Cytomegalovirus, Rubella, Toxoplasmosis, Herpes Simplex Virus, and Varicella

Diagnosis.

The diagnosis of clinically suspected maternal CMV infection is based on serology. The new appearance of CMV-specific immunoglobulin (Ig)G is diagnostic of new acute infection. IgM is not a reliable marker for acute infection or timing exposure for several reasons:

• IgM may remain positive for over 1 year following acute infection.

• IgM may revert to positive from negative in women with reactivation or reinfection with a new viral strain.

• It is present in 75%–90% of those with acute infection, and there exists a high false-positive rate for IgM assays performed in commercial, nonreference laboratories.

In the absence of documented IgG seroconversion, the IgG avidity assay may be used to more accurately determine the acuity of infection and thus vertical transmission risk. Antibodies produced at the time of primary infection have lower antigen avidity than those produced during a nonprimary response. Low avidity IgG (<0.3) indicates a recent infection. With time and antibody maturation, the antigen avidity will increase and reach even higher avidity levels (≥0.65), indicative of past infection.

Despite the availability of avidity testing, the diagnosis of acute infection may remain elusive as intermediate results are difficult to interpret and the appropriate cutoff for low avidity is not universally defined. In the setting of maternal infection and/or findings on ultrasound (US) suggestive of fetal infection (echogenic fetal bowel, cerebral periventricular echogenicities, hepatic calcifications, microcephaly, fetal growth restriction), amniocentesis should be considered to perform polymerase chain reaction (PCR) for CMV DNA in amniotic fluid. Timing of this procedure is critical as test sensitivity is highest after 21 weeks' gestation and greater than 6 weeks between maternal infection and procedure. This 6-week lag time allows for placental viral replication, transmission to fetus, viral replication in the fetal kidney, and excretion into amniotic fluid. If amniocentesis is performed earlier in gestation or soon after diagnosis of maternal infection, it is reliable evidence of fetal infection if positive, but should be repeated later in gestation if negative.

PCR is the preferred test, as sensitivities of viral isolation from amniotic fluid vary from 45%–80%. The prognostic value of DNA quantification of CMV in amniotic fluid is controversial. Lazzarotto et al. reported that with viral loads less than 10 ³ copies/mL, there is a low risk of symptomatic neonatal infection. Benoist et al. did not find a correlation between viral load and the likelihood of symptomatic neonatal CMV.

Ultrasound.

Between 16 and 36 weeks' gestation, women with primary CMV infection and newborns with symptomatic CMV have significantly thicker placentas than control women without CMV. At 20 weeks' gestation, placental thickness in control pregnancies without CMV was 20 mm compared with 40 mm ( Fig. 165.5 ) in CMV-infected pregnancies. Some of the US findings associated with CMV (e.g., intrauterine growth restriction [IUGR]) may be caused by placental dysfunction ( Fig. 165.6 ) rather than from direct viral infection. This placental dysfunction may partly explain why CMV DNA load in amniotic fluid does not correlate with the severity of abnormalities associated with congenital CMV infection visualized on US.

Of congenital infections, CMV is the major cause of destructive cerebral lesions ( Table 165.2 and Fig. 165.7 ). Brain damage is caused by a direct cytopathic effect and an immune inflammatory response to CMV. Because the fetal brain is a focus of all congenital infectious evaluations, transvaginal US should always be attempted when the vertex is in a suitable position to detect subtle abnormalities.

Neurons form between 8 and 20 weeks' gestation; migration of neuronal cells to the cerebral cortex continues until 24 to 26 weeks' gestation. Both neuronal loss and a disturbance in neuronal migration may play a role in the development of microcephaly associated with CMV infection.

A periventricular halo (see Fig. 165.7E ) is indicative of white matter injury and is detected before brain calcifications. The periventricular halo is initially noncontinuous and may be appreciated only with transvaginal US. As white matter damage progresses, the halo coalesces and is detectable with transabdominal US. The duration and severity of the cerebral infection determine whether ventriculomegaly is present at the time of the periventricular halo. Focal symmetric periventricular cysts generally cannot be detected until the third trimester.

Cerebral calcifications associated with CMV are generally periventricular in location. Calcifications associated with toxoplasmosis are scattered throughout the brain.

Lenticulostriate vasculitis results in the deposit of amorphous material in the walls of the vessels within the basal ganglia and thalamus. Although the vessels are echogenic, they are not occluded. Resolution of the lesions may occur. However, with severe infections, the vessel walls eventually may become calcified. These linear echogenicities have also been found with other infections (rubella, syphilis), chromosomal abnormalities (trisomies 21 and 18), and prematurity.

Anomalies of the cerebellum (i.e., vermian hypoplasia) suggest that the CMV infection occurred before 18 weeks' gestation, when cerebellar formation is complete. Lissencephaly is a disturbance of neuronal migration between 3 and 5 months' gestation. US diagnosis of lissencephaly can be made at around 28 weeks' gestation. The presence of cerebellar hypoplasia (see Fig. 165.7F ) in association with lissencephaly should suggest a diagnosis of congenital CMV infection.

In one series of 73 in utero CMV infections, 34 of 73 (52%) had US findings; 27 of 34 (79%) infections involved the central nervous system (CNS). There were isolated extracerebral US abnormalities in 11 (32.4%) infections. Simon-Bouy et al. prospectively evaluated 682 cases of fetal echogenic bowel ( Fig. 165.8 ). CMV was found in 15 (2.2%) fetuses. In 11 of 15 fetuses with CMV, echogenic bowel was the only US abnormality detected. Echogenic bowel or bowel dilatation is caused by viral enterocolitis.

Isolated hepatic echogenic foci are infrequently associated with infection and are usually caused by a vascular accident. Multiple hepatic calcifications secondary to hepatitis are more likely associated with congenital infection. Hepatosplenomegaly is common with severe symptomatic congenital CMV ( Fig. 165.9 ).

Occasionally, hydrops ( Fig. 165.10 ; see Fig. 165.5 ) secondary to CMV infection is detectable by 16 weeks' gestation. This early manifestation of hydrops is secondary to hepatic dysfunction, liver congestion, and subsequent anemia. Myocarditis can also play a role in the development of hydrops. Isolated fetal ascites is caused by hepatic dysfunction. When the liver recovers, the ascites resolves. IUGR is present in 50% of symptomatic infants infected with CMV; the prematurity rate is 34% in this subgroup. Renal involvement may result in temporary or persistent oligohydramnios and, occasionally, polyhydramnios. Calcifications of the retina secondary to chorioretinitis have been detected on third-trimester US examinations of fetuses with CMV.

The reported US markers associated with congenital CMV are outlined in Table 165.2 . These findings may be transient or become manifest only late in pregnancy, requiring serial US examinations to be detected. Although the possible US markers are numerous, they are not specific.

The US detection rate of congenital CMV is difficult to assess because of the variables listed in Table 165.3 . Crino combined data from three studies to obtain a 30% sensitivity, 98% specificity, 90% positive predictive value, and 70% negative predictive value for the detection of congenital CMV with US. In one study, 23 of 154 congenitally infected fetuses (14.9%) had identifiable US findings. The positive predictive value of US in detecting congenital infections was 35.3% for all fetuses of mothers with primary CMV and 78.3% for fetuses with documented infection. In two series of 62 infected fetuses with US abnormalities, approximately half of abnormalities were detected between 18 and 22 weeks' gestation. The remaining 50% of the detectable anomalies associated with congenital CMV were identified after a gestational age of 22 weeks. A normal second-trimester US examination does not exclude an abnormal US examination at a later gestational age or the birth of an infant with significant CMV sequelae.

Prognosis is based mainly on the presence of fetal brain abnormalities. However, all detectable brain lesions do not have the same prognostic significance. Even ventriculomegaly, considered one of the most ominous US findings, does not invariably result in long-term sequelae. When US abnormalities are detected, neonates may still escape significant morbidity. Nonspecific isolated US findings (i.e., echogenic bowel) are not associated with a poor outcome.

Magnetic Resonance Imaging.

MRI may provide additional information in the assessment of a fetus suspected to have congenital CMV. Even with a normal fetal anatomic survey, MRI has detected subtle brain abnormalities, increasing the positive predictive value of prenatal assessment. Although brain anomalies associated with CMV infection may be detected on MRI before 24 weeks' gestation, the results can be misleading. Repeat MRI in the third trimester is required to better elucidate the prognostic reliability of the earlier MRI examination or to monitor previously diagnosed brain abnormalities.

The type of brain abnormalities detected on MRI helps to approximate the time of fetal infection. Lissencephaly suggests a brain injury before 16 to 18 weeks' gestation, whereas polymicrogyria is associated with an injury between 18 and 24 weeks' gestation. The development of a normal gyral pattern indicates the fetus was not infected until the third trimester. Despite the possibility of detecting abnormalities, MRI use remains controversial as normal brain imaging does not necessarily predict normal neurodevelopmental outcomes.

Ultrasound.

The most common US findings associated with rubella infection include cardiac defects (atrial and ventricular septal defects, pulmonary artery hypoplasia, and after birth, patent ductus arteriosus), ocular anomalies (cataracts and microphthalmia), microcephaly, hepatomegaly, splenomegaly, and growth restriction. Less common anomalies include peripheral pulmonic stenosis, glaucoma, meningocele, renal disorders, hypospadias, meconium peritonitis, and hyperechoic bowel as well as intracranial calcifications and subependymal pseudocysts.

In pregnancies suspected to be complicated by rubella infection, a detailed fetal US should be performed, with special attention to intracranial, ophthalmic, and cardiac structures. If necessary, transvaginal US should be performed for optimal intracranial imaging. A fetal echocardiogram should also be performed.

Magnetic Resonance Imaging.

The CNS findings make MRI an ideal modality to assess the fetus in the late second or third trimester. MRI may be more sensitive than US for minor atrophic changes and white matter lesions.