Arne Ohlsson1, Janet Lacy2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
2Paediatrics, Scarborough, Canada
Citation example: Ohlsson A, Lacy J. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD001239. DOI: 10.1002/14651858.CD001239.pub3.
Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation
University of Toronto
600 University Avenue
Toronto Ontario M5G 1X5
Canada
E-mail: aohlsson@mtsinai.on.ca
| Assessed as Up-to-date: | 10 February 2010 |
|---|---|
| Date of Search: | 15 December 2009 |
| Next Stage Expected: | 10 February 2012 |
| Protocol First Published: | Issue 4, 1998 |
| Review First Published: | Issue 4, 1998 |
| Last Citation Issue: | Issue 3, 2010 |
| Date / Event | Description |
|---|---|
| 11 February 2010 Updated | This updates the review "Intravenous immunoglobulin for suspected or subsequently proven infection in neonates" published in The Cochrane Database of Systematic Reviews, Issue 1, 2004 (Ohlsson 2004). Search updated December 2009. One additional trial added (Ahmed 2006). In this update there is a statistically significant reduction in mortality for infants with either suspected or subsequently proven infection and in the length of stay of 4 days for preterm infants with suspected infection and of 3 days for term infants with proven infection. However, because of the concerns regarding study quality, a clear recommendation for the use of IVIG for suspected infection cannot be made. The results of the soon to be reported INIS trial will most likely confirm or refute the findings of this review. |
| 11 February 2010 New citation: conclusions changed | Conclusions changed. |
| Date / Event | Description |
|---|---|
| 24 April 2008 Amended | Converted to new review format. |
| 18 July 2007 Updated | This updates the review "Intravenous immunoglobulin for suspected or subsequently proven infection in neonates" published in The Cochrane Library, Issue 1, 2004 (Ohlsson 2004). |
| 11 November 2003 New citation: conclusions changed | Substantive amendment |
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 begins several months after birth. The administration of intravenous immunoglobulin (IVIG) may improve immune function by providing IgG that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence.
To assess the effect of IVIG on mortality/morbidity caused by suspected infection in neonates and in those neonates who had suspected infection on study entry and later were confirmed as being infected.
We searched MEDLINE, EMBASE, The Cochrane Library, the reference lists of identified studies, meta-analyses and personal files in December 2009.
We selected randomized or quasi-randomised controlled trials of IVIG for the treatment of suspected bacterial/fungal infection compared to placebo or no intervention in newborn infants (< 28 days old).
Statistical analyses included Typical Relative Risk (RR), Risk Difference (RD), weighted mean difference (WMD), the number needed to treat to benefit (NNTB) (all with with 95% confidence intervals (CI) and the I2 statistic to examine statistical heterogeneity.
The updated search identified one new study. Ten studies of variable quality undertaken in 8 countries are included in this review.
Mortality in infants with clinically suspected infection was reduced following IVIG treatment [7 studies (n = 378); typical RR 0.58 (95% CI; 0.38, 0.89); typical RD -0.10 (95% CI; - 0.18, -0.03); NNTB 10 (95% CI; 6, 33); I2 = 0%]. Mortality in cases of subsequently proven infection was reduced [seven trials (n = 262); typical RR 0.55 (95% CI; 0.31, 0.98);I2 = 0%].
Because of concerns about study quality, there is still insufficient evidence to support the routine administration of IVIG to prevent mortality in infants with suspected or subsequently proved neonatal infection. A large study of the effectiveness of IVIG in neonates with suspected infection has recently been completed. Results of the International Neonatal Immunotherapy Study (INIS trial), which enrolled 3,493 infants, are expected to be published in 2010 (http://www.npeu.ox.ac.uk). The results of that trial should establish the usefulness of IVIG for suspected infection in newborns.
Infants may acquire infections while in the womb or in the hospital after birth, especially if the require intensive care. Such infections may cause serious illness or death. Maternal transport of immunoglobulins (substances in the blood that can fight infections) to the fetus mainly occurs after 32 weeks gestation and infants do not begin to produce immunoglobulins until several months after birth. Theoretically, the adverse effects of infections could be reduced by the administration of intravenous immunoglobulin. There is currently insufficient evidence from the 10 studies conducted to fate to support the routine administration of intravenous immunoglobulins to prevent death in infants with suspected neonatal infection. A very large trial that has enrolled 3,493 infants is soon to be completed by the National Perinatal Epidemiology Unit in Oxford, England. The results of that trial should establish the usefulness of intravenous immunoglobulins for suspected infection in newborns.
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 (1991to1993) 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 five 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. Therefore, 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 randomised 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 (typical 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 randomised 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) that evaluated 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 typical risk difference 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-randomised 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. In another meta-analysis, Jenson 1997 included 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). In a meta-analysis of five studies of IVIG to treat neonatal sepsis, Haque 1997 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 randomised 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 (four 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) Disk Issue 1, 2004 ( Ohlsson 2004) and in July 2007 when no new trials were identified.
Primary objective
To assess the effect of IVIG on 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 randomised 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). Species specific immunoglobulins (such as for staphylococcus aureus or epidermidis) were not included as they are reviewed separately by others within the Cochrane Collaboration.
The search strategy used to identify studies was according to the guidelines of the Cochrane Neonatal Review Group (CNRG).
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 randomised 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.
For this update, the same search strategy was applied for all the databases in December 2009.
The search was initiated by review of personal files. The reference lists of identified studies and subsequently retrieved articles were scanned for additional references.
Progress on the ongoing International Neonatal Imunotherapy Study (INIS) trial was obtained from the trial web site (http://www.npeu.ox.ac.uk/inis) and by communication with the principal investigator Dr. Peter Brocklehurst in February 2010.
Data collection and analysis was done according to the recommendations of the CNRG.
The criteria used to select studies for inclusion in this overview were:
The titles (and abstracts when available) in the MEDLINE, EMBASE and The 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. Additional information was requested from authors of published studies, and we received six replies as of September, 2003.
All identified trials are listed in the table 'Characteristics of Included Studies' or in the table 'Characteristics of Excluded Studies'.
The two review authors 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. This update was conducted by one reviewer (AO).
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 randomisation, 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. For this update, the Risk of Bias (RoB) tables were completed by one reviewer (AO).
The statistical measures used to assess treatment effects are listed under data synthesis below.
Statistically significant heterogeneity was noted and reported. The I-squared test (I2) statistic was included. Length of hospital stay was analysed separately for preterm and mainly term infants as this outcome is dependent on postmenstrual age at birth.
The statistical package (RevMan 5.023) 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 was found the number needed to treat to benefit (NNTB) was calculated. For this update and the previous update the RD and the NNTB were not calculated 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.
Details of the included studies are provided in the Table "Characteristics of Included Studies".
Ten studies (Ahmed 2006; Chen 1996; Christensen 1991; Erdem 1993; Haque 1988; Mancilla-R 1992; Samatha 1997; Shenoi 1999; Sidiropoulos 1981; Weisman 1992) met the inclusion criteria.
Ahmed 2006 (new inclusion) randomized 60 neonates with suspected infection to receive IVIG or placebo. The outcomes for all infants were reported. Blood cultures were positive in 76.7% (23 infants) in the IVIG group and 73.3% (22 infants) in the control group. Results were reported as an intention to treat analysis with proven cases of sepsis combined with suspected cases of sepsis.
Chen 1996 randomized 141 neonates with suspected infection to receive IVIG or placebo. The author did not report on how many infants were randomized to each group and outcomes were reported only on the 56 neonates with positive blood cultures. The author was asked 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 (six 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. Based on correspondence, the authors 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: 500 mg/kg for three consecutive days of Octagam (Ahmed 2006); 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 - 1 g 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.
For details see Risk of Biast table. All 10 included studies (Ahmed 2006; Chen 1996; Christensen 1991; Erdem 1993; Haque 1988; Mancilla-R 1992; Samatha 1997; Shenoi 1999; Sidiropoulos 1981; Weisman 1992) were of small size (24 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 three studies (Ahmed 2006; 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. Four studies (Ahmed 2006; Erdem 1993; Samatha 1997; Sidiropoulos 1981) did not use a placebo.
In all but one study, infants were enrolled because of suspected infections. It is our interpretation that randomization and initiation of treatment occurred at this stage. However, only five of the studies (Ahmed 2006; 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 proven infections at birth were analysed and reported by the authors. In the study by Shenoi (Shenoi 1999), 58 newborns with suspected sepsis were 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. Ahmed (Ahmed 2006) defined mortality as those infants who died in hospital either due to sepsis, prematurity or its complications. 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. In the other studies, it was assumed that all deaths during the initial hospitalisation were accounted for. Ahmed (Ahmed 2006) defined hospital stay as the time needed to cure from the problem or its associated complications and discharge. 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 ten small studies were performed in eight countries [Bangladesh, 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.
One new trial was identified in this update (Ahmed 2006) for a total of ten trials (Ahmed 2006; Chen 1996; Christensen 1991; Erdem 1993; Haque 1988; Mancilla-R 1992; Samatha 1997; Shenoi 1999; Sidiropoulos 1981) that have evaluated the effects 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 (Chen 1996; Mancilla-R 1992; Shenoi 1999).
IVIG vs. PLACEBO OR NO INTERVENTION FOR SUSPECTED INFECTION (Comparison 1):
The following outcome was reported for infants with suspected infection:
Mortality from any cause (Outcome 1.1) (Figure 1):Seven studies (n = 378) reported on the outcome of mortality from any cause in patients with clinically suspected infection. The results showed a statistically significant reduction in mortality [typical RR 0.58 (95% CI; 0.38, 0.89), typical RD -0.10 (95% CI; -0.03, -0.18); NNT 10 (95% CI; 6, 33)]. There was no statistically significant between-study heterogeneity for this outcome, I2 = 0%.
Length of hospital stay (mainly preterm infants) (Outcome 1.2):One study (Ahmed 2006) reported on this outcome. There was a statistically significant reduction n the length of hospital stay (mean difference -3.77 days (95% CI -6.6, -0.94). Tests for heterogeneity not applicable.
IVIG vs. PLACEBO OR NO INTERVENTION FOR PROVEN INFECTION (Comparison 2):
The following outcomes were reported for infants with subsequently proven infection:
Mortality from any cause (Outcome 2.1) (Figure 2):
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. Treatment with IVIG 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)]. The RD and the NNTB were not calculated 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 (mainly term infants) (Outcome 2.2):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 [typical WMD -3 days (95% CI -5.7, -0.3)]. There was statistically significant between-study heterogeneity [(p = 0.007), I2 = 80.0%].
Length of hospital stay (mainly preterm infants) (Outcome 2.3):
Two studies (Chen 1996; Weisman 1992) reported on this outcome in a total of 51 infants. There was no statistically significant reduction in length of hospital stay following IVIG treatment [typical WMD 1.39 days (95% CI -12.18, 14.96)]. There was no statistically significant between-study heterogeneity for this outcome (I2 = 0%). 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.
Delayed psychomotor development at two years of age (Outcome 2.4):
Only Sidiropoulos 1981 reported on delayed psychomotor development at two years of age in 29 patients. There was no statistically significant difference between the two groups [RR 1.22 (95% CI 0.12, 11.95)].
Growth (weight, height, head circumference) < 3rd centile at two years of age (Outcome 2.5):Only Sidiropoulos 1981 reported on growth at two years of age in 29 patients. There was no statistically significant difference between the two groups [RR 0.92 (95%CI 0.18, 4.65)].
Increased number of infections to two years of age (Outcome 2.6):Only Sidiropoulos 1981 reported on this outcome in 29 patients. There was no statistically significant difference between the two groups [RR 0.41 (95% CI 0.08, 2.07)].
No other clinical outcomes were reported.
Serum IgG levels:
An increase in serum IgG levels was noted in the studies that measured levels (Ahmed 2006; 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 venepuncture sites was noted in both groups and did not differ between groups (personal communication Mancilla-Ramirez 2002).
One new trial (Ahmed 2006) was identified for this update of our previously updated reviews (Ohlsson 2001; Ohlsson 2004). Those reviews 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 proven 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 was in contrast to our earlier meta-analysis in The Cochrane Library (Ohlsson 1998b) that 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) that 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). The reviews of Baley and Fanaroff (Baley 1992), Jenson & Pollock (Jenson 1997) and Haque (Haque 1997) included a quasi-randomized study (Sidiropoulos 1981). Our 2001 review (Ohlsson 2001) included five studies (Chen 1996; Erdem 1993; Samatha 1997; Shenoi 1999; Mancilla-R 1992) that were not included in the reviews by Baley and Fanaroff (Baley 1992), Lacy and Ohlsson (Lacy 1995), Jenson & Pollock (Jenson 1997), Haque (Haque 1997) or Jenson and Pollock (Jenson 1998). Alejandria (Alejandria 2001) included four 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 is now known to be a quasi-randomized trial. Our updated meta-analyses (Ohlsson 2001; Ohlsson 2004), therefore, had increased power to provide a more precise estimate of the possible advantage of IVIG treatment for neonatal sepsis compared to previous reviews. The current updated review adds an additional 60 infants. The results now show a statistically significant reduction in mortality in cases of suspected infection with a NNT of 10 infants (95% CI; 6, 33) to avoid one death. The results for infants with subsequently proven infection remain statistically significant as no new studies were identified.
In the previous reviews (Ohlsson 2001; Ohlsson 2004), there was no statistically significant reduction in length of hospital stay for preterm infants but for term infants. In this update there is a statistically significant reduction in the length of stay of four days for preterm infants with suspected infection. However, for the population of term infants with subsequently proven infection, there is 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.
Methodological weaknesses identified in several of these studies included: lack of sample-size calculation (in general very small cohorts were recruited), uncertainty about concealed allocation, 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.
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).
These updated meta-analyses demonstrate a statistically significant reduction in mortality following IVIG treatment in cases with suspected infection and in cases of subsequently proven infection as well as a significant reduction in hospital stay for preterm infants.
A substantial reduction in mortality with a low NNTB of 10 is a clinically very important finding. However, because of the concerns about study quality of the included trials the potential benefits suggested from these meta-analyses warrant further evaluation of the effectiveness of IVIG in the treatment of suspected neonatal infections. Results from the very large INIS trial, that has enrolled 3493 infants, are expected this year. The results of that trial will inform clinicians and researchers about the effectiveness of IVIG in reducing mortality and long-term adverse outcomes.
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. However, The use of antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants has recently been reviewed and is currently not recommended (Shah 2009).
Although the current update of this review found statistically significant and clinically important reductions in mortality following the use of IVIG, the poor methodological quality of most of the included studies warrants caution in the use of IVIG in cases of suspected or subsequently proven neonatal infections. It is advisable to wait for the soon to be published results of the INIS trial before a decision is made to recommend or not to recommend IVIG for suspected neonatal infections.
In view of the concerns about the methodological quality of the studies published to date and the statistically significant reduction in mortality in neonates with suspected and subsequently proven infection, further research is justified. 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 (INIS) has been funded by the Medical Research Council (U.K.) and recruitment of 5,000 infants started in 2001 (Brocklehurst 2001). For the 2007 update of this review, progress on the ongoing INIS trial was obtained from the trial web site (http://www.npeu.ox.ac.uk/inis). The sample size was reduced to 3,500 neonates following a decision by the Data Monitoring Committee in December 2005. Trial recruitment was stopped after 3493 infants had been enrolled and 97% of the data have been collected (personal communication Dr. Peter Brocklehurst February, 2010)
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, 2003 and 2010 on the INIS trial directly related to this topic and which started recruiting patients in 2001.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Arne Ohlsson:
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Verifying and entering data into RevMan
Writing text of review
Performing this update
Janet Lacy:
Literature search and identification of trials for inclusion
Evaluation of methodologic quality of included trials
Abstraction of data
Writing text of review
Both review authors contributed to the previous updates of the review. One author (AO) conducted the 2009 update.
| Methods | Randomized, controlled trial (no placebo) |
|---|---|
| Participants | 60 infants with suspected infection. June 2000 to November 2001 Single centre, Bangladesh |
| Interventions | 30 preterm infants; mean GA (SD) 30.93 =/-1.96 wk, mean BW (SD) 1.45 +/- 0.29; mean (SD) age on admission 9.80 +/- 4.13 days, received 500 mg/kg of IVIG (Octagam, Octapharma AG) once daily for three consecutive days. 30 preterm infants; mean GA (SD) 30.87 +/- 1.80 wk, mean BW (SD) 1.56 +/- 0.30; mean (SD) age on admission 10.30 +/- 4.06 days, received no placebo |
| Outcomes | Mortality, length of hospital stay |
| Notes |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Insufficent information to permit judgement of "yes" or "no". |
| Allocation concealment? | Unclear | Insufficent information to permit judgement of "yes" or "no". |
| Blinding? | No | The control group did not receive a placebo. Lack of blinding is not likely to influence the reporting of mortality. |
| Incomplete outcome data addressed? | Yes | Outcomes reported for all 60 enrolled infants. |
| Free of selective reporting? | Unclear | Insufficent information to permit judgement of "yes" or "no". |
| Free of other bias? | Unclear | Appears to be free of other biases. |
| Methods | Randomized, placebo-controlled trial |
|---|---|
| Participants | 141 infants with suspected infection. |
| Interventions | 10 preterm infants; 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. |
| Outcomes | Mortality |
| Notes | Mortality associated with proved serious infection could be ascertained from this study. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Insufficient information about the sequence generation process to permit judgement of "yes' or "no" |
| Allocation concealment? | Unclear | Insufficient information about the method of concealment to permit judgement of 'yes' or "no" |
| Blinding? | Yes | Placebo was used to blind the intervention and the outcome assessments |
| Incomplete outcome data addressed? | Yes | Even if the number of patients randomised to each group is not stated in the paper, it is possible to ascertain from the text and the tables that the data were reported for all randomised infants with culture proven sepsis The outcomes reported on were: mortality from any cause, length of hospital stay, side effects |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of 'yes" or "no" |
| Free of other bias? | Yes | The study appears to be free from other sources of bias |
| Methods | Randomized, placebo controlled trial |
|---|---|
| Participants | 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. |
| Interventions | 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. |
| Outcomes | Mortality from "suspected sepsis". |
| Notes | Mortality associated with suspected infection could be ascertained from this study. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | "..neonates were randomly selected, by means of a random number table. In an attempt to provide an equal distribution of smaller infants and larger infants two randomisation tables were employed. Central allocation. Pharmacy controlled. |
| Allocation concealment? | Yes | The iv preparation was dispensed from the hospital pharmacy. |
| Blinding? | Yes | The iv preparation was dispensed from the hospital pharmacy in identical units so that investigators and caretakers were not aware of which patients received IVIG and which received placebo. |
| Incomplete outcome data addressed? | Yes | 24 neonates were enrolled in the study. Two were excluded from the study before the infusion was given, one because of treatment with extracorporeal membrane oxygenation and the other because of death before the infusion was given. No adverse drug reactions were reported. The outcomes reported were: mortality from any cause, side effect. |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of "yes" or "no". |
| Free of other bias? | Yes | The study appears to be free of other sources of bias. |
| Methods | Quasi-randomized controlled trial |
|---|---|
| Participants | 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". |
| Interventions | 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. |
| Outcomes | Mortality for cases of "proved sepsis" and "suspected sepsis". |
| Notes | This is a quasi randomised trial - "alternating basis". Mortality associated with suspected and proved infection could be ascertained from this study. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | No | Allocation of patients on "alternating basis" (information provided by the author on request). |
| Allocation concealment? | No | Allocation of patients on "alternating basis" (information provided by the author on request). |
| Blinding? | No | No blinding, but the outcome measured was mortality from any cause is not likely to be influenced by lack of blinding. |
| Incomplete outcome data addressed? | Yes | No missing outcome data. The outcome measured was mortality from any cause. |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of "yes" or "no" |
| Free of other bias? | Yes | The study appears to be free of other sources of bias. |
| Methods | Randomized, placebo-controlled trial. |
|---|---|
| Participants | 60 preterm infants (GA 28 to 37 weeks) with suspected sepsis. |
| Interventions | 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. |
| Outcomes | Mortality |
| Notes | Mortality associated with suspected and proved infection could be ascertained from this study. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Insufficent information to permit judgement of "yes" or "no". |
| Allocation concealment? | Yes | "Whenever sepsis was suspected for the first time in a preterm infant a sealed was drawn, and the infant was allocated to receive either supportive and antibiotic therapy (control group) or supportive and antibiotic therapy .. plus IgM enriched IVIG.." |
| Blinding? | Yes | Blinding of the key personnel was ensured. |
| Incomplete outcome data addressed? | Unclear | The outcomes measured were: mortality from any cause, side effects. No missing outcome data. All deaths in the study population were reported (information provided by the principal investigator). There were no major side effects of the therapy. |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of "yes" or "no". |
| Free of other bias? | Yes | The study appears to be free from other sources of bias. |
| Methods | Randomized, placebo-controlled trial |
|---|---|
| Participants | 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). |
| Interventions | 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 |
| Outcomes | Mortality |
| Notes | Mortality associated with proved serious infection could be ascertained from this study. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | Randomization referred to a table of random numbers (information provided by the author on request) |
| Allocation concealment? | Yes | The investigators were blinded to the group of allocation as cards with codes were used (information provided by principal investigator on request). |
| Blinding? | Yes | Blinding of both intervention and outcome assessors (information provided by principal investigator on request). |
| Incomplete outcome data addressed? | Yes | The outcomes measure were mortality from any cause, length of hospital stay. No missing outcome data. All deaths among all 37 randomised infants with subsequently proven infection were reported (information provided by principal investigator on request). |
| Free of selective reporting? | Unclear | Insufficient information provided to permit judgement of "yes" or "no". |
| Free of other bias? | Unclear | The study appears to be free of other sources of bias. |
| Methods | Randomized controlled trial (no placebo) |
|---|---|
| Participants | 60 neonates with suspected sepsis were enrolled. 44 were born preterm and 51 were LBW |
| Interventions | 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. |
| Outcomes | Mortality from any cause |
| Notes | Mortality from any cause and mortality from sepsis and hospital stay could be ascertained from this study. No adverse effect were noted. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Insufficient information to make judgement of "yes" or "no". |
| Allocation concealment? | Unclear | The method of concealment is not described. |
| Blinding? | No | No blinding, but the outcome of mortality from any cause is unlikely to be influenced by lck of blinding. |
| Incomplete outcome data addressed? | Yes | Complete for mortality. Insufficient reporting on attrition to permit judgement on the outcome of length of hospital stay. |
| Free of selective reporting? | No | The outcome "length of hospital stay" is reported incompletely so that it cannot be entered in a meta-analysis. |
| Free of other bias? | Yes | The study appears to be free of other sources of bias. |
| Methods | Randomized controlled trial (no placebo) |
|---|---|
| Participants | 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). |
| Interventions | 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) |
| Outcomes | Mortality |
| Notes | Mortality associated with suspected sepsis and Duration of hospital stay could be ascertained from this study. No adverse effects were noted. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | A random table was used to assign the randomisation sequence (information provided by the principal investigator on request). |
| Allocation concealment? | Yes | Random number allocation was done at the co-ordinating centre and the sealed, numbered envelopes with the allocations were sent to three centres. On entry of a neonate into the trial a sealed, numbered envelop was opened and therapy/placebo instituted |
| Blinding? | No | No blinding but the outcome of mortality is not likely to be influenced by lack of blinding. A non-identical placebo was used in the control group. Length of stay could be influenced by lack of blinding. |
| Incomplete outcome data addressed? | No | 58 neonates with suspected sepsis were allocated to IVIG treatment or placebo. 7 neonates who qualified but did not receive either IVIG or placebo were taken into a separate control group, and one infant who received only one dose of IVIG was excluded from the analyses. Twenty infants were confirmed as having a positive blood culture, whereas in 30 infants bacteraemia was not confirmed. Outcomes were reported for these 50 randomised patients. No adverse effects were reported. |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of "yes" or "no". |
| Free of other bias? | Unclear | The study was terminated in May 1996 as the company (Sandoz India) withdrew support. The attained sample size is much less than intended, but no explanation is given and no stopping rules are reported. |
| Methods | Quasi-randomized controlled trial. |
|---|---|
| Participants | 82 newborns with clinical evidence of sepsis (suspected sepsis) |
| Interventions | 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). |
| Outcomes | Mortality |
| Notes | This is a quasi randomised trial; infants were allocated to IVIG or no IVIG on an alternating basis. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | No | Infants were allocated to IVIG or no IVIG on an alternating basis. |
| Allocation concealment? | No | Infants were allocated to IVIG or no IVIG on an alternating basis. |
| Blinding? | No | No blinding of either the intervention or the outcome measurements except mortality are likely to be influenced by the lack of blinding. |
| Incomplete outcome data addressed? | Yes | No missing outcome data |
| Free of selective reporting? | Unclear | Insufficient information to permit judgment of "yes" or "no". |
| Free of other bias? | Yes | The study appears to be free from other sources of bias. |
| Methods | Randomized, double-blind, controlled trial. |
|---|---|
| Participants | 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. |
| Interventions | 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). |
| Outcomes | Mortality to 56 days of life |
| Notes | Mortality associated with proved serious infection could be ascertained from this study (during the 56 days study period). |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Yes | Central randomisation. |
| Allocation concealment? | Yes | Drug vials were randomly selected in groups of 50 by institution to contain either IVIG or albumin. Each enrolled infant received the next vial of drug available at that institution. The drug vial was reconstituted by the pharmacy. Central allocation, pharmacy controlled. |
| Blinding? | Yes | Lyophilized albumin was provided in identical vials to those described for the study drug and its concentration were selected to ensure that visual and textural characteristics of both products were similar. |
| Incomplete outcome data addressed? | Yes | The outcomes reported were mortality from any cause,length of hospital stay (measured in preterm infants) , side effects. |
| Free of selective reporting? | Unclear | Insufficient information to permit judgement of "yes" or "no". |
| Free of other bias? | Yes | The study appears to be free from other sources of bias. |
Abbreviations:
Bw = birth weight
g = gram
GA = gestational age
IgG = immunoglobulin
iv = intravenous(ly)
IVIG = intravenous immunoglobulin
kg = kilogram
LBW = low birth weight (< 2.5kg)
mg = miligram SEM = standard error of the mean
SD = standard deviation
wk = week (s)
| Reason for exclusion | 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). |
|---|
| Reason for exclusion | 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 name | International Neonatal Immunotherapy Study (INIS) |
|---|---|
| Methods | |
| Participants | 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 |
| Interventions | Intravenous infusion of IVIG [500 mg (10 ml) per kg] or matching placebo, repeated after 48 hours |
| Outcomes | (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 |
| Starting date | The sample size was reduced to 3,500 neonates following a decision by the Data Monitoring Committee in December 2005. Trial recruitment was stopped after 3493 infants had been enrolled and 97% of the data have now been collected (personal communication Dr. Peter Brocklehurst February, 2010) |
| Contact information | Dr. Peter Brocklehurst. E-mail address: Peter.Brocklehurst@perinatal-epidemiology.oxford.ac.uk |
| Notes | Information available at (http://www.npeu.ox.ac.uk/inis/inis_downloads/INIS_update_06-07.pdf.). |
Ahmed SS, Chowdhury MAKA, Hoque MM, Begum D, Ahmed ASMNU. Role of intravenous immunoglobulin (IVIG) as an adjuvant in the treatment of neonatal sepsis in preterm babies. Journal of Bangladesh College of Physicians and Surgeons 2006;24:97-104.
Chen J-Y. Intravenous immunoglobulin in the treatment of full-term and premature newborns with sepsis. Journal of the Formosan Medical Association 1996;95:839-44.
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. Journal of Pediatrics 1991;118:606-14.
Erdem G, Yurdakok, Tekinalp G, Ersoy F. The use of IgM-enriched intravenous immunoglobulin for the treatment of neonatal sepsis in preterm infants. Turkish Journal of Pediatrics 1993;35:277-81.
Haque KN, Zaidi MH, Bahakim H. IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. American Journal of Diseases of Children 1988;142:1293-6.
Mancilla-Ramirez J, Gonzalez-Yunes R, Castellanos-Cruz C, Garcia-Roca P, Santos-Preciado JI. Immunoglobulina intravenosa en el tratamiento de septicemia neonatal. Boletín Médico del Hospital Infantil de México 1992;49:4-11.
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 Pediatric Journal 1997;11:1-6.
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 Pediatrics 1999;36:1113-8.
Sidiropoulos D, Boehme U, von Muralt G, Morell A, Barandun S. Immunoglobulin supplementation in prevention or treatment of neonatal sepsis. Pediatric Infectious Disease 1986;5:S193-4.
Sidiropoulos D, Bohme U, von Muralt G, Morell A, Barandun S. Immunoglobulinsubstitution bei der Behandlung der neonatalen Sepsis. Schweizerische Medizinische Wochenschrift 1981;111:1649-55.
Weisman LE, Stoll B, Kuesar T, Rubio T, Frank G, Heiman H. Intravenous immunoglobulin (IVIG) therapy of neonatal sepsis. Pediatric Research 1990;27:277A.
Weisman LE, Stoll BJ, Kueser TJ, et al. Intravenous immune globulin therapy for early-onset sepsis in premature neonates. Journal of Pediatrics 1992;121:434-43.
Alejandria MM, Lansang MA, Dans LF, Mantaring JBV. Intravenous immunoglobulin for treating sepsis or septic shock. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD001090. DOI: 10.1002/14651858.CD001090.
Baker CJ. New uses of intravenous immune globulin in newborn infants. Journal of Clinical Immunology 1990;10:47S-55S.
Baley JE. Neonatal sepsis: the potential for immunotherapy. Clinics in Perinatology 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. American Journal of Perinatology 1990;7:1-4.
Haque K. Should intravenous immunoglobulins be used in the treatment of neonatal sepsis? British Journal of 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. Seminars in Perinatology 1998;22:50-63.
Lacy JB, Ohlsson A. Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: meta-analyses. Archives of Disease in Childhood 1995;72:F151-5.
Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane Database of Systematic Reviews 1998, Issue 2.
Shah PS, Kaufman DA. Antistaphyloccoccal immunoglobulins to prevent staphylococcal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD006449. DOI: 10.1002/14651858.CD006449.pub2 .
Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates. Cochrane Database of Systematic Reviews 1998, Issue 4.
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Mortality from any cause | 7 | 378 | Risk Ratio (M-H, Fixed, 95% CI) | 0.58 [0.38, 0.89] |
| 1.2 Length of hospital stay (preterm infants) | 1 | 60 | Mean Difference (IV, Fixed, 95% CI) | -3.77 [-6.60, -0.94] |
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 2.1 Mortality from any cause | 7 | 262 | Risk Ratio (M-H, Fixed, 95% CI) | 0.55 [0.31, 0.98] |
| 2.2 Length of hospital stay (mainly term infants) | 3 | 123 | Mean Difference (IV, Fixed, 95% CI) | -2.99 [-5.67, -0.32] |
| 2.3 Length of hospital stay (preterm infants) | 2 | 51 | Mean Difference (IV, Fixed, 95% CI) | 1.39 [-12.18, 14.96] |
| 2.4 Delayed psychomotor development at 2 years of age | 1 | 29 | Risk Ratio (M-H, Fixed, 95% CI) | 1.22 [0.12, 11.95] |
| 2.5 Growth (weight, height, head circumference) < 3rd centile at 2 years of age | 1 | 29 | Risk Ratio (M-H, Fixed, 95% CI) | 0.92 [0.18, 4.65] |
| 2.6 Increased number of infections to 2 years of age | 1 | 29 | Risk Ratio (M-H, Fixed, 95% CI) | 0.41 [0.08, 2.07] |
This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2010 (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. |
