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

Author
Morven S Edwards, MD
Section Editors
Leonard E Weisman, MD
Sheldon L Kaplan, MD
Deputy Editor
Melanie S Kim, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Sep 2013. |This topic last updated: jul 9, 2013.
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, including death, is of such great consequence that caregivers should
have a low threshold for evaluation and treatment for possible sepsis in any infant regardless of the
birth weight or gestational age.
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 and topics on neonatal sepsis in the preterm infants are discussed separately. (See
"Treatment and outcome of sepsis in term and late preterm infants" and "Clinical features and
diagnosis of bacterial sepsis in the preterm infant" and "Treatment and prevention of bacterial
sepsis in the preterm infant".)
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/or isolation of a bacterial pathogen from
the blood stream [1].

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 between 34 and
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 within the first days of life.
There is variability of the age at onset, with some experts defining early-onset sepsis
as bloodstream infection at 72 hours of age [3], and others defining early-onset group
B streptococcal (GBS) disease as infection with the onset of symptoms through day
six of life [4].

Late-onset sepsis is defined as the onset of symptoms after the first days of life.
Similar to early-onset sepsis, there is variability in its definition ranging from an onset

at >72 hours or 7 days of age [3,4]. (See "Group B streptococcal infection in

neonates and young infants", section on 'Terminology'.)
PATHOGENESIS
Early-onset sepsis Early-onset infection is usually due to vertical transmission by ascending
contaminated amniotic fluid or during vaginal delivery from bacteria colonizing or infecting the
mother's lower genital tract [5]. As a result, the risk for sepsis increases from 1 to 4 percent in
neonates born to mothers with chorioamnionitis.
Maternal group B streptococcal (GBS) bacteriuria during the current pregnancy, prior delivery of an
infant with GBS disease, and maternal colonization are risk factors for early-onset GBS sepsis.
(See "Group B streptococcal infection in neonates and young infants", section on 'Risk factors'.)
Late-onset sepsis Late-onset infections can be acquired by the two following mechanisms:

Maternal vertical transmission, resulting in initial neonatal colonization that evolves

into later infection.

Horizontal transmission from direct 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. Risk factors
can include use of forceps during delivery or electrodes placed for intrauterine monitoring, which
penetrate the neonatal defensive epithelial barriers of the skin and mucosa [6].
Metabolic factors, including hypoxia, acidosis, hypothermia, and inherited metabolic disorders (eg,
galactosemia), are likely to contribute to risk for and severity of neonatal sepsis. These factors are
thought to disrupt the neonate's host defenses (ie, immunologic response) [6].
EPIDEMIOLOGY The overall incidence of neonatal sepsis ranges from one to five cases per
1000 live births. The estimated incidence is lower in term infants, with a reported rate of one to two
cases per 1000 live births [7].
The increased risk of sepsis in preterm infants was illustrated in a population-based cohort study of
neonatal group B streptococcal (GBS) disease with reported attack rates that were sevenfold higher
for infants with a birth weight <1500 g compared with infants with a birth weight 2500 g [8]. In late
preterm infants, the reported incidences of early- and late-onset sepsis were four and six per 1000
admissions to neonatal intensive care units (NICU), respectively [9]. Black race has been identified
as an independent risk factor for early- and late-onset GBS sepsis. Reasons for the
disproportionately high disease burden among black populations cannot be fully explained by
prematurity, adequacy of prenatal care, or socioeconomic status [10]. (See "Group B streptococcal
infection in neonates and young infants", section on 'Epidemiology'.)

The incidence of early-onset sepsis has decreased primarily as a reduction of GBS infections due to
the use of intrapartum antibiotic prophylaxis [10-13]. This was illustrated by a retrospective review of
data (blood, urine, and cerebrospinal fluid cultures) from 322 neonatal units managed by Pediatrix
Medical group from two time periods before (1997 to 2001) and after (2002 to 2010) the initiation of
universal intrapartum antibiotics [14]. The following findings were noted:

The incidence of early-onset serious bacterial infections (SBIs) due to GBS decreased
from 3.5 to 2.6 per 1000 admissions between the two time periods. In this cohort,
early-onset GBS disease was mainly observed in term infants (74 percent) and late
preterm infants (10 percent).

In contrast, the incidence of late-onset GBS disease increased from 0.8 to 1.1 per
1000 admissions. Late-onset GBS disease was primarily seen in preterm infants with
a gestational age below 34 weeks (83 percent).

The incidence for early-onset SBIs due to Escherichia coli (E. coli) remained stable
(1.4 per 1000 admissions), whereas the incidence of late-onset E. coli SBIs increased
from 2.2 to 2.5 per 1000 admissions between the two time periods. SBIs due to E. coli
were observed primarily in preterm infants for both early-onset (90 percent of cases)
and late-onset disease (88 percent).

The overall incidence in the United States of early-onset GBS invasive infection
reported through the Centers for Disease Control and Prevention Active Bacterial Cole
Surveillance network has declined from 0.6 per 1000 live births in 2000 to 0.25 per
1000 live births in 2011 [15,16]. The incidence of late-onset GBS invasive infection
has remained stable in the same interval (0.4 per 1000 live births in 2000 and 0.29 per
1000 live births in 2011).

In a study using prospective data from the National Institute of Child Health and Human
Development (NICHHD) Neonatal Network of infants born between 2006 and 2009, the overall rate
of early-onset sepsis (defined as positive blood or cerebrospinal fluid cultures) was 0.98 cases per
1000 live births [17]. Infection rate increased with decreasing gestational age.
ETIOLOGIC AGENTS The bacteria that commonly cause neonatal sepsis and their relative
frequency in early- and late-onset sepsis are shown in the linked table (table 1). The patterns of
pathogens associated with neonatal sepsis have changed over time as reflected by longitudinal
databases from single tertiary centers [11,12].
Currently, Group B streptococcus (GBS) and Escherichia coli (E. coli) are the most common causes
of both early- and late-onset sepsis. The incidence of early-onset GBS has declined by 80 percent
with the use of intrapartum antibiotic prophylaxis (IAP); however, GBS and E. coli continue to
account for approximately two-thirds of early-onset infection [11,18,19]. The use of IAP to prevent
early-onset GBS infection appears to also reduce the risk of early-onset E. coli infection in term
infants [20]. In the previously mentioned report from the National Institute of Child Health and
Human Development (NICHHD) Neonatal Network, most of the infants with GBS sepsis were term

infants (73 percent), whereas the majority of infants with E coli infections were preterm (81 percent)
[17]. In this cohort of almost 400,000 infants, GBS screening was performed in 67 percent of
mothers with infected term infants and in 58 percent of infected preterm infants. (See
"Chemoprophylaxis for the prevention of neonatal group B streptococcal disease".)
Other bacterial agents associated with neonatal sepsis include:

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 [21,22].

Staphylococcus aureus (S. aureus), including community-acquired methicillin-resistant

S. aureus, is an emerging pathogen in neonatal sepsis [23]. 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 the neonatal intensive care units (NICU) [24].

Coagulase negative staphylococcus often is a cause of nosocomial infection in ill

infants (especially premature infants and/or infants who have indwelling intravascular
catheters). It may be considered a contaminant in otherwise healthy term infants who
have not undergone invasive procedures.

CLINICAL MANIFESTATIONS Because the signs and symptoms of sepsis are subtle and
nonspecific, identification of risk factors and any deviation from an infant's usual pattern of activity
or feeding should be regarded as a possible indication of systemic bacterial infection [6].
Common clinical signs include temperature instability (primarily fever), as well as respiratory,
gastrointestinal, and neurologic abnormalities (table 2) [6]. In addition, fetal and neonatal distress
during labor and delivery are associated with neonatal sepsis.
Fetal and delivery room distress Fetal and neonatal distress during labor and delivery can be
the earliest sign of neonatal sepsis.

Intrapartum fetal tachycardia can be due to fetal stress, which can be caused by
intraamniotic infection that presents as early-onset neonatal sepsis. (See "Overview of
the general approach to diagnosis and treatment of fetal cardiac arrhythmias", section
on 'Tachyarrhythmias'.)

Meconium-stained amniotic fluid can be another sign of fetal distress. It is associated

with a twofold increase for sepsis in infants who did not receive intrapartum antibiotics

[25]. (See "Clinical features and diagnosis of meconium aspiration syndrome", section
on 'Meconium passage'.)

Low Apgar score, a measure of neonatal distress in the first minutes after delivery, is
associated with neonatal sepsis. In a case-control study from the state of Washington,
infants with an Apgar score 6 at five minutes had a 36-fold higher likelihood of sepsis
compared with those with Apgar scores 7 [26].

Temperature instability The temperature of a septic infant can be elevated, depressed, or

normal. Term infants with sepsis are more likely to be febrile than preterm infants, whereas, preterm
infants are more likely to be hypothermic [6].
Temperature elevation without infection in full-term infants is concerning and, if persistent, is
indicative of neonatal infection [27,28]. This was illustrated in an observational study of term infants
that found 1 percent of all infants cared for in the normal nursery were febrile, defined as a
temperature 37.8C (100F) [28]. Of these 100 febrile infants, 10 had culture-proven sepsis (10
percent), and 45 had symptoms compatible with bacterial disease.
Other findings Other findings associated with neonatal sepsis and their approximate
frequencies are listed below (table 2) [6]:

Jaundice: 35 percent

Respiratory distress (tachypnea, grunting, flaring of the nasal alae, retractions, and
decreased breath sounds): 33 percent

Hepatomegaly: 33 percent

Anorexia: 28 percent

Vomiting: 25 percent

Lethargy: 25 percent

Cyanosis: 24 percent

Apnea: 22 percent

Abdominal distension: 17 percent

Irritability: 15 percent

Diarrhea: 11 percent

EVALUATION Because the signs and symptoms of sepsis are subtle and nonspecific, laboratory
evaluation is performed in any infant with identifiable risk factors, physical findings consistent with
sepsis, or who deviates in any way from the usual pattern of activity or feeding [5,6]. This approach
is consistent with that outlined by the 2012 American Academy of Pediatrics (AAP) clinical report for
infants with suspected or proven early-onset sepsis [5].
The routine newborn assessment includes a review of the pregnancy, labor, and delivery, including
risk factors for sepsis and a comprehensive physical examination. (See "Assessment of the
newborn infant" and 'Clinical manifestations' above.)

Maternal and neonatal risk factors Each neonate should be evaluated for the presence of the
following maternal and neonatal factors that are associated with an increased risk of sepsis,
particularly Group B streptococcal (GBS) infection [5,25].

Intrapartum maternal temperature 38C (100.4F)

Delivery at <37 weeks gestation

Chorioamnionitis (see "Intraamniotic infection (chorioamnionitis)", section on

'Diagnosis of clinical chorioamnionitis')

Five minute Apgar score 6 [26]

Evidence of fetal distress

Maternal GBS colonization

Membrane rupture 18 hours The risk of proven sepsis increases 10-fold to 1

percent when membranes are ruptured beyond 18 hours [29].

The use and duration of maternal intrapartum antibiotic prophylaxis (IAP) also should be noted, as
IAP reduces the risk of GBS infection. However, in the previously mentioned National Institute of
Child Health and Human Development (NICHHD) report, about half of the mothers who delivered
infants with early-onset sepsis received intrapartum antibiotics [17], so one cannot exclude the
possibility of sepsis on the basis that an infant's mother was administered intrapartum antibiotics.
(See "Chemoprophylaxis for the prevention of neonatal group B streptococcal disease".)
In a case-control study of infants >34 weeks gestation born between 1993 and 2004, multivariate
analysis demonstrated an increasing risk of neonatal sepsis as intrapartum temperature rose above
38.1C (100.5F), with increasing duration of rupture of membranes, and with both late preterm and
postterm delivery [30]. Decreased risk of infection was associated with administration of any form of
intrapartum antibiotic given >4 hours before delivery. These factors were used to develop a
predictive model for neonatal sepsis, which needs to be validated in future prospective studies.
The management of infants whose mother has received IAP for GBS infection is reviewed
separately (algorithm 1). (See "Management of the infant whose mother has received group B
streptococcal chemoprophylaxis", section on 'Overview of management'.)
Laboratory evaluation Laboratory assessment includes 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 blood culture to detect neonatal bacteremia is dependent upon the number of
cultures obtained and the volume of blood used to inoculate each culture bottle. The blood culture
can be obtained by venipuncture or arterial puncture, or by sampling from a newly inserted umbilical
artery catheter.

Number of cultures The sensitivity of one blood culture to detect neonatal

bacteremia is approximately 90 percent [6,31]. However, multiple cultures can delay
the initiation of therapy, which can increase mortality and morbidity in this highly
vulnerable population. As a result, we obtain at least one culture prior to initiating
empirical antibiotic therapy in neonates with a high clinical suspicion for sepsis,
although other institutions may routinely obtain two blood cultures. The clinical course
and other tests can be used to make a clinical diagnosis of sepsis in a small subset of
infants with a sterile blood culture(s), who are then treated with a complete course of
antibiotic therapy.

Volume of blood When a single blood culture bottle is used, a minimum blood
volume of 1 mL is desirable for optimal detection of bacteremia [5]. Dividing this
volume into two aliquots of 0.5 mL to inoculate anaerobic and aerobic culture bottles is
likely to decrease the sensitivity, as in vitro data suggest that a 0.5 mL sample would
not reliably detect low levels of bacteremia [32]. However, in patients with a high level
of bacteremia, smaller volumes usually are adequate for a positive blood culture.

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, a blood culture will become positive within 24 to 36 hours.
This was illustrated in a study of 455 positive blood cultures from 222 preterm and term infants
evaluated for neonatal sepsis. An automated blood culture system identified 77, 89, and 94 percent
of all microorganisms within 24, 36, and 48 hours of incubation in aerobic conditions, respectively
[33]. When common bacterial pathogens for neonatal sepsis were reviewed, 97 and 99 percent of
cultures were positive by 24 and 36 hours. These pathogens included GBS, S. agalactiae, E. coli, L.
monocytogenes, S. aureus, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae,
Morganella morganii, Pseudomonas aeruginosa, Enterococcus, and Streptococcus pyogenes.
Complete blood count A complete blood count (CBC) obtained 6 to 12 hours after delivery may
be helpful in the evaluation of early-onset sepsis. Although both the absolute neutrophil and the
ratio of immature to total neutrophil counts (I/T ratio) have been used as markers for neonatal
sepsis, they are more useful in identifying neonates who are unlikely to have sepsis than identifying
those with sepsis [5].
In a multicenter study of 67,623 infants born at 34 weeks gestation, in whom both a blood culture
and CBC were performed within the first 24 hours of life, low white blood cell count (WBC)
(<5000/microL); absolute neutropenia (<1000 neutrophils/microL), relative neutropenia (<5000
neutrophils/microL); or an I/T ratio of 0.3 or higher were associated with blood culture-proven, earlyonset disease [34]. However, none of the tests were sufficiently sensitive to reliably predict neonatal
sepsis. The authors also found that a CBC was more helpful as a predictor for sepsis if obtained
after four hours of age because the WBC and absolute neutrophil count (ANC) normally increase
during the first six hours of life.

Similar results were seen in another multicenter study of 166,092 neonates with suspected earlyonset of sepsis [35]. This study included both term and preterm infants, and the mean gestational
age of the cohort was 34.6 weeks. The probability of a positive blood culture within the first three
days of life increased with a low WBC (<5000/microL), absolute neutropenia (<1000
neutrophils/microL), and an elevated I/T ratio. However, sensitivities of all indices were poor and
insufficient to accurately diagnose neonatal sepsis.
In another analysis of the same cohort of patients, late-onset sepsis (defined as a positive culture
between day of life 4 and 120) was associated with both low and high WBC (<1000 and
>50,000/microL), high absolute neutrophil count (>17,670/microL), elevated I/T ratio of 0.2 or
higher, and low platelet count (<50,000/microL) [36]. However, sensitivity also was inadequate to
reliably make the diagnosis of late-onset sepsis.
Total neutrophil count Although both elevated WBC and low neutrophil counts can be
predictive of neonatal sepsis, neutropenia may be a better marker because it has greater specificity,
as few conditions other than sepsis and preeclampsia depress the neutrophil count of neonates [5].
Defining neutropenia in the neonate can be challenging, as neutrophil counts vary with gestational
age (neutrophil counts decrease with decreasing gestational age), type of delivery (they are lower in
infants born by cesarean delivery), site of sampling (neutrophil counts are lower in arterial than in
venous samples), altitude (neutrophil counts are higher at elevated altitudes) and timing after
delivery. In a study of 30,254 infants born at 23 to 42 weeks of gestation that used modern cellcount instruments to determine neutrophil counts, the lower limit of a normal neutrophil count for
infants >36 weeks of gestation was 3500/microL at birth and 7500/microL six to eight hours after
delivery (figure 1). For infants born at 28 through 36 weeks of gestation, the lower limits of normal
for neutrophil counts at birth and at six to eight hours after birth were 1000/microL and 1500/microL,
respectively (figure 2). These results were similar to those obtained by an earlier study published in
1979, which had defined neutropenia in term infants as below 7800 microL, 12 to 14 hours after
delivery (figure 3) [37,38]. Total neutrophil counts decreased with decreasing gestational age.
I/T ratio An elevated I/T ratio has the best sensitivity of the neutrophil indices for predicting
th

neonatal sepsis. In healthy term infants, the 90 percentile for I/T ratio is 0.27. Exhaustion of the
bone marrow reserves will result in low band counts and lead to falsely low ratios.
However, this test is limited by the wide range of normal values, which reduces its positive
predictive value, especially in asymptomatic patients [39]. The high negative predictive value (96 to
100 percent) of the I/T ratio in combination with other tests or the presence of risk factors may be
useful as an initial screen for neonatal sepsis [25,40,41]. This was illustrated in a study of 3154
neonates who had a blood culture drawn at less than 24 hours and two serial WBC measurements
with manual differentials [42]. In this cohort, 31 infants had a positive blood culture, of which 23
were considered to have true sepsis (0.73 percent) and eight (0.25 percent) to have contaminants.
An abnormal I/T ratio was observed in all neonates with true sepsis and 119 with presumed sepsis

as well as 1473 neonates without infection. (See 'Clinical diagnosis' below and "Evaluating
diagnostic tests", section on 'How well does the test perform in specific populations?'.)
Other blood tests A number of acute phase reactants have been used to identify the septic
newborn. Many of these tests are highly sensitive (ie, do not miss cases of sepsis); however, they
lack specificity (ie, they do not reliably exclude sepsis when it is not present), resulting in a poor
predictive value [43]. (See 'Clinical diagnosis' below and "Evaluation and management of fever in
the neonate and young infant (less than three months of age)", section on 'Inflammatory
mediators'.)

C-reactive protein (CRP) CRP, an acute phase reactant, increases in inflammatory

conditions, including sepsis. A CRP value that is greater than 1.0 mg/dL is 90 percent
sensitive in detecting neonatal sepsis but is nonspecific because of the number of
other noninfectious inflammatory conditions including maternal fever, fetal distress,
stressful delivery, perinatal asphyxia, meconium aspiration, and intraventricular
hemorrhage [44]. In addition, CRP is not a sensitive test at birth because it requires an
inflammatory response to increase its level [5]. As a result, a single measurement of
CRP soon after birth is not a useful marker in the diagnosis of neonatal sepsis.
However, sequential assessment of CRP values is useful in supporting a diagnosis of
sepsis. If the CRP level remains persistently normal, neonatal bacterial sepsis is
unlikely [5]. It also is helpful in guiding the duration of antibiotic therapy in suspected
neonatal bacterial infection. Infants with elevated CRP levels that decrease to <1.0
mg/dL 24 to 48 hours after the start of antibiotic therapy typically are uninfected and
generally do not require further antibiotic treatment [45]. However, data are insufficient
to determine the duration of antibacterial therapy in an infant with an elevated value 1
mg/dL.

Cytokines Both proinflammatory (interleukin-2 [IL-2], IL-6, interferon gamma, and

tumor necrosis factor alpha) and anti-inflammatory cytokines (IL-4 and IL-10) are
increased in infected infants compared with those without infections [46-48]. However,
these cytokines are not routinely measured because of their high cost of testing and
because no single biomarker or panel of tests is sufficiently sensitive to reliably detect
neonatal sepsis [46].

Procalcitonin Procalcitonin 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
procalcitonin may be a useful marker to detect serious bacterial infections in young
febrile infants [49]. Limited data in preterm infants report that elevated procalcitonin
(greater than 0.5 ng/mL) is equivalent or better than CRP in detecting bacterial
infection [46]. Although procalcitonin is a promising marker, it appears not to be

sufficiently reliable as the sole or main diagnostic indicator for neonatal sepsis, and, at
this time, it is not routinely available in hospital laboratories.
Further research, which better understands 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 [46]. 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.
Lumbar puncture A lumbar puncture (LP) should be considered in all neonates for whom blood
culture evaluation for sepsis is performed, because clinical signs suggesting meningitis can be
lacking in young infants.
In a retrospective study of all neonates born in United States army hospitals from 1988 to 1992, 8 of
the 36 term infants with meningitis had no symptoms referable to the central nervous system, and
had sterile blood cultures [50]. In addition, three infants with both positive cerebrospinal fluid (CSF)
and blood cultures were asymptomatic.
In our practice, we always perform a LP for symptomatic term infants. For asymptomatic term
infants, meningeal doses of ampicillin and gentamicin in combination are initiated after evaluation
that includes a blood culture. The CSF should be sent for culture, Gram stain, cell count, and
protein and glucose concentration to determine whether the infant has meningitis. (See "Clinical
features and diagnosis of bacterial meningitis in the neonate" and 'Clinical diagnosis' below.)
The decision of whether or when to perform a LP (for CSF analysis and culture) remains
controversial. The approach outlined by the 2012 AAP clinical report recommends that LP be
performed for an infant with any of the following clinical conditions [5]:

A positive blood culture

Clinical findings that are highly suggestive of sepsis (see 'Clinical manifestations'
above)

Laboratory data strongly suggestive of sepsis

Worsening clinical status while on antibiotic therapy

When an infant is critically ill or likely to have cardiovascular or pulmonary compromise from the
procedure, the LP can be deferred until the patients status has stabilized.
It is our practice to provide meningeal doses of ampicillin and gentamicin after a sepsis evaluation
that does not include an initial LP. Blood culture can be negative in as many as 38 percent of
infants with meningitis [5,51,52].
When CSF is obtained, it should be sent for Gram stain, routine culture, cell count with differential
and protein and glucose concentrations.

The clinical features and diagnosis of neonatal bacterial meningitis are discussed separately. (See
"Clinical features and diagnosis of bacterial meningitis in the neonate".)
Urine culture Urine culture obtained by catheter or bladder tap should be included in the sepsis
evaluation for infants >6 days of age. 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 [5,53]. (See "Urinary tract
infections in newborns".)
Other sites In patients with late-onset infection, cultures should be obtained from any other
potential foci of infection (eg, purulent eye drainage or pustules).
In infants with early-onset infection, Gram stains of gastric aspirates are of limited values as are
bacterial cultures of body surface areas (eg, axilla, groin, and external ear canal) [5].
Tracheal aspirate specimens can be of value if obtained immediately after intubation [5]. However,
they may reflect lower respiratory tract colonization rather than indicating a causative pathogen in
an infant who has been intubated for several days.
Chest radiography Chest radiography should be obtained in an infant with respiratory distress.
Localized infiltrates may be due to pneumonia.
DIAGNOSIS The isolation of a pathogenic bacterium from a blood culture is the only method to
truly confirm the diagnosis of neonatal sepsis. However, there is a significant time lag before blood
culture results are available, and blood cultures may lead to false negative results in about 10
percent of septic cases. As a result, clinical assessment and laboratory tests are used to identify
neonates at significant risk for sepsis so that empiric antibiotic treatment may be initiated while
awaiting blood culture results. In addition, clinical assessment, subsequent laboratory tests, and the
clinical course are used to make a clinical diagnosis of sepsis in the small subset of infants with
probable sepsis but with a sterile blood culture, who would than receive a complete course of
antibiotic therapy.
Clinical diagnosis The goals of clinical diagnosis are to identify and treat all infants with
bacterial sepsis, and minimize the testing and treatment of patients who are not infected. Making a
clinical diagnosis is challenging, as there is no specific finding or test that reliably identifies septic
asymptomatic infants from uninfected patients [54]. Screening protocols used to identify serious
bacterial infections (SBI) in febrile infants two to three months of age are inadequate in neonates,
as they have an unacceptable rate of failing to identify neonates with SBI [50]. (See "Strategies for
the evaluation of fever in neonates and infants (less than three months of age)", section on
'Limitations in neonates' and 'Evaluation' above.)
Despite these difficulties, a composite of observational assessment and laboratory testing is
typically used to make the clinical diagnosis of neonatal sepsis [40]. The criteria used are usually

broad, thereby ensuring that all infected infants are identified and treated, but at the cost of testing
and treating a significant number of uninfected infants.
These points were illustrated in a study conducted during the birth hospitalization of infants born
with a birth weight of at least 2000 g without a major congenital anomaly at six Kaiser Permanente
hospitals between 1995 and 1996 as follows [25]:

Evaluation with a complete blood count and/or blood culture for sepsis was performed
in 15 percent of the entire cohort of 18,299 infants. Laboratory testing was performed
by 12 hours of age for 90 percent of the patients.

Of the 2785 infants evaluated for sepsis, about half had clinical signs consistent with
infection.

Among the 1275 assessed infants who were asymptomatic, evaluation for sepsis was
performed because of identified risk factors, including rupture of membranes for longer
than 18 hours (34 percent), maternal chorioamnionitis (33 percent), maternal fever
>100.4F (25 percent), maternal Group B streptococcal septicemia (GBS) colonization
(5 percent), and foul smelling amniotic fluid (3 percent).

Only 22 patients (0.8 percent of evaluated infants) had proven sepsis with a positive
blood culture, and 40 (1.2 percent) had a diagnosis of probable sepsis based upon a
clinical course that strongly suggested the presence of systemic infection (eg, CSF
pleocytosis). Of the 62 infants (2 percent) with proven or probable sepsis, 12 were
asymptomatic or had transient clinical signs. Four patients with infection died.

Multivariate analyses showed that in an initially symptomatic infant, absolute

neutrophil counts below 10th percentile for age, presence of meconium-stained fluid,
and maternal antepartum temperature greater than 101.5F were associated with an
increased risk of infection. In infants without maternal intrapartum antibiotic therapy,
maternal chorioamnionitis and rupture of membranes >12 hours were associated with
an increased risk of infection.

CDC guidelines In 2010, the Centers for Diseases Control (CDC) and Prevention updated
guidelines for the prevention of early-onset GBS disease among newborns (algorithm 1). The
revisions were based on data that had been collected after the issuing of the 2002 guidelines. The
intent of the proposed changes was to improve the identification of asymptomatic neonates at risk
for early-onset GBS disease and thereby decrease unnecessary evaluation and antibiotic exposure.
A retrospective analysis of neonates (gestational age 35 weeks) evaluated for early-onset of GBS
disease suggested that a quarter of the evaluations would have been eliminated if the 2010 CDC
guidelines were available and used. Half of this cohort received empiric antibiotics [55].
The guidelines are discussed in greater detail elsewhere. (See "Management of the infant whose
mother has received group B streptococcal chemoprophylaxis", section on 'Management
approach'.)

Our approach In our practice, a presumptive diagnosis of sepsis, which results in the start of
empiric antibiotic therapy, is based upon the presence and timing of neonatal symptoms and risk
factors, including the maternal GBS status, a history of maternal fever, prolonged rupture of
membranes, and whether the mother received adequate intrapartum antibiotics, if indicated.
Our approach in the evaluation and initial management of neonatal sepsis is consistent with the
2010 CDC guidelines for the prevention of early-onset GBS disease among newborns (algorithm 1)
and the 2012 American Academy of Pediatrics (AAP) clinical report [5,56]. (See "Management of
the infant whose mother has received group B streptococcal chemoprophylaxis", section on
'Overview of management'.)

Asymptomatic term infant The minimal laboratory evaluation for early-onset neonatal
sepsis in asymptomatic term infants consists of a blood culture. Some experts also
suggest a complete blood count (CBC), including a differential [40]. Management of
initially asymptomatic infants depends upon the clinical settings.

If the asymptomatic infant is born to a mother who has fever (>100.4F) before
delivery or within 24 hours after delivery; and maternal chorioamnionitis, systemic
bacterial infection, or additional risk factors for neonatal sepsis exist, a blood
culture is obtained, and empiric antibiotic therapy is started.

An asymptomatic infant delivered after membrane rupture 18 hours without

maternal fever or other signs suggestive of neonatal sepsis is observed in the
hospital for 48 hours. If signs suggesting sepsis develop, a CBC and cultures of
blood and CSF are obtained, and empiric antibiotic therapy is started.

If an asymptomatic term infant develops signs of sepsis after the initiation of

antibiotics, re-evaluation with a CBC, lumbar puncture for cerebrospinal fluid
(CSF) culture, and repeat blood culture should be undertaken. Cultures from other
sites (ie, urine and skin lesions) should be obtained as clinically indicated.

Symptomatic term infant The minimal evaluation for early-onset sepsis in

symptomatic term infants consists of a CBC and cultures of blood and CSF. Further
evaluation can include testing for inflammation (eg, C-reactive protein). Empiric
antibiotic therapy is started.

For a term infant with signs suggestive of late-onset sepsis, the minimal evaluation includes a CBC
with differential and cultures of blood, CSF, and urine. As indicated, cultures of sites such as skin
lesions, bone, joint or peritoneal fluid also should be obtained. Empiric antibiotic therapy is started.
DIFFERENTIAL DIAGNOSIS Because the findings are nonspecific, it is often difficult to
differentiate neonatal sepsis from other diseases. As a result, empiric antibiotic therapy is started
until blood culture results are available.

The differential diagnosis for neonatal sepsis in the term or near-term infant generally includes the
following systemic infections. Appropriate culture and/or serology distinguish these infections from
neonatal sepsis.

Viral infections Enteroviruses, herpes simplex virus, cytomegalovirus, influenza

viruses, respiratory syncytial virus, etc

Spirochetal infections Syphilis

Parasitic infections Congenital malaria, toxoplasmosis

Fungal infection Candidiasis

Other bacterial infections include urinary tract infection (particularly in the setting of a
congenital genitourinary tract malformation), osteomyelitis or septic arthritis,
pneumonia, and tuberculosis

Other diagnoses that may present with similar nonspecific findings of neonatal sepsis include
neonatal hypoxia, in-born errors of metabolism, cyanotic congenital heart disease, and neonatal
respiratory distress. The clinical history and course of disease distinguish these disorders from
neonatal sepsis.
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,
th

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at the 5 to 6 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,
th

th

more sophisticated, and more detailed. These articles are written at the 10 to 12 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 information: Sepsis in newborn babies (The Basics)")

SUMMARY AND RECOMMENDATIONS Although the incidence of sepsis in term and late
preterm infants is low, the potential for serious adverse outcomes, including death, is of such great
consequence that caregivers should have a low threshold for evaluation and treatment for possible
sepsis in any infant regardless of the birth weight or gestational age. (See 'Epidemiology' above.)

Neonatal sepsis is classified by the infant's age into early-onset sepsis (3 to 7 days)
and late-onset sepsis (>3 or 7 to 28 days). (See 'Terminology' above.)

Early-onset sepsis is caused by maternal vertically transmitted bacteria acquired either

in-utero or during vaginal delivery. Late-onset sepsis can be acquired vertically at birth
or horizontally from care providers or the environment. (See 'Pathogenesis' above.)

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

Risk factors for neonatal sepsis in term and late preterm infants include intrapartum
maternal temperature 38C (100.4F), chorioamnionitis, five minute Apgar score 6,
maternal GBS colonization, and membrane rupture 18 hours. (See 'Maternal and
neonatal risk factors' above.)

Clinical manifestations are nonspecific and include fetal and neonatal distress;
temperature instability (usually fever); and respiratory, gastrointestinal, and neurologic
abnormalities (table 2). (See 'Clinical manifestations' above.)

Evaluation of neonates with suspected sepsis should include a prenatal history,

delivery, complete physical examination, and a laboratory evaluation that minimally
includes a blood culture. Other laboratory tests include a complete blood count (CBC)
with a differential, lumbar puncture prior to antibiotic therapy to determine whether
meningitis is present, urine culture for infants >6 days of age, and culture of any other
potential foci of infection (eg, pustule). (See 'Evaluation' above.)

The isolation of a pathogen from a blood culture is the only method to confirm the
diagnosis of neonatal sepsis. A composite of clinical and laboratory findings are used
to identify infants with a high suspicion for sepsis, and who are treated empirically until
culture results are available. (See 'Diagnosis' above and "Treatment and outcome of
sepsis in term and late preterm infants", section on 'Empiric antibiotic therapy'.)

The differential diagnosis of neonatal sepsis includes other systemic infections,

neonatal hypoxia, in-born errors of metabolism, and neonatal respiratory distress.
Use of UpToDate is subject to the Subscription and License Agreement.
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