Etiology and Pathogenesis

Overall, the incidence of neonatal sepsis is 3 to 4 per 1000 births; it accounts for 25 of 1000 preterm live births. The overall mortality rate is approximately 25%. To aid in identification of likely pathogens, neonatal sepsis is divided into two classifications, early- and late-onset sepsis.

Early-onset sepsis represents infection acquired from the maternal genital tract, whether via ascension into the uterus following rupture of membranes or during passage through the vaginal canal during the birth process. As such, it generally presents within the first five to seven days of life with a sudden onset and fulminant course. Ports of entry include the conjunctivae, respiratory tract, umbilicus, skin, and oropharynx. Implicated organisms include group B β-hemolytic streptococci (GBS), Escherichia coli, and less commonly other gram-negative enteric organisms and Listeria monocytogenes.

GBS infections account for a large number of cases of early-onset sepsis and have been a focus of Centers for Disease Control and Prevention guidelines because of significant mortality. GBS colonizes the genital tract of 30% of women, and all pregnant women are screened for vaginal and rectal colonization at 35 to 37 weeks of gestation. Colonized women are treated with intrapartum penicillin chemoprophylaxis when delivering vaginally; since the institution of these guidelines, mortality from GBS disease has declined by 80%.

Late-onset sepsis may represent organisms acquired from the maternal genital tract but more often are transmitted horizontally by caregivers. Late-onset disease is more common after the first week of life and is more likely to present with urinary tract infection or meningitis caused by hematogenous seeding of end organs. The most common organisms are gram-positive organisms, such as Staphylococcus aureus and GBS, in addition to E. coli and other gram negative organisms. In the community, viral infection should also be included in the differential diagnosis. For hospitalized infants, the most common pathogen is Staphylococcus epidermidis; other organisms to consider include Pseudomonas aeruginosa, Candida spp., anaerobes, and methicillin-resistant S. aureus.

Clinical Presentation

Neonatal sepsis may present as a constellation of nonspecific symptoms including one or more of the following: progressive lethargy or irritability, apnea, temperature instability, poor feeding, changes in tone, abdominal distension, vomiting or loose stools, or decreased urine output. Fever in a neonate is defined as a temperature of 38.0°C or greater. Clinicians should have a very high index of suspicion for sepsis in an ill-appearing or febrile infant.

Evaluation and Management

A thorough birth history should be obtained including the following: gestational age (prematurity is the most significant risk factor in the evaluation of neonatal sepsis); duration of rupture of membranes; presence of meconium stained amniotic fluid; indicators of chorioamnionitis, including maternal fever in the peripartum period, fundal tenderness, and foul-smelling amniotic fluid; and invasive procedures such as fetal scalp electrodes. For reasons that are unclear, male infants are four times as likely as female infants to develop early-onset sepsis. The antepartum history is equally as important and should include maternal infections or exposures during pregnancy, the duration of prenatal care, and results of prenatal testing if available. The U.S. Preventative Services Task Force recommends routine screening of mothers for the following: syphilis (rapid plasma reagin [RPR]), hepatitis B (hepatitis B surface antigen [HBsAg]), rubella (titers), HIV, gonorrhea, chlamydia, and GBS.

A thorough physical examination should be performed with special attention to the following findings: growth parameters including head circumference, overall appearance of the infant, presence of a bulging fontanel, eye discharge and ophthalmologic examination, nasal discharge, hydration status, respiratory symptoms, perfusion and cardiac examination, abdominal distension, organomegaly, erythema or drainage from the umbilicus, skin lesions including petechiae and vesicles, jaundice, and the overall neurologic examination, including tone.

Newborns with historical factors putting them at significant risk for early-onset sepsis should receive serial screening complete blood counts (CBCs) and C-reactive protein levels in the newborn nursery, regardless of their clinical appearance. For infants who are septic appearing in the first days of life, a complete evaluation, including blood culture and lumbar puncture with cerebrospinal fluid (CSF) culture, should be obtained and the infant initiated on appropriate antibiotic coverage until culture results are negative for at least 48 hours. GBS and Listeria coverage with a β-lactam and gram-negative coverage with an aminoglycoside (usually ampicillin and gentamicin) is recommended. Antibiotic therapy may be tailored to cover organisms common to a particular nursery, as indicated.

Infants who present after 5 to 7 days of life with any of the symptoms detailed above should be evaluated for late-onset sepsis. Blood, urine, and CSF studies, including cultures before the initiation of antibiotics, should be obtained. Exact laboratory criteria for the diagnosis of late-onset sepsis is somewhat controversial; however, an elevated white blood cell count on an enhanced urinalysis specimen, CSF specimen, or peripheral blood sample is concerning for serious bacterial infection. As in early-onset sepsis, infants should be started on appropriate antibiotics until all culture results are negative. Because meningitis features more prominently in late-onset sepsis, a third-generation cephalosporin (usually cefotaxime) may be substituted for gentamicin if concern for meningitis is high based on clinical examination or lumbar puncture results.

Etiology and Pathogenesis

The TORCH (toxoplasmosis or Toxoplasma gondii, other infections, rubella, cytomegalovirus [CMV], and herpes simplex virus [HSV]) infections are congenital infections that are transmitted transplacentally from mother to fetus. As a rule, the likelihood of transmission to a fetus is greatest when primary maternal infection occurs. Gestational age at the time of exposure determines the severity of the disease. Neonates who appear most severely infected at birth have most likely been infected during the first trimester; exposure during the first few weeks of gestation may also result in intrauterine demise. TORCH is an acronym that represents the most common pathogens responsible for transplacentally transmitted infections. Historically, these include toxoplasmosis or T. gondii, other infections, rubella, CMV, and HSV.

Clinical Presentation

TORCH infections are often part of a large differential diagnosis and share many overlapping features. These infections may result in dysmorphic facies, developmental delay, or symmetric intrauterine growth retardation. Other signs and symptoms common to vertically transmitted infections are hepatosplenomegaly, micro- or macrocephaly, and abnormal tone.

Toxoplasmosis generally presents within the second or third decade of life with visual and learning difficulties. Eighty-five percent of affected infants appear normal at birth. The most severe form is noted in the first month of life with intrauterine growth restriction, hepatosplenomegaly, micro- or macrocephaly, abnormal tone, or seizures. The classic triad of chorioretinitis, intracranial calcifications, and hydrocephalus presents in fewer than 10% of infants.

Congenital syphilis is similar to the acquired form of syphilis in that it presents with early and late manifestations. Most cases are detected by routine maternal screening. Early syphilis presents within the first 2 years of life, with one-third of patients symptomatic at birth. Symptoms can affect almost any organ system and include the following: hepatosplenomegaly, jaundice, Coombs’-negative hemolytic anemia, thrombocytopenia, rhinitis (snuffles), condylomatous skin or mucous membrane lesions, diffuse mucocutaneous rash involving the palms and soles, osteochondritis presenting as pain and refusal to move the affected limb (pseudoparalysis of Parrot), periosteitis, chorioretinitis, failure to thrive, or renal disease (Figure 105-1). Late manifestations are not detailed here but result from chronic tissue inflammation, most commonly involving the central nervous system (CNS), bones, and teeth, and present within the first 2 decades of life.

Figure 105-1 Manifestations of congenital syphilis.

With an incubation of 2 to 6 months, hepatitis B is an unlikely cause of neonatal cholestasis and can remain asymptomatic for years. After 2 months of age, hepatitis B presents with self-limited hepatitis, fulminant hepatitis, or insidious onset of cirrhosis and progression to liver failure.

HIV screening is recommended for all pregnant women because of advances in antiretroviral prophylaxis. The median age of onset in infants who acquire the virus perinatally is 12 to 18 months if left untreated, and it carries a 20% mortality rate in the first 4 years of life. Briefly, the clinical presentation can vary from mild systemic symptoms with recurrent fever or failure to thrive, recurrent mild infections, to serious bacterial infections and AIDS-defining illnesses.

Congenital rubella presents with many of the common symptoms of TORCH infections. Unique features include patent ductus arteriosus and extramedullary hematopoiesis, resulting in the characteristic rash known as “blueberry muffin baby.”

Cytomegalic inclusion disease is apparent at birth and is the most severe form of CMV disease, representing 10% of all cases. Other features of TORCH infections are also present, including intrauterine growth restriction, hepatosplenomegaly, thrombocytopenia, and dermal erythropoiesis. CNS manifestations include ventriculomegaly, microcephaly, chorioretinitis, and sensorineural hearing loss.

Infection with HSV acquired in the perinatal period presents within the first 4 weeks of life with one of three presentations. Approximately 45% of patients present with skin, eye, and mouth disease; other presentations include CNS involvement only (seizures, hypotonia) and disseminated disease (CNS, liver, adrenal, and pulmonary disease). Congenital HSV represents intrauterine infection and presents at birth with microcephaly, vesicular lesions, and micro-ophthalmia.

Evaluation and Management

Toxoplasmosis

If in utero infection is suspected based on prenatal ultrasonographic findings, amniotic fluid can be sent for Toxoplasmosis polymerase chain reaction (PCR). Postnatally, the recommended workup includes ophthalmologic, neurologic, and audiologic evaluations, as well as CSF PCR testing for Toxoplasma and head computed tomography (CT). For infected newborns, treatment with pyrimethamine, sulfadiazine, and leucovorin is the most widely accepted regimen and results in improved ocular outcomes. All pregnant women should be counseled to avoid changing cats’ litter boxes and to wear gloves when in contact with soil (Figure 105-2).

Figure 105-2 Life cycle of Toxoplasma gondii.

Etiology and Pathogenesis

Neisseria gonorrhoeae is a gram-negative diplococcus that resides intracellularly. The gonococcus is transmitted when the neonate passes through the vaginal canal. Chlamydia trachomatis is an obligate intracellular bacteria with 18 serologic variants. Neonatal acquisition from the vaginal canal is approximately 50%, and the nasopharynx is the most commonly primarily infected site.

Clinical Presentation

Gonococcal infection generally presents as purulent unilateral or bilateral eye discharge and conjunctival erythema, termed ophthalmia neonatorum (Figure 105-3). Scalp abscess after fetal monitoring has also been noted. Less commonly, meningitis or disseminated disease can present and should be included in the differential diagnosis of a septic-appearing infant. Similarly, chlamydial disease presents as purulent eye discharge and may form a membrane on the conjunctivae. Neonatal pneumonia is another classic presentation of neonatal chlamydial infection, presenting with staccato cough, tachypnea, and occasionally nasal congestion within the first 2 to 3 months of life.

Figure 105-3 Gonococcal ophthalmia.

Etiology and Management

Future Directions

The laboratory criteria for diagnosis, hospital admission, and antibiotic administration in the setting of suspected neonatal sepsis continue to undergo rigorous evaluation, as are new laboratory markers for sepsis. Clinicians should maintain a high suspicion in all infants presenting with parental concerns as above because neonatal sepsis can have devastating consequences.