This large multicentre analysis suggests that VLBW infants who are small for gestational age are at increased risk of nosocomial infection. To our knowledge this is the largest study of nosocomial infection in preterm growth‐retarded infants, including variables such as length of hospital stay and device application. Overall 36% of infants had at least one nosocomial sepsis or pneumonia. Others have reported 19.6% for infants
and 14.4% for all newborns admitted to NICU.9
The proportion of infants developing nosocomial infection was larger in this study probably due to the extreme prematurity and fairly narrow gestational age limits of our study population.
Bloodstream infection is the most common nosocomial infection in the NICU setting.28
Case fatality rates range from 2% to 50%.29
Overall in the present study, 33% of infants had at least one sepsis. This proportion is similar to those reported in some,10
but not all other studies in this field.14
We found a 41% increased risk of sepsis for SGA infants. VLBW infants were at increased risk for nosocomial infection, even after adjusting for length of NICU stay.33
The most important risk factors for nosocomial infection in this study were gestational age (adjusted ORs 1.35–2.01) and length of stay (adjusted ORs 2.03–5.74). Both were highly correlated, but length of stay seemed to increase the risk even more than gestational age and showed a dose–response‐like relationship to the risk of sepsis.
Our results with regard to pneumonia have to be interpreted with caution because of the small numbers. Chandra stated that upper and lower respiratory tract infections are three times more frequent in SGA than AGA infants but did not offer any details or pathophysiological explanations.34
Moreover, the diagnosis may not always be valid due to imprecise diagnostic criteria and misclassification in favour of sepsis.7
Therefore we additionally analysed having developed sepsis or
pneumonia. The adjusted odds ratio of 1.41 (95% CI 1.09 to 1.84) confirmed our results for sepsis.
Sepsis and NEC are the most common infections in VLBW infants.33
Moreover, NEC is the most frequent surgical emergency.37
Immaturity, ischaemia, enteral feeding, damaged intestinal mucosa and pathogenic organisms are major risk factors.12
Although NEC is not regarded as a nosocomial infection, it is included in the surveillance system because of its potentially clustered incidence.39
The overall occurrence of 5% in the present study is lower than that reported by others.40
We observed a slightly increased adjusted odds ratio of 1.20 (95% CI 0.75 to 1.94) for SGA newborns. Some authors have reported an increased incidence of NEC in growth‐retarded infants,6
with suspicion of end‐organ damage in utero.41
However, our results may be not be reliable owing to our small numbers, and further studies are required to investigate whether and how growth retardation increases susceptibility to NEC.
A striking finding was the increased adjusted odds ratio for NEC in high‐volume hospitals (adjusted OR 3.14, 95% CI 1.99 to 5.17). This may be due to larger NICUs preferentially being linked to departments of paediatric surgery; severely ill newborns will be transferred to these large perinatal centres.12
We included relatively little information on maternal, pregnancy and perinatal variables. However, we do not consider this a major limitation since these variables may be less meaningful when analysing nosocomial (late‐onset) infections. Insufficient casemix adjustment due to missing values in the CRIB score variable may have biased the results. However, we incorporated information on length of stay and device use, which are important potential confounders and have rarely been adjusted for in other studies. This information is particularly important for interpreting results based on the assumption of equal exposure probability. Documentation of device‐associated infections was rather non‐specific, eg a “device‐associated infection” was not linked to a specific infection if more than one infection occurred. There were similar proportions of SGA and AGA newborns with “device‐associated infections” (p
What is the biological plausibility of our finding? The present study was not designed to investigate mechanisms. Hence we cannot explain the apparent association between nosocomial infection and SGA status. Although previously reported in a study from India,17
the association may be spurious. Early studies, however, suggested possible interactions between immunological function and nutritional status, or decreased T‐lymphocyte numbers in SGA newborns, and a more pronounced hypogammaglobulinaemia compared with AGA infants.42
Thymic atrophy and prolonged impairment of cell‐mediated immunity (eg, reduced lymphocyte numbers and deranged CD4:CD8 ratios) have been found in SGA infants and animal models of intrauterine growth retardation.18
In summary, preterm SGA infants seem to be at increased risk of nosocomial infection, but this is not related to a specific group of pathogens and is independent of the duration of hospital stay. Our findings should alert clinicians to this additional risk in preterm SGA infants and reinforce the focus on immunological research in growth‐retarded newborns. Since there is an increased risk of mortality among SGA newborns1
and sepsis has a major impact on survival in NICU,44
this association should be investigated in more detail.