Viral, Protozoan, and Related Intracranial Infections

Fetal Infection

Clinically significant infection with CMV occurs during intrauterine life by transplacental passage of the virus. CMV reaches the fetus through the placenta where replication and placentitis occur. CMV can subsequently reach the brain by hematogenous route or through the cerebrospinal fluid (CSF). CMV can disrupt the blood-brain barrier to facilitate the spread of viral particles into the brain parenchyma. The organism is transmitted to the fetus usually during a primary maternal infection (less commonly during nonprimary infection) with viremia and subsequent placentitis. Recent data, however, suggest that maternal immunity prior to pregnancy cannot be viewed as protective in terms of altering long-term outcome and that the outcome of infants infected following primary and nonprimary infections is remarkably similar. The maternal infection is usually asymptomatic but may be manifested by a mononucleosis-like illness (≈10%) or a more serious systemic illness. Maternal infection is very common; cytomegaloviruria occurs in 3% to 6% of unselected pregnant women. Cervical CMV infection is several times more common than cytomegaloviruria but tends to occur late in pregnancy and is probably less likely to result in significant fetal infection. Clinically significant fetal CMV infection probably occurs principally in the first or second trimesters, particularly if CNS disease is the outcome measure. The possibility of CNS involvement and an adverse outcome after CMV infection in the third trimester is considered unlikely. The nature of the neuropathological features in some infected infants, however, is consistent with CNS involvement secondary to infection relatively late in pregnancy (see later discussion).

The timing of intrauterine transmission after primary CMV infection is an important determinant of neurological involvement. A recent systematic review of 17 studies evaluated intrauterine transmission rates after primary CMV infection in the pre- and periconceptional period, first, second or third trimester. The pooled rates of vertical transmission in 10 studies and 2942 fetuses at the preconception period, first, second and third trimester were 5.5% (95% CI 0.1% to 10.8%), 21.0% (95% CI 8.4% to 33.6%), 36.8% (95% CI 31.9% to 41.6%), 40.3% (95% CI 35.5% to 45.1%), and 66.2% (95% CI 58.2% to 74.1%), respectively ( Table 38.2 ). The overall transmission rates significantly increased with the trimester of pregnancy, with highest transmission rate in the third trimester. However, they also showed a decline in the pooled rates of fetal insult (CNS involvement) in case of transmission (10 studies, 796 fetuses) with 28.8% (95% CI 2.4% to 55.1%), 19.3% (95% CI 12.2% to 26.4%), 0.9% (95% CI 0% to 2.4%), and 0.4% (95% CI 0% to 1.5%), for maternal infection at the periconception period, first trimester, second trimester, and third trimester, respectively. The pooled rates of SNHL for maternal infection at the first, second, and third trimester were 22.8% (95% CI 15.4% to 30.2%), 0.1% (95% CI 0% to 0.8%), and 0% (95% CI 0% to 0.1%), respectively. Similarly, several studies showed a significantly higher risk of cranial ultrasound (cUS) abnormalities when maternal infection occurred during the preconceptional or periconceptional periods and the first trimester, compared with risk with infection acquired in later trimesters. No symptomatic neonatal infection was noted when maternal infection occurred after 14 weeks of gestation. Hearing loss developed in 5% to 10% of asymptomatic infants.

The relative impact of primary versus nonprimary infection during pregnancy is another important determinant of CNS outcome. Approximately 30% to 40% of infants whose mothers experience primary infection during pregnancy develop congenital infection. Cytomegaloviruria has been observed in approximately 0.5% to 2% of infants in the neonatal period. Because a period of approximately 4 to 8 weeks is required between the time of infection and the viruria, these neonatal examples reflect intrauterine infection and not perinatal acquisition from parturitional or postnatal exposure. In these cases of cCMV infection, involvement of the CNS may be overt in the neonatal period or may not become apparent for months or years thereafter (see later discussion). In a prospective series of more than 117,986 infants screened, the overall CMV birth prevalence estimate was 0.7%. The percentage of infected children with CMV-specific symptoms at birth was 12.7%. The percentage of symptomatic children with permanent sequelae was 40% to 58%. The percentage of children without symptoms at birth who developed permanent sequelae was estimated to be 13.5%. The true burden of cCMV infection is unclear because data on important outcomes, such as visual impairment, are lacking and follow-up of infected children has often been too short to fully identify late-onset sequelae. Clinically apparent congenital infection after recurrent (nonprimary) maternal infection (i.e., infection in women with preexisting seroimmunity) is no longer considered a rare event because of the large prevalence of latent maternal CMV infection among women of childbearing age and the failure of maternal antibodies to prevent transmission during pregnancy. This phenomenon of intrauterine transmission in the presence of substantial maternal immunity has been attributed to reactivation of endogenous virus in some cases and to reinfection with different strains of CMV in other instances. In contrast to earlier notions, the majority of cCMV infections are due to nonprimary infections. Although the risk of intrauterine transmission is low after nonprimary infection, the number of seropositive women of reproductive age is very high. A higher prevalence was found in developing countries than for Europe and North America because of the higher maternal CMV seroprevalence. Data derived from 11 studies from Africa, Asia, and Latin America and involving numbers of newborns tested ranging from 317 to 12,195 showed maternal CMV seroprevalence ranging from 84% to 100%. cCMV birth prevalence varied from 0.6% to 6.1%.

Parturitional and Postnatal Infections

Parturitional and postnatal exposures cause an additional 10% to 15% of infants to acquire CMV infection in the first 4 to 8 weeks of life. Clinical signs and symptoms of pCMV infection in very or extremely preterm infants include pneumonia, enteritis, cholestasis, hepatosplenomegaly, sepsis-like syndrome, thrombocytopenia, and neutropenia. Postnatal CMV infection has also been associated with an increased risk for bronchopulmonary dysplasia and retinopathy of prematurity. In one study, 42% of infected infants developed clinical or laboratory abnormalities (neutropenia and thrombocytopenia). Another study showed a mean incubation time of 42 days (95% CI 28 to 69) with symptoms in about 50% of the infected infants and 4 of 33 with sepsis-like symptoms. In a study from the Netherlands the majority of CMV infected infants (85%) did not develop any symptoms of pCMV infection. The most important, independent risk factors of pCMV infection were non-native Dutch maternal origin (odds ratio [OR] 9.6 [95% CI 4.3 to 21.5]) and breast milk (OR 13.2 [95% CI 1.7 to 104.5]). The risk of infection significantly increased in infants with lower GA (OR 0.7 [95% CI 0.5 to 0.9]). Lenticulostriate vasculopathy (LSV) was significantly more often present at term equivalent age in infants with pCMV infection (OR 4.1 [95% CI 1.9 to 8.8]). Breast milk is probably the single most important source of CMV exposure in premature infants. It has been documented that 96% of CMV seropositive women have CMV reactivation with shedding of virus or the presence of CMV DNA in breast milk within several days after delivery. In a meta-analysis, among 299 infants fed untreated breast milk, 19% (11% to 32%) acquired pCMV infection and 4% (2% to 7%) developed pCMV-sepsis like syndrome (SLS). Among 212 infants fed frozen breast milk, 13% (7% to 24%) developed CMV infection and 5% (2% to 12%) an SLS, yielding slightly lower rates of breast milk–acquired CMV infection (4.4%; 2.4% to 8.2%) but similar rates of CMV-SLS (1.7%; 0.7% to 4.1%). The benefits of breast milk are still considered to outweigh the risks of severe disease from breast milk–acquired CMV infection in the neonatal period, which has so far not been associated with delayed development, SNHL, or clear cognitive impairment. Short-term pasteurization or freeze-thawing has been recommended in extremely preterm infants, with the latter preserving the bioactive compounds of the maternal milk and decreasing CMV transmission rate.

Blood transfusion has been a particularly important source in low-birth-weight (LBW) infants, but with the introduction of transfusion of CMV-seronegative and leukoreduced blood products, transmission of CMV to very-low-birth-weight infants has been effectively prevented. Although the results of one study raised the possibility of an increased risk of neurological sequelae in premature infants who acquire pCMV infection during the first 8 weeks of life, most data have indicated that CNS involvement does not occur with parturitional or early postnatal infection. However, recent long-term outcome studies raise some concern. Although no effect of pCMV infection was obvious at assessments between 2 and 4.5 years of age, differences in outcome were noted when 42 children were assessed again during adolescence ( n = 42, 11.6 to 16.2 years, mean = 13.9; 15 girls; 19 with and 23 without an early pCMV infection). Assessed with the German version of the Wechsler Intelligence Scale and the Developmental Test for Visual Perception, adolescents born preterm with early pCMV infection scored significantly lower than those without this infection regarding overall cognitive abilities (92.67 [14.71] vs. 102.75 [13.67], P = 0.030) but not visuoperceptive abilities (91.22 [10.88] vs. 98.96 [13.45], P > 0.05). However, the group of children is small and the data were not adjusted for known independent risk factors, such as postnatal corticosteroids, duration of mechanical ventilation, sepsis, other congenital infections, necrotizing enterocolitis, surgery, or socioeconomic status. The last of these is predictive of poor cognitive outcome and could be an important confounder. The reasons for the difference in propensity to affect the CNS between early prenatal versus natal or postnatal acquisitions of CMV remain to be determined.

Meningoencephalitis

Meningoencephalitis is characterized by the following features: (1) inflammatory cells in the meninges; (2) perivascular infiltrates with inflammatory cells; (3) necrosis of brain parenchyma, with all cellular elements affected, especially in the periventricular region, and often associated with calcification; (4) reactive microglial and astroglial proliferation; and (5) occurrence of enlarged cells (neuronal and glial elements) with intranuclear inclusions ( Fig. 38.1 ). Electron microscopic studies have revealed virions in brain tissue, a finding attesting to the primary infection of the CNS by the organism. Recovery of virus from the brain confirmed this conclusion. A role for the inflammatory response itself in causing tissue destruction is suggested by the disparity between the detection of cytomegaloviral DNA by in situ hybridization and the extent of the tissue necrosis.

The cellular and regional targets of the meningoencephalitis include especially the germinative ventricular-subventricular zones, radial glial cells, cerebral white matter, subplate neurons, and cerebral cortex. Germinal matrix necrosis and cysts are prominent. Subsequent matrix calcification is important in determining the periventricular distribution of calcifications. The particular tropism for progenitor cells in the ventricular-subventricular zones, radial glial cells, and subplate neurons has been identified recently. Periventricular cerebral white matter also is a site of injury, sometimes with cyst formation and subsequent calcification. A predilection for the parietal white matter may mimic periventricular leukomalacia (PVL). In addition, a predilection for anterior temporal white matter is particularly suggestive of CMV infection. Cerebral cortical atrophy is a later feature.

Microcephaly

Microcephaly is a common feature in the neonatal period and is still more prominent later in infancy. The small size of the brain appears to relate to the encephaloclastic effects of the virus and probably also to a disturbance of cell proliferation in the developing brain. The latter disturbance relates to the propensity of the virus to affect progenitor cells in the ventricular and subventricular zones (see earlier). A predilection for involvement of proliferative cells is also suggested by the frequency of intrauterine growth retardation in cCMV infection and by the observation in a variety of tissues of a decrease in absolute number of cells. A recent study in a pooled cohort of 2,338,580 pregnancies showed that CMV infection increases the prevalence of microcephaly at birth by at least sevenfold.

Disturbances of Neuronal Migration

Disturbances of neuronal migration have been described repeatedly in cCMV infection. Indeed, polymicrogyria has been documented in approximately 65% of well-studied cases. The polymicrogyria may involve cerebellar ( Fig. 38.2 ) and cerebral cortex. Although polymicrogyria has been observed most commonly, lissencephaly, pachygyria, schizencephaly, and neuronal heterotopias have also been reported. These observations demonstrate the teratogenic potential of CMV and suggest the occurrence of infection in the latter part of the first trimester and in the second trimester, when neuronal migration begins and then becomes active (see Chapter 6 ). The usual coexistence of inflammatory, destructive lesions indicates persistent infection by the organism. These cases also may be relevant to the notion that cerebral cortical neuronal injury late in the second trimester may underlie other examples of polymicrogyria (see Chapter 6 ). One careful study of four affected brains from infants with cCMV infection provided evidence of neuronal destruction in the lower cortical layers within areas of polymicrogyria and suggested that the cortical neuronal injury led ultimately to the gyral abnormality. At any rate, CMV infection was until recently the only congenital infection that is associated with overt disturbances of gyral development, and the pathogenesis thereof may include a combination of teratogenic and encephaloclastic mechanisms. Zika virus infection (see later) may exhibit similar disturbances of gyral development.

Cerebellar Hypoplasia

Cerebellar hypoplasia , best detected by magnetic resonance imaging (MRI), is a feature in at least 50% of symptomatic cases. This finding likely is primarily a proliferative disturbance, although, as noted earlier, migrational disturbances may also be seen in the cerebellum. The finding of cerebellar hypoplasia in the clinical setting of an intrauterine infection is highly suggestive of cCMV.

Other Findings

Porencephaly, hydranencephaly, hydrocephalus, focal subcortical cysts, impaired myelination, and more diffuse cerebral calcifications also have been described to variable extents in cCMV infection.

Incidence of Clinically Apparent Infection

Although cCMV infection occurs frequently, clinical manifestations thereof do not. Indeed, available data indicate that approximately 90% of affected infants are asymptomatic in the newborn period.

Clinical Features

The most frequent clinical features of symptomatic cCMV infection are shown in Table 38.4 . The most common findings relate to disturbance of the reticuloendothelial system. Hepatosplenomegaly and a petechial rash, usually related to thrombocytopenia, are encountered very frequently. Infants are often small for GA; moreover, approximately one-third of affected infants have a GA of 37 weeks or less. Inguinal hernia is a helpful clinical sign when present (≈25% of cases).

The neurological syndrome is variable in presentation. Seizures may be prominent, although only approximately 10% of symptomatic patients exhibit overt neonatal seizures. Microcephaly is a most consistent manifestation in patients with severe disease and appears in approximately 50% of all symptomatic patients. Cerebral calcification, usually periventricular in location, occurs in 50% to 60% of cases. Germinolytic cysts and LSV are also suggestive of CMV infection. CSF findings of encephalitis (e.g., pleocytosis, elevated protein content) are found in the majority of patients, but precise data are not available. In a more recent study, CSF β2-m levels were increased and of prognostic value of neurodevelopmental outcome.

The clinical course is most commonly that of a static process. Rare evidence of progressive encephaloclastic disease, documented by computed tomography (CT) scan, was provided by a report of two such cases. Similarly, postnatal evolution of cerebral calcification and of subependymal necrosis has been documented. Progression of hearing loss during infancy and early childhood has been described clearly (see later). The observation that virus is still recoverable in urine in 50% of cases at 5 years of age demonstrates persistence of infection and further raises the possibility of progressive disease.

Clinical Diagnosis

The diagnosis of cCMV infection may be suspected with a high degree of accuracy on the basis of certain clinical features. These features include the periventricular locus of the cerebral calcification, the presence of germinolytic cysts and LSV, best seen with cranial ultrasonography , microcephaly, CSF pleocytosis, and intrauterine growth retardation. Cerebellar hypoplasia and neuronal migrational abnormalities are also distinctive features and are best recognized with MRI. The absence of the “salt-and-pepper” chorioretinitis of congenital rubella and the relative infrequency of the grossly scarring chorioretinitis of congenital toxoplasmosis are also helpful.

It is recommended to distinguish between mildly, moderately, and severely symptomatic. “Mild” disease includes those with isolated (one or two at most), otherwise, clinically insignificant or transient findings, such as petechiae, mild hepatomegaly or splenomegaly, or biochemical/hematological abnormalities (e.g., thrombocytopenia, anemia, leukopenia, borderline raised liver enzyme abnormalities, or conjugated hyperbilirubinemia) or small for GA without microcephaly. “Moderate” disease includes those with persistent (e.g., more than 2 weeks’ duration) abnormalities of hematological/biochemical indices or more than two “mild” disease manifestations. “Severe” disease includes those with CNS involvement (abnormal neurological or ophthalmological examination, microcephaly, or neuroimaging consistent with cCMV disease [e.g., calcifications, moderate to severe ventriculomegaly, cysts, white matter signal intensity changes on MRI, cerebral or cerebellar hypoplasia, hippocampal dysplasia, and neuronal migration abnormalities]).

Diagnosis During Pregnancy

Most CMV infections encountered during pregnancy are asymptomatic. In about 5% there is a history of a flu-like episode. Only negative CMV serology (immunoglobulin M [IgM] and immunoglobulin G [IgG]) can exclude a cCMV infection. Both primary and nonprimary CMV infections (reinfection/reactivation) can lead to cCMV infection. The diagnosis of a primary CMV infection can be made by detection of seroconversion. In most countries women are not routinely screened for CMV antibodies prior to their pregnancy. The presence of anti-CMV IgM antibodies is considered to be a good indicator of an acute or recent CMV infection, but IgM antibodies are only present in 70% of infected babies, and in only less than 10% of IgM–positive women is the fetus infected. When the infection takes place preconception or very early in the pregnancy, IgM may have become negative by the time the suspicion of cCMV infection is raised. Pregnant women can also produce IgM during reactivation or reinfection and false positive results are not uncommon, because IgM may be found in mothers who have another viral illness (cross-reactive IgM), such as B19 or Epstein-Barr virus. A relationship between low total IgM values and clinical symptoms in newborns with cCMV infection has also been reported. This relationship can be explained by the longer period since the occurrence of the CMV infection, early in pregnancy, resulting in lower total IgM in symptomatic cases. Severe fetal sequelae were also reported in six fetuses despite maternal immunity for CMV confirmed by the detection of IgG with no IgM in previous pregnancies or early in the current pregnancy. cUS showed ventriculomegaly, cerebral calcification, and LSV, and amniocentesis confirmed presence of CMV by polymerase chain reaction (PCR) in all six.

The anti-CMV IgG avidity test is the most reliable procedure to identify primary infection in pregnant women. The avidity indices may vary with the tests used. Low avidity indices indicate low avidity IgG antibodies in serum caused by acute or recent primary CMV infection, whereas high avidity indices (high-avidity serum IgG) indicate no current or recent primary infection. The determination of anti-CMV IgG avidity, performed before the 16th to 18th weeks of pregnancy, identifies all women who will have an infected fetus/newborn (sensitivity 100%). After 20 weeks’ gestation, sensitivity is drastically reduced (62.5%). A high avidity index during the first 12 to 16 weeks’ gestation can be considered a good indicator of past infection. The presence of true IgM combined with low/moderate avidity index has the same diagnostic value as seroconversion. Although not quite as powerful as a high avidity result, an intermediate-avidity result during the first trimester also indicates a low risk of intrauterine transmission. In contrast, an intermediate-avidity or high-avidity result during the second or third trimester does not rule out postconception primary infection and is associated with increased risk of transmission. At present there are no validated tools to diagnose nonprimary CMV infection. There may be CMV-IgG prior to conception or early in pregnancy in combination with a positive CMV-IgM and CMV-IgG with high avidity or by a significant increase in CMV-IgG titer during gestation.

A reliable prenatal diagnosis is obtained by performing a PCR on the amniotic fluid, even though a negative PCR on amniotic fluid does not rule out CMV infection. Amniocentesis is best performed between the 21st and 22nd weeks of gestation. CMV is a slowly replicating virus, and 6 to 9 weeks are required after maternal infection for the virus to be eliminated in the fetal urine in amounts sufficient to be detected in the amniotic fluid. There is a risk of a false negative test, when the amniocentesis is carried out earlier when little virus is shed by the fetal kidney. The sensitivity and specificity (90% to 98% and 92% to 98%, respectively) for PCR analysis in the amniotic fluid are high with respect to viral transmission from mother to fetus. The risk of a severe infection with a high risk of severe sequelae occurs when the infection is contracted in the first 12 to 16 weeks of gestation.

Serological Studies

Many serological tests have been used, but the role of these tests have become less important with the use of the PCR. The commonly used complement fixation test depends on IgG, and because this fraction is primarily derived by passive transfer from the infected mother, titers are high in the neonatal period. Persistence of an elevated titer in the neonate suggests infection of the infant, because passively transferred maternal antibody is degraded with an approximate half-life of 21 to 23 days. A faster and more useful test depends on the detection of CMV-specific IgM, which is primarily derived from the infected fetus and infant.

Virus Isolation

Whereas viral isolation in urine has been the gold standard for the diagnosis of cCMV infection in the newborn for many years, PCR on urine is now the preferred diagnostic tool in a newborn before 21 days of life. PCR has also been shown to detect the virus in CSF, serum, saliva, and specimens of umbilical cord, and the use of saliva especially has recently been recommended for screening. In a prospective, multicenter screening study of newborns, comparing real-time PCR (rtPCR) assays of liquid-saliva and dried-saliva specimens with rapid culture of saliva specimens obtained at birth, 85 infants (0.5%) had positive results on both culture and PCR assay. The sensitivity and specificity of the liquid-saliva PCR assay were 100% (95% CI 95.8% to 100%) and 99.9% (95% CI 99.9% to 100%), respectively. Seventy-four newborns screened by means of the dried-saliva PCR assay were positive for CMV, whereas 76 (0.4%) were found to be CMV-positive on rapid culture. Sensitivity and specificity of the dried-saliva PCR assay were 97.4% (95% CI 90.8% to 99.7%) and 99.9% (95% CI 99.9% to 100%), respectively. As rtPCR assays of both liquid- and dried-saliva specimens showed high sensitivity and specificity for detecting CMV infection, the investigators suggested use of saliva-rtPCR as a potential screening tool for CMV in newborns. In another study enrolling 73,239 infants screened for CMV, 284 (0.4%) tested positive by rtPCR or rapid culture of saliva with a 94.7% concordance between rtPCR and rapid culture of saliva. Of 14 infants with discordance, 13 were correctly identified with saliva rtPCR but were missed with rapid culture. This discrepancy might be due to a decrease in the amount of infectious virus during storage, which occurs after 1 week even when stored at 4° C. The discordance could not be explained by a difference in viral load. Use of the rtPCR in saliva in preterm infants with postnatal CMV infection was recently reported to be less reliable. The virus was detected in 42 saliva samples (sensitivity 89.4%; CI 76.9% to 96.5%) among 47 infants with pCMV infection. Of 214 children without pCMV infection, one saliva sample tested positive for CMV (specificity 99.5%; CI 97.4% to 99.9%). Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose pCMV infections in preterm infants. This could be due to the lower mean viral shedding in infants with pCMV compared with infants with cCMV infection.

A recent study assessed the value of dried blood spots (DBS) among 12,554 individuals, with 56 confirmed to have PCR-urine-confirmed CMV infection. Combined DBS results from the University of Minnesota and the U.S. Centers for Disease Control and Prevention (CDC) had a sensitivity of 85.7% (48 of 56; 95% CI 74.3% to 92.6%), specificity of 100.0% (95% CI 100.0% to 100.0%), positive predictive value (PPV) of 98.0% (95% CI 89.3% to 99.6%), and negative predictive value (NPV) of 99.9% (95% CI 99.9% to 100.0%). The investigators suggest that these results are better than reported previously due to more sensitive DNA extraction and improved PCR methods. The use of DBS is worth considering in infants referred with hearing loss or developmental delay. Of 401 children with cerebral palsy DBS were available in 80% and could be used, and CMV DNA was present in 31 of the 323 samples (9.6%; 95% CI 6.8% to 13.3%).

Diagnostic Studies

CSF characteristically exhibits the findings of meningoencephalitis. In a study of 18 infants with neurological manifestations, the mean white blood cell count was 42, including predominantly lymphocytes, and the mean protein content was 192 mg/dL. In another study of 56 infants (which included 30% with no CT abnormalities), CSF protein exceeded 120 mg/dL in 50%. There is, however, no current evidence that performing a lumbar puncture is needed for the diagnosis of CMV or to improve prediction of outcome. In a study of 136 neonates, 17/21 (81%) with a positive CSF-PCR were symptomatic at birth compared with 52.2% of infants in the negative group (OR 3.86; 95% CI 1.28 to 14.1; P = 0.01). There were no differences between groups regarding the rate of microcephaly, neuroimaging abnormalities, neurological sequelae at 6 months of age, or plasma viral load. In another study of 168 infants, positive CSF-PCR for CMV was associated with a higher rate of CNS damage, both SNHL and MRI abnormalities, but only 23 (13.7%) had positive PCR results in the CSF and many infants did have CNS involvement in the absence of a positive CSF-PCR. In a multivariable regression analysis SNHL (OR 7.18; 95% CI 1.75 to 29.34; P = 0.006), cystic lesions on the MRI (OR 5.29; 95% CI 1.31 to 21.36; P = 0.02) and calcifications on MRI (OR 7.19; 95% CI 1.67 to 30.97; P = 0.008) were significant independent predictors of positive CSF-PCR results.

Skull radiographs formerly were used to demonstrate the periventricular calcifications ( Fig. 38.3 ). CT scanning is more sensitive than skull radiography for detection of calcifications ( Fig. 38.4 ). In a series of 41 infants with symptomatic cCMV infection, a CT-detected abnormality was present in 78%. Of those with abnormalities, periventricular calcifications occurred in 75%, varying degrees of cortical and white matter abnormalities were seen in 30%, and ventriculomegaly was reported in 40%. CT scanning was recommended in the past as the gold standard to assess cerebral involvement in infants with cCMV infection, but CT scanning is no longer recommended in such infants. cUS and MRI are safer, reliable alternatives.

cUS frequently demonstrates abnormalities. These findings consist of periventricular cysts, especially in the region of the subependymal germinal matrix (see Figs. 38.5 and 38.6 ), ventriculomegaly, periventricular (and more diffuse) calcifications, and periventricular echolucencies (consistent with cerebral white matter cysts) ( Fig. 38.6 ). The correlations with neuropathological findings (see previous discussion) are obvious. An additional ultrasonographic finding, overt in approximately one-third of cases, is the presence of branched echodensities in basal ganglia and thalamus ( Fig. 38.6 ). That the echodensities are alongside the lenticulostriate arteries has been shown by Doppler ultrasound examination and they are therefore referred to as LSV ( Fig. 38.6 ). In two series, 15% to 40% of infants with such echodensities had cCMV infection. (Other diagnoses included congenital rubella, congenital syphilis, trisomy 13, trisomy 21, fetal alcohol syndrome, metabolic disorders, and “neonatal asphyxia.”) One pathological study defined hypercellular vessel walls and a mineralizing vasculopathy, probably secondary to perivascular inflammation ( Fig. 38.8 ).

MRI is of particular value for detection of the disorders of neuronal migration, cerebral parenchymal destruction, delays in myelination, and cerebellar hypoplasia observed with cCMV ( Figs. 38.7 and 38.9 to 38.11 ). In a series of MRI-documented lissencephaly pachygyria, CMV infection was present in 6 of 23 cases. Several studies have compared cUS and MRI findings and have shown the techniques to be complementary, with cUS being superior in identifying LSV and germinolytic cysts and MRI in identifying migrational disorders and signal intensity abnormalities in the white matter. In a study of 40 infants with cCMV infection cUS and cMRI were performed within the first month of life. Six newborns showed pathological cMRI and cUS findings (pseudocysts, ventriculomegaly, calcifications, cerebellar hypoplasia), but MRI provided additional information (white matter abnormalities in three cases, lissencephaly/polymicrogyria in one and a cyst of the temporal lobe in another one); cerebral calcifications were detected in 3 of 6 infants by cUS but in only 2 of 6 by MRI. Four of these six infants showed severe neurodevelopmental impairment, and five showed deafness on follow-up. Three newborns had a normal cUS, but MRI documented white matter abnormalities and in one case also cerebellar hypoplasia; all showed neurodevelopmental impairment and two were deaf at follow-up. In another study, 36 infants with cCMV infection were studied, with MRI available in 20, allowing comparison of cUS and MRI. Migrational disorders were diagnosed only with MRI in 9 of the 20 infants assessed with this technique. Seven out of 10 infants infected during the first trimester had severe abnormalities on cUS (five confirmed on MRI) and adverse sequelae; three had no/mild abnormalities on cUS/MRI and a normal outcome. Six out of 7 infants infected during the second or third trimester with no/mild abnormalities on cUS/MRI had a normal outcome; one with mild cUS and MRI abnormalities developed SNHL. As expected the worst outcome was seen in 16 of 26 symptomatic infants with severe cUS/MRI abnormalities (neuronal migration disorders only seen on MRI, cerebellar hypoplasia, ventriculomegaly, extensive periventricular calcifications, white matter cysts). In 1 of 16 infants with only mild abnormalities on cUS (germinolytic cysts and LSV), occipital cysts and extensive polymicrogyria were noted with MRI ( Fig. 38.9 ), highlighting the need for MRI even in the absence of severe cUS abnormalities. The study again showed that infants with CMV infection acquired during the first trimester of pregnancy are at increased risk of symptomatic presentation with severe cerebral abnormalities, mortality, and subsequent development of adverse sequelae such as cerebral palsy and SNHL. One recent study compared all three neuroimaging techniques (cUS, CT, and MRI) in 112 symptomatic infants. Migrational abnormalities were recognized in 3 (2.9%) infants with cUS, 2 (1.9%) with CT, and 12 (11.8%) with MRI. White matter abnormalities were never identified with cUS, in 18 (17.8%) with CT, and 43 (42.2%) with MRI. In the largest imaging study thus far, 480 infants with CMV infection had both cUS and MRI, and approximately 20% (93 of 480) of those with normal cUS had abnormalities on MRI. Based on these MRI abnormalities, 37 (39.8%) were diagnosed as having a severely symptomatic CMV infection. These MRI findings were mostly extensive white matter abnormalities and ventriculomegaly. Of the 93 infants, 58 were treated with valganciclovir, and in 47 the decision was made based on MRI findings only.

The presence of hippocampal malrotation was evaluated on coronal MRI in 17 children with cCMV infection and compared with 17 age-matched controls. Hippocampal malrotation was present in 17 of 34 hippocampi (50%) in the cCMV infection group and 1 of 34 hippocampi (2.9%) in controls. The presence of hippocampal malrotation was not related to worse cognitive outcome or the presence of autism spectrum disorder or epilepsy.

Delays in myelination and increased signal on T2-weighted images (see Figs. 38.8 and 38.9 ) have been observed in approximately one-half of infants with CMV studied by MRI. Indeed, the predilection of abnormal cerebral white matter signal, including cystic change, for posterior parietal regions may mimic PVL. Thus in an MRI series of 152 infants (mean age, 22 months) with “static leukoencephalopathy of unknown etiology,” 10% were found to have cCMV, based on retrospective PCR testing of neonatal blood spots. A recent study from Japan assessed dried umbilical cord samples and found that 30 of 31 children with a positive test result had signal intensity abnormalities in the deep white matter, most in the parietal lobe ( n = 25). The effect of these isolated signal intensity changes in the white matter on neurodevelopmental outcome depend on extent and site, and were found to be associated with an adverse outcome when located in the temporal pole. Cerebellar hypoplasia, a finding in 40% to 70% of infants with CMV infection, is detected best by MRI scanning ( Fig. 38.10 ). Notably, MRI is less sensitive than CT and similar to cUS for detection of cerebral calcifications. Two MRI scores have been reported, one based on a combination of postnatal cUS and MRI findings, and a more recent one only on MRI findings.

Antenatal neuroimaging combining cUS and MRI has shown characteristic findings, also seen on postnatal imaging. Many of the common findings in cCMV are illustrated in a review by Averill and colleagues. Dilated occipital horns of the lateral ventricles with thin septations can be well visualized with cUS and MRI. These characteristic occipital “cysts” are usually bilateral and will become less conspicuous with time ( Figs. 38.10 and 38.11 ). Polymicrogyria is likely to be missed with cUS, is easier to detect on postnatal MRI, and is often seen with too many infoldings for GA, a thickened cortical ribbon with irregular gyration or unclear gray-white matter border. Although polymicrogyria may at least be suspected on fetal MRI, it can be difficult, and confirmation on a postnatal MRI is recommended. Several studies have compared fetal cUS and MRI. In a study by Doneda and coworkers, prenatal cUS and MRI findings were compared in 30 fetuses with a proven cCMV infection. Fetal MRI did show higher sensitivity than cUS in predicting symptomatic infection (83% vs. 33%). However, both modalities showed low PPVs (36% with MRI vs. 29% with cUS). In another study of fetal cUS and MRI in 38 cases of cCMV infection, MRI was shown to add important details, especially with regard to detection of gyrational anomalies, cerebellar hypoplasia, and white matter abnormalities. In both studies and a more recent study, a negative fetal brain MRI finding was reassuring for a good clinical outcome, although development of hearing loss may still occur with time. In a recent study 123 fetuses with a primary CMV infection in the first trimester were studied with fetal cUS and an MRI at 32 weeks of gestation. Abnormal cUS findings were present in 30.9%. Abnormal MRI findings were present in 30.1% of all fetuses and in 14% of fetuses with normal cUS. Of 85 with a normal cUS, 12 had abnormalities on MRI, and in five (5.9%) there were clear anatomical findings, including periventricular and temporal lobe cysts. SNHL was diagnosed in 7 of 25 with cUS abnormalities but also in 11 of 83 (13.3%) with normal imaging findings. Neurodevelopmental disability was seen in 5 of 25 (20%) of those with abnormal imaging but also in 7 of 83 (8.4%) with normal imaging.

Hearing loss caused by cCMV infection was first reported in 1964 and is the most common sequela of cCMV infection. Hearing loss is thought to be due to cytopathic effects and localized inflammatory responses. This infection is now known to be the most common cause of nonhereditary SNHL, involving 10% to 20% of hearing impaired children. Testing of brainstem auditory evoked responses in the neonatal period and subsequently demonstrates the high likelihood of SNHL, including the delayed onset and the postnatal progression of this loss. In four series of 281 infants with symptomatic cCMV infections, 30% to 75% exhibited hearing loss on follow-up. Although approximately 60% of those with hearing loss had hearing loss at birth or in the neonatal period, fully 40% had delayed-onset loss (i.e., not apparent until months after the neonatal period). Additionally, progressive hearing loss was noted in approximately 60% of the infants with hearing loss. Progression of hearing loss has also been observed in infants with asymptomatic CMV infection. Thus in one series, 3% of such patients had hearing loss detected in the neonatal period, but by the age of 6 years, 11% of the previously asymptomatic patients had hearing loss. In a meta-analysis of 14 longitudinal and 13 retrospective studies, among infants with a proven cCMV infection 12.6% (95% CI 10.2% to 16.5%) were shown to have hearing loss: 1 out of 3 symptomatic children and 1 out of 10 asymptomatic children. Bilateral hearing loss was present in most children with symptomatic cCMV infection, while unilateral hearing was more common in those with asymptomatic cCMV infection. Hearing loss may have a delayed onset and may vary over time. Foulon and colleagues showed that the risk of cCMV-related SNHL was highest when the infection occurred during the first trimester (4 of 5; 80%), rare after an infection during the second trimester (1 of 12; 8%), and nonexistent in their 11 children with cCMV acquired during the third trimester. In a prospective study by the same group, 157 infants with CMV infection were enrolled, seven of these being symptomatic. Hearing loss was diagnosed in 20 (12.7%), and nine (5.7%) required hearing aids. Improvement was seen in nine (45%), progressive hearing loss in seven (53.8%), and fluctuations in 5.7%. Hearing loss was significantly more common in case of a symptomatic infection ( P = 0.017), a primary infection ( P = 0.029) and neuroimaging abnormalities ( P < 0.001). The same group studied a larger group of 411 infants with CMV infection. Of these 164 (40%) were symptomatic and a significant relation was once again noted between the presence of cUS and MRI abnormalities and hearing loss, but not with the development of delayed-onset hearing loss. Specificity and sensitivity of an abnormal cUS to predict hearing loss at final follow-up were 84% and 43%, respectively, compared with 78% and 39% for MRI. The risk of delayed hearing loss was shown to be associated with the presence of symptoms at birth, with children who passed initial audiologic examinations but who had cCMV-related symptoms at birth (e.g., jaundice, petechiae, microcephaly) nearly six times more likely to develop hearing loss than children asymptomatic at birth. A longer duration of viral shedding may also be a predictor of delayed hearing loss. The value and importance of serial studies throughout infancy are obvious .

Relation to Time of Onset of Fetal Infection and Antenatal Neuroimaging Findings

In a large prospective study, enrolling 145 fetuses during pregnancy, with a primary CMV infection obtained during the first and second trimesters of pregnancy in 71 and 74 patients, respectively, the risk of an adverse outcome was significantly higher when the infection occurred during the first trimester and when imaging abnormalities were found as well ( Table 38.5 ). Abnormal prenatal findings on ultrasound examination were associated with increased risk of sequelae. In a study of 121 fetuses, MRI was performed at 27 and/or 33 weeks (51 at both timepoints). A five-grade classification was used: grade 1 for normal findings, grade 2 for the presence of isolated frontal or parietooccipital periventricular T2-weighted signal hyperintensity, grade 3 for the presence of isolated temporal periventricular T2-weighted signal hyperintensity, grade 4 for the presence of cysts and/or septa in the temporal and/or occipital lobe, and grade 5 for the presence of migration disorders, cerebellar hypoplasia, and microcephaly. Isolated periventricular T2-weighted signal hyperintensity was a very common finding in cCMV infection (41%) but was not associated with adverse postnatal outcome, except for 3 of the 21 neonates (14.3%) with isolated hyperintensity of the temporal lobes who also had SNHL. The NPV was especially high: 96% in the absence of any MRI abnormalities.

Relation to Neonatal Clinical Syndrome

The outcome relates to the severity of the neuropathological findings, and these findings correlate with the neonatal clinical syndrome ( Table 38.6 ). Although the data depicted in Table 38.6 are based on a sample that was selected to a certain degree, the observations are useful regarding the relationship between the neonatal clinical signs and the neurological outcome in cCMV infection. Thus of those infants with the overt neurological syndrome (i.e., microcephaly, intracranial calcifications, or chorioretinitis), approximately 95% had major neurological sequelae (e.g., intellectual retardation, seizures, deafness, and motor deficits) or died. Infants with less obvious (“other”) neurological phenomena had slightly better prognoses. Approximately 70% of these infants with neonatal neurological signs also experienced systemic phenomena. In the large series ( n = 80) of MacDonald and Tobin, of the group of infants with systemic signs but no neonatal neurological deficits, approximately 50% were normal, and only 16% exhibited major neurological sequelae or died (see Table 38.6 ). Further insight into the spectrum of cCMV infection is provided by the results of a more recent study of 178 infants by Dreher and colleagues. Comparison was made between a group of 78 recognized by newborn screening and 100 infants referred with clinical symptoms which led to the diagnosis of cCMV infection. Two or more clinical findings were detected at birth in 91% of referred infants, and only 58% of screened infants ( P < 0.001). Significantly more children in the referred group had hearing loss compared with screened infants ( P = 0.009). Fifty-one percent of screened children were free of sequelae at follow-up compared with only 28% of the referred group ( P < 0.003). Another study collected data from over 50,000 newborns born in Sweden and the United Kingdom. Of 176 CMV-infected neonates 19 (11%) were symptomatic, but only one of them had neurological symptoms. There were significantly more children (8 of 19; 42%) with sequelae among those who were symptomatic at birth, compared with those who were asymptomatic (19 of 135; 14%; P = 0.006).

For more reliable prediction of neurological sequelae, MRI is currently recommended, especially in the presence of any cUS abnormality. MRI allows assessment of additional migrational abnormalities not recognized with cUS ( Fig. 38.7 ). The major neurological deficits include pronounced cognitive deficits, most commonly with intelligence quotient (IQ) scores lower than 70, spastic motor deficits, seizure disorders, and bilateral hearing loss. In two series of 97 infants with symptomatic cCMV infection, intellectual retardation (IQ < 70) developed in 45% (IQ < 50 in 36%), cerebral palsy in 45%, seizures in 11%, and SNHL in 60%. Outcome was accurately predicted based on abnormal cUS findings in 12 of 57 (21%) neonates. cUS lesions were more frequent in newborns with clinical and laboratory signs of cCMV infection at birth (10 of 18) than in newborns who had no symptoms at birth (2 of 39; P < 0.001). cUS abnormalities consisted of a combination of calcifications, LSV, ventriculomegaly, cysts, and cerebellar abnormalities. Additional neuroimaging, including MRI, performed in eight infants, provided more information in six, including migrational disorders and white matter abnormalities. At least one sequela developed in all symptomatic neonates who had abnormal cUS results, whereas none of the neonates with symptoms without cUS abnormalities had long-term sequelae ( P < 0.001). In the population without symptoms, SNHL developed in 3 of 37 (8.1%) neonates with normal cUS results, whereas severe sequelae developed in 1 of 2 neonates with abnormal cUS results. Another study of symptomatic infants showed relative microcephaly, CSF β2-m (beta ₂ microglobulin) concentrations, and grade 2 to 3 neuroimaging abnormalities: in grade 1, single punctate calcification and/or LSV; in grade 2, multiple discrete periventricular calcifications and/or moderate to severe ventriculomegaly; and in grade 3, extensive periventricular calcifications and/or brain atrophy to be significantly associated with unfavorable outcome. The combination of CSF β2-m greater than 7.9 mg/L and moderate-severe neuroimaging alterations improved predictive ability (area under the curve, 0.92 ± 0.06; sensitivity, 87%; specificity, 100%).

Outcome With Asymptomatic Congenital Infection

The asymptomatic group has been the particular focus of numerous investigators. In these studies, the most consistent sequela was SNHL ( Table 38.7 ). Approximately 11% of the infants developed bilateral hearing loss, with moderate to profound loss in 6%. In a recent study 34 infants were identified by targeted CMV screening and a normal physical examination. One or more abnormalities were noted in 56% (19 of 34): 39%, elevated alanine transaminase concentration; 45%, abnormal neuroimaging (five, LSV; six, intraventricular hemorrhage; four, calcifications); 12%, anemia; 16%, thrombocytopenia; 3%, chorioretinitis); 21% had SNHL. Often, hearing deficits were not detected until serious impairment of language development occurred. Indeed, as noted with symptomatic disease, with more frequent serial measurements, it became clear that hearing impairment often did not become clearly apparent until, and progressed during, infancy and early childhood (see earlier discussion). In a large longitudinal study of 307 infants, 7.2% exhibited SNHL, and among these infants, 50% exhibited progression (median age at onset of progression, 18 months), and 18% exhibited delayed onset (median age of detection, 27 months). Seventy-seven of 580 children had hearing loss at birth, and 38 additional children developed delayed hearing loss by the end of follow-up. In multivariate analyses, delayed hearing loss was strongly associated with symptomatic infection at birth (OR 5.9; 95% CI 1.8 to 18.9) and modestly associated with older age at last culture-positive visit (OR = 1.6; 95% CI 1.1 to 2.0, comparing 1-year age differences). Between the ages of 6 months and 8 years, delayed hearing loss can be expected to occur in 6.9% of asymptomatic children and in 33.7% of symptomatic children. In a study of 388 infants, as noted earlier, 3% of asymptomatic infants had SNHL in the first month, and 11% had hearing loss by 6 years of age. In a more recent series of 300 affected infants born after nonprimary ( n = 124) or primary ( n = 176) infection, although bilateral hearing loss occurred equally in both groups (10% to 11%), infants born after primary maternal infection were more likely to have severe or profound hearing loss (63% vs. 15%). The diagnosis of hearing loss was made earlier in the infants born after primary maternal infection (mean age, 13 months vs. 39 months). Histopathological and immunofluorescent studies of the inner ear in two affected infants revealed destruction of cells of the organ of Corti and the neurons of the eighth cranial nerve, as well as the presence of viral antigen. Thus involvement of cochlear structures with cCMV infection and the consequent disturbance of hearing may be an enormous public health problem, in view of the prevalence of the infection. Assessment of the viral load in blood at birth may aid in the prediction of the development of such late-onset sequelae in asymptomatic cCMV infection. This conclusion was supported by a study of 33 newborns with asymptomatic cCMV infection born to women with primary CMV infection during pregnancy. Ten showed postnatal sequelae, including isolated SNHL in seven, and these sequelae were significantly related with DNAemia at birth, with a risk of hearing deficit apparent with a blood viral load of greater than 17,000 copies/mL.

The possibility of later subtle disturbances of intellectual function in asymptomatic newborns was initially suggested by studies conducted by Hanshaw and coworkers, who demonstrated a statistically significant lower mean IQ score in asymptomatic patients versus matched controls (102 vs. 112). Subsequent large-scale studies did not document definite impairment of intellectual function in asymptomatic infants, particularly when hearing-impaired children were excluded. A recent study assessed intelligence, language, and academic achievement through 18 years of age in 89 infants who were identified by newborn screening. Those ( n = 78) who had normal hearing at 2 years of age had full-scale intelligence and receptive vocabulary scores similar to controls, but those with SNHL ( n = 11) had full-scale intelligence and receptive vocabulary scores that were 7.0 and 13.1 points lower, respectively, compared with controls. More data on intellectual outcome in hearing impaired children will be important because the virus clearly has entered the CNS in this subgroup of infected infants. Several reports do suggest that an asymptomatic neonatal period may be followed by varying combinations of developmental delay, microcephaly, ataxia, SNHL, and seizures, usually recognized in the first year of life. CT and MRI have shown cerebral calcification, abnormal cerebral white matter signal, delayed myelination, polymicrogyria, focal subcortical areas of abnormality, or cerebellar hypoplasia. The possibility of late intrauterine acquisition of infection has been suggested in some of these asymptomatic infants but most studies suggest that although the risk of intrauterine transmission after primary maternal infection in the third trimester is high, the risk of neonatal disease is low. In the study by Enders and colleagues no symptoms were observed in infected newborns of mothers with primary infection in the preconceptional period and in the third trimester.

The important clinical point is that CMV infection should be considered later in infancy in the presence of such neurological or neuroradiological features, or both, even if the neonatal period was unremarkable . More data are needed on these issues.

Prevention

cCMV infection is related to primary infection of the pregnant woman, presumably early in pregnancy. Two preventive approaches may be used: one to prevent or treat the primary infection and the other to terminate the pregnancy. First of all, education about hygienic measures (avoid contact with bodily fluids of young children) is important, especially in a household where the first child in the family is attending daycare. Prevention of the primary maternal infection by vaccination has received initial investigation, with variable results. However, more information is needed about the effectiveness, hazards, and feasibility of this approach. Treatment of the primary maternal infection with hyperimmune gamma globulin is a possibility, but the difficulty in detecting most maternal infections has been a major problem with this approach. The results of the first randomized trial with hyperimmune gamma globulin or placebo enrolled 124 women with primary CMV infection. There was no difference in viral load in the amniotic fluid and newborn urine and no difference in cCMV infection. There was a nonsignificant increase in adverse obstetrical events, including preterm birth, preeclampsia, and fetal growth restriction. A very recent randomized controlled trial (RCT) was stopped early for futility. A total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation and 712 tested positive (0.35%). Of the 399 (56%) who participated, 46 of 203 women (22.7%) in the group that received hyperimmune globulin and 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% CI 0.80 to 1.72; P = 0.42) had CMV infection or fetal or neonatal death.

Termination of a pregnancy complicated by a primary maternal infection has been difficult because the exact risks of fetal infection are not entirely known. Detection of the infected fetus by amniocentesis and identification of the virus or DNA by culture or PCR, respectively, are the principal approach. The sensitivity for detection of fetal infection increases markedly after 21 weeks of gestation. The fetal condition can then be assessed further by ultrasonography, which may show intracranial calcification or other evidence of parenchymal disease, and, if desired, by cordocentesis, with evaluation of fetal blood for abnormal liver function tests, CMV-specific IgM, anemia, or thrombocytopenia. In one series, the risk of identification of neonatal neurological abnormality by neurological examination, cranial ultrasonography, or hearing assessment was only 19% when no prenatal ultrasonographic abnormalities were present. Ultrasonographic abnormalities were detected prenatally in 21%, and nearly all these pregnancies were terminated.

Supportive Therapy

From the neonatal neurological standpoint, supportive therapy consists principally of control of seizures.

Antimicrobial Therapy

Prenatal therapy with CMV-specific hyperimmune immunoglobulin is controversial, with recent clinical trials refuting earlier claims of improved outcomes. Investigation of maternal oral treatment with valacyclovir is currently in clinical trials as well. Following a multicenter, open-label, phase II study in 43 fetuses treated with oral valacyclovir (8 g daily) in utero, the same group performed a case-control study in a longitudinal cohort of pregnancies with CMV infection diagnosed before 14 weeks of gestation by serology screening. Sixty-five fetuses were treated with valaciclovir from around 13 weeks of gestation with a median duration of 5 weeks. Using multivariate logistic regression, fetal infection was lower in the treated group (OR 0.318; 95% CI 0.120 to 0.841; P = 0.021). In a randomized, double-blind, placebo-controlled trial, 100 women with serological evidence of a primary CMV infection acquired either periconceptionally or during the first trimester of pregnancy were enrolled and 90 treated until an amniocentesis was performed at 21 to 22 weeks of gestation. Five (11%) of 45 amniocenteses were positive in the valaciclovir group, compared with 14 (30%) of 47 amniocenteses in the placebo group (OR 0.29; 95% CI 0.09 to 0.90 for vertical CMV transmission; P = 0.027). One pregnancy in the valaciclovir group and two pregnancies in the placebo group were terminated because of CMV-related fetal damage observed on fetal brain ultrasound and MRI. A further three pregnancies were terminated on maternal request in the placebo group after a positive amniocentesis but without any evidence of CMV-related damage. Bilateral SNHL was diagnosed in six infants, five of whom were in the placebo group. No moderate-severe neuroimaging abnormalities were noted.

Treatment in the neonatal period is more clearly established and is instituted in infants with evidence of brain involvement, including SNHL and other serious end organ disease. Several antiviral agents, including adenine arabinoside (Ara-A), 5-iodo-2′-deoxyuridine (IDU), cytosine arabinoside (Ara-C), and acyclovir, have been studied because of their effectiveness in vitro. Ara-A and acyclovir are the least toxic of these agents, but early trials did not provide reason for optimism. Ganciclovir, an acyclovir derivative, has been shown to be effective in prophylaxis and treatment of CMV infections in immunocompromised adults and children. Initial data with infants were promising. An earlier study of 12 infants with cCMV infection suggested distinct clinical benefit (e.g., loss of hepatosplenomegaly, improvement in tone) with a 3-month course of therapy. The most impressive data with ganciclovir involved an RCT of the effect of the agent on hearing in symptomatic cCMV disease involving the CNS ( Table 38.8 ). The treated infants received ganciclovir, 6 mg/kg per dose administered intravenously every 12 hours for 6 weeks. Hearing deficits either improved or remained static in 56% of the ears of treated infants versus only 17% of those of the control infants (see Table 38.8 ). Progression of deficits occurred in only 21% in the ganciclovir group versus 61% in the control group. The beneficial effect of ganciclovir was accompanied by significant neutropenia in approximately 65% of treated infants. These findings were supported by an observational study enrolling 23 asymptomatic infants with cCMV infection. Twelve infants were treated just after diagnosis of cCMV infection in the newborn period, with ganciclovir 10 mg/kg body weight for 21 days. The other 11 infants were observed without therapy. All 23 infants had normal sensorineural hearing at 1-year follow-up. A total number of 18 children were seen over the 4- to 11-year follow-up period. SNHL occurred in two (11.1%) children who did not receive ganciclovir in the newborn period. None of the nine ganciclovir-treated children developed SNHL. During ganciclovir therapy, moderate neutropenia occurred as a side effect in 2 out of 12 (16.6%) treated children.

The experience with ganciclovir illustrated the need for an agent that has less toxicity and can be administered orally. Valganciclovir, shown to be effective in adults with CMV retinitis, proved to be such an agent. In a randomized, placebo-controlled trial of valganciclovir therapy in 96 neonates with symptomatic cCMV disease, the effect of 6 months of therapy was compared with 6 weeks of therapy ( Table 38.8 ). The primary end point was the change in hearing in the better ear (“best-ear” hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for CNS involvement at baseline. Eighty-six of the initial 96 neonates could be evaluated at 6 months. There was no difference for best-ear hearing at 6 months. Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month treatment group compared with the 6-week treatment group (73% vs. 57%; P = 0.01). This benefit was still present at 24 months (77% vs. 64%; P = 0.04). At 24 months, the 6-month group, compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component ( P = 0.004) and on the receptive-communication scale ( P = 0.003). Neutropenia was not uncommon and occurred in 27% of those in the 6-week treatment group. In the 6-month treatment group neutropenia occurred in 19% of the infants during the first 6 weeks and in 21% during the next 4.5 months. Because migrational disorders are associated with the most severe adverse neurological sequelae and evolve in utero, it is unlikely that either 6 weeks or 6 months of treatment with valganciclovir will have a positive effect on such neurological sequelae. Preservation of hearing, however, would be of benefit and the policy of 6 months of therapy is now recommended. Treatment of 12 months with a combination of ganciclovir and valganciclovir was reported recently. Hearing impairment was diagnosed at birth in 59 (18%) of the 329 infants diagnosed with symptomatic cCMV and was unilateral in 38 (64.4%) and bilateral in 21 (35.6%). After 1 year of antiviral treatment and a long-term follow-up of the 80 affected ears at baseline, 55 (68.8%) had improved, 23 (28.7%) remained unchanged, and 2 (2.5%) had deteriorated. Most improved ears (53 of 55; 96.3%) returned to normal hearing. Improvement was most likely to occur in infants born with mild or moderate hearing loss and less in those with severe impairment. A recent systematic review assessed hearing outcome in 682 symptomatic infants with hearing loss from 18 studies who were treated with (val)ganciclovir. Improvement in hearing was present in 44.5% in treated versus 9.4% in the untreated group. Deterioration in hearing was noted in 6.3% of the treated versus 28.2% of the untreated group.

There is at present no agreement about the beneficial role of treatment with valganciclovir in preterm infants with pCMV infection. Most clinicians are reluctant to use a potentially toxic drug in preterm infants and restrict therapy to those with a sepsis-like illness. Ultimately, treatment of asymptomatic infants would be ideal if the risk-to-benefit ratio of the agent were favorable.

Fetal Infection

Clinically significant infection with toxoplasmosis occurs during intrauterine life by transplacental passage of the parasite. The sequence of events is (1) primary infection of the mother or reactivation in a previously T. gondii –immune pregnant woman who is severely immunocompromised during pregnancy, or after reinfection with a new more virulent strain; (2) parasitemia; (3) placentitis; and (4) hematogenous spread to the fetus. The parasite can cross the blood-brain barrier in three ways: migration directly through the tight junctions of the endothelial layer, infection of the endothelial cells with replication within these cells and then egress into the brain, and facilitated entry within and infected antigen-presenting leukocyte. The organism can be cultured consistently from the placenta when the fetus is infected. As with CMV, the mother infected with toxoplasmosis is usually asymptomatic. The most common clinical presentation of the mother is localized or generalized lymphadenopathy, sometimes with fever and other features suggestive of infectious mononucleosis.

The incidence of primary maternal infection during pregnancy varies around the world. In Paris, when consumption of undercooked meat was relatively common, the value was as high as 5 per 100 pregnancies. At a comparable time, the rate in the United States was approximately 1.1 per 1000 pregnancies. More recent incidences (2006 to 2014) of congenital toxoplasmosis are 0.23 cases per 10,000 live births in the United States with an estimated number of 170 infected newborns each year. These rates should be contrasted with the approximately 20-fold increase in rates for CMV infection during pregnancy (see earlier discussion). Despite increasing maternal age, seroprevalence for toxoplasmosis for U.S.-born women of childbearing age decreased steadily from 15% in 1988 to 1994 to 9% during the most recent period studied (2009 to 2010). Seroprevalence was, however, as high as 60% to 80% in Mexico and Brazil. The unusual susceptibility of the human fetus and newborn to severe infection with T. gondii appears to relate, in large part, to inadequate cellular defenses. Mononuclear phagocytes are the principal defense against such infection, and a decreased generation of macrophage-activating material by fetal lymphocytes has been demonstrated. Moreover, the response to this activating material by macrophages in the neonate is also deficient. Unchecked replication of the organism is the expected result.

Importance of Time of Maternal Infection

The likelihood and severity of congenital toxoplasmosis bear a distinct relation to the time of maternal infection ( Table 38.9 ). After the introduction of prenatal screening in France in 1992, a significant reduction in the rate of congenital infection and a better outcome at 3 years of age in infected children was reported. Among 2048 mother-infant pairs, 93% of mothers received prenatal treatment and 513 (25%) fetuses were infected. Probabilities of congenital infection were less than 10% for maternal infections before 12 weeks of gestation, 20% at 19 weeks, to 52% at 28, and almost 70% at 39 GA weeks, respectively. More recent data from the United States reported that 15% (13% to 17%) of infants will be infected after maternal seroconversion at 13 weeks, 44% (40% to 47%) at 26 weeks, and 71% (66% to 76%) at 37 weeks. These data have not changed from data published by Dunn and colleagues in 1999. However, although fetal infection is less likely earlier in pregnancy, the severity of the disease is greater. Indeed, most infants infected in the first trimester exhibit severe disease, manifested by CNS and ocular involvement (see Box 38.2 ). As a result of these counterbalancing effects, in one large series the highest risk of bearing an infected infant with early clinical manifestations (10%) occurred in women who seroconverted at 24 to 30 weeks of gestation. A CT study of 31 infants further documented the severity of the CNS lesions as a function of the time of intrauterine infection. Therefore it appears that although a fetal-maternal barrier to infection may be operative early in pregnancy, once fetal infection is established at that time, it is a potentially devastating disease. Treatment of the infected mother alters both the likelihood of fetal transmission and the severity of the disease (see later discussion).

Meningoencephalitis

The meningoencephalitis of toxoplasmosis has a striking multifocal, necrotizing, granulomatous quality and is characterized by the following: (1) inflammatory cells in the meninges, especially over focal lesions; (2) perivascular infiltrates with inflammatory cells, the latter often including eosinophils; (3) multifocal and diffuse necrosis of brain parenchyma, with all cellular elements affected, involving cerebrum, brainstem, and spinal cord, and often associated with calcification; (4) reactive microglial and astroglial proliferation; and (5) miliary granulomas, containing large epithelioid cells and free, intracellular, or encysted organisms ( Fig. 38.12 ).

Porencephaly and Hydranencephaly

With particularly severe, diffuse, cerebral destructive disease, porencephalic cysts or hydranencephaly may develop. Of the 33 fetuses with congenital toxoplasmosis studied by Hohlfeld and coworkers, all exhibited areas of brain necrosis, the initial lesions that evolve to porencephaly and hydranencephaly. The development of these large areas of tissue dissolution is particularly likely if aqueductal block and increased intraventricular pressure are associated.

Hydrocephalus

Two processes appear to be operative in the periventricular region with toxoplasmosis and may underlie the propensity for aqueductal block and consequent hydrocephalus in this disorder. First, the inflammation with toxoplasmosis has a predilection for the periventricular region, as with CMV infection (although in toxoplasmosis more severe diffuse disease is present elsewhere, and calcified areas of necrosis are present throughout the cerebrum). Second, it is believed that Toxoplasma organisms enter the ventricular system from the parenchymal lesions and disseminate there. This highly antigenic ventricular fluid then seeps through the damaged ependyma to periventricular blood vessels, where an antigen-antibody reaction may occur at the vessel wall, thereby causing thrombosis and periventricular infarction. This additional necrosis apparently causes the serious aqueductal block that results in the common complication, hydrocephalus. Among 33 infected fetuses identified in utero by Hohlfeld and coworkers, 19 (58%) had ventricular dilation at autopsy after elective termination of pregnancy.

Microcephaly

Although hydrocephalus is a more common result of congenital infection with T. gondii and is more frequent in this variety of congenital infection than in any other, microcephaly does occur in a significant percentage of patients, approximately 15% (see subsequent discussion). The microcephaly relates to the multifocal necrotizing encephalitis, particularly of the cerebral hemispheres. Indeed, even in those patients with hydrocephalus, it is clear that a serious loss of brain substance, in addition to the effects of the hydrocephalus, invariably has occurred.

Incidence of Clinically Apparent Infection

As with CMV, clinically asymptomatic cases of congenital toxoplasmosis outnumber symptomatic cases. However, a larger proportion of infants with congenital toxoplasmosis than with cCMV infection can be detected clinically in the newborn period.

Of 156 children with congenital toxoplasmosis who were monitored prospectively from the time of maternal infection, approximately 18% had CNS and ocular involvement, 2% had CNS involvement without ocular involvement, 12% had ocular involvement only, and 68% were asymptomatic. Thus 20% of infants with congenital toxoplasmosis had observable CNS involvement in the newborn period in this study. The incidence of subclinical infection is higher in infants of women treated during pregnancy than in infants of women not treated (see later discussion). These earlier findings are quite similar compared with a later prospective study covering a 20-year period (1985 to 2005), where all mothers received spiramycin, alone or associated with pyrimethamine-sulfadoxine, and underwent amniocentesis and monthly ultrasound screening. Of 666 liveborn children, 112 (17%) had congenital toxoplasmosis and 107 were followed up for 12 to 250 months: 79 were asymptomatic (74%) and 28 had chorioretinitis (26%). There was only one infant with serious neurological involvement.

Clinical Features

Symptomatic patients (not treated in utero) often can be divided into those with predominantly neurological syndromes and those with predominantly systemic syndromes ( Table 38.10 shows combined data for both syndromes). The neurological syndrome accounts for approximately two-thirds of the cases and consists principally of abnormal CSF and other signs of meningoencephalitis, seizures, diffuse intracranial calcification, hydrocephalus, or, less commonly, microcephaly (see Table 38.10 ). At least 90% of these patients exhibit chorioretinitis (also termed retinochoroiditis ). In congenital toxoplasmosis, chorioretinitis is typically bilateral and prominent in the macular regions ( Fig. 38.13 ) and is of major diagnostic importance. Initially, the lesion appears in the fundus as yellowish-white, cotton-like patches with indistinct margins. These patches evolve over the ensuing months into sharply demarcated, “punched-out,” pigmented lesions, often accompanied by optic atrophy. Although the chorioretinitis is most commonly apparent in the newborn period, particularly by indirect ophthalmoscopy, it may not develop for months or even years, and these ocular lesions may relapse after birth despite pre- and postnatal treatment. In a study by Wallon and colleagues 477 cases of confirmed congenital toxoplasmosis were followed for a median of 10.5 years (75th percentile: 15.0 years). Almost one-third (29.8%) showed at least one ocular lesion. The lesion was unilateral in about two-thirds (69.0%), and lesions were first manifested at a median age of 3.1 (0.0 to 20.7) years. In one-third (33.8%) of the children, recurrences or new ocular lesions occurred up to 12 years after the appearance of the first lesion. Early maternal infection, prematurity, and nonocular congenital toxoplasmosis lesions at the time of diagnosis of congenital toxoplasmosis were associated with a higher risk of chorioretinitis.

The systemic syndrome of congenital toxoplasmosis is dominated by signs referable to the reticuloendothelial system, especially hepatosplenomegaly, hyperbilirubinemia, and anemia (see Table 38.10 ). A petechial rash may occur but is less common than with CMV infection. Overt clinical evidence of neurological involvement is often lacking in these patients, but CSF abnormalities, frequently with a disproportionately elevated protein content for the degree of pleocytosis, occur in approximately 85% and reflect concomitant meningoencephalitis. Chorioretinitis is observed in at least two-thirds of patients with systemic cases, and this finding underscores the importance of careful evaluation of the fundus, especially by indirect ophthalmoscopy, when congenital toxoplasmosis is possible.

An unknown but probably very considerable number of infants with no neurological or systemic signs of congenital toxoplasmosis (i.e., asymptomatic disease ) will exhibit chorioretinitis, detectable in the newborn period by indirect ophthalmoscopy. Although most of the retinal lesions observed later probably develop in the weeks and months after delivery (see subsequent discussion), further data are needed regarding the proportion detectable in the newborn period. In a series of 48 asymptomatic infants in whom infection was detected by newborn blood screening, two had active chorioretinitis and seven others had retinal scars; thus 19% had retinal disease. Moreover, approximately 20% had cerebral calcifications detectable by CT, and 25% had CSF findings consistent with encephalitis. The later development of neurological deficits and visual loss is appreciable and is discussed in the Prognosis section.

The clinical course of the disease is not readily predicted, and indeed, evidence of progression of retinal and cerebral disease has been presented. Because many patients with symptomatic congenital toxoplasmosis exhibit very severe neurological deficits from the neonatal period, the frequency of progression is difficult to quantitate.

Clinical Diagnosis

Certain clinical features are helpful in suggesting the diagnosis of congenital toxoplasmosis. A particularly noteworthy constellation of features includes evidence of meningoencephalitis, focal and multifocal cerebral necrosis, diffuse cerebral calcifications, hydrocephalus, and scarring chorioretinopathy in the macular regions. Intrauterine growth retardation or prematurity is generally not a prominent feature, as in infants with cCMV or rubella infections, and microcephaly is less common than in cCMV infection. The systemic syndrome may cause confusion when differentiating toxoplasmosis from other congenital infections, but a petechial rash is relatively less common in congenital toxoplasmosis.

Toxoplasma Isolation

Determination of T. gondii as the responsible microbe in the newborn with congenital toxoplasmosis depends principally on serological tests, rather than isolation of the organism per se. Nevertheless, the organism or associated DNA can be isolated from placental tissue, ventricular or lumbar CSF, blood and amniotic fluid. Parasitemia is more readily demonstrated in the first week after birth (71%) than in the second to fourth weeks (33%), and it is detected most easily in generalized rather than in neurological disease. The isolation procedures for toxoplasmosis require specialized techniques and an experienced, skilled laboratory staff. Detection of T. gondii in amniotic fluid by PCR with a sensitivity of 80% has suggested that this rapid test (result available in ≤6 hours) is very important in the diagnosis when the technique is applied to biological fluids of the newborn infant. Even better overall sensitivity of 92.2% (95% CI 81% to 98%) was reported in another study, where PCR was performed on 261 amniotic fluid samples. There were four negative results in fetuses who were infected. PCR performed in the CSF was found to be positive in 27 of the 58 (46.5%) congenitally infected infants and negative in each of the 103 infants without congenital toxoplasmosis. The CSF PCR was positive in 70.9%, 53.3%, and 50.9% of those with hydrocephalus, cerebral calcifications, and/or eye disease, respectively. Of six infants who were negative for both IgM and IgA antibodies, three had a positive PCR in their CSF as the confirmatory test for diagnosis of congenital toxoplasmosis. IgM and IgA antibodies and CSF PCR, when combined, yielded a higher sensitivity for diagnosis of congenital toxoplasmosis compared with the performance of each test alone. The sensitivity of PCR on placental tissue is only approximately 60%.

Serological Studies

The identification of most cases of congenital toxoplasmosis is established by serological techniques, including toxoplasma IgM enzyme-linked immunoassay (ELISA), IgG dye test, and Ig avidity test. IgG antibodies are positive within 1 to 2 weeks after the infection and persist indefinitely. IgM antibodies arise within the first week of infection, rapidly increase, reach the highest level about 1 month after the infection, remain stable for about 1 more month, and thereafter decline and disappear at highly variable rates. A negative IgM test essentially rules out a recently acquired infection. However it should be noted that commercial kits used to detect IgM antibodies in nonreference laboratories may be unreliable, with false positive rates as high as 60%. The avidity test of IgG antibodies helps to discriminate between a recently acquired infection and those obtained in the more distant past. In women with a gestation of 16 weeks or less, a high avidity essentially rules out infection acquired in the past 3 to 4 months. Reactivation can be seen in immunocompromised women, and this has been reported in a HIV-infected woman. The Toxoplasma-specific IgM-fluorescent antibody technique is faster and more specific. This test measures fetally produced IgM antibody to the organism. Killed organisms are used to bind specific IgM, which is then detected by exposure to fluorescein-antiserum to human IgM. The reliability of this test is hindered by certain factors that impair both sensitivity and specificity. The more recently developed IgM-capture ELISA , which isolates and concentrates the infant’s IgM, increases the sensitivity markedly (90% of infected infants are detected), and false-positive reactions are unusual. This test has been adapted to filter paper blood specimens. Finally, the use of a comparative analysis of mother/newborn IgG and IgM by Western blot, first described by Remington and coworkers, has also been advocated. Tissot Dupont and colleagues reported a sensitivity of 82.6% for the detection of IgG, IgM, and IgA by Western blot within the first 3 months of life, whereas at birth, the same combination had a sensitivity of 65.2%. The combination of IgG and IgM yielded the best score, whereas IgA detection was the least sensitive. The combination of Western blot and conventional serological analysis increased the sensitivity at birth to 78% and within the first 3 months of life to 85%. Amniocentesis is important to diagnose a fetal infection by detection of toxoplasma DNA in the amniotic fluid. Amniocentesis should not be performed until 4 weeks after maternal infection and performed after 18 gestational weeks. False negative results can occur when the DNA concentration is low and sensitivity is less than 90%.

Neurodiagnostic Studies

Neurodiagnostic studies that particularly suggest congenital toxoplasmosis are evaluations of CSF and brain imaging. Pleocytosis and elevated protein content of CSF indicate meningoencephalitis and may be observed in asymptomatic and symptomatic patients. Particularly characteristic of congenital toxoplasmosis is the finding of a very high protein content in the ventricular fluid, usually reflecting the aqueductal obstruction and stagnation of infection within the lateral ventricles. Although skull radiographs are effective in demonstrating the diffuse and periventricular cerebral calcification ( Fig. 38.14 ), CT scan is more effective and allows identification of calcification more distant from the lateral ventricles, in contrast to CMV in which calcifications are mostly adjacent to the lateral ventricles. ( Fig. 38.15 ). CT data indicate that calcifications of the basal ganglia are more common than previously suspected. CT is however no longer recommended in the newborn, and the calcifications associated with congenital toxoplasmosis, especially of the periventricular type or of the basal ganglia, can also be reliably detected by cUS ( Figs. 38.15 and 38.16 ). In a recent multicenter survey from France, fetal ultrasound findings were reported in 88 fetuses with congenital toxoplasmosis infection. Maternal infection occurred in most during the first trimester (81 of 88). Just over half (51.1%) had cerebral abnormalities only, and 35 (39.8%) had cerebral and extracerebral abnormalities. Intracranial hyperechogenic nodular foci were the most common finding ( n = 60), and 20 of these were isolated. Ventriculomegaly ( n = 44) was also common, and this often increased further during follow-up. In 12 cases round subcortical echolucent lesions with an echogenic rim were observed and were referred to as abscesses. These lesions may be areas of focal granulomatous inflammation, described in neuropathological studies. In another fetal ultrasound study, 5 of 9 fetuses with congenital toxoplasmosis showed hyperechogenic foci in the cerebral parenchyma as an isolated finding. All but 1 of these 4 children had normal neurological development. In contrast to cCMV, data on MRI in congenital toxoplasmosis are limited. In a small study of eight cases with antenatal imaging, MRI was performed before and after 3 weeks of spiramycin treatment, showing similar findings. MRI scan provides the most detailed assessment of parenchymal necroses ( Fig. 38.17 ).

Relation to Neonatal Clinical Syndrome

As with CMV, the outcome of untreated congenital toxoplasmosis relates to the severity of the neuropathology, which correlates to a modest extent with the neonatal clinical syndrome ( Table 38.11 ). Infants with congenital toxoplasmosis with prominent neonatal neurological features do poorly; only 9% are normal on follow-up. Most of the remaining infants exhibit serious disturbances of cerebral function (i.e., mental retardation, seizures, and spastic motor deficits). Essentially all such patients have chorioretinitis and may also have optic atrophy; as a consequence, approximately 70% have severe visual impairment.

Somewhat unlike cCMV infection, congenital toxoplasmosis with a neonatal syndrome characterized by prominent systemic signs, if untreated, also results in a poor neurological outcome. Approximately 50% of such patients with CMV are normal on follow-up, whereas only approximately 16% of patients with congenital toxoplasmosis are normal (see Table 38.11 ). Although the nature of the study populations differs, it seems reasonable to conclude that CNS involvement in congenital toxoplasmosis is more prominent than in cCMV infection when nonneurological features dominate the neonatal syndrome. Again, chorioretinitis is found in the majority of such patients with toxoplasmosis, and severe visual impairment occurs in approximately 40%. Antiparasitic treatment, begun in the first 2½ months of life, has a beneficial effect on outcome in symptomatic congenital toxoplasmosis (see later discussion).

Outcome With Asymptomatic Congenital Infection

Infants with subclinical infection (i.e., the majority [about 85%] of cases of congenital toxoplasmosis) are an important group. For example, in the United States, approximately 400 to 4000 such infants are affected yearly. Previous studies emphasized that such infants had a relatively high frequency of chorioretinitis and a modest impairment of intellect. A prospective study of 13 asymptomatic infants identified by serological screening in the newborn period and evaluated by particularly detailed serial, ocular, neurological, and audiological follow-up studies indicated that few such asymptomatic children escape without deficits ( Table 38.12 ). Thus 11 infants in this study developed chorioretinitis (3 with unilateral blindness), and 5 had neurological sequelae (1 with severe mental retardation and microcephaly). The neurological sequelae were always associated with retinochoroiditis. The mean IQ score for the group was only 89. SNHL occurred in 3 of 10 infants so tested, although in none was moderate or severe bilateral loss observed. However, diagnosis by neonatal screening and prompt institution of therapy result in a markedly better outcome (see later discussion).

Prevention

Four major approaches to prevention include (1) avoidance of primary maternal infection, (2) treatment of maternal infection, (3) abortion in the presence of maternal infection, and (4) treatment of the affected fetus. The first of these approaches is the most important. Pregnant women who have seronegative test results must avoid primary acquisition of Toxoplasma infection; the two measures necessary are avoiding ingestion of infective cysts (e.g., in raw meat) and contact with sporulating oocysts (e.g., in animal intestine and feces). Ingestion of infective cysts occurs when infected meat is undercooked. It is recommended that consumption of raw or undercooked meat be completely avoided and that handling of raw meat be done with gloves on or followed by careful hand washing. Contact with sporulating oocysts is principally through household cats that carry oocysts in their intestines. It is recommended that pregnant women avoid contact with cat feces and that contact with soil or other materials potentially contaminated with cat feces be avoided or performed while wearing gloves. Cost-to-benefit analyses (relative to other approaches to prevention) demonstrate the particular desirability of a health education campaign to encourage these practices. In a study performed in Finland the total annual costs of congenital toxoplasmosis without screening amount to US $128/pregnancy/year, and with systematic serological screening, US $95/pregnancy/year, thus reducing the costs by 25%. Thus screening for toxoplasma infections during pregnancy is economically worthwhile even in a country with a low incidence. The investigators recommended systematic screening for maternal primary toxoplasma infections combined with health education for preventon.

Primary maternal infection has been treated with the antibiotic spiramycin. A large series from the 1970s showed a significant reduction in cases of congenital infection in treated (24%) versus untreated (45%) mothers. The approximately 50% decrease in incidence of congenital toxoplasmosis was confirmed by subsequent data. Moreover, a multicenter study showed a marked decrease in the incidence of neonatal chorioretinitis and intracranial lesions when prenatal treatment (spiramycin) was instituted within but not after 3 weeks of diagnosis of maternal seroconversion and continued until the end of pregnancy. If vertical transmission is confirmed, fetal infection should be treated by spiramycin only for 1 week, followed by pyrimethamine plus sulfadiazine plus folinic acid throughout the pregnancy, and the infant should be treated for 1 further year. It is important to realize that even when fetal imaging studies remain normal, there is a 30% risk for long-term sequelae, especially chorioretinitis. Monthly fetal ultrasound monitoring is recommended. In a recent RCT a significant reduction in vertical transmission was reported when the combined drug treatment was given (18.5%) compared with administration of spiramycin only (30%). None of the 73 infants in the combined group, compared with 6 of 70 (8.5%) in spiramycin group, had cerebral abnormalities.

Abortion has been performed in women who have exhibited serological evidence for primary infection during early pregnancy. This approach is less desirable for several reasons, one of which is the finding that only 17% to 25% of women infected in the first and second trimesters transmit the infection to the fetus (see Table 38.9 ). However, initial work by Desmonts and coworkers, and subsequently by others, demonstrated the feasibility of prenatal diagnosis of congenital toxoplasmosis. Sampling of fetal blood by cordocentesis under ultrasound guidance for serological indicators of infection is less useful, and evaluation of pregnant women for possible fetal infection with toxoplasmosis is based principally on sampling amniotic fluid by amniocentesis and detection of the organism’s DNA by PCR. It is recommended to carry out amniocentesis after 18 weeks of gestation and at least 4 weeks after the estimated date of maternal infection, to minimize the risk of a false-negative result because of the late passage of the parasite across the placenta into the fetus. Ultrasonography of the fetal cranium at approximately 19 to 20 weeks of gestation provides information concerning cerebral abnormality. Fetal cranial ultrasonography may show ventriculomegaly, evidence of tissue necrosis, and cerebral calcifications. The diagnosis of fetal infection has also been made by isolation of the organism from fetal blood or from amniotic fluid and by identification in fetal blood of hematological abnormalities (e.g., eosinophilia, thrombocytopenia), elevated gamma-glutamyltransferase activity, and Toxoplasma -specific IgM.

The positive identification of fetal infection provides the possibility of treatment of the fetus . In the classic study of Hohlfeld and coworkers, fetal treatment consisted of administration to the mother of alternating 3-week courses of spiramycin and of pyrimethamine, sulfadiazine, and folinic acid (see above). (The latter three agents are not used before the 18th week of gestation because of the teratogenic potential of pyrimethamine.)

The beneficial effect on the severity of fetal infection was dramatic (see Table 38.13 ). Although, as in pretreatment years, the incidence of severe fetal infection increased the earlier in pregnancy the infection was acquired, only 11% of first trimester infections treated in utero resulted in severe manifestations in the neonatal period. Moreover, of the third trimester fetal infections treated in utero, all resulted in asymptomatic newborns. Continuation of antimicrobial therapy postnatally in 53 infants was accompanied after relatively short-term follow-up by normal neurological development and examination in 52 (98%) and by the development of peripheral chorioretinitis, with no visual impairment, in 5 (9%). These favorable outcomes represent a dramatic improvement compared with outcomes in the pretreatment era (see Table 38.11 ). A larger study ( n = 112) also showed a beneficial effect of fetal treatment. The mother was treated during pregnancy with pyrimethamine-sulfadoxine. Follow-up was available in 107 for 12 to 250 months: 79 were asymptomatic (74%) and 28 had chorioretinitis (26%). Only one child had serious neurological involvement. A longer-term study confirmed the favorable effects of combined fetal and postnatal therapy, although delayed onset of chorioretinitis was shown ( Table 38.14 ). During follow-up, almost one-third of the 142 patients (29.8%) manifested at least one ocular lesion. Lesions were unilateral in 98 individuals (69%) and caused no visual loss in 81%. Lesions were first manifested at a median age of 3.1 (0.0 to 20.7) years. In 48 (34%) of the children, recurrences or new ocular lesions occurred up to 12 years after the appearance of the first lesion. However, severe bilateral visual impairment did not occur. Nevertheless, careful long-term follow-up is imperative.

Supportive Therapy

Such therapy is carried out as described for cCMV infection.

Antimicrobial Therapy

Although significant injury has already occurred in many cases of untreated congenital toxoplasmosis by the time of birth, good evidence indicates that some of this injury is reversible and continuing postnatal injury is preventable by therapy directed against the organism. The drugs of choice are pyrimethamine and sulfadiazine, with the addition of folinic acid to counteract the folic acid antagonistic effect of pyrimethamine on the bone marrow. Pyrimethamine is highly effective in experimental infection with Toxoplasma and, because of its high lipid solubility, appears to be concentrated in the brain. Sulfadiazine acts synergistically with pyrimethamine such that their combined activity is eight times that expected if additive effects were operative. Caution must be exercised with sulfadiazine, particularly in infants with hyperbilirubinemia. The combination of pyrimethamine and sulfadoxine (Fansidar) is more convenient because it can be administered every 2 weeks rather than daily. Thrombocytopenia is a particularly early manifestation of pyrimethamine toxicity, and folinic acid is particularly effective in correcting this phenomenon. These antimicrobials kill actively multiplying parasites but not resistant cyst stages. Therefore treatment must begin promptly and must continue until the infant’s immune system has matured sufficiently to control the infection. The total recommended duration of therapy in both symptomatic and asymptomatic disease is 1 year. In infants with evidence of severe inflammation, manifested by markedly elevated CSF protein (≥1 g/dL) or by severe chorioretinitis, corticosteroids have been recommended. Doses and modes of administration of these various agents are discussed elsewhere. The beneficial effects of postnatal onset of therapy in congenital toxoplasmosis, either clinically symptomatic or detected by newborn blood screening (“asymptomatic”), are illustrated by the data in Table 38.15 .

Fetal Infection

Clinically significant infection with rubella virus occurs during intrauterine life by transplacental passage of the virus. As with CMV infection and toxoplasmosis, the sequence of events is primary maternal infection, viremia, placental infection, and, finally, fetal infection. Cases of asymptomatic maternal infection are common, outnumbering those of symptomatic infection by nearly 2 to 1. Viremia occurs during the week before the onset of clinical manifestations, which include fever, cervical adenopathy, and a maculopapular rash lasting 3 days.

Importance of Time of Maternal Infection

The likelihood and the severity of fetal infection are functions of the time of maternal infection. The risk to the fetus begins when the rash in the mother appears at least 12 days after the last menstrual period (i.e., the likely time of conception); in a series of 38 carefully studied pregnancies in the periconceptional period, no cases of fetal infection occurred when the rash appeared at 11 days or less after the last menstrual period. In general, both the frequency of occurrence of infection and the severity of clinical disease are greater the earlier in pregnancy the maternal infection occurs ( Table 38.16 ). Thus it is different from the situation with toxoplasmosis, in which the likelihood of infection is less but the severity of disease greater when acquired early in pregnancy. With congenital rubella, ocular and cardiac defects are particularly common when infection occurs in the first and second months, but they become essentially nonexistent when infection occurs after the first trimester. However, hearing loss , although most common with early infection, is still found in approximately half of infants infected in the fourth month; later maternal infection appears not to be dangerous in this regard. Neurological deficits , especially intellectual retardation and motor deficits, are most common with infection in the first 2 months and are not observed with infection past the fourth month.

The most critical gestational periods concerning the major defects have been defined particularly closely. In a series of 55 children from carefully dated, affected pregnancies, cataracts were observed with maternal infection between 26 and 57 days of GA; heart disease occurred in maternal infection between 25 and 93 days of GA; deafness occurred in maternal infection between 16 and 131 days of GA; and severe intellectual retardation occurred in maternal infection between 26 and 45 days of GA. The placenta may play the greatest role in determining the decreasing incidence of fetal infection with progression of gestation. Maturational factors of host tissue may be most important in determining the concomitant changes in organ susceptibility.

Meningoencephalitis

The meningoencephalitis of rubella infection is similar in certain respects to the other neonatal encephalitides and is characterized by (1) inflammatory cells in the meninges; (2) perivascular infiltrates with inflammatory cells; (3) necrosis of brain parenchyma, with all cellular elements affected; and (4) reactive microglial and astroglial proliferation.

Vasculopathy

An additional, prominent, and distinctive feature of rubella infection is vasculopathy. Involvement of blood vessels is observed in many organs and prominently in the brain. In the well-studied series of Rorke and Spiro, involvement of large leptomeningeal vessels and, particularly, smaller intraparenchymal vessels and capillaries was defined. Destruction of one or more layers of the vessel wall occurs, with replacement by deposits of amorphous granular material ( Fig. 38.18 ). Associated with these vascular lesions are focal areas of ischemic necrosis, especially in the cerebral white matter (centrum semiovale, periventricular regions, and corpus callosum) and in the basal ganglia. The vascular abnormalities may account for the echogenic vessels observable on cranial ultrasonography of the affected newborn (see later discussion) ( Fig. 38.19 ).

Microcephaly and Impaired Myelination

Two additional features of congenital rubella (i.e., microcephaly and impaired myelination) may relate to the effect of the virus on cellular replication. Microcephaly does not appear to be accounted for readily by destructive disease and, indeed, is often not prominent until months after birth. The possibility that the decreased brain mass is related to a decrease in the number of neurons and glia is supported by the observations that rubella disturbs mitotic activity of human fetal cells in culture and also causes a reduced number of cells in a variety of organs in affected infants. In addition to the microcephaly, a cellular deficit may account for the moderately impaired myelination observed by Rorke and Spiro and by Kemper and coworkers. Indeed, although quantitative data are lacking, an apparent decrease in oligodendrocytes has been observed in association with the delay in myelination. Notably, rubella binds to myelin oligodendrocyte glycoprotein and sphingomyelin, which are mainly expressed in oligodendrocytes and are important in myelin development.

Incidence of Clinically Apparent Infection

The devastating rubella pandemic of the mid-1960s afforded the opportunity to define the enormous clinical spectrum of congenital rubella. Because the largest portion of available data was derived from studies of infants identified at birth, the spectrum of manifestations as a function of maternal infection has been more difficult to define than for cCMV infection or toxoplasmosis. Nevertheless, it does appear that the likelihood of asymptomatic congenital rubella infection is more comparable to that of congenital toxoplasmosis than to that of cCMV infection. Thus approximately two-thirds of patients are asymptomatic in the neonatal period. However, most of these infants do develop evidence of disease in the first several years of life, a finding imparting clinical significance to observations that prolonged viral replication is an important feature of this disease.

Clinical Features

The clinical features in symptomatic patients are shown in Table 38.17 . Intrauterine growth retardation (followed by postnatal growth failure) is a particularly common feature. Disturbances of the reticuloendothelial system are also prominent and are characterized particularly by hepatosplenomegaly and thrombocytopenia with or without purpura. The purpura should be distinguished from the peculiar dermal erythropoiesis that results in the small purple lesions of the “blueberry muffin” syndrome. Cardiovascular defects are characteristic and consist principally of peripheral pulmonic stenoses and patent ductus arteriosus. Myocardial injury can be demonstrated in a few patients by abnormal electrocardiographic findings, as well as pathologically, and it may contribute to the occurrence of congestive heart failure. Other lesions, apparent in 20% to 50% of patients, are linear areas of radiolucency of the metaphyses of long bones (i.e., “celery stalk lesions”), prominent especially around the knee, and interstitial pneumonitis. The latter abnormalities usually subside in the first few months of life.

Neurological phenomena in the newborn period are prominent in approximately 50% to 75% of the cases (see Table 38.17 ). The most common manifestations relate to meningoencephalitis, seen most clearly in most patients by elevated levels of CSF protein and mononuclear cells. The anterior fontanelle is full in 25% to 50% of patients. The most common initial neurological features are “lethargy” and hypotonia, accompanied and followed shortly by prominent irritability. The irritability may relate to meningeal irritation, which probably also accounts for the occurrence of retrocollis and opisthotonos. These signs of meningeal irritation may worsen in the first weeks or months of life. Seizures appear in approximately 10% to 15% of infants. Definite microcephaly is unusual at birth. Most of the acute clinical features subside over the first several months and evolve to the sequelae outlined subsequently.

The ocular lesions consist principally of cataracts, usually white or pearly, especially centrally, and chorioretinitis, which may be more common than was previously appreciated. Indirect ophthalmoscopy is especially helpful to demonstrate the characteristic spotty pigmentation (i.e., “salt-and-pepper”) appearance, which may be particularly prominent peripherally. Microphthalmia is sometimes difficult to appreciate when it is bilateral and is associated particularly with cataract.

The auditory lesion may be difficult to demonstrate in the newborn, although the application of brainstem evoked response audiometry has improved detection. In one series, approximately 20% of infants had suspected or definite hearing loss by behavioral testing in the neonatal period. The basis for the hearing loss in congenital rubella is a cochlear inflammatory and destructive lesion. A significant minority of infants subsequently will exhibit disturbances in response to sound that appear to be on a “central” basis, although the locus of this central pathology is unclear. In a detailed study of hearing loss in children with congenital rubella, the hearing deficit was usually uniform over all frequencies, symmetrical, and severe (mean threshold, 93 dB). As many as 60% to 80% of infants with congenital rubella are found later to have hearing loss as children. This increase in incidence from early infancy to childhood relates to a combination of inadequate testing in infancy with delayed diagnosis and progression of disease in the auditory apparatus; the relative importance of each of these factors remains unclear.

Clinical Diagnosis

Clinical features that favor the diagnosis of congenital rubella are intrauterine growth retardation, CSF pleocytosis, salt-and-pepper chorioretinopathy, cataracts, cardiovascular defects, and skeletal lesions. The absences of prominent cerebral calcification, hydrocephalus, overt microcephaly, and vesicular rash are the clinical features that best differentiate congenital rubella from congenital toxoplasmosis, CMV infection, and HSV infection. After an outbreak in Vietnam a peak incidence of 7.8 per 1000 live births was seen, and 38 infants could be studied in detail. LBW (71%), cardiovascular defects (72%), suspected hearing impairment (93%), hepatosplenomegaly (68%), thrombocytopenia (76%), and developmental delays (73%) were noted. Fully 84% of the patients presented with characteristic hemorrhagic purpuric eruptions, the so-called blueberry muffin syndrome. Twenty-four of the infants (67%) had a significant persistent ductus arteriosus, and notably this finding was associated with pulmonary hypertension in 16 of the 24 infants. Thirteen infants (34%) died. Pulmonary hypertension, hepatosplenomegaly, and severe thrombocytopenia were more frequently observed among those who died. In a recent surveillance study from India, 645 suspected CRS patients were enrolled during 2 years. Of these 645 patients, 137 (21.2%) were classified as laboratory confirmed congenital rubella. Common clinical features were structural heart defects in 108 (78.8%), one or more eye abnormalities (cataract, glaucoma, pigmentary retinopathy) in 82 (59.9%), and hearing impairment in 51 (38.6%). Thirty-three (24.1%) laboratory confirmed CRS patients died over a period of 2 years.

Virus Isolation

Determination of rubella virus as the responsible microbe depends particularly on isolation of the virus and serological tests. The virus can be isolated best from the nasopharynx and urine, but it can also be isolated from stool and CSF (and various tissues, including lens and brain). Circulating rubella viruses are mostly members of two genotypes, 1E and 2B, with genotype 2B being most widely distributed. Approximately 55% to 85% of patients exhibit positive cultures. Performance of multiple cultures increases the yield appreciably. The virus has been isolated from approximately 30% to 45% of CSF samples examined. This relatively high frequency of isolation of virus from CSF is unlike other congenital viral encephalitides. The chronicity of rubella infection is emphasized by the finding of positive CSF cultures in infants as old as 18 months. A similar conclusion can be derived from isolation of virus from the cataractous lens of a child aged 2 years, 11 months. Moreover, as many as one-third of infants with congenital rubella are still excreting virus at 8 months of age.

Serological Studies

All women of childbearing age should have been vaccinated against rubella as a child or before conception. Women who have been vaccinated should be considered immune. As seroconversion is not 100%, serological testing is indicated in vaccinated women who have a known exposure or a rash and illness consistent with rubella to rule out acute primary infection or reinfection. Serological diagnosis during pregnancy may be based on maternal blood studies. If negative for IgM (IgM−), the IgG results determine whether the woman is seropositive (immune) or seronegative (not immune). If the mother is IgG negative at the first visit, the woman should be retested monthly for seroconversion until the end of the fifth month of pregnancy. If the maternal blood is positive for IgM (IgM+) and IgG (IgG−), the next step would be an IgG avidity assay on the same blood sample to estimate the time of infection, with low avidity indicative of recent primary infection. The same tests should be repeated on a second blood sample obtained 2 to 3 weeks later. If the results remain the same (IgM+ IgG−), the IgM result is considered nonspecific, indicating that the woman has not been infected; however, she is seronegative and should be followed until the end of the fifth month. If the woman has seroconverted (IgM+ IgG+), recent primary infection is confirmed, and a prenatal diagnosis should be made if the woman wishes to continue her pregnancy. After birth, the fastest and most useful test is determination of IgM-specific antibody; this is the most definitive serological diagnostic test in the first few weeks of life. IgM antibody can be detected in the infant’s cord blood or serum and persists for about 6 to 12 months.

Neurodiagnostic Studies

No specific neurodiagnostic tests are available, although a high rate of viral isolation from the CSF and the frequency of CSF signs of inflammation are very helpful in diagnosis. CT and ultrasound scan are useful in the detection of the focal areas of ischemic necrosis secondary to the vasculopathy and the less common calcification in the basal ganglia. CT scans performed between 1 and 3 years of age have demonstrated cerebral white matter hypodensity and multiple calcified nodules in the centrum semiovale, presumably reflecting the impaired myelination and focal ischemic lesions described earlier in the section on neuropathology. When available, MRI should be used instead of CT. MRI scan is most useful for detection of the presumed ischemic lesions in cerebral white matter and impairment of myelination. cUS scan may show focal areas of calcification, subependymal cysts, and echogenic vessels in the basal ganglia and thalamus (see Fig. 38.19 ). In a series of 12 infants with echogenic vessels in basal ganglia, 2 patients had congenital rubella.

Relation to Neonatal Clinical Syndrome

Although the outcome is related to the neonatal clinical features, the relationships are not so obvious as with cCMV infection and toxoplasmosis. This fact may relate to the particular chronicity of congenital rubella, as well as to the relative infrequency of completely asymptomatic neonatal disease. In a population of 100 carefully studied infants, 90% of whom were overtly symptomatic in the neonatal period and very early infancy, only 9% appeared to be free of deficits at 18 months ( Table 38.18 ). Neuromotor deficits (i.e., spastic motor deficits and delayed neurological development) were severe in approximately 50% of the patients. Fully 81% of these infants had microcephaly, and 72% had definite hearing loss or other apparent disturbances related to auditory perception. In a subsequent report of the same population, of patients followed to 16 to 18 years of age, 28% exhibited mental retardation, and an additional 25% exhibited low-average intelligence. Of 14 children with “suspect” hearing loss at 18 months, 13 were definitely hearing impaired. In another prospective series of infants with congenital rubella, approximately similar outcomes were observed; approximately 45% of such infants exhibited “psychomotor retardation,” and 50% of these infants were moderately or severely affected.

Long-Term Hearing Deficits and Other Sequelae

Even those infants who appear to be less severely affected often show evolution of disabling auditory, motor, behavioral, and learning deficits as they grow older ( Table 38.19 ). A multidisciplinary, longitudinal study of 29 “nonretarded” infants with congenital rubella demonstrated definite hearing loss in 1 infant in the first 2 months, in 12 infants by 12 months, in 22 infants by 24 months, in 25 infants by 48 months, and in an additional 2 infants by 11 years, for a total of 27, or 93% of the children. This accretion of patients with definite hearing loss may reflect continuing cochlear injury. The analogy with the delayed onset of hearing loss in cCMV infection and of chorioretinopathy in congenital toxoplasmosis is apparent.

In the longitudinal study just mentioned, early disturbances of motor development and of tone were followed by impairments of motor coordination and muscle weakness in approximately 50% of the children. Behavioral disturbances, which in the early years included impaired attention span and hyperkinesis, evolved to emotional irritability and persisting distractibility in approximately 50%. A propensity for congenital rubella infection to lead to impairment of behavioral and emotional development is also apparent in other studies by a 6% incidence of subsequent autism. Moreover, although IQ scores remained within the normal range in the study of Desmond and coworkers, learning deficits and visual-perceptual-motor deficits were prominent in approximately 50%. These abnormalities had a major influence on the adaptation of the children to educational and home environments and underscore the necessity for careful follow-up and appropriate interventions in infants with congenital rubella.

An interesting relationship between the rate of linear growth and cognitive outcome was apparent in a 20-year follow-up of 105 cases of CRS. Children with normal growth had normal cognitive development, and those with linear growth at less than the 5th percentile exhibited moderate to severe mental retardation.

Late Progressive Panencephalitis

A rare complication of congenital rubella, the precise frequency and importance of which are not clear, is the occurrence of progressive panencephalitis with onset, usually in the second decade, of intellectual and motor deterioration, elevated CSF protein levels, and elevated antibody titers to rubella virus in serum and CSF. The virus has been isolated from the brain. Whether this disorder represents reactivated infection or bears a relation to the role of measles virus in subacute sclerosing panencephalitis, or both, remains to be determined.

Prevention

Preventive measures present the realistic hope of eradication of CRS. Of the three major approaches to prevention (avoidance of maternal infection, treatment of maternal infection, and abortion in the presence of maternal infection), the first has been accomplished in large part through vaccination.

Active immunization with a live attenuated rubella vaccine has been accomplished by two major approaches. In the United States, mass vaccination of all children aged 1 year to puberty has been used to limit the spread of infection to the pregnant woman by curtailing circulation of virus in the community. In the United Kingdom and in many other European countries, selected immunization, especially of girls from ages 11 to 14 years, was used initially to provide protection for the childbearing years. Mass vaccination of all children in the second year of life was instituted in the United Kingdom in 1988. The policy in the United States has been effective; the incidence of congenital rubella declined by approximately fivefold in the decade after the initiation of this vaccination regimen. Since 2004, the rubella incidence has remained below 1 case per 10 million population, and the incidence of the CRS has been below 1 case per 5 million births. However, some questions still remain concerning how long vaccine-induced protection will last or whether inapparent reinfection of the mother with transmission to the fetus may occur. In 1996 it was estimated that 110,000 infants with CRS were born annually in developing countries. In 2000, the WHO published the first rubella vaccine position paper to guide introduction of RCV in national childhood immunization schedules. From 1996 to 2009, the number of countries that introduced RCV into their national routine childhood immunization programs increased by 57% from 83 countries in 1996 to 130 countries in 2009. By December 2016, 152 (78%) of 194 countries were using the vaccine. This introduction of the RCV resulted in a decrease in reported rubella cases from 670,894 cases in 2000, to 94,277 cases in 2012, to 22,361 cases in 2016. Elimination of rubella and CRS was verified in the WHO Region of the Americas in 2015, and 33 (62%) of 53 countries in the European Region have now eliminated endemic rubella and CRS. Among WHO Member States, 168 (87% of 194) used rubella vaccination in 2018; 69% of the world’s infants were vaccinated against rubella in 2018. Rubella control and prevention of CRS can be accelerated by integrating with current global measles mortality reduction and regional elimination activities. All women identified to be seronegative during pregnancy should be vaccinated postpartum .

Passive immunization with immune globulin may be useful in the special case of a susceptible pregnant woman exposed to rubella. The effectiveness of this approach is controversial, but it is necessary to recognize that passive immunization is useful to prevent viremia and fetal infection and therefore must be given promptly.

Abortion in the woman infected with rubella requires understanding of the risks of fetal infection as they relate to the timing of the infection in pregnancy. The demonstration of prenatal diagnosis by fetal blood sampling in the 20th week of gestation may help prevent abortion of the unaffected fetus.

Supportive Therapy

Supportive therapy is carried out principally as described for cCMV infection. In addition, recognition and prompt control of cardiac failure are critical, particularly in view of cerebral vasculopathy and therefore already compromised cerebral perfusion. Careful auditory assessment, with brainstem evoked response audiometry and with behavioral studies, is critical to detect hearing loss and to provide appropriate intervention as early as possible. Similarly, detection of cataract is important because delay of surgery into the second and third years of life prevents useful vision. However, opinions differ about the optimal time of therapy. Nevertheless, the infant with auditory and visual deficits is at great risk for subsequent disturbances of language and other aspects of neurological development, and the earliest interventions regarding vision and audition are critical.

Antimicrobial Therapy

No known effective chemotherapeutic agents of value exist in the treatment of congenital (or postnatal) rubella infection.