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Review

Early onset neonatal sepsis: diagnostic dilemmas

and practical management
A R Bedford Russell, R Kumar
Neonatal Unit, Birmingham
Womens NICU, Birmingham,
UK
Correspondence to
Dr A R Bedford Russell,
Neonatal Unit, Birmingham
Womens NICU, Mindelsohn
Way, Birmingham B15 2TG,
UK;
Alison.bedfordrussell@nhs.net
Received 28 July 2014
Revised 30 October 2014
Accepted 5 November 2014
Published Online First
25 November 2014

ABSTRACT
Early onset neonatal sepsis is persistently associated with
poor outcomes, and incites clinical practice based on the
fear of missing a treatable infection in a timely fashion.
Unnecessary exposure to antibiotics is also hazardous.
Diagnostic dilemmas are discussed in this review, and
suggestions offered for practical management while
awaiting a more rapidly available gold standard test; in
an ideal world, this test would be 100% sensitive and
100% specic for the presence of organisms.
INTRODUCTION
Culture-proven early onset neonatal infection is
conrmed in <1%1 of admissions to neonatal
units, yet accounts for up to 16%2 of all neonatal
mortality and contributes to signicant morbidity.
Culture-negative infection occurs more frequently.
Fear of infection results in the majority of newborns who are given antibiotics, receiving them
unnecessarily.3 The hazards are beyond the fact that
antibiotic therapy drives antibiotic resistance.
Antibiotics also disrupt maternal and the newborns
faecal ora, and in so doing, disrupt normal
development of the nascent immune system.4
Neonatologists are constrained by the availability of
insufciently sensitive and specic microbiological
diagnostic tools, which would allow more judicious
antibiotic prescribing.
In recognition of the number of dilemmas
regarding diagnosis and management of early onset
neonatal infection which contribute to variations in
practice, the UK National Institute for Health and
Care Excellence (NICE) commissioned a clinical
guideline development group (CGDG), consisting
of a wide range of stakeholders, to systematically
review all available evidence and develop a guideline which would prioritise the treatment of sick
newborn babies and use antibiotics more selectively.5 Recently published evidence has strengthened the original NICE CGDG reccomendations.6

DEFINITION, INCIDENCE AND CAUSES OF

EARLY ONSET NEONATAL SEPSIS

To cite: Bedford Russell AR,

Kumar R. Arch Dis Child
Fetal Neonatal Ed
2015;100:F350F354.
F350

Early onset neonatal sepsis (EONS) is variably

dened as infection occurring within 48 h172 h2
of birth.
The incidence is around 0.901 (UK) to 0.982
(USA) per 1000 live births, and 0.9% of all neonatal admissions.1 In all studies, the risk of sepsis
and mortality increases with decreasing gestational
age and birth weight,7 increasing to approximately
1% in babies 4011500 g,2 and is highest in babies
<1000 g, with 26% of all admissions <1000 g
experiencing one or more episodes of infection
during their neonatal stay.1

Group B streptococcus (GBS) and Escherichia coli

are the most common causative organisms of
EONS, excluding coagulase-negative staphylococci
(CoNS). CoNS are frequent skin contaminants
accounting for 20%1 (UK) to 24%2 (USA) of positive cultures. EONS secondary to GBS is dened as
infection at <7 days7 and may present as a fulminating septicaemic illness, often complicated by pneumonia. Some centres consider all EONS CoNS
isolates as true infections; others consider all as
contaminants. Rigorous blood culture drawing technique is key. Because of the wide variation in interpretation, many studies exclude cases whereby a
single culture is positive for CoNS2 or only include
such cases when deemed clinically relevant.1 GBS
accounts for 43%2 (USA)58%1 (UK) and E coli for
18%1 (UK) to 29%2 (USA) of EONS bacteraemias,
respectively. Listeria and Staphylococcus aureus
(methicillin-sensitive staphylococcus aureus) are
infrequently isolated. In an American study,2 73%
infants with GBS isolates were term, and 81% with
E coli were preterm. In the UK, while the absolute
number of term babies with GBS EONS is higher
than for preterm babies, spontaneous preterm delivery alone represents a risk factor for infection with
the incidence of GBS EONS in babies <1500 g
being 4/1000 versus 0.38/1000 for term babies.
The incidence of EONS secondary to GBS has
not reduced in the UK as it has in the USA2 and
Australasia1 8 subsequent to the introduction of
universal antenatal screening for GBS at 35
37 weeks gestation, and intrapartum antibiotic
prophylaxis (IAP) is offered to those women who
are GBS-colonised, at the onset of labour.
In the UK, the National Screening Committee
(UKNSC) has controversially not recommended a
universal maternal GBS screening programme. This
is currently under review. The Royal College of
Obstetricians Green Top guideline9 recommends a
risk-factor-based strategy to prevent GBS. IAP is,
however, recommended for prevention of GBS
infection if a woman is found to be colonised with
GBS when incidentally tested, or has had a previous baby with invasive GBS disease, or as part of
broad-spectrum antibiotic therapy if she is febrile
in labour, or has evidence of chorioamnionitis.
Antenatal risk factors for GBS infection can be
identied in up to 60% of cases and include preterm
delivery (<37 weeks), prolonged rupture of membranes (PROM 18 h) or known genital carriage of
GBS during pregnancy.7 GBS can also cross intact
membranes, and the absence of PROM does not
negate the risk of GBS infection: while membranes
were ruptured for >18 h in 44% of babies with
culture-proven GBS EONS, 56% with GBS EONS
were not born following PROM. Successive studies

Bedford Russell AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F350F354. doi:10.1136/archdischild-2014-306193

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Review
have demonstrated that a risk-factor-based approach to prevention of GBS is limited, with frequent missed opportunities for
prevention of GBS sepsis when risk factors are present.10 11

those of non-infectious aetiologies. The repertoire of ancillary

laboratory tests is also limited and not always reliable.14 Over
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 insufciently robust to be reliable in making a diagnosis of EONS.
A number of risk factor scores have been devised for asymptomatic neonates at risk of EON,12 none of which has been shown
to be sufciently robust for widespread use. NICE CGDG noted
the lack of good quality evidence to guide management of neonatal early onset sepsis. In producing best practice guidance on
management, NICE CGDG reached consensus view to stratify
risk factors and clinical indicators of EONS5 attributing Red
Flags to indicators that should prompt a high level of concern
(box 1). Any baby with one Red Flag indicator or risk factor, or
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 reect publication of relevant new information,6 none of
which has any potential impact on the original guidance
(box 3). It is notable that while epidural anaesthesia may be a
risk factor for early onset neonatal fever, it is not associated
with a higher incidence of EONS. Hence, it is suggested that it
is unnecessary to investigate febrile offspring of mothers who
have had epidurals, unless fever persists or the baby has other
signs or risk factors for neonatal sepsis.6
More recently, pulse oximetry has gained momentum as a
screening tool to detect illnesses including EONS in addition to
congenital heart disease, which the PulseOx study was originally designed to investigate.13 Of 208 babies who failed initial
pulse oximetry, 55 had pneumonia (with radiological features
and raised C-reactive protein/CRP), two had culture-proven
GBS sepsis and 28 had raised CRPs with clinical signs suggesting
culture-negative sepsis. Pulse oximetry is currently being considered by the UKNSC for inclusion as a screening test adjunctive
to the newborn and infant physical examination.

DIAGNOSIS OF EONS
Early diagnosis of EONS is challenging because clinical
characteristics are non-specic and difcult to differentiate from

Box 1 National Institute for Health and Care Excellence

Red Flag risk factors and clinical indicators for early
onset neonatal infection (EONS) which should prompt a
high level of concern of EONS 5
Maternal and neonatal risk factors
Parenteral antibiotic treatment to woman for conrmed or
suspected invasive bacterial infection at any time during
labour or in the 24 h periods before and after the birth.
Suspected or conrmed infection in another baby in the case
of a multiple pregnancy.
Neonatal clinical indicators
Respiratory distress starting >4 h after birth.
Seizures.
Need for mechanical ventilation in a term baby.
Signs of shock.
Any baby with one Red Flag indicator or risk factor, should
be promptly assessed for infection and treated with
antibiotics without delay.

MICROBIAL CULTURE
The gold standard for diagnosing infection is, historically, a
positive blood or cerebrospinal uid (CSF) culture with a
minimum reporting delay of 3648 h. Microbial cultures suffer
from low sensitivity and specicity: a negative blood culture
result is almost inevitable for a large proportion of blood cultures because of the submission of inadequate volumes of blood,
and only one culture being drawn.15 16 A false positive culture
of CoNS is common,1 making diagnosis of EONS using the historical gold standard, a challenge.17

Box 2 National Institute for Health and Care Excellence

non-Red Flag risk factors for, and indicators of, early
onset neonatal sepsis
Maternal
Invasive group B streptococcal infection in a previous baby.
Maternal group B streptococcal colonisation, bacteriuria or
infection in the current pregnancy.
Prelabour rupture of membranes.
Preterm birth following spontaneous labour (before 37 weeks
gestation).
Suspected or conrmed rupture of membranes for more than
18 h in a preterm birth.
Intrapartum fever higher than 38C, or conrmed or
suspected chorioamnionitis.
Neonatal clinical indicators
Altered behaviour or responsiveness.
Altered muscle tone (eg, oppiness).
Feeding difculties (eg, feed refusal).
Feed intolerance, including vomiting, excessive gastric
aspirates and abdominal distension.
Abnormal heart rate (bradycardia or tachycardia).
Signs of respiratory distress.
Hypoxia (eg, central cyanosis or reduced oxygen saturation
level).
Jaundice within 24 h of birth.
Apnoea.
Signs of neonatal encephalopathy.
Need for cardiopulmonary resuscitation.
Need for mechanical ventilation in a preterm baby.
Persistent fetal circulation ( persistent pulmonary
hypertension).
Temperature abnormality (lower than 36C or higher than
38C) unexplained by environmental factors.
Unexplained excessive bleeding, thrombocytopenia or
abnormal coagulation (International Normalised Ratio >2.0).
Oliguria persisting beyond 24 h after birth.
Altered glucose homeostasis (hypoglycaemia or
hyperglycaemia).
Metabolic acidosis (base decit of 10 mmol/L or greater).
Local signs of infection (eg, affecting the skin or eye).
Any baby with two or more non-red Flag indicators should
be promptly assessed for infection and treated with
antibiotics without delay.

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Box 3 Summary of key points regarding new evidence
reviewed for National Institute for Health and Care
Excellence Antibiotics for early onset neonatal infection
guideline,6 with no potential impact on guidance
Key Points
Risk factor for infection and clinical indicators of possible
infection
Epidural analgesia may be a risk factor for early onset
neonatal fever, irrespective of intrapartum fever, but is not
associated with a higher incidence of neonatal infection.
Investigations before starting antibiotics in the baby
Full blood count indices may not be sufciently sensitive to
rule out early onset infection in neonates.
Serum procalcitonin concentration: the heterogeneity of
available evidence on use of procalcitonin concentrations,
prevents conclusions regarding the value of this marker.
Antibiotics for suspected infection
Gentamicin dosing 5 mg/kg every 3648 h according to
gentamicin level at 22 h can achieve effective and safe
gentamicin levels in very preterm as well as term babies.
Duration of antibiotic treatment
Serial C-reactive protein (CRP) measurements Antibiotic
treatment can safely be stopped at 48 h in culture-negative
very low birth weight infants who have CRP concentrations
<10 mg/L at presentation and at 48 h.

To avoid false positive cultures, blood for culture should be

drawn from a freshly punctured blood vessel using a strict
aseptic technique and a closed system. The skin disinfectant
should be left to dry for at least 1 min to insure maximal killing
of skin organisms. The common practice of using an open
system (insertion of cannula from which blood is aspirated with
a separate syringe and needle placed in the hub of the cannula),
risks the dilemma of how to interpret a false positive culture
result. There is also a risk of false positives if blood is drawn
from an indwelling vascular device.17
Positive cultures from sites such as the umbilicus, groin, ear,
nose, throat, pharynx and rectum and gastric aspirates are
informative about colonisation, but are of limited value in diagnosis.5 Colonisation of babies without clinical signs of infection
does not warrant antibiotic treatment. The same applies to a
GBS-positive maternal vaginal swab, which indicates colonisation but not necessarily invasive infection unless the baby has
symptoms and signs of infection.5
The ideal diagnostic test would be rapid, sensitive, specic
and not affected by maternal antibiotic therapy. Reliable diagnostic techniques may better inform antibiotic management of
the newborn, and negative results enable clinicians to have condence in prescribing antibiotics for shorter periods of time or
not at all.

specicity (>0.95) to replace microbial cultures in the diagnosis

of neonatal sepsis. Although real-time PCR and broad-range
conventional PCR amplication methods had higher sensitivity
(0.9; 95% CI 0.78 to 0.95) and specicity (0.96; 95% CI 0.94
to 0.97), than other assays, molecular assays still do not have
sufcient sensitivity to replace microbial cultures in the diagnosis of neonatal sepsis but may perform well as add-on tests.
A variety of technological advances are needed before PCR
can replace conventional culture, including: improved recovery
of micro-organisms in whole-blood extractions, increased assay
sensitivity, simpler testing platforms that could easily be run
24 h a day, and more assays to detect antibiotic-resistant genes,
so reducing reliance on culture-based protocols for antimicrobial
susceptibility testing.19

LUMBAR PUNCTURE
A lumbar puncture (LP) should be performed to obtain CSF
prior to starting antibiotics if it is thought safe to do so, and
there is a strong clinical suspicion of infection, or there are clinical symptoms or signs suggestive of meningitis.5 Antibiotic
therapy should not be delayed in order to perform an LP.
In a retrospective case review of infants who developed meningitis in the rst 72 h of life, selective criteria for performing
an LP would have delayed or missed the diagnosis of meningitis
in up to 37% of those evaluated. Those with meningitis
included preterm babies with respiratory distress syndrome
(RDS), asymptomatic term infants with positive blood cultures
as well as term infants with no neurological signs or symptoms,
and negative blood cultures.20 Positive CSF cultures, despite
negative blood cultures, have also been reported for very low
birthweight neonates, without specic neurological clinical manifestations, undergoing screens for suspected late-onset sepsis,
and support a lower threshold for performing an LP as part of a
late-onset sepsis screen.20
Pronounced variation in performance of LP for EONS, even
when adjusting for clinical conditions that would prompt LP,
have been reported in the USA21 22 and may also be a feature in
the UK in spite of NICE guidance.

INTERPRETATION OF CSF MICROSCOPY

Interpretation of neonatal CSF parameters is difcult if white
blood cell (WBC) counts are marginally raised or the tap is traumatic. An upper limit of CSF WBC count >21/mm3 gives 79%
sensitivity and 81% specicity for the diagnosis of meningitis.21
CSF WBC counts and protein levels are higher and decline
more slowly with postnatal age in preterm infants compared
with term infants.23 The various formulas and ratios applied to
traumatic taps to compare observed with predicted WBC counts
or protein levels in CSF samples are unreliable. Adjustment
merely results in a loss of sensitivity, with marginal gain in specicity, and tends to over-correct the result.24 In suspicious clinical cases, the only course is to repeat the LP after 2448 h.

THE ROLE OF CHEST RADIOGRAPH

MOLECULAR ASSAYS
Advances in molecular microbiology have provided new
molecular assays based on PCR, which amplies specic target
regions in the microbial genome, and helps to detect specic
bacterial proteins in body uids and swabs. The advantages
include the speed with which results become available, and the
ability to tailor antimicrobial therapy to those results.
A recent systematic review and meta-analysis18 assessed
whether molecular assays have sufcient sensitivity (>0.98) and
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Pneumonia is a common presentation of EONS,7 and may be

missed if a chest radiograph is not performed. GBS pneumonia
mimics RDS,25 and should be considered if a baby with radiographic appearances of RDS, is disproportionately sick. NICE
guidelines5 do not give a directive on the role of chest radiography as part of a screen for EONS, however, it is notable that
even in older children pneumonia may be present with limited
clinical signs, and there is signicant added value of chest radiography in the diagnosis of pneumonia.26

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EVALUATION OF DIAGNOSTIC METHODS
Leucocyte indexes and C-reactive protein
CRP concentrations may be normal in the early stages of infection,3 and values are subject to physiological variation during
the rst few days of life limiting the use of single values.
Following antigenic stimulation, it takes at least 12 h for a CRP
level to become raised;27 serial measurements in the rst 24
48 h of symptoms increases the test sensitivity, and normal CRP
values during this period have a 99% negative predicted value
for diagnosis of infection.28 The CRP should be measured at
presentation and again after 1824 h in order to facilitate decisions regarding LP (if initial CRP >10 mg/L), and decision
making at 36 h, regarding duration of antibiotic therapy.5
Studies including two systematic reviews of the likelihood
ratios for leucocyte indexes and CRP to predict sepsis have all
concluded that there is too much heterogeneity within the
studies and no such ideal test or combination of tests.29 30
Leucopenia and neutropenia, as well as high immature to total
neutrophil ratio (I:T ratio) are undoubtedly associated with
increasing odds of infection (ORs 5.38, 6.84 and 7.90, respectively); however, the test sensitivities for detection of sepsis are
low.31 The combination of two normal I:T ratios within 24 h
and a negative blood culture has been suggested as indicative of
a non-infected neonate, and may be a contributory marker to
assist with the decision to stop antibiotics.32 Having reviewed
the more recent evidence, NICE evidence update advisory
group (NICE EUAG) does not recommend full blood count for
the diagnosis of EONS as the indices are insufciently sensitive
to exclude EONS6 (box 2).

Serum procalcitonin
Procalcitonin (PCT) is the prehormone of calcitonin, normally
secreted by thyroid C-cells, and rises within 36 h of exposure
to infection. It has been suggested that elevated serum PCT concentrations are more sensitive and specic in the differentiation
between neonatal infection and inammation than CRP and
may also differentiate between bacterial and viral infection. In a
meta-analysis of 16 studies (1959 neonates), the sensitivity and
specicity for diagnosing infection were 81% and 79%, respectively.33 Limitations of the evidence included variation in denition of neonatal sepsis, differences in age and gestation of
neonates and a high level of statistical heterogeneity among
studies analysed. Hence, NICE EUAG concluded that the value
of PCT in diagnosis of infection requires further research, and
PCT concentration cannot be recommended within the current
guideline (box 3).

Cytokine proles and neutrophil/monocyte adhesion

molecules
Multiple cytokines, for example, interleukins 6, 8 and 10, and
tumour necrosis factor-, and leucocyte adhesion molecules, for
example, CD64, CD11b, have been studied for diagnosis of
neonatal sepsis. All lack sufcient sensitivity and specicity to be
recommended as diagnostic tools for EONS.14

Antimicrobial therapy
Antibiotic therapy drives antibiotic resistance and also alters the
types of colonising microbial ora, especially in the gut leading
to skewing of immune development. E coli EONS has, at best,
remained stable in the USA, but approximately 82% of E coli
isolates are resistant to amoxicillin or gentamicin in preterm
infants.2 Because gut ora drive the nascent immune system,
peripartum antibiotic exposure is increasingly recognised as a

major driver of immune dysregulation, resulting in an increasing

incidence of atopy and asthma in childhood.4
Antibiotic therapy should be stopped after 36 h if cultures are
negative, if two CRP measurements are negative5 and if there
are no further signs of infection. Alternatively, when there is a
suspicion that clinical progress is suboptimal, consideration
should always be given to an empiric change of antibiotic
therapy to include a broader spectrum of pathogens.
A multiple logistic regression analysis revealed that empiric
treatment failure of EONS could be predicted at 24 h using the
following variables: need for vasoactive treatment (OR 2.83
(1.21 to 6.66)); WBC <5000 or >20 000 per mm3 on day 1
(2.51 (1.09 to 5.81)); I:T ratio >0.2 on day 1 (2.79 (1.10 to
7.11)) and platelet count per 10 000 mm3 increase on day 1
(0.92 (0.86 to 0.98)).34 Such analyses should be validated in
other datasets but have the potential to improve neonatal
outcome by ensuring that appropriate antibiotics are used as
early as possible. Once a bacterium is identied, the antibiotic
regimen should be targeted appropriately.
An initial gentamicin dose of 5 mg/kg regardless of gestation
has been recommended by NICE CGDG5 but not universally
adopted by UK neonatologists, who have concerns regarding
renal clearance of gentamicin in very immature babies. If a
second dose is required, it is recommended that this should be
given at 36 h, with a trough level immediately prior to the
second dose, and adjustment of the dose to achieve a trough
concentration of <2 mg/L. A retrospective analysis in babies
<28 weeks, demonstrated that giving 5 mg/kg every 3648 h
achieves safe and effective peak and trough gentamicin concentrations, according to levels taken at 22 h.35 This evidence is
reassuring and supports NICE recommendations.6

Antimicrobial stewardship
Antimicrobial stewardship (AMS) refers to the coordinated interventions to prescribe and measure the most appropriate,
pathogen-specic, narrow-spectrum drug regimen, dose, duration of therapy and route of administration.36 Department of
health guidance provides an outline of evidence-based AMS in
the secondary healthcare setting promoting a Start SmartThen
Focus approach for all antibiotic prescriptions (box 4). Elements
of an AMS should also include an assessment of acute-trust AMS
activities using the self-assessment toolkit, a trust AMS

Box 4 Antimicrobial Stewardship Programme: Start

SmartThen Focus36
Start Smart
Do not start antibiotics in the absence of clinical infection.
Use local guidelines to initiate prompt effective antibiotic
treatment if there is evidence/suspicion of infection.
Document on drug chart and in medical records: clinical
indication, duration of review date, route and dose.
Obtain cultures rst.
Then Focus
Review the clinical diagnosis and continuing need for
antibiotics by 48 h and make a clear plan of action: the
Antimicrobial Prescribing Decision.
The Antimicrobial Prescribing Decisions relevant to neonates
are: Stop, Change or Continue.
It is essential to document the review and subsequent
decision in the medical records.

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management team/committee, ward-focused antimicrobial teams
and evidence-based antimicrobial-prescribing guidelines. Some
recommendations are not applicable to the neonatal context, for
example, changing intravenous to oral antibiotics at the nearest
opportunity, however, neonatal-specic recommendations have
previously been published in this journal37 along with broader
guidelines on managing and preventing Gram-negative infections
in neonatal units.38
The tension between the need to investigate a baby at risk of
EONS and to prescribe antibiotics promptly, versus the fact that
most newborn babies given antibiotics do not have infection but
become exposed to the risks of antimicrobial therapy, has been
recognised by NICE. Exposure to antibiotics must be minimised
safely. NICE Quality Standards Advisory Committee and Project
Team are developing quality standards with the aim of reducing
infant mortality, reducing admissions and readmissions to neonatal
units, maternity and neonatal length of stay and improving neonatal neurological and auditory development. Implementation of
NICE antibiotics for neonatal infection quality standards are
anticipated to shape future neonatal antibiotic prescribing practice
from birth to 28 days of life in the UK, and likely beyond.

SUMMARY
The main diagnostic dilemmas in managing EONS centre on
the lack of a rapid and reliable test, which is 100% specic and
sensitive for presence of microbes in sterile sites. Recent evidence has been reviewed and does not alter NICE guidelines,
which were developed using robust methodology and which
should be used to manage babies at risk and with clinical indicators of EONS. All neonatal units must adopt an AMS programme; while antibiotics can be life saving, they are by no
means harmless to those who do not need them.
Contributors ARBR wrote the rst and nal drafts. RK conducted an extensive
literature review and updated the appropriate sections.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.

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Bedford Russell AR, et al. Arch Dis Child Fetal Neonatal Ed 2015;100:F350F354. doi:10.1136/archdischild-2014-306193

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Early onset neonatal sepsis: diagnostic

dilemmas and practical management
A R Bedford Russell and R Kumar
Arch Dis Child Fetal Neonatal Ed 2015 100: F350-F354 originally
published online November 25, 2014

doi: 10.1136/archdischild-2014-306193
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