**6. Use of immunoglobulins in the prevention of neonatal sepsis**

88 Neonatal Bacterial Infection

favouring immunoglobulin therapy.

CI; 6, 33) to avoid one death.

efficacy of IVIG.

neonates and especially preterm infants, therapy with polyclonal immunoglobulins should be understood much more as a substitutional therapy than as an adjunctive therapy as for adults or older children (43). Comparing the two treatment modalities (IgGAM vs. IgG) in neonates, Kreymann et al. (30) only found a slight difference without statistical significance. A major limitation of this meta-analysis is the inclusion of the study of El Nawawy (32), who originally included infants of 1 to 24 months of age hospitalized at a pediatric intensive care unit, of which 50 were proven septic patients. This study strongly influenced study results

Ohlsson and Lacy (44) recently reviewed IVIG for suspected or subsequently proven infection in neonates including randomized or quasi-randomized controlled trials comparing IVIG treatment to placebo or no intervention in newborn infants below 28 days of age. They found 10 studies meeting their inclusion criteria that differed to the above mentioned analysis (30) by additional including the small study of Christensen et al. (45) and a new study by Ahmend et al. (46) and not including the studies by El Nawawy (32), Gökalp (38), and Gunes (31).The results showed a statistically significant reduction in mortality in cases of proven and also of suspected infection with a NNT of 10 infants (95%

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 (44). However, the use of antistaphylococcal immunoglobulins to prevent staphylococcal infection in very low birth weight infants has

A very recent study published by the International Neonatal Immunotherapy Study (INIS) Collaborative group enrolled 3493 infants with birth weight less than 1500g receiving antibiotics for suspected or proven serious infection and randomly assigned them to receive two infusions of either IgG immune globulin (at a dose of 500 mg per kilogram of body weight) or matching placebo 48 hours apart (48). The researchers found no significant between-group difference in the rates of death or major disability at the age of two years (39 and 39%, respectively). Similarly, there were no significant differences in the rates of secondary outcomes including the incidence of subsequent sepsis episodes. In the 2-years follow-up of the study participants there were no differences in the rates of major or nonmajor disability or of adverse events. Thus, IgG IVIG was not found to be helpful in diminishing the risk of major complications or adverse outcomes in neonates with suspected or proven sepsis. The duration of hospital stay also did not differ between groups (48).

The clinical efficacy of IgM-enriched IVIG (currently there is only one preparation available, Pentaglobin®) has been reviewed by Norrby-Teglund et al. (49) for both adult and paediatric/neonatal patients. The authors concluded that patients most likely to benefit are Gram-negative septic shock patients. Therefore it is important to emphasize that selection of study patients as well as microbiological aetiology are of high relevance affecting the

recently been reviewed and is currently not recommended (47).

There have been published a lot of studies and reviews on the preventive use of IVIG in preterm infants and I herewith report ("pars pro toto") two multicenter randomized, double-blind, placebo-controlled trial published early in the New England Journal of Medicine (50,51) with divergent results and the latest Cochrane Review (52).

Baker et al. (50) included 588 infants with a birth weight of 500 - 1750 g and age of 3 - 7 days from six centres in the U.S. between 1987 and 1988. The trial was randomized, double-blind, placebo-controlled with 287 infants having received 500 mg/kg of IVIG at enrolment (age 3 to 7 days), one week later, and then every 14 days until a total of five infusions had been given or until hospital discharge, whichever came first, and 297 controls having received an equal volume of a sterile solution of 5 % albumin and 0.9 % sodium chloride. Outcomes included proven infection - clinical findings of sepsis and at least one of the following: a positive blood culture of either bacteria or fungi (the isolation of a pathogen from a normally sterile other body site or urine obtained by suprapubic or bladder catheterization, or the isolation of virus from an infant with clinical deterioration), necrotizing enterocolitis stage II or III, intraventricular haemorrhage grade 1 to 4, bronchopulmonary dysplasia, death, and total days in hospital. There were 50 episodes of sepsis among 287 infants (17.4%) in the IVIG group and 75 episodes of sepsis among 297 infants (25.3%) in the placebo group. The cumulative relative risk reduction was 0.7 (CI 95% 0.5-0.9).

In a prospective, multicenter, two-phase controlled trial, Fanaroff et al. (51) stratified 2416 infants according to birth weight (501 to 1000 g and 1001 to 1500 g) and randomly assigned to an IVIG (n = 1204) or a control group (n = 1212). Control infants were given placebo infusions during phase 1 of the study (n = 623) but were not given any infusions during phase 2 (n = 589). Infants weighing 501 to 1000 g at birth were given 900 mg of immune globulin per kilogram of body weight, and infants weighing 1001 to 1500 g at birth were given a dose of 700 mg per kilogram. The immune globulin infusions were repeated every 14 days until the infants weighed 1800 g, were transferred to another center, died, or were sent home from the hospital. Nosocomial infections of the blood, meninges, or urinary tract occurred in 439 of the 2416 infants (18.2 %): 208 (17.3 %) in the immune globulin group and 231 (19.1%) in the control group (relative risk, 0.91; CI 95% 0.77 to 1.08). Septicemia occurred in 15.5% of the immune globulin recipients and 17.2% of the controls. The predominant organisms included gram-positive cocci (53%), gram-negative bacilli (22.4%), and candida species (16%). Adverse reactions were rarely observed during the infusions. Immune globulin therapy had no effect on respiratory distress syndrome, bronchopulmonary dysplasia, intracranial hemorrhage, the duration of hospitalization, or mortality. The incidence of necrotizing enterocolitis was 12% in the immune globulin group and 9.5" in the control group. Thus, the authors concluded that the prophylactic use of IVIG failed to reduce the incidence of hospital-acquired infections in very-low-birth-weight infants (51).

The prophylactic administration of intravenous immunoglobulins (IVIG) to prevent nosocomial infections has been studied in >5,000 neonates from 19 studies enrolled in randomised controlled trials (52). The results of these meta-analyses showed a statistically significant reduction in sepsis (number needed to treat – NNT - 36) and/or any serious infection (NNT 31), but no reduction in mortality from infection. The reviewers concluded that IVIG administration resulted in a 3% reduction in sepsis and a 4% reduction in any serious infection of one or more episodes. Nevertheless it was not associated with reductions in other important outcomes including necrotizing enterocolitis intraventricular haemorrhage, or length of hospital stay. Most importantly, IVIG administration did not have any significant effect on mortality from any cause or from infections. There were no adverse events observed to be associated with prophylactic use of IVIG. From a clinical perspective a 3-4% reduction in nosocomial infections without a reduction in mortality or other important clinical outcomes might be of marginal importance and has to be outweighed by the costs and the values assigned to the clinical outcomes (52). This Cochrane review ends with the statement that there is no justification for further randomized trials testing the efficacy of previously studied IVIG preparations to reduce nosocomial infections in preterm and/or low birth weight infants. In contrast, these results should encourage basic scientists and clinicians to pursue other avenues to prevent nosocomial infections (52).

Immunoglobulins in the Prevention and Treatment of Neonatal Sepsis 91

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