Chapter 50. Congenital TORCH Infections

Congenital TORCH infections comprise a group of diseases that affect the fetus and the newborn. Classically, the term TORCH represented Toxoplasmosis, other, traditionally referring to syphilis, rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV). Recent additions to the acronym have expanded its repertoire to include infections such as human immunodeficiency virus (HIV), enterovirus, parvovirus, and varicella. These congenital infections share many clinical manifestations. Consequently, the differential diagnosis of one TORCH infection includes the remaining TORCH infections. The prevalence of the TORCH infections is variable. Infection due to rubella and toxoplasmosis is rarely seen in the United States, while CMV is common, representing a significant public health concern. Table 50–1 lists the classically defined TORCH infections and their common manifestations weighted according to their prevalence among infected neonates. The following chapter will discuss the epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, and management strategies for affected infants.

Definitions and Epidemiology

Cytomegalovirus, a ubiquitous pathogen, is the most common cause of congenital viral infections. It is a double-stranded, species-specific DNA virus of the herpes family.1,2 Infection in the immunoincompetent, vulnerable fetus can have devastating effects. Congenital CMV infection is a leading cause of sensorineural hearing loss (SNHL) and neurodevelopmental disturbances resulting from central nervous system involvement.3

The incidence of primary CMV infection in pregnancies is estimated to range from 0.15% to 4%, with vertical transmission rates as high as 40%.2,4 Over 27,000 women per year in the United States experience a primary CMV infection during pregnancy. Primary infection in pregnancy is not evenly distributed across racial, ethnic, and socioeconomic groups. Young women of Mexican American descent and non-Hispanic blacks are disproportionately at higher risk of acquiring primary infection in pregnancy.5

In a study of 1018 blood donors screened over a 2-month period, Munro et al. demonstrated that CMV seroprevalence rises with increasing age. Rates of seropositivity increased from 35% in blood donors younger than 20 years old to 73% by the age of 50.4 The seroconversion rate in pregnancy is ∼2%.6 Lower seropositivity rates in women of childbearing age pose a potential risk to their offspring. A review of multiple studies that screened infants and fetuses for CMV revealed that the maternofetal transmission rate was 32% in primary maternal infection compared to 1.4% in recurrent infection.7

Pathogenesis

Infants may acquire CMV infection through transplacental transmission prior to birth, during vaginal delivery through an infected birth canal, or through the administration of infected breast milk or blood products in the postpartum period. Maternal CMV infections pose the greatest threat to the fetus when they are acquired during early gestation. Postnatal infection occurs more frequently than transplacental infection and usually results in benign disease. While most infants who acquire the infection through contaminated breast milk or CMV-contaminated blood products remain asymptomatic, premature infants compose a unique population at higher risk for symptomatic infection. Approximately one-fourth of preterm infants develop symptoms when transfused with CMV-positive blood.1,2,8

The incidence of congenital CMV disease among all live-born infants has been estimated as high as 1% and this may be an underestimation. The impact on child health is significant. A recent review of 117,986 infants screened for congenital CMV reported that 12.7% of infected children manifested symptoms in the immediate newborn period and 40–58% of these infants developed long-term sequelae. In addition, 13.5% of the initially asymptomatic group also developed long-term sequelae.1,9,10 These data indicate that congenital CMV represents a substantial burden to public health.

Consequently, prevention of CMV infection in women of childbearing age is an important step in reducing this societal burden and decreasing the numbers of affected children. Vaccines, hyperimmunoglobulin, and ganciclovir have been evaluated for their potential to reduce the risk of maternal–fetal transmission. Currently, no effective vaccine is available and the efficacy of ganciclovir has not been clearly defined in randomized controlled trials.12 One study suggested that administration of oral valacyclovir to women carrying fetuses with symptomatic CMV infection led to therapeutic drug levels in both amniotic fluid and fetal sera and a reduction in viral load in fetal blood. Larger randomized studies are required to determine the efficacy of this therapy for congenital CMV infection.11

Few studies have evaluated the effect of passive immunization with CMV-specific immunoglobulin on the rate of fetal infection. One study suggested that the use of CMV-specific hyperimmunoglobulin prevented fetal infection in mothers with primary CMV infection in pregnancy.6 No randomized controlled trials have been conducted and further investigation is required.

Clinical Presentation

Common complications associated with primary CMV infection in pregnancy include spontaneous abortion, premature delivery, intrauterine growth restriction, and hydrops fetalis. Placental dysfunction brought about by inflammation is thought to contribute to these complications,12 as well as to complications during labor and delivery.13

Most (85–90%) infants with congenital CMV infection manifest no signs or symptoms of disease at the time of delivery. However, late sequelae such as developmental delay, learning disability, or SNHL occur in 8–15%.1,14 Among symptomatic newborns, 80–90% have severe neurologic manifestations2,14,15 and overall mortality is 20–30%.13,14

The virus infects many organs with a predilection for the reticuloendothelial and central nervous systems.2 Among symptomatic newborns, the most common presenting symptoms include hepatosplenomegaly, petechiae, intrauterine growth restriction, and microcephaly.1,15Table 50–2 summarizes common clinical and laboratory findings in a series of 106 infants with symptomatic congenital CMV infection. Dermal erythropoiesis, commonly referred to as “blueberry muffin rash,” may be seen in infants with CMV (Figure 50–1), although it is more classically identified with congenital rubella syndrome.

While many of the initial manifestations of congenital CMV infection (Table 50–2) resolve over time, central nervous system sequelae are permanent.8 Anatomic abnormalities associated with congenital CMV infection include periventricular and intracranial calcifications (Figure 50–2), microcephaly, ventriculomegaly, and migration defects. Other findings include hypotonia, seizures, chorioretinitis, and SNHL.1,2,12,15

Congenital CMV infection is the most common cause of SNHL in children.2,8 Often progressive, SNHL may be detected at birth, or in infancy and childhood.15Table 50–3 represents the cumulative incidence of hearing loss in a cohort of 388 children diagnosed with congenital CMV infection. Rates of SNHL rose steadily from 5.2% at birth to 8.4% by 12 months, reaching 15.4% by 6 years of age.16 The adequacy of current hearing screening programs performed in the immediate neonatal period has been called into question because of the high numbers of initially asymptomatic infants with congenital CMV infection at risk for late onset SNHL.16

Diagnosis

Congenital CMV infection should be suspected in cases of primary maternal CMV infection during or just before pregnancy, maternal exposure to the virus during gestation, or where fetal findings on prenatal ultrasonography are attributable to CMV infection. The most common ultrasound findings suggestive of fetal CMV infection include hyperechogenic bowel, ascites, cardiomegaly, and oligohydramnios. Other common findings include ventriculomegaly, intracranial calcifications, microcephaly, intrauterine growth restriction (IUGR), hydrops, hepatic echodensities, and increased placental thickness.17,18

The diagnosis of congenital CMV infection must be made in the first 2–3 weeks of life; otherwise findings may reflect postnatally acquired infection (Table 50–4). The gold standard diagnostic technique is culture of the virus from samples of urine or saliva. While culture methods can take up to 2 weeks, rapid centrifugation-enhanced culture techniques combined with antibody studies can be completed in ∼24 hours. Polymerase chain reaction (PCR) techniques for detection of CMV in urine, saliva, leukocytes, or other tissues are also being used more commonly to diagnose congenital CMV infection.2,8 The limited sensitivity and specificity of CMV-specific IgM antibody assays call into question their utility in diagnosing congenital CMV infection, and its use as a diagnostic method is currently not recommended.8,17

Once a diagnosis of congenital CMV is made, a thorough evaluation is required to assess for multisystem involvement. A complete blood cell count to detect thrombocytopenia and anemia, and liver enzymes and bilirubin levels to detect hepatitis and liver dysfunction are recommended. If respiratory symptoms are present, a chest radiograph searching for interstitial pneumonitis should be obtained. A fundoscopic examination to detect chorioretinitis and otologic evaluation to detect hearing loss should be performed.2

At a minimum, screening cranial ultrasonography to detect central nervous system abnormalities should be obtained. In one study, 57 newborns with congenital CMV infection were screened with cranial ultrasound and then followed with audiologic and neurodevelopmental evaluations. Neonates with signs and symptoms of congenital infection at birth had findings on cranial ultrasonography more often than asymptomatic newborns. At follow-up, all symptomatic infants with an abnormal ultrasound in the immediate neonatal period developed at least one long-term severe complication of the disease.19

Management/Treatment

The treatment of congenital CMV is largely supportive. Small studies have sought to describe the pharmacokinetics and safety of various oral and intravenous anti-CMV therapeutic agents in this population.20,21 The use of ganciclovir has not yet been proven efficacious in the treatment of congenital CMV infection in randomized, blinded controlled studies. Only one study has reported any significant benefit associated with the use of ganciclovir. In 2003, Kimberlin et al. identified a cohort of congenitally infected newborns with central nervous system (CNS) abnormalities. Infants were evaluated at baseline with repeated assessments at 6 months and 1 year or later. Investigators reported that 84% of treated infants versus 59% of controls demonstrated unchanged or improved hearing. None of the treated infants versus 41% of the nontreated infants had worsened hearing loss at 6 months. Among infants assessed at 1 year or later, 21% of treated infants and 68% of untreated infants developed further hearing loss. This small study suggests that ganciclovir may reduce the progression of SNHL. Neutropenia was the most common adverse effect with 63% of treated infants developing neutropenia necessitating either a dose reduction or halt in therapy.22 Preliminary results of further follow-up of this trial suggested that ganciclovir use may be related to improved neurodevlopmental outcome. Further investigation is required to determine the strength of this association.23

Serial physical examinations and follow-up hearing tests every 3 months in the first year are recommended. After the first year of life, follow-up may be modified as indicated by the presence and degree of hearing loss.2

Definitions and Epidemiology

Neonatal infection with HSV, a double-stranded DNA virus, may be associated with severe morbidity and mortality. The majority of infections in the neonate, ∼70%, are due to infection with HSV-2, the virus commonly associated with genital herpes. The remaining 30% are due to infections with HSV-1, the virus commonly associated with cold sores. HSV infections are described as primary, recurrent, and nonprimary first episodes. Primary infection occurs in an individual without prior history of the disease. Recurrent infections occur in individuals with prior history of HSV infection. A nonprimary first episode is an HSV infection in a person with history of another type of HSV infection.2,24

Approximately one in 3000–20,000 live births is complicated by neonatal HSV infection and disease. The infection can be acquired in utero, through an infected birth canal, or postnatally through contact with an infected person, for example, oral lesion(s), herpetic whitlow, etc. The majority of neonatal infections (85–95%) are acquired during labor and delivery.2,24,25

Pathogenesis

Several risk factors have been associated with maternal–fetal transmission of HSV with the most significant risk factor being maternal primary infection close to the time of labor and birth. Other risk factors include rupture of membranes greater than 4 hours, prematurity, and fetal instrumentation, for example, use of scalp electrodes.2,26

The risk of maternal–fetal transmission can be influenced by maternal serologic status and the type of maternal HSV disease.27 The risk of perinatal HSV is 44% when the mother has a primary genital HSV infection at the time of delivery compared with 1.3% when the mother has recurrent genital lesions. Nonhispanic white women are more likely to be seronegative and their infants are at greatest risk for neonatal herpes infection.28

Rates of neonatal disease in infants born vaginally to women with primary HSV infection range from 33% to 50%. This high rate of infection is attributed to several factors including higher viral loads in women with primary HSV disease and decreased maternal anti-HSV antibodies. Many primary HSV infections result in vague symptomatology. As a result, more than 75% of infants with HSV infection are born to women who had no clinical history or manifestations of HSV during their pregnancy. Rates of neonatal disease in recurrent maternal infection are less than 5%.2,24

Clinical Presentation

The onset of neonatal disease varies from birth to 3 weeks of age, usually between days 11 and 17. The infection can manifest in one of three forms, classified as disseminated disease, localized CNS disease, or skin-eye-mouth (SEM) disease. Each type occurs with equal frequency and there can be substantial overlap between classifications.2

In disseminated disease, manifestations most often occur between 10 and 12 days of life, but symptoms may appear as early as the first day of life. The most common presentation is a sepsis-like syndrome with prominent liver and lung involvement. Signs and symptoms may include respiratory distress, seizures, petechiae, disseminated intravascular coagulation, hepatosplenomegaly, and vesicles. However, more than 20% of affected newborns have no vesicular skin lesions. Mortality results from respiratory failure, severe hepatic dysfunction, and/or coagulopathy.2,24,25

Localized CNS disease usually presents during the second to third week of life. Signs and symptoms include lethargy, bulging fontanel, irritability, temperature instability, seizures, and vesicles. Mortality is secondary to acute neurologic dysfunction secondary to the massive brain destruction caused by HSV.2,24,25

SEM disease most frequently presents in the first 2 weeks of life. Manifestations are limited to the skin and mucous membranes, particularly at sites of trauma. Common findings include lesions on the skin (85%), in the oropharynx, and ophthalmic manifestations including conjunctivitis and keratitis.2,25

Morbidity and mortality rates remain high despite appropriate treatment in infants with disseminated and CNS disease. In disseminated disease, the risk of mortality is 30% with less than 20% of survivors suffering long-term neurologic complications. In CNS disease, the risk of mortality is 5%, with greater than 60% of survivors suffering long-term neurologic sequelae including microcephaly, spastic cerebral palsy, epilepsy, blindness, and developmental delay.2,24,25 Morbidity and mortality associated with SEM disease are low, both accounting for 1–2% of treated infants.25

Preterm infants are a particularly vulnerable population to HSV infection. Disseminated and CNS diseases predominate and mortality is high. These observations have been attributed to immunologic immaturity and lack of maternally derived antibodies.26

Differential Diagnosis

The variable manifestations of neonatal HSV infection overlap with many other newborn diseases leading to a broad differential diagnosis. Other potential infectious causes include bacteria (e.g., group B streptococci, Staphylococcus aureus, Listeria monocytogenes, enteric gram-negative rods, and Treponema pallidum) and other viruses (e.g., varicella zoster virus, enteroviruses, CMV, toxoplasmosis, and Rubella). Noninfectious causes of severe illness include surfactant deficiency, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis. Other causes of skin rashes that may resemble the lesions of HSV include erythema toxicum, neonatal melanosis, acrodermatitis, incontinentia pigmenti, and histiocytosis.25

Diagnosis

The gold standard for the diagnosis of neonatal HSV infection is the identification of the virus in the culture of urine, stool, blood, cerebrospinal fluid (CSF), and lesions of the skin and mucous membranes. Of sites routinely cultured, skin and eye/conjunctival cultures yield HSV in 90% of infants with neonatal infection.29 Rapid viral detection assays such as direct fluorescent antibody (DFA) or enzyme immunoassay (EIA) are specific but slightly less sensitive than culture.2,24,25,29

PCR to detect HSV DNA in CSF is the gold standard for HSV meningoencephalitis; the test, when properly performed, has nearly 100% sensitivity and more than 90% specificity. False-negative results may occur when the test is performed early in the course of illness. If the clinical findings suggest HSV but the CSF HSV PCR test is negative, the test should be repeated several days later.25 PCR testing of vesicular swabs and mucosal surfaces is more sensitive than DFA testing. A positive HSV PCR test from peripheral blood also confirms the diagnosis of HSV, however the sensitivity of this approach is uncertain.

Other studies to consider in the evaluation of a newborn with suspected HSV disease include complete blood count, coagulation studies, and liver function testing. CSF findings, typically 50–100 WBC/mm3 with a lymphocyte predominance, elevated protein, and low glucose, are nonspecific. In infants with respiratory symptomatology, chest radiographs demonstrate a central pattern of involvement that evolves peripherally to involve the entire lung within 1–3 days.2 Computerized tomography or magnetic resonance imaging of the brain may reveal focal or diffuse necrosis in cases of CNS disease.

Management

Timely recognition of HSV disease in the newborn represents a unique challenge because a high index of suspicion is required and delay in initiating antiviral therapy may lead to devastating sequelae.

The management of the symptomatic infant with a positive maternal history of HSV infection or active lesions at the time of delivery is straightforward. These infants should be evaluated with surface swabs for HSV detection by PCR, DFA, or culture from the rectum, mouth, nasopharynx, and conjunctivae. Cultures from blood, urine, stool, and CSF should be obtained and CSF sent for HSV PCR. Treatment with intravenous acyclovir 60 mg/kg/d divided three times per day should be initiated. Duration of therapy is 14 days for infants with SEM disease and 21 days for those with disseminated or CNS disease.24 Patients with a positive CSF PCR require repeat CSF examination at the end of therapy to document a negative PCR. If the test remains positive, some experts recommend continuing acyclovir until the CSF PCR is negative; while a positive CSF HSV PCR test at the end of therapy portends a worse prognosis, it is not clear whether treating for a longer period of time necessarily improves outcomes.24

Controversy exists in the evaluation and treatment of the asymptomatic newborn exposed to maternal HSV infection. Multiple factors such as the mode of delivery, presence of active maternal lesions, and the type of maternal disease affect the risk of transmission and should be considered in risk assessment and management decisions. Figure 50–3 outlines current recommendations for the evaluation and treatment of newborns with suspected disease or potential exposure to HSV.2,24,30

Neonates with HSV disease and those whose mothers had active lesions at the time of delivery should be placed in contact precautions. Contact precautions may not be necessary if a cesarean section was performed while membranes were intact or ruptured for less than 4 hours. Infants whose mothers have a history of recurrent genital herpes without active lesions at time of delivery do not require special isolation.2,24

Disease relapse in infants with SEM and CNS disease have been described. Management of these infants is controversial and infectious disease consultation is suggested. Infants with three or more recurrences of cutaneous vesicles within the first 6 months of life have a substantially worse neurologic outcome and the use of suppressive oral acyclovir therapy reduces the frequency of recurrences. However, the impact of suppressive therapy on long-term neurologic outcome is not clear and studies are ongoing.24,25,31 However, infants with frequent recurrent skin lesions in the first 6 months are at increased risk for CNS disease.2 Cutaneous recurrences can negatively impact infants and their families, interfering with family activities and ability to access childcare.25

Follow-up to monitor for disease recurrence, especially for infants with SEM disease, or development of long-term sequelae, especially for infants with CNS disease, is required.25

Definitions and Epidemiology

Syphilis is one of the “great pretenders” because the disease may manifest with a broad range of signs and symptoms that mimic many other diseases. It has been a serious public health concern for centuries. The infection causes disease in both adults and children and, when acquired during pregnancy, poses a serious threat to the fetus.

Syphilis is caused by T. pallidum, a motile spirochete and one of four treponomemal pathogens that cause human disease. A significant peak in the incidence of acquired and congenital syphilis occurred in the late 1980s and early 1990s, with a dramatic decrease in the rates of both types of disease in the last decade (Figure 50–4). The incidence of disease varies by race and region with the highest rates of infection found in African Americans and Latinos living in urban areas of the southern and northeast United States.2,32–34

Pathogenesis

Outside the newborn period, syphilis is primarily transmitted through sexual contact with an infected individual. Involvement with multiple sexual partners, poverty, illicit drug use, and coinfection with HIV are the risk factors most consistently associated with disease acquisition.34,35

In congenital syphilis, the disease is transmitted from mother to infant via transplacental passage or through contact with infectious lesions at the time of delivery. The infection can be transmitted at any stage although risk of transmission varies with the stage of disease in the mother. Pregnant women with untreated primary or secondary syphilis have a 60–90% transmission rate compared to a 10–30% transmission rate in latent disease.2,32 Lack of, or inadequate, prenatal care is a major contributor to vertical transmission rates of infection from mother to infant and the disease is almost completely preventable when detected and treated during pregnancy.34,35

Clinical Presentation

Thirty to forty percent of women with untreated syphilis in early pregnancy suffer complications such as spontaneous abortion, stillbirth, or preterm delivery. Other complications include placentomegaly, hydrops fetalis, and perinatal death.2,34 Up to one-third of surviving infants with congenital syphilis are symptomatic at birth. Manifestations of congenital syphilis are divided into early and late findings.34 Early signs and symptoms occur in the first 2 years of life, mainly presenting in the first 3–8 weeks. Early symptoms, attributable to active infection and inflammation, include low birth weight, failure to thrive, lymphadenopathy, hydrocephalus, edema, fever, or a maculopapular rash that later desquamates. Respiratory and gastrointestinal manifestations include respiratory distress, bloody rhinitis called “snuffles,” hepatosplenomegaly, hepatitis, and jaundice. Hematologic findings include Coombs-negative hemolytic anemia and thrombocytopenia. Bony lesions, frequently seen in untreated infants, are often symmetric and occur at multiple sites. They include osteochondritis of joints, periostitis, and cortical demineralization of long bones. Painful lesions give rise to “pseudoparalysis of Parrot,” a condition where an infant refuses to move an affected extremity.2,32–34

Late manifestations, those appearing after the age of 2 years, occur in ∼40% of untreated infants. These findings are typically the result of tissue scarring due to initial infection. These findings include frontal bossing, destruction of the nasal cartilage (saddle nose deformity), anterior bowing of shins (or saber shins), multicuspid first molars (mulberry molars), peg-shaped upper incisors (Hutchinson teeth), linear scars from the corners of the mouth (rhaghades), seizures, interstitial keratitis, and eighth nerve deafness.2,32,34

Neurosyphilis may be either an early or late manifestation of congenital infection. It is often asymptomatic and may present in an acute or chronic manner. Acutely, the disease may manifest as meningitis with signs of increased intracranial pressure and abnormal CSF findings.32,34 Neurosyphilis may also present in a chronic manner with evidence of progressive and evolving disease, characterized by cranial nerve abnormalities, loss of developmental milestones, seizures, hydrocephalus, and strokes.34

Diagnosis

A variety of tests are available for the diagnosis of syphilis. A direct diagnosis can be made if spirochetes are visualized with special stains, by DFA, or by dark-field microscopy in specimens of placenta, cord, amniotic fluid, or infectious lesions. While direct visualization of the organism provides a clear and definitive diagnosis, it is not always practical or possible. Serologic diagnosis is possible using available treponemal-specific and nontreponemal-specific testing.32–34

Nontreponemal tests are screening tests that include the Venereal Disease Research Laboratory (VDRL) slide test, the rapid plasma reagin (RPR) test, the automated reagin test (ART). They provide quantitative results that can be used to follow treatment efficacy and disease status. Adequate treatment is indicated by a fourfold decrease in antibody titer, usually seen by 6 months, while reinfection or failure of antibiotic therapy is detected by a fourfold increase. Negative serologic status is expected after adequate treatment within 1–2 years. Nontreponemal tests have a high rate of false-positive results attributable to other infections or medical conditions such as varicella, Epstein–Barr virus, systemic lupus erythematosus, and other collagen vascular disease, or tuberculosis. A reactive nontreponemal test must be confirmed by a treponemal-specific test.32,34

Occasionally, a surplus of antibody in blood samples inhibits antibody–antigen complexes, resulting in false-negative reactions. This reaction, termed the prozone phenomenon, is a rare occurrence that can be overcome by dilution of the serum sample. Dilution should be performed when suspicion of infection is high, the infant or fetus has signs suggestive of congenital infection yet maternal serology is negative.32,33

Confirmatory treponemal-specific tests, which detect antibodies to surface proteins, include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutination for T. pallidum (MHA-TP). Once these tests become positive, they remain so for life and cannot be used to evaluate treatment or disease status. False positives occur in the face of infections caused by other spirochetes such as Yaws (caused by Treponema pertenue, a subspecies of T. pallidum), Pinta (caused by Treponema carateum), and Lyme disease (caused by Borrelia burgdorferi).32,33

Prenatal diagnosis and treatment of syphilis significantly reduces the risk of vertical transmission. With the recent resurgence of syphilis, particularly in communities with limited resources, careful and tenacious follow-up of pregnant women with the disease and efficient identification of infected newborns is critical in combating this preventable childhood infection.36 Accordingly, the Centers for Disease Control (CDC) and American Association of Pediatrics (AAP) recommend comprehensive screening for the infection in pregnant women. Nontreponemal testing should be routinely obtained during early prenatal care at the beginning of pregnancy. For women in high-risk categories, testing should be repeated at the beginning of the third trimester as well as at the time of delivery. Maternal serology should be known prior to the discharge of all infants. A reactive VDRL or RPR should be confirmed with a treponemal-specific test. If syphilis is diagnosed in pregnancy, repeat serologies are required at the end of treatment to document response to therapy and to evaluate for possible reinfection.32,33

The diagnosis of congenital syphilis is classified as confirmed, presumptive, or possible based on both maternal and infant factors. The classification aids clinicians in evaluation and treatment decisions. Box 50–1 represents clinical and surveillance definitions adapted from the recommendations of the Committee on Infectious Disease, American Academy of Pediatrics.32–34

Any newborn whose mother has a positive serology should have a thorough physical examination and blood sent for the same serologic test as its mother to facilitate comparison of titers. Table 50–5 serves as a guide for the interpretation of serologic tests obtained in women with suspected disease and their infants. The combination of nontreponemal- and treponemal-specific tests and the comparison between maternal and infant results allows for risk assessment of disease. Infants merit a complete investigation if their titers are fourfold greater than their mothers, if they manifest disease, or if their mothers’ titers have risen fourfold.32 Due to the potentially devastating effects of untreated syphilis, evaluation of newborns is also warranted when maternal serologies are reactive and questions exist regarding the adequacy of maternal treatment.32 Infants with suspected disease by any of the above criteria should be evaluated for stigmata of disease by physical examination, radiologic evaluation, and laboratory testing.2,32

Management/Treatment

Infants with congenital disease require treatment to avoid the long-term and serious sequelae of untreated congenital syphilis such as deafness, blindness, mental retardation, and facial deformities. Congenital syphilis is treated with aqueous crystalline penicillin (PCN) G 50,000 units/kg every 12 hours for first week of life and then every 8 hours for a total of 10 days or Procaine PCN G 50,000 units/kg/d administered intramuscularly for 10 days. If more than 1 day of therapy is missed, the entire treatment course must be repeated.2,32–34

Adequate follow-up for infants initially evaluated and treated is essential in the assessment of late manifestations of disease. After completion of treatment, current recommendations suggest follow-up clinical examination at 1, 2, 4, 6, and 12 months of age. Serologic testing is recommended at 2, 4, 6, and 12 months after completion of therapy or until the results are nonreactive or the titers have fallen fourfold. Titers should be undetectable by 6 months. Persistent or rising titers between 6 and 12 months of age are an indication for further evaluation including CSF sampling and retreatment with PCN G for 10–14 days.2,32

Infants with clinical or laboratory findings consistent with neurosyphilis require repeat CSF evaluations every 6 months until the CSF examination is normal. Patients whose 6-month CSF samples demonstrate positive VDRL reactivity or persistent leukocytosis at 2 years require retreatment.2,32

Definitions and Epidemiology

Toxoplasmosis is a parasitic infection that is typically asymptomatic, but may cause significant disease in the fetus and the immunocompromised host. Toxoplasmosis is typically acquired through exposure to oocysts in contaminated soil, feline litter boxes, or through the ingestion of oocysts in undercooked meat.2,37 Primary maternal infection poses a significant risk to the developing fetus. Both the rate of infection and the severity of disease vary with the gestational age at time of initial maternal infection. Maternal–fetal transmission rates are 15% in the first trimester, 30% in the second trimester, and up to 60% in the third trimester. Infants infected in the first trimester typically suffer devastating sequelae while the bulk of infants infected in the third trimester are asymptomatic at birth. However, if these asymptomatic infants are not treated, up to 85% will develop late sequelae. The severity of maternal disease has no significant impact on the transmissibility of the infection or resulting severity of fetal disease.37

Estimated rates of seroprevalence vary by country and region. In the National Health and Examination Survey (NHANES), the seroprevalence of individuals in the United States between the ages of 12 and 49 is estimated at 16%.37 Up to one-third of pregnant women and nonpregnant women of childbearing age have Toxoplasma antibodies.38 Once an individual has seroconverted, anti-Toxoplasma antibodies persist for life. As a result, the rates of seroprevalence increase with age. In the United States, the incidence of congenital toxoplasmosis infection is estimated at 1:1000–10,000 live births.39

Pathogenesis

Cats are the definitive hosts for the Toxoplasma gondii parasite. Felines shed oocysts in stool. Humans acquire infection by direct ingestion of oocysts from contaminated sources (e.g., soil, cat litter, garden vegetables) or from the ingestion of tissue cysts present in undercooked tissues from infected animals. Fetal infection typically occurs following acute maternal infection in pregnancy though it can also occur following reactivation of latent infection in immunocompromised women. After ingestion, oocysts give rise to bradyzoites or sporozoites that spread, replicate, and invade maternal tissues. The parasite becomes widely dispersed and may invade the placenta and infect the susceptible fetus.2,37

Clinical Presentation

Congenital toxoplasmosis infection can lead to stillbirth, premature delivery, or intrauterine growth restriction. Live born infants may (1) have manifestations of infection at birth (10–30% of all infants with congenital toxoplasmosis), (2) be asymptomatic at birth but develop manifestations in the first few months of life (70–90% of all infants with congenital toxoplasmosis), (3) develop symptoms in late infancy or childhood, typically in undiagnosed cases, or (4) the disease may remain subclinical.2,37 Infants who are asymptomatic at birth may later develop serious sequelae such as learning difficulties or visual problems.39

Chorioretinitis is a complication in up to 85% of asymptomatic, untreated newborns. It is difficult to ascertain whether these infants are truly asymptomatic at birth or whether early manifestations are undiagnosed.2,37 In one prospective, longitudinal observational study of chorioretinitis due to congenital toxoplasmosis, a subgroup of 108 infants out of an initial 132 treated with standard therapy were followed for the emergence of new eye lesions. Of these infants, 31% developed one new lesion, 14% developed new central lesions, and 25% were found to have previously undetected peripheral lesions. The development of previously undetected lesions occurred after the age of 10 years in 41% of cases, highlighting the importance of long-term follow up.40

In 10–30% of infants symptomatic at birth, the effects of infection may be extensive. The classic triad includes obstructive hydrocephalus, diffuse intracranial calcifications, and chorioretinits. Some infants may manifest general signs such as fever, jaundice, lymphadenopathy, hepatosplenomegaly, or maculopapular rash. Neurologic manifestations include microcephaly, seizures, diffuse intracranial calcifications, and increased CSF protein. The most common manifestation of neonatal disease is chorioretinitis. Other ophthalmologic findings include cataracts, microophthalmia, optic atrophy, glaucoma, or leukocoria.2,38,39Table 50–6 lists the signs and symptoms described by Couvreur et al. in 210 infants with confirmed congenital toxoplasmosis infection.

Diagnosis

The majority of toxoplasma infections in adults result in asymptomatic infection or nonspecific manifestations of a flu-like illness.2,37 Subsequently, clinical presentation cannot be relied upon to make a diagnosis of maternal infection, since up to 90% of cases are asymptomatic. A high index of suspicion is required for the diagnosis of infection during pregnancy.39 Abnormalities detected on routine ultrasound such as hydrocephalus, intracranial or intrahepatic calcifications, hepatosplenomegaly, or ascites should raise suspicion of toxoplasmosis and prompt further investigation.2,37

The aim of prenatal diagnosis is to identify acute maternal infection and determine the timing of the infection in pregnancy. Available serologic studies include serum Toxoplasma IgG, IgM, IgA, IgE, and IgG avidity testing. Antibody levels are helpful in distinguishing acute from remote infection.37,39,41 If maternal infection is highly suspected, fetal diagnosis should be pursued through the examination of amniotic fluid via the PCR or isolation of T. gondii via murine or tissue culture inoculation. The sensitivity and specificity of PCR on amniotic fluid is 64% and 100%, respectively. Monthly ultrasounds should be obtained to monitor the fetus for evolving hydrocephalus.2,37,39

The evaluation of infants born to women with suspected congenital toxoplasmosis should include paired maternal and infant serology, PCR of neonatal peripheral white blood cells and/or CSF, and, when available, placental and amniotic fluid samples. The diagnosis of congenital infection is made by demonstrating (1) neonatal toxoplasma-specific IgM or IgA; (2) persistently positive IgG or rising titers when compared to maternal titers; (3) detection of T. gondii DNA by PCR; (4) isolation of T. gondii from placenta, blood, or CSF.39

Since maternally derived IgM or IgA may result in false-positive results, titers should be repeated 10 days after initial positive results.2,39 In one study, the specificity of serologic testing of neonatal blood (99%) was better than cord blood (92–96%) and the sensitivity of IgA antibody was better than IgM. Antibody assays were less sensitive in infants whose mothers acquired the infection in early pregnancy.41 This led the authors to conclude that infants at greatest risk for teratogenic effects are less likely to be identified with standard serologic testing. Inclusion of placental evaluation has been found to increase the sensitivity of diagnosis of congenital infection.42

Infants with suspected congenital toxoplasmosis should be evaluated with a complete blood cell count, platelet count, liver function tests, CSF analyses, cranial imaging, ophthalmologic examination, and hearing screening.2,39,43

Treatment/Management

The efficacy of treatment of acute primary infection in pregnancy has been inconclusive.37,39,43 All infants with congenital toxoplasmosis, whether symptomatic or not, should undergo treatment. Current therapy includes pyrethamine, sulfadiazine, and folinic acid for 1 year.2 This regimen has potential adverse effects such as renal toxicity and risk to the glucose-6-phosphate dehydrogenase-deficient infant. Optimal doses and duration of therapy have not been conclusively defined. Consultation with an infectious disease specialist is recommended when considering treatment.37,39

Close followup of congenitally infected infants is critical as common complications include progressive visual loss, seizures, and cerebral palsy.2 Serial pediatric, neurodevelopmental, and ophthalmologic assessments should be performed.43 The development of potential adverse drug effects should be monitored.

Definitions and Epidemiology

Rubella is a rare, mild, or asymptomatic infection caused by an enveloped RNA togavirus. Maternal rubella during pregnancy can result in fetal infection and ultimately the potentially devastating congenital rubella syndrome (CRS).

Rubella epidemics occurred every 6–9 years in the United States prior to introduction of the vaccination program in 1969.44 These epidemics were followed by an increase in the numbers of infants with CRS. After adoption of routine vaccination, rates of CRS have significantly decreased. In 2005, cases of rubella decreased to record lows. Between 2001 and 2004, 9 to 23 cases of rubella infection per year were reported to the Centers for Disease Control and Prevention (CDCP). During this period, only four cases of CRS were reported, with three of the four cases occurring in the infants of mothers who were foreign born.44–46Figure 50–5 illustrates the decrease in rates of both rubella and CRS in the postvaccine era. Despite routine vaccination programs and an overall decrease in the number of cases of rubella, susceptibility to the virus has been reported in as many as 10% of individuals born in the United States.44,45 Other potential reservoirs for the virus are unimmunized and inadequately immunized individuals.

A primary maternal infection during pregnancy carries the greatest risk for vertical transmission to the fetus. The risk of transmission varies inversely with the gestational age at time of infection. A maternal infection in the first trimester carries an 80% risk of transmission compared to 10–20% risk in the second and 25–50% risk in the third trimester.2 The severity of disease is also inversely related to the timing of infection and a reliable predictor of outcome.44,47 Fetal viremia in the first four months of pregnancy causes deleterious cellular alterations responsible for the typical manifestations associated with CRS.48

Pathogenesis

Rubella is transmitted hematogenously from infected mother to fetus and through contact with the infectious secretions outside of the neonatal period. Postnatal infection in susceptible hosts results in mild, vague manifestations that are rarely attributed to rubella. The duration of infectivity spans from days before rash is seen to weeks after the rash has resolved. Subsequently, the virus cycles among the reservoir of susceptible hosts, remaining an infrequent but present public health hazard.2,44,47

Clinical Presentation

When acquired in pregnancy, rubella may infect the placenta, resulting in spontaneous abortion, stillbirth, and intrauterine growth restriction. Fetal infection may lead to CRS. Fifty to seventy percent of the infected infants are asymptomatic at birth. However, symptomatic infants manifest the teratogenic effects of CRS with multiple organ system involvement, particularly infection of the central nervous system, heart, skin, eyes, bones, and the auditory system. Table 50–1 outlines common findings in children with congenital rubella syndrome. Common cardiac abnormalities include patent ductus arteriosus, peripheral pulmonary artery stenosis, and pulmonary vascular stenosis. Hematologic abnormalities include thrombocytopenia, hemolysis, anemia, and dermal erythropoiesis (i.e., blueberry muffin rash). Genitourinary malformations such as testicular or renal agenesis, polycystic kidneys, and renal artery stenosis may also occur. Mortality rates range from 10% to 15%.2,44

Diagnosis

Rubella is diagnosed by detection of anti-Rubella IgM or increasing anti-Rubella IgG titer over many months. Virus can be cultured from various sources including the nasopharynx, blood, urine, and CSF, especially in infants with CRS.2,44 PCR-based strategies may detect rubella RNA or DNA. After 1 year of age, it becomes difficult to diagnose congenital infection.

The evaluation of an infant with suspected or known CRS includes a complete blood count to evaluate for neutropenia, thrombocytopenia and anemia, liver enzymes and bilirubin levels to detect hepatitis and liver dysfunction, and analysis of protein and cell count in CSF suggestive of central nervous system infection are recommended. Screening neuroimaging via cranial ultrasonography or computerized tomography of the head to detect central nervous system abnormalities should be performed. Comprehensive ophthalmic examination, audiologic evaluation, and radiographs of the long bones are also recommended.2

Treatment/Management

There is no specific therapy for rubella infection, with management consisting of supportive measures. Limited studies evaluating the efficacy of antiviral agents and immunoglobulin have been inconclusive.47

Attempts at controlling the spread of disease have consisted mainly of vaccination and isolation of infected persons.44,47 Routine vaccination against rubella is standard practice and most individuals have received the vaccine through childhood immunization programs. The live-attenuated vaccine should not be given to pregnant women. However, in the case of vaccination during or within 28 days of becoming pregnant, the risk of symptomatic infection to the infant is very small and termination of pregnancy is not indicated.44

Infants with CRS, who may shed virus for greater than 1 year, represent another potential source of infection. It has been recommended that infants with confirmed or suspected CRS be placed in contact isolation during the first year of life or until two nasopharyngeal and urine cultures are negative after the age of 3 months.44 Infants with congenital cataracts due to CRS may shed virus for years and, if hospitalized for cataract surgery, should be placed under contact precautions.44 Neurodevelopmental, ophthalmologic, and audiologic follow-up are recommended for infants with CRS.