Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

Official reprint from UpToDate® www.uptodate.com

©2021 UpToDate®

Clinical features, evaluation, and diagnosis of sepsis in

term and late preterm infants
Author: Morven S Edwards, MD
Section Editors: Sheldon L Kaplan, MD, Joseph A Garcia-Prats, MD
Deputy Editor: Carrie Armsby, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2021. | This topic last updated: Apr 30, 2021.

INTRODUCTION

Sepsis is an important cause of morbidity and mortality among newborn infants. Although
the incidence of sepsis in term and late preterm infants is low, the potential for serious
adverse outcomes is of such great consequence that caregivers should have a low threshold
for evaluation and treatment for possible sepsis in neonates.

The epidemiology, clinical features, diagnosis, and evaluation of sepsis in term and late
preterm infants will be reviewed here. The management and outcome of sepsis in term and
late preterm infants, neonatal sepsis in preterm infants, and evaluation of febrile and ill-
appearing neonates after discharge from the birth hospitalization are discussed separately:

● (See "Management and outcome of sepsis in term and late preterm infants".)
● (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks
gestation".)
● (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks
gestation".)
● (See "Febrile infant (younger than 90 days of age): Outpatient evaluation".)
● (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

TERMINOLOGY

The following terms will be used throughout this discussion on neonatal sepsis:

● Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested

by systemic signs of infection and isolation of a bacterial pathogen from the
bloodstream. A consensus definition for neonatal sepsis is lacking [1]. (See 'Diagnosis'
below.)

● Term infants are those born at a gestational age of 37 weeks or greater.

● Late preterm infants (also called near-term infants) are those born from 34 through 36
completed weeks of gestation [2]. (See "Late preterm infants".)

● Preterm infants are those born at less than 34 weeks of gestation [2].

Sepsis is classified according to the infant's age at the onset of symptoms.

● Early-onset sepsis is defined as the onset of symptoms before seven days of age,
although some experts limit the definition to infections occurring within the first 72 hours
of life [3].

● Late-onset sepsis is generally defined as the onset of symptoms at ≥7 days of age [3].
Similar to early-onset sepsis, there is variability in the definition, ranging from an onset at
>72 hours of life to ≥7 days of age [3,4].

Infants with early-onset sepsis typically present with symptoms during their birth
hospitalization. Term infants with late-onset sepsis generally present to the outpatient setting
or emergency department unless comorbid conditions have prolonged the birth
hospitalization. The approach to evaluation of neonates in the outpatient setting is discussed
separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)" and
"Febrile infant (younger than 90 days of age): Management".)

PATHOGENESIS
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

The pathogenesis differs based on the timing of onset:

● Early-onset infection – Early-onset infection is usually due to vertical transmission by

ascending contaminated amniotic fluid or during vaginal delivery from bacteria in the
mother's lower genital tract [5]. Maternal chorioamnionitis (or intraamniotic infection) is a
well-recognized risk factor for early-onset neonatal sepsis [6,7]. Maternal group B
streptococcal (GBS) colonization is another important risk factor. (See 'Maternal risk
factors' below and "Group B streptococcal infection in neonates and young infants",
section on 'Risk factors'.)

Use of forceps during delivery and electrodes placed for intrauterine monitoring have
been implicated in the pathogenesis of early-onset sepsis because they penetrate the
neonatal defensive epithelial barriers [8].

● Late-onset infection – Late-onset infections can be acquired by the following

mechanisms:

• Vertical transmission, resulting in initial neonatal colonization that evolves into later
infection
• Horizontal transmission from contact with care providers or environmental sources

Disruption of the intact skin or mucosa, which can be due to invasive procedures (eg,
intravascular catheter), increases the risk of late-onset infection. Late-onset sepsis is
uncommonly associated with maternal obstetrical complications.

Metabolic factors, including hypoxia, acidosis, hypothermia, and inherited metabolic

disorders (eg, galactosemia), are likely to contribute to risk for and severity of neonatal sepsis
(including both early- and late-onset). These factors are thought to disrupt the neonate's host
defenses (ie, immunologic response) [8].

EPIDEMIOLOGY

The overall incidence of neonatal sepsis ranges from 1 to 5 cases per 1000 live births [9-11].
Estimated incidence rates vary based on the case definition and population studied. In a

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

systematic review and meta-analysis of population-based studies from around the world, the
estimated pooled incidence of neonatal sepsis was 22 per 1000 live births, with an associated
mortality rate of 11 to 19 percent [12]. This translates to a global incidence of 3 million cases
of neonatal sepsis per year [12]. Globally, neonatal sepsis and other severe infections were
responsible for an estimated 430,000 neonatal deaths in 2013, accounting for approximately
15 percent of all neonatal deaths [13].

Rates of neonatal sepsis increase with decreasing gestational age:

● Term neonates (≥37 weeks gestational age) – The estimated incidence of sepsis (both
early- and late-onset) in term neonates is 1 to 2 cases per 1000 live births [9,10]. In a
prospective national surveillance study (2006 to 2009), the incidence of early-onset sepsis
(defined as positive blood or cerebrospinal fluid cultures) was 0.98 cases per 1000 live
births; the rate among infants with birth weight >2500 g was 0.57 per 1000 [11].

● Late preterm neonates (34 through 36 weeks gestational age) – The incidence is higher in
late preterm than term infants. In an observational cohort study (1996 to 2007), the
reported incidences of early- and late-onset sepsis (defined as positive blood culture) in
late preterm neonates were 4.4 and 6.3 per 1000, respectively [14].

● Preterm neonates <34 weeks gestational age – The incidence of sepsis in preterm
neonates is discussed separately. (See "Clinical features and diagnosis of bacterial sepsis
in preterm infants <34 weeks gestation", section on 'Incidence'.)

The incidence of early-onset sepsis in the United States has decreased, primarily due to
reduction in group B streptococcal (GBS) infections, owing to the use of intrapartum antibiotic
prophylaxis (IAP) [15-19]. Early-onset GBS infection rates in the United States reported
through the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance
Report have declined from 0.6 per 1000 live births in 2000 to 0.25 per 1000 live births in 2018
[20,21]. Late-onset GBS infection rates have remained relatively stable in the same interval
(0.4 per 1000 live births in 2000 and 0.28 per 1000 live births in 2018). (See "Group B
streptococcal infection in neonates and young infants", section on 'Epidemiology'.)

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

ETIOLOGIC AGENTS

Group B Streptococcus (GBS) and Escherichia coli are the most common causes of both early-
and late-onset sepsis, accounting for approximately two-thirds of early-onset infections
[16,22-24].

Other bacterial agents associated with neonatal sepsis include (table 1):

● Listeria monocytogenes, although a well-recognized cause of early-onset sepsis, only

accounts for rare sporadic cases of neonatal sepsis and is more commonly seen during
an outbreak of listeriosis [25,26].

● Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, is a

potential pathogen in neonatal sepsis [27]. Bacteremic staphylococcal infections in term
infants usually occur in association with skin, bone, or joint sites of involvement.

● Enterococcus, a commonly encountered pathogen among preterm infants, is a rare cause

of sepsis in otherwise healthy term newborn infants.

● Other gram-negative bacteria (including Klebsiella, Enterobacter, and Citrobacter spp)

and Pseudomonas aeruginosa are associated with late-onset infection, especially in
infants admitted to neonatal intensive care units [28].

● Coagulase-negative staphylococci often are a cause of hospital-associated infection in ill

infants (primarily in premature infants and/or infants who have indwelling intravascular
catheters). Coagulase-negative staphylococci may be considered a contaminant in
otherwise healthy term infants who have not undergone invasive procedures.

The patterns of pathogens associated with neonatal sepsis have changed over time, as
reflected by longitudinal databases from single tertiary centers [16,17]. The incidence of early-
onset GBS has declined by 80 percent in the United States with the use of intrapartum
antibiotic prophylaxis (IAP). GBS prevention efforts have not led to an increasing burden of
early-onset E. coli infection [23]. (See "Early-onset neonatal group B streptococcal disease:
Prevention".)

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

Common nonbacterial agents associated with neonatal sepsis include (see 'Differential
diagnosis' below):

● Herpes simplex virus (see "Neonatal herpes simplex virus infection: Clinical features and
diagnosis")

● Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Clinical

features, laboratory diagnosis, treatment, and prevention", section on 'Neonates' and
"Nosocomial viral infections in the neonatal intensive care unit", section on 'Sepsis-like
illness and meningitis/encephalitis')

● Candida (see "Clinical manifestations and diagnosis of Candida infection in neonates",

section on 'Invasive infection')

MATERNAL RISK FACTORS

Maternal factors that are associated with an increased risk of early-onset sepsis in the
neonate, particularly group B Streptococcus (GBS) infection, include chorioamnionitis
(intraamniotic infection), intrapartum maternal fever, maternal GBS colonization, preterm
delivery, and prolonged rupture of the membranes [5,6,29]. The approach to identifying
pregnancies at risk for neonatal early-onset sepsis and indications for maternal intrapartum
antibiotic prophylaxis (IAP) are discussed separately. (See "Early-onset neonatal group B
streptococcal disease: Prevention", section on 'Identification of pregnancies at increased risk
for early-onset neonatal GBS' and "Early-onset neonatal group B streptococcal disease:
Prevention", section on 'Intrapartum antibiotic prophylaxis'.)

Maternal GBS screening and IAP reduces the risk of GBS infection but does not eliminate it. In
a prospective national surveillance study that included 117 term neonates with early-onset
GBS infection, 66 percent were born to mothers who did not receive IAP, because maternal
GBS screening culture was either not performed (29 percent of mothers) or was negative (51
percent of mothers), and there were no other indications for IAP [11].

CLINICAL MANIFESTATIONS
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

Clinical manifestations range from subtle symptoms to profound septic shock. Signs and
symptoms of sepsis are nonspecific and include temperature instability (primarily fever),
irritability, lethargy, respiratory symptoms (eg, tachypnea, grunting, hypoxia), poor feeding,
tachycardia, poor perfusion, and hypotension (table 2) [8].

Because the signs and symptoms of sepsis can be subtle and nonspecific, it is important to
identify neonates with risk factors for sepsis and to have a high index of suspicion for sepsis
when an infant deviates from his or her usual pattern of activity or feeding [8].

Signs and symptoms of neonatal sepsis include:

● Fetal and delivery room distress – The following signs of fetal and neonatal distress
during labor and delivery may be early indicators of neonatal sepsis:

• Intrapartum fetal tachycardia, which may be due to intraamniotic infection (see "Fetal
arrhythmias", section on 'Tachyarrhythmias')

• Meconium-stained amniotic fluid, which is associated with a twofold increased risk of

sepsis [6] (see "Meconium aspiration syndrome: Pathophysiology, clinical
manifestations, and diagnosis", section on 'Meconium composition and passage')

• Apgar score ≤6, which is associated with a 36-fold increased risk of sepsis [30] (see
"Overview of the routine management of the healthy newborn infant", section on
'Apgar score')

● Temperature instability – The temperature of an infected infant can be elevated,

depressed, or normal. Term infants with sepsis are more likely to be febrile than preterm
infants who are more likely to be hypothermic [8]. Temperature elevation in full-term
infants is concerning and, if persistent, is highly indicative of infection [31,32].

● Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are

common in infected neonates. Approximately 85 percent of newborns with early-onset
sepsis present with respiratory distress (eg, tachypnea, grunting, flaring, use of accessory
muscles) [11]. Apnea is less common, occurring in 38 percent of cases, and is more likely
in preterm than term infants. Apnea is a classic presenting symptom in late-onset group

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

B streptococcal (GBS) sepsis. Early-onset disease can be associated with persistent

pulmonary hypertension of the newborn. (See "Persistent pulmonary hypertension of the
newborn".)

Tachycardia is a common finding in neonatal sepsis but is nonspecific. Bradycardia may

also occur. Poor perfusion and hypotension are more sensitive indicators of sepsis, but
these tend to be late findings. In a prospective national surveillance study, 40 percent of
neonates with sepsis required volume expansion and 29 percent required vasopressor
support [11].

● Neurologic symptoms – Neurologic manifestations of sepsis in the neonate include

lethargy, poor tone, poor feeding, irritability, and seizures [8]. Seizures are an uncommon
presentation of neonatal sepsis but are associated with a high likelihood of infection. In a
prospective study in a single neonatal unit, 38 percent of neonates with seizures had
sepsis as the etiology [33]. Seizures are a presenting feature in 20 to 50 percent of infants
with neonatal meningitis [34]. (See "Bacterial meningitis in the neonate: Clinical features
and diagnosis" and "Etiology and prognosis of neonatal seizures".)

● Other findings – Other findings associated with neonatal sepsis and their approximate
frequencies are listed below (table 2) [8,11]:

• Jaundice – 35 percent
• Hepatomegaly – 33 percent
• Poor feeding – 28 percent
• Vomiting – 25 percent
• Abdominal distension – 17 percent
• Diarrhea – 11 percent

EVALUATION AND INITIAL MANAGEMENT

Neonates with signs and symptoms of sepsis (table 2) require prompt evaluation and
initiation of antibiotic therapy [5,8]. Because the signs and symptoms of sepsis are subtle and
nonspecific, laboratory testing is performed in any infant with identifiable risk factors and/or

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

signs and symptoms concerning for sepsis. Our approach is generally consistent with
guidelines published by the American Academy of Pediatrics [5,35].

Early-onset sepsis — The evaluation of a neonate with suspected early-onset sepsis includes
all of the following:

● Review of the pregnancy, labor, and delivery, including risk factors for sepsis and the use
and duration of maternal intrapartum antibiotic prophylaxis (IAP) (see 'Maternal risk
factors' above)
● Comprehensive physical examination (see "Assessment of the newborn infant")
● Laboratory testing (see 'Laboratory tests' below)

The extent of the diagnostic evaluation for sepsis is directed by the infant's symptoms and
maternal risk factors.

Early-onset sepsis calculator — Multivariate predictive models for risk of early-onset

sepsis have been developed and validated in clinical use, including the early-onset sepsis
calculator [29,36-38]. The early-onset sepsis calculator is a web-based tool that can be used to
estimate the risk of early-onset sepsis in individual patients based on risk factors (eg,
newborn clinical condition, highest intrapartum maternal temperature, maternal group B
Streptococcus [GBS] status, administration of maternal IAP, gestational age, duration of
rupture of membranes). The calculator requires the user to input the local incidence of early-
onset sepsis. If the local incidence of early-onset sepsis is unknown, the users should enter
"0.5 per 1000." The calculator provides guidance on the diagnostic evaluation and empiric
antibiotic treatment. The threshold used to trigger evaluation and empiric treatment varies
depending on the clinical circumstances. The early-onset sepsis calculator is not valid for
preterm infants (<34 weeks gestation) and does not apply to late-onset sepsis.

Symptomatic neonates — Infants with signs and symptoms of sepsis (table 2) should
undergo a full diagnostic evaluation and should receive empiric antibiotic treatment. (See
'Clinical manifestations' above and 'Empiric antibiotic therapy' below.)

A full diagnostic evaluation includes (see 'Laboratory tests' below):

● Blood culture
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants
● Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure and it
will not delay initiation of antibiotic therapy) (see 'Lumbar puncture' below)
● Complete blood count (CBC) with differential and platelet count
● Chest radiograph (if respiratory symptoms are present)
● Cultures from tracheal aspirates if intubated
● C-reactive protein (CRP) and/or procalcitonin (PCT) levels – These tests are not routinely
required but may be helpful in determining length of therapy if followed serially (see
'Other inflammatory markers' below)

Well-appearing neonates — Well-appearing infants with identified risk factors for

neonatal sepsis, particularly GBS, should be observed for 36 to 48 hours. Based on the nature
of the risk factor(s) and the use and duration of maternal IAP, they may require a limited
diagnostic evaluation (ie, blood culture). Accepted approaches to determining the need for
laboratory evaluation and empiric antibiotics include categorical risk assessment (algorithm 1
), clinical observation (algorithm 2), and the early-onset sepsis calculator. The early-onset
sepsis calculator is discussed above (see 'Early-onset sepsis calculator' above). The other two
approaches are discussed in detail separately. (See "Management of neonates at risk for
early-onset group B streptococcal infection", section on 'Approaches to risk assessment'.)

Late-onset sepsis — Infants presenting with signs and symptoms at ≥7 days of age should
undergo prompt evaluation and empiric antibiotic treatment. (See "Management and
outcome of sepsis in term and late preterm infants", section on 'Late-onset sepsis'.)

A full diagnostic evaluation should be performed. In addition to the tests described above
for early-onset sepsis (see 'Symptomatic neonates' above), the following should also be
obtained:

● Urine culture
● Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated,
purulent eye drainage, or pustules)

Infants with late-onset sepsis generally present to the outpatient or emergency department
setting unless comorbid conditions have prolonged the birth hospitalization. (See "Approach
to the ill-appearing infant (younger than 90 days of age)" and "Febrile infant (younger than 90

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

days of age): Management".)

Empiric antibiotic therapy — Indications for empiric antibiotic therapy (after obtaining
cultures) include:

● Ill appearance (see "Approach to the ill-appearing infant (younger than 90 days of age)")

● Concerning symptoms, including temperature instability or respiratory, cardiocirculatory,

or neurologic symptoms (see 'Clinical manifestations' above)

● Cerebrospinal fluid pleocytosis (white blood cell [WBC] count of >20 to 30 cells/microL) (
table 3) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section
on 'Interpretation of cerebrospinal fluid')

● Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see

'Maternal risk factors' above)

● High estimated sepsis risk based on a validated risk calculator (see 'Early-onset sepsis
calculator' above)

The empiric antibiotic regimen should include agents active against GBS and other organisms
that most commonly cause neonatal sepsis (eg, E. coli and other gram-negative pathogens) (
table 1). The combination of ampicillin and gentamicin or ampicillin and an expanded-
spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) are
appropriate regimens that provide empiric coverage for these organisms until culture results
are available. Ampicillin and gentamicin is generally the preferred regimen; however, local
antibiotic resistance patterns must be considered. Our suggested empiric regimens in special
circumstances are summarized in the table (table 4) and discussed in greater detail
separately. (See "Management and outcome of sepsis in term and late preterm infants",
section on 'Initial empiric therapy'.)

LABORATORY TESTS

The goals of the diagnostic evaluation are to identify and treat all infants with bacterial sepsis
and minimize the treatment of patients who are not infected. Laboratory assessment includes
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

cultures of body fluids that confirm the presence or absence of a bacterial pathogen and
other studies that are used to evaluate the likelihood of infection.

Blood culture — A definitive diagnosis of neonatal sepsis is established by a positive blood

culture. The sensitivity of a single blood culture to detect neonatal bacteremia is
approximately 90 percent.

● Blood sampling – The following considerations are important when obtaining a blood
culture:

• Sampling site – Blood cultures can be obtained by venipuncture or arterial puncture

or by sampling from a newly inserted umbilical artery or vascular access catheter.
Positive culture results of blood drawn from indwelling umbilical or central venous
catheters can be difficult to interpret since they can indicate contamination or
catheter colonization rather than a true systemic infection. In such circumstances,
obtaining a peripheral blood culture may help determine if there is a true
bloodstream infection [8].

• Number of cultures – We obtain at least one culture prior to initiating empiric

antibiotic therapy in neonates with a high clinical suspicion for sepsis, although other
institutions may routinely obtain two blood cultures.

• Volume of blood – The optimal volume of blood is based on the weight of the infant.
A minimum blood volume of 1 mL is desirable for optimal detection of bacteremia
when a single blood culture bottle is used [5]. At the author's institution, the
suggested optimal volume is 2 mL for infants weighing ≤3 kg and 3 mL for those who
weigh >3 to 5 kg. Dividing this volume into two aliquots to inoculate an anaerobic as
well as the aerobic culture bottle may optimize recovery of rare strict anaerobic
species, and most neonatal pathogens grow under anaerobic conditions.

● Time to positivity – Automated systems for continuous monitoring of blood cultures are
routinely used in the United States and have shortened the time to identify positive blood
cultures. In most cases of neonatal sepsis, blood cultures become positive within 24 to 36
hours [39].

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants
● Distinguishing infection from contamination – A positive blood culture is diagnostic of
sepsis when a known bacterial pathogen is isolated (table 1). Isolation of skin flora (eg,
diphtheroids) suggests contamination rather than infection. Contamination is also
suggested when multiple species grow in culture. Coagulase-negative staphylococci may
be pathogenic in patients with indwelling vascular catheters or other invasive devices,
whereas a single blood culture positive for coagulase-negative staphylococci is likely to
represent a contaminant in full-term infants without these risk factors [8].

Lumbar puncture — The clinical presentation of neonatal meningitis is indistinguishable

from that of neonatal sepsis without meningitis. Specific clinical signs of meningitis (eg,
bulging fontanelle, nuchal rigidity) are often lacking in neonates. For this reason, we suggest
performing a lumbar puncture as part of the diagnostic evaluation in symptomatic neonates.
Lumbar puncture should ideally be performed before the initiation of antibiotics for infants in
whom the clinical suspicion for sepsis is high, particularly those with critical illness. However,
lumbar puncture should be deferred if the procedure would compromise the infant's clinical
condition or if the procedure would delay initiation of antibiotics [5].

Lumbar puncture is indicated in neonates with:

● Clinical findings concerning for sepsis (table 2)

● Positive blood culture
● Worsening clinical status while on antibiotic therapy

Cerebrospinal fluid should be sent for Gram stain, routine culture, cell count with differential,
and protein and glucose concentrations. The interpretation of cerebrospinal fluid needs to
account for variations due to gestational age, chronologic age, and birth weight (table 3).

The clinical features and diagnosis of neonatal bacterial meningitis are discussed separately.
(See "Bacterial meningitis in the neonate: Clinical features and diagnosis".)

Urine culture — Urine culture obtained by catheter or bladder tap should be included in the
sepsis evaluation for infants one week of age or older. A urine culture need not be routinely
performed in the evaluation of an infant ≤6 days of age, because a positive urine culture in
this setting is a reflection of high-grade bacteremia rather than an isolated urinary tract
infection [5]. (See "Urinary tract infections in neonates".)
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Other cultures — In patients with late-onset infection, cultures should be obtained from any
other potential foci of infection (eg, purulent eye drainage or pustules).

Tracheal aspirates can be of value if obtained immediately after intubation. However, they
may reflect lower respiratory tract colonization rather than indicating a causative pathogen in
an infant who has been intubated for several days.

Gram stain or culture of other sites (eg, gastric aspirate, body surface sites [eg, axilla, groin,
and external ear canal]) add little to the evaluation and should not be performed [5].

Complete blood count — A complete blood count (CBC) is used to evaluate the likelihood of
sepsis in a neonate with risk factors or signs of infection. Abnormal findings on a CBC cannot
be used to establish the diagnosis of sepsis.

Early-onset sepsis — For most neonates with suspected early-onset sepsis, we suggest
obtaining a CBC as part of the diagnostic evaluation. In neonates who are undergoing
evaluation because they have identified risk factors for group B Streptococcus (GBS) and who
are otherwise well appearing, it is reasonable to omit the CBC (ie, obtain only a blood culture)
[35]. (See "Management of neonates at risk for early-onset group B streptococcal infection",
section on 'Diagnostic evaluation'.)

The CBC does not perform well in predicting risk of infection in neonates and should not be
used as the sole determinant of whether to treat empirically with antibiotics [40-44]. However,
when used in conjunction with other assessments, it may be useful in the evaluation of
infants with suspected early- or late-onset sepsis. The CBC is more useful in identifying
neonates who are unlikely to have sepsis than in identifying infants with sepsis [5,8]. When
used in the evaluation of early-onset sepsis, the predictive value of the CBC improves if
obtained after four to six hours of age [41,45].

Two large multicenter studies have evaluated the diagnostic value of CBCs in early-onset
neonatal sepsis [40,41]. These studies found that low white blood cell (WBC) count
(<5000/microL), absolute neutropenia (absolute neutrophil count [ANC] <1000
neutrophils/microL), relative neutropenia (ANC <5000 neutrophils/microL), and elevated ratio
of immature to total neutrophil counts (I/T ratio) were associated with culture-proven sepsis.
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

However, none of the tests was sufficiently sensitive to reliably predict neonatal sepsis.

CBCs obtained 6 to 12 hours after delivery are more predictive of sepsis than those obtained
immediately after birth because the WBC and ANC normally increase during the first six hours
of life [40,46].

The following neutrophil indices are used to determine the likelihood of infection:

● I/T ratio – An elevated I/T ratio (≥0.2) has the best sensitivity of the neutrophil indices for
predicting neonatal sepsis and can be helpful as an initial screen when used in
combination with risk factors, clinical assessment, and/or other tests [6,47]. A normal I/T
ratio can help rule out sepsis; however, an elevated value is not highly predictive of sepsis
and may be observed in 25 to 50 percent of uninfected infants [6,47,48].

The I/T ratio is limited by the wide range of normal values, which reduces its positive
predictive value, especially in asymptomatic patients [49]. Inter-reader differences in
band neutrophil identification with manual differential counts is another limitation. In
addition, exhaustion of the bone marrow reserves, which may occur during critical illness,
will result in low band counts and lead to falsely low ratios. (See "Evaluating diagnostic
tests", section on 'How well does the test perform in specific populations?'.)

● ANC – Although both elevated and low neutrophil counts can be associated with neonatal
sepsis, neutropenia has greater specificity since few conditions other than sepsis and
preeclampsia depress the neutrophil count in neonates.

Neutrophil counts vary with gestational age (counts decrease with decreasing gestational
age), type of delivery (counts are lower in infants born by cesarean delivery), site of
sampling (counts are lower in arterial than in venous samples), altitude (counts are
higher at elevated altitudes), and timing after delivery (counts increase during the first six
hours of life) [40].

The lower limit of a normal neutrophil count for infants >36 weeks of gestation is
3500/microL at birth and 7500/microL six to eight hours after delivery (figure 1) [50]. For
infants born at 28 through 36 weeks of gestation, the lower limits of normal neutrophil
counts at birth and at six to eight hours after birth are 1000/microL and 1500/microL,
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

respectively (figure 2).

Late-onset sepsis — CBCs are frequently used to support the diagnosis of late-onset
sepsis. In this setting, CBCs are less variable than in the first days of life. However, WBC
indices still perform poorly in identifying neonates with late-onset sepsis.

In a study of 37,826 neonates (mostly infants continuously hospitalized from birth) who
underwent evaluation for late-onset (defined as 4 to 120 days) sepsis with blood culture and
CBC, abnormal WBC (<1000 or >50,000/microL), high ANC (>17,670/microL), elevated I/T ratio
(≥0.2), and low platelet count (<50,000/microL) were associated with culture positivity [51].
However, sensitivity was inadequate to reliably predict late-onset sepsis.

Screening protocols used to identify serious bacterial infections in febrile infants two to three
months of age are inadequate in neonates as they fail to accurately identify neonates with
serious bacterial infections [52]. (See "Febrile infant (younger than 90 days of age): Outpatient
evaluation", section on 'Traditional criteria'.)

Other inflammatory markers — A number of acute phase reactants have been used to
identify infected newborns. Many of these tests have a high sensitivity; however, they lack
specificity, resulting in a poor predictive value [53]. No single biomarker or panel of screening
tests is sufficiently sensitive to reliably detect neonatal sepsis [54].

● C-reactive protein (CRP) – CRP is increased in inflammatory conditions, including sepsis.

A variety of noninfectious inflammatory conditions can also cause elevated CRP, including
maternal fever, fetal distress, stressful delivery, perinatal asphyxia, meconium aspiration,
and intraventricular hemorrhage [55].

A single measurement of CRP is not a useful aid in the diagnosis of neonatal sepsis,
because it lacks sufficient sensitivity and specificity [56]. However, sequential assessment
of CRP values may help support a diagnosis of sepsis. If the CRP level remains
persistently normal (<1 mg/dL [10 mg/L]), neonatal bacterial sepsis is unlikely [5].

CRP levels can be helpful in guiding the duration of antibiotic therapy in suspected
neonatal bacterial infection. Infants with elevated CRP levels that decrease to <1 mg/dL
(10 mg/L) 24 to 48 hours after initiation of antibiotic therapy typically are not infected and
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generally do not require further antibiotic treatment if cultures are negative. However,
routine use of serial CRP measurements can be associated with longer length of hospital
stay [57].

An elevated CRP level alone does not justify continuation of empiric antibiotics for more
than 36 to 48 hours in well-appearing infants with negative culture results [58]. Additional
evaluation may be warranted to investigate alternative explanations for persistently
elevated CRP values.

● Procalcitonin (PCT) – PCT is the peptide precursor of calcitonin. It is released by

parenchymal cells in response to bacterial toxins, leading to elevated serum levels in
patients with bacterial infections. Several observational studies have suggested that PCT
may be a useful marker to identify neonates who are infected [59-61]. In a 2015
systematic review of 18 studies, the sensitivity of PCT for detection of neonatal sepsis
ranged from 72 to 79 percent and the specificity ranged from 72 to 90 percent [61]. Thus,
although PCT is a promising marker, it does not appear to be reliable as the sole or main
diagnostic indicator for neonatal sepsis.

PCT may have utility in guiding the duration of antibiotic therapy in neonates with
suspected sepsis. In a multicenter randomized trial involving 1710 neonates with
suspected early-onset sepsis, infants assigned to a treatment protocol in which duration
of antibiotic therapy was guided by serial PCT measurements in addition to standard
criteria (ie, clinical examination, blood culture results, WBC, and CRP) had shorter
duration of antibiotic therapy compared with infants managed according to standard
criteria without PCT measurements (55.1 versus 65.0 hours, respectively) [62]. The rate of
reinfection was low in both groups (0.7 percent for the PCT group, and 0.6 percent for the
control group). However, the study protocol's suggested duration of antibiotic therapy
was overruled by the treating clinician in 45 percent of infants in the PCT group and 41
percent of those in the control group. The findings reinforce the concept that when serial
PCT levels are obtained, they should be used in conjunction with other clinical indicators
of sepsis and should not be the sole basis of decision-making.

● Cytokines, chemokines, and other biomarkers – Both proinflammatory cytokines, such

as interleukin-6 and tumor necrosis factor-alpha, and antiinflammatory cytokines
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

(interleukin-4 and interleukin-10) are increased in infected infants compared with those
without infections [63-66]. Elevations of serum amyloid A and the cell surface antigen
CD64 also have high sensitivity for identifying infants with sepsis [61,67]. However, these
biomarkers are generally not used in clinical practice.

Further research aimed at better understanding the neonatal inflammatory response to

sepsis may result in the identification of sensitive and specific markers of inflammation or the
development of pathogen-specific rapid diagnostic tests for early detection of neonatal
sepsis. With a sensitive and specific marker for systemic bacterial infection, the management
of neonatal sepsis would be significantly altered so that antimicrobial therapy could be safely
withheld in infants for whom sepsis is unlikely.

DIAGNOSIS

Culture-proven sepsis — The isolation of pathogenic bacteria from a blood culture is the
gold standard to confirm the diagnosis of neonatal sepsis. A positive blood culture is
diagnostic of sepsis when a bacterial pathogen is isolated (table 1). Isolation of skin flora (eg,
diphtheroids and coagulase-negative staphylococci) in culture suggests contamination rather
than infection, although coagulase-negative staphylococci can be pathogenic in patients with
indwelling vascular catheters or other devices [8]. (See 'Blood culture' above and
"Management and outcome of sepsis in term and late preterm infants", section on 'Culture-
proven sepsis'.)

Probable sepsis — In some cases, a pathogen may not be isolated in culture, yet the neonate
has a clinical course that is concerning for sepsis (eg, ongoing temperature instability;
ongoing respiratory, cardiocirculatory, or neurologic symptoms not explained by other
conditions; or ongoing laboratory abnormalities suggestive of sepsis [ie, cerebrospinal fluid
pleocytosis, elevated ratio of immature to total neutrophil counts, or elevated C-reactive
protein (CRP)]).

A composite of observational assessment and serial laboratory testing is typically used to

make a diagnosis of probable sepsis [68]. The criteria used are usually broad, in an attempt to
ensure that all infected infants are identified, but at the cost of testing and treating a number
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

of uninfected infants. There is no consensus definition for the diagnosis of probable sepsis in
neonates [1].

Alternative diagnoses (table 5) should also be entertained when an infant with suspected
sepsis has negative cultures. (See "Management and outcome of sepsis in term and late
preterm infants", section on 'Probable but unproven sepsis' and 'Differential diagnosis'
below.)

Infection unlikely — Infants with mild and/or transient symptoms (ie, fever alone or other
symptoms that quickly resolve) who remain well-appearing with normal laboratory values and
negative cultures at 36 to 48 hours are unlikely to have sepsis. Empiric antibiotic therapy
should be discontinued after 36 to 48 hours in these neonates [5,69].

In a retrospective study of 2785 newborns who underwent evaluation for sepsis based on
clinical symptoms (54 percent) or risk factors (46 percent), 22 infants (0.8 percent) were found
to have culture-proven sepsis and 40 (1.4 percent) had probable sepsis (ie, culture-negative
clinical sepsis) [6].

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of neonatal sepsis includes systemic viral, fungal, and parasitic
infections and noninfectious causes of temperature instability and respiratory,
cardiocirculatory, and neurologic symptoms (table 5). Appropriate microbiologic testing
distinguishes neonatal bacterial sepsis from nonbacterial systemic infections. The clinical
history, disease course, chest radiograph, electrocardiogram (ECG), hyperoxia testing, drug
screening, neuroimaging, blood glucose, serum electrolytes, and newborn screening may
assist in distinguishing noninfectious disorders from neonatal sepsis.

It is often difficult to differentiate neonatal sepsis from other conditions. However, given the
morbidity and mortality of neonatal sepsis, empiric antibiotic therapy should be provided
(after cultures are obtained) to infants with suspected sepsis pending definitive culture-based
diagnosis.

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Sepsis in neonates"
and "Society guideline links: Group B streptococcal infection in pregnant women and
neonates".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Epidemiology and microbiology – Sepsis is an important cause of morbidity and

mortality in newborn infants.

• Incidence – Although the incidence of sepsis in term and late preterm infants is low
(approximately 1 to 6 cases per 1000 births), the potential for serious adverse
outcomes, including death, is of such great consequence that caregivers should have

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

a low threshold for evaluation and treatment for possible sepsis. (See 'Epidemiology'
above.)

• Common pathogens – Group B Streptococcus (GBS) and Escherichia coli are the most
common bacteria causing neonatal sepsis (table 1). (See 'Etiologic agents' above.)

• Maternal risk factors – Maternal risk factors for neonatal sepsis include
chorioamnionitis (intraamniotic infection), intrapartum fever, preterm delivery,
maternal GBS colonization, and prolonged rupture of membranes. (See "Early-onset
neonatal group B streptococcal disease: Prevention", section on 'Identification of
pregnancies at increased risk for early-onset neonatal GBS'.)

● Clinical manifestations – Clinical manifestations are nonspecific and include fetal

distress, low Apgar score, temperature instability (usually fever), respiratory and
cardiocirculatory symptoms (most commonly, respiratory distress and tachycardia),
neurologic symptoms (irritability, lethargy, poor tone, and seizures), and gastrointestinal
abnormalities (poor feeding, vomiting, and abdominal distension) (table 2). (See 'Clinical
manifestations' above.)

● Evaluation – Evaluation and initial management of neonates with suspected sepsis

should include a review of the pregnancy, labor, and delivery; complete physical
examination; laboratory evaluation; and prompt initiation of empiric antibiotics (after
obtaining cultures). Our suggested empiric antibiotic regimens are summarized in the
table (table 4) and are discussed in detail separately. (See 'Evaluation and initial
management' above and "Management and outcome of sepsis in term and late preterm
infants", section on 'Initial empiric therapy'.)

• Early-onset – In neonates <7 days old, the approach to the evaluation depends upon
whether the neonate is symptomatic or well appearing.

Symptomatic neonates should undergo a full diagnostic evaluation including (see

'Symptomatic neonates' above and 'Laboratory tests' above):

- Blood culture
- Complete blood count (CBC) with differential
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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

- Lumbar puncture (if the infant is clinically stable enough to tolerate the
procedure and it will not delay initiation of antibiotic therapy)
- Chest radiograph (if respiratory symptoms are present) and cultures from
tracheal aspirates (if intubated)
- C-reactive protein (CRP) and/or procalcitonin (PCT) levels are not routinely
required but may be helpful in determining length of therapy if followed serially

Empiric antibiotics should be provided to these neonates pending culture results (

table 4). (See 'Symptomatic neonates' above and "Management and outcome of
sepsis in term and late preterm infants", section on 'Early-onset sepsis'.)

For well-appearing newborns who have risk factors for early-onset sepsis, decisions
regarding evaluation and use of empiric antibiotics are based upon the nature of the
risk factor(s) and whether or not the mother received adequate intrapartum
antibiotic prophylaxis (IAP). Accepted approaches include categorical risk assessment
(algorithm 1), clinical observation (algorithm 2), and the early-onset sepsis calculator.
This is discussed in detail separately. (See "Management of neonates at risk for early-
onset group B streptococcal infection", section on 'Approaches to risk assessment'.)

• Late-onset – Neonates presenting with signs and symptoms of late-onset sepsis

(onset of symptoms from 7 to 28 days of life) should undergo a full diagnostic
evaluation similar to that described above for early-onset sepsis but also including a
urine culture and cultures from potential foci of infection. Empiric antibiotic
treatment should be initiated in these infants pending culture results (table 4). (See
'Late-onset sepsis' above and "Management and outcome of sepsis in term and late
preterm infants", section on 'Late-onset sepsis' and "Febrile infant (younger than 90
days of age): Management".)

● Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of

neonatal sepsis. (See 'Diagnosis' above.)

The differential diagnosis of neonatal sepsis includes other systemic infections and
noninfectious conditions including respiratory diseases (eg, transient tachypnea of the
newborn and respiratory distress syndrome), cardiac diseases (eg, congenital heart

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Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants

disease and supraventricular tachycardia), neurologic injury (eg, from anoxia or

hemorrhage), inborn errors of metabolism, and neonatal abstinence syndrome (table 5).
(See 'Differential diagnosis' above.)

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