KEY POINTS

• 1.
  

  Early-onset sepsis (EOS) is defined by blood and/or cerebrospinal fluid culture-confirmed infection occurring 0 to 6 days after birth.

  
  
• 2.
  

  Incidence is highest among preterm infants, particularly those born with low gestational ages and with birth weight <1500 g.

  
  
• 3.
  

  Pathogenesis commonly involves ascending colonization of the uterine compartment with maternal flora, with subsequent colonization of the fetus and transition to invasive infection in utero or in the hours and days after birth

  
  
• 4.
  

  Risk factors include low gestational age, duration of rupture of membranes, colonization with high-risk organisms such as group B Streptococcus (GBS), and evidence of maternal intraamniotic infection, such as intrapartum maternal fever.

  
  
• 5.
  

  The most common causative organisms are GBS and Escherichia coli .

  
  
• 6.
  

  Newborns with EOS may be well-appearing at birth, but ∼90% have signs of infection within 24 hours after birth.

  
  
• 7.
  

  Ampicillin and gentamicin are currently the recommended choice for empiric antimicrobial therapy. Broader-spectrum therapy should be considered for critically ill newborns at highest risk of EOS, until culture results are known.

Introduction

Early-onset sepsis (EOS) among term infants is a low-incidence but potentially fatal complication of birth. Among preterm, particularly low-gestation, very low birth weight (VLBW, birth weight <1500 g) and extremely low birth weight (ELBW, birth weight <1000 g) infants, EOS is more common and a significant contributor to morbidity and mortality. EOS is defined by isolation of a pathogenic species from blood or cerebrospinal fluid (CSF) culture in the first week after birth. Among continuously hospitalized, primarily preterm infants, EOS diagnosis is limited to infection occurring ≤72 hours after birth. For these infants, risk factors for infection and microbiology of infection both transition away from the perinatal period to reflect nosocomial factors around this time frame. Among term infants, EOS diagnosis is most commonly made at <48 hours after birth; for example, 95% of EOS caused by group B Streptococcus (GBS) occurs at <48 hours of age. Rarely, otherwise healthy infants may be discharged from the birth hospital and develop EOS in the first week after birth. Bacteria are the primary cause of EOS; fungal species are very occasionally isolated. ^,

Epidemiology

The incidence of EOS is inversely related to gestational age at birth. National surveillance conducted by the Centers for Disease Control and Prevention (CDC) demonstrates that overall US national incidence was constant from 2005 to 2014 at 0.7 to 0.8 cases/1000 live births. Among infants born at ≥37 weeks’ gestation, the incidence is approximately 0.5 cases/1000 live births. In contrast, prospective surveillance among centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) from 2015 to 2017 found an incidence of 18.5 cases/1000 live births occurring at 22 to 28 weeks gestation and 6.2/1000 among those born at 29 to 33 weeks’ gestation. This study observed an incidence of 13.9 cases/1000 live birth among VLBW infants.

Pathophysiology

The pathogenesis of EOS begins with invasion of the intraamniotic compartment with bacterial species from maternal sources. The pathologic processes of EOS were described in seminal papers by Benirschke and Blanc, who described the “amniotic infection syndrome” as the cause of congenital bacterial sepsis and pneumonia, contrasting this entity with the transplacental, hematogeneous origin of congenital viral infection. ^, Rarely, pathogenic bacteria infecting the maternal bloodstream may cause EOS via the transplacental route. The classic example is EOS caused by Listeria monocytogenes, a foodborne pathogen with placental tropism that can cause fetal infection via the maternal bloodstream. Most commonly, EOS pathogenesis begins by ascending colonization via the cervix into the uterine compartment with bacteria normally resident in the maternal gastrointestinal and genitourinary colonizing flora. Transition from fetal colonization to invasive infection via membranous surfaces then occurs, either in utero or after birth. Fetal infection may also occur in utero by aspiration of infected amniotic fluid. This pathogenesis primarily proceeds during labor and is promoted by membrane rupture but rarely can occur before the onset of labor.

Risk Factors

Factors that promote or reflect intraamniotic infection (IAI) may be used to assess risk of EOS. Preterm birth and low birth weight are strong risk factors for infection: IAI infection is a significant cause of preterm birth itself, ^, and the preterm infant is immunologically more vulnerable to bacterial infection compared with those born at term gestation. Neonatal immune defenses derive primarily from innate immune responses including transplacentally acquired, maternally derived antibody. Effective immune response to the majority of organisms causing EOS require neutrophil and complement-mediated defense mechanisms that are poorly developed among preterm infants. Preterm infants are also relatively deficient in maternally derived antibodies, which are primarily transferred from mother to fetus late in the third trimester. At the other end of the gestational age spectrum, postterm infants born after 41 weeks’ completed gestation are also at slightly higher (∼1.6-fold) risk of EOS compared with those born at 37 to 40 weeks’ gestation. The etiology of increased risk associated with postterm birth is unclear, but changes in the integrity of the amniotic membranes and cervical mucosa as well as placental senescence may contribute to decreased barrier defenses to infection.

Multiple intrapartum characteristics are also predictive of EOS. Duration of rupture of membranes (ROM) is a risk factor for EOS among term and late preterm infants, as longer ROM promotes ascending colonization and infection of the uterine and fetal compartments. Preterm, prelabor rupture of membranes (PPROM) is associated with increased risk of EOS among preterm infants, but the exact relationship between duration of PPROM and infection is modified by the administration of latency antibiotics and obstetric management. Signs of maternal IAI (previously referred to as clinical chorioamnionitis) are strong predictors of neonatal infection. These signs include maternal intrapartum fever, maternal tachycardia, and uterine tenderness, all of which are reasonably sensitive for but lack specificity for predicting EOS. The American College of Obstetricians and Gynecologists (ACOG) provides guidance for the definitive and suspected diagnosis of maternal IAI. The diagnosis of IAI is confirmed by amniotic fluid culture, gram stain and/or biochemical analysis consistent with infection, and placental histopathology consistent with infection and inflammation. Amniotic fluid-based diagnostic information is usually obtained when assessing a pregnant woman who presents with preterm labor and is less relevant to women laboring at term, for whom definitive evidence of IAI is more often obtained by placental histopathology. Suspected IAI is diagnosed in the laboring woman when a maternal intrapartum temperature ≥39.0°C occurs alone or a maternal temperature in the 38.0°C to 38.9°C range occurs when maternal leukocytosis, purulent cervical drainage, or fetal tachycardia is present. Isolated maternal fever is defined as the occurrence of a maternal intrapartum temperature ≥39.0°C alone or a persistent maternal temperature in the 38.0°C to 38.9°C range without additional clinical risk factors. The ACOG recommends the administration of maternal intrapartum antibiotics for confirmed or suspected IAI, as well as for isolated intrapartum maternal fever, due to the risks to both the pregnant woman and the fetus from progressive IAI, if indeed present.

Maternal vaginal-rectal colonization with GBS is a predictor for GBS-specific EOS. Vertical transmission of GBS from mother to fetus and newborn is almost exclusively the source of neonatal early-onset GBS disease, in contrast to late-onset neonatal GBS disease, which may be due to either vertical or horizontal maternal transmission or horizontal transmission from nonmaternal caregivers and household sources. The risk posed by maternal GBS colonization is significantly reduced by administration of intrapartum antibiotic prophylaxis to laboring GBS-colonized mothers. ^, The widespread implementation of recommended practices for maternal antenatal culture-based screening for GBS colonization and appropriate administration of IAP has been associated with a nearly 10-fold decline in the incidence of GBS-specific EOS in the United States.

Higher rates of both EOS and GBS-specific EOS have been found among infants born to US mothers of Black race compared with those who identify as of white non-Hispanic background. Obstetric practices such as the frequency of vaginal exams during labor and the use of invasive fetal monitoring have been associated with increased risk of GBS-specific EOS in some observational studies. These findings are confounded by their associations with other factors such as length of labor, ROM, and preterm delivery and are therefore difficult to interpret. Current ACOG guidance for prevention of perinatal GBS disease states that such procedures should be performed as clinically indicated and notes that GBS IAP will likely minimize the impact of these factors.

Microbiology

EOS is associated with organisms vertically acquired from the maternal gastrointestinal and genitourinary tract. The distribution of organisms causing EOS in surveillance or cohort studies conducted by the CDC, NRN, and within the Pediatrix Medical Group–affiliated neonatal intensive care units (NICUs) is shown in Table 30.1 and Fig. 30.1 . Gram-positive organisms compose 50% to 70% of all infections. Fungal infections were reported in the NRN surveillance, composing 1% to 2% of all infections and occurring exclusively among preterm infants. Despite use of targeted IAP, GBS is the most common organism isolated in EOS case infants born at ≥37 weeks’ gestation, whereas Escherichia coli is the predominant organism isolated among those born at <37 weeks’ gestation. The differential between these two most common causes of EOS is greater with decreasing gestational age: among those born at 22 to 28 weeks’ gestation, the rate of E. coli disease is 120-fold higher than among those born at ≥37 weeks’ gestation (12 cases/1000 among low-gestation versus 0.10 cases/1000 among term infants).

Distribution of Early-Onset Sepsis Organisms .

(A) Term infants. and (B) Preterm infants. (A, Adapted from Stoll BJ, Puopolo KM, Hansen NI, et al. Early-onset neonatal sepsis 2015 to 2017, the rise of escherichia coli, and the need for novel prevention strategies. JAMA Pediatr . 2020;174(7):e200593; B, Adapted from Puopolo KM, Draper D, Wi S, et al. Estimating the probability of neonatal early-onset infection on the basis of maternal risk factors. Pediatrics . 2011;128(5):e1155–e1163.)

Clinical Features

The signs of EOS among newborns are often nonspecific and may be especially difficult to distinguish from transitional instability that may occur among term infants and from cardiorespiratory immaturity commonly displayed among preterm infants. Vital sign instability is often present, including tachycardia, tachypnea, and temperature instability. Respiratory signs may range from mild tachypnea, with or without a requirement for supplemental oxygen, to profound respiratory failure due to pneumonitis, surfactant deficiency, and/or pulmonary hypertension with persistent fetal circulation. Cardiovascular systemic symptoms range from poor perfusion and metabolic acidosis to hypotension, tachycardia and cardiac dysfunction. Severe sepsis may be complicated by hypoxic-ischemic encephalopathy with or without meningitis. Septic shock may evolve to multisystem organ failure with oliguria, liver dysfunction including coagulopathy, bone marrow suppression with leukopenia, neutropenia, and thrombocytopenia. Approximately 50% to 70% of infants with EOS will present with signs of illness at the time of birth and the majority will present by 24 hours of age. ^, However, a small proportion of term infants can present after 24 hours of age, particularly those ultimately determined to be infected with GBS, despite negative maternal antenatal screening results and no significant intrapartum risk factors for EOS. Such cases may represent infants born to mothers who screened falsely negative for GBS or whose colonization status changed during the period between screening and delivery.

Risk Assessment

Term and near-term infants should be considered separately from preterm infants. Among term infants (defined as those born ≥35 0/7 weeks’ gestation), the pathogenesis of EOS most commonly develops during the course of labor. Given the relatively low incidence of EOS among term infants (approximately 1/2000 live births), the goal of risk assessment is to determine which newborns are at high enough risk to warrant EOS evaluation and empiric antibiotic therapy. In contrast, the majority of infants born preterm are born due to spontaneous preterm labor with or without preterm ROM, meaning that infection may be both a cause and a complication of preterm birth. Further, the baseline risk is as high as 1/50 live births for infants born at <29 weeks’ gestation—meaning that the goal of EOS risk assessment among preterm infants is to determine which infants are at low enough risk to be spared initiation of empiric antibiotics.

EOS Risk Assessment Among Infants Born at ≥35 0/7 Weeks’ Gestation

There are three basic approaches that can be taken to determine empiric antibiotic administration for EOS risk among term and late preterm infants. Each approach has advantages and limitations; centers can assess their local resources and their view of the risk/benefit balance of empiric antibiotic therapies to determine the approach best suited to their local care structure. Table 30.2 outlines the three approaches currently recommended by the American Academy of Pediatrics (AAP) and summarizes the primary advantages and limitations of each. The categorical approach uses dichotomous cutoff values for risk factors, assigning risk on the basis of the presence or absence of specific risk factors, and recommends laboratory evaluation and empiric therapy be administered when the risk factor is present. This approach was recommended in GBS perinatal prevention guidance from 1996 to 2010 and widely applied to the evaluation of newborns for all microbial causes of EOS. The categorical approach to EOS risk assessment was not prospectively evaluated prior to recommendation, but retrospective studies among infants born at ≥35 to 36 weeks’ gestation demonstrate that implementation results in 5% to 12% of infants treated with empiric antibiotics. ^{, ,} Multivariate prediction models have been developed that utilize specific risk factors for EOS and account for use of intrapartum antibiotics and the evolving clinical condition of the newborn over the first 6 to 12 hours after birth. These models provide estimated risk of EOS for the individual infant and have been formulated as a web-based “ Neonatal Early-Onset Sepsis Calculator ” ( https://neonatalsepsiscalculator.kaiserpermanente.org ). Prospective implementation studies in large birth cohorts demonstrate that this approach can reduce the rate of EOS evaluation and empiric antibiotic administration without safety concerns. Depending on the thresholds used for specific clinical actions, empiric antibiotic rates of 2.6% to 3.7% have been reported among infants born at ≥35 to 36 weeks’ gestational age using the sepsis risk calculator. ^, The final recommended approach to EOS evaluation relies on the use of serial observation only among infants categorized as at risk for EOS. Centers that have studied this approach have utilized it by first categorizing infants as at risk based on categorical criteria such as the obstetric diagnosis of chorioamnionitis. Infant who are clinically ill at birth are provided empiric antibiotic treatment and those who are well-appearing undergo serial, structured physical assessments for 24 to 36 hours after birth. A single center in the United States has reported on the use of this approach among infants born to mothers diagnosed with chorioamnionitis, which the center had previously universally treated with empiric antibiotics. Depending on the criteria set for illness and the environment used for serial observation, the use of empiric antibiotic administration declined from 100% to 10% to 20% among initially well-appearing infants flagged for observation. ^,

Table 30.2

EOS Risk Assessment Among Infants Born ≥35 0/7 Weeks’ Gestation

	Categorical Approach	Neonatal Early-Onset Sepsis Calculator a	Observation Only
Risk factors considered	• Signs of newborn clinical illness • Maternal intrapartum temperature ≥100.4°F (≥38°C) • Inadequate IAP in a GBS-colonized mother	• GA at birth • Highest maternal intrapartum temperature • Duration of ROM • Maternal GBS status • Type and duration of intrapartum antibiotic • Infant clinical status over the first 6–12 hours of age	• Signs of newborn clinical illness • Maternal intrapartum temperature ≥100.4°F (≥38°C) • Inadequate IAP in a GBS-colonized mother
Infant clinical status	Determination of what constitutes “signs of newborn clinical illness” is left to local center determination	Guidance on content and duration of vital signs and specifics of clinical status provided to determine whether infant is well-appearing, equivocal, or clinically ill	Determination of what constitutes “signs of newborn clinical illness” is left to local center determination
Recommended clinical actions	• Blood culture and empiric antibiotics recommended for infants: ○ with clinical illness ○ born to mothers with intrapartum temperature ≥38°C/100.4°F • Clinical observation for 24–36 hours in the birth hospital for infants born to mothers with inadequate GBS IAP	Recommended actions are provided based on final risk estimate at birth and the risk estimate adjusted for clinical condition.	• Blood culture and empiric antibiotics recommended for infants with clinical illness • At-risk infants who appear well at birth should have serial, structured clinical assessments from birth through 36–48 hours of age and undergo EOS evaluation if signs of illness develop
Advantages	• Familiar • Multiple retrospective studies available	• Prospectively validated in large cohorts • Individualized management • Overall lower use of empiric antibiotics compared with categorical approach	Overall lower use of empiric antibiotics compared with categorical and (possibly) multivariate approach
Limitations	• Poor discrimination within risk categories • Higher use of empiric antibiotics compared with multivariate and observation-only approaches	• Requires structures for risk calculation • Require process for enhanced newborn observation at some levels of estimated risk	• Validation in small cohorts where risk was primarily determined by obstetric diagnosis of chorioamnionitis • Requires structures for serial newborn observation and development of rules for evaluation and empiric treatment

 

a Neonatal Early-Onset Sepsis Calculator found at: https://neonatalsepsiscalculator.kaiserpermanente.org/ . EOS, Early-onset sepsis; GA, gestational age; GBS, group B Streptococcus ; IAP, intrapartum antibiotic prophylaxis; ROM, rupture of membranes.

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