The neonatal death rate (deaths among infants aged <28 days) in England and Wales has remained constant at 3.4 to 3.9 per 1000 live-births over the past decade.1 This rate is substantially lower than the global neonatal mortality rate of 30 per 1000 live-births.2 In England and Wales, as other industrialized countries, the most significant cause of neonatal mortality is prematurity and its complications, with infection playing a smaller role.2 National surveillance through routine reporting of births and deaths,1 or reporting of invasive isolates by hospital laboratories help define the contribution of specific pathogens to the burden of infection in different age groups, but provide little clinical or outcome data,3 whereas reports focusing on specific hospitals cannot be extrapolated to the general population. This study used anonymized extracts of death registrations in England and Wales to determine the contribution of infections to neonatal deaths and to describe associations between specific pathogens and comorbidities, including prematurity.
The completion of a death certificate by a clinician is a legal requirement in England and Wales. The methodology for this study has been described elsewhere.4 Briefly, the Health Protection Agency routinely receives anonymized infectious disease-related death registration data from the Office for National Statistics (ONS) for public health surveillance purposes. For this study, an automated search of anonymized death registrations was undertaken for infants aged <28 days who died between January 2003 and December 2005, using predefined ICD-10 codes for infection (A00-B99, G00-G09, I00-I02, J00-J22, L00-L08, O75.3, O85, O86, O98, P35-P39). The ICD-10 codes and the corresponding death certificate terms were then manually scrutinized and any record that did not indicate an infection was excluded. Neonates with no gestational age recorded on the death certificate were assumed to have been born at term, while neonates with no reported comorbidities were considered to have been previously healthy and were analyzed separately from those with comorbidities recorded on the death certificate. National neonatal death statistics for 2003–2005 were obtained from the ONS website.1 Proportions were compared using χ2 test or Fisher exact test, as appropriate. Ethical approval was not required because all data were anonymized at source.
There were 6700 neonatal deaths in England and Wales between 2003 and 2005 (neonatal mortality rate, 3.5/1000 live-births). Automated screening of death certificates identified 851 potential infection-related neonatal deaths, but manual scrutiny excluded 23 cases that were not infection-related. In a further 60 cases, the death certificate noted infection in the mother only with no further information on the neonate—these cases were not included in subsequent analyses despite a high likelihood that they were also infection-related. There were, therefore, 768 infection-related deaths recorded in neonates over the 3-year period, accounting for 11% of all neonatal deaths (0.4/1000 live births). Of these, 280 (36%) were recorded in term, 129 (17%) in preterm (28–36 weeks gestation), and 359 (47%) in extremely preterm (22–28 weeks) neonates. Overall, 57% of all neonates and 49% of term neonates with an infection-related death had at least one comorbidity recorded on the death certificate (Table, Supplemental Digital Content 1, https://links.lww.com/INF/A755).
Type of Infection.
Septicemia was the most commonly recorded clinical presentation (594 cases, 77%), followed by pneumonia (100 cases, 13%) and meningitis (42 cases, 6%). The proportion of neonates with reported septicemia increased with the degree of prematurity: 162/280 (58%) of term versus 105/129 (81%) of preterm versus 327/359 (91%) of extremely preterm neonates (χ2 for linear trend = 97.5; P < 0.01). In contrast, pneumonia was more commonly reported among term neonates (88/280 [31%] vs. 7/129 [5%] vs. 15/359 (4%] cases), as was meningitis (29/280 [10%] vs. 8/129 [6%] vs. 5/359 [1%] cases).
Data for preterm neonates with and without comorbidities were combined because the pattern of reported infections was similar (Table, Supplemental Digital Content 2, https://links.lww.com/INF/A756). A pathogen was recorded in 339 (44%) neonates—273 (81%) were bacterial, 37 (11%) fungal, and 29 (9%) viral. Among bacterial deaths, Gram-positive pathogens were reported in 58% of cases and the rate was higher among term neonates with no recorded comorbidities than in extremely preterm neonates (52/65 [80%] vs. 58/120 [48%]; χ2 = 17.5; P < 0.001). Group B Streptococcus was reported in almost one-third (87/273 cases, 32%) of neonatal deaths where a bacterial infection was specified and in 11% (87/768 cases) of all infection-related neonatal deaths. A higher proportion of deaths among term neonates with no recorded comorbidities were attributed to group B streptococci than among premature neonates (58/111 [52%] vs. 29/162 [18%] of bacterial infections; χ2 = 35.8; P < 0.0001). In contrast, staphylococcal infections, primarily coagulase-negative staphylococci, were more commonly reported among deaths in extremely premature neonates. Deaths due to Gram-negative pathogens were reported mainly among preterm and extremely preterm neonates (84/111 cases, 76%). Escherichia coli was reported in one-third (37/110 cases, 34%) of neonatal deaths caused by Gram-negative pathogens. In a further third, a “Gram-negative” infection was recorded on the death certificate, but the responsible pathogen was not mentioned. Viral infections were uncommonly reported, except herpes simplex virus which almost exclusively affected term neonates with no recorded comorbidities. Deaths because of respiratory syncytial virus were also rarely reported, irrespective of prematurity status, whereas fungal infections were reported mainly among extremely preterm neonates and were mostly due to Candida spp.
Infection was recorded on the death certificates of 11% of neonatal deaths in England and Wales, and two-thirds of infection-related deaths were reported among preterm and extremely preterm neonates. Group B Streptococcus was the single most important pathogen associated with death, not least because it mainly affected neonates with no recorded comorbidities. In contrast, Gram-negative bacteria, fungal infections, and coagulase-negative staphylococci were more commonly reported among preterm neonatal deaths although, where a pathogen was specified on the death certificate, group B Streptococcus was equal to Candida as the most common pathogen, even in this group.
The limitations of data collection using death certificates are well-documented.4–6 In particular, the contribution of specific pathogens to death and the role of any documented comorbidities must be interpreted with caution because the information contained within death certificates is known to be limited and may be incomplete. In some cases, an infection may not be stated on the death certificate when it clearly contributed to the death,5 particularly in children with multiple comorbidities where an infectious cause may not have been identified at the time of death or the infection was not considered to directly contribute to death.6 In addition, certifiers may only state the clinical manifestation of the infection (eg, pneumonia) or may preferentially state specific organisms (eg, methicillin-resistant Staphylococcus aureus).6 In our study, the contribution of infection may also have been underestimated if the predefined ICD-10 codes used to extract infection-related deaths were not comprehensive enough. Finally, it was not possible to determine the age at onset of infection within the neonatal period, which may be important in identifying potential prevention strategies.
While acknowledging these limitations, our study provides minimum estimates for the contribution of infections to neonatal deaths and, because it is population-based, provides a broad overview of the types of infections associated with both term and preterm neonatal deaths. Of note, our estimates are almost 3-fold higher than the 3.6% reported by the ONS in 2005, perhaps because of the different methodology used to ascertain and/or categorize the cause of death in this age-group.7 On the other hand, our estimates are similar to the 9.8% reported by the 2007 Confidential Enquiry into Child and Maternal Health.8 The overall infection-related neonatal death rate in the 2007 Confidential Enquiry into Child and Maternal Health report was 0.3 per 1000 live-births, with 120/212 deaths (57%) occurring in the first week of life (ie, early neonatal deaths), although the pathogens responsible and any associations with prematurity or other comorbidities are not described.8
Group B Streptococcus was identified as the most common pathogen recorded on neonatal death certificates, accounting for 1 in 9 infection-related neonatal deaths and supporting the call for improved strategies for preventing this infection.9 Interestingly, invasive methicillin-resistant S. aureus infections in neonates are extremely uncommon in the United Kingdom,10 but it was recorded in 4 of the 9 S. aureus-related deaths, although in 19 other cases, the staphylococcal species was not recorded (Table, Supplemental Digital Content 2, https://links.lww.com/INF/A756). Similarly, neonatal Listeria infections are rare in England and Wales,11 but this pathogen was reported in 1.1% of infection-related death certificates in this age group.
Gram-negative bacterial infections and fungal infections were more common among preterm and extremely preterm neonates and are likely to reflect their relatively immature immune system, as well as increased exposure to risk factors such as prolonged hospital stays, indwelling catheters, and prolonged use of multiple broad-spectrum antibiotics.12–14
In conclusion, we have for the first time established a minimum estimate of the contribution of specific infections to neonatal deaths in England and Wales. An integrated approach to linking microbiological, prescribing and clinical outcome data would provide a strong evidence base to prioritize research and identify key interventions to reduce infection-related deaths in this highly vulnerable age group.
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