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

Intravenous immunoglobulin for suspected or subsequently proven infection in neonates  Lacy J, Ohlsson A. Lacy J, Ohlsson A. Arch Dis Child 1995;72:F151-5Arch Dis Child 1995;72:F151-5

Ohlsson A, Lacy J. Cochrane Library, January 1998Ohlsson A, Lacy J. Cochrane Library, January 1998

Ohlsson A, Lacy J. Cochrane Library, February 2001 Ohlsson A, Lacy J. Cochrane Library, February 2001

Unpublished update September, 2003Unpublished update September, 2003

Background Nosocomial infections continue to be a significant Nosocomial infections continue to be a significant

cause of morbidity and mortality among preterm cause of morbidity and mortality among preterm and/or low birth weight infantsand/or low birth weight infants

Maternal transport of immunoglobulins to the Maternal transport of immunoglobulins to the

fetus occurs mainly after 32 weeks gestationfetus occurs mainly after 32 weeks gestation Endogenous synthesis does not begin until several Endogenous synthesis does not begin until several

months after birth months after birth

Background

Administration of intravenous  Administration of intravenous  immunoglobulin provides IgG that can:immunoglobulin provides IgG that can: bind to cell surface receptors bind to cell surface receptors provide opsonic activityprovide opsonic activity activate complementactivate complement promote antibody dependent cytotoxicity promote antibody dependent cytotoxicity improve neutrophilic chemoluminescence improve neutrophilic chemoluminescence

IgG

IgM

IVIG has the potential of:

Preventing serious nosocomial infectionsPreventing serious nosocomial infections

Altering the course of congenital or Altering the course of congenital or nosocomial infectionsnosocomial infections

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

weight infants

Objectives

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

Search strategy MEDLINE, EMBASE, and Cochrane Library were MEDLINE, EMBASE, and Cochrane Library were

searched in November 1997 using keywords: searched in November 1997 using keywords: [immunoglobulin] AND [infant-newborn] AND [random [immunoglobulin] AND [infant-newborn] AND [random

allocation OR controlled trial OR randomized controlled allocation OR controlled trial OR randomized controlled trial (RCT)]. The reference lists of identified RCTs, trial (RCT)]. The reference lists of identified RCTs, personal files and Science Citation Index were searched. personal files and Science Citation Index were searched.

No language restrictions were appliedNo language restrictions were applied Search repeated in February 2001 [+ 4 RCTs; Search repeated in February 2001 [+ 4 RCTs;

additional data on 298 neonates)additional data on 298 neonates) Search repeated in September 2003 (no new data)Search repeated in September 2003 (no new data)

Criteria used to select studies for inclusion in this (prevention) review were:

Design: RCTs in which administration of IVIG Design: RCTs in which administration of IVIG was compared to a control group that received a was compared to a control group that received a placebo or no intervention placebo or no intervention

Population: preterm (< 37 weeks gestational age) Population: preterm (< 37 weeks gestational age) and/or LBW (<2500 g) infants and/or LBW (<2500 g) infants

Criteria used to select studies for inclusion in this review were:

Intervention: IVIG for the Intervention: IVIG for the preventionprevention of of bacterial/fungal infection during initial hospital bacterial/fungal infection during initial hospital stay (> 7 days) stay (> 7 days)

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

Criteria used to select studies for inclusion in this review were: At least one of the following outcomes was reported: At least one of the following outcomes was reported:

sepsissepsis any serious infectionany serious infection death from all causesdeath from all causes death from infectiondeath from infection length of hospital staylength of hospital stay intraventricular haemorrhage intraventricular haemorrhage necrotizing enterocolitis necrotizing enterocolitis bronchopulmonary dysplasia bronchopulmonary dysplasia

Data collection & analysis Two reviewers (AO, JL) independently abstracted Two reviewers (AO, JL) independently abstracted

information for each outcome reported in each study on information for each outcome reported in each study on pre-designed data abstraction formspre-designed data abstraction forms

One reviewer (AO) checked for any discrepancies and One reviewer (AO) checked for any discrepancies and entered the data following consensus into RevManentered the data following consensus into RevMan

Accuracy of data entry was checked by the two reviewers Accuracy of data entry was checked by the two reviewers (AO, JL) comparing RevMan printouts to data abstraction (AO, JL) comparing RevMan printouts to data abstraction forms and discrepancies were resolved by consensusforms and discrepancies were resolved by consensus

One reviewer (AO) pooled the data in RevManOne reviewer (AO) pooled the data in RevMan

Statistical analyses

Relative Risk (RR) and Risk Difference Relative Risk (RR) and Risk Difference (RD) with 95% confidence intervals (CIs) (RD) with 95% confidence intervals (CIs) using the fixed effects model are reportedusing the fixed effects model are reported

When a statistically significant RD was When a statistically significant RD was found the Number Needed to Treat (NNT) found the Number Needed to Treat (NNT) was also calculated with 95% CIs was also calculated with 95% CIs

Statistical analyses

The results include all accepted studies in The results include all accepted studies in which the outcome of interest was reportedwhich the outcome of interest was reported

Statistically significant heterogeneity was Statistically significant heterogeneity was reportedreported

Attempts were made to explain statistically Attempts were made to explain statistically significant heterogeneity significant heterogeneity

Main results (as of September 2003)   Twenty studies met inclusion criteriaTwenty studies met inclusion criteria

Included approximately 5,000 preterm Included approximately 5,000 preterm and/or LBW infantsand/or LBW infants

Reported on at least one of the outcomes Reported on at least one of the outcomes of interest for this systematic review of interest for this systematic review

Main results When 10 studies (n = 3,975) were combined When 10 studies (n = 3,975) were combined

there was a statistically significant reduction there was a statistically significant reduction in in sepsis sepsis (one or more episodes)(one or more episodes) RR 0.85 (95% CI 0.74, 0.98)RR 0.85 (95% CI 0.74, 0.98) RD –0.03 (95% CI 0.00, - 0.05)RD –0.03 (95% CI 0.00, - 0.05) NNT 33NNT 33 Test for heterogeneity (p = 0.02)Test for heterogeneity (p = 0.02)

Main results When 16 studies (n = 4,986) were When 16 studies (n = 4,986) were

combined there was a statistically combined there was a statistically significant reduction in significant reduction in any serious any serious infection infection (one or more episodes)(one or more episodes) RR 0.82 (95% CI 0.74, 0.92)RR 0.82 (95% CI 0.74, 0.92) RD –0.04 (95% CI –0.02,-0.06)RD –0.04 (95% CI –0.02,-0.06) NNT 25 (95% CI 17, 50)NNT 25 (95% CI 17, 50) Test for heterogeneity (p = 0.0006)Test for heterogeneity (p = 0.0006)

Main results There were no statistically significant differences for:There were no statistically significant differences for:

mortality from all causesmortality from all causes mortality from infectionmortality from infection NEC, BPD, IVHNEC, BPD, IVH length of hospital staylength of hospital stay no major adverse effects of IVIG were reported in no major adverse effects of IVIG were reported in

any of the studiesany of the studies a rise in serum IgG was noted in all studies that a rise in serum IgG was noted in all studies that

reported on this outcomereported on this outcome

Attempts to explain across study heterogeneity in a systematic review of prophylactic administration of intravenous immunoglobulin (IVIG) in neonates

Beyene J, Shah V, Ohlsson A

Comparison: IVIG vs placebo/no treatment Outcome: Any serious infection (RR)

Funnel Plot: IVIG vs placebo or no treatment. Outcome: Any serious infection (RR)

Comparison: IVIG vs placebo/no treatment Outcome: Any serious infection (RD)

IVIG vs placebo/no treatment Outcome: Any serious infection (RD)

Cumulative meta-analysis: IVIG vs Placebo or No Treatment

RR 0.82 (95% CI; 0.74,0.92) RD 0.04% (95% CI 0.02, 0.06)

Conclusions Statistically significant in-between study Statistically significant in-between study

heterogeneity was present due to differences in heterogeneity was present due to differences in control group event ratescontrol group event rates

IVIG administration results in a 3-4% reduction in IVIG administration results in a 3-4% reduction in sepsis and/or any serious infectionsepsis and/or any serious infection

Is not associated with reductions in other Is not associated with reductions in other morbidities: NEC, IVH, length of hospital stay or morbidities: NEC, IVH, length of hospital stay or mortalitymortality

Prophylactic use of IVIG is not associated with any Prophylactic use of IVIG is not associated with any short term serious side effects short term serious side effects

Conclusions The decision to use prophylactic IVIG will depend The decision to use prophylactic IVIG will depend

on the costs and the values assigned to the clinical on the costs and the values assigned to the clinical outcomes outcomes

There is no justification for further RCTs testing There is no justification for further RCTs testing the efficacy of previously studied IVIG the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preparations to reduce nosocomial infections in preterm and/or LBW infants preterm and/or LBW infants

The results of these meta-analyses should The results of these meta-analyses should encourage basic scientists and clinicians to pursue encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infectionsother avenues to prevent nosocomial infections

Intravenous immunoglobulin for suspected or subsequently

proven infection in neonates  

Lacy J, Ohlsson A. Lacy J, Ohlsson A. Arch Dis Child 1995;72:F151-5Arch Dis Child 1995;72:F151-5

Ohlsson A, Lacy J. Cochrane Library, January 1998Ohlsson A, Lacy J. Cochrane Library, January 1998

Ohlsson A, Lacy J. Cochrane Library, February 2001 Ohlsson A, Lacy J. Cochrane Library, February 2001

Unpublished update September, 2003Unpublished update September, 2003

Objectives

To assess the effectiveness of intravenous To assess the effectiveness of intravenous immunoglobulin (IVIG) to reduce immunoglobulin (IVIG) to reduce mortality/morbidity caused by suspected infection mortality/morbidity caused by suspected infection in newborn infantsin newborn infants

In secondary analyses to assess the effectiveness of In secondary analyses to assess the effectiveness of IVIG to reduce mortality/morbidity in those IVIG to reduce mortality/morbidity in those neonates, who entered into the studies with neonates, who entered into the studies with suspected infection and who later were confirmed suspected infection and who later were confirmed as being infected.as being infected.

Selection criteria

   Design: RCT (including quasi-randomized Design: RCT (including quasi-randomized

trials) trials) Newborn infants (< 28 days old)Newborn infants (< 28 days old)

Selection criteria

Intervention: IVIG for treatment of Intervention: IVIG for treatment of suspected (and in some infants subsequently suspected (and in some infants subsequently proved) bacterial/fungal infection compared proved) bacterial/fungal infection compared to placebo or no interventionto placebo or no intervention

Suspected infection was defined as clinical Suspected infection was defined as clinical symptoms and signs consistent with symptoms and signs consistent with infection without isolation of causative infection without isolation of causative organismorganism

Selection criteria

Proved infection was defined as: clinical Proved infection was defined as: clinical symptoms and signs consistent with symptoms and signs consistent with infection in association with isolation of infection in association with isolation of causative organism from either blood causative organism from either blood culture, cerebrospinal fluid culture, urine culture, cerebrospinal fluid culture, urine culture (urine obtained by suprapubic tap) culture (urine obtained by suprapubic tap) or a normally sterile site (e.g., liver, spleen, or a normally sterile site (e.g., liver, spleen, meninges, lung) at autopsy. meninges, lung) at autopsy.

Selection criteria

At least one of the following outcomes was At least one of the following outcomes was reported: reported: mortality during initial hospital staymortality during initial hospital stay length of hospital staylength of hospital stay side effectsside effects psychomotor development/growth at psychomotor development/growth at

follow up.follow up.

Search strategy, data collection and statistical analyses In general as per systematic review of IVIG for prevention of In general as per systematic review of IVIG for prevention of

nosocomial infectionnosocomial infection Update February 2001Update February 2001

Two additional studies were included (total n = 110)Two additional studies were included (total n = 110) Additional information was obtained from 5 previously Additional information was obtained from 5 previously

published studiespublished studies One ongoing international, multi-centre trial based on our One ongoing international, multi-centre trial based on our

previous reviews was identifiedprevious reviews was identified Update September 2003 (no new data)Update September 2003 (no new data)

Main results Six of 9 identified studies (n = 318) reported on Six of 9 identified studies (n = 318) reported on

the outcomes of all randomized patients with the outcomes of all randomized patients with clinically suspected infectionclinically suspected infection Mortality was not reduced (borderline statistical Mortality was not reduced (borderline statistical

significance)significance)RR 0.63 (95% CI; 0.40, 1.00)RR 0.63 (95% CI; 0.40, 1.00)RD – 0.09 (95% CI; 0.00, - 0.17)RD – 0.09 (95% CI; 0.00, - 0.17)No statistically significant between study No statistically significant between study

heterogeneity heterogeneity

Main resultsTreatment with IVIG (seven trials,Treatment with IVIG (seven trials, n = 262) in cases of n = 262) in cases of subsequently proved subsequently proved

infectioninfection did result in a statistically did result in a statistically significant reduction in mortality significant reduction in mortality

• RR 0.55 (95% CI; 0.31, 0.98)RR 0.55 (95% CI; 0.31, 0.98)• RD -0.09 (95% CI; - 0.01, - 0.18)RD -0.09 (95% CI; - 0.01, - 0.18)• NNT 11 (95% CI; 6, 100)NNT 11 (95% CI; 6, 100)• There was no statistically significant There was no statistically significant

between-study heterogeneitybetween-study heterogeneity

Methodological concerns

Quasi-randomizationQuasi-randomization Lack of blindingLack of blinding Lack of a preset sample sizeLack of a preset sample size Lack of “undistinguishable” placeboLack of “undistinguishable” placebo Small sample sizeSmall sample size

Methodological strengths/weaknesses Nine studies conducted in seven countries:Nine studies conducted in seven countries:

India = 2India = 2 MexicoMexico Saudi ArabiaSaudi Arabia SwitzerlandSwitzerland TaiwanTaiwan TurkeyTurkey U.S = 2U.S = 2

Conclusions The addition of the results of two small studies The addition of the results of two small studies

(n = 110) changed the presence of statistical (n = 110) changed the presence of statistical significance for the two major outcomes; significance for the two major outcomes; Mortality in suspected cases of infectionMortality in suspected cases of infection

(previously significant to non-significant)(previously significant to non-significant) Mortality in subsequently proved infectionMortality in subsequently proved infection

(previously non-significant to significant) (previously non-significant to significant)

Conclusions

The reduced mortality following treatment The reduced mortality following treatment with IVIG for suspected sepsis and the with IVIG for suspected sepsis and the imprecise estimate of the effect size to imprecise estimate of the effect size to prevent one death (NNT 11, 95% CI; 6, prevent one death (NNT 11, 95% CI; 6, 100) justify further research100) justify further research

Conclusions

The role of IVIG preparations with high The role of IVIG preparations with high concentrations of antibodies to specific concentrations of antibodies to specific organisms should be evaluatedorganisms should be evaluated

If such trials are to be undertaken, the If such trials are to be undertaken, the design should include long-term follow-up design should include long-term follow-up assessment and cost-effectiveness assessment and cost-effectiveness evaluationevaluation

Conclusions

Researchers should be encouraged to Researchers should be encouraged to undertake well-designed trials to confirm or undertake well-designed trials to confirm or refute the effectiveness of IVIG to reduce refute the effectiveness of IVIG to reduce adverse outcomes in neonates with adverse outcomes in neonates with suspected infectionsuspected infection

Globalize the EvidenceLocalize the Decision Making