Original Article
Intravenous Immune Globulin for the Prevention of Nosocomial Infection in Low-Birth-Weight Neonates
N Engl J Med 1992; 327:213-219July 23, 1992
- Abstract
- Abstract
Background.
Nosocomial infection is a major risk for premature infants with very low birth weights. One reason for their susceptibility to infection may be antibody deficiency, since there is little transfer of maternal IgG to the fetus before 32 weeks' gestation.
Methods.
We conducted a multicenter, double-blind study of neonates weighing 500 to 1750 g at birth. A total of 588 neonates were randomly assigned, with stratification for birth weight, to receive periodic intravenous infusions of either immune globulin (500 mg per kilogram of body weight per day) or a placebo. Mortality, morbidity, and nosocomial infection during the next 56 days were assessed.
Results.
The infusions were well tolerated; mild, reversible adverse reactions occurred in five infants in each group. There was a significant reduction in the risk of a first nosocomial infection in the recipients of immune globulin as compared with the placebo recipients (relative risk, 0.7; 95 percent confidence interval, 0.5 to 0.9). About 85 percent of the nosocomial infections were bacterial; the majority of these were caused by coagulase-negative staphylococci or Staphylococcus aureus. The neonates who received immune globulin had fewer mean days of hospitalization than the controls (62 vs. 68, P = 0.15); among the infants with infections, the difference in the mean length of the hospital stay was even greater (80 days vs. 101 days, P = 0.02).
Conclusions.
For premature infants weighing between 500 and 1750 g at birth, treatment with intravenous infusions of immune globulin is safe and reduces the risk of nosocomial infection. (N Engl J Med 1992;327: 213–9.)
Media in This Article
Figure 1
Mean Serum IgG Levels at Enrollment, before Each Infusion Was Given, and One Week after the Final Infusion, According to Birth-Weight Category, in the Placebo Group and the Immune Globulin Group.Table 1
Frequency of Maternal Complications and Characteristics of the Infants at Study Entry, According to Study Group.*Article Activity
- Article
SURVIVAL has improved for premature neonates. An increasing proportion of the morbidity and mortality among such infants is now the result of nosocomial infection; this is particularly true among those who weigh less than 1500 g at birth (very-low-birth-weight infants).1 , 2 Such infections prolong hospitalization, further increasing the already substantial cost of care for these babies.3 Their enhanced susceptibility to systemic infection results from a number of factors, including immaturity of the humoral and cellular immune systems.1 , 4
There is little transport of maternal IgG to the fetus before 32 weeks' gestation, and endogenous synthesis does not begin until about 24 weeks after birth.4 5 6 7 Thus, in low-birth-weight infants serum IgG levels by three months of age are only 60 to 150 mg per deciliter,7 8 9 10 as compared with 100 to 350 mg per deciliter for infants born at term. The commercial availability of highly purified monomeric suspensions of IgG in the form of human intravenous immune globulin, combined with its efficacy in preventing infections in IgG-deficient adults,11 , 12 led to the hypothesis that if given as prophylaxis to premature infants, IgG would reduce the incidence of nosocomial infection.5 This hypothesis is supported by studies demonstrating the opsonic activity of these preparations against several neonatal pathogens13 14 15 16 17 and by their protective activity in animal models of systemic infection.17
We conducted a multicenter, randomized, double-blind study to determine whether periodic intravenous infusions of immune globulin would reduce the incidence of systemic nosocomial infection and the resulting morbidity among low-birth-weight infants during the first two months of life.
Methods
Study Population
Premature infants weighing between 500 and 1750 g at birth were eligible for the study if they were three to seven days of age, had stable cardiovascular function, were expected to survive for more than 48 hours, and required intravenous access for medical therapy. Infants with severe congenital anomalies, those already enrolled in experimental intervention protocols, and those who had received intravenous immune globulin or transfusions of whole blood, platelets, or fresh-frozen plasma before enrollment were excluded. Infants who required blood products after enrollment remained in the study. The experimental protocol was approved by the humaninvestigation review committees at each of the six participating institutions and hospitals, and informed consent was obtained from one or both parents before randomization.
Study Design
This study was conducted at six institutions in the United States. At entry, infants were randomly assigned to study groups that were stratified according to 250-g birth-weight categories. Each study site had its own randomization table balanced in blocks of six to ensure equal distribution of infants to the treatment (immune globulin) and placebo groups. Infants were randomly assigned by the pharmacist at the study site to receive an intravenous infusion of either immune globulin (500 mg per kilogram of body weight) or an equal volume (10 ml per kilogram) of placebo (a sterile solution of 5 percent albumin and 0.9 percent sodium chloride).
Infusions were administered at enrollment (age, 3 to 7 days), 1 week later, and then every 14 days until a total of five infusions had been given or until hospital discharge, whichever came first. We used a lyophilized, highly purified preparation of intact IgG prepared from pooled units of human plasma by Cohn fractionation, followed by ultrafiltration and ion-exchange adsorption (Gammagard, Baxter Healthcare, Hyland Division, Glendale, Calif.). Four different lots of 0.5-g vials of immune globulin were used during the study.
In this double-blind study, only the pharmacist knew whether the infant received immune globulin or placebo. The initial infusion rate was slow, with increases as tolerated by the infant; each infusion was completed within two hours. During each infusion, the physical appearance, activity, and vital signs of the infant were closely monitored and recorded by the care giver. Blood was collected from all patients before each infusion, one week after the final infusion, and whenever an episode of suspected infection occurred. Serum was separated from clotted whole blood by centrifugation and stored at -70°C until testing. Serum IgG levels were determined by nephelometry at a central laboratory.
Demographic data were collected from the medical records of the infants and their mothers at entry; clinical data were collected at entry and then daily for 56 days. For infants hospitalized beyond this period, only the date of discharge or death was routinely recorded.
An independent oversight committee consisting of a neonatologist, a pediatric immunologist, a specialist in pediatric infectious diseases, and a biostatistician reviewed interim results of the trial. This committee monitored unexpected outcomes, including any unacceptable adverse effects of treatment. Moreover, it was charged with halting the study before the planned termination after the enrollment of 600 patients if there was no evidence of benefit from immune globulin prophylaxis.
Whenever systemic infection was suspected on clinical grounds, blood samples and often cerebrospinal fluid and urine samples were obtained for bacterial culture. In addition, samples from sites of focal inflammation, such as abscesses, or of pleural, peritoneal, or joint fluids, were also cultured as clinically indicated. If viral infection was suspected, specimens were obtained for culture at the discretion of the attending physician. The criteria for proved infection included one or more clinical findings of neonatal sepsis1 and at least one of the following: a culture of a blood sample obtained from a peripheral vessel yielding a bacterial or fungal pathogen, the isolation of a pathogen from a normally sterile body site (cerebrospinal, pleural, peritoneal, or joint fluid; bone; soft-tissue; or urine obtained by suprapubic puncture or bladder catheterization), or the isolation of virus from an infant with clinical deterioration. An episode of rotavirus infection was identified by antigen-detection assay (Rotazyme assay) in the stool of an infant with gastrointestinal symptoms. Infection due to coagulase-negative staphylococci was confirmed by two or more positive cultures of blood obtained from separate peripheral-blood vessels or a positive culture of blood and a positive culture from a normally sterile body site, both growing organisms of identical species and antimicrobial susceptibility.
Evaluation of Morbidity and Mortality
After enrollment, infants were followed for 56 days or until hospital discharge, whichever came first. Measures of morbidity included episodes of infection, duration of mechanical ventilation, oxygen therapy, xanthine therapy, use of pressors, intensive care, inability to take oral feedings, intravascular catheterization, parenteral nutrition, phototherapy, antibiotic therapy, length of hospitalization, and the need for transfusions of blood products or surgery. The occurrence and severity of complications of prematurity, such as hyaline membrane disease, pulmonary interstitial emphysema, bronchopulmonary dysplasia, patent ductus arteriosus, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, were also tabulated. Intraventricular hemorrhage was classified as grade I through IV18 and necrotizing enterocolitis as stage I through III,19 both defined according to standard criteria.
Statistical Analysis
Data obtained at entry and during the study were analyzed for the comparability of maternal and neonatal clinical characteristics between the two groups with use of parametric or nonparametric methods, as appropriate. The chi-square test was used for qualitative data, and the two-sample t-test (two-tailed) for quantitative data.20 The relative risk of a first infection was calculated per patient-day (on the basis of the length of time at risk until the first infection), adjusted for the birth-weight category and weighted according to the directly pooled estimation scheme described by Rothman.21 Confidence intervals for relative risks were also calculated. The modification of treatment effect (for example, by birth-weight category or study site) was evaluated by comparing stratum-specific estimates with the pooled estimates with the chi-square test. The distribution of the lengths of time to the first infection was estimated with the product—limit method of Kaplan and Meier.22 The median lengths of time to the first proved infection were compared by the Cox—Mantel test.23
Results
Between July 16, 1987, and December 12, 1988, 588 low-birth-weight infants were randomly assigned to study groups at the six centers. Eleven of these patients were later found to be ineligible but were included in the analyses on an intention-to-treat basis. Each of these 11 infants was ineligible because of a protocol violation (6 in the placebo group and 5 in the immune-globulin group). Three infants had received immune globulin, platelets, or fresh-frozen plasma before enrollment, four received the wrong treatment (two in each group), and four had unstable cardiovascular status after randomization and died without having received an infusion. The last four were included only in the analysis of the comparability of the groups. Except in the heaviest birth-weight group, in which intravenous therapy was often not required after 72 hours of age or physicians or parents decided that an infant was "too healthy" to enter the study, the number of infants enrolled at each center reflected the number of eligible premature neonates at that site, as follows: 69 in Chicago, 105 in Honolulu, 199 in Houston, 93 in Kansas City, 71 in San Antonio, and 51 in Winston-Salem.
Maternal Complications and Characteristics of the Infants at Study Entry
To ensure that there was no difference due to an imbalance between the groups, we determined the frequency of selected maternal complications and neonatal characteristics at entry. The frequency of these variables was similar in both groups (Table 1Table 1
Frequency of Maternal Complications and Characteristics of the Infants at Study Entry, According to Study Group.*), except for the significantly higher number of infants with appropriate birth weights for gestational age in the immune globulin group.Tolerance and Safety of Intravenous Immune Globulin
Of the 584 infants given infusions during the study, 297 received 1163 infusions of placebo and 287 received 1125 infusions of immune globulin (mean, 3.9 infusions per infant in each group). Adverse reactions were noted during 10 infusions (5 in each study group, or <1 percent). These consisted of mild increases or decreases in blood pressure, heart rate, or temperature that were reversed when the rate of infusion was slowed. Two infants in each group had fluid overload after an infusion and were treated with single doses of furosemide. Serum aspartate and alanine aminotransferase levels were determined as part of routine follow-up or for clinical reasons in 42 infants in the placebo group and 35 in the immune globulin group at the age of two months or more. Only 1 of 61 asymptomatic infants evaluated after hospital discharge had elevated levels of serum aspartate and alanine aminotransferase; this child had received placebo. Of the 16 evaluated for clinical reasons, 6 (4 in the placebo group and 2 in the immune globulin group) had elevations, and most of these were attributed to cholestasis associated with total parenteral nutrition or to proved bacterial sepsis.
Serum IgG Levels before and during the Study
We analyzed the serum IgG concentrations at enrollment, before each infusion was given, and one week after the fifth infusion. At enrollment, the mean (±SD) IgG level in the placebo recipients was 520±231 mg per deciliter, a value similar to that in the immune globulin group (536±222 mg per deciliter, P = 0.174 by the two-sample t-test). Among patients given placebo, this initial IgG level fell progressively to 443±174 mg per deciliter one week after study entry, 303±120 mg per deciliter at three weeks, 215±101 mg per deciliter at five weeks, 181±128 mg per deciliter at seven weeks, and 167±139 mg per deciliter at eight weeks. The mean serum IgG levels in infants given immune globulin were significantly higher at each of these times: 651±221, 549±165, 487±141, 468±116, and 591±150 mg per deciliter, respectively (P<0.001 for all comparisons). As expected, serum IgG concentrations at enrollment were directly related to birth weight and declined according to the expected half-life of IgG (Fig. 1Figure 1
Mean Serum IgG Levels at Enrollment, before Each Infusion Was Given, and One Week after the Final Infusion, According to Birth-Weight Category, in the Placebo Group and the Immune Globulin Group.). In each birth-weight category, receipt of immune globulin (at a dose of 500 mg per kilogram) was associated with trough IgG levels 14 days after infusion (days 21, 35, and 49 of the study) that were equal to or greater than the IgG levels at enrollment (Fig. 1).Infectious Episodes
The infants who received immune globulin had a significantly lower risk of a first infection than the placebo recipients (relative risk adjusted for birth-weight category, 0.7; 95 percent confidence interval, 0.5 to 0.9) (Table 2Table 2
Incidence of Initial Infections during the Study, According to Birth-Weight Category and Study Group.*). This effect was consistent in all birth-weight categories (P = 0.77) and at all study sites (P = 0.73). Since there was a significant imbalance between the two study groups in the proportion of infants who had appropriate birth weights for gestational age, we performed an additional analysis, adjusting for both gestational age and birth-weight category. The resulting relative risk of a first infection in recipients of immune globulin was 0.6 (95 percent confidence interval, 0.4 to 0.8), comparable to the results of the original analysis. This similarity suggests that gestational age was not a confounding variable.The distribution of the lengths of time to the first infection was significantly shifted to the right (increased) for recipients of immune globulin (P = 0.015). Most infants who had infections in both study groups had a single infection. More than one infection occurred in 18 (6 percent) of the immune globulin recipients and 29 (10 percent) of the placebo recipients (P = 0.09). Among the immune globulin recipients, 14 had two infections, 3 had three infections, and 1 had four infections. For placebo recipients the comparable numbers were 24, 5, and 0. Too few infants had multiple infections to permit us to calculate the relative risks for two or more infections.
Causal Agents and Sites of Infection
Table 3Table 3
Causes of Infections, According to Study Group.* summarizes the causal agents isolated from all infected infants. Most infections were bacterial, accounting for 87 percent in the immune globulin group and 85 percent in the placebo group. Among the pathogens, gram-positive aerobic organisms predominated. The agents most frequently isolated were coagulase-negative staphylococci, Staphylococcus aureus, enterococcus, and klebsiella, and the distribution of causal agents was similar in the two groups.Most of the bacterial infections were severe and were manifested as septicemia without other foci of infection. Among placebo recipients, septicemia occurred in 75 (64 percent) of the bacterial infections, soft-tissue or urinary tract infection in 34 (29 percent), peritonitis in 6, meningitis in 3, and osteomyelitis in 1. Similarly, among immune globulin recipients, 50 (62 percent) had septicemia; 24 (30 percent) had soft-tissue infections, cellulitis, subcutaneous abscess, or urinary tract infection; 5 had peritonitis; and 2 had osteomyelitis. Since cultures of cerebrospinal fluid and urine were not performed for every infant with suspected infection, the prevalence at these two sites may have been underestimated.
Frequency of Complications of Prematurity during the Study
In addition to assessing the number of nosocomial infections, we also sought to determine whether other beneficial or adverse outcomes might accompany therapy with immune globulin. Table 4Table 4
Complications of Prematurity According to Study Group.* summarizes the frequency of complications of prematurity in all the infants. Periodic infusions of immune globulin were not associated with statistically significant decreases or increases in the frequency of any of these complications. Variables reflecting morbidity were then compared between the study groups (Table 5Table 5
Duration and Use of Various Therapies, According to Study Group.*). The recipients of immune globulin had shorter durations of several therapies than placebo recipients, but for only two measures were the reductions statistically significant (Table 5). There was a reduction in the mean number of days of hospitalization in the immune globulin group (62 vs. 68, P = 0.15). This difference was more striking when we compared only the infants in the two groups who had infections (80 vs. 101 days, P = 0.02); this finding suggests that even when an infant who received immune globulin had a nosocomial infection, it was less severe and the infant consequently less often required prolonged hospitalization than was the case in the placebo group.During the 56 days of the study, 14 (5 percent) of the infants given placebo and 10 (3 percent) of those given immune globulin died (relative risk, 0.9; 95 percent confidence interval, 0.4 to 2.1 ). All but two deaths (both in placebo recipients) occurred in infants with birth weights below 1250 g. An additional 12 infants in the placebo group and 10 in the immune globulin group died after the study period.
Discussion
In this multicenter, randomized, placebo-controlled, double-blind trial, the periodic administration of intravenous immune globulin significantly reduced the incidence of nosocomial invasive infection of late onset in premature neonates weighing 500 to 1750 g at birth. These findings are consistent with the hypothesis that IgG deficiency and the consequent impaired capacity for opsonization of bacterial pathogens4 , 5 , 24 is a major risk factor for the development of nosocomial infection in low-birth-weight infants.
Our finding that intravenous immune globulin is well tolerated and reduces the incidence of late-onset infection in low-birth-weight infants is similar to that reported in two hospitals in the United States,25 , 26 but it differs from a recent report from Baltimore that indicated no reduction.27 Given the observed rates of infection and the sample sizes in these studies, however, the Type II error in assessing efficacy in each case was presumably rather large; each used immune globulin preparations that differed from that used in our trial; all used distinct dosages and infusion schedules; and more than a third of the infants studied by Kinney et al.27 had birth weights above 1500 g. Thus, direct comparison of our results with those of previous studies is impossible.
Nosocomial infection was not completely eliminated by periodic infusions of intravenous immune globulin. This fact could be related to the use of suboptimal doses or scheduling of infusions, insufficient amounts of protective antibodies in the preparation used, a minor role for IgG in host defense against some nosocomial pathogens, or the influence of other factors on the risk of infection in our patients. In fact, each of these possible explanations may have affected our results.
Regarding the optimal dose of intravenous immune globulin and the best schedule for its administration, data on the half-life of serum IgG suggest that an infusion given every 14 days will maintain or increase base-line levels in healthy neonates. Wide variability among infants within the same birth-weight category has been reported, however.8 , 9 , 28 Furthermore, both infectious and noninfectious events may increase the catabolism of exogenous IgG, making it necessary to use higher doses and more frequent infusions to maintain a given level.5 If a target level25 of 700 mg per deciliter (the lower limit of normal serum IgG levels in the cord blood of term infants) is chosen as ideal, infants weighing less than 1000 g at birth require a minimum of 900 mg per kilogram, but even at this dose they often do not sustain the target level for two weeks.29 Although higher doses might be used, they necessitate large fluid loads and are more likely to cause adverse effects; moreover, in neonatal animal models of infection, doses of 2000 mg per kilogram enhance the lethal effect of infection.30
As to the pathogen-specific effect of the immune globulin preparation used in this study, nosocomial infections with coagulase-negative staphylococci were reduced in number, but not eliminated. This finding is consistent with the results of experiments indicating that antibody is important in the opsonization and phagocytosis of the organisms in vitro31 , 32 and provides protection in an animal model33; it also agrees with the observation that antibody is associated with improvement in the neutrophil and complementmediated responses to septicémie infection in neonates.34 Perhaps the infections that occurred in some infants who received immune globulin resulted from the failure to achieve protective antibody levels or to sustain those levels between infusions, or from the fact that the immune globulin contained low concentrations of antibody against some staphylococcal species. It seems more likely, however, that complex interactions among host responses, as well as differences in virulence among various bacterial strains, explain the occurrence of infections. Additional studies will be necessary to confirm or disprove the existence of specific effects of immune globulin against some but not all nosocomial pathogens in low-birth-weight infants.
Previous controlled studies of adults with primary hypogammaglobulinemia11 or chronic lymphocytic leukemia12 and of children with human immunodeficiency virus infection35 have shown that immune globulin therapy reduces the incidence of bacterial infection and its attendant morbidity without changing mortality rates. Similarly, our clinical trial and smaller controlled studies25 , 27 have not shown a reduction in case-fatality rates among premature neonates given immune globulin. We anticipated this finding because the estimated mortality in very-low-birth-weight infants with nosocomial bacterial infections is only 3 to 7 percent.1 , 24 , 25 , 27 Our study was therefore not designed with the expectation that it would show an effect on mortality. Although the number of deaths associated with infections was lower among the infants who received immune globulin, a larger number of patients would be required to elucidate this issue.
Nonetheless, considerable benefit was associated with the administration of immune globulin — notably a lower risk of infection and fewer days of hospitalization. Lassiter et al.24 found that neonates weighing less than 1500 g at birth in whom nosocomial sepsis developed had longer hospitalizations than weight-matched infants without infections (104±12 vs. 70±5 days). Among infants weighing 901 to 1000 g at birth, Hernandez et al.3 reported a mean duration of hospitalization of 62 days in 1984 through 1985, at an average cost of $47,801 per infant, or $771 per day. Cost estimates now exceed $1,200 per day. Our study indicates an average decrease of six days in the length of the hospital stay for recipients of immune globulin, as compared with controls, and an even greater decrease among the infants who had one or more infections. Only small doses of immune globulin were required by low-birth-weight infants, and its administration was limited to the period when intravenous access was required for other medical therapies. Thus, the benefits of immune globulin that were observed in our study clearly justified its minimal cost. The results of other multicenter controlled trials should allow additional refinements in the use of immune globulin as a new method of prophylaxis in neonatal medicine.
Supported in part by grants from Baxter Healthcare Corporation and the National American Red Cross.
*The following were also members of the study group: J.A. Garcia-Prats, M.A. Rench, D. Hesketh, M. Brown, S. Pelke, L. Hayen, G. Kurth, V. Meade, R. Ramamurthy, M.S. Driscoll, M. Drummond, B. Pollock, V. Sutherland, D. Chudwin, K. Kopischke, and T. Reavis. Also included were B.A. Bagby, S.G. Courter, and M.L. Lee, from Baxter Healthcare Corporation, Hyland Division.
Source Information
From the Baylor College of Medicine and Jefferson Davis Hospital, Houston (C.J.B.); the John A. Burns School of Medicine, University of Hawaii, and Kapiolani Medical Center, Honolulu (M.E.M.); the University of Missouri—Kansas City School of Medicine and Children's Mercy Hospital, Kansas City, Mo. (R.T.H.); the University of Texas Health Sciences Center at San Antonio, (D.T.C.); Rush–Presbyterian–St. Luke's Medical Center, Chicago (U.V.); and Bowman Gray School of Medicine, Wake Forest University and Brenner Children's Hospital, Winston-Salem, N.C. (L.B.G.). Address reprint requests to Dr. Baker at the Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
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