Approach to risk assessment and initial management of newborns with risk factors for early-onset sepsis

INTRODUCTION — Sepsis is an important cause of morbidity and mortality among newborn infants. Although the incidence of sepsis in the general newborn population is low, prompt recognition and early initiation of appropriate antimicrobial therapy is necessary to minimize morbidity and mortality among the cases that continue to occur.

This topic will review the approach to risk assessment and initial management of newborns born to mothers who received or had an indication to receive intrapartum antibiotic prophylaxis (IAP).

Other related topics include:

●Details regarding IAP and group B streptococcal (GBS) infections in pregnant individuals (see "Group B streptococcal infection in pregnant individuals" and "Prevention of early-onset group B streptococcal disease in neonates")

●The evaluation and treatment of clinically suspected sepsis in term neonates (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates" and "Management and outcome of sepsis in term and late preterm neonates")

●The evaluation and treatment of clinically suspected 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")

●Epidemiology, evaluation, and treatment of confirmed GBS infection in neonates and young infants (See "Group B streptococcal infection in neonates and young infants".)

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

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

MATERNAL INTRAPARTUM ANTIBIOTIC PROPHYLAXIS

Rationale — Group B Streptococcus (GBS; or Streptococcus agalactiae) is an encapsulated gram-positive bacterium that colonizes the human gastrointestinal and genital tracts. GBS is one of the most common bacterial pathogens causing invasive infections in neonates. The other major pathogen is Escherichia coli. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Microbiology'.)

Maternal GBS colonization, in the absence of preventive measures, is the single most important risk factor for early-onset GBS infection in the newborn [1,2]. Screening pregnant women for GBS colonization and administering intrapartum antibiotic prophylaxis (IAP) against GBS is the recommended approach to the prevention of early-onset infection in neonates [3,4]. However, this approach does not prevent all cases of early-onset GBS disease and does not reduce the risk for late-onset GBS disease [5]. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Limitations of GBS prevention programs'.)

Guidelines for maternal screening, indications for maternal IAP, and administration of IAP are discussed in detail 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'.)

"Adequate" intrapartum antibiotic prophylaxis — For the purposes of infant management, "adequate" IAP is defined as intravenous penicillin, ampicillin, or cefazolin given ≥4 hours prior to delivery [4]. The four-hour interval is counted from the beginning of the antibiotic infusion because it is easier to determine accurately than from the end of the infusion. In all approaches to neonatal risk assessment discussed below, the use of other agents (including clindamycin or vancomycin, which are commonly administered to women with high-risk penicillin allergy), or shorter durations are considered inadequate for prevention of early-onset GBS infection. (See "Prevention of early-onset group B streptococcal disease in neonates", section on 'Antibiotic regimen'.)

MANAGEMENT OF THE NEONATE — Clinicians should have a low threshold for evaluation and treatment of possible early-onset sepsis (EOS) because of the potential for serious adverse outcomes, including death. (See "Group B streptococcal infection in neonates and young infants", section on 'Outcome'.)

In the era of universal screening of pregnant women for GBS colonization and the use of intrapartum antibiotic prophylaxis (IAP) when warranted, most cases of early-onset GBS among term infants occur in infants born to women who had negative prenatal GBS cultures, were screened but results were not available at hospital admission, or were not screened [5-8].

Management of the infant whose mother received or had an indication to receive IAP is based upon gestational age, intrapartum risk factors for neonatal infection (including obstetric concern for intraamniotic infection [also called clinical chorioamnionitis]), adequacy of maternal IAP, and the clinical appearance of the neonate at birth and during the hospital observation period [4].

Our recommendations are consistent with guidelines published by the American Academy of Pediatrics (AAP) [4,9,10]. (See 'Society guideline links' below.)

Institutional protocols — Health care centers that care for newborns should have protocols in place to ensure consistent practice regarding evaluation and management of neonates at risk for early-onset sepsis (EOS). These should include the following general components:

●They should be based upon one of three AAP-recommended approaches (ie, categorical risk assessment, EOS calculator, or clinical observation)

●They should include clinical processes for monitoring newborns

●There should be a process for ongoing surveillance once the protocol is implemented to ensure compliance and effectiveness

Approaches to risk assessment

Neonates ≥35 weeks gestation — The following sections address approaches to assessing risk of EOS in neonates born at ≥35 weeks gestation. There are three equally acceptable approaches. The choice of approach is generally based upon institutional preference:

●Categorical risk assessment (algorithm 1)

●EOS calculator

●Clinical observation (algorithm 2)

The approach to evaluating term and near-term neonates for clinically suspected EOS is discussed in greater detail separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Evaluation and initial management'.)

Categorical risk assessment — The categorical risk assessment approach uses specific risk factors to identify infants at increased risk for EOS (algorithm 1). This is the approach that has been recommended since the first consensus guidelines for prevention of perinatal GBS disease were published in 1996 [11]. Risk factors are based on infection epidemiology. In this approach, neonates with clinical signs of illness, as well as well-appearing neonates born to mothers with intrapartum temperature >38°C (100.4°F), undergo evaluation and receive empiric antibiotics. Infants born to mothers who had an indication for but did not receive adequate IAP are carefully observed for signs of illness in the hospital for a minimum of 36 to 48 hours after birth. Infants who develop signs of infection should undergo a sepsis evaluation and have empiric antibiotics administered. (See 'Empiric antibiotic therapy' below and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests'.)

Early-onset sepsis calculator — The web-based Neonatal Early-Onset Sepsis Calculator is based on multivariate risk models and provides a clinical assessment and management tool for newborns at risk of EOS. The risk calculator is a combination of two multivariate risk models, one based on factors known at birth (gestational age, highest maternal intrapartum temperature, maternal GBS colonization status, duration of rupture of membranes, and type and duration of IAP administration) and one based on the newborn's evolving clinical condition over the first 12 hours after birth [12-14]. The clinical management algorithm was validated in a study of over 200,000 live births ≥35 weeks of gestation [14]. 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." When selecting a response to the question regarding type of intrapartum antibiotics, only penicillin, ampicillin, or cefazolin should be considered as "GBS-specific antibiotics" and the timing threshold is at least two hours prior to delivery. If clindamycin or vancomycin was used for IAP, this should be entered into the calculator as "no antibiotics." The models used by the EOS calculator are intended to predict EOS caused by any pathogen (not just GBS), and they also factor in the use of other types of intrapartum antibiotics, such as those administered for women who are at risk for or have signs of intraamniotic infection. Additional details on the EOS calculator are provided separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Early-onset sepsis calculator'.)

Clinical observation — Using this approach, only infants who appear ill at birth or who develop signs of illness are evaluated for infection and given empiric antibiotics (algorithm 2). Well-appearing infants born to mothers with intrapartum temperature >38°C (100.4°F) and those born to mothers who did not receive adequate indicated IAP undergo serial clinical examinations. Infants who develop signs of illness should have cultures obtained and empiric antibiotics administered. (See 'Empiric antibiotic therapy' below.)

Two studies from a single center in the United States reported their experience using this approach [15-17]. Each study included 250 to 350 infants ≥34 weeks gestational age who were evaluated in the setting of obstetric concern for intraamniotic infection, and, ultimately, 5 to 15 percent of neonates were treated with antibiotics. In a report from the same center on the impact of adopting this management approach, the authors reported that >20,000 neonates had been safely managed with the clinical observation approach over five years and that it was associated with a 63 percent reduction in antibiotic use [17].

Similarly, in a study from Norway that evaluated clinical outcomes and rates of antibiotic use before and after transitioning from a risk factor-based approach to an approach based on serial clinical examinations, the latter approach was associated with a 57 percent relative reduction in antibiotic use (from 2.9 percent before to 1.3 percent after) without apparent increase in adverse outcomes [18].

Neonates <35 weeks gestation — For preterm infants born at <35 weeks gestation, EOS risk assessment is based upon the circumstances leading to preterm birth and the clinical condition of the neonate [4]. The approach is summarized in the algorithm (algorithm 3) and discussed in greater detail separately. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Early-onset (first 72 hours)'.)

Diagnostic evaluation — The decision to perform laboratory evaluation for EOS should be based upon one of the assessment approaches discussed above. When the decision is made to perform laboratory testing, the evaluation should minimally include a blood culture.

●Blood cultures – Cultures can be obtained via phlebotomy or from newly inserted catheters placed at the time of sepsis evaluation. A minimum of 1 mL blood should be obtained per blood culture bottle. Collecting two blood cultures may increase the sensitivity for isolating a pathogen and may aid in the determination of a contaminant species; however, it is not required.

Additional details regarding blood sampling and diagnostic yield of blood cultures in neonates undergoing evaluation for EOS are provided separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Blood culture'.)

●Lumbar puncture (LP) – LP is not routinely necessary for the evaluation of well-appearing term infants assessed as at-risk of EOS. However, LP should be performed when there is a strong clinical suspicion for infection (eg, ill-appearing neonate or a neonate who has concerning signs of infection) regardless of maternal IAP status. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Lumbar puncture'.)

●Limited role of laboratory markers of inflammation – The complete blood count (CBC), white blood cell count and differential, and C-reactive protein (CRP) do not perform well in predicting early-onset infection in neonates [19-22]. Clinical signs are more sensitive than these tests in predicting neonatal sepsis, particularly if the infant is initially well appearing.

If the decision is made to obtain a CBC, the predictive value is improved if it is obtained after four hours of age [20,21]. Interpretation of the CBC should consider the timing of the evaluation, gestational age of the infant, and maternal morbidities that may influence the fetal bone marrow. Additional details regarding the diagnostic performance of CBCs in the evaluation of suspected neonatal sepsis are provided separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Complete blood count'.)

The predictive value of a single CRP result at birth is poor. Serial monitoring of CRP levels has been used to guide antibiotic therapy since if the values remain normal over the first 48 hours after birth, infection is unlikely [22]. However, including routine CRP measurements in the evaluation and management of infants at risk for early-onset sepsis is associated with higher rates of initiating antibiotics and longer duration of hospitalization without any clear benefit [22,23]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Other inflammatory markers'.)

●Other tests – Additional testing should be tailored to the individual infant's presentation and may include a chest radiograph (eg, if the neonate has respiratory symptoms).

Empiric antibiotic therapy — The empiric antibiotic regimen should include agents active against the most common causes of neonatal sepsis (ie, GBS and E. coli) (table 1). We suggest ampicillin plus an aminoglycoside (eg, gentamicin) based upon current United States epidemiology [2]. However, local antibiotic resistance patterns must be considered. Empiric antibiotic therapy for suspected neonatal EOS is discussed in greater detail separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

Empiric therapy is administered until culture results are known, typically for 36 to 48 hours. If cultures are sterile, antibiotic therapy should be discontinued.

Definitive therapy — Treatment of confirmed neonatal GBS disease is summarized in the table (table 2) and discussed in greater detail separately. (See "Group B streptococcal infection in neonates and young infants", section on 'Definitive therapy'.)

Definitive therapy for other EOS pathogens is discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Pathogen-specific therapy'.)

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

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th 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 10^th to 12^th 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 email 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 topic (see "Patient education: Group B strep and pregnancy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Maternal screening – Guidelines for maternal screening for group B streptococcus (GBS) and administration of intrapartum antibiotic prophylaxis (IAP) are discussed in detail separately. (See 'Society guideline links' above and "Prevention of early-onset group B streptococcal disease in neonates".)

●Evaluation and management of the newborn – For newborns born to mothers who received or had an indication to receive IAP, the need for laboratory evaluation and empiric antibiotic therapy depends upon the newborn's gestational age (GA) at birth, clinical appearance, risk factors for EOS (including obstetric concern for intraamniotic infection), and adequacy of maternal IAP. (See 'Approaches to risk assessment' above.)

•Neonates born at GA ≥35 weeks – For term and near-term newborns (GA ≥35 weeks), there are three equally acceptable approaches to risk assessment. The choice of approach is generally based upon institutional preference (see 'Neonates ≥35 weeks gestation' above):

-Categorical risk assessment (algorithm 1) (see 'Categorical risk assessment' above)

-Early-onset sepsis calculator (see 'Early-onset sepsis calculator' above)

-Clinical observation (algorithm 2) (see 'Clinical observation' above)

Commonalities of the three approaches are:

-When EOS is suspected based upon one of these assessment approaches, the diagnostic evaluation should minimally include a blood culture. Lumbar puncture (LP) should be performed if there is clinical concern for meningitis. Complete blood count (CBC) with differential and other markers of inflammation should not be used alone to determine risk of EOS. (See 'Diagnostic evaluation' above.)

-Neonates who are ill-appearing or have clinical signs of infection should undergo a full diagnostic evaluation and receive empiric antibiotics, as discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests' and "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

-Diagnostic testing is generally not necessary for well-appearing infants whose mothers had indications for IAP (other than chorioamnionitis) and received adequate IAP. Most infants in this category should receive routine newborn care.

•Neonates born at GA <35 weeks – The approach to risk assessment for preterm infants born at <35 weeks gestation is based upon the circumstances leading to preterm birth and the clinical condition of the newborn (algorithm 3). (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Early-onset (first 72 hours)'.)

●Empiric antibiotic therapy – If, based on one of the above risk assessment methods, the decision is made to start empiric antibiotic therapy, the regimen should include agents active against GBS and other organisms that most commonly cause neonatal sepsis (table 1). In most cases, we suggest a regimen of ampicillin plus an aminoglycoside (eg, gentamicin) rather than other regimens (Grade 2C). Local antibiotic resistance patterns should be considered. (See 'Empiric antibiotic therapy' above and "Management and outcome of sepsis in term and late preterm neonates", section on 'Initial empiric therapy'.)

●Definitive treatment – Definitive treatment of infants with confirmed GBS infection is summarized in the table (table 2) and discussed in detail separately. (See "Group B streptococcal infection in neonates and young infants", section on 'Management'.)

Definitive therapy for other EOS pathogens is discussed separately. (See "Management and outcome of sepsis in term and late preterm neonates", section on 'Pathogen-specific therapy'.)