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

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

The epidemiology, clinical features, diagnosis, and evaluation of bacterial sepsis in term and late preterm neonates will be reviewed here. The management and outcome of bacterial sepsis in term and late preterm neonates are discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates".)

Other related topics include:

●Sepsis in preterm neonates (see "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation" and "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation")

●Group B streptococcal (GBS) infection in neonates and infants, including management of well-appearing newborns at risk for GBS (see "Group B streptococcal infection in neonates and young infants" and "Management of neonates at risk for early-onset group B streptococcal infection")

●Outpatient evaluation and management of febrile neonates (see "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management")

●Evaluation and management of ill-appearing infants (see "Approach to the ill-appearing infant (younger than 90 days of age)")

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

●Term neonates are those born at a gestational age [GA] ≥37 weeks.

●Late preterm neonates (also called near-term neonates) are those born from 34 to <37 weeks GA [1]. (See "Late preterm infants".)

●Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger, manifested by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream. (See 'Diagnosis' below.)

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

•Early-onset sepsis (EOS) is defined as the onset of symptoms before 72 hours of age [2-4], although some experts extend the definition to infections occurring within the first seven days after birth.

•Late-onset sepsis (LOS) is generally defined as the onset of symptoms at ≥72 hours of age [2]. Similar to EOS, there is variability in the definition, ranging from an onset at >72 hours of life to ≥7 days of age.

Newborn infants with EOS typically present with symptoms during their birth hospitalization. Term neonates with LOS generally present to the outpatient setting or emergency department unless comorbid conditions have prolonged the birth hospitalization. The approach to evaluating febrile neonates in the outpatient setting is discussed separately. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Neonates 8 to 21 days old'.)

PATHOGENESIS — The pathogenesis differs based on the timing of onset:

●Early-onset sepsis (EOS) – EOS is usually due to vertical transmission of maternal genitourinary and gastrointestinal flora during vaginal delivery or by ascending contaminated amniotic fluid [3]. Maternal chorioamnionitis (or intra-amniotic infection) is a well-recognized risk factor for EOS [5,6]. Maternal group B streptococcal (GBS) colonization is another important risk factor. (See 'Maternal risk factors' below and "Group B streptococcal infection in neonates and young infants", section on 'Risk factors'.)

Use of forceps during delivery and electrodes placed for intrauterine monitoring have been implicated in the pathogenesis of EOS because they penetrate the neonatal defensive epithelial barriers [7]. However, it is unclear if these are independent risk factors.

●Late-onset sepsis (LOS) – LOS can be acquired by the following mechanisms:

•Vertical transmission, resulting in initial neonatal colonization that evolves into later infection

•Horizontal transmission from contact with care providers or environmental sources

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

Metabolic factors including hypoxia, acidosis, hypothermia, and inherited metabolic disorders (eg, galactosemia) are likely to contribute to risk for and severity of neonatal sepsis (including both EOS and LOS). These factors are thought to disrupt the neonate's host defenses (ie, immunologic response) [7].

EPIDEMIOLOGY — Estimated incidence rates vary based on the case definition and population studied. In a systematic review and meta-analysis of population-based studies from around the world, reported rates of neonatal sepsis varied widely, from as low as four cases per 100,000 in resource-abundant countries to as high as 170 cases per 100,000 live births in resource-limited countries [8]. The overall pooled incidence of neonatal sepsis worldwide was 22 per 1000 live births, with an associated mortality rate of 11 to 19 percent [8]. This translates to a global incidence of three million cases of neonatal sepsis per year [8]. Globally, neonatal sepsis and other severe infections were responsible for an estimated 430,000 neonatal deaths in 2013, accounting for approximately 15 percent of all neonatal deaths [9].

Rates of neonatal sepsis increase with decreasing gestational age (GA):

●Term neonates (GA ≥37 weeks) – The estimated incidence of bacterial sepsis (including both early- and late-onset) in term neonates is approximately 1 to 2 cases per 1000 live births [10-14]. Early-onset sepsis (EOS) accounts for approximately one-third to one-half of all cases. For example, in a surveillance study from the United States from 2015 to 2017, the incidence of EOS among term newborns was 0.6 cases per 1000 live births.

●Late preterm neonates (GA 34 to <37 weeks) – Late preterm neonates have a slightly higher risk of bacterial sepsis, with estimated incidence rates of approximately four to five cases per 1000 [13,15].

●Preterm neonates <34 weeks gestational age – In preterm neonates, the incidence of bacterial sepsis increases with decreasing GA, as discussed separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Incidence'.)

The incidence of EOS in the United States has decreased, primarily due to reduction in group B streptococcal (GBS) infections, owing to the use of intrapartum antibiotic prophylaxis (IAP) [16-20]. Early-onset GBS infection rates in the United States reported through the Centers for Disease Control and Prevention's Active Bacterial Core Surveillance Report have declined from 0.6 per 1000 live births in 2000 to 0.2 per 1000 live births in 2021 [21,22]. Over the same interval, rates of late-onset GBS infection have remained stable at approximately 0.3 to 0.4 cases per 1000 live births, with relatively little year-to-year variation [21,22]. (See "Group B streptococcal infection in neonates and young infants", section on 'Epidemiology'.)

GBS prevention efforts have not increased the burden of early-onset Escherichia coli infection [23].

ETIOLOGIC AGENTS — Group B Streptococcus (GBS) and E. coli are the most common causes of both EOS and LOS, accounting for approximately two-thirds of early-onset infections [13,17,23,24].

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

●Listeria monocytogenes, although a well-recognized cause of EOS, only accounts for rare sporadic cases of neonatal sepsis and is more commonly seen during an outbreak of listeriosis [25,26].

●Staphylococcus aureus, including community-acquired methicillin-resistant S. aureus, is a potential pathogen in late-onset sepsis [27]. In term neonates, S. aureus bacteremia most commonly occurs in association with skin, bone, or joint infections. S. aureus is a more common pathogen in preterm neonates. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Etiologic agents'.)

●Enterococcus, a commonly encountered pathogen among preterm neonates, is a rare cause of sepsis in otherwise healthy term newborn infants.

●Other gram-negative bacteria (including Klebsiella, Enterobacter, and Citrobacter spp) and Pseudomonas aeruginosa are associated with LOS, especially in neonates admitted to neonatal intensive care units [28].

●Coagulase-negative staphylococci often are a cause of hospital-associated infection in ill neonates (primarily in preterm neonates and/or neonates who have indwelling intravascular catheters). Coagulase-negative staphylococci may be considered a contaminant in otherwise healthy term neonates who have not undergone invasive procedures. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'CoNS: Pathogen or contaminant?'.)

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

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

●Enterovirus and parechovirus (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Neonates')

●Candida (see "Clinical manifestations and diagnosis of Candida infection in neonates", section on 'Invasive infection')

MATERNAL RISK FACTORS — Maternal factors that are associated with an increased risk of EOS in the neonate, particularly group B Streptococcus (GBS) infection, include intra-amniotic infection (clinical chorioamnionitis), intrapartum maternal fever, maternal GBS colonization, preterm birth, and prolonged rupture of the membranes (PROM) [3,5,29]. The approach to identifying pregnancies at risk for neonatal EOS and indications for maternal intrapartum antibiotic prophylaxis (IAP) are discussed separately. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Identification of pregnancies at increased risk for early-onset neonatal GBS' and "Prevention of early-onset group B streptococcal disease in neonates", section on 'Intrapartum antibiotic prophylaxis'.)

Maternal GBS screening and IAP reduce the risk of GBS infection but do not eliminate it. In an analysis of 1277 neonates with early-onset GBS infection, only 30 percent of mothers had received IAP prior to delivery (though in most of these cases, IAP was started <4 hours before delivery) [30]. Among newborns who were born to mothers who did not receive IAP, there were indications for maternal IAP in one-third of cases (ie, missed opportunities), whereas two-thirds did not have indications for maternal IAP (eg, negative maternal GBS screening).

CLINICAL MANIFESTATIONS — Clinical manifestations range from subtle symptoms to profound septic shock. Signs and symptoms of sepsis are nonspecific and include temperature instability (hypothermia or fever), irritability, lethargy, respiratory symptoms (eg, tachypnea, grunting, hypoxia), poor feeding, tachycardia, poor perfusion, and hypotension (table 2) [7].

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 a newborn deviates from their usual pattern of activity or feeding [7].

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 intra-amniotic infection (see "Fetal arrhythmias", section on 'Tachyarrhythmias')

•Meconium-stained amniotic fluid, which is associated with a twofold increased risk of sepsis [5] (see "Meconium aspiration syndrome: Pathophysiology, clinical manifestations, and diagnosis", section on 'Meconium composition and passage')

•Low 5- or 10-minute Apgar score, particularly if concerning findings persist (see "Overview of the routine management of the healthy newborn infant", section on 'Apgar score')

●Temperature instability – The temperature of an infected neonate can be elevated, depressed, or normal. Term neonates with sepsis are more likely to mount a febrile response to infection; whereas preterm neonates are more likely to be hypothermic [7]. In term newborns, persistent fever is highly indicative of infection [31,32].

●Cardiorespiratory symptoms – Respiratory and cardiocirculatory symptoms are common in infected neonates. Approximately 85 percent of newborns with EOS present with respiratory distress (eg, tachypnea, grunting, flaring, use of accessory muscles) [12]. EOS can be associated with persistent pulmonary hypertension of the newborn. (See "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

Apnea is less common, occurring in 30 to 40 percent of cases, and is more likely in preterm than term neonates. Apnea is a classic presenting symptom in late-onset group B streptococcal (GBS) sepsis.

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 [12].

●Neurologic symptoms – Neurologic manifestations of sepsis in the neonate include lethargy, poor tone, poor feeding, irritability, and seizures [7]. Seizures are an uncommon presentation of neonatal sepsis but are associated with a high likelihood of infection. In a prospective study in a single neonatal unit, 38 percent of neonates with seizures had sepsis as the etiology [33]. Seizures are a presenting feature in 20 to 50 percent of neonates with neonatal meningitis [34]. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis" and "Etiology and prognosis of neonatal seizures".)

●Other findings – Other findings associated with neonatal sepsis, and their approximate frequencies are listed below (table 2) [7,12]:

•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 clinical signs of sepsis (table 2) require prompt evaluation and initiation of antibiotic therapy [3,7]. Because the signs and symptoms of sepsis are subtle and nonspecific, the threshold for performing laboratory testing is low. Our approach is generally consistent with guidelines published by the American Academy of Pediatrics [3,35]. (See 'Society guideline links' below.)

Early-onset presentation — The evaluation of a neonate with suspected EOS (onset within first 72 hours after birth) includes all of the following:

●Review of the pregnancy, labor, and delivery, including risk factors for sepsis and the use and duration of maternal intrapartum antibiotic prophylaxis (IAP). (See 'Maternal risk factors' above.)

●Comprehensive physical examination. (See "Assessment of the newborn infant".)

●Laboratory testing – The extent of the evaluation is directed by the neonate's signs and symptoms (if present) and maternal risk factors, as discussed in the following sections.

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

Symptomatic neonates — Neonates with clinical signs of EOS (table 2) without a clear alternative explanation (eg, delayed transition, retained fetal lung fluid) should undergo a full diagnostic evaluation and should receive empiric antibiotic treatment. (See 'Empiric antibiotic therapy' below.)

The evaluation includes:

●Blood culture. (See 'Blood culture' below.)

●Lumbar puncture (LP) – Practice has shifted regarding performing LP in neonates undergoing evaluation for clinically suspected EOS [3]. In our practice, we perform LP if the newborn is ill-appearing (provided they can tolerate the procedure) or if there are other concerning signs (irritability, bulging fontanelle, seizures). In addition, if the blood culture is positive, then LP should be performed [3]. Other experts advise performing LP in all neonates undergoing evaluation for clinically suspected EOS. (See 'Lumbar puncture' below.)

LP is not necessary in well-appearing newborns undergoing evaluation for EOS based upon identified risk factors, as discussed below. (See 'Well-appearing neonates' below.)

●Chest radiograph if there are respiratory findings.

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

Late-onset presentation — Neonates presenting with signs of infection at ≥72 hours of age should undergo prompt evaluation and empiric antibiotic treatment. (See 'Empiric antibiotic therapy' below.)

At a minimum, the evaluation should include all of the following tests to evaluate for bacterial sepsis:

●Blood culture (see 'Blood culture' below)

●LP (if the neonate is clinically stable enough to tolerate the procedure and it will not delay initiation of antibiotic therapy) (see 'Lumbar puncture' below)

●Chest radiograph (if respiratory symptoms are present)

●Urine culture (see 'Urine culture' below)

●Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated, purulent eye drainage, or pustules) (see 'Other cultures' below)

Neonates with LOS generally present to the outpatient or emergency department (ED) setting unless a comorbid condition prolongs the birth hospitalization. Neonates presenting to the outpatient or ED setting with fever or other concerning findings may require additional evaluation for nonbacterial causes. The approach is discussed in separate topics:

●Febrile well-appearing neonates – The approach to evaluating well-appearing febrile neonates presenting to the outpatient or ED setting is summarized in the figure (algorithm 3) and discussed in detail separately. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on '8 to 21 days old'.)

●Ill-appearing neonates – Although infection is one of the most common causes of ill appearance in young infants, many other clinical conditions have similar manifestations (table 3). The approach to evaluating an ill-appearing neonate is discussed in detail separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

●Evaluation for viral etiology – In addition to tests to identify bacterial pathogens, diagnostic testing for viral etiologies may be warranted in selected patients:

•Herpes simplex virus (HSV) – Infants with clinical suspicion for HSV infection warrant additional blood and cerebrospinal fluid (CSF) studies, surface viral cultures, and scraping from skin vesicles or mucous membranes for additional testing, as summarized in the table (table 4) and described separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

•Other viruses – Testing for common viral infections (eg, respiratory syncytial virus [RSV], influenza, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), may be warranted depending on the season and constellation of findings. Neonates <28 days of age who are diagnosed with viral infections still have a significant risk for bacterial sepsis and warrant a full sepsis evaluation and empiric treatment pending cultures. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Ancillary studies' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Diagnosed with viral infections'.)

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

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

●Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or neurologic symptoms (see 'Clinical manifestations' above)

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

●CSF pleocytosis (white blood cell [WBC] count of >20 to 30 cells/microL) (table 5) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of cerebrospinal fluid')

●Positive blood, urine, or CSF culture

The empiric antibiotic regimen should include agents active against GBS and other organisms that most commonly cause neonatal sepsis (eg, E. coli and other gram-negative pathogens) (table 1). Our suggested empiric regimens are summarized in the table (table 6) and discussed in greater detail separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

LABORATORY TESTS — The goals of the diagnostic evaluation are to identify and treat all neonates 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 (with ≥1 mL of blood) to detect neonatal bacteremia approaches 90 percent [39].

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

•Sampling site – Blood cultures can be obtained by venipuncture or arterial puncture or by sampling from a newly inserted umbilical artery or vascular access catheter. Positive culture results of blood drawn from indwelling umbilical or central venous catheters can be difficult to interpret since they can indicate contamination or catheter colonization rather than a true systemic infection. In such circumstances, obtaining a peripheral blood culture may help determine if there is a true bloodstream infection [7].

•Number of cultures – We obtain at least one culture prior to initiating empiric antibiotic therapy in neonates with a high clinical suspicion for sepsis, although other institutions may routinely obtain two blood cultures.

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

●Time to positivity – Automated systems for continuous monitoring of blood cultures are routinely used in the United States and have shortened the time to identify positive blood cultures. In most cases of neonatal sepsis, blood cultures become positive within 24 to 36 hours [40,41].

●Distinguishing infection from contamination – A positive blood culture is diagnostic of sepsis when a known bacterial pathogen is isolated (table 1). Isolation of skin flora (eg, diphtheroids) suggests contamination rather than infection. Contamination is also suggested when multiple species grow in culture. Coagulase-negative staphylococci may be pathogenic in patients with indwelling vascular catheters or other invasive devices, whereas a single blood culture positive for coagulase-negative staphylococci is likely to represent a contaminant in full-term neonates without these risk factors [7].

Lumbar puncture — Specific clinical signs of meningitis (eg, bulging fontanelle, nuchal rigidity) may be lacking in neonates. For this reason, we suggest performing LP in all neonates with suspected LOS, provided the neonate is stable enough to tolerate the procedure and it will not delay initiation of antibiotics. We also suggest performing LP in the evaluation of suspected EOS if the newborn is ill appearing or has other concerning findings (irritability, bulging fontanelle, seizures). Other experts advise performing LP in all neonates undergoing evaluation for clinically suspected EOS. LP is not necessary in well-appearing newborns undergoing evaluation for EOS based upon identified risk factors, as discussed above (see 'Well-appearing neonates' above). However, LP should be performed if the blood culture is positive [3].

If LP is performed, cerebrospinal fluid should be sent for Gram stain, routine culture, cell count with differential, and protein and glucose concentrations. The interpretation of cerebrospinal fluid needs to account for variations due to gestational age, chronologic age, and birth weight (table 5).

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 evaluation for LOS (ie, onset at ≥72 hours after birth). A urine culture need not be routinely performed in the evaluation of suspected EOS (onset within the first 72 hours after birth), because a positive urine culture in this setting is a reflection of high-grade bacteremia rather than an isolated urinary tract infection [3]. (See "Urinary tract infections in neonates".)

Other cultures — In neonates 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 first intubation. However, the trachea and proximal bronchi are not sterile, so a positive tracheal culture may represent colonization rather than infection, particularly in a neonate who has been intubated for several days.

Gram stain or culture of other sites (eg, gastric aspirate, body surface sites [eg, axilla, groin, and external ear canal]) add little to the evaluation and should not be performed [3].

Complete blood count — The CBC has poor sensitivity and specificity and cannot establish or exclude the diagnosis of neonatal sepsis.

●Early-onset sepsis – For most neonates with suspected EOS, we suggest not obtaining a CBC as part of the diagnostic evaluation. The CBC does not perform well in predicting risk of EOS in neonates, it adds little information, and does not impact clinical decisions. If a CBC is obtained, it should not be used as the sole determinant of whether to treat empirically with antibiotics [42-46]. The CBC can be used in combination with risk factors, clinical assessment, and/or other tests. However, it adds little to these other assessments. CBCs obtained 6 to 12 hours after delivery are more predictive of sepsis than those obtained immediately after birth because the white blood cell count (WBC) and absolute neutrophil count (ANC) normally increase during the first six hours after birth [42,43,47,48].

Large multicenter studies have evaluated the diagnostic value of CBCs in neonatal EOS [5,42,43,49-51]. These studies demonstrated correlations between various WBC parameters (including WBC count, ANC, and ratio of immature to total neutrophils [I/T ratio]) and culture-proven sepsis; however, none were sufficiently sensitive or specific to reliably predict neonatal sepsis.

●Late-onset sepsis – CBCs are less variable at >72 hours after birth than they are in the first few days of life. However, WBC indices still perform poorly in identifying neonates with LOS [52]. At the authors institution, we do not use CBCs in the evaluation of suspected LOS among infants who remain hospitalized since birth. The role of CBCs in the outpatient evaluation of well-appearing febrile neonates is discussed separately. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on '8 to 21 days old'.)

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

●C-reactive protein (CRP) – CRP is increased in inflammatory conditions, including sepsis. A variety of noninfectious inflammatory conditions can also cause elevated CRP, including maternal fever, fetal distress, stressful delivery, perinatal asphyxia, meconium aspiration, and intraventricular hemorrhage [55].

A single measurement of CRP is not a useful aid in the diagnosis of neonatal sepsis, because it lacks sufficient sensitivity and specificity [56]. However, sequential assessment of CRP values may help to exclude the diagnosis of sepsis since if the CRP level remains persistently normal (<1 mg/dL [10 mg/L]), bacterial sepsis is unlikely [3].

However, we do not routinely use serial CRP measurements for this purpose since this practice appears to be associated with higher rates of initiating antibiotics and longer duration of hospitalization without any clear benefit [57,58].

An elevated CRP level alone does not justify continuation of empiric antibiotics for more than 36 to 48 hours in well-appearing neonates with negative culture results [59]. Additional evaluation may be warranted to investigate alternative explanations for persistently elevated CRP values.

●Procalcitonin (PCT) – PCT is the peptide precursor of calcitonin. It is released by parenchymal cells in response to bacterial toxins, leading to elevated serum levels in patients with bacterial infections. Several observational studies have suggested that elevated PCT levels are associated with infection in neonates [60-62]. In a systematic review of 18 studies, the sensitivity of PCT for detecting neonatal sepsis ranged from 72 to 79 percent, and the specificity ranged from 72 to 90 percent [62]. Thus, although PCT is a promising marker, it does not appear to be reliable as the sole or main diagnostic indicator for neonatal sepsis.

A randomized clinical trial suggested that adding serial PCT measurements to other standard assessments (ie, clinical examination and culture results) may shorten duration of antibiotic therapy [63]. However, in this trial, the treating clinicians overruled the study protocol's suggested duration of antibiotic therapy in >40 percent of the enrolled neonates, which limits the certainty of the study's findings. Additional data are needed before monitoring PCT levels can be adopted into routine neonatal clinical practice. If PCT levels are obtained, they should be used in conjunction with other clinical indicators of sepsis and should not be the sole basis of decision-making.

●Cytokines, chemokines, and other biomarkers – Both proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha, and anti-inflammatory cytokines (interleukin-4 and interleukin-10) are increased in infected neonates compared with those without infections [64-67]. Elevations of serum amyloid A and the cell surface antigen CD64 also have high sensitivity for identifying neonates with sepsis [62,68]. However, these biomarkers are generally not used in clinical practice.

DIAGNOSIS — The diagnosis of sepsis is based upon isolating a pathogenic organism in culture. Few neonates who undergo sepsis evaluation are ultimately diagnosed with sepsis.

This was demonstrated in a retrospective study of 2785 newborns who underwent evaluation for sepsis based on clinical symptoms (54 percent) or risk factors (46 percent) [5]. Culture-proven sepsis was identified in 22 neonates (0.8 percent) and culture-negative clinical sepsis ("probable sepsis") was diagnosed in 40 neonates (1.4 percent).

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 pathogenic organism 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 [7]. (See 'Blood culture' above and "Management and outcome of sepsis in term and late preterm neonates", 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 laboratory abnormalities suggestive of sepsis [cerebrospinal fluid pleocytosis, persistently elevated C-reactive protein]).

A composite of observational assessment and serial laboratory testing is typically used to make a diagnosis of probable sepsis [69]. The criteria used are usually broad in an attempt to ensure that all infected neonates are identified, but at the cost of testing and treating a number of uninfected neonates. There is no consensus definition for the clinical diagnosis of probable sepsis in neonates [70].

Alternative diagnoses (table 7) should also be entertained when a neonate with suspected sepsis has negative cultures. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Probable but unproven sepsis' and 'Differential diagnosis' below.)

Infection unlikely — Neonates with mild and/or transient symptoms (ie, fever alone or other symptoms that quickly resolve) who remain well-appearing with negative cultures at 36 to 48 hours are unlikely to have sepsis. Empiric antibiotic therapy should be discontinued after 36 to 48 hours in these neonates [3,71].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of neonatal sepsis includes systemic viral, fungal, and parasitic infections and noninfectious causes of temperature instability and respiratory, cardiocirculatory, and neurologic symptoms (table 7). The clinical history, disease course, and laboratory findings may help to distinguish neonatal sepsis from other infectious and noninfectious disorders. Ultimately, appropriate microbiologic testing is required to confirm the diagnosis.

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 obtaining cultures) to infants with suspected sepsis pending definitive culture-based diagnosis.

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

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

SUMMARY AND RECOMMENDATIONS

●Epidemiology and microbiology – Sepsis is an important cause of morbidity and mortality in newborn infants.

•Incidence – The incidence of bacterial sepsis in term neonates is approximately one to two cases per 1000 live births; the rate is slightly higher in late preterm neonates (approximately four to five cases per 1000 births). (See 'Epidemiology' above.)

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

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

●Clinical manifestations – Clinical manifestations are nonspecific and include (table 2) (see 'Clinical manifestations' above):

•Fetal distress

•Temperature instability (fever or hypothermia)

•Respiratory and cardiocirculatory symptoms (most commonly respiratory distress and tachycardia)

•Neurologic symptoms (irritability, lethargy, poor tone, and seizures)

•Gastrointestinal abnormalities (poor feeding, vomiting, and abdominal distension)

●Evaluation of suspected early-onset sepsis (EOS) – The evaluation of a neonate with suspected sepsis within first 72 hours after birth includes review of the pregnancy, labor, and delivery; physical examination; and laboratory evaluation directed by the neonate's signs and symptoms (if present) and maternal risk factors (see 'Early-onset presentation' above):

•Symptomatic newborns – Neonates with clinical signs of EOS (table 2) should undergo a full diagnostic evaluation and should receive empiric antibiotic treatment as summarized in the table (table 6) and discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Early-onset sepsis'.)

The evaluation includes:

-Blood culture (see 'Blood culture' above)

-Lumbar puncture (LP) if the newborn is ill-appearing or if there are other concerning signs (irritability, bulging fontanelle, seizures) (see 'Lumbar puncture' above)

-Chest radiograph if there are respiratory findings

•Well-appearing newborns – The approach to evaluating well-appearing newborns who have risk factors for EOS is discussed separately. (See "Management of neonates at risk for early-onset group B streptococcal infection".)

●Evaluation of suspected late-onset sepsis (LOS) – Neonates presenting with clinical signs of sepsis at ≥72 hours after birth should undergo a full diagnostic evaluation and should receive empiric antibiotic treatment as summarized in the table (table 6) and discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Early-onset sepsis'.)

At a minimum, the evaluation for LOS should include all of the following tests to evaluate for bacterial sepsis (see 'Late-onset presentation' above):

•Blood culture (see 'Blood culture' above)

•LP (provided the neonate is stable enough to tolerate the procedure and it will not delay antibiotic therapy) (see 'Lumbar puncture' above)

•Chest radiograph (if respiratory symptoms are present)

•Urine culture (see 'Urine culture' above)

•Cultures from any other potential foci of infection (eg, tracheal aspirates if intubated, purulent eye drainage, or pustules) (see 'Other cultures' above)

Neonates <28 days presenting to the outpatient or emergency department setting with fever or other concerning findings may require additional evaluation for nonbacterial causes. The approach is discussed in separate topics. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Evaluation' and "Approach to the ill-appearing infant (younger than 90 days of age)".)

●Diagnosis – Isolation of a pathogen from a blood culture confirms the diagnosis of neonatal sepsis. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of neonatal sepsis includes other systemic infections and noninfectious conditions including respiratory diseases (eg, transient tachypnea of the newborn and respiratory distress syndrome), cardiac diseases (eg, congenital heart disease and supraventricular tachycardia), neurologic injury (eg, from anoxia or hemorrhage), inborn errors of metabolism, and neonatal abstinence syndrome (table 7). (See 'Differential diagnosis' above.)