Clinical Features, Evaluation, and Diagnosis of Sepsis in Term and Late Preterm Infants PDF
Clinical Features, Evaluation, and Diagnosis of Sepsis in Term and Late Preterm Infants PDF
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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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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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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"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.)
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REFERENCES
1. Edwards MS, Baker CJ. Sepsis in the Newborn. In: Krugman's Infectious Diseases of Children, 11th ed,
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
17-Sep-16 8:27 PM
Clinical features, evaluation, and diagnosis of sepsis in term and late pre...
12 of 27
http://www.uptodate.com/contents/clinical-features-evaluation-and-diagn...
17-Sep-16 8:27 PM
Clinical features, evaluation, and diagnosis of sepsis in term and late pre...
13 of 27
http://www.uptodate.com/contents/clinical-features-evaluation-and-diagn...
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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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
Non-enteric gram-negatives*
Viridans streptococci
Staphylococcus aureus
+++
Citrobacter spp.
Salmonella spp.
Coagulase-negative staphylococci
Enterococcus spp.
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Frequency*
Hyperthermia
+++
Respiratory distress
+++
Tachycardia
+++
Lethargy
++
Poor feeding
++
Apnea
++
Bradycardia
++
++
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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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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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)
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)
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)
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]
9 (0 to 29)
57.2 percent
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]
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<1000 g
0 to 7 days
(n = 6)
3 (1 to 8)
11 percent (0 to
50)
70 (41 to 89)
8 to 28 days
(n = 17)
4 (0 to 14)
8 percent (0 to
66)
68 (33 to 217)
29 to 84
days
4 (0 to 11)
2 percent (0 to
36)
49 (29 to 90)
4 (1 to 10)
4 percent (0 to
74 (50 to 96)
59 (39 to 109)
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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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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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.
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Distinguishing features
Diagnostic tests
protein, thrombocytopenia,
hepatitis
Enteroviruses
encephalitis
Parechovirus
Cytomegalovirus
Encephalitis/meningitis, rash on
CDC)
Thrombocytopenia,
periventricular intracranial
calcifications, microcephaly,
sensorineural hearing loss,
chorioretinitis
Influenza viruses
Spirochetal infections
Syphilis
Respiratory symptoms,
rhinorrhea, gastrointestinal
symptoms
antigen detection or
immunofluorescence assay
Respiratory symptoms,
rhinorrhea, cough, apnea,
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
Detection of parasitemia on
blood smear
Toxoplasmosis
Intracranial calcifications
(diffuse), hydrocephalus,
T. gondii serology
Persistent hyperglycemia,
thrombocytopenia, multiorgan
failure
temperature
nonpharmacologic measures
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Dehydration
Neonatal abstinence
syndrome
seizures
Hypothyroidism
Congenital adrenal
hyperplasia
Hypotonia, lethargy,
newborn screen
Abnormal
17a-hydroxyprogesterone level
salt-wasting (hyponatremia,
hyperkalemia, dehydration)
on newborn screen
cardiomegaly, prominent
vascular markings, fluid in the
interlobar fissures, and pleural
effusions
Respiratory distress
syndrome
48 hours of life
Meconium aspiration
Pneumothorax
History of meconium-stained
after birth
herniation of abdominal
contents into hemithorax; TEF
Neonatal abstinence
syndrome
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Abnormal ECG
abnormal echocardiography
Increased neuromuscular
Generalized hypotonia,
respiratory depression and
hemorrhage)
Congenital CNS
malformations (eg,
hydrocephalus)
Neonatal abstinence
syndrome
Otherwise unexplained
acid-base disorders,
hyperammonemia,
hypoglycemia, hematologic
abnormalities, liver dysfunction,
and renal disease
Pyridoxine deficiency
Refractory seizures
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.
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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.
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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
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