Effi cacy of intravenous immunoglobulins in the prophylaxis of neonatal sepsis

Between weeks 30-32 of gestation, intrauterine transplacental transfer of maternal immunoglobulins (IgG) to the fetus accelerates, conferring passive immunity [7]. There is an incremental rise in foetal IgG with gestational age, thus preterm and low birth weight neonates are born with a true de iciency of IgG antibodies [7]. As low serum IgG has been reported to increase the risk of infection, IgG replacement therapy offers hope of enhancing immune competence and decreasing infectious episodes in this vulnerable population [8]. Summary


Introduction
37% of neonatal deaths in 2010 were attributable to infectious causes [1]. Preterm neonates are particularly susceptible due to numerous factors including the requirement of more invasive supportive interventions in the Neonatal Intensive Care Unit (NICU) as well as an inherent de iciency of humoral immunity [3].
Between weeks 30-32 of gestation, intrauterine transplacental transfer of maternal immunoglobulins (IgG) to the fetus accelerates, conferring passive immunity [7]. There is an incremental rise in foetal IgG with gestational age, thus preterm and low birth weight neonates are born with a true de iciency of IgG antibodies [7]. As low serum IgG has been reported to increase the risk of infection, IgG replacement therapy offers hope of enhancing immune competence and decreasing infectious episodes in this vulnerable population [8].

Summary
Despite critical care advances, robust antibiotic therapy and improved strategies in early detection and prevention of infection, the incidence of morbidity and mortality from neonatal sepsis worldwide in preterm and low birth weight neonates remains overwhelmingly high. Neonatal sepsis is characterised by a clinical syndrome of systemic signs of infection and bloodstream bacteraemia in newborns within the fi rst months of life.
The risk of sepsis in neonates is inversely proportional to gestational age and birth weight due to defi ciency in humoral immunity and the need for more invasive supportive neonatal intensive care unit interventions. Adverse eff ects such as necrotising enterocolitis associated with antimicrobial therapy are serious enough to warrant exploration of alternative therapeutic strategies. Immunoglobulin replacement therapy off ers hope of enhancing immune competence and reducing infection rates in vulnerable populations.
It is evident from the relevant studies to date that the benefi ts off ered by intravenous immunoglobulin prophylaxis may not be signifi cant enough for routine hospital implementation. Further research to better understand the mechanisms underlying immunodefi ciency will lead to the realisation of alternative therapeutic and prophylactic interventions.
This paper is a review article that aims to evaluate all relevant research to date regarding prophylaxis of neonatal sepsis by intravenous IgG replacement therapy in preterm and low birth weight neonates.

Methodology
Articles were searched using the following databases: ScienceDirect, Medline, PubMed, Google Scholar. Inclusion criteria were: All published studies of intravenous immunoglobulin (IVIG) usage in the prophylaxis of infection in preterm and low birth weight infants from 1986 to present. Exclusion criteria: studies involving the use of IVIG in the active treatment of sepsis, studies involving neonates ≥ 37 weeks or ≥ 2500 g at birth.

Discussion
The effectiveness of IVIG as a prophylactic agent has been reported in many studies, both prospective and retrospective, ranging in population from 20 to 2416. Most of these studies were performed between the mid-'80s to late '90s.
The use of immunoglobulins for the prevention of sepsis followed Bruton's discovery in 1952 in which he reported the case of a young boy with agammaglobulinemia and recurrent streptococcal bacteraemia who subsequently had a reduced number of infections following administration of serum IgG. The study demonstrated the potential use of immunoglobulins for susceptible individuals with low serum IgG levels [22].
Haque, et al. and Chirico, et al. [8,9] conducted randomised control trials in Saudi Arabia and Italy respectively which suggested that intravenous IgG offered a protective bene it against infection and septicaemia in high-risk infants. However, neither study was blinded or placebo-controlled. Later trials by Stabile, et al. and Conway, et al. [10,11] offered less promise, concluding there was little difference in septicaemia rates between the treated and placebo groups.
Clapp, et al. [4] was one of the most in luential early studies to explore this subject. This randomised control pilot study trialled 115 infants weighing < 2000 g. The IgG recipient group had a target serum level of 700 mg/dL. No infants who received IgG developed nosocomial sepsis. All nine infants who developed sepsis in the placebo group had an IgG concentration of < 400 mg/dL. This inding, that IgG below a certain threshold puts neonates are higher risk of sepsis, was monumental in instigating further studies into exploring the use of IgG for infection prevention.
Ambiguous results in these smaller study populations prompted the emergence of larger trials. Baker, et al. [13] performed the irst large multicentre, randomised, doubleblinded trial in which 400 mg/kg of IVIG was given to 287 infants on ive occasions, with a control group of 297 subjects receiving placebo. Among the IVIG recipient group, the rate of infection was 32.4%, compared to 46.8% in the group receiving placebo. In those with identi ied infection in both groups, the length of hospital stay was lower in the group receiving IVIG prophylaxis. Baker, et al. [13] found that while no reduction in case-fatality rates among preterm neonates given IVIG was noted, a considerable bene it was associated with IVIG administration, infection risk and hospitalisation duration.
The Fanaroff, [14] study was a much larger multicentre trial enrolling 2416 preterm infants that accounted for between 42.7% and 61% of the statistical weighting in all meta-analyses and systematic reviews to date. When considering sepsis only, the phase 1 trial showed a rate of sepsis of 11.6% in the immune globulin group and 16.4% in the control group. The study went from being double-blinded (in phase 1) to non-blinded (in phase 2) due to concerns over higher rates of Necrotising Enterocolitis (NEC) development in the group receiving IVIG prophylaxis. In phase 2, the rate of septicaemia became higher in the immune globulin group than in the control. With the introduction of potential bias, the change in pattern of outcome variables puts into question the validity of the study and consequently brings the validity of the larger reviews into question.
A post hoc analysis of the study revealed that while the immunoglobulin therapy appeared to have little effect on nosocomial infections caused by gram-negative species, there was a considerable reduction in infections caused by Group B Streptococcus (GBS). Furthermore, only one lot out of four IVIG preparations was shown to have a statistically signi icant reduction in the rate of nosocomial infection. Both of these indings may indicate variability across IVIG preparations and that the antibodies within certain preparations may or may not have an af inity for speci ic neonatal pathogens. This demonstrates the possibility that within the donor pool of a particular preparation, there could exist discrepancy regarding antibodies with the right antigenic af inity for GBS. If this is the case, it could offer a justi ication for the inconsistencies across studies, as well as support the future research of antigen-speci ic antibody preparations [14].
A further large multicentre trial was conducted by Weisman, et al. [15] who used a single immunoglobulin preparation of 500 mg/kg within the irst twelve hours of birth. They noted that while this appeared to be a safe dose to give neonates to maintain higher levels of serum IgG, no signi icant difference was noted between the control population who received albumin and the treatment group. The authors suggested further studies examine antigenspeci ic immunoglobulin assays which would be more speci ic to the pathogens common in speci ic neonatal intensive care units.
In the irst meta-analyses performed by Lacy and Ohlson, [16] it was concluded that routine administration of IVIG was not recommended for the prevention of infection in preterm infants. Although recognised variations across donor pools of IVIG preparations were noted as a limitation in this study.
Subsequently, a meta-analysis by Jenson and Pollock, [17] demonstrated that the use of IVIG in addition to standard therapy is of minimal but demonstrable bene it when administered prophylactically. As studies that con irmed sepsis by diagnosis through means other than true positive blood cultures were excluded by this meta-analysis, the more subtle bene its of IVIG may have been overlooked.
Jenson and Pollock [17] challenged the previously proposed notion that variations in IVIG preparations could lessen the validity of the prior study outcome. They performed a subclinical analysis of 6 studies that all used the same IVIG preparation, Sandoglobulin, and found no change in heterogeneity. This conclusion was consistent with the overall meta-analyses' indings [18]. However, it was recognised in a more up to date meta-analysis by Lacy and Ohllson, [6] that the necessary antibodies for combatting infection may yet still be absent from the IVIG preparation.
Sandberg, et al. [18] conducted a multicentre prospective randomised control trial which unlike previous studies on the topic excluded neonates with serum IgG levels > 4 g/L. Only 85 neonates of the anticipated sampled size of 400 neonates were included, as they were identi ied as having serum IgG levels of < 4 g/L taken within 24 hours of gestation. While the paper found no evidence that vulnerable neonates bene it from IVIG prophylaxis, the paper noted that the rate of infection was signi icantly lower in neonates born with a higher serum IgG. This speaks to the prognostic importance of IgG concentration at birth. Sandberg ultimately recommended alternative strategies that may improve the immature components of the neonatal immune system be explored.
Lacy and Ohlson, [6] combined data from 19 studies involving a total of 5000 infants. Of the 19 studies, only one study by Ratriswadi found a statistically signi icant reduction in sepsis. With all studies combined, results showed a statistically signi icant (p = 0.02) reduction in sepsis of 3%. Results for the secondary outcome; serious infection, also showed a statistically signi icant reduction in IVIG subjects of 4%. The quality of this meta-analysis was challenged by potential bias and substantial heterogeneity. Five studies were considered high quality, while bias could not be excluded for the remaining fourteen. Based on these indings, the authors concluded that such a small reduction does not warrant the use of IVIG and advised further RCT's in IVIG prophylaxis should not be considered.
A more recent small trial was performed in Iran by Goodarzi, et al. [21] more recently. The results of this singleblinded randomised control trial support the likelihood of IVIG conferring bene it to preterm low birth weight neonates. However, the reported results should be taken tentatively due to the limited number of patients as well as the potential introduction of bias with a single-blinded.
While the studies over the past 20-30 years have led to considerable ambiguity over the ef icacy of prophylactic IVIG, the collective body of research illustrates a message that is quite clear. Whether a bene it from prophylactic IVIG does or does not exist, the degree of bene it found is so minimal that IVIG prophylactic administration cannot be justi ied for routine use. Even considering the limitations of the larger review studies, on evaluation of each individual study, the meta-analyses seem to offer a fair representation of IVIG ef icacy.
The reason for the ineffectiveness of immunoglobulins in these infants remains unknown. However, researchers have suggested several factors; the presence of signi icant risk factors in these infants; concern over the ef icacy of antibody https://doi.org/10.29328/journal.japch.1001029 preparations for use against neonatal infection; and the immune immaturity beyond that of antibody de iciency all offer some insight.
The overall immaturity of the neonatal immune system extends beyond that of antibody de iciency. Stabile, et al. [10] highlighted that immunoglobulins only correct the immunological de icit in part. One of the main functions of IgG is opsonization. According to studies, opsonic activity in exogenous IgG recipients remains decreased [15]. In addition, several papers suggest that the humoral factors which work synchronously with antibodies, crucial for optimal function, are also impaired [14]. Despite this, studies have shown a direct correlation between increased maternal antibodies and decreased infectious episodes. Given the study results, this indicates a potential difference in immune coverage offered by maternal IgG and exogenous IgG. This is further highlighted by Hill, [19] who proposed that maternal immunoglobulins may contain speci ic antibodies to pathogens with which the mother and therefore her infant is more likely to be colonised.
Given the disappointing results of IgG immunotherapy, the use of antigenic-speci ic formulations may offer more promise. In 1998, a monoclonal antibody, Palivizumab, was licensed by the FDA for use in infants and young children with Respiratory Syncytial Virus (RSV) as it resulted in a substantial reduction in hospital stay, duration and infection severity. Developments like this may ensue for speci ic neonatal pathogens, but currently, further studies are needed [20].
At present, there appear to be a number of critical gaps in the knowledge informing these studies, particularly concerning the more complex interactions between neonatal defence mechanisms and bacterial virulence factors [16].

Recommendation
Further studies are needed to better our understanding of the neonatal immune response to sepsis. Without this understanding, the opportunities to discover therapies to treat and prevent these devastating infections remain limited.