PEDIATRICS Vol. 99 No. 2 February 1997,
p. e2
Copyright ©1997 by the American Academy of Pediatrics
ELECTRONIC ARTICLE:
Meta-analyses of the Effectiveness of Intravenous Immune Globulin
for Prevention and Treatment of Neonatal Sepsis
and
From the Departments of * Pediatrics and
Microbiology,
University of Texas Health Science Center, San Antonio, Texas and the
Departments of § Health Policy and Epidemiology and
Pediatrics,
University of Florida College of Medicine, Gainesville, Florida.
Objective. To determine the effectiveness of intravenous immune globulin (IVIG) in the prevention and treatment of neonatal sepsis.
Design. All published studies of IVIG for the prevention or treatment of neonatal sepsis were reviewed. Peer-reviewed, prospective, randomized trials with high merit were analyzed by two meta-analyses. The effect of prophylactic IVIG was evaluated by comparison of the numbers of cases of sepsis (bacteremia in the presence of systemic manifestations of sepsis), and of therapeutic IVIG by comparison of the numbers of deaths resulting from early-onset sepsis.
Results. Meta-analysis of 4933 evaluable newborns in 12 studies of IVIG prophylaxis showed a statistically significant negative association with the incidence of sepsis in premature low birth weight newborns given IVIG shortly after birth (P = .0193, two-sided). The heterogeneity across these studies precluded estimation of a common odds ratio. Meta-analysis of 110 evaluable cases of neonatal sepsis in three studies of IVIG treatment of neonatal sepsis showed a significant decrease in the mortality rate for neonates with sepsis given IVIG (P = .007, two-sided). The common odds ratio was .173 (95% confidence interval = .031 to .735).
Conclusions. Using conservative and objective outcome rating criteria, the addition of IVIG to standard therapies is of minimal but demonstrable benefit in preventing sepsis when administered prophylactically to premature low birth weight newborns, and of unequivocal benefit in preventing death when administered therapeutically for early-onset neonatal sepsis. The likelihood of newborns with sepsis living past the neonatal period was improved nearly sixfold when IVIG was administered in addition to standard therapies. neonatal sepsis, immune globulin.
Humoral immunity of the human newborn is provided primarily by maternal immunoglobulin G (IgG) transferred transplacentally beginning at 8 to 10 weeks of gestation and accelerating during the last trimester. The lack of opsonic antibody is an important risk factor for susceptibility of newborns to infections caused by many bacteria with polysaccharide capsules (eg, group B Streptococcus, Escherichia coli, Haemophilus influenzae type b, Streptococcus pneumoniae) that cause serious bacterial infections in newborns.1,2 Premature infants, compared to full-term infants, have lower levels of IgG at birth that further decreases during the first few weeks of life. The relative deficiency of humoral immunity in premature newborns may contribute to the inverse correlation of birth weight and rate of neonatal sepsis, with an 86-fold increased rate of sepsis in newborns of birth weight 600 to 999 grams compared to newborns of birth weight of more than 2500 grams.3 Infants born prematurely are also at risk for nosocomial infections resulting from prolonged hospitalization.4
The benefit of passive immunization by prophylactic administration of intravenous immune globulin (IVIG) for prevention of bacterial infections has been established for patients with primary agammaglobulinemia and with symptomatic human immunodeficiency virus infection.5,6 Routine administration of IVIG for other immunocompromised hosts has not consistently been shown to clearly decrease the incidence of bacterial infections. Therapeutic IVIG and monoclonal antibodies to gram negative bacteria have been studied as adjunctive treatment for bacterial sepsis and shock but their effectiveness remains controversial.7
Exogenous immune globulin given at birth to premature low birth weight newborns may be beneficial for prevention of early-onset sepsis after peripartum transmission of maternal vaginal flora in the setting of low maternal antibody levels1 and for late-onset and late, late-onset (occurring after 30 days from birth)4 nosocomial infections.8 The earliest studies using immune serum globulin as prophylactic immune globulin therapy in newborns failed to demonstrate effectiveness in prevention of bacterial infections probably because of the low doses of immune globulin necessitated by the intramuscular route of administration.9 At least 20 English language, peer-reviewed, prospective, randomized studies from 1984 to 1994 have commented on the effectiveness of IVIG for prophylaxis of neonatal infections. These studies included populations ranging in number from 20 to 2416 newborns. The conclusions of the authors have ranged from definite or apparent reduction of infection,12 to no or limited reduction (including the two largest studies),18 to a possible deleterious effect of IVIG.30,31
At least four prospective, randomized studies published from 1986 to 1992 have evaluated the effect of IVIG in addition to standard therapies for the treatment of neonatal sepsis.32 These prospective studies included small sample sizes of 22, 31, 35, and 60 neonates with proven sepsis. Two of these studies33,35 reported a beneficial effect with administration of IVIG. None of the four prospective studies adding IVIG to conventional treatments has individually demonstrated a statistically significant survival advantage. An additional report of the effectiveness of IVIG for treatment of sepsis suggested a beneficial effect of IVIG but used historical controls.36
These conflicting studies and the controversial role of exogenous IVIG in neonates for prevention and treatment of neonatal sepsis have been the subject of editorials in major medical journals that have underscored the putative and likely benefits of IVIG administration but concluded that routine use should await further definitive studies.37
Because the effectiveness of IVIG administration for prevention or treatment of neonatal sepsis remains unclear, in part due to relatively small or heterogeneous study populations, meta-analyses of these numerous small studies may be useful to: (1) assess the effectiveness of prophylactic IVIG administration in neonates to prevent sepsis; and (2) assess the effectiveness of IVIG administration as additional therapy to prevent death for neonates with proven sepsis. Meta-analysis is possible because several studies have been published in which the eligibility criteria were explicit, the schema for IVIG administration were described, definitions of proven sepsis were clear and appropriate, and the frequencies of specific outcomes (sepsis or death) were provided for treatment and control groups.
Studies Utilized
All published studies of the effectiveness of IVIG given either prophylactically to prevent neonatal sepsis or therapeutically to treat documented neonatal sepsis were identified by personal knowledge or bibliographic search using MEDLINE. Each study was carefully scrutinized for quality of study design and rigor of scientific investigation including enrollment criteria, intervention, and description of outcomes permitting uniform application of meta-analysis criteria. Inclusion criteria for meta-analysis included: English-language (to allow our scrutiny of the study); peer-review publication; a prospective, randomized study design that included a concurrent control group receiving either a placebo or no IVIG treatment; intervention of IVIG administration either given shortly after birth for prophylaxis, or on clinical diagnosis of sepsis for treatment; ability to combine studies (including enrollment criteria, intervention, and description of outcomes); and substantial scientific merit. A meta-analysis weighted by individual study quality was not performed because of disparities resulting from use of a particular scale40 and the recognition that, for this situation, the determination of quality can not be measured by a checklist or a unidimensional scale alone.41Statistical Analysis
Two-by-two contingency tables were constructed to determine the relationship between IVIG administration and outcome. For determination of effectiveness, newborns were dichotomized into IVIG treated and untreated categories. For prophylactic effectiveness, outcome was dichotomized into no sepsis and sepsis groups. For therapeutic effectiveness, outcome was dichotomized into survived and died groups. Survival was narrowly defined as living past the acute episode of sepsis and did not require ultimately surviving hospitalization. Hypothesis testing was performed using asymptotic tests (
2) with the Robins, Breslow, and Greenland variance estimates used to calculate P values.44 For
sparse data, exact tests of proportions were used. The magnitude of
association between IVIG treatment and outcome was represented by the
odds ratio (OR) and 95% confidence interval (CI). A test of
homogeneity across studies was performed; the criterion of
P < .10 was used to reject the null hypothesis of
homogeneity across studies. Where appropriate, summary measures across
studies were estimated as a Mantel-Haenszel common OR. All statistical
analyses were performed using the StatXact Turbo software (CYTEL
Software Corporation, Cambridge, MA).
Twelve studies of the effectiveness of IVIG prophylaxis (Table 1) and three studies of the effectiveness of IVIG treatment (Table 2) fulfilled the criteria for meta-analysis. The numbers indicated in Tables 1 and 2 for each study may differ from those reported in the original studies' conclusions because meta-analysis outcome criteria required blood culture-positive sepsis. The study by Clapp et al14 reported results for a total of 200 patients, 115 of whom were randomly assigned to IVIG and placebo groups in a double-blind fashion. The additional 85 patients were not randomly assigned due to parental refusal. These 85 patients were excluded from the meta-analysis because they were not randomized. The study by Bussel et al15 reported episodes of sepsis in the first 30 days and for the first 70 days of life. Because IVIG was administered only as late as 15 to 21 days of life, and for comparison with other studies, the meta-analysis included only episodes of sepsis occurring during the first 30 days of life.
|
Table 1. Studies of the Efficacy of IVIG in Prevention of Neonatal Sepsis |
|
Table 2. Studies of the Efficacy of IVIG in the Treatment of Neonatal Sepsis |
1300 to
2000 grams (centered around 1500 grams). Two studies also included a
few term infants requiring intensive care, in addition to including
preterm infants.13,25
IVIG for Prevention of Neonatal Sepsis
The 12 studies represent a total of 4933 neonates including 2481 infants receiving IVIG and 2452 infants as controls. All 12 studies were prospective and randomized; 7 were placebo-controlled (usually albumin), double-blinded trials. The prophylactic effectiveness of IVIG using our outcome criteria individually and collectively for each of the 12 studies is shown in Figure 1. Five studies12,17,22 demonstrated a statistically significant protective advantage for IVIG in preventing early-onset sepsis. In contrast, one study30 showed a statistically higher sepsis rate for subjects who did receive IVIG. The remaining six studies15,20,25,29 failed to show a statistically significant difference between newborns who received or did not receive IVIG treatment.
Fig. 1. Separate results for the 12 studies examining the relationship between prophylactic IVIG use in neonates and the development of sepsis. Studies are listed in chronologic order. The closed circles represent the OR and the horizontal lines represent the 95% CI. The solid vertical line indicates an OR of 1.0 (no difference between neonates treated with IVIG compared to those who were not treated with IVIG). The result of the Breslow and Day homogeneity test of effect across studies is shown.46 A two-sided test for the overall association between IVIG use and prevention of sepsis showed statistically significant association (P = .0193). Asymptotic methods were used for all estimates and significance tests except for the study by Clapp et al14 for which the OR and 95% CI were calculated using exact methods.
[View Larger Version of this Image (18K GIF file)]
2 statistic = 22.49, 11 degrees of freedom, P = .021).46 Therefore,
a common OR cannot be estimated by pooling data across these studies.
This is consistent with the visual impression of Figure 1, that the study direction for the effect of IVIG therapy was not uniform across
studies. A summary statistical test was performed to test the
hypothesis that prophylactic IVIG administration was associated with
the risk of sepsis. Data were pooled and a stratified analysis was
performed. IVIG use was significantly associated with a the rate of
sepsis (P = .0193, two-sided). The addition of
IVIG to other therapies appears to offer a slight protective advantage in the prevention of sepsis in low birth weight premature newborns. However, given the heterogeneity of these studies a positive protective advantage cannot be proven. The magnitude of protection appears to be
relatively small. Including the nine episodes of sepsis in the 85 infants (10.6% incidence of sepsis) in the study by Clapp et
al14 not randomized due to parental refusal would have strengthened the finding of a beneficial effect of IVIG for the prevention of sepsis.
1000 grams; a second study provided sufficient information
to evaluate newborns <1500 or
1500 grams. The remaining eight
studies provided insufficient information to evaluate subgroups of
patients. The other two studies enrolled primarily premature but also a
few full-term newborns requiring neonatal intensive care but provided
insufficient information to evaluate outcome of these two groups by
birth weight. From these studies it is not possible to distinguish the
possible differences in benefit based on term vs preterm birth, or
based on birth weight divisions. There is no evidence of a
gradient-response effect for studies ranked by the inclusion of
extremely low-, very-low-, and low birth weight babies. However,
exclusion of the two studies that included a few full-term infants did
not alter the conclusions of the meta-analysis.
2 statistic = 12.25, 5 degrees of freedom, P = .0316) as well as the six other studies
(Breslow and Day homogeneity test
2 statistic = 13.49, 5 degrees of freedom, P = .0192). Neither
subgroup showed statistically significant association of IVIG with
prevention of sepsis (P = .07 for each group).
IVIG for Treatment of Neonatal Sepsis
The three studies that addressed treatment of sepsis represent a total of 120 episodes of neonatal sepsis including 55 infants who received IVIG and the 55 infants included as controls. All three studies were prospective and randomized; two were placebo-controlled (albumin), double-blinded trials. A consistent relationship between IVIG treatment for neonates and decreased death rate was observed for all three studies (Fig 2). A test for homogeneity failed to reject the null hypothesis (Breslow and Day homogeneity test
2 statistic = 1.4, 2 degrees of freedom,
P = .49)46 permitting calculation of a
common OR. There was a statistically significant relationship between
IVIG administration and a decreased death rate (common OR = .173, 95% CI = .031 to .735; P = .007, two-sided). A
common OR below 1.0 would reflect a lower mortality rate in the cohort
receiving IVIG. The advantage of IVIG administration given in addition
to conventional therapies is additive and increases the likelihood of
survival of early-onset neonatal sepsis nearly sixfold.
Fig. 2. Separate results for the three studies examining the relationship between therapeutic IVIG use and case fatality from neonatal sepsis. Studies are listed in chronologic order. Exact methods were used for all estimates and significance tests for the assessment of treatment. The closed circles represent the OR and the horizontal lines represent the 95% CI. The solid vertical line marks an OR of 1.0 (no difference between neonates treated with IVIG compared to those who were not treated with IVIG). The result of the Breslow and Day homogeneity test of effect across studies is shown.46 The dashed vertical line indicates the average reduction in death (common OR). The exact estimates of the common OR (closed circle) and overall 95% CI (bottom horizontal line) are shown. An exact test for homogeneity is shown at the bottom. An exact two-sided test for the overall association between IVIG treatment and decreased death rate showed statistically significant association (P = .007).
[View Larger Version of this Image (10K GIF file)]
The absence of type-specific opsonic antibody in the neonate has been demonstrated to predispose to bacterial infection for type Ia, Ib, and III strains of group B Streptococcus as a result of diminished opsonization.1 Opsonic antibody is probably important for other neonatal pathogens as well, including coagulase-negative Staphylococcus.47 The benefit of correcting this immune deficit should be most directly demonstrable in premature low birth weight newborns who do not receive a full measure of transplacental maternal antibody, and in premature or full-term newborns who clinically demonstrate this deficit as sepsis. Such benefit may not be easily detectable given the complex interactions of bacterial virulence factors (eg, attachment factors, protective factors, growth and spreading factors, toxins) and neonatal host defenses (mucosal barriers, mucosal immunity, strain type-specific antibody, complement activity, and the number and function of phagocytes) that may obscure therapeutic benefit from improvement of a single immunologic factor. Administration of IVIG probably exerts its major effect on neonatal host defenses by providing opsonic antibody against neonatal pathogens that enhance phagocytosis and killing of bacteria by neutrophils.1,18 IVIG may also neutralize toxins, immunomodulate T cells and macrophages, especially cytokine synthesis, and affect B cell function and the complement system.48 The beneficial effect of IVIG for treatment of sepsis is not due solely to the hemodynamic effect of colloid infusion as 75 of the 110 infants (68%) with sepsis were in the two placebo-controlled trials. The purpose of these meta-analyses was to determine any beneficial or detrimental effect regardless of the actual mechanisms that may be responsible.
2 statistic = 25.85, 14 degrees of freedom
[one study was uninformative], P = .027, the
heterogeneity precluded estimation of a common OR; association of IVIG
use with a decreased rate of sepsis P = .027, two-sided).46
= .05, one-sided). For comparison, detection of a 5% difference would have
required 1237 subjects in each group. A statistically significant
difference (P = .0193) was found in the
meta-analysis of all studies with a combined total of 4933 newborns,
suggesting an increase in statistical power derived by the pooling of
data across studies. Thus, it is not surprising that the benefit of
IVIG for prophylaxis was not statistically significant even in the
largest single study of 2416 neonates.27
Received for publication Jun 25, 1996; accepted Apr 11, 1996.
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Pediatrics (ISSN 0031 4005). Copyright ©1997 by the American Academy of Pediatrics
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