and radiologic symptoms
were present.
3 infants in the control group who died within 24 hours after
birth were excluded from the analysis by the authors.
Notes: The outcomes of sepsis, any serious infection, NEC,
length of hospital stay, death from all causes and deaths from
infections could be ascertained from this study. The 3 infants
in the control group who died within 3 days of life are included
in our analyses as per intention to treat.
No side effects were observed after IVIG administration.
Study: Christensen 1989
Method: Randomized, double-blind, placebo-controlled study
I Blinding of randomization - yes
II Blinding of intervention - yes
III Complete follow-up - yes
IV Blinding of outcome measurement - yes
Participants: 20 preterm neonates, weight < 2000 g at
entry to study and < 7 days of age.
Single center, U.S.
Dates not given.
Interventions: 10 neonates received IVIG (Gamimmune-N,
Cutter Biologicals, Berkeley, Calif.) 5% IgG in 10% maltose at
15 ml/kg BW as a single infusion.
10 neonates received equal volume of 0.1% albumin in 10% maltose.
Outcomes: Nosocomial infection (not defined)
Survival
Notes: This study provides information on deaths from infections
and deaths from all causes.
There were no differences in heart rate, respiratory rate, rectal
temperature, and urine output before, during and after the infusions
of IVIG or placebo (no differences between the groups)
Study: Clapp 1989
Method: Randomized, double-blind, placebo-controlled trial
I Blinding of randomization - yes
II Blinding of intervention - yes
III Complete follow-up - yes
IV Blinding of outcome measurement - yes
Participants: 115 infants with birth weight of 600 to 2000
g and < 48 hours of age.
Single center, U.S.
November 1, 1986 - August 31, 1987.
Interventions: 56 neonates (GA = 30 weeks; BW 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 weeks; BW 1.3 +/- 0.4 kg) received placebo
(equal volume of 6% or 10% sucrose solution). When an infant receiving
IVIG required an extra dose, the paired patient in the placebo
group also received an additional infusion.
Outcomes: Sepsis (systemic clinical deterioration with
a positive blood culture, cerebrospinal fluid, or aspirate of
another normally sterile body cavity).
NEC (abdominal distension with gastric retention, abdominal erythema,
or bloody stools, with radiographic evidence of pneumatosis intestinalis,
portal venous gas, or pneumoperitoneum and staged by the modified
Bell's criteria)
Length of hospital stay.
Deaths from all causes.
Deaths from infection.
BPD (requiring O2 at 28 days for BPD)
IVH (Papile classification)
Notes: From the data presented the outcomes of sepsis,
any serious infection, NEC, BPD, IVH, length of hospital stay,
deaths from all causes and deaths from infection could be ascertained.
Three episodes of sepsis/proved infection occurred in (an) infant(s)
born at 24 weeks GA and BW of 600 g. We assumed that this was
only one infant and assigned only one outcome in the meta-analyses.
Transient tachycardia and a decrease in blood pressure was noted
in one infant who received IVIG. Transient rise in the alanine
aminotransferase level was noted in one infant who received IVIG
and one who received placebo.
Study: Conway 1980
Method: Randomized controlled trial without the use of
a placebo
I Blinding of randomization - yes
II Blinding of intervention - no
III Complete follow-up - no
IV Blinding of outcome measurement - no
Participants: 66 neonates of < 30 weeks GA.
2 centers in the U.K.
Dates not given.
Interventions: 34 infants received 200 mg/kg IVIG (Intraglobin
F, Biotest Pharma, FRG) within 48 hours of birth and at 3-weekly
intervals until discharge from the neonatal unit. On clinical
suspicion of infection, neonates in the treatment group only were
given a supplementary dose of IVIG 100 mg/kg. A further 100 mg/kg
was given within the next 48 hours if infection was confirmed.
32 infants received routine intensive care.
Outcomes: Sepsis (blood-culture-proven infection).
NEC (clinical findings and pneumatosis intestinalis on abdominal
X-ray, or confirmed at autopsy).
IVH (no definition given)
BPD (no definition given)
Length of stay in NICU (median and range)
Eleven infants, 6 in the control group and 5 in the treatment
group, were withdrawn from the trial due to early death from extreme
prematurity (n=7), early return to the referring hospital (n=3),
and elective treatment with IVIG for severe congenital septicemia
(n=1).
Notes: The outcomes of sepsis and NEC could by ascertained.
We used as denominators all randomized patients. We included the
infants that were withdrawn because of early death in the outcome
of mortality (all causes). One infant with two episodes of NEC
was counted as one outcome.
Side effects were not reported
Study: Didato 1988
Method: Randomized controlled trial without the use of
a placebo
I Blinding of randomization - yes
II Blinding of intervention - no
III Complete follow-up - yes
IV Blinding of outcome measurement - no
Participants: 80 infants with a BW of 2000 g or less.
Single center, Italy.
June 1985 - December 1986.
Interventions: 40 infants received 0.5 g/kg/week 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
Outcomes: Sepsis defined as clinical manifestations, microbiologic
findings (positive blood culture or CSF culture) and non microbiologic
laboratory findings (total and differential white blood cell count,
erythrocyte sedimentation rate, C-reactive protein, platelet count,
tests of hemostatic function).
Notes: Any serious infection, deaths from all causes and
deaths from infection could be ascertained in this study. As sepsis
included neonates with positive CSF cultures the results were
included in the any serious infection category only. Data could
not be separated between sepsis and meningitis.
No side effects or adverse reactions were observed following IVIG
administration.
Study: Fanaroff 1994
Method: Multicentre, two-phase controlled trial. Phase
I was placebo controlled and double-blinded; phase II was not
placebo controlled.
I Blinding of randomization - yes
II Blinding of intervention - yes/no*
III Complete follow-up - yes
IV Blinding of outcome measurement - yes/no*
* This study had two phases; in phase 1 a placebo was used but
not in phase 2.
Participants: 2,416 infants with birthweight 501-1500 g
and randomized at a mean age of 44 +/- 25 hours after birth.
8 centers in the U.S.
January 1, 1988 - March 31, 1991 (or through April, 1991).
Interventions: In phase I
595 infants received IVIG (Sandoglobulin, Sandoz Pharmaceuticals,
East Hanover, N.J.)
623 infants received placebo - equal volume of 5 % albumin solution
in the same vehicle prepared by the manufacturer of the immune
globulin. The infants received their first dose of study drug
within 24 hours of randomization. To achieve a target level of
700 mg of immune globulin/dl, infants weighing 501 to 1000 g were
given 900 mg of immune globulin per kg of body weight and infants
weighing 1001 to 1500 g were given 700 mg per kg. The infusions
were repeated every two weeks until the infants weighed 1800 g,
were transferred to another hospital, died or were sent home.
In phase II
609 infants received IVIG as per above (Phase I)
589 received no intervention
Outcomes: Sepsis (symptoms compatible with infection and
a positive blood culture for bacteria or fungi obtained at least
96 hours after birth and before 120 days of life; for commensals
the diagnosis required two positive blood cultures obtained no
more than 4 days apart).
The diagnosis of meningitis required a positive culture of CSF.
The diagnosis of urinary tract infection required a pure culture
from urine obtained by catheterization or suprapubic puncture.
Proved infection (including septicemia, meningitis, or urinary
tract infection) during the first 120 days of life.
NEC (Bell's modified classification)
BPD (Not defined)
Days in hospital
Notes: The following outcomes could be ascertained from
this study; sepsis, any serious infection, NEC, death from all
causes, death from infection, days in hospital.
The infusions were discontinued in < 1% of infants (10 in the
IVIG group and 11 in the placebo group) because of tachycardia
or acute changes in blood pressure.
Study: Fanaoff-I 1994
Method: Phase I of Fanaroff 1994, placebo-controlled
Study: Haque 1986
Method: Randomized controlled trial, without the use of
a placebo
I Blinding of randomization - yes
II Blinding of intervention - no
III Complete follow-up - yes
IV Blinding of outcome measurement - no
Participants: 150 neonates of 28 to 37 weeks gestational
age and less than 4 hours of age.
Single center, Saudi Arabia.
Dates not given.
Interventions: 50 neonates received IVIG (Intraglobulin,
Biotest Pharma, West Germany) 120 mg/kg within 2-4 hours of birth
50 neonates received IVIG (Intraglobulin) 120mg/kg on day 1 and
8 of life
50 neonates received no intervention
Outcomes: Sepsis was defined as presence of clinical features
and a positive culture of blood or cerebrospinal fluid.
Notes: Sepsis, any serious infection, death from all causes
and death from infection could be ascertained in this study. One
infant developed pneumonia in the control group.
The mean age at onset of infection was 46.3 hrs (range 8 to 76
hrs), suggesting that some infants had infection acquired in utero
and were infected at the time of enrollment.
No adverse effect of the therapy was noted during the study and
at 6-month follow-up.
Study: Magny 1991b
Method: Multicentre, randomized controlled, double-blind
study.
I Blinding of randomization - can't tell
II Blinding of intervention - yes
III Complete follow-up - yes
IV Blinding of outcome measurement - yes
Participants: 235 neonates of less than or equal to 32
weeks gestation, hospitalized before 25 hours of life and having
endotracheal tube and/or umbilical catheter on admission.
4 centers in Paris, France.
1987 - 1989.
Interventions: 120 neonates received 500 mg (10ml) 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.
Outcomes: Deaths from infection
Certain nosocomial infection [clinical signs of infection, positive
cultures (blood, urine, cerebrospinal fluid, tracheal aspirate,
stools, gastric aspirate), at least two biological signs of infection
(abnormal number of leukocytes, immature leukocytes > 5%, thrombocytopenia
< 150 000/mm3, rise in fibrinogen levels > 4.5g/L, rise
in C-reactive protein levels > 20 mg/L.]
NEC was diagnosed when bloody stools were associated with radiologic
pneumatosis.
Neonatal infection and infection occurring within the first 4
days of life, potentially of maternal origin were not counted
as evaluation criteria.
In 46 infants (21 in the IVIG; 25 in the placebo group) irregularities
occurred in the protocol (one dose forgotten or no follow-up until
45 days of life because of transfer out of the unit).
Notes: Deaths from infection could be ascertained in this
study. The definition of nosocomial infection did not meet our
criteria for sepsis or any serious infection. The number of infants
with one or more episodes of NEC could not be ascertained. The
46 infants in which the protocol was broken were maintained in
the statistical analyses.
"There were neither clinical nor biologic side effects in
any of the patients after Ig infusion".
Study: Ratrisawadi 1991
Method: Randomized controlled trial, without the use of
a placebo group
I Blinding of randomization - can't tell
II Blinding of intervention - no
III Complete follow-up - can't tell
IV Blinding of outcome measurement - no
Participants: 68 infants with a birth weight of 1000 -
1500 g.
Single center, Bangkok, Thailand.
February 1988 - March 1990.
Interventions: 34 neonates received 250 mg/kg of IVIG (Biotest
Pharma, West Germany) within 4 hours of birth
34 neonates received 500 mg/kg of IVIG within 4 hours of birth
34 neonates received no intervention
Outcomes: Sepsis (presence of clinical findings of sepsis
plus positive blood cultures).
Infants (number not stated) who expired within 24 hours of life
or required blood exchange transfusion were excluded from the
study. In spite of these exclusions the number of patients in
each group is identical (n= 34).
Notes: The outcomes of sepsis and deaths from all causes
could be ascertained in this study.
"No adverse effects were observed during the period of study".
Study: Spady 1994
Method: Randomized double-blind trial
Published in abstract form only - full quality assessment not
possible
Participants: 111 very LBW infants
Interventions: 54 infants were given 300 mg/kg of IVIG
(name of product not given) as 5% solution, once between 24-72
hours of age and again 72 hours later.
57 infants were given the same volumes as 5% dextrose
Outcomes: The outcome of sepsis was not defined in this
abstract, but according to the authors sepsis occurred in 17 infants
in the IVIG group and in 15 in the control group.
Hospital stay.
Notes: The length of hospital stay could be ascertained
from this study published in abstract form only.
Respiratory rate increased in the IVIG group following the first
infusion. No other side effects occurred.
Study: Stabile 1988
Method: Single centre, randomized controlled trial without
the use of a placebo group.
I Blinding of randomization - can't tell
II Blinding of intervention - no
III Complete follow-up - no
IV Blinding of outcome measurement - no
Participants: 94 neonates, GA </= 34 weeks gestation,
or BW </= 1500 g.
Single center, Rome, Italy.
May 1984 - June 1986.
Interventions: 0.5 g/kg IVIG (Venogamma Polivalente, Ismunit,
Pomezia, Italy) on the 1st, 2nd, 3rd, 7th, 14th, 21st, and 28th
day of life (treatment group) or no intervention (control group)
Outcomes: Sepsis was defined as clinical signs of systemic
infection and positive blood or CSF culture for a pathogen.
14 neonates were excluded from the analysis. 6 neonates in the
treatment group were excluded; 3 underwent exchange transfusion,
2 died from severe respiratory distress syndrome and one had suspected
prenatal infection. 8 control neonates were excluded; 2 underwent
exchange transfusion, 3 died of severe respiratory distress syndrome,
one died of respiratory distress syndrome and IVH, and two had
suspected prenatal infection.
Notes: Sepsis, any serious infection, deaths from all causes
and deaths from infection could be ascertained from this study.
Infants that died and were excluded by the authors are included
in our analysis.
"..no newborn infant showed any local or general reaction
either during or after infusions. Three infants showed a temporary
increase in IgE from 10-18 to 28-38 IU/ml without concurrent side
effects".
Study: Van Overmeire 1993
Method: Randomized controlled trial without the use of
a placebo group.
I Blinding of randomization - yes
II Blinding of intervention - no
III Complete follow-up - yes
IV Blinding of outcome measurement - no
Participants: 116 neonates of < 32 weeks GA and <1500
g BW.
Single center, Antwerp, Belgium.
Dates not given.
Interventions: 56 neonates received 500 mg IVIG (Sandoglobulin)
in 10 ml of saline over a period of 30 min within the first 12
h of life. This infusion was repeated every 24 h until the 7th
day of life, then administered weekly for another 3 weeks.
60 neonates received no placebo or other intervention
Outcomes: The diagnosis of any serious infection was made
when the clinical diagnosis, in association with suggestive laboratory
data, was confirmed by a positive blood or CSF culture.
Notes: Any serious infection, hospital stay and death from
all causes could be ascertained in this study.
Shortlasting hypotension was observed shortly after IVIG administration
in one patient.
Study: Weisman 1994a
Method: Multicentre, randomized, double-blind, placebo-controlled
trial
I Blinding of randomization - yes
II Blinding of intervention - yes
III Complete follow-up - yes
IV Blinding of outcome measurement - yes
Participants: 753 neonates with a BW of 500 to 2000 gm,
GA </= 34 weeks, postnatal age </= 12 hours
9 centers in the U.S.
June 1985 - April 1989.
Interventions: 372 neonates received a single intravenous
infusion of 10 ml/kg of IVIG (500 mg/kg) (Sandoglobulin)
381 neonates received a single infusion of albumin 5mg/kg
Outcomes: All outcomes were recorded during the first 8
weeks (56 days) of life
Sepsis was defined as clinical symptoms and signs consistent with
sepsis in association with isolation of a causative organism from
a blood culture specimen. For the diagnosis of sepsis caused by
S. epidermidis two positive cultures were required.
Infection was defined as clinical signs and symptoms and isolation
of a causative organism from either blood culture, CSF culture,
urine culture by bladder tap or catheterization, or culture of
a specimen from a normally sterile site during hospitalization
or at autopsy.
BPD was defined as need for continued oxygen or ventilatory support
at 28 days of age for reasons other than apnea and either a chest
radiograph or histopathologic criteria compatible with the diagnosis.
IVH was graded on a scale of 1-4 according to Papile. Bell's classification
of stage II or greater was used to define NEC. After enrollment
it was determined that 9 patients (5 received albumin and 4 IVIG)
did not meet the entry criteria, and for 10 patients (5 received
albumin and 5 received IVIG) the protocol was violated during
the study, but all were included in the intention-to-treat analysis.
Notes: Sepsis, any serious infection, NEC, and death from
infection could be ascertained from this study. Although the outcomes
of IVH and BPD were well defined, figures for these outcomes were
not reported by group.
The IVIG-treated infants had slower heart rate during the infusion
than before the infusion and higher systolic blood pressure for
2 hours after the infusion than before the infusion. Both groups
tolerated the infusions similarly.
Study identifier: Acunas 1994
Reason for exclusion: This is an RCT comparing the effect
of fresh frozen plasma or gammaglobulin on humoral immunity in
neonatal sepsis. This study did not meet the inclusion criteria
as a randomized untreated control group was not included. A non-randomized
concurrent group of infants without suspicion of infection and
matched for age, birth weight, and gestational age served as a
control group.
Study identifier: Adhikari 1996
Reason for exclusion: This is a double-blind placebo-controlled
RCT assessing the efficacy of prophylactic use of IVIG in 21 pairs
of ventilated neonates weighing more than 1500 g. The mean weight
in the IVIG group was 2702 g and in the placebo group 2679 g;
thus most neonates did not fulfill the entry criterion of a weight
< 2500g. In this study IVIG did not significantly reduce the
rate of infection, the duration of ventilation or the time to
clinical recovery.
Study identifier: Kacet 1991
Reason for exclusion: The authors do not provide enough
information regarding definitions of outcomes for inclusion in
this systematic review.
Study identifier: Kinney 1991
Reason for exclusion: This is a double-blind RCT designed
to determine whether IVIG administration modifies the incidence
of infections in high-risk neonates. 170 infants were enrolled.
The study population included neonates of > 1500 g birth weight
with no upper limit stated by the authors. This study did thus
not meet our inclusion criteria. The authors "found no evidence
that the administration of IVIG affected parameters that might
be related to the occurrence of systematic or localized infectious
processes".
Study identifier: Malik 1990
Reason for exclusion: This study has been published in
abstract form only, and the authors do not provide enough information
regarding definitions of outcomes for inclusion in this systematic
review.
Study identifier: Monintja 1989
Reason for exclusion: Immunoglobulin was given intra-muscularly.
It is unclear whether this is an RCT. Sepsis was not clearly defined.
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01.00.00 IVIG vs placebo or no treatment
01.01.00 Sepsis, one or more episodes
01.02.00 Any serious infection, one or more episodes
01.03.00 NEC, one or more episodes
01.04.00 Mortality (total)
01.05.00 Mortality (infectious)
01.06.00 Duration of hospitalization
01.07.00 Bronchopulmonary dysplasia
01.08.00 Intraventricular haemorrhage any grade
01.09.00 Intraventricular haemorrhage grade 3 or 4
02.00.00 IVIG vs placebo or no treatment, high quality studies
02.01.00 Sepsis, one or more episodes
02.02.00 Any serious infection, one or more episodes
02.03.00 NEC, one or more episodes