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Early Onset Neonatal Sepsis. Diagnostic Dilemmas and Practical Management
Early Onset Neonatal Sepsis. Diagnostic Dilemmas and Practical Management
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Neonatal Unit, Birmingham ABSTRACT Group B streptococcus (GBS) and Escherichia coli
Women’s NICU, Birmingham, Early onset neonatal sepsis is persistently associated with are the most common causative organisms of
UK
poor outcomes, and incites clinical practice based on the EONS, excluding coagulase-negative staphylococci
Correspondence to fear of missing a treatable infection in a timely fashion. (CoNS). CoNS are frequent skin contaminants
Dr A R Bedford Russell, Unnecessary exposure to antibiotics is also hazardous. accounting for 20%1 (UK) to 24%2 (USA) of posi-
Neonatal Unit, Birmingham Diagnostic dilemmas are discussed in this review, and tive cultures. EONS secondary to GBS is defined as
Women’s NICU, Mindelsohn
suggestions offered for practical management while infection at <7 days7 and may present as a fulminat-
Way, Birmingham B15 2TG,
UK; awaiting a more rapidly available ‘gold standard’ test; in ing septicaemic illness, often complicated by pneu-
Alison.bedfordrussell@nhs.net an ideal world, this test would be 100% sensitive and monia. Some centres consider all EONS CoNS
100% specific for the presence of organisms. isolates as true infections; others consider all as
Received 28 July 2014 contaminants. Rigorous blood culture drawing tech-
Revised 30 October 2014
Accepted 5 November 2014 nique is key. Because of the wide variation in inter-
Published Online First INTRODUCTION pretation, many studies exclude cases whereby a
25 November 2014 Culture-proven early onset neonatal infection is single culture is positive for CoNS2 or only include
confirmed in <1%1 of admissions to neonatal such cases when deemed clinically relevant.1 GBS
units, yet accounts for up to 16%2 of all neonatal accounts for 43%2 (USA)–58%1 (UK) and E coli for
mortality and contributes to significant morbidity. 18%1 (UK) to 29%2 (USA) of EONS bacteraemias,
Culture-negative infection occurs more frequently. respectively. Listeria and Staphylococcus aureus
Fear of infection results in the majority of new- (methicillin-sensitive staphylococcus aureus) are
borns who are given antibiotics, receiving them infrequently isolated. In an American study,2 73%
unnecessarily.3 The hazards are beyond the fact that infants with GBS isolates were term, and 81% with
antibiotic therapy drives antibiotic resistance. E coli were preterm. In the UK, while the absolute
Antibiotics also disrupt maternal and the newborn’s number of term babies with GBS EONS is higher
faecal flora, and in so doing, disrupt normal than for preterm babies, spontaneous preterm deliv-
development of the nascent immune system.4 ery alone represents a risk factor for infection with
Neonatologists are constrained by the availability of the incidence of GBS EONS in babies <1500 g
insufficiently sensitive and specific microbiological being 4/1000 versus 0.38/1000 for term babies.
diagnostic tools, which would allow more judicious The incidence of EONS secondary to GBS has
antibiotic prescribing. not reduced in the UK as it has in the USA2 and
In recognition of the number of dilemmas Australasia1 8 subsequent to the introduction of
regarding diagnosis and management of early onset universal antenatal screening for GBS at 35–
neonatal infection which contribute to variations in 37 weeks gestation, and intrapartum antibiotic
practice, the UK National Institute for Health and prophylaxis (IAP) is offered to those women who
Care Excellence (NICE) commissioned a clinical are GBS-colonised, at the onset of labour.
guideline development group (CGDG), consisting In the UK, the National Screening Committee
of a wide range of stakeholders, to systematically (UKNSC) has controversially not recommended a
review all available evidence and develop a guide- universal maternal GBS screening programme. This
line which would prioritise the treatment of sick is currently under review. The Royal College of
newborn babies and use antibiotics more select- Obstetricians Green Top guideline9 recommends a
ively.5 Recently published evidence has strength- risk-factor-based strategy to prevent GBS. IAP is,
ened the original NICE CGDG reccomendations.6 however, recommended for prevention of GBS
infection if a woman is found to be colonised with
DEFINITION, INCIDENCE AND CAUSES OF GBS when incidentally tested, or has had a previ-
EARLY ONSET NEONATAL SEPSIS ous baby with invasive GBS disease, or as part of
Early onset neonatal sepsis (EONS) is variably broad-spectrum antibiotic therapy if she is febrile
defined as infection occurring within 48 h1–72 h2 in labour, or has evidence of chorioamnionitis.
of birth. Antenatal risk factors for GBS infection can be
The incidence is around 0.901 (UK) to 0.982 identified in up to 60% of cases and include preterm
(USA) per 1000 live births, and 0.9% of all neo- delivery (<37 weeks), prolonged rupture of mem-
natal admissions.1 In all studies, the risk of sepsis branes (PROM ≥18 h) or known genital carriage of
and mortality increases with decreasing gestational GBS during pregnancy.7 GBS can also cross intact
age and birth weight,7 increasing to approximately membranes, and the absence of PROM does not
To cite: Bedford Russell AR, 1% in babies 401–1500 g,2 and is highest in babies negate the risk of GBS infection: while membranes
Kumar R. Arch Dis Child <1000 g, with 26% of all admissions <1000 g were ruptured for >18 h in 44% of babies with
Fetal Neonatal Ed experiencing one or more episodes of infection culture-proven GBS EONS, 56% with GBS EONS
2015;100:F350–F354. during their neonatal stay.1 were not born following PROM. Successive studies
F350 Bedford Russell AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F350–F354. doi:10.1136/archdischild-2014-306193
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Review
have demonstrated that a risk-factor-based approach to preven- those of non-infectious aetiologies. The repertoire of ancillary
tion of GBS is limited, with frequent missed opportunities for laboratory tests is also limited and not always reliable.14 Over
prevention of GBS sepsis when risk factors are present.10 11 95% of babies treated with antibiotics for suspected infection
ultimately prove to have no evidence of infection.3
CLINICAL INDICATORS AND RISK FACTORS FOR EONS
Risk factors contribute to a clinical diagnosis but are insuffi-
ciently robust to be reliable in making a diagnosis of EONS. MICROBIAL CULTURE
A number of risk factor scores have been devised for asymptom- The ‘gold standard’ for diagnosing infection is, historically, a
atic neonates at risk of EON,12 none of which has been shown positive blood or cerebrospinal fluid (CSF) culture with a
to be sufficiently robust for widespread use. NICE CGDG noted minimum reporting delay of 36–48 h. Microbial cultures suffer
the lack of good quality evidence to guide management of neo- from low sensitivity and specificity: a negative blood culture
natal early onset sepsis. In producing best practice guidance on result is almost inevitable for a large proportion of blood cul-
management, NICE CGDG reached consensus view to stratify tures because of the submission of inadequate volumes of blood,
risk factors and clinical indicators of EONS5 attributing ‘Red and only one culture being drawn.15 16 A false positive culture
Flags’ to indicators that should prompt a high level of concern of CoNS is common,1 making diagnosis of EONS using the his-
(box 1). Any baby with one Red Flag indicator or risk factor, or torical gold standard, a challenge.17
two or more ‘Non-red Flag’ indicators (box 2) should be
promptly assessed for infection and treated with antibiotics
without delay. The guideline evidence has recently been updated
to reflect publication of relevant new information,6 none of Box 2 National Institute for Health and Care Excellence
which has any potential impact on the original guidance ‘non-Red Flag’ risk factors for, and indicators of, early
(box 3). It is notable that while epidural anaesthesia may be a onset neonatal sepsis
risk factor for early onset neonatal fever, it is not associated
with a higher incidence of EONS. Hence, it is suggested that it Maternal
is unnecessary to investigate febrile offspring of mothers who ▸ Invasive group B streptococcal infection in a previous baby.
have had epidurals, unless fever persists or the baby has other ▸ Maternal group B streptococcal colonisation, bacteriuria or
signs or risk factors for neonatal sepsis.6 infection in the current pregnancy.
More recently, pulse oximetry has gained momentum as a ▸ Prelabour rupture of membranes.
screening tool to detect illnesses including EONS in addition to ▸ Preterm birth following spontaneous labour (before 37 weeks
congenital heart disease, which the ‘PulseOx study’ was origin- gestation).
ally designed to investigate.13 Of 208 babies who ‘failed’ initial ▸ Suspected or confirmed rupture of membranes for more than
pulse oximetry, 55 had pneumonia (with radiological features 18 h in a preterm birth.
and raised C-reactive protein/CRP), two had culture-proven ▸ Intrapartum fever higher than 38°C, or confirmed or
GBS sepsis and 28 had raised CRPs with clinical signs suggesting suspected chorioamnionitis.
culture-negative sepsis. Pulse oximetry is currently being consid- Neonatal clinical indicators
ered by the UKNSC for inclusion as a screening test adjunctive ▸ Altered behaviour or responsiveness.
to the newborn and infant physical examination. ▸ Altered muscle tone (eg, floppiness).
▸ Feeding difficulties (eg, feed refusal).
DIAGNOSIS OF EONS ▸ Feed intolerance, including vomiting, excessive gastric
Early diagnosis of EONS is challenging because clinical aspirates and abdominal distension.
characteristics are non-specific and difficult to differentiate from ▸ Abnormal heart rate (bradycardia or tachycardia).
▸ Signs of respiratory distress.
▸ Hypoxia (eg, central cyanosis or reduced oxygen saturation
level).
Box 1 National Institute for Health and Care Excellence
▸ Jaundice within 24 h of birth.
Red Flag risk factors and clinical indicators for early
▸ Apnoea.
onset neonatal infection (EONS) which should prompt a
▸ Signs of neonatal encephalopathy.
high level of concern of EONS 5
▸ Need for cardiopulmonary resuscitation.
▸ Need for mechanical ventilation in a preterm baby.
Maternal and neonatal risk factors ▸ Persistent fetal circulation ( persistent pulmonary
▸ Parenteral antibiotic treatment to woman for confirmed or hypertension).
suspected invasive bacterial infection at any time during ▸ Temperature abnormality (lower than 36°C or higher than
labour or in the 24 h periods before and after the birth. 38°C) unexplained by environmental factors.
▸ Suspected or confirmed infection in another baby in the case ▸ Unexplained excessive bleeding, thrombocytopenia or
of a multiple pregnancy. abnormal coagulation (International Normalised Ratio >2.0).
Neonatal clinical indicators ▸ Oliguria persisting beyond 24 h after birth.
▸ Respiratory distress starting >4 h after birth. ▸ Altered glucose homeostasis (hypoglycaemia or
▸ Seizures. hyperglycaemia).
▸ Need for mechanical ventilation in a term baby. ▸ Metabolic acidosis (base deficit of 10 mmol/L or greater).
▸ Signs of shock. ▸ Local signs of infection (eg, affecting the skin or eye).
▸ Any baby with one Red Flag indicator or risk factor, should ▸ Any baby with two or more ‘non-red Flag’ indicators should
be promptly assessed for infection and treated with be promptly assessed for infection and treated with
antibiotics without delay. antibiotics without delay.
Bedford Russell AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F350–F354. doi:10.1136/archdischild-2014-306193 F351
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management team/committee, ward-focused antimicrobial teams 11 Bekker V, Bijlsma MW, van de Beek D, et al. Incidence of invasive group B
and evidence-based antimicrobial-prescribing guidelines. Some streptococcal disease and pathogen genotype distribution in newborn babies in the
Netherlands over 25 years: a nationwide surveillance study. Lancet Infect Dis
recommendations are not applicable to the neonatal context, for 2014;14:1083–9.
example, changing intravenous to oral antibiotics at the nearest 12 Singh M, Narang A, Bhakoo ON. Predictive perinatal score in the diagnosis of
opportunity, however, neonatal-specific recommendations have neonatal sepsis. J Trop Pediatr 1994;40:365–8.
previously been published in this journal37 along with broader 13 Singh A, Rasiah SV, Ewer AK. The impact of routine predischarge pulse oximetry
screening in a regional neonatal unit. Arch Dis Child Fetal Neonatal Ed 2014;99:
guidelines on managing and preventing Gram-negative infections
F297–302.
in neonatal units.38 14 Camacho-Gonzalez A, Spearman PW, Stoll BJ. Neonatal infectious diseases:
The tension between the need to investigate a baby at risk of evaluation of neonatal sepsis. Pediatr Clin North Am 2013;60:367–89.
EONS and to prescribe antibiotics promptly, versus the fact that 15 Connell TG, Rele M, Cowley D, et al. How reliable is a negative blood culture
most newborn babies given antibiotics do not have infection but result? Volume of blood submitted for culture in routine practice in a children’s
hospital. Pediatrics 2007;119:891–6.
become exposed to the risks of antimicrobial therapy, has been 16 Buttery JP. Blood cultures in newborns and children: optimising an everyday test.
recognised by NICE. Exposure to antibiotics must be minimised Arch Dis Child Fetal Neonatal Ed 2002;87:F25–8.
safely. NICE Quality Standards Advisory Committee and Project 17 Chiesa C, Panero A, Osborn JF, et al. Diagnosis of neonatal sepsis: a clinical and
Team are developing quality standards with the aim of reducing laboratory challenge. Clin Chem 2004;50:279–87.
18 Pammi M, Flores A, Leeflang M, et al. Molecular assays in the diagnosis of
infant mortality, reducing admissions and readmissions to neonatal
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NICE antibiotics for neonatal infection quality standards are 20 Stoll BJ, Hansen N, Fanaroff AA, et al. To tap or not to tap: high likelihood of
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from birth to 28 days of life in the UK, and likely beyond. 21 Patrick SW, Schumacher RE, Davis MM. Variation in lumbar punctures for early
onset neonatal sepsis: a nationally representative serial cross-sectional analysis,
SUMMARY 2003–2009. BMC Pediatr 2012;12:134.
22 Garges HP, Moody A, Cotton CM, et al. Neonatal meningitis: what is the
The main diagnostic dilemmas in managing EONS centre on correlation among cerebrospinal fluid cultures, blood cultures, and the cerebrospinal
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sensitive for presence of microbes in sterile sites. Recent evi- 23 Srinivasan L, Shah SS, Padula MA, et al. Cerebrospinal fluid reference ranges in
dence has been reviewed and does not alter NICE guidelines, term and preterm infants in the neonatal intensive care unit. J Pediatr
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which were developed using robust methodology and which
24 Greenberg RG, Smith PB, Cotten CM, et al. Traumatic lumbar punctures in
should be used to manage babies at risk and with clinical indica- neonates: test performance of the cerebrospinal fluid white blood cell count. Pediatr
tors of EONS. All neonatal units must adopt an AMS pro- Infect Dis J 2008;27:1047–51.
gramme; while antibiotics can be life saving, they are by no 25 Ablow RC, Gross I, Effmann EL, et al. The radiographic features of early onset
means harmless to those who do not need them. Group B streptococcal neonatal sepsis. Radiology 1977;124:771–7.
26 Ayalon I, Glatstein MM, Zaidenberg-Israeli G, et al. The role of physical
Contributors ARBR wrote the first and final drafts. RK conducted an extensive examination in establishing the diagnosis of pneumonia. Pediatr Emerg Care
literature review and updated the appropriate sections. 2013;29:893–6.
27 Black S, Kushner I, Samols D. C-reactive protein. J Biol Chem 2004;79:48487–90.
Competing interests None. 28 Hengst JM. The role of C-reactive protein in the evaluation and management of
Provenance and peer review Commissioned; externally peer reviewed. infants with suspected sepsis. Adv Neonatal Care 2003;3:3–13.
29 Malik A, Hui CP, Pennie RA, et al. Beyond the complete blood cell count and
C-reactive protein: a systematic review of modern diagnostic tests for neonatal
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F354 Bedford Russell AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F350–F354. doi:10.1136/archdischild-2014-306193
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Notes