Clinical Features, Evaluation, and Diagnosis of Sepsis in Term and Late Preterm Infants PDF

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Clinical features, evaluation, 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
Carrie Armsby, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2016. | This topic last updated: Apr 11, 2016.
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 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 the preterm infant (<34 weeks gestation)".)
(See "Treatment and prevention of bacterial sepsis in the preterm infant (<34 weeks gestation)".)
(See "Febrile infants (younger than 90 days of age): Outpatient evaluation".)
(See "Approach to the septic-appearing 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 isolation of a bacterial pathogen from the blood stream [1]. A consensus definition for neonatal
sepsis is lacking [2]. (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 between 34 and 36 completed weeks of
gestation [3]. (See "Late preterm infants".)
Preterm infants are those born at less than 34 weeks of gestation [3].
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 7 days of age, although some experts limit the
definition to infections occurring within the first 72 hours of life [4].
Late-onset sepsis is generally defined as the onset of symptoms at 7 days of age [4]. Similar to early-onset
sepsis, there is variability in its definition, ranging from an onset at >72 hours of life to 7 days of age [4,5].
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 septic-appearing infant" and "Febrile young infant (younger than 90
days of age): Management", section on 'Neonates (28 days of age and younger)'.)
PATHOGENESIS 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 [6]. Maternal chorioamnionitis
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is a well-recognized risk factor for early-onset neonatal sepsis [7,8]. 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'.)
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 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. 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 [9].
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) [9].
EPIDEMIOLOGY The overall incidence of neonatal sepsis ranges from one to five cases per 1000 live births.
Estimated incidence rates vary based on the case definition and the population studied. Infection rates increase with
decreasing gestational age. The incidence of early-onset sepsis has decreased primarily due to reduction in group B
streptococcal (GBS) infections owing to the use of intrapartum antibiotic prophylaxis [10-14].
The estimated incidence of sepsis (both early- and late-onset) in term neonates is one to two cases per 1000 live
births [15,16]. 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 grams was 0.57 per 1000 [17].
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 [18].
Early-onset GBS infection rates in the United States reported through the Centers for Disease Control and
Prevention's (CDC) Active Bacterial Core Surveillance Report have declined from 0.6 per 1000 live births in 2000 to
0.25 per 1000 live births in 2013 [19,20]. Late-onset GBS infection rates have remained relatively stable in the same
interval (0.4 per 1000 live births in 2000 and 0.27 per 1000 live births in 2013).
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'.)
ETIOLOGIC AGENTS Group B Streptococcus (GBS) and Escherichia coli (E. coli) are the most common causes
of both early- and late-onset sepsis, accounting for approximately two-thirds of early-onset infection [11,21,22].
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 [23,24].
Staphylococcus aureus (S. aureus), including community-acquired methicillin-resistant S. aureus, is an
emerging pathogen in neonatal sepsis [25]. Bacteremic staphylococcal infections in term infants often 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
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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 (NICUs) [26].
Coagulase-negative staphylococci often are 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.
The patterns of pathogens associated with neonatal sepsis have changed over time as reflected by longitudinal
databases from single tertiary centers [11,12]. The incidence of early-onset GBS has declined by 80 percent with the
use of intrapartum antibiotic prophylaxis (IAP). IAP appears to also reduce the risk of early-onset E. coli infection
[27]. (See "Neonatal group B streptococcal disease: Prevention".)
Common non-bacterial 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 "Clinical manifestations and diagnosis of enterovirus and parechovirus
infections", section on 'Infections in 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 'Systemic
infections')
MATERNAL RISK FACTORS The following maternal factors are associated with an increased risk of sepsis,
particularly GBS infection [6,7,28].
Chorioamnionitis Chorioamnionitis may reflect intrauterine onset of infection [29]. Consultation with obstetric
providers to determine suspicion for chorioamnionitis is an important aspect of neonatal management. (See
"Intra-amniotic infection (clinical chorioamnionitis or triple I)", section on 'Diagnosis of intra-amniotic infection'.)
Intrapartum maternal temperature 38C (100.4F).
Delivery at <37 weeks gestation.
Maternal GBS colonization and other findings that increase the risk of GBS infection in the neonate, including
any of the following:
Positive GBS vaginal-rectal screening culture in late gestation during current pregnancy
Previous infant with GBS disease
Documented GBS bacteriuria during the current pregnancy
Intrapartum nucleic acid amplification test positive for GBS
Membrane rupture 18 hours The risk of proven sepsis increases 10-fold to 1 percent when membranes are
ruptured beyond 18 hours [30].
GBS screening and maternal intrapartum antibiotic prophylaxis (IAP) reduces the risk of GBS infection but does not
eliminate it. In a prospective national surveillance study (2006 to 2009), the GBS screening culture was negative in
81 percent of mothers of term infants with early-onset GBS [17]. Approximately one-half of infants who developed
early-onset sepsis were born to mothers who received intrapartum antibiotics. (See "Neonatal group B streptococcal
disease: Prevention".)
CLINICAL MANIFESTATIONS 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) [9].
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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 [9].
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 "Overview of the general
approach to diagnosis and treatment of fetal arrhythmias", section on 'Tachyarrhythmias'.)
Meconium-stained amniotic fluid, which is associated with a twofold increased risk of sepsis [7]. (See
"Clinical features and diagnosis of meconium aspiration syndrome", section on 'Meconium passage'.)
Apgar score 6, which is associated with a 36-fold increased risk of sepsis [31]. (See "Neonatal
resuscitation in the delivery room", section on 'Apgar scores'.)
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 [9].
Temperature elevation in full-term infants is concerning and, if persistent, is highly indicative of infection [32,33].
Respiratory and cardiocirculatory 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) [17]. 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 GBS sepsis. Early-onset disease can be associated with persistent pulmonary hypertension of the
newborn (PPHN). (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 [17].
Neurologic symptoms Neurologic manifestations of sepsis in the neonate include lethargy, poor tone, poor
feeding, irritability, and seizures [9]. 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 were found to have sepsis as the etiology [34]. Seizures are a presenting feature in 20
to 50 percent of infants with neonatal meningitis [35]. (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) [9,17]:
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 require prompt
evaluation and initiation of antibiotic therapy [6,9]. Because the signs and symptoms of sepsis are subtle and
nonspecific, laboratory testing is performed in any infant with identifiable risk factors and/or signs and symptoms
concerning for sepsis. This approach is consistent with guidelines published by the American Academy of Pediatrics
(AAP) and the Center for Disease Control (CDC) [6,36].
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Early-onset sepsis Evaluation for early-onset neonatal sepsis should include 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)
A 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.
Symptomatic neonates Infants with signs and symptoms of sepsis should undergo a full diagnostic
evaluation and should receive empiric antibiotic treatment (algorithm 1). (See 'Clinical manifestations' above and
'Empiric antibiotic therapy' below.)
A full diagnostic evaluation includes (see 'Laboratory tests' below):
Blood culture
Lumbar puncture (if the infant is clinically stable enough to tolerate the procedure)
Complete blood count with differential and platelet count
Chest radiograph (if respiratory symptoms are present)
Cultures from tracheal aspirates if intubated
C-reactive protein (CRP) levels 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 a minimum of 48 hours. They may require a limited diagnostic evaluation based on the
nature of the risk factor and the use and duration of maternal IAP (algorithm 1). (See "Management of the infant
whose mother has received group B streptococcal chemoprophylaxis".)
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,
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 septic-appearing infant" and "Febrile
young infant (younger than 90 days of age): Management", section on 'Neonates (28 days of age and younger)'.)
Empiric antibiotic therapy Indications for empiric antibiotic therapy include:
Ill-appearance (see "Approach to the septic-appearing infant")
Concerning symptoms, including temperature instability, or respiratory, cardiocirculatory, or neurologic
symptoms (see 'Clinical manifestations' above)
Cerebrospinal fluid (CSF) 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 CSF')
Confirmed or suspected maternal chorioamnionitis (see 'Maternal risk factors' above)
The empiric antibiotic regimen should include agents active against GBS and other organisms that cause neonatal
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sepsis (eg, E. coli and other gram-negative pathogens). The combination of ampicillin and gentamicin or ampicillin
and cefotaxime are potential regimens that provide empiric coverage for these organisms until culture results are
available. Ampicillin and gentamicin is generally preferred; however, local antibiotic resistance patterns must be
considered. In the era of GBS IAP, approximately 30 percent of early-onset sepsis is due to ampicillin-resistant
gram-negative organisms [13]. The addition of a third-generation cephalosporin to the empiric treatment of
early-onset sepsis is warranted among neonates with suspected meningitis. (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 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 may indicate contamination or catheter colonization rather
than a true systemic infection [9].
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. Anaerobic cultures are generally not necessary.
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
[6]. 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 is discouraged as it is likely to decrease the sensitivity. Anaerobic cultures are
generally not necessary and in vitro data suggest that small sample volumes do not reliably detect low
levels of bacteremia [37].
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 [38].
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 (CoNS) may be pathogenic in patients with indwelling vascular catheters or other invasive
devices, whereas a single blood culture positive for CoNS is likely to represent a contaminant in full-term
infants without these risk factors [9].
Lumbar puncture A lumbar puncture (LP) should be performed in neonates undergoing evaluation for sepsis,
because clinical signs suggesting meningitis can be lacking in young infants. When an infant is critically ill or likely to
have cardiovascular or pulmonary compromise from the procedure, the LP can be deferred until the patient's status
has stabilized.
Cerebrospinal fluid (CSF) should be sent for Gram stain, routine culture, cell count with differential, and protein and
glucose concentrations. The interpretation of CSF needs to account for variations due to gestational age,
chronologic age, and birth weight (table 3).
The approach outlined by the 2012 American Academy of Pediatrics (AAP) clinical report recommends that LP be
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performed in an infant with any of the following clinical conditions [6]:

A positive blood culture
Clinical findings that are highly suggestive of sepsis (see 'Clinical manifestations' above)
Laboratory data strongly suggestive of sepsis (see 'Complete blood count' below)
Worsening clinical status while on antibiotic therapy
Blood culture may be negative in as many as 38 percent of infants with meningitis [6,39]. In a retrospective study, 8
of the 36 term infants with meningitis had no symptoms referable to the central nervous system, and had sterile
blood cultures [40]. In addition, three infants with both positive CSF and blood cultures were asymptomatic.
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 [6,41]. (See "Urinary tract infections in neonates".)
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 [6]. However, they may reflect lower
respiratory tract colonization rather than indicating a causative pathogen in an infant who has been intubated for
several days.
In infants with early-onset infection, Gram stains of gastric aspirates are of limited value as are bacterial cultures of
body surface sites (eg, axilla, groin, and external ear canal) [6].
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 We obtain a CBC in any infant undergoing diagnostic evaluation (either full or limited) for
early-onset neonatal sepsis. CBC results are used in combination with clinical symptoms and risk factors to
determine the likelihood of sepsis and need for antibiotic treatment.
Abnormal neutrophil indices (including elevated or depressed absolute neutrophil count [ANC] and elevated ratio of
immature to total neutrophil counts [I/T ratio]) are associated with neonatal sepsis. However, these tests are more
useful in identifying neonates who are unlikely to have sepsis than in identifying infants with sepsis [6].
Two large multicenter studies have evaluated the diagnostic value of CBCs in early-onset neonatal sepsis [42,43].
These studies found that low white blood cell count (WBC) (<5000/microL), absolute neutropenia (ANC <1000
neutrophils/microL), relative neutropenia (ANC <5000 neutrophils/microL), and elevated I/T ratio were associated
with culture-proven sepsis. However, none of the tests were 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 [6,42,44].
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 and/or other tests
[7,45,46]. A single determination of the I/T ratio has high specificity and hence a normal value 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].
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In a study of 3154 neonates who underwent evaluation for early-onset sepsis with blood culture and two serial
WBC measurements, the I/T ratio was 0.2 in all 142 neonates with culture-positive or clinical sepsis as well as
in 1473 neonates without infection [47].
The I/T ratio is limited by the wide range of normal values, which reduces its positive predictive value,
especially in asymptomatic patients [48]. Inter-reader differences in band neutrophil identification with manual
differential counts is another limitation [6]. 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?'.)
Absolute neutrophil count Although both elevated and low neutrophil counts can be associated with
neonatal sepsis, neutropenia has greater specificity, as few conditions other than sepsis and preeclampsia
depress the neutrophil count of neonates [6].
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).
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) [49]. 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, 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 absolute neutrophil count (>17,670/microL), elevated I/T ratio (0.2), and low platelet count (<50,000/microL)
were associated with culture positivity [50]. However, sensitivity was inadequate to reliably predict late-onset sepsis.
Screening protocols used to identify serious bacterial infections (SBI) in febrile infants two to three months of age are
inadequate in neonates, as they fail to accurately identify neonates with SBI [40]. (See "Febrile infants (younger than
90 days of age): Outpatient evaluation", section on 'Traditional approaches'.)
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 [51].
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 [52].
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 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 [6].
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 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 [53].
An elevated CRP level alone does not justify continuation of empiric antibiotics for more than 48 hours in
well-appearing infants with negative culture results [54]. Additional evaluation may be warranted to investigate
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alternative explanations for persistently elevated CRP values.

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 [55]. Limited data in preterm infants suggest that elevated procalcitonin
(greater than 0.5 ng/mL [0.5 mcg/L]) is equivalent or better than CRP in detecting bacterial infection [56]. In a
meta-analysis of 16 studies, the pooled sensitivity of procalcitonin for detection of neonatal sepsis was 81
percent and the specificity was 79 percent [57]. Thus, although procalcitonin is a promising marker, it does not
appear to be reliable as the sole or main diagnostic indicator for neonatal sepsis.
Cytokines Both proinflammatory (interleukin-2 [IL-2], IL-6, IL-8, 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 [56,58-60]. However, these cytokines are not routinely measured because of the cost of
testing and because no single biomarker or panel of tests is sufficiently sensitive to reliably detect neonatal
sepsis [56].
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 [56]. 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 The diagnosis of neonatal sepsis can be established only by a positive blood culture. Other than
blood culture, no specific finding or test reliably identifies infected infants [61].
Ongoing research is focused on developing validated risk stratification strategies based on maternal risk factors and
neonatal presentation that will improve the predictive ability to detect neonatal sepsis [62].
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 [9]. (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]).
A composite of observational assessment and serial laboratory testing is typically used to make a diagnosis of
probable sepsis [45]. 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 of uninfected infants. There is no consensus definition for
the diagnosis of probable sepsis in neonates [2].
Alternative diagnoses (table 4) 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 48 hours are unlikely to
have sepsis. Empiric antibiotic therapy should be discontinued after 48 hours in these neonates [6,63].
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
17-Sep-16 8:27 PM
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percent) had probable sepsis (ie, culture-negative clinical sepsis) [7].

DIFFERENTIAL DIAGNOSIS The differential diagnosis of neonatal sepsis includes systemic viral, fungal, and
parasitic infections and non-infectious causes of temperature instability, and respiratory, cardiocirculatory, and
neurologic symptoms (table 4). Appropriate microbiologic testing distinguishes neonatal bacterial sepsis from
non-bacterial 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 non-infectious 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.
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 5 th 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
Although the incidence of sepsis in term and late preterm infants is low (approximately one to six cases per
1000 births), 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. (See 'Epidemiology'
above.)
Group B Streptococcus (GBS) and Escherichia coli are the most common bacteria causing neonatal sepsis
(table 1). (See 'Etiologic agents' above.)
Maternal risk factors for neonatal sepsis in term and late preterm infants include chorioamnionitis, intrapartum
maternal temperature 38C (100.4F), delivery at <37 weeks gestation, maternal GBS colonization, and
prolonged rupture of membranes (18 hours). (See 'Maternal risk factors' above.)
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 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. (See 'Evaluation and initial management' above and "Management and outcome of sepsis
in term and late preterm infants", section on 'Initial empiric therapy'.)
Neonates with signs or symptoms of early-onset sepsis (onset of symptoms before seven days of age) should
undergo a full diagnostic evaluation including blood culture, complete blood count (CBC) with differential,
lumbar puncture, and chest radiograph (if respiratory symptoms are present). Empiric antibiotics should be
provided to these neonates pending blood culture results. (See 'Symptomatic neonates' above and
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"Management and outcome of sepsis in term and late preterm infants", section on 'Early-onset sepsis'.)
Well-appearing newborns born to mothers colonized with GBS require observation for a minimum of 48 hours.
The need for a limited diagnostic evaluation (which consists of a blood culture and CBC) in these asymptomatic
infants is determined by the nature of the risk factor(s) and whether or not the mother received adequate
intrapartum antibiotic prophylaxis (IAP) (algorithm 1). Infants born to mothers with proven or suspected
chorioamnionitis should receive empiric antibiotic treatment while awaiting culture results. (See 'Well-appearing
neonates' above and "Management and outcome of sepsis in term and late preterm infants", section on
'Early-onset sepsis' and "Management of the infant whose mother has received group B streptococcal
chemoprophylaxis".)
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 [eg, tracheal aspirates if intubated, purulent
eye drainage, or pustules]). Empiric antibiotic treatment should be initiated in these infants pending blood
culture results. (See 'Late-onset sepsis' above and "Management and outcome of sepsis in term and late
preterm infants", section on 'Late-onset sepsis' and "Febrile young infant (younger than 90 days of age):
Management", section on 'Neonates (28 days of age and younger)'.)
Isolation of a pathogen from a blood culture confirms the diagnosis of neonatal sepsis. (See 'Diagnosis' above
and "Management and outcome of sepsis in term and late preterm infants", section on 'Initial empiric therapy'.)
The differential diagnosis of neonatal sepsis includes other systemic infections and non-infectious conditions
including respiratory diseases (eg, transient tachypnea of the newborn and respiratory distress syndrome);
cardiac diseases (eg, congenital heart disease and supraventricular tachycardia); neurologic injury (eg, from
anoxia or hemorrhage); in-born errors of metabolism; and neonatal abstinence syndrome (table 4). (See
'Differential diagnosis' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
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Gershon AA, Hotez PJ, Katz SL (Eds), Mosby, Philadelphia 2004. p.545.
2. Wynn JL, Wong HR, Shanley TP, et al. Time for a neonatal-specific consensus definition for sepsis. Pediatr
Crit Care Med 2014; 15:523.
3. Raju TN, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late-preterm (near-term) infants:
a summary of the workshop sponsored by the National Institute of Child Health and Human Development.
Pediatrics 2006; 118:1207.
4. American Academy of Pediatrics. Group B streptococcal infections. In: Red Book: 2015 Report of the
Committee on Infectious Diseases, 30th ed, Kimberlin DW (Ed), American Academy of Pediatrics, 2015.
p.745.
5. Rao SC, Ahmed M, Hagan R. One dose per day compared to multiple doses per day of gentamicin for
treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev 2006; :CD005091.
6. Polin RA, Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset
bacterial sepsis. Pediatrics 2012; 129:1006.
7. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants >/=2000 grams at birth: A
population-based study. Pediatrics 2000; 106:256.
8. Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol
1999; 94:274.
9. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the Fetus and Newborn Infant, 7th
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ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010. p.222.

10. Phares CR, Lynfield R, Farley MM, et al. Epidemiology of invasive group B streptococcal disease in the United
States, 1999-2005. JAMA 2008; 299:2056.
11. Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventy-five years of neonatal sepsis at Yale:
1928-2003. Pediatrics 2005; 116:595.
12. van den Hoogen A, Gerards LJ, Verboon-Maciolek MA, et al. Long-term trends in the epidemiology of neonatal
sepsis and antibiotic susceptibility of causative agents. Neonatology 2010; 97:22.
13. Puopolo KM, Eichenwald EC. No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis
over 18 years. Pediatrics 2010; 125:e1031.
14. Bauserman MS, Laughon MM, Hornik CP, et al. Group B Streptococcus and Escherichia coli infections in the
intensive care nursery in the era of intrapartum antibiotic prophylaxis. Pediatr Infect Dis J 2013; 32:208.
15. Bailit JL, Gregory KD, Reddy UM, et al. Maternal and neonatal outcomes by labor onset type and gestational
age. Am J Obstet Gynecol 2010; 202:245.e1.
16. Weston EJ, Pondo T, Lewis MM, et al. The burden of invasive early-onset neonatal sepsis in the United States,
2005-2008. Pediatr Infect Dis J 2011; 30:937.
17. Stoll BJ, Hansen NI, Snchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and
E. coli disease continues. Pediatrics 2011; 127:817.
18. Cohen-Wolkowiez M, Moran C, Benjamin DK, et al. Early and late onset sepsis in late preterm infants. Pediatr
Infect Dis J 2009; 28:1052.
19. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections
Program Network, Group B Streptococcus 2000. http://www.cdc.gov/abcs/reports-findings/survreports
/gbs00.pdf (Accessed on March 29, 2013).
20. Centers for Disease Control and Prevention. 2013. Active Bacterial Core Surveillance Report, Emerging
Infections Program Network, Group B Streptococcus, 2013-provisional. www.cdc.gov/abcs/reports-findings
/survreports/gbs13.pdf (Accessed on March 27, 2015). (Accessed on March 27, 2015).
21. Wu JH, Chen CY, Tsao PN, et al. Neonatal sepsis: a 6-year analysis in a neonatal care unit in Taiwan. Pediatr
Neonatol 2009; 50:88.
22. Kuhn P, Dheu C, Bolender C, et al. Incidence and distribution of pathogens in early-onset neonatal sepsis in
the era of antenatal antibiotics. Paediatr Perinat Epidemiol 2010; 24:479.
23. Gottlieb SL, Newbern EC, Griffin PM, et al. Multistate outbreak of Listeriosis linked to turkey deli meat and
subsequent changes in US regulatory policy. Clin Infect Dis 2006; 42:29.
24. Okike I, Lamont R, Heath P. Do We Really Need to Worry About Listeria in Newborn Infants? Pediatr Infect Dis
J 2013; 32:405.
25. Fortunov RM, Hulten KG, Hammerman WA, et al. Community-acquired Staphylococcus aureus infections in
term and near-term previously healthy neonates. Pediatrics 2006; 118:874.
26. Gordon A, Isaacs D. Late onset neonatal Gram-negative bacillary infection in Australia and New Zealand:
1992-2002. Pediatr Infect Dis J 2006; 25:25.
27. Schrag SJ, Hadler JL, Arnold KE, et al. Risk factors for invasive, early-onset Escherichia coli infections in the
era of widespread intrapartum antibiotic use. Pediatrics 2006; 118:570.
28. Puopolo KM, Draper D, Wi S, et al. Estimating the probability of neonatal early-onset infection on the basis of
maternal risk factors. Pediatrics 2011; 128:e1155.
29. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases, National Center for Immunization and
Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B
streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep 2010; 59:1.
30. Herbst A, Klln K. Time between membrane rupture and delivery and septicemia in term neonates. Obstet
Gynecol 2007; 110:612.
31. Soman M, Green B, Daling J. Risk factors for early neonatal sepsis. Am J Epidemiol 1985; 121:712.
32. Osborn LM, Bolus R. Temperature and fever in the full-term newborn. J Fam Pract 1985; 20:261.
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33. Voora S, Srinivasan G, Lilien LD, et al. Fever in full-term newborns in the first four days of life. Pediatrics 1982;
69:40.
34. Anand V, Nair PM. Neonatal seizures: Predictors of adverse outcome. J Pediatr Neurosci 2014; 9:97.
35. Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infect Dis Clin North Am 1999; 13:711.
36. Verani JR, McGee L, Schrag SJ, Division of Bacterial Diseases, National Center for Immunization and
Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B
streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep 2010; 59:1.
37. Schelonka RL, Chai MK, Yoder BA, et al. Volume of blood required to detect common neonatal pathogens. J
Pediatr 1996; 129:275.
38. Garcia-Prats JA, Cooper TR, Schneider VF, et al. Rapid detection of microorganisms in blood cultures of
newborn infants utilizing an automated blood culture system. Pediatrics 2000; 105:523.
39. Garges HP, Moody MA, Cotten CM, et al. Neonatal meningitis: what is the correlation among cerebrospinal
fluid cultures, blood cultures, and cerebrospinal fluid parameters? Pediatrics 2006; 117:1094.
40. Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age.
Arch Pediatr Adolesc Med 1999; 153:508.
41. Visser VE, Hall RT. Urine culture in the evaluation of suspected neonatal sepsis. J Pediatr 1979; 94:635.
42. Newman TB, Puopolo KM, Wi S, et al. Interpreting complete blood counts soon after birth in newborns at risk
for sepsis. Pediatrics 2010; 126:903.
43. Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in early-onset neonatal
sepsis. Pediatr Infect Dis J 2012; 31:799.
44. Rozycki HJ, Stahl GE, Baumgart S. Impaired sensitivity of a single early leukocyte count in screening for
neonatal sepsis. Pediatr Infect Dis J 1987; 6:440.
45. Gerdes JS. Diagnosis and management of bacterial infections in the neonate. Pediatr Clin North Am 2004;
51:939.
46. Russell GA, Smyth A, Cooke RW. Receiver operating characteristic curves for comparison of serial neutrophil
band forms and C reactive protein in neonates at risk of infection. Arch Dis Child 1992; 67:808.
47. Murphy K, Weiner J. Use of leukocyte counts in evaluation of early-onset neonatal sepsis. Pediatr Infect Dis J
2012; 31:16.
48. Jackson GL, Engle WD, Sendelbach DM, et al. Are complete blood cell counts useful in the evaluation of
asymptomatic neonates exposed to suspected chorioamnionitis? Pediatrics 2004; 113:1173.
49. Schmutz N, Henry E, Jopling J, Christensen RD. Expected ranges for blood neutrophil concentrations of
neonates: the Manroe and Mouzinho charts revisited. J Perinatol 2008; 28:275.
50. Hornik CP, Benjamin DK, Becker KC, et al. Use of the complete blood cell count in late-onset neonatal sepsis.
Pediatr Infect Dis J 2012; 31:803.
51. Malik A, Hui CP, Pennie RA, Kirpalani H. Beyond the complete blood cell count and C-reactive protein: a
systematic review of modern diagnostic tests for neonatal sepsis. Arch Pediatr Adolesc Med 2003; 157:511.
52. Pourcyrous M, Bada HS, Korones SB, et al. Significance of serial C-reactive protein responses in neonatal
infection and other disorders. Pediatrics 1993; 92:431.
53. Mukherjee A, Davidson L, Anguvaa L, et al. NICE neonatal early onset sepsis guidance: greater consistency,
but more investigations, and greater length of stay. Arch Dis Child Fetal Neonatal Ed 2015; 100:F248.
54. Benitz WE, Wynn JL, Polin RA. Reappraisal of guidelines for management of neonates with suspected
early-onset sepsis. J Pediatr 2015; 166:1070.
55. Maniaci V, Dauber A, Weiss S, et al. Procalcitonin in young febrile infants for the detection of serious bacterial
infections. Pediatrics 2008; 122:701.
56. Arnon S, Litmanovitz I. Diagnostic tests in neonatal sepsis. Curr Opin Infect Dis 2008; 21:223.
57. Vouloumanou EK, Plessa E, Karageorgopoulos DE, et al. Serum procalcitonin as a diagnostic marker for
neonatal sepsis: a systematic review and meta-analysis. Intensive Care Med 2011; 37:747.
58. Panero A, Pacifico L, Rossi N, et al. Interleukin 6 in neonates with early and late onset infection. Pediatr Infect
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Dis J 1997; 16:370.

59. Sherwin C, Broadbent R, Young S, et al. Utility of interleukin-12 and interleukin-10 in comparison with other
cytokines and acute-phase reactants in the diagnosis of neonatal sepsis. Am J Perinatol 2008; 25:629.
60. Zhou M, Cheng S, Yu J, Lu Q. Interleukin-8 for diagnosis of neonatal sepsis: a meta-analysis. PLoS One 2015;
10:e0127170.
61. Flidel-Rimon O, Galstyan S, Juster-Reicher A, et al. Limitations of the risk factor based approach in early
neonatal sepsis evaluations. Acta Paediatr 2012; 101:e540.
62. Escobar GJ, Puopolo KM, Wi S, et al. Stratification of risk of early-onset sepsis in newborns 34 weeks'
gestation. Pediatrics 2014; 133:30.
63. Polin RA, Watterberg K, Benitz W, Eichenwald E. The conundrum of early-onset sepsis. Pediatrics 2014;
133:1122.
Topic 5043 Version 37.0
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GRAPHICS
Common bacterial agents causing neonatal sepsis in term infants
Frequency of
isolation
Bacterial species
Early-onset
Late-onset
Group B Streptococcus
+++
+++
Escherichia coli
+++
++
Klebsiella spp.
Enterobacter spp.
Listeria monocytogenes
Other enteric gram-negatives
Non-enteric gram-negatives*
Viridans streptococci
Staphylococcus aureus
+++
Citrobacter spp.
Salmonella spp.
Coagulase-negative staphylococci
Enterococcus spp.
+++: commonly associated; ++: frequently associated; +: occasionally associated; 0: rarely

associated.
* Includes nontypable Hemophilus influenzae and Neisseria meningitidis.
Adapted from: Edwards MS, Baker CJ. Bacterial infections in the neonate. In: Principles and Practice of
Pediatric Infectious Disease, 4th ed, Long SS, Pickering LK, Prober CG. Elsevier Saunders, Philadelphia
2012.
Graphic 61061 Version 6.0
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Clinical findings in neonatal sepsis

Finding
Frequency*
Hyperthermia
+++
Respiratory distress
+++
Tachycardia
+++
Lethargy
++
Poor feeding
++
Apnea
++
Bradycardia
++
Poor perfusion / hypotension
++
Vomiting
++
Jaundice
++
Hepatomegaly
++
Cyanosis
Hypothermia
Irritability
Seizures
Abdominal distension
Diarrhea
* +++: commonly associated (50 percent of cases); ++: frequently associated (25 to 50 percent); +:
occasionally associated (<25 percent).
References:
Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious Diseases of the Fetus and Newborn Infant,
7th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010. p.244.
Stoll BJ, Hansen NI, Snchez PJ, et al. Early onset neonatal sepsis: the burden of group B Streptococcal and
E. coli disease continues. Pediatrics 2011; 127:817.
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Secondary prevention of early-onset group B

streptococcal (GBS) disease among newborns
* Full diagnostic evaluation includes a blood culture, a complete blood count

(CBC) including white blood cell differential and platelet counts, chest
radiograph (if respiratory abnormalities are present), and lumbar puncture (if
patient is stable enough to tolerate procedure and sepsis is suspected).
Antibiotic therapy should be directed toward the most common causes of
neonatal sepsis, including intravenous ampicillin for GBS and coverage for
other organisms (including Escherichia coli and other gram-negative
pathogens), and should take into account local antibiotic resistance patterns.
Refer to UpToDate topics on management of sepsis in neonates for details on
empiric antibiotic therapy.
Consultation with obstetric providers is important to determine the level of
clinical suspicion for chorioamnionitis. Chorioamnionitis is diagnosed
clinically, and some of the signs are nonspecific.
Limited evaluation includes blood culture (at birth) and CBC with
differential and platelets (at birth and/or at 6 to 12 hours of life).
Refer to UpToDate topics on neonatal GBS prevention for detailed
discussion of indications for GBS prophylaxis.
If signs of sepsis develop, a full diagnostic evaluation should be conducted
and antibiotic therapy initiated.
If 37 weeks' gestation, observation may occur at home after 24 hours if
other discharge criteria have been met, access to medical care is readily
available, and a person who is able to comply fully with instructions for home
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observation will be present. If any of these conditions is not met, the infant
should be observed in the hospital for at least 48 hours and until discharge
criteria are achieved.
Some experts recommend a CBC with differential and platelets at age 6 to
12 hours.
Adapted from: American Academy of Pediatrics. Group B streptococcal
infections. In: Red Book: 2015 Report of the Committee on Infectious
Diseases, 30th, Kimberlin DW. (Ed), American Academy of Pediatrics, 2015.
p.745.
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Characteristics of cerebrospinal fluid in term and preterm neonates

without bacterial meningitis
Mean
WBC/mm 3
Age
ANC/mm 3 or
Mean protein
percent
(mg/dL)
PMNs
(range or
(range)
SD)
(range or
90th
percentile)
Mean
glucose
(mg/dL)
(range or
SD)
Term neonates evaluated in the nursery setting

0 to 24 hours
(n = 135)* [1]
5 (0 to 90)
3/mm 3 (0 to 70)
63 (32 to 240)
51 (32 to 78)
0 to 10 days
8.2 (0 to 32)
61.3 percent
90 (20 to 170)
52 (34 to 119)
0 to 32 days
11 (1 to 38)
21 percent (0 to
NR
NR
(n = 87) [2]
(n = 24) [3]
100)
Term neonates evaluated in the emergency department setting

0 to 7 days
(n = 17) [4]
15.3 (1 to 130)
4.4/mm 3 (0 to
65)
80.8 (30.8)
45.9 (7.5)
0 to 7 days
(n = 118) [5]
8.6 (90 th
percentile: 26)
NR
106.4 (90 th
percentile: 153)
NR
1 to 28 days
(n = 297) [6]
6.1 (0 to 18)
NR
75.4 (15.8 to
131)
45.3 (30 to 61)
0 to 30 days
7.3 (0 to 130)
0.8/mm 3 (0 to
64.2 (24.2)
51.2 (12.9)
77.6 (90 th
NR
(n = 108) [4]
8 to 14 days
(n = 101) [5]
65)
3.9 (90 th
NR
percentile: 9)
percentile: 103)
8 to 14 days
5.4 (0 to 18)
0.1/mm 3 (0 to 1)
69 (22.6)
54.3 (17)
15 to 22 days
(n = 107) [5]
4.9 (90 th
percentile: 9)
NR
71 (90 th
percentile: 106)
NR
15 to 21 days
(n = 25) [4]
7.7 (0 to 62)
0.2/mm 3 (0 to 2)
59.8 (23.4)
46.8 (8.8)
22 to 28 days
(n = 141) [5]
4.5 (90 th
percentile: 9)
NR
68.7 (90 th
percentile: 85)
NR
22 to 30 days
4.8 (0 to 18)
0.1/mm 3 (0 to 1)
54.1 (16.2)
54.1 (16.2)
(n = 33) [4]
(n = 33) [4]
Preterm or low birth weight neonates

0 to 28 days
9 (0 to 29)
57.2 percent
115 (65 to 150)
50 (24 to 63)
0 to 32 days
(n = 22 ) [3]
7 (0 to 28)
16 percent (0 to
100)
NR
NR
(n = 30 ) [2]
Very low birth weight neonates [7]
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<1000 g
0 to 7 days
(n = 6)
3 (1 to 8)
11 percent (0 to
50)
162 (115 to 222)
70 (41 to 89)
8 to 28 days
(n = 17)
4 (0 to 14)
8 percent (0 to
66)
159 (95 to 370)
68 (33 to 217)
29 to 84
days
4 (0 to 11)
2 percent (0 to
36)
137 (76 to 269)
49 (29 to 90)
4 (1 to 10)
4 percent (0 to
136 (85 to 176)
74 (50 to 96)
137 (54 to 227)
59 (39 to 109)
122 (45 to 187)
47 (31 to 76)
(n = 15)
1000 to 1500 g
0 to 7 days
(n = 8)
8 to 28 days
28)
7 (0 to 44)
(n = 14)
29 to 84
days
10 percent (0 to
60)
8 (0 to 23)
11 percent (0 to
48)
(n = 11)
WBC: white blood cell count; ANC: absolute neutrophil count; PMNs: polymorphonuclear leukocytes; SD:
standard deviation; NR: not reported; CSF: cerebrospinal fluid.
* CSF obtained from term neonates without any obvious pathology.
CSF obtained from hospitalized neonates at high risk for infection (eg, unexplained jaundice, prolonged
rupture of membranes, maternal fever, etc); infection excluded by sterile cultures (CSF, blood, urine) and
lack of clinical evidence of bacterial or viral infection.
CSF obtained in the emergency department during evaluation for possible infection; infection was
excluded by sterile cultures (CSF, blood, urine, and negative polymerase chain reaction for enterovirus).
Only two infants had CSF WBC >30/mm 3: one <7 days of age with 130 WBC/mm 3, and one 15 to 21
days of age with 62 WBC/mm 3.
Includes 29 preterm infants and 1 infant who was 2190 g at 40 weeks' gestation.
Includes all infants with birth weight <2500 g.
References:
1. Naidoo BT. The cerebrospinal fluid in the healthy newborn infant. S Afr Med J 1968; 42:933.
2. Sarff LD, Lynn H, Platt MD, et al. Cerebrospinal fluid evaluation in neonates: Comparison of high risk
infants with and without meningitis. J Pediatr 1976; 88:473.
3. Pappu L. CSF cytology in the neonate. Am J Dis Child 1982; 136:297.
4. Ahmed A. Cerebrospinal fluid values in the term neonate. Pediatr Infect Dis J 1996; 15:298.
5. Chadwick SL, Wilson JW, Levin JE, Martin JM. Cerebrospinal fluid characteristics of infants who
present to the emergency department with fever: establishing normal values by week of age. Pediatr
Infect Dis J 2011; 30:e63.
6. Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr
2011; 158:130.
7. Rodriguez AF, Kaplan SL, Mason EO. Cerebrospinal fluid values in the very low birth weight infant. J
Pediatr 1990; 116:971.
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Range of neutrophil count for newborn infants born with

a gestational age >36 weeks during the first 72 hours of
life
Neutrophils per microL of blood during the first 72 hours after the birth of term
and near-term (>36 weeks of gestation) neonates. A total of 12,149 values were
obtained for the analysis. The 5th percentile, the mean, and the 95th percentile
values are shown.
Reprinted by permission from Macmillan Publishers Ltd: Schmutz N, Henry E, Jopling J,
Christensen RD. Expected ranges for blood neutrophil concentrations of neonates: the
Manroe and Mouzinho charts revisited. J Perinatol 2008; 28:275.
http://www.nature.com/jp/index.html. Copyright 2008.
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Normal range of neutrophil count for newborn infants with a

gestational age between 28 and 36 weeks during the first 72 hours
of life
Neutrophils per microL of blood during the first 72 hours after the birth of 28- to 36-week
gestation preterm neonates. A total of 8896 values were obtained for the analysis. The 5th
percentile, the mean, and the 95th percentile values are shown.
Reprinted by permission from: Macmillan Publishers Ltd: Schmutz N, Henry E, Jopling J, Christensen
RD. Expected ranges for blood neutrophil concentrations of neonates: the Manroe and Mouzinho
charts revisited. J Perinatol 2008; 28:275. http://www.nature.com/jp/index.html. Copyright 2008.
17-Sep-16 8:27 PM
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Differential diagnosis of neonatal sepsis

Diagnosis
Distinguishing features
Diagnostic tests
Other systemic neonatal infections

Viral infections:
Herpes simplex virus
Mucocutaneous vesicles, CSF

pleocytosis, elevated CSF
Viral culture; HSV PCR
protein, thrombocytopenia,
hepatitis
Enteroviruses
Fulminant systemic disease,

myocarditis, hepatitis,
Viral culture; EV PCR
encephalitis
Parechovirus
Cytomegalovirus
Encephalitis/meningitis, rash on
HPeV PCR (available through
palms and soles
CDC)
Thrombocytopenia,
periventricular intracranial
Viral culture; CMV PCR
calcifications, microcephaly,
sensorineural hearing loss,
chorioretinitis
Influenza viruses
Respiratory syncytial virus
Spirochetal infections
Syphilis
Respiratory symptoms,
Viral culture; influenza-specific
rhinorrhea, gastrointestinal
symptoms
antigen detection or
immunofluorescence assay
Respiratory symptoms,
rhinorrhea, cough, apnea,
Viral culture; RSV-specific

antigen detection or
pneumonia
immunofluorescence assay
Skeletal abnormalities
(osteochondritis and periostitis),
RPR or VDRL
pseudoparalysis, persistent
rhinitis, maculopapular rash
(particularly on palms and soles
or in diaper area)
Parasitic infections:
Congenital malaria
Anemia, splenomegaly, jaundice
Detection of parasitemia on
blood smear
Toxoplasmosis
Intracranial calcifications
(diffuse), hydrocephalus,
T. gondii serology
chorioretinitis, mononuclear CSF

pleocytosis, elevated CSF
protein
Fungal infection Candidiasis
Persistent hyperglycemia,
Isolation of Candida in blood,
thrombocytopenia, multiorgan
failure
urine or CSF culture
Non-infectious causes of temperature instability in neonates

Altered environmental
Transient; no other systemic symptoms; resolves with simple
temperature
nonpharmacologic measures
17-Sep-16 8:27 PM
24 of 27
Dehydration
Clinical history of poor feeding or fluid losses (eg, vomiting and/or

diarrhea)
Neonatal abstinence
History of maternal drug use;
syndrome
sweating, sneezing, nasal

stuffiness, and yawning
CNS insult (eg, anoxia or

hemorrhage)
History of perinatal asphyxia;

focal neurologic findings or
Positive drug screening tests
Abnormal neuroimaging studies
seizures
Hypothyroidism
Congenital adrenal
hyperplasia
Hypotonia, lethargy,
Abnormal T4 or TSH level on
hypothermia, large fontanels
newborn screen
Ambiguous genitalia (females),

adrenal insufficiency and
Abnormal
17a-hydroxyprogesterone level
salt-wasting (hyponatremia,
hyperkalemia, dehydration)
on newborn screen
Non-infectious causes of respiratory and cardiocirculatory symptoms in neonates

Transient tachypnea of the
newborn
Onset of symptoms within two

hours after delivery; symptoms
CXR findings include increased

lung volumes, mild
usually resolve within 24 hours
cardiomegaly, prominent
vascular markings, fluid in the
interlobar fissures, and pleural
effusions
Respiratory distress
Most common in preterm
CXR findings include low lung
syndrome
infants; rare in term infants;

onset of symptoms within first
volume and diffuse

reticulogranular ground glass
few hours after delivery,

progressively worsens over first
appearance with air

bronchograms
48 hours of life
Meconium aspiration
Pneumothorax
History of meconium-stained
Initial CXR may show streaky,
amniotic fluid; respiratory

distress occurs immediately
linear densities; as the disease

progresses, the lungs may
after birth
appear hyperinflated with

diffuse patchy densities
Asymmetric chest rise,

decreased breath sounds on
CXR will usually detect

symptomatic pneumothoraces
affected side; hypotension (in

cases of tension pneumothorax)
Congenital anomalies
Often occur with other
CDH is often diagnosed by
(including trachealesophageal fistula, choanal
congenital anomalies including

VACTERL and CHARGE
routine antenatal ultrasound

screening; postnatal CXR shows
atresia, and diaphragmatic

hernia)
associations; choanal atresia is

characterized by noisy labored
herniation of abdominal
contents into hemithorax; TEF
breathing while feeding
is diagnosed with upper

gastrointestinal series and/or
bronchoscopy
Neonatal abstinence
syndrome

17-Sep-16 8:27 PM
25 of 27
Cardiac arrhythmias (eg,

supraventricular tachycardia)
Abrupt onset and termination of

rapid heart rate
Abnormal ECG
Congenital heart disease
Infants with ductal-dependent
Abnormal hyperoxia test;
lesions may initially lack

symptoms then develop
abnormal echocardiography
cyanosis and rapid clinical

deterioration as the PDA closes
in the first few days of life
Non-infectious causes of neurologic symptoms in neonates
Hypoglycemia
Common in infants who are
Abnormal blood glucose level
large for gestational age and/or

infants of diabetic mothers
Hypercalcemia
Increased neuromuscular
Abnormal serum calcium level
irritability and seizures;

associated with prematurity,
maternal diabetes, and
perinatal asphyxia
Hypermagnesemia
Generalized hypotonia,
respiratory depression and
Abnormal serum magnesium

level
apnea; typically results from

maternal treatment with
magnesium sulfate
CNS insult (eg, anoxia or
History of perinatal asphyxia;
hemorrhage)
focal neurologic findings or

seizures
Congenital CNS
Abnormal head circumference

malformations (eg,
hydrocephalus)
Neonatal abstinence
syndrome

Inborn errors of metabolism
Otherwise unexplained
Positive newborn screen for
acid-base disorders,
hyperammonemia,
inborn errors of metabolism
hypoglycemia, hematologic
abnormalities, liver dysfunction,
and renal disease
Pyridoxine deficiency
Refractory seizures
Abnormal plasma pyridoxal5-phophate level
HSV: herpes simplex virus; PCR: polymerase chain reaction; CSF: cerebral spinal fluid; HPeV: human
parechovirus; EV: enterovirus; CMV: cytomegalovirus; RSV: respiratory syncytial virus; RPR: rapid plasma
reagin; VDRL: venereal disease research laboratory; CNS: central nervous system; T4: thyroxine; TSH:
thyrotropin; CXR: chest radiograph; TEF: tracheoesophageal fistula; CDH: congenital diaphragmatic hernia;
VACTERL: malformations of the vertebrae, anus, cardiac structures, trachea, esophagus, renal system, and
limbs; CHARGE: coloboma of the iris or choroid, heart defect, atresia of the choanae, retarded growth and
development, genitourinary abnormalities, and ear defects; ECG: electrocardiogram; PDA: patent ductus
arteriosus.
17-Sep-16 8:27 PM
26 of 27
Adapted from: Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Infectious diseases of the fetus and
newborn infant, 7th ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010.
17-Sep-16 8:27 PM
27 of 27
Contributor Disclosures
Morven S Edwards, MD Grant/Research/Clinical Trial Support: Pfizer Inc. [Group B Streptococcus]. Leonard E
Weisman, MD Grant/Research/Clinical Trial Support: Vax-Immune [Ureaplasma diagnosis, vaccines, and
antibodies]. Consultant/Advisory Boards: Glaxo-Smith Kline [Malaria vaccine]; NIAID [Staphylococcus aureus
(Mupirocin)]. Patent Holder: Baylor College of Medicine [Ureaplasma diagnosis, vaccines, antibodies, process for
preparing biological samples]. Equity Ownership/Stock Options: Vax-Immune [Ureaplasma diagnosis, vaccines, and
antibodies]. Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: Pfizer [S. pneumoniae (PCV13,
Linezolid)]; Cubist [S. aureus (Tedizolid)]; Forest Lab [Osteomyelitis (Ceftaroline)]. Consultant/Advisory Boards:
Pfizer [S. pneumoniae (PCV13, Linezolid); S. aureus (vaccine development)]; Theravance [S. aureus (Telavancin)].
Carrie Armsby, MD, MPH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support
the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy
17-Sep-16 8:27 PM

Clinical Features, Evaluation, and Diagnosis of Sepsis in Term and Late Preterm Infants PDF

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Clinical features, evaluation, and diagnosis of sepsis in term and late pre...

Official reprint from UpToDate

otherwise healthy term newborn infants.

performed in an infant with any of the following clinical conditions [6]:

alternative explanations for persistently elevated CRP values.

percent) had probable sepsis (ie, culture-negative clinical sepsis) [7].

ed, Remington JS, et al (Eds), Elsevier Saunders, Philadelphia 2010. p.222.

Dis J 1997; 16:370.

Other enteric gram-negatives

+++: commonly associated; ++: frequently associated; +: occasionally associated; 0: rarely

Clinical findings in neonatal sepsis

Poor perfusion / hypotension

Secondary prevention of early-onset group B

* Full diagnostic evaluation includes a blood culture, a complete blood count

Characteristics of cerebrospinal fluid in term and preterm neonates

Term neonates evaluated in the nursery setting

Term neonates evaluated in the emergency department setting

45.3 (30 to 61)

Preterm or low birth weight neonates

115 (65 to 150)

Very low birth weight neonates [7]

162 (115 to 222)

159 (95 to 370)

137 (76 to 269)

136 (85 to 176)

137 (54 to 227)

122 (45 to 187)

Range of neutrophil count for newborn infants born with

Normal range of neutrophil count for newborn infants with a

Differential diagnosis of neonatal sepsis

Other systemic neonatal infections

Mucocutaneous vesicles, CSF

Viral culture; HSV PCR

Fulminant systemic disease,

Viral culture; EV PCR

HPeV PCR (available through

palms and soles

Viral culture; CMV PCR

Respiratory syncytial virus

Viral culture; influenza-specific

Viral culture; RSV-specific

Anemia, splenomegaly, jaundice

chorioretinitis, mononuclear CSF

Isolation of Candida in blood,

urine or CSF culture

Non-infectious causes of temperature instability in neonates

Transient; no other systemic symptoms; resolves with simple

Clinical history of poor feeding or fluid losses (eg, vomiting and/or

History of maternal drug use;

sweating, sneezing, nasal

CNS insult (eg, anoxia or

History of perinatal asphyxia;

Positive drug screening tests

Abnormal neuroimaging studies

Abnormal T4 or TSH level on

hypothermia, large fontanels

Ambiguous genitalia (females),

Non-infectious causes of respiratory and cardiocirculatory symptoms in neonates

Onset of symptoms within two

CXR findings include increased

usually resolve within 24 hours

Most common in preterm

CXR findings include low lung