Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Verifying and entering data into RevMan
Writing text of review
Janet Lacy
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Writing text of review
For this update conducted in October 2003 no new trials were identified
from the Cochrane Library, MEDLINE nor from EMBASE. In February 2002 Mancilla-Ramirez
et al. provided unpublished information that changed the rating of their
trial from B to A. For this update we did not calculate the absolute risk
difference and the number needed to treat for the subset of patients, who
entered the trials with suspected sepsis and who were subsequently proven
to have sepsis. Such estimates are meaningless as the clinician is unaware
at the point of starting treatment whether the infant will have proven sepsis
or not.
For this update we added the I squared statistic.
In the 2001 version the addition of results from two small studies changed the statistical significance of effect on two major outcomes: mortality in suspected cases of infection (previously significant - currently of borderline statistical significance) and mortality in subsequently proven infection (previously not significant - currently significant). Thus, there is the need for further well-designed research to identify the role of IVIG in suspected/subsequently proved neonatal infection.
The ongoing trial (INIS) by Brocklehurst et al. has recruited more than 600 patients as of September 2003.
Congenital and nosocomial infections are important causes of neonatal morbidity and mortality. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence. Theoretically infectious morbidity and morbidity could be reduced by the administration of intravenous immunoglobulin.
To assess the effectiveness of intravenous immunoglobulin (IVIG) to reduce mortality/morbidity caused by suspected infection in newborn infants. In secondary analyses to assess the effectiveness of IVIG to reduce mortality/morbidity in those neonates who entered into the studies with suspected infection and who later were confirmed as being infected.
MEDLINE, EMBASE and the Cochrane Library were searched in September 2003. The reference lists of identified RCTs, meta-analyses and personal files were searched. No language restrictions were applied. Unpublished information was requested from and obtained from five researchers (Erdem 1993; Gokalp 1994; Haque 1988; Mancilla-R 1992; Shenoi 1999). For this update no new trials were identified but additional information on one trial (Mancilla-R 1992) was obtained in February 2002.
The criteria used to select studies for inclusion were:
1) Design: RCT (including quasi-randomized trials)
2) Newborn infants (< 28 days old)
3) Intervention: IVIG for treatment of suspected (and in some infants subsequently
proved) bacterial/fungal infection compared to placebo or no intervention.
4) At least one of the following outcomes was reported: mortality during
initial hospital stay; length of hospital stay; side effects; psychomotor
development/growth at follow up.
Two reviewers independently abstracted information for the outcomes of
interest and one researcher (AO) checked for any discrepancies and pooled
the results.
Typical Relative Risk (RR) and Risk Difference (RD) with 95% confidence
intervals (CI) using the fixed effects model are reported for dichotomous
outcomes and weighted mean difference (WMD) for continuous data. NNT were
to be calculated for outcomes that showed a statistically significant reduction
in RD. For this update we did not calculate the RD and the NNT for the subset
of patients, who entered the trials with suspected sepsis and who were subsequently
proven to have sepsis. Such estimates are meaningless as the clinician is
unaware at the point of starting treatment, whether the infant will have proven
sepsis or not. For this update we added the I2 statistic.
Five hundred fifty three neonates with suspected infection have been enrolled in RCTs to evaluate the effect of IVIG on neonatal outcomes. These studies were undertaken in seven countries.
Six studies (n = 318) reported on the outcome of mortality for randomized patients with clinically suspected infection. The results showed a reduction in mortality following IVIG treatment [typical RR 0.63 (95% CI; 0.40, 1.00), RD -0.09 (95% CI; 0.00, -0.17) of borderline statistical significance.
Treatment with IVIG (seven trials, n = 262) in cases of subsequently proven infection did result in a statistically significant reduction in mortality [typical RR 0.55 (95% CI; 0.31, 0.98)
In spite of different geographical locations of the studies, differences in the mortality in the control groups (range 0% - 43.8%), the use of different IVIG preparations, and different dosing regimens, there was no statistically significant between-study heterogeneity for the outcome of mortality in the two analyses. I2 = 0%.
The conclusions did not change in this updated review. There is insufficient evidence to support the routine administration of IVIG preparations investigated to date to prevent mortality in infants with suspected or subsequently proved neonatal infection.
Researchers should be encouraged to undertake well-designed trials to confirm or refute the effectiveness of IVIG to reduce adverse outcomes in neonates with suspected infection. Such a trial is currently ongoing in the UK and Australia (Brocklehurst 2001). The sample size is 5000 neonates and as of September 2003 more than 600 patients have been enrolled.
Congenital and nosocomial bacterial and fungal infections continue to be a significant cause of neonatal morbidity and mortality. In a cohort of 7,861 very low birth weight (VLBW) neonates admitted during a 32 month period (1991-1993) to the 12 National Institute of Child Health and Human Development (NICHD) Network centres, blood culture-proved early-onset (occurring within 72 hours of birth) sepsis occurred in 1.9% of infants (Stoll 1996a). In contrast to the low incidence of proved early-onset sepsis, almost 50% of the infants in the cohort were considered to have clinical sepsis and were treated with antibiotics for more than 5 days. Neonates with early-onset sepsis were more likely to have later co-morbidities/complications (severe intraventricular haemorrhage, patent ductus arteriosus, and prolonged assisted ventilation). Decreasing gestational age was associated with increased rates of infection; 26% of the VLBW infants with early-onset sepsis died. However, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For infants who survived to discharge, early-onset sepsis was associated with a statistically significantly longer hospital stay (86 vs 69 days, p < 0.02). From the same 12 centres a 25% incidence of late onset infection has been reported in a cohort of 6,911 VLBW infants who survived beyond 3 days of life (Stoll 1996b). 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).
Maternal transport of immunoglobulins to the fetus occurs mainly after 32 weeks gestation and endogenous synthesis does not begin until about 24 weeks after birth. Thus infants born at term and especially premature infants are at high risk for morbidity and mortality from infections acquired in utero as well as from exposure to infectious sources in neonatal intensive care units (Baker 1990). The rationale for treating neonatal infections with intravenous immunoglobulin (IVIG) is based on the evidence that administration of IVIG provides IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence (Baley 1988).
The prophylactic administration of intravenous immunoglobulins (IVIG) to prevent nosocomial infections has been studied in > 5,000 neonates enrolled in randomized controlled trials (RCTs) (Ohlsson 1998a). The results of these meta-analyses (Ohlsson 1998a) show a statistically significant reduction in sepsis (RD -2.8%; NNT 36) and/or any serious infection (RD -3.2%; NNT 31), but no reduction in mortality from infection.
The effectiveness of IVIG as an adjunct to standard treatment with antibiotics to reduce mortality from suspected infection has been less well studied. In clinical practice the number of infants with suspected infection considerably outweighs the number of infants eventually proved to have systemic infection. To study the effectiveness of IVIG to reduce mortality and morbidity from infections in the clinical setting, neonates with suspected infection should be entered and randomized into such trials and the outcomes on an "intention to treat basis" should be reported. Baley 1992 presented a systematic review based on three studies (Sidiropoulos 1981, Haque 1988, Weisman 1992) to evaluate the effect of administration of IVIG to neonates with suspected sepsis on mortality. However, the study by Weisman (Weisman 1992) included only infants with subsequently proved infection. Although the meta-analysis showed a statistically significant risk difference (RD) for mortality of -14.5% (95% CI -4.5, -24.5) the authors stressed that the analysis must be viewed with caution as only a small number of infants had been studied (173 neonates were included in their review). Lacy 1995 excluded the study by Sidiropoulos (1986) in a meta-analysis, as the original study published in German (Sidiropoulos 1981) indicated that it was a quasi-randomized trial (a group of 82 newborns with suspected infection were treated either with antibiotics alone or antibiotics and immune globulin on an alternating basis). The authors of the meta-analysis concluded that there was no statistically significant reduction in mortality following IVIG administration for the treatment of neonatal infection. Jenson 1997 included in a meta-analysis the same three studies as Baley 1992 but concluded that IVIG administration is "of unequivocal benefit in preventing death when administered therapeutically for early-onset neonatal sepsis". In a subsequent publication they concluded "The additional benefit of decreasing the risk of acute mortality indicates that the inclusion of IVIG should be considered a part of the routine therapy of neonatal sepsis" (Jenson 1998). Haque 1997 in a meta-analysis of 5 studies of IVIG to treat neonatal sepsis concluded that IVIG treatment results in a significant reduction in mortality (typical odds ratio 0.32 ; 95% CI 0.21, 0.48). Two of the included studies lacked a randomized control group (Friedman 1990, Haque 1995). A Cochrane review (Alejandria 2001) conducted after the publication of the first version of our Cochrane review (Ohlsson 1998b) included all age groups. The authors found a reduction in overall mortality in patients of all ages who received polyclonal IVIG. In a subgroup analysis in neonates (4 studies, 191 infants) there was no statistically significant reduction in the all cause mortality (typical RR 0.60; 95% CI 0.31, 1.14). The analyses by Alejandria (Alejandria 2001) included fewer studies than did the previous version of our systematic review in the Cochrane Library (Ohlsson 1998b).
This review updates our existing Cochrane review, Intravenous immunoglobulin for suspected or subsequently proven infection in neonates, published in The Cochrane Library, Disk Issue 4, 1998 (Ohlsson 1998b) and updated in The Cochrane Library, Disk Issue 3, 2001 (Ohlsson 2001).
Primary objective: To assess the effectiveness of IVIG to reduce mortality/morbidity from suspected infection in newborn infants. Secondary objective: To assess the same outcomes in the neonates enrolled in these RCTs and who were subsequently confirmed as having culture proven infection. Suspected infection was defined as clinical symptoms and signs consistent with infection without isolation of causative organism. Proved infection was defined as: clinical symptoms and signs consistent with infection in association with isolation of a causative organism (bacteria or fungi) from either blood culture, cerebrospinal fluid culture, urine culture (urine obtained by suprapubic tap) or a normally sterile site (e.g., liver, spleen, meninges, lung) at autopsy.
Studies in which neonates were randomized to receive IVIG or either a placebo or no intervention to prevent mortality/morbidity from suspected infection during initial hospital stay. Studies that reported on length of hospital stay, side effects, long term psychomotor development or growth following IVIG treatment for serious infection were also included.
Newborn (28 days of age) infants with suspected or subsequently proven serious infection.
IVIG to treat suspected bacterial or fungal infection versus control (placebo or no treatment).
Mortality/morbidities during initial hospital stay and/or length of hospital stay for all infants and for survivors, side effects, long term psychomotor development and growth, and increased number of infections during childhood.
The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group.
The search was initiated by review of personal files. The reference lists of identified studies and subsequently retrieved articles were scanned for additional references. MEDLINE was searched from 1966 to September 2003. EMBASE (Excerpta Medica online) was searched from 1980 to September 2003. The Cochrane Library, Issue 3, 2003, was searched. The following keywords were used: immunoglobulin and infant-newborn, and random allocation, or controlled trial, or randomized controlled trial (RCT). 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 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: Newborns ( <28 days of age)
3) Intervention: IVIG to treat suspected infection. Studies in which neonates
with suspected infection were randomized, but the authors only reported
on the outcomes of neonates who were later confirmed as having proven infection,
were included in secondary analyses.
4) The outcome of mortality during initial hospital stay and/or length
of hospital stay was reported. Data for side effects and other morbidities
were also noted when reported by the authors.
The titles (and abstracts when available) in the MEDLINE, EMBASE, Cochrane Library 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 was retrieved. No systematic attempt was made to locate unpublished studies. We requested additional information from authors of published studies, and received six replies as of September, 2003.
All identified trials 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 Neonatal Cochrane 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 scoring, the two assessors discussed
the scores for each study and any discrepancies were resolved.
Data Abstraction.
The two reviewers independently abstracted information on each study and
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 (mortality/morbidities,
length of hospital stay, long-term follow up, side effects) was abstracted.
Statistical Analysis
The statistical package (RevMan 4.2) provided by the Cochrane Collaboration
was used. Typical Relative risk (RR) and Risk Difference (RD) with 95% confidence
intervals (CIs) using the fixed effects model are reported for dichotomous
data and weighted mean difference (WMD) for continuous data. When a statistically
significant reduction in the RD were to be found the NNT were to be calculated.
For this update we did not calculate the RD and the NNT for the subset of
patients, who entered the trials with suspected sepsis and who were subsequently
proven to have sepsis. Such estimates are meaningless as the clinician is
unaware at the point of starting treatment , whether the infant will have
proven sepsis or not. Statistically significant heterogeneity was noted
and reported. The I2 statistic was included. Length of hospital
stay was analysed separately for preterm and mainly term infants.
Details of the included studies are provided in the Table "Characteristics
of Included Studies".
Nine studies (Chen 1996, Christensen 1991, Erdem 1993, Haque 1988,
Mancilla-R 1992, Samatha 1997, Shenoi
1999, Sidiropoulos 1981, Weisman 1992) met the inclusion criteria.
Chen 1996 randomized 141 neonates with suspected
infection to receive IVIG or placebo. The author does not report on how
many infants were randomized to each group and outcomes were reported only
on the 56 neonates with positive blood cultures. We have asked the author
to provide information on the 85 neonates with suspected but not proved infection.
Christensen 1991 randomized 24 infants
with suspected sepsis to receive IVIG or placebo. Two infants were excluded
from the analysis and the authors do not state to which group(s) these infants
belonged. Fifteen patients (6 of the 11 IVIG recipients and 9 of the 11
placebo recipients) had bacteria recovered from their blood or trachea or
identified by bacterial antigen detection. Cases with proven infection according
to the criteria for this review could therefore not be identified. Further
information will be sought from the authors.
Erdem 1993 entered 44 infants with suspected
sepsis. Twenty were randomly chosen to receive IVIG and 24 were controls.
Fifteen infants in each group had blood culture proven sepsis and the remaining
infants were classified as having suspected but not proven infection. Outcomes
were reported on all randomized infants. We wrote to the authors and they
indicated that allocation was performed on an "alternating basis".
Haque 1988 randomized 60 infants with suspected infection to either antibiotics alone or antibiotics with IVIG. Forty-four infants had proven infection and 16 had suspected but not proven infection. Outcomes were reported on all infants. All deaths in the study population were reported (information provided by the author).
Mancilla-R 1992 randomized 84 neonates with suspected sepsis using a table of random numbers and the investigators were blinded to the group of allocation as cards with codes were used (information provided by the author on request). Outcomes in neonates without culture proved sepsis were excluded. Outcomes in 37 randomized infants with subsequently proven infection were reported.
Samatha 1997 assigned 60 neonates, who satisfied the criteria for possible sepsis, by picking up lots to receive standard treatment or standard treatment plus IVIG. Outcomes were reported on all infants.
Shenoi 1999 allocated 58 newborns with suspected sepsis to IVIG treatment or placebo. Seven neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one baby who received only one dose of IVIG was excluded from the analysis. Twenty infants were confirmed as having a positive blood culture whereas in 30 infants bacteremia was not confirmed. Outcomes were reported for these 50 randomized patients. On request the author reported that a random table was used to assign the randomization sequence and that sealed envelopes were used to allocate the neonates to treatment or control groups. A non-identical placebo was used in the control group.
Sidiropoulos 1981 allocated (alternating basis) 82 newborns with suspected sepsis to IVIG treatment or no IVIG treatment. Thirty-five of the neonates were confirmed as having sepsis whereas in 47 infants bacteremia was not confirmed. Outcomes were reported for all randomized patients.
Weisman 1992 randomized 753 neonates (less than or equal to 12 hours of age) who were at risk of (but not necessarily suspected of) having infection to receive either IVIG or placebo. Early-onset sepsis was diagnosed in 31 infants and the outcomes of these patients were reported.
Different IVIG preparations, amounts and dosing schedules were used: a single dose of 500 mg/kg of Intraglobin (Chen 1996); a single dose of 750 mg/kg of Gamimmune-N (Christensen 1991); 5 ml /kg/day of Pentaglobin for three days (Erdem 1993; Samatha 1997); 5 ml/kg/d of Pentaglobin for four days (Haque 1988); a single dose of 500 mg/kg of Gamimmune-N (Mancilla-R 1992); a daily dose of 0.5 - 1g for six days of Immunoglobulin SRK (Sidiropoulos 1981); 1g/kg of Sandoglobulin on three consecutive days (Shenoi 1999); and a single dose of 500 mg/kg of Sandoglobulin (Weisman 1992).
Two studies were excluded; Gokalp 1994 and Haque 1995.
On contact with Gokalp it became clear that patients were randomized and treated only after they were known to have a positive culture for salmonella, not when they were first suspected to have an infection.
Haque 1995 did not include a randomized control group.
All 9 included studies (Chen 1996, Christensen 1991, Erdem 1993, Haque 1988, Mancilla-R 1992, Samatha 1997, Shenoi 1999, Sidiropoulos 1981, Weisman 1992) were of small size (22 to 82 infants were enrolled). In only two studies was a sample size calculation reported as part of the study design (Shenoi 1999, Weisman 1992). Blinding of randomization was certain in five studies (Christensen 1991, Haque 1988, Mancilla-R 1992, Shenoi 1999, Weisman 1992 ). Information on blinding of randomization was lacking for two studies (Chen 1996, Samatha 1997). In the studies by Sidiropoulos 1981 and Erdem 1993 allocation to IVIG or control group was on an alternating basis. Five studies used a placebo to blind the intervention and the outcome measurement (Chen 1996, Christensen 1991, Haque 1988, Mancilla-R 1992, Weisman 1992). One study (Shenoi 1999) did use a placebo which was not prepared by the pharmaceutical company providing the IVIG but by the investigators following the random allocation to the placebo group. Three studies (Erdem 1993, Samatha 1997, Sidiropoulos 1981) did not use a placebo.
Infants were enrolled in all but one study because of suspected infections.
It is our interpretation that randomization and initiation of treatment
occurred at this stage. However, only four of the studies (Erdem 1993, Haque 1988,
Samatha 1997, Sidiropoulos 1981) report on outcomes as
per intention to treat. Christensen (Christensen
1991) did not report on the allocation of two infants who were excluded
from the study (one infant died). In the study by Weisman (Weisman 1992) patients at risk of infection were
enrolled as part of a larger RCT of prophylaxis of nosocomial infections
with IVIG; patients with subsequently proved infections at birth were analysed
and reported by the authors. In the study by Shenoi (Shenoi 1999) 58 newborns with suspected sepsis
was allocated to IVIG treatment or placebo. Seven neonates who qualified
but did not receive either IVIG or placebo were taken into a separate control
group, and one baby who received only one dose of IVIG was excluded from
the analysis.
It is uncertain whether reported deaths represented total mortality from
all causes in all studies. Haque (Haque 1988)
stated that the deaths were from sepsis, but some reported deaths occurred
in neonates with suspected sepsis. Haque has confirmed that all deaths in
the study population were reported (personal communication, 1998). Weisman
(Weisman 1992) stated a study period (56 days)
during which the main outcomes (except for length of hospital stay) were
reported. (We assumed that in the other studies all deaths during the initial
hospitalisation were accounted for). In the study by Weisman (Weisman 1992) length of hospital stay was reported
for survivors only. In the studies by Chen (Chen 1996)
and Mancilla-Ramirez (Mancilla-R 1992) length
of hospital stay included all patients (our interpretation for the study
by Chen and verified by Mancilla-Ramirez in 2002).
These nine small studies were performed in seven countries [India (n = 2), Mexico, Saudi Arabia, Switzerland, Taiwan, Turkey and the U.S. (n = 2)]. The level of intensive care offered to these neonates was poorly described and is likely to have varied.
Methodological weaknesses identified in several of these studies included: lack of sample-size calculation (in general very small cohorts were recruited), uncertainty about blinding of randomization and how randomization was undertaken, lack of a placebo, outcomes not ascertained blinded to group allocation and outcomes not reported as per intention-to-treat.
Five-hundred-fifty-three neonates with suspected infection (Chen 1996, Christensen 1991, Erdem 1993, Haque 1988, Mancilla-R 1992, Samatha 1997, Shenoi 1999, Sidiropoulos 1981) have been enrolled in RCTs to evaluate the effect of IVIG on important outcomes. In the study by Weisman (Weisman 1992) patients at risk of infection were enrolled as part of a larger RCT of prophylaxis of nosocomial infections with IVIG. In several trials the outcomes of the populations as randomized have not been reported. The outcome of mortality was reported in 318 of the 553 randomized neonates with suspected infection. These studies were undertaken in seven countries (India, Mexico, Saudi Arabia, Switzerland, Taiwan, Turkey, and the U.S.).
The following outcome was reported for infants with suspected infection:
Mortality:
Six studies (n = 318) reported on the outcome of patients with clinically
suspected infection. The results showed a reduction in mortality of borderline
statistical significance [RR 0.63 (95% CI; 0.40, 1.00), RD -0.09 (95% CI;
0.00, -0.17). There was no statistically significant between-study heterogeneity
for this outcome. I2 = 0%.
The following outcomes were reported for infants with subsequently proven infection:
A total of 262 neonates with subsequently proven infection have been enrolled in seven RCTs to evaluate the effectiveness of IVIG vs. placebo or no treatment to prevent mortality/morbidities. Treatment with IVIG in cases of subsequently proven infection did result in a statistically significant reduction in mortality [RR 0.55 (95% CI; 0.31, 0.98)]. For this update we did not calculate the RD and the NNT for the subset of patients who entered the trials with suspected sepsis and who were subsequently proven to have sepsis. Such estimates are meaningless as the clinician is unaware, at the point of starting treatment, whether the infant will have proven sepsis or not. In spite of different geographical locations of the studies, large differences in the mortality in the control group (range 0.0% - 43.8%), the use of different IVIG preparations, and different dosing regimens, there was no statistically significant between-study heterogeneity. I2 = 0%.
Length of hospital stay (preterm infants)
Two studies (Chen 1996, Weisman 1992) reported on this outcome in a total
of 51 infants. There was no statistically significant effect on length of
hospital stay following IVIG treatment [WMD 1.4 days (95% CI -12.2, 15.0)].
There was no statistically significant between-study heterogeneity for this
outcome. Samantha (Samatha 1997) reported
on the mean and range of hospital stay: for the IVIG group 20 (4 - 52) and
for the control group 29 (6 - 62) days. I2 = 0%.
Length of hospital stay (mainly term infants).
Information on this outcome was available from three studies (Chen 1996, Mancilla-R
1992, Shenoi 1999) with a total of 123
infants enrolled. There was a statistically significant reduction in length
of hospital stay for mainly term infants with serious infection [WMD -3.0
days (95% CI -0.32, -5.7)]. There was statistically significant between-study
heterogeneity (p = 0.007). I2 = 79.8%
Long term follow-up
Only Sidiropoulos 1981 reported on psychomotor
development, growth (weight, height, head circumference < 3rd centile)
at approximately two years of age and increased number of infections to
two years of age. There were no statistically significant differences between
the groups.
No other clinical outcomes were reported.
Serum IgG levels
An increase in serum IgG levels was noted in the studies that measured
levels (Chen 1996, Christensen 1991, Haque 1988, Mancilla-R
1992, Sidiropoulos 1981, Weisman 1992).
Adverse effects
Six studies reported on possible side effects (Chen
1996, Christensen 1991, Samatha 1997, Shenoi
1999, Sidiropoulos 1981, Weisman 1992). In the study by Weisman (1992)
(381 infants received albumin and 372 IVIG) four adverse reactions occurred
in the albumin group (1.0%) and two in the IVIG group (0.5%) (p = 0.70).
Hypotension was present in five infants (one received IVIG) and hypoglycaemia
in one infant (who received IVIG). No adverse effects were noted in five
other studies (Chen 1996; Christensen 1991, Samatha 1997, Shenoi
1999, Sidiropoulos 1981). No serious
adverse effects were observed in the study by Mancilla-Ramirez (Mancilla-R 1992). Hyperemia at the venae-puncture
sites was noted in both groups and did not differ between groups (personal
communication Mancilla-Ramirez 2002).
No new trials were identified for this update of our previously updated review (Ohlsson 2001). That review found that in neonates with suspected infection, treatment with IVIG resulted in a reduction in mortality of borderline statistical significance. Treatment with IVIG in cases of subsequently proved infection did result in a statistically significant reduction in mortality [typical RR 0.55 (95% CI; 0.31, 0.98) and if valid would be of major importance. This finding is in contrast to our previous meta-analysis in the Cochrane Library (Ohlsson 1998b) which showed the reverse; a statistically significant reduction in mortality in neonates with suspected infection but no statistically significant reduction in mortality following treatment with IVIG in cases with subsequently proved infection. It is also in contrast to one previous meta-analysis (Lacy 1995), but in agreement with four other meta-analyses (Baley 1992, Jenson 1997, Haque 1997, Jenson 1998), which claim a statistically significant reduction in mortality following treatment with IVIG for neonatal sepsis. Haque (Haque 1997) included two studies that lacked a randomized control group (Friedman 1990, Haque 1995). Baley & Fanaroff (Baley 1992), Jenson & Pollock (Jenson 1997) and Haque (Haque 1997) included a quasi-randomized study (Sidiropoulos 1981). Our 2001 review (Ohlsson 2001) included 5 studies (Chen 1996, Erdem 1993, Samatha 1997, Shenoi 1999, Mancilla-R 1992) that were not included in the reviews by Baley & Fanaroff (Baley 1992), Lacy & Ohlsson (Lacy 1995), Jenson & Pollock (Jenson 1997), Haque (Haque 1997) or Jenson & Pollock (Jenson 1998). Alejandria (Alejandria 2001) included 4 studies in her analysis of IVIG for treatment of sepsis (Chen 1996, Erdem 1993, Haque 1988, Weisman 1992). In her analysis studies that reported deaths among neonates with either suspected or subsequently proved infection were combined. She excluded the trial by Sidiropoulos 1981, as it was a quasi randomized trial, but included the trial by Erdem 1993, that we now know is also a quasi randomized trial. Our updated meta-analysis (Ohlsson 2001) therefore had increased power to provide a more precise estimate of the possible advantage of IVIG treatment for neonatal sepsis compared to previous reviews.
In that review there was no statistically significant reduction in length of hospital stay for preterm infants but for term infants. However, for the population of term infants there was statistically significant between-study heterogeneity. The I2 is 80%. Length of hospital stay is dependent on a number of factors not directly related to the condition of the neonate. Hospital policies and the social situation of the family influence the need for continued hospital stay and may explain some of the heterogeneity.
It is possible that the various IVIG preparations used by the authors in different geographical locations were not optimally targeted for the bacteria commonly isolated. No serious short term side effects were reported in these studies, a finding that is consistent with a previous meta-analysis of prophylactic IVIG in preterm and or low-birth-weight infants (Ohlsson 1998a).
This meta-analysis lacked the power to demonstrate a statistically significant reduction in mortality following IVIG treatment in cases with suspected infection. The results were of borderline statistical significance. However, treatment with IVIG in cases of subsequently proven infection did result in a statistically significant reduction in mortality.
The potential benefits suggested from these meta-analyses warrant further evaluation of the effectiveness of IVIG in the treatment of suspected neonatal infections. IVIG preparations with high concentrations of antibodies to bacteria that are commonly isolated from neonates in specific local settings or geographical areas may be more effective in reducing adverse outcomes.
There is currently insufficient evidence to support the routine administration of IVIG preparations investigated to date to prevent mortality from suspected or subsequently proven neonatal infection.
The borderline statistical significance for the outcome of mortality in neonates with suspected infection, the reduced mortality following treatment with IVIG for subsequently proven infection and the imprecise estimate of the effect size justify further research. Researchers should be encouraged to undertake well-designed trials to confirm or refute the effectiveness of IVIG to reduce adverse outcomes in neonates with suspected infection. The role of targeted IVIG preparations (IVIG preparations with high concentrations of antibodies to specific organisms commonly causing infection in a local setting) should be evaluated. If such trials are to be undertaken, the primary outcome should be a combination of mortality and impairments at 18 to 24 months of age (corrected for gestational age at birth). The design should include cost-effectiveness evaluations. Such a trial has been funded by the Medical Research Council (U.K.) and recruitment of 5,000 infants started in 2001 (Brocklehurst 2001) and as of September 2003 more than 600 neonates have been enrolled in the UK and Australia. The investigators plan to enrol neonates from other European countries in the near future. Other potentially more effective interventions to prevent or treat neonatal infections should also be explored.
We would like to acknowledge the help of:
Ms. Elizabeth Uleryk, Director of the Hospital Library at the Hospital
for Sick Children for developing search strategies of the literature conducted
in February, 2001 and September 2003.
Dr. Orlando DaSilva translated one of the reports included in this review
from Spanish to English.
Drs. Erdem, Gokalp, Haque, Mancilla-Ramirez and Shenoi provided information
on their trials in addition to what was previously published in journal
articles.
Dr. Shenoi provided us with the publication by Dr. Samantha et al from
the Karnataka Paediatric Journal.
Dr. Peter Brocklehurst volunteered information in 2001 and 2003 on a trial
directly related to this topic and which started recruiting patients in
2001.
None
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Chen 1996 | Randomized, placebo-controlled trial I Blinding of randomization - Can't tell II Blinding of intervention - Yes III Complete follow up - Yes IV Blinding of outcome measurement - Yes |
141 infants with suspected infection. Results were reported for 56 neonates with culture proved sepsis (clinical signs of infection and bacteria isolated from a blood sample). January 1993 to April 1995 Single center, Taiwan |
10 preterm; mean GA (SD) 30.6 +/- 1.3 wk, mean BW (SD) 1.35
+/- 0.27 kg, Mean age (SD)16.5 +/- 9.5 days, received a single dose of 500
mg/kg of IVIG (Intraglobin, Biotest Pharma, Frankfurt, Germany) in a total
volume of 10 ml during a 2 hour period. 10 preterm; mean GA (SD) 31.0 +/- 1.1 weeks, mean BW (SD)1.39 +/- 0.14 kg, mean age (SD) 17.4 +/- 9.9 days received 0.9 % sodium chloride i. v. 18 term; mean GA (SD) 39.2 +/- 1.1 weeks, mean BW (SD) 3.1 +/- 0.3 kg, mean age (SD) 11.3 +/- 8.5 days received a single dose of 500 mg/kg of IVIG (Intraglobin, Biotest Pharma, Frankfurt, Germany) in a total volume of 10 ml during a 2 hour period. 18 term; mean GA (SD) 39.4 +/- 1.3 wk, mean BW (SD) 3.1 +/- 0.4 kg, mean age (SD) 12.3 +/- 7.1 days received 0.9 % sodium chloride i. v. |
Mortality Length of hospital stay for preterm and term infants. Serum IgG Suspected adverse effects included: flushing, fever, emesis, restlessness, irritability or a significant deterioration of vital signs. |
Mortality associated with proved serious infection could be ascertained
from this study. Length of hospital stay for term and preterm infants could be ascertained separately. No adverse effects were reported. |
B |
| Christensen 1991 | Randomized, placebo controlled trial I Blinding of randomization - Yes II Blinding of intervention - Yes III Complete follow up - Yes IV Blinding of outcome measurement - Yes |
24 neonates with suspected infection. 15 patients had bacteria
recovered from their blood or trachea or identified by bacterial antigen
detection. Two were excluded from the study before the infusion, one because
of treatment with extracorporeal membrane oxygenation and the other because
of death before the infusion. Dates not given Single center, USA |
11 neonates; mean GA (SD) 33 +/- 4 wk; mean BW (SD) 2.222 +/- 0.984 kg; mean age (SD) 1.2 +/- 0.4 days received a single dose of 750 mg/kg of IVIG (5% human immune globulin in a sterile 10% maltose solution) (Gamimmune-N, Cutter Biological. Miles Inc., Berkeley, Calif.). 11 neonates; mean GA (SD) 31 +/- 7 wk; mean BW (SD) 1.725 +/-1.138 kg; mean age (SD) 1.5 +/- 0.5 days received human albumin 0.1% in a sterile 10% maltose solution. | Mortality from "suspected sepsis". White blood cell response, Serum IgG. Mechanical ventilation, intubation, oxygen administration, serum electrolytes, urine output. |
Mortality associated with suspected infection could be ascertained
from this study. Neutropenia resolved in patients receiving IVIG. The ratio of arterial oxygen tension to fraction of inspired oxygen increased in infants receiving IVIG but not after control infusions. No differences were observed in the duration of mechanical ventilation, intubation, or oxygen administration. Serum IgG concentrations increased after IVIG infusions. |
A |
| Erdem 1993 | Quasi-randomized controlled trial I Blinding of randomization - No II Blinding of intervention - No III Complete follow up - Yes IV Blinding of outcome measurement - No |
44 preterm infants (GA 31 - 37 weeks) with suspected sepsis (Tollner's
Sepsis Scoring System). Cases having a positive blood culture were classified
as "proved sepsis" and others as "suspected sepsis". There were 16 infants with proved infection in the control group and 15 in the IVIG group. Dates not given. Single center, Turkey. |
20 infants mean GA (SD) 34.4 +/- 1.9 wk, mean BW (SD) 2085 +/-
352 g) with suspected or proved sepsis received 5 ml/kg/d of IgM-enriched
IVIG (Pentaglobin, Biotest Pharma, Frankfurt, Germany) consisting of IgM
6 mg, IgA 6 mg and IgG 38 mg/ml daily for three days. All infants received antibiotic therapy and fresh frozen plasma and/or whole blood transfusion. 24 infants mean GA (SD) 34.9 +/- 1.7 wk, mean BW (SD) 2050 +/- 369 g) with suspected or proved sepsis received no placebo. |
Mortality for cases of "proved sepsis" and "suspected sepsis". | This is a quasi randomized trial - "alternating basis". Mortality
associated with suspected and proved infection could be ascertained from
this study. No other outcomes were reported. There was no mention of adverse reactions. |
C |
| Haque 1988 | Randomized, placebo-controlled trial. I Blinding of randomization - Yes II Blinding of intervention - Yes III Complete follow up - Yes IV Blinding of outcome measurement - Yes |
60 preterm infants (GA 28 to 37 weeks) with suspected sepsis. Sepsis was defined as clinical features of sepsis, abnormal white cell indices, and a positive blood or cerebrospinal fluid culture. 23 infants in the control group and 21 in the IVIG group had proved sepsis. Dates not given (6 months period) Single centre, Saudi Arabia |
30 infants mean GA (SD) 33.4 wk, mean BW (SD) 1.32 kg with suspected
sepsis received 5 ml/kg/day of IgM enriched IVIG (Pentaglobin, Biotest Pharma,
Frankfurt, Germany. Immunoglobulin therapy was administered over 2 hours
per day for four days. 30 infants; mean GA (SD) 35 wk, mean BW (SD) 1.48 kg with suspected sepsis received 5 ml/kg/day of 10% dextrose for four days. |
Mortality Serum immunoglobulin concentrations |
Mortality associated with suspected and proved infection could
be ascertained from this study. Adverse reactions were not reported. |
A |
| Mancilla-R 1992 | Randomized, placebo-controlled trial I Blinding of randomization - yes II Blinding of intervention - Yes III Complete follow up - Yes IV Blinding of outcome measurement - Yes |
84 newborns with suspected infection were entered into the study.
Results were reported for 37 neonates (0 - 28 days of age) with culture
proved sepsis (Sepsis = Symptoms of infection and bacteria isolated from
a blood sample). April 1987 - September 1988 Single Center, Mexico |
19 neonates received a single dose of 500 mg/kg of IVIG (Gamimmune-N,
Cutter Biological). Mean age (SD) at entry 10.5 +/- 5.26 days, mean GA (SD)
37.6 +/- 2.2 wk, mean weight (SD) 2330 +/- 540 g. Gender M:F 12:7 18 neonates received a corresponding volume of 10% maltose solution. Mean age (SD) at entry 9.7 +/- 6.98 days, mean GA (SD) 37.5 +/- 3.1 wk, mean weight (SD) 2310 +/- 830 g, Gender M:F 10:8. |
Mortality Length of hospital stay Serum IgG levels |
Mortality associated with proved serious infection could be ascertained
from this study. Length of hospital stay (mainly term infants) could be ascertained. Adverse reactions were not reported. The author informed us upon request that randomization was established by a table of random numbers. |
A |
| Samatha 1997 | Randomized controlled trial (no placebo) I. Blinding of randomization - can't tell II. Blinding of intervention - no III. Complete follow up - yes IV. Blinding of outcome measurement - No |
60 neonates with suspected sepsis were enrolled. 44 were born
preterm and 51 were LBW Single centre, India January 1993 to December 1993 |
30 neonates (26/30 preterm and 27/30 LBW) received 5 ml/kg/day of IgM enriched IVIG (Pentaglobin) for 3 days. 30 (18/30 preterm, 24/30 LBW) neonates received antibiotics only. | Mortality from any cause Mortality from sepsis Length of hospital stay |
Mortality from any cause and mortality from sepsis and hospital stay could be ascertained from this study. No adverse effect were noted. | B |
| Shenoi 1999 | Randomized controlled trial (no placebo) I Blinding of randomization - Yes II Blinding of intervention - no III Complete follow up - no IV Blinding of outcome measurement - No |
58 neonates with suspected infection (suspected clinically to
have sepsis with C-reactive protein greater than 6 mg/dl and at least one
of the following rapid diagnostic tests positive - absolute neutrophil count,
thrombocytopenia, toxic granulation in the peripheral smear, and a band
count of greater than 500/cubic mm: and the blood culture being negative).
(Confirmed sepsis as above plus a blood, urine, or cerebrospinal fluid culture
yielding an organism). 7 neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one baby who received only one dose of IVIG was excluded from the analysis. Three centres, India October 1995 to May 1996 |
25 neonates mean BW (SEM) 2072 +/- 682 g Mean GA (SEM) 35.8 +/- 3.52 wk received 1 g/kg of Sandoglobulin on three consecutive days, 25 infants, mean BW (SEM) 2144 +/- 675 g; mean GA (SEM) 37.0 +/- 3.56 wk received an equivalent amount of 0.15% saline 10% dextrose placebo (this placebo was not provided by the pharmaceutical company) | Mortality Duration of hospital stay |
Mortality associated with suspected sepsis and Duration of hospital stay could be ascertained from this study. No adverse effects were noted. | A |
| Sidiropoulos 1981 | Quasi-randomized controlled trial. I Blinding of randomization - No II Blinding of intervention - No III Complete follow up - Yes IV Blinding of outcome measurement - No |
82 newborns with clinical evidence of sepsis (suspected sepsis) 35 had proved neonatal sepsis, 47 did not have bacteremia 1976 - 1979 Single centre, Switzerland |
41 infants with suspected or proved sepsis received IVIG (Immunoglobulin
SRK) (preterm infants received 0.5 g/day for 6 days and term infants 1.0
g/day for 6 days). 41 infants with suspected sepsis or proved sepsis received no placebo 20 infants with proved sepsis Mean GA (SD) 35 +/- 5 wk, mean BW (SD) 2280 +/- 960 g) received IVIG 15 infants with proved sepsis mean GA (SD) 35 +/- 5 wk, mean BW (SD) 2300 +/- 1170 g received no placebo |
Mortality Psychomotor development and growth in the IVIG group (n=18) at 2 4/12 +/- 1 5/12 years of age; in the control group (n=11) at 2 6/12 +/- 1 2/12 years of age Serum IgG. Suspected adverse effects respiratory rate, heart rate, temperature, blood gas analysis. |
This is a quasi randomized trial; infants were allocated to IVIG
or no IVIG on an alternating basis. Mortality associated with suspected/proved serious infection could be ascertained from this study. This study also provides long term follow up. No adverse effects were reported. |
C |
| Weisman 1992 | Randomized, double-blind, controlled trial. I Blinding of randomization - Yes II Blinding of intervention - Yes III Complete follow up - Yes IV Blinding of outcome measurement - Yes |
This clinical trial was one of two arms of a study designed to
evaluate immunity in the same patient population (n = 753). The purpose
of this arm was to evaluate the efficacy of IVIG treatment of early-onset
infection in high-risk neonates. Sepsis was defined as clinical symptoms
and signs consistent with sepsis in association with isolation of a causative
organism from either blood culture, cerebrospinal fluid culture, or a sterile
site (e.g., liver, spleen, meninges, lung) at autopsy. June 1985 - April 1989 9 centers in the U.S. |
14 neonates with sepsis mean GA (SD) 28.2 +/- 2.6 wk, mean BW
(SD) 1236 +/- 410 g received 10 ml of IVIG (500 mg/kg) (Sandoglobulin).
17 neonates with sepsis; mean GA (SD) 28.5 +/- 2.8 wk, BW 1250 +/- 341 g received 10 ml of albumin (5 mg/kg). |
Mortality to 56 days of life Hospital stay among survivors Total serum IgG Serum GBS type-specific IgG Adverse reactions |
Mortality associated with proved serious infection could be ascertained
from this study (during the 56 days study period). Length of hospital stay among survivors (preterm infants) could be ascertained. There were six suspected infusion-related adverse reactions, four in the albumin group and two in the IVIG group. |
A |
| Study | Reason for exclusion |
| Gokalp 1994 | The purpose of this study was to determine the role of IVIG administration in preterm infants with S. typhimurium infection (including both intestinal and extra intestinal S. typhimurium infections). Randomization took place after the infants were known to have a positive culture for Salmonella. This study did not meet our inclusion criterion of IVIG for treatment of suspected infection. In this study infants were randomized when they were known to be infected with Salmonella. (Information provided by the author). |
| Haque 1995 | In a prospective randomized double-blind study, standard IVIG
was compared with IgM-enriched IVIG in the treatment of neonatal sepsis. The
two treatment groups were also compared to a group of non-treated matched
controls. This is not a true RCT as not every baby entering the study had
the same chance of entering into one of the three groups (two treatment
groups and one control group).
There was no statistical difference (p = 0.25) in the mortality between the two immunoglobulin therapy groups (the two groups that were randomized); mortality in the standard IVIG group was 6/42 (14.2%) and in the IgM-enriched IVIG group it was 3/44 (6.8%). |
| Study | Trial name or title | Participants | Interventions | Outcomes | Starting date | Contact information | Notes |
| Brocklehurst 2001 | International Neonatal Immunotherapy Study (INIS) | Infants are eligible if (i) they are receiving antibiotics with clinical evidence of serious or life-threatening infection; (ii) they have at least one of the following: birth weight less than 1500 g; evidence of infection in blood culture, CSF or usually sterile body fluid; respiratory support via an endotracheal tube (iii) there is substantial uncertainty that IVIG is indicated | Intravenous infusion of IVIG [500 mg (10 ml) per kg] or matching placebo, repeated after 48 hours | (i) mortality or major disability at two years (corrected for gestational age at birth), (ii) mortality, chronic lung disease or major cerebral abnormality before hospital discharge, (iii) length of hospital stay | Mid 2001 As of September 2003 more than 600 infants had been recruited in the UK and Australia |
Dr. Peter Brocklehurst. E-mail address: Peter.Brocklehurst@perinatal-epidemiology.oxford.ac.uk |
Chen J-Y. Intravenous immunoglobulin in the treatment of full-term and premature newborns with sepsis. J Formos Med Assoc 1996;95:839-44.
Christensen 1991 {published data only}
Christensen RD, Brown MS, Hall DC, Lassiter HA, Hill HR. Effect of neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis. J Pediatr 1991;118:606-14.
Erdem 1993 {published and unpublished data}
Erdem G, Yurdakok, Tekinalp G, Ersoy F. The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. Turk J Pediatr 1993;35:277-81.
Haque 1988 {published and unpublished data}
Haque KN, Zaidi MH, Bahakim H. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child 1988;142:1293-6.
Mancilla-R 1992 {published and unpublished data}
Mancilla-Ramirez J, Gonzalez-Yunes R, Castellanos-Cruz C, Garcia-Roca P, Santos-Preciado JI. Immunoglobulina intravenosa en el tratamiento de septicemia neonatal. Bol Med Hosp Infant Mex 1992;49:4-11.
Samatha 1997 {published data only}
Samatha S, Jalalu MP, Hegde RK, Vishwanath D, Maiya PP. Role of IgM enriched intravenous immunoglobulin as an adjuvant to antibiotics in neonatal sepsis. Karnataka Pediatr J 1997;11:1-6.
Shenoi 1999 {published and unpublished data}
Shenoi A, Nagesh NK, Maiya PP, Bhat SR, Rao SDS. Multicentre randomized placebo controlled trial of therapy with intravenous immunoglobulin in decreasing mortality due to neonatal sepsis. Indian Pediatr 1999;36:1113-1118.
Sidiropoulos 1981 {published data only}
Sidiropoulos D, Boehme U, von Muralt G, Morell A, Barandun S. Immunoglobulin supplementation in prevention or treatment of neonatal sepsis. Pediatr Inf Dis 1986;5:S193-4.
Sidiropoulos D, Bohme U, von Muralt G, Morell A, Barandun S. Immunoglobulinsubstitution bei der Behandlung der neonatalen Sepsis. Schweiz med Wschr 1981;111:1649-55.
Weisman 1992 {published data only}
Weisman LE, Stoll B, Kuesar T, Rubio T, Frank G, Heiman H. , et al. Intravenous immunoglobulin (IVIG) therapy of neonatal sepsis. Pediatr Res 1990;27:277A.
Weisman LE, Stoll BJ, Kueser TJ, et al. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. J Pediatr 1992;121:434-43.
Gokalp AS, Toksoy HB, Turkay S, Bakici MZ, Kaya R. Intravenous immunoglobulin in the treatment of Salmonella typhimurium infections in preterm neonates. Clin Pediatr 1994;33:349-52.
Haque 1995 {published data only}
Haque KN, Remo C, Bahakim H. Comparison of two types of intravenous immunoglobulins in the treatment of neonatal sepsis. Clin Exp Immunol 1995;101:328-33.
Brocklehurst P, Tarnow-Mordi W, Haque K, Stenson B, Leslie A, Johnson A. International Neonatal Immunotherapy Study.
* indicates the primary reference for the study
Alejandria MM, Lansang MA, Dans LF, Mantaring JBV. Intravenous immunoglobulin for treating sepsis or septic shock (Cochrane Review). In: The Cochrane Library, Issue 1, 2001. Oxford: Update Software.
Baker CJ. New uses of intravenous immune globulin in newborn infants. J Clin Immun 1990;10:47S-55S.
Baley JE. Neonatal sepsis: the potential for immunotherapy. Clin Perinatol 1988;15:755-71.
Baley JE, Fanaroff AA. Neonatal infections, Part 2: Specific infectious diseases and therapies. In: Sinclair JC, Bracken MB, editor(s). Effective care of the newborn infant. Oxford: Oxford University Press, 1992:477-506.
Friedman CA, Wender DF, Temple DM, Rawson JE. Intravenous gamma globulin as adjunct therapy for severe group B streptococcal disease in the newborn. Am J Perinatol 1990;7:1-4.
Haque K. Should intravenous immunoglobulins be used in the treatment of neonatal sepsis? Br J Intensive Care 1997;7:12-6.
Jenson HB, Pollock BH. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis. Pediatrics 1997;99:e2.
Jenson HB, Pollock BH. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol 1998;22:50-63.
Lacy JB, Ohlsson A. Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: meta-analyses. Arch Dis Child 1995;72:F151-5.
Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants (Cochrane Review). In: The Cochrane Library, Issue 2, 1998. Oxford: Update Software.
Stoll BJ, Gordon T, Korones SB, et al. Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:72-80.
Stoll BJ, Gordon T, Korones SB, et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 1996;129:63-71.
Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates (Cochrane Review). In: Cochrane Library, Issue 4, 1998. Oxford: Update Software.
Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates (Cochrane Review). In: Cochrane Library, Issue 3, 2001. Oxford: Update Software.
| Comparison or outcome | Studies |
Participants |
Statistical method |
Effect size |
|---|---|---|---|---|
| 01 IVIG vs placebo or no intervention for suspected infection | ||||
| 01 Mortality from any cause | 6 |
318 |
RR (fixed), 95% CI |
0.63 [0.40, 1.00] |
| 02 IVIG vs placebo or no intervention for proven infection | ||||
| 01 Mortality from any cause | 7 |
262 |
RR (fixed), 95% CI |
0.55 [0.31, 0.98] |
| 02 Length of hospital stay (mainly term infants) | 3 |
123 |
WMD (fixed), 95% CI |
-2.99 [-5.67, -0.32] |
| 03 Length of hospital stay (preterm infants) | 2 |
51 |
WMD (fixed), 95% CI |
1.39 [-12.18, 14.96] |
| 04 Delayed psychomotor development at 2 years of age | 1 |
29 |
RR (fixed), 95% CI |
1.22 [0.12, 11.95] |
| 05 Growth (weight, height, head circumference) < 3rd centile at 2 years of age | 1 |
29 |
RR (fixed), 95% CI |
0.92 [0.18, 4.65] |
| 06 Increased number of infections to 2 years of age | 1 |
29 |
RR (fixed), 95% CI |
0.41 [0.08, 2.07] |
01 IVIG vs placebo or no intervention for suspected infection
01.01 Mortality from any cause
02 IVIG vs placebo or no intervention for proven infection
02.01 Mortality from any cause
02.02 Length of hospital stay (mainly term infants)
02.03 Length of hospital stay (preterm infants)
02.04 Delayed psychomotor development at 2 years of age
02.05 Growth (weight, height, head circumference) < 3rd centile at 2 years of age
02.06 Increased number of infections to 2 years of age
| This review is published as a Cochrane review in The Cochrane
Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence emerges
and in response to feedback. The Cochrane Library should be consulted
for the most recent version of the review. |
