Sometimes, therapies that are widely available and have a strong rationale for use still disappoint when subjected to clinical trials.
Hospital-acquired (nosocomial) infection is a serious problem in preterm or very-low-birthweight infants. Rates of nosocomial infection have decreased over the past 12 years, from 21.4% in 2000 to 13.7% in 2011. These decreases have in part been due to improvements in the quality of care, including initiatives for improvement of hand washing and central venous line placement and care. However, neonatal infection remains a serious complication that is associated with poor neurodevelopmental outcome and mortality.
Preterm infants are deficient in immunoglobulin, the glycoprotein that forms antibodies. Endogenous synthesis of immunoglobulin does not begin until 24 weeks after birth, and preterm infants are robbed of the maternal 'gift' of immunoglobulin that occurs mainly after 32 weeks' gestation. This relative deficiency of immunoglobulin leaves preterm infants particularly vulnerable to infection. The idea of preventing or treating infection with intravenous pooled, polyvalent immunoglobulin G (IgG) is attractive, as it can provide IgG that combines to cell surface receptors, provides opsonic activity, activates compliment, promotes antibody-dependent cytotoxicity, and improves neutrophilic chemoluminescence.
Administration of intravenous immunoglobulin (IVIG) to very-low-birthweight infants has been extensively studied. Ohlsson and Lacy have recently updated Cochrane Reviews on the use of IVIG to prevent or treat nosocomial infection in premature new-borns.[4,5] In the review of prophylactic IVIG, Ohlsson and Lacy synthesised the information from 19 randomised controlled trials enrolling approximately 5000 preterm and/or very-low-birthweight infants. A significant reduction of sepsis was noted, with typical relative risk (RR) 0.85 (95% confidence interval (CI) 0.74 to 0.98) and typical risk difference (RD) -0.03 (95% CI 0.00 to -0.05). The number of infants needed to treat with prophylactic IVIG administration to potentially prevent one infant from acquiring a nosocomial bacterial infection is 33, with a 95% CI that ranges from as few as 20 infants to an infinite number of infants. Other than this reduction in sepsis, the review found no benefit for other important clinical outcomes, including mortality, necrotising enterocolitis, chronic lung disease, or hospital length of stay. Ohlsson and Lacy concluded that although a reduction in sepsis was noted, the decision to use prophylactic IVIG will depend on the costs and the values assigned to the clinical outcomes.
Less can be said about the use of IVIG in the treatment of suspected or proven infections. Mortality during hospital stay in infants with clinically suspected infection at trial entry was not significantly different after IVIG treatment (8 studies involving 2425 infants; typical RR 0.94, 95% CI 0.80 to 1.12). In the one study that reported on death or major disability at two years corrected age, there was no significant difference in infants with suspected infection after IVIG treatment (RR 0.98, 95% CI 0.88 to 1.09).
Few investigators have made a stand regarding the use of prophylactic IVIG. There are no published guidelines from any of the neonatal organisations worldwide that recommend prophylactic pooled IVIG for use in very-low-birthweight infants. Ohlsson and Lacy note that it is possible that the IVIG preparations used in these studies did not contain the necessary antibodies to prevent infection and that the use of preparations with known specific antibodies against common pathogens in a specific neonatal intensive care unit might be more effective. However, studies of such products have also shown little benefit. Various types of specific antibodies targeted at different antigenic markers of Staphylococcus have shown promise in animal models, but a Cochrane Review of these products, included three studies, found no significant differences the risk of staphylococcal infection (typical RR 1.07, 95% CI 0.94 to 1.22).
IVIG is one of the best-tested therapies for the prevention and treatment of nosocomial bacterial infection, but there is little benefit to show for this treatment. The authors of the Cochrane Reviews note that there is no longer a need for further trials and that the routine administration of IVIG to either prevent or treat sepsis in very-low-birthweight infants is not recommended. It is best to focus on practices that have shown to reduce nosocomial infections (including appropriate hand hygiene, nutrition, skin care, and vascular access care) and improving a culture of intensive care that dedicates itself to this goal.
Roger F Soll
Co-ordinating Editor, Cochrane Neonatal Review Group, University of Vermont College of Medicine, Burlington, VT, USA Roger.Soll@vtmednet.org
How to cite: Soll RF. Calling time on intravenous immunoglobulin for preterm infants? [editorial]. Cochrane Database of Systematic Reviews 2013;7:ED000062. dx.doi.org/10.1002/14651858.ED000062
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Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request) and declares (1) no receipt of payment or support in kind for any aspect of the article; (2) RFS has received payment from the Vermont Oxford Network for directing trials and follow-up, but has no other financial relationships with any entities that have an interest related to the submitted work; (3) the Cochrane Neonatal Review Group, and RFS's role as Co-ordinating Editor, have been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and RFS has received payment from multiple hospitals and perinatal societies for lectures, but there are no other relationships or activities that could be perceived as having influenced, or giving the appearance of potentially influencing, what was written in the submitted work.
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