Sepsis Neonatorum
INTRODUCTION
Neonatal sepsis or sepsis neonatorum is an important cause of morbidity and mortality among newborns 28 days of life or younger. It presents with the systemic signs of infection or isolation of a bacterial pathogen from the bloodstream.1 According to the infant’s age at the onset of symptoms, sepsis is classified as early or late.
Early-onset sepsis (EOS), discussed in this chapter, has the onset of symptoms within the first days of the newborn’s life. Perinatally acquired bacterial neonatal sepsis is a low-incidence, high-risk disease that can be defined as a bloodstream infection at 72 hours of age or less2 or, in the case of early-onset group B streptococcal (GBS) disease, as infection with the onset of symptoms through day 6 of life.3 Presentation of EOS is within 24 hours of life in 85%, in 24–48 hours in 5%, and within 48–72 hours in the rest of the neonates. Infections present earlier in preterm neonates.
EPIDEMIOLOGY
Neonatal sepsis incidence is 1–5 cases/1000 live births. In term neonates, incidence is lower than in preterm, with 1–2 cases/1000 live births.4
Risk factors for neonatal sepsis include chorioamnionitis, intrapartum maternal fever (temperature ≥ 38°C [100.4°F]); rupture of membranes for 18 hours or longer5; delivery at less than 37 weeks’ gestation; 5-minute Apgar score 6 or less; maternal GBS colonization; maternal GBS or gram-negative bacteriuria during the current pregnancy; and prior delivery of neonate with GBS disease. Additional risk factors are the use of instrumentation, such as forceps, or placement of electrodes for intrauterine monitoring during labor and delivery.6 Black race is a risk factor for both early- and late-onset GBS sepsis, and the reasons behind this are not fully understood.7
PATHOPHYSIOLOGY
Sepsis is a clinical syndrome that complicates severe infection, characterized by systemic inflammation and widespread tissue injury. Tissues remote from the original insult display the signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation. “Dysregulation” of the normal inflammatory response, with a massive and uncontrolled release of proinflammatory mediators, initiates a chain of events leading to widespread tissue injury. This host response, not the primary disease, is typically responsible for multiple-organ failure.
In an EOS, the most common route of transmission is vertical transmission by ascending contaminated amniotic fluid or bacteria colonizing or infecting the mother’s lower genitourinary tract.8
Clinical picture and outcome of neonatal sepsis depend on time of onset, maturity of the host defense mechanisms, associated complications, timing of initiation of appropriate antibiotics, and supportive therapy.
Factors contributing to neonatal susceptibility to bacterial infections are the following:
• Anatomic and biochemical immaturity of skin and mucosal barriers (eg, lung, gut epithelia),
• Reduced numbers or function of macrophages and dendritic cells in peripheral tissues (eg, lung),
• Lower numbers of neutrophils in the bone marrow,
• Decreased immunoglobulin (Ig) G and complement levels, especially in premature infants, and
• Inability to respond to bacterial carbohydrate antigens.
During microbial invasion, the immune system produces cytokine to protect the host, but overproduction may have deleterious effects, resulting in multiple-organ injury. Cytokines, phospholipid-derived mediators, and coagulation factors produce widespread vascular endothelial injury, with increased vascular permeability, thrombosis, disseminated intravascular coagulopathy (DIC), and hypotension. Vascular endothelium is a target of tissue injury, where loss of tight junctions allows capillary leakage. In the case of gram-negative sepsis, endotoxins cause global depression of mitochondrial function, as well as damage to endothelium.
The following are the major lung lesions associated with sepsis:
• Pulmonary hypertension (early and late onset)
• Pulmonary parenchymal disease secondary to vascular injury
Pulmonary capillary endothelial cells are damaged by leukocyte-induced pulmonary microvascular injury. Increasing alveolar capillary permeability results in transudation of proteins, infiltration of inflammatory cells, and increased lung water, leading to parenchymal injury. The clinical picture is characterized with decreased pulmonary compliance and pulmonary edema, systemic hypoxemia, and tissue oxygen deprivation.
Increased mean airway pressure, required for maintaining ventilation in wet and noncompliant lungs, increases resistance to venous return and reduces cardiac output. In addition, pulmonary hypertension may impair right ventricular output, resulting in a negative impact on left ventricular output, causing reduction of overall cardiac output, potentially leading to heart and renal failures.
Clinical Presentation
The septic neonate can have a dramatic clinical presentation characterized by respiratory failure, persistent pulmonary hypertension of the newborn, DIC, hypotension, or multiorgan failure. However, signs and symptoms may be subtle and nonspecific, and considering severity of potential consequences, a high index of suspicion should be used in evaluation of neonates for potential sepsis.
Presentation may start as early as labor and delivery; the signs and symptoms may be intrapartum fetal tachycardia, meconium-staining of amniotic fluid (2-fold increase in sepsis if the mother did not receive intrapartum antibiotics9), and low Apgar scores (neonates with an Apgar score ≤ 6 or less at 5 minutes had a 36-fold higher likelihood10 of sepsis than those with Apgar scores ≥ 7).
After delivery, clinical signs of sepsis can be nonspecific and subtle. They include:
• Temperature instability (fever or hypothermia, with fever more common in term and hypothermia in preterm neonates11),
• Apnea, tachypnea, respiratory distress (flaring, grunting, retractions or decreased breath sounds), pulmonary hemorrhage,
• Tachycardia or bradycardia, hypotension, prolonged capillary refill time, cool and clammy skin,
• Lethargy or irritability, hypotonia, weak cry, poor suck, seizures,
• Cyanosis, pallor, jaundice, mottled appearance, petechiae, purpura,
• Abdominal distension, feeding intolerance, emesis, diarrhea, bloody stools, hepatomegaly, and
• Oliguria.
Etiology
The most common causes of early-onset sepsis are Group B Streptococcus (GBS) and Escherichia coli (E. coli). In the National Institute of Child Health and Human Development (NICHD) Neonatal Network study of 396,586 neonates, those affected with GBS sepsis were mostly term (73%) infants and with E. coli sepsis mostly preterm (81%).8 In this study, overall mortality was 16% of all infected infants, and it was the most frequent with E. coli sepsis (33%). Other, less-frequent, causes of EOS are Listeria monocytogenes, usually seen during listeriosis outbreaks,12 and Staphylococcus aureus. A culture-independent, molecular-based study detected previously unrecognized, uncultivated, or difficult-to-cultivate species as causes of EOS.13
Prevention
Currently, the most important intervention in prevention of neonatal sepsis is the use of intrapartum antibiotic prophylaxis (IAP) in mothers with documented GBS colonization, GBS bacteriuria during the current pregnancy, or a previous birth of an infant with GBS disease. The 2010 revised GBS prevention guidelines of the Centers for Disease Control and Prevention (CDC) recommended chemoprophylaxis for women with risk factors at delivery who have unknown GBS colonization status at the time of labor onset, even with negative intrapartum screening cultures.14 The use of IAP decreased the incidence of early-onset GBS by 80%, and it appeared to reduce the risk of early-onset E. coli infection in term infants as well.15–19 However, if the mother received intrapartum antibiotics, it does not mean that the neonate cannot become infected and septic, as the 2011 NICHD study showed that in 53% of infants with EOS, mothers received intrapartum antibiotics within 72 hours prior to delivery (38% of infants with GBS, 79% with E. coli sepsis). Other interventions include prevention of preterm births, as well as early detection and treatment of urinary tract infection in mothers.
DIFFERENTIAL DIAGNOSIS
History, physical examination, laboratory evaluation, clinical course, microorganism cultures, or serology can distinguish bacterial neonatal sepsis from other diagnoses with similar clinical presentation.
Differential diagnosis includes:
1. Infections caused by organisms other then bacteria:
• Viral infections: herpes simplex virus (HSV), cytomegalovirus (CMV), enteroviruses, and others,
• Fungal infection: candidiasis, particularly in preterm neonates,
• Parasitic infections: congenital toxoplasmosis,
• Spirochetal infections: syphilis,
• Nonbloodstream bacterial infections, including osteomyelitis, congenital pneumonia, septic arthritis, myositis, pericarditis, and urinary tract infection (frequently associated with congenital genitourinary tract malformation)
2. Neonatal asphyxia
3. Inborn errors of metabolism
4. Congenital heart disease, such as transposition of great vessels (TGV), total anomalous pulmonary venous return (TAPVR), pulmonary atresia (PA), hypoplastic left heart syndrome (HLHS), etc.
5. Neonatal respiratory distress: respiratory distress syndrome (RDS), especially in infants of diabetic mothers; transient tachypnea of the newborn (TTN); idiopathic persistent pulmonary hypertension of the newborn (PPHN); meconium aspiration syndrome (MAS); congenital diaphragmatic hernia (CDH); pulmonary hypoplasia; etc.
6. Necrotizing enterocolitis (NEC), malrotation with volvulus, bowel obstruction
7. Hemolytic disease of newborn
EVALUATION AND DIAGNOSTIC TESTS
The evaluation of the neonate includes a review of the pregnancy course, labor and delivery, maternal laboratory values, the use and timing of maternal IAP, determination of the risk factors for sepsis,20 and a detailed physical examination. This includes overtly symptomatic septic infants who are admitted after delivery directly to the neonatal intensive care unit (NICU) because of the severity of their presentation, neonates with subtle signs and symptoms suggestive of infection, as well as initially well-appearing infants with identifiable risk factors. In a 2012 clinical report, the American Academy of Pediatrics (AAP) Committee on the Fetus and Newborn proposed a management approach for infants with suspected or proven EOS.21
The “gold standard” for diagnosis of neonatal sepsis is still a positive blood culture growing a pathogen. Currently, it may still take 24 hours or more for conventional culture to provide a result, and as many as 10% of neonates with sepsis can have false-negative cultures (for various reasons, the most frequent is an inadequate specimen). Therefore, a careful history and physical examination and use of clinical judgment in conjunction with currently available laboratory tests can identify neonates with likely sepsis for which empiric antibiotic treatment and close monitoring should be started in a timely fashion while waiting for the results of blood culture.
The criteria used in evaluation for sepsis should be broad, ensuring that all infected infants are identified and treated; however, a significant number of uninfected infants will end up being tested and treated.22 Therefore, vigilance should be used by close follow-up of bacterial cultures and timely discontinuation of the antibiotics to avoid using antibiotics in well-appearing infants for extended periods of time.
Laboratory Evaluation
The laboratory evaluation includes bacterial cultures and polymerase chain reaction (PCR) tests of body fluids to determine the presence or absence of a pathogen, as well as other studies used to evaluate the likelihood of infection.
Blood Culture
The sensitivity of a blood culture is approximately 90%; the recommended volume obtained is a minimum of 1 mL. At least 1 culture should be obtained prior to initiating empirical antibiotic therapy. In a symptomatic infant who has a negative blood culture, however, if the clinical course and other tests are strongly suggestive of sepsis, a diagnosis of clinical sepsis can be made and the patient treated with a complete course of antibiotic therapy. With automated systems for continuous monitoring of blood cultures in most cases of neonatal sepsis, a blood culture will become positive within 24 to 36 hours.23 In a study by Garcia-Prats et al, 97% and 99% of cultures were positive by 24 and 36 hours, respectively, if common bacterial pathogens were detected.24
Cerebrospinal Fluid Analysis and Culture
As clinical signs of meningitis and a positive blood culture can be absent in a neonate with meningitis,25–27
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