History
An awareness of the many risk factors associated with neonatal sepsis prepares the clinician for early identification and effective treatment, thereby reducing morbidity and mortality. Among these risk factors are the following:
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Maternal group B Streptococcus (GBS) status
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Prolonged and/or premature rupture of membranes (PPROM)
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Premature delivery
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Chorioamnionitis
Maternal GBS status
The most common cause of neonatal bacterial sepsis remains GBS, despite a decreased overall incidence in the age of universal GBS prophylaxis. There are nine serotypes, each of which is related to the polysaccharide capsule of the organism. Types I, II, and III are commonly associated with neonatal GBS infection. The type III strain has been shown to be most highly associated with central nervous system (CNS) involvement in early-onset infection, whereas types I and V have been associated with early-onset disease without CNS involvement.
The GBS organism colonizes the maternal gastrointestinal (GI) tract and birth canal. Approximately 25% of women have asymptomatic GBS colonization during pregnancy. GBS is responsible for approximately 50,000 maternal infections per year in women, but only 0.36 neonates per 1000 live births are infected.
Women with heavy GBS colonization and chronically positive GBS culture results have the highest risk of perinatal transmission. Also, heavy colonization at 23-26 weeks’ gestation is associated with prematurity and low birth weight. Colonization at delivery is associated with neonatal infection.
Intrapartum chemoprophylaxis for women with positive GBS culture results has been shown to reduce transmission of the organism to the neonate during delivery. Mothers may have a negative prenatal culture for GBS but a positive one at the time of labor. [5]
Premature rupture of membranes
PROM may occur in response to an untreated urinary tract infection (UTI) or birth canal infection. Other risk factors are previous preterm delivery, uterine bleeding in pregnancy, and heavy cigarette smoking during pregnancy. Rupture of membranes without other complications for more than 24 hours before delivery is associated with a 1% increase in the incidence of neonatal sepsis; however, when chorioamnionitis accompanies the rupture of membranes, the incidence of neonatal infection increases four-fold.
A multicenter study demonstrated that clinical chorioamnionitis and maternal colonization with GBS are the most important predictors of subsequent neonatal infection after PROM. [31] Exposure to more than six vaginal digital examinations, which may be carried out as part of the evaluation for PROM, is associated with neonatal infection even when considered separately from the presence of chorioamnionitis. [31]
When membranes have ruptured prematurely before 37 weeks’ gestation, a longer latent period precedes vaginal delivery, increasing the likelihood that the infant will be infected. The duration of membrane rupture before delivery and the likelihood of neonatal infection are inversely related to gestational age. Thus, the more premature an infant is, the longer the delay between rupture of membranes and delivery, and the higher the likelihood of neonatal sepsis.
Prematurity
In addition to the relationship between preterm PROM and neonatal sepsis, there are other associations between prematurity and neonatal sepsis that increase the risk for premature infants.
Preterm infants are more likely to require invasive procedures, such as umbilical catheterization and intubation. Preterm delivery is associated with infection from cytomegalovirus (CMV), herpes simplex virus (HSV), hepatitis B virus (HBV), Toxoplasma,Mycobacterium tuberculosis, Campylobacter fetus, and Listeria species. Intrauterine growth retardation and low birth weight are also observed in CMV infection and toxoplasmosis.
Premature infants have less immunologic ability to resist and combat infection. Consequently, they are more susceptible to infection caused by common organisms such as coagulase-negative Staphylococcus, an organism usually not associated with severe sepsis.
Chorioamnionitis
The relationship between chorioamnionitis and other risk variables is strong. Suspect chorioamnionitis in the presence of fetal tachycardia, uterine tenderness, purulent amniotic fluid, an elevated maternal white blood cell (WBC) count, and an unexplained maternal temperature higher than 38°C (100.4°F).
The diagnosis of chorioamnionitis has been a trigger point for sepsis evaluation and initiation of empiric antibiotics based on guidelines from the Centers for Disease Control and Prevention (CDC), [25] American College of Obstetricians and Gynecologists (ACOG), [24, 32] and American Academy of Pediatrics (AAP). [22] This approach has been criticized based upon the low incidence of culture-positive early-onset sepsis and the growing evidence of deleterious effects from unnecessary antibiotic exposure. In 2015, a panel of experts recommended that the term “chorioamnionitis” be replaced with “intrauterine inflammation or infection or both” (triple I), emphasizing that isolated maternal fever does not automatically equate to chorioamnionitis. [33]
A newer approach to this issue has used a multivariate predictive model that takes into account maternal GBS status, appropriateness of intrapartum GBS coverage, gestational age, duration of rupture of membranes, highest intrapartum maternal temperature, along with the neonate’s examination following birth. This model, commonly referred to as the “Kaiser Sepsis Calculator” has allowed for a dramatic reduction in the use of empiric antibiotics (from 5.0% of all births before implementation to 2.8% of all births afterward) and obtaining blood cultures (12.8% of all births before implementation to < 5% of all births afterward), without an increase in the rate of morbidity or mortality or readmissions for early-onset sepsis. [34, 35]
Physical Examination
The clinical signs of neonatal sepsis are nonspecific and are associated with the characteristics of the causative organism and the body’s response to the invasion. These nonspecific clinical signs can also be associated with other neonatal diseases, such as respiratory distress syndrome (RDS), metabolic disorders, intracranial hemorrhage, and a traumatic delivery, making the diagnosis based on physical examination alone difficult.
To obtain the most information from the examination, systematic physical assessment of the infant is best performed in a series that should include observation, auscultation, and palpation, in that order. Changes in findings from one examination to the next provide important information about the presence and evolution of sepsis. [36]
Congenital pneumonia and intrauterine infection
Inflammatory lesions are observed postmortem in the lungs of infants with congenital and intrauterine pneumonia. These may result not from the action of the microorganisms themselves but, rather, from aspiration of amniotic fluid containing maternal leukocytes and cellular debris. Tachypnea, irregular respirations, retractions, apnea, cyanosis, and grunting may be observed.
Neonates with intrauterine pneumonia may be critically ill immediately upon birth and require high levels of ventilatory support. The chest radiograph may depict bilateral consolidation or pleural effusions.
Congenital pneumonia and intrapartum infection
Neonates who are infected during the birth process may acquire pneumonia through aspiration of microorganisms from the maternal genitourinary tract during delivery. Klebsiella species and S aureus are especially likely to generate severe lung damage, producing microabscesses and empyema. Early-onset group B streptococcal (GBS) pneumonia has a particularly fulminant course, with significant mortality in the first 48 hours of life.
Intrapartum aspiration may lead to infection with pulmonary changes, infiltration, and destruction of bronchopulmonary tissue. This damage is partly due to the release of prostaglandins and leukotrienes from granulocytes. Fibrinous exudation into the alveoli leads to inhibition of pulmonary surfactant function and respiratory failure, with a presentation similar to that of RDS. Vascular congestion, hemorrhage, and necrosis may occur. Infectious pneumonia is also characterized by pneumatoceles within the pulmonary tissue.
Coughing, grunting, retractions, nasal flaring, tachypnea or irregular respiration, rales, decreased breath sounds, and cyanosis may be observed. Infants who aspirate meconium, blood, or other proinflammatory material during labor may be symptomatic at birth, whereas infants primarily impacted by an infectious process may not show symptoms in the first hours after birth. Radiographic evaluation may demonstrate segmental or lobar atelectasis or a diffuse reticulogranular pattern, much like what is observed in RDS. Pleural effusions may be observed in advanced disease.
Postnatal infection
Postnatally acquired pneumonia may occur at any age. If the infant has remained hospitalized in a neonatal intensive care unit (NICU), especially with endotracheal intubation and mechanical ventilation, the organisms may include Staphylococcus, Pseudomonas species, Klebsiella, or others.
Additionally, these hospital-acquired organisms frequently demonstrate multiple antibiotic resistances. Therefore, the choice of antibiotic agents in such cases requires knowledge of the likely causative organisms and local antibiotic-resistance patterns.
Cardiac signs
In overwhelming sepsis, an initial early phase characterized by pulmonary hypertension, decreased cardiac output, and hypoxemia may occur. This phase is followed by further progressive decreases in cardiac output with bradycardia and systemic hypotension. The infant manifests overt shock with pallor, poor capillary perfusion, and edema. These late signs of shock are indicative of severe compromise and are strongly associated with mortality.
Metabolic signs
Hypoglycemia, hyperglycemia, metabolic acidosis, and jaundice are all metabolic signs that commonly accompany neonatal sepsis. The infant has an increased glucose requirement as a result of the septic state. Hypoglycemia accompanied by hypotension may be secondary to an inadequate response from the adrenal gland and may be associated with a low cortisol level.
Metabolic acidosis is due to a conversion to anaerobic metabolism, with the production of lactic acid. When infants are hypothermic or are not kept in a neutral thermal environment, efforts to regulate body temperature can cause metabolic acidosis. Jaundice occurs in response to decreased hepatic glucuronidation caused by both hepatic dysfunction and increased erythrocyte destruction.
Neurologic signs
Meningitis is the common manifestation of central nervous system (CNS) infection. Acute and chronic histologic features are associated with specific organisms.
Meningitis due to early-onset neonatal sepsis usually occurs within 24-48 hours and is dominated by nonneurologic signs. Neurologic signs may include stupor and irritability. Overt signs of meningitis occur in only 30% of cases. Even culture-proven meningitis may not demonstrate white blood cell (WBC) changes in the cerebrospinal fluid (CSF).
Meningitis due to late-onset disease is more likely to demonstrate neurologic signs (80%-90%); however, many of these physical examination findings are subtle or inapparent. Neurologic signs may include the following:
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Impairment of consciousness (ie, stupor with or without irritability)
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Coma
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Seizures
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Bulging anterior fontanelle
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Extensor rigidity
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Focal cerebral signs
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Cranial nerve signs
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Nuchal rigidity
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Central apnea or periodic breathing
Temperature instability is observed with neonatal sepsis and meningitis, either in response to pyrogens secreted by the bacterial organisms or from sympathetic nervous system instability. The neonate is most likely to be hypothermic. The infant may also have decreased tone, lethargy, and poor feeding. Signs of neurologic hyperactivity are more likely when late-onset meningitis occurs.
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Neonatal sepsis. Incidence of early-onset and late-onset invasive group B Streptococcus (GBS) disease. Graph from Verani JR, McGee L, Schrag SJ, for the 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 Nov 19. 59 (RR-10):1-36. Online at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm.
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Neonatal sepsis. Indications and nonindications for intrapartum antibiotic prophylaxis to prevent early-onset group B streptococcal (GBS) disease. Table from Verani JR, McGee L, Schrag SJ, for the 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 Nov 19. 59 (RR-10):1-36. Online at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm.
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Neonatal sepsis. Recommended regimens for intrapartum antibiotic prophylaxis for prevention of early-onset group B streptococcal (GBS) disease. Diagram from Verani JR, McGee L, Schrag SJ, for the 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 Nov 19. 59 (RR-10):1-36. Online at: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm.
