Evidence-Based Neonatal Infections

CHAPTER 2

Epidemiology

2.1 Incidence and mortality

Neonatal infections are an important and sadly neglected cause of mortality and morbidity globally. In 2008, neonatal infections caused an estimated 29% of the 3.6 million neonatal deaths worldwide1 (see Figure 2.1 and Table 2.1) or about one million deaths, almost all in developing countries.1 Neonates comprised 41% of the estimated 8.8 million deaths in children under 5 years old worldwide in 2008.1 Community-based studies in developing countries attribute up to 42% of neonatal deaths in the community to infection.2

Table 2.1 Causes of death in neonates globally.

Cause of death Number of deaths in millions (%) Pre-term birth complications 1.033 (29%) Birth asphyxia 0.814 (22%) Sepsis 0.521 (15%) Other 0.409 (11%) Pneumonia 0.386 (11%) Congenital abnormalities 0.272 (8%) Diarrhoea 0.079 (2%) Tetanus 0.059 (2%) TOTAL 3.575 Source: Adapted from Reference 1 with permission from Elsevier. Copyright © 2010 Elsevier.

Figure 2.1 Global causes of neonatal deaths. Adapted from Reference 1 with permission from Elsevier. Copyright © 2010 Elsevier.

The mortality from neonatal infections is considerably lower in resource-rich countries. Intrapartum antibiotic use to prevent group B streptococcus (GBS) infection has reduced mortality significantly in countries with a high incidence.2-4

Newborn babies have rates of infection as high as children and adults whose immunity is compromised for almost any other reason, including most oncology patients and the elderly. Although newborn babies, and particularly pre-term newborns, are immunocompromised, additional factors contribute to the high rates of neonatal infection and will be considered in Section 2.2.

Knowledge of the incidence of neonatal infections is important for planning preventive and intervention strategies and for comparisons within and between countries, which can help inform clinical practice and help assess the quality of care. However, such comparisons are not necessarily straightforward.

In developing countries, most deliveries occur in the home, so hospital-based studies of incidence and aetiology may give misleading or inaccurate results. Infections are usually diagnosed clinically without cultures, and deaths from infection are frequently under-reported. Community studies report rates of clinical neonatal sepsis ranging from 49 per 1000 live births in babies >24 hours old in Guatemala to 170 per 1000 live births in rural India.2 The reported rate of blood culture-confirmed cases is far lower: a minimum of 5.5 per 1000 live births in a rural hospital in Kenya,5 a highly uncertain figure because of incomplete sampling. Infection-specific mortality rates reported in 32 studies varied from 2.7 per 1000 live births in South Africa to 38.6 per 1000 in Somalia.2

In industrialized Western countries where most de liveries occur in hospital, hospital-based studies of incidence are more representative.

The reported incidence of neonatal infection depends on how neonatal infection is defined and reported. Definitions may vary considerably. Examples include how contaminants in blood cultures and cerebrospinal fluid (CSF) are defined; whether or not contaminants are excluded; whether or not clinical sepsis with evidence of raised inflammatory markers is accepted as being infection; and whether infections are confined to positive cultures of blood and/or CSF or also include positive cultures from normally sterile sites, such as urine, bone, joint fluid or pulmonary fluid.

2.1.1 Early-onset infection

It is conventional to divide the reporting of neonatal infections into early- and late-onset infections. Early infections are presumed to be due to organisms acquired from the mother shortly before (e.g. Listeria) or at the time of birth (e.g. GBS) whereas late infections are primarily caused by environmental organisms, acquired nosocomially (i.e. in hospital) or in the community. However, ‘early onset’ has been defined as anything from the first 2 days to the first 7 days after birth. Furthermore, environmental organisms may grow from blood cultures in the first 48 hours after birth, while the classic early-onset organisms like GBS and Listeria can cause late- as well as early-onset sepsis. Methicillin-resistant Staphylococcus aureus (MRSA), originally confined to hospitals or patients associated with hospitals, is a common community-acquired pathogen in many countries and can colonize pregnant women and cause both early- and late-onset neonatal infections.

There are two major considerations in defining early-onset infection, clinical and epidemiologic.

Question: Does it matter how we define early-onset infection clinically? The clinical problem with defining early-onset infection as infections in the first 7 days after birth, as opposed to those in the first 48 hours say, comes if the empiric antibiotic regimen for early-onset sepsis does not cover organisms that may be acquired from 3 to 7 days. For example, say penicillin and gentamicin are recommended for early-onset sepsis, gentamicin has only modest anti-staphylococcal activity so this regimen provides little cover against S. aureus infections. Yet data from Western countries6,7 show that S. aureus bloodstream infections are not uncommon between days 3 and 7 (Figures 2.2 and 2.3). Recommendation: It is critical for the clinician that empiric antibiotic regimens reflect the local epidemiology and cover the organisms likely to cause sepsis.

Figure 2.2 Timing of neonatal infection by organism. Adapted from Reference 6. CoNS, Coagulase-negative staphylococci; Other GNB, Other Gram-negative bacilli; Gp B Strep, Group B streptococci.

Figure 2.3 Pathogens according to the day of onset of infection, UK 2006–2008. Reprinted from Reference 7 with permission. CoNS, Coagulase-negative staphylococci; GBS, Group B streptococci.

Question: Is there a correct way of reporting early-onset infection? The incidence of early-onset infections is conventionally reported as the number of infections per 1000 live births in a defined period, for example, the number of infections in babies born in a maternity hospital (excluding babies transferred from other hospitals or home) divided by the number of live births over a defined time period. Various countries have established neonatal infection surveillance networks, including Australia,6 the United Kingdom,7 Canada (http://www.canadianneonatalnetwork.org/portal/), the US National Institute of Child Health and Human Development (http://www.nichd.nih.gov),3 Germany (http://www.nrz-hygiene.de/surveillance/kiss/neo-kiss/) and the Vermont Oxford Network (http://www.vtoxford.org/) has established a global network. The Australian, Canadian and US NICHD report all neonatal infections, whereas the other networks focus on low birth-weight babies in tertiary centres. Comparisons depend on definitions and completeness of reporting.6-8 Data on early infections inform public health interventions. For example, the rate of early-onset GBS infection determines whether or not prevention strategies are cost-effective.9-12 Epidemiology should be a critical driver of public health. The clinician wants data to inform empiric choice of antibiotics. Whether organisms are reported separately6 (Figure 2.2) or all organisms combined on a single day7 (Figure 2.3), clearly there is some overlap between organisms likely to have been maternally and those probably nosocomially acquired. An alternative approach is to separate infections into those in babies <;48 hours old (early onset), in babies aged 3–7 days (intermediate sepsis) and in babies >7 days (late sepsis).8 Failure to exclude contaminants can give misleading results. For example, one single-centre study reported coagulase-negative staphylococci (CoNS) as their commonest cause of early-onset neonatal infection.10 Excluding all likely contaminants (e.g. CoNS, diphtheroids, micrococci, α-haemolytic streptococci and anaerobes) is probably not valid, because these organisms occasionally cause serious infection, even meningitis. One option is to include all organisms cultured while acknowledging most are probably contaminants.7 Another possibility is to use a combined clinical and laboratory definition of infection, and only report likely contaminants if the baby also has abnormal laboratory parameters, for example, elevated C-reactive protein (CRP), abnormal white cell or platelet count.6 In Western countries, early-onset infection is mainly due to GBS, although less frequently in countries using intrapartum antibiotic chemoprophylaxis, Gram-negative enteric bacilli (Enterobacteriaceae), notably...