This chapter provides an overview and approach to the diagnosis and management of the more common infections that occur in the fetus and newborn infant. Details about how each organism affects the fetus and newborn, as well as information on diagnosis and management, are covered in the pathogen-specific and disease-specific chapters of this edition.
Viral Infections of the Fetus and Neonate
Viral infections are an important cause of fetal and neonatal morbidity and mortality. The cumulative frequency of viral infections in the fetus or newborn infant may be as high as 6% to 8% of all live births, whereas systemic bacterial disease occurs in only 1% to 2% of neonates. Viral infections of the fetus and newborn may be divided into congenital, perinatal or natal, and postnatal time periods of acquisition.
Pathogenesis
Congenital Viral Infections
Congenital viral infections are transmitted to the developing fetus during a maternal infection. Most congenital viral infections are from maternal primary infections, but some viruses (cytomegalovirus [CMV]) may be transmitted to the fetus during a recurrent (reactivation or reinfection) maternal infection. Congenital viral infections can result in resorption of the embryo; spontaneous abortion or miscarriage; stillbirth; congenital malformation; prematurity; intrauterine growth restriction (IUGR); or acute disease apparent in utero, at birth, or shortly thereafter. Congenital infection with Ebola virus is uniformly fatal. In contrast, most congenital CMV infections are asymptomatic in the fetal or neonatal period yet may be associated with persistent postnatal infection, sequelae later in life, or a normal infant with no apparent sequelae.
Most fetal infections are preceded by a systemic viral infection in the mother, with hematogenous spread of the virus to the placenta and subsequently to the fetus ( Fig. 66.1 ). Ascending infection through amniotic membranes also may occur while the fetus is still in utero. With most viruses well known to cause fetal infection—CMV, rubella virus, herpes simplex virus (HSV), varicella zoster virus (VZV), Ebola virus, Zika virus, Dengue, and vaccinia virus—placental involvement by the virus also has been documented ( Table 66.1 ). Viruses may reach the fetal circulation by (1) replication through the layers of the placenta; (2) production of virus-induced vascular lesions in the placenta, resulting in abnormal communications between the maternal and fetal circulation; or (3) diapedesis of virus-infected maternal leukocytes through the layers of the placenta to the fetal circulation.
Viruses | Congenital | Natal | Postnatal |
---|---|---|---|
Adenovirus | + | + | + |
Chikungunya | ++ | + | − |
Cytomegalovirus | ++ | ++ | ++ |
Dengue | ++ | − | − |
Ebola virus | ++ | + | + |
Echoviruses | + | + | + |
Epstein-Barr | + | − | + |
Hepatitis A | − | ++ | + |
Hepatitis B | + | ++ | + |
Hepatitis C | + | ++ | − |
Herpes simplex | + | ++ | + |
Herpesvirus-6 | + | − | + |
Human | |||
immunodeficiency virus | + | ++ | + |
Human parvovirus B19 | + | − | − |
Influenza | (+) | − | + |
Lymphocytic | |||
choriomeningitis virus | ++ | − | − |
Measles | + | − | + |
Mumps | + | − | − |
Parechovirus | − | + | + |
Polioviruses | + | + | + |
Rubella | ++ | − | − |
Smallpox | + | + | + |
St. Louis encephalitis | (+) | – | (+) |
Type B coxsackieviruses | + | + | + |
Vaccinia | + | + | + |
Varicella zoster | ++ | + | + |
West Nile virus | + | − | + |
Western equine encephalitis | + | − | + |
Zika virus | ++ | ? | (+) |
Developmental malformations also may occur. Rubella virus is the classic known teratogen, causing disturbances in organogenesis, cardiac disease, and cataracts. VZV and Zika virus have been shown to cause limb hypoplasia and developmental malformations of the eye and brain. Other viruses that result in congenital abnormalities, such as CMV and HSV, usually cause inflammatory, destructive lesions of already developed organs. Type B coxsackieviruses and other enteroviruses have been associated with a variety of congenital malformations of the heart, and mumps has been linked to endocardial fibroelastosis. Chikungunya virus also may cause congenital infection and disease.
Damage to the fetus also may occur in the absence of actual fetal viral infection as a result of severe systemic illness in the mother, such as measles or influenza, or alteration of placental function.
Natal or Perinatal Viral Infections
Natal or perinatal infections are the result of exposure of the newborn to virus replicating in the maternal cervicovaginal tract (i.e., CMV, HSV, or hepatitis B virus) or perirectal area (e.g., enteroviruses). Natal or perinatal infections with some viruses can cause acute systemic illness leading to death, persistent infection with late sequelae (HSV, HBV), self-limited disease with no discernible damage (CMV), or asymptomatic infection (see Fig. 66.1 and Table 66.1 ). Because the incubation periods of HSV and enteroviruses are short, acute postnatal disease may appear in the neonate within 5 to 7 days of age. In contrast, the incubation periods of CMV and hepatitis B virus (HBV) are longer, and clinically apparent disease from perinatal exposure, if it occurs, may not be observed for several weeks or even months after birth. Persistent postnatal infection can occur after perinatal infection with CMV, HSV, and HBV.
Postnatal Viral Infections
Postnatal infections in the neonate may be transmitted to the neonate from the mother, family members, caretakers in extended family, health care workers, outbreaks in neonatal care units, or community exposures (see Fig. 66.1 ). Neonatal infections and hospital-associated outbreaks of enterovirus and parechovirus, respiratory syncytial virus (RSV), rotavirus, adenovirus, rhinovirus, parainfluenza virus, human metapneumovirus, and influenza virus infection have occurred. In addition, health care–associated HSV infections have occurred in neonates (see Table 66.1 ). Although the maternal respiratory and gastrointestinal tracts are the most common sites from which virus can be transmitted to the neonate postnatally, other viruses, including human immunodeficiency virus (HIV), human T-cell leukemia virus types 1 and 2 (HTLV I and II), CMV, West Nile virus, rubella virus, hepatitis C virus (HCV), Zika virus, and HBV, have been recovered from breast milk. HSV and VZV lesions on the breast of a mother also may be a source of transmission of virus for the breastfeeding neonate, even though these viruses probably are not present in the breast milk. Finally, HIV, CMV, and HBV have been transmitted to newborn infants by blood transfusion. Although most postnatal infections are acute, self-limited processes, severe disease and fatalities have been reported, especially in preterm infants infected with CMV, enteroviruses, HSV, adenoviruses, or RSV, and persistent postnatal infection may occur with CMV and HBV.
Approach to Diagnosis
Evaluation of the Mother
Fetal viral infection may be suspected if the mother is exposed to or experiences an infection with a virus known to transmit to the fetus. A history of recent illness, travel, or exposures to the mother should be obtained to uncover circumstantial evidence for a viral infection in the fetus or newborn. For example, the occurrence of maternal viral illness with an associated maculopapular rash suggests rubella or enterovirus or Zika virus infection in the neonate, exposure to mosquitoes suggests St. Louis encephalitis virus, West Nile virus, or Zika virus, ulcerative genital lesions suggest HSV, and heterophile-negative infectious mononucleosis is suggestive of CMV. Hemorrhagic fever after travel to Africa suggests Ebola virus. Maternal rash with arthralgias also may be caused by parvovirus B19, especially if there is recent exposure to fifth disease in the community. Since viral infections in the mother may be asymptomatic, the absence of symptoms in the mother does not rule out the possibility of a viral infection in the neonate.
Clinical Features in Fetus and Newborn
Abnormalities detected on routine fetal ultrasound also may suggest fetal infection. These findings include IUGR; microcephaly; cerebral ventriculomegaly or hydrocephalus; cataracts; hepatosplenomegaly; hepatic or intracranial calcifications; and cortical maldevelopment syndromes such as polymicrogyria, hydrocephalus, microcephaly, in utero central nervous system (CNS) vasculitis, echogenic bowel, fetal ascites, cardiomegaly, congestive heart failure, fetal hydrops, enlarged or swollen placenta, or polyhydramnios or oligohydramnios. Intrauterine cardiac abnormalities, myocarditis, and heart failure may be associated with HIV, parvovirus B19, mumps virus, CMV, Zika virus, or adenovirus, and cardiac structural defects may be associated with rubella virus. Limb deformities or dysplasias, especially if they are associated with eye or CNS abnormalities, may be caused by intrauterine VZV or HSV infection and possibly Zika virus.
In more than 80% of CMV, 60% of rubella virus, and most HBV infection in the neonate are asymptomatic. In contrast, less than 1% of HSV infections and no Ebola virus infections are subclinical in the neonate.
Clinical manifestations of viral disease in the neonate may provide helpful clues to the specific etiologic agent. The presence of cataracts, congenital heart disease, bone lesions, or microphthalmos is highly suggestive of rubella, whereas chorioretinitis, cerebral calcifications, and hydrocephaly are more common with congenital infection with CMV, lymphocytic choriomeningitis virus (LCMV), Zika virus, or HSV. The features in neonates with perinatal or postnatal enterovirus, HSV, or adenovirus disease resemble those associated with bacterial sepsis: lethargy or irritability, fever or hypothermia, respiratory distress, cyanosis, anorexia or vomiting, hepatomegaly, seizures, or abnormal movements. Laboratory abnormalities in disseminated viral disease may show neutropenia, lymphocytosis, lymphopenia, thrombocytopenia, elevated liver transaminases, hyperbilirubinemia, and cerebrospinal fluid (CSF) pleocytosis. Aseptic meningitis in the neonate may be caused by perinatal or postnatal infection with HSV1 or 2, enteroviruses, or parechoviruses. In neonates with persistent severe viral infections that are slow or minimally responsive to antiviral therapy, a primary immune deficiency disorder of T-, B-, or natural killer (NK)-cell function should be considered.
Differential Diagnosis
The differential diagnosis in a fetus or newborn infant with a suspected viral infection includes but is not limited to bacterial or fungal sepsis, toxoplasmosis, syphilis, erythroblastosis fetalis, metabolic inborn errors of metabolism, genetic chromosomal abnormalities, and other forms of congenital malformations.
Laboratory Diagnosis
Prenatal diagnosis of fetal viral infection may be established by testing amniotic fluid for viral culture and polymerase chain reaction (PCR) or by fetal blood sample for viral-specific immunoglobulin (Ig)M and PCR studies. The placenta may also be sent for histopathologic studies.
In neonates, urine, saliva, and blood for CMV; throat, cataracts, and occasionally CSF or urine for rubella; skin vesicles, blood, CSF, conjunctivae, throat, stool, and urine for HSV; throat, stool, urine, CSF, or blood for enteroviruses; and skin vesicles and blood for VZV should be sent for virus isolation or virus detection by PCR. In addition, isolation or molecular detection by PCR of virus can be attempted from biopsy or autopsy specimens. Electron-microscopic examination of vesicle fluid or tissue can demonstrate typical herpesvirus particles in both HSV and VZV infection but cannot distinguish between the two. Dried blood spots archived after completion of newborn screening for metabolic and immunodeficiency disorders may be retrieved with maternal permission from state newborn screening agencies and tested for the presence of viral DNA. Such approaches have reliably allowed the retrospective diagnosis of congenital CMV. Research evaluating urine and saliva as screening specimens for congenital CMV infection have also been conducted.
Three approaches can be used to make a serologic diagnosis of viral infection in a newborn infant: (1) assay of maternal serum and serum specimens from the infant at birth and at 5 to 6 months of age for antiviral antibody (predominantly IgG activity), (2) assay of neonatal serum for IgM antibody against a specific viral agent, and (3) assay of neonatal serum for quantitative IgM levels, a nonspecific indication of antigenic challenge in utero. Maternal IgG, antibody against viruses to which the mother has been exposed, passes transplacentally, beginning at midgestation. Peak levels are reached in fetal serum at the time of birth (umbilical cord blood); they decline to undetectable levels by the time that the infant reaches 6 to 12 months of age, depending on the virus. Maternal IgM antibody normally is not passed transplacentally, but a fetus challenged in utero with a virus can have specific IgM antibodies against the viral agent as well as elevated levels of the total IgM fraction. Often a fetus with detectable virus-specific IgM will have severe in utero disease caused by the virus.
Treatment
Intravenous acyclovir followed by long-term oral suppression with oral acyclovir is the mainstay for antiviral treatment of neonatal herpes simplex virus infection. Congenital CMV disease, especially if it is severe or involves the CNS or sensory organs such as the eye and ear, may be treated with intravenous ganciclovir or oral valganciclovir. Neonates with influenza virus may receive antiviral medications such as oseltamivir, and ribavirin for severe RSV disease.
Bacterial Diseases of the Fetus and Newborn
Worldwide, millions of neonates die every year of bacterial infection. In the United States, the infant mortality rate is approximately 6.85 infant deaths/1000 live births. Neonatal bacterial sepsis corresponds to the eighth leading cause of fatality. The incidence of neonatal sepsis ranges from 1 to 8/1000 live births, with the higher figures corresponding to developing countries. Low birth weight, male sex, and congenital malformation are important risk factors. Extreme prematurity is the greatest risk factor for early-onset sepsis and is associated with an increased risk for having adverse outcomes. The highest age-specific incidence of bacterial meningitis appears to occur during the first month of life.
Epidemiology and Pathogenesis
The human birth canal is host to large numbers of aerobic and anaerobic bacteria, Mycoplasma, Ureaplasma, Chlamydia, fungi, yeast, and viruses. Staphylococcus epidermidis, lactobacilli, diphtheroids, and α-hemolytic streptococci are found in 50% to 100% of vaginal cultures of pregnant women and constitute the predominant aerobic flora. Significant but less common isolates include Gardnerella vaginalis, Proteus, and Klebsiella spp. and group B and D streptococci; Staphylococcus aureus and miscellaneous organisms, such as Citrobacter, Acinetobacter, and the Campylobacter group, are identified even less commonly. Approximately 85% of women with genital colonization by anaerobes harbor Bacteroides spp., including Bacteroides fragilis in a third of cases. Anaerobic streptococci, Peptostreptococcus and Peptococcus, are found in approximately 40% of women, and Clostridium is present in 20%. Uncommon anaerobic isolates include Veillonella, Bifidobacterium, and Eubacterium .
Certain microorganisms are associated with the occurrence of stillbirths. Among these bacterial agents are Escherichia coli, group B streptococci (GBS), Ureaplasma urealyticum, Listeria monocytogenes, and Treponema pallidum .
Streptococcus agalactiae, or GBS, is a major pathogen for the neonate, causing both early-onset sepsis and late-onset disease, usually meningitis, but also other manifestations ( Box 66.1 ). The acute early-onset form of GBS disease can be caused by any of the group B types (B I to B VIII ), and the specific B type causing disease in the infant usually is found in the maternal vaginal tract. GBS meningitis is caused almost exclusively by the B III organism. These organisms also may be acquired from nonmaternal sites. Clusters of three or four cases of GBS meningitis have occurred in nurseries during short intervals, suggesting that health care–associated outbreaks may occur. The administration of intrapartum antibiotics, such as ampicillin, has reduced the incidence of early-onset GBS disease in neonates. E. coli is the other important agent implicated in neonatal bacterial disease, including sepsis, meningitis, and urinary tract infection, with an annual incidence of approximately 6.8/1000 live births; it is the most common gram-negative bacterium causing meningitis during this period. Ampicillin-resistant and multidrug-resistant E. coli strains have emerged. Neonatal colonization with E. coli often results from maternal transmission during delivery. Klebsiella pneumoniae is another important neonatal pathogen causing sepsis and meningitis, with an incidence of between 4.1 and 6.3/1000 live births and fatality rates of 18% to 68%. It is the second most frequent gram-negative organism associated with late-onset sepsis in developed nations. L. monocytogenes is a foodborne colonizer of the human gastrointestinal tract, and one of the host factors that increases the risk for Listeria infection and disease is pregnancy. Perinatal infection constituted 34% (470/1378) of cases of listeriosis. Transmission to the fetus in utero may produce granulomatous fetal disease and an early-onset sepsis syndrome or a late-onset meningitis.
Gram-Negative Organisms
Escherichia coli
Haemophilus influenzae
Citrobacter
Enterobacter spp.
Pseudomonas spp.
Acinetobacter
Neisseria meningitidis
Gram-Positive Organisms
Group B streptococci (Streptococcus agalactiae)
Viridans streptococci
Enterococci
Streptococcus pneumoniae
Other streptococci
Listeria monocytogenes
Coagulase-negative staphylococci
Staphylococcus aureus