Infants can acquire infection prenatally through transplacental transfer, perinatally during birth, or postnatally. Newborn infants are relatively immunocompromised and at high risk of developing infections. The immune system of the newborn is immature and their skin, an important barrier to infection, is not fully developed. Infants admitted to the NICU often require invasive methods of support (eg, central venous lines or endotracheal tubes), which can serve as routes for infection. Infections result in significant mortality and both short- and long-term morbidities among survivors. In this chapter, we will discuss infections occurring in the newborn period, how these infections are treated, and long-term complications in survivors.

1. 
   

   Cytomegalovirus infection

   
   
   
   
   1. 
      

      Incidence

      
      
      
      
      1. 
         

         Cytomegalovirus (CMV), the most common congenital viral infection, affects 0.4% to 2.3% of all live births.

         
         
      2. 
         

         CMV infections occur during all seasons and the incidence is inversely proportional to socioeconomic status.

      
      
   2. 
      

      Pathophysiology (mode of transmission)

      
      
      
      
      1. 
         

         Transmission can occur through contact with infected body fluids including blood, amniotic fluid, saliva, human milk, and urine.

         
         
      2. 
         

         Infants can become infected prenatally, during delivery, or postnatally.

         
         
      3. 
         

         Fetal transmission occurs during maternal primary infection, reactivation, or reinfection with another strain, though fetal transmission is most likely during maternal primary infection.

         
         
      4. 
         

         15% to 59% of preterm infants exposed to CMV positive maternal breast milk develop CMV infection.

         
         
      5. 
         

         Freezing breast milk reduces the rate of CMV transmission, but does not eliminate it.

         
         
      6. 
         

         Blood products that are leukoreduced reduce the chance of CMV transmission, but do not eliminate it.

      
      
   3. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         Ninety percent of prenatally infected term infants are asymptomatic at birth.

         
         
      2. 
         

         Symptomatic infants can present with intrauterine growth restriction, microcephaly, hepatosplenomegaly, blueberry muffin rash, and intracranial calcifications (Table 35-1).

         
         
      3. 
         

         Few term infants develop symptomatic infection postnatally because of transplacentally acquired antibody.

         
         
      4. 
         

         15% to 25% of infants exposed to CMV via breast milk will develop a sepsis-like condition.

         
         
      5. 
         

         CMV infection is the most common cause of acquired sensorineural hearing loss in infants.

         
         
         
         
         • 
           

           Five percent of infants born with congenital CMV have hearing loss at birth, and 15% will have hearing loss by 72 months of age.

           
           
         • 
           

           Infants with symptomatic infection at birth are more likely to have hearing loss.

         
         
      6. 
         

         Seventy percent of symptomatic infants develop mental retardation, making CMV one of the most common infectious causes of mental retardation (Table 35-2).

      
      
   4. 
      

      Diagnosis

      
      
      
      
      1. 
         

         Start with urine or saliva CMV shell-vial culture.

         
         
      2. 
         

         If urine CMV is negative, and clinical presentation is suspicious, the uroepithelium may not have yet been seeded. Send blood CMV PCR or repeat urine CMV culture.

         
         
      3. 
         

         If infant CMV urine/saliva culture is positive and congenital CMV transmission is suspected, the following testing should be completed.

         
         
         
         
         • 
           

           Blood CMV quantitative PCR

           
           
         • 
           

           CBC with differential, LFTs

           
           
         • 
           

           Eye examination

           
           
         • 
           

           Hearing evaluation

           
           
         • 
           

           Head ultrasound and if indicated, brain MRI

           
           
         • 
           

           If CNS involvement is suspected, LP for cell counts, protein, glucose, and CMV PCR

      
      
   5. 
      

      Management

      
      
      
      
      1. 
         

         If CNS involvement is proven or suspected (hearing loss, retinal findings), at least 6 weeks of antiviral treatment is indicated.

         
         
      2. 
         

         If pneumonitis/colitis is severe and lasting, treatment could be considered.

         
         
      3. 
         

         If no evidence of CNS involvement, yet other signs of CMV infection are present, such as hematologic abnormalities, hepatitis, colitis, and/or pneumonitis, antiviral treatment effect on outcome is unknown.

         
         
      4. 
         

         If signs or symptoms of postnatal CMV infection are mild and self-resolve, treatment may not be indicated, yet the infant needs to be followed to monitor for hearing loss, BPD, or other developmental problems.

         
         
      5. 
         

         Referral to pediatric infectious disease clinic upon discharge for follow-up.

         
         
      6. 
         

         Ganciclovir/valganciclovir

         
         
         
         
         • 
           

           Oral valganciclovir serum levels in term neonates are similar to that of IV ganciclovir—therefore, oral valganciclovir could be substituted for IV ganciclovir during the course or for the entire course.

           
           
         • 
           

           Dose of Valganciclovir is 15 to 20 mg/kg PO every 12 hours, and should be weight adjusted monthly.

           
           
         • 
           

           Adherence is important to preventing resistance.

           
           
         • 
           

           VGC/GC treatment requires CBC with differential monitoring due to risk of neutropenia and CMV quantitative PCR monitoring to screen for resistance (weekly to monthly).

           
           
         • 
           

           Monthly follow-up while on medication (Table 35-3).

   
   
2. 
   

   Herpes simplex virus

   
   
   
   
   1. 
      

      Incidence: Neonatal herpes simplex virus (HSV) infections occur in one out of every 3000 to 20,000 births.

      
      
   2. 
      

      Pathophysiology (mode of transmission)

      
      
      
      
      1. 
         

         HSV is acquired most frequently during birth, but can be acquired prenatally through ascending infection.

         
         
      2. 
         

         HSV type 2 causes the majority of infections in the newborn period.

         
         
      3. 
         

         The risk of HSV transmission for an infant born vaginally to a mother with a primary genital infection is between 35% and 50%.

         
         
      4. 
         

         Mothers with a history of HSV can intermittently shed virus; however, the chance of transmitting disease to the infant is <5%.

         
         
      5. 
         

         Rates of transmission can be reduced by cesarean delivery.

      
      
   3. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         Neonatal HSV can present in one of three ways (disseminated, central nervous system [CNS], and skin, eye, and mouth [SEM] disease), though there is often overlap (Table 35-1).

         
         
      2. 
         

         Disseminated disease typically presents with the symptoms of sepsis and should be considered if there is no clinical improvement in an infant on antibiotics with negative cultures. Liver function tests are commonly elevated. Skin lesions may appear, but this often occurs late in the course. CNS disease should be considered in the presence of irritability, lethargy, seizures, or abnormal cerebrospinal fluid (CSF) parameters.

         
         
      3. 
         

         SEM disease usually presents with herpetic lesions of the skin and mucous membranes. If left untreated, SEM may progress to disseminated disease.

         
         
      4. 
         

         Even with appropriate antiviral treatment, the mortality of disseminated (53%) and CNS (13%) disease is high.

         
         
      5. 
         

         HSV has serious implications for the neurodevelopmental outcomes of surviving infants (Table 35-2). 29% of those with CNS disease and 78% with disseminated disease had a normal neurological outcome at 12 months of age, with similar neurodevelopmental outcomes at 2 years of age. Developmental delays are seen in both cognitive and motor domains.

         
         
      6. 
         

         If treated properly with acyclovir, infants with SEM disease have <2% chance of developing neurodevelopmental delay, though the risk of a poor outcome increases if multiple recurrences of herpetic lesions occur before 6 months of age.

      
      
   4. 
      

      Diagnosis

      
      
      
      
      1. 
         

         Viral cultures isolating HSV is the gold standard diagnostic method. Skin and mucous membrane surfaces are scraped and plated on the appropriate medium for cell culture.

         
         
      2. 
         

         Lumbar puncture should be performed on all suspected infants. Cell count may show increased WBC, RBC, and elevated protein. PCR should be performed on CSF.

      
      
   5. 
      

      Management

      
      
      
      
      1. 
         

         All infants with neonatal HSV require antiviral treatment.

         
         
      2. 
         

         The current recommended medication is intravenous acyclovir. Infants with SEM disease should be treated for 14 days. Disseminated or CNS disease should be treated for 21 days or until CSF parameters normalize.

         
         
      3. 
         

         There is evidence for improved neurologic outcomes in infants with disseminated or CNS disease who receives oral acyclovir for 6 months or longer after the initial course of intravenous acyclovir is completed.

   
   
3. 
   

   Toxoplasmosis

   
   
   
   
   1. 
      

      Incidence: Toxoplasma gondii causes infection in 400 to 4000 live births in the United States every year, making it the most common congenital parasitic infection.

      
      
   2. 
      

      Pathophysiology (mode of transmission)

      
      
      
      
      1. 
         

         Infection can occur after ingesting oocysts found in the feces of 12% of cats. The oocysts may also be present in undercooked meat.

         
         
      2. 
         

         Pregnant women should cook all meat appropriately, avoid cat litter, wash all fruits and vegetables well, and wear gloves during gardening in order to prevent infections.

         
         
      3. 
         

         While most infected women are asymptomatic, the infection can still be transmitted to the fetus.

         
         
      4. 
         

         Risk of transmission is only 2% to 5% in early pregnancy but rises to 60% to 80% in late pregnancy.

         
         
      5. 
         

         The risk of serious infection in the fetus is highest with infections occurring in the first trimester.

      
      
   3. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         Seventy to ninety percent of infants with congenital Toxoplasmosis are asymptomatic at birth.

         
         
      2. 
         

         While term infants generally have mild symptoms including lymphadenopathy, jaundice, maculopapular rash, and hepatosplenomegaly, symptomatic preterm infants are more likely to develop severe disease including CNS and ocular manifestations (Table 35-1).

         
         
      3. 
         

         Long-term follow-up is important in cases of congenital Toxoplasmosis as sequelae can appear months to years after birth (Table 35-2).

         
         
      4. 
         

         Ocular disease is a common outcome of congenital toxoplasmosis.

         
         
      5. 
         

         Infants with congenital toxoplasmosis are also at risk for learning disabilities or mental retardation.

      
      
   4. 
      

      Diagnosis

      
      
      
      
      1. 
         

         Serologic testing with toxoplasma-specific IgG and IgM can be performed. Positive IgM suggests an acute infection and necessitates confirmation through a reference laboratory.

         
         
      2. 
         

         Lumbar puncture should be performed in suspected infants, showing xanthochromia, mononuclear pleocytosis, and high protein level on cell count. CSF PCR should be sent.

         
         
      3. 
         

         Head CT may reveal characteristic, diffuse intracranial calcifications.

         
         
      4. 
         

         Ophthalmologic examination shows choreoretinitis.

      
      
   5. 
      

      Management

      
      
      
      
      1. 
         

         A combination of pyrimethamine and sulfadiazine with leucovorin for up to 1 year is the treatment of choice.

         
         
      2. 
         

         Studies show infants treated with this regimen for 1 year had improved neurologic outcomes, with decreased occurrence of new eye lesions and less hearing loss compared to infants who were untreated or treated for only 1 month.

   
   
4. 
   

   Rubella

   
   
   
   
   1. 
      

      Incidence

      
      
      
      
      1. 
         

         Rubella is an enveloped RNA virus and is rarely seen in the United States because of high vaccination rates, but remains prevalent in other parts of the world. A vaccine became available in the late 1960s, leading to a 99% decrease of the disease in the United States.

         
         
      2. 
         

         In 2004, the incidence of congenital rubella was 0.005/100,000 in the United States.

      
      
   2. 
      

      Pathophysiology (mode of transmission)

      
      
      
      
      1. 
         

         Mothers who become infected while pregnant risk transmitting the infection to their fetus.

         
         
      2. 
         

         Those who become infected in the first 12 weeks of pregnancy have the highest transmission rates and the highest risk for severe disease in the infant.

      
      
   3. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         There is a clinical presentation of congenital rubella that ranges from asymptomatic to severe (Table 35-1).

         
         
      2. 
         

         Common findings include ophthalmologic, auditory, cardiac, and neurologic manifestations.

         
         
      3. 
         

         Infants may present with growth restriction, hepatosplenomegaly, bone lucencies on x-ray, pneumonitis, thrombocytopenia, and/or a blueberry muffin rash.

         
         
      4. 
         

         Infants with congenital rubella are at risk for many serious long-term outcomes (Table 35-2).

         
         
      5. 
         

         They may suffer from cataracts, retinopathy, or glaucoma and require close ophthalmology follow-up.

         
         
      6. 
         

         Audiology follow-up is also required due to the possibility of sensorineural hearing loss. Affected infants may present with meningoencephalitis, and even in the absence of neurologic disease at birth, can develop learning difficulties or mental retardation later in childhood.

      
      
   4. 
      

      Diagnosis

      
      
      
      
      1. 
         

         Serologic testing for congenital rubella syndrome is diagnostic when rubella-specific IgM is detected in serum or oral fluid prior to 3 months of age.

         
         
      2. 
         

         CSF may reveal encephalitis with an increase in WBCs and protein.

      
      
   5. 
      

      Management

      
      
      
      
      1. 
         

         There is no current treatment for congenital rubella.

         
         
      2. 
         

         Infants should have ophthalmology and audiology, as well as regular assessments of neurodevelopment.

   
   
5. 
   

   Syphilis

   
   
   
   
   1. 
      

      Incidence: Syphilis is caused by the spirochete Treponema pallidum. In the United States, the incidence of congenital syphilis decreased to 8.2 cases per 100,000 live births in 2005 but subsequently increased to 10.1 cases per 100,000 live births in 2008.

      
      
   2. 
      

      Pathophysiology (mode of transmission)

      
      
      
      
      1. 
         

         Infection may occur transplacentally as early as week 9 or through contact with infected lesions at birth.

         
         
      2. 
         

         Syphilis has four stages: primary, secondary, latent, and tertiary, and transmission is most likely during the first two stages. Rate of transmission from mother to fetus is 80%.

      
      
   3. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         Syphilis causes spontaneous abortion, stillbirth, or perinatal death in 40% of cases.

         
         
      2. 
         

         Infants can develop early signs (first 2 years of life) or late signs (after 2 years of age).

         
         
      3. 
         

         Early clinical manifestations include hepatosplenomegaly, skin lesions, lymphadenopathy, hemolytic anemia, thrombocytopenia, snuffles, osteochondritis, edema, or rash (Table 35-1).Some infants present with a sepsis-like syndrome.

         
         
      4. 
         

         Chronic neurovascular syphilis can present with hydrocephalus, seizures, nerve palsies, or neurological regression.

      
      
   4. 
      

      Diagnosis

      
      
      
      
      1. 
         

         Nonspecific regain antibody tests, VDRL or RPR, are used to screen for congenital syphilis. A titer of at least fourfold higher in the infant than in the mother suggests active infection.

         
         
      2. 
         

         Positive screening should be verified by specific treponemal tests.

         
         
      3. 
         

         CNS disease should be evaluated by testing CSF serologies (VDRL or FT-ABS).

      
      
   5. 
      

      Management

      
      
      
      
      1. 
         

         Children with congenital syphilis need close monitoring during the first year of life (Table 35-2).

         
         
      2. 
         

         Nontreponemal tests should be repeated at 2, 4, 6, and 12 months or until a nonreactive result or fourfold decrease is obtained.

         
         
      3. 
         

         Infants with neurosyphilis should have repeat CSF evaluations every 6 months until CSF results normalize.

         
         
      4. 
         

         Treatment should initially focus on treating women who screen positive for syphilis.

         
         
      5. 
         

         Infants requiring treatment based on laboratory or clinical examination results should, in most circumstances, receive penicillin G for 10 days.

         
         
      6. 
         

         If congenital syphilis is left untreated, 40% of children develop late signs such as saddle nose due to cartilage injury, Hutchinson teeth, frontal bossing from periostitis, saber shins (bowing of the tibia), glaucoma, corneal scarring, interstitial keratitis, or hearing loss due to nerve damage.

   
   
6. 
   

   Chorioamnionitis

   
   
   
   
   1. 
      

      Definition: Chorioamnionitis is an inflammation of the placental membranes.

      
      
   2. 
      

      Incidence: Chorioamnionitis affects 1% to 4% of births in the United States and is more common among preterm infants.

      
      
   3. 
      

      Pathophysiology

      
      
      
      
      1. 
         

         Chorioamnionitis is most commonly due to ascending bacterial infection.

         
         
      2. 
         

         While less common, other routes of infection include hematogenous spread and complications from procedures such as amniocentesis.

         
         
      3. 
         

         Common causative organisms includeEscherichia coli, Mycoplasma hominis, Ureaplasma urealyticum, group B Streptococcus (GBS), and Staphylococcus spp.

      
      
   4. 
      

      Risk factors: Risk factors for chorioamnionitis include ruptured membranes, first pregnancy, African American ethnicity, three or more vaginal examinations, maternal GBS colonization, use of internal monitoring such as fetal scalp probe, and prolonged labor.

      
      
   5. 
      

      Clinical presentation

      
      
      
      
      1. 
         

         Signs of clinical chorioamnionitis include maternal fever, tender uterus, maternal and/or fetal tachycardia, and purulent amniotic fluid.

         
         
      2. 
         

         Alternatively, there may be no clinical signs in the mother, and the diagnosis is made only by histologic examination of the placenta.

         
         
      3. 
         

         Sometimes, as in the case of chorioamnionitis caused by Candida, there may be small yellow nodules noted on the umbilical cord.

      
      
   6. 
      

      Diagnosis may be clinical or through histological examination of the placenta.

      
      
   7. 
      

      Management

      
      
      
      
      1. 
         

         Treatment of the mother should be initiated as soon as clinical signs develop in order to decrease the chance of sepsis in the infant.

         
         
      2. 
         

         According to the recently revised GBS guidelines, infants born to mothers with chorioamnionitis should have both a complete blood count, blood culture obtained, and receive empirical antibiotics.

      
      
   8. 
      

      Outcomes

      
      
      
      
      1. 
         

         Adverse short- and long-term outcomes include death, sepsis, intraventricular hemorrhage, white matter injury, and cerebral palsy (Table 35-2).

         
         
      2. 
         

         In both term and preterm infants, chorioamnionitis has been shown to be a risk factor for cerebral palsy. The systemic inflammatory reaction that occurs with chorioamnionitis increases cytokine levels in the infant, increasing production of nitric oxide synthase and free radicals that may play a role in the resulting brain injury.

         
         
      3. 
         

         In preterm infants, chorioamnionitis is associated with risk of intraventricular hemorrhage, retinopathy of prematurity, respiratory distress syndrome, and pneumonia.