212 Congenital cytomegalovirus infection is the most common congenital infection in neonates in the US, affecting approxi- mately 0.5–1.5% of all live births and 30,000–40,000 newborns annually. Congenital infections result from transplacental trans- mission of cytomegalovirus (CMV).
GENETICS/BASIC DEFECTS
1. Human cytomegalovirus
a. A DNA virus belonging to the herpesvirus group (herpes simplex, varicella zoster, Epsein-Barr) b. Ability of the virus
i. To destroy host cells (lytic infection) ii. To infect a wide range of cells and tissues iii. To evade and interfere with host defense mech-
anisms
iv. To persist indefinitely in the host
v. To infect and destroy cells during productive infection (with release of progeny virus) 2. Transmission of CMV
a. Horizontal transmission: close intimate contact with another person shedding the virus in body fluids (saliva, blood, cervical secretions, semen, urine, or respiratory droplets)
b. Vertical transmission: from mother to infant
i. In utero by transplacental passage of maternal bloodborne virus
ii. At birth by passage through an infected maternal genital tract
iii. Postnatally by ingestion of CMV-positive human milk from seropositive mothers
c. Infected organ or bone marrow transplantation d. Infected blood transfusion from CMV-seropositive
donors
3. Primary sources of CMV infection for women of child- bearing age
a. Young children b. Sexual contacts 4. Types of CMV infection
a. Primary (first experience) b. Secondary (recurrent)
i. Reactivation of the original endogenous CMV ii. Reinfection with a new strain of CMV
c. Latent infection: sites at kidney, bone marrow, mono- cytes
5. The most common vertically transmitted viral infection from mother to fetus in pregnancy
a. Recurrent infection: 1% risk of vertical transmission b. Primary infection: 1–4% risk of vertical transmission 6. Symptomatic congenital infections observed primarily
among women undergoing a primary infection
7. Greatest risk occurring with infection during the first 22 weeks of gestation
8. Congenitally infected newborns: may shed the virus for many years
9. Perinatal CMV infection acquired during birth or from mother’s milk: not associated with newborn illness or CNS sequelae, except perhaps in very preterm newborns who have very low levels of passively acquired CMV antibody at the time of infection
CLINICAL FEATURES
1. Symptomatic at birth in 5–10% of congenital CMV infec- tions
a. Approximately 20% of these will die
b. 90% of survivors will develop major neurological sequelae
2. Asymptomatic or “silent” congenital infections at birth in vast majority (85–90%) of cases. 10–15% of the asymp- tomatic newborns will be afflicted by late sequelae such as mental retardation, deafness or hearing defects, usually during the first 2 years of life
3. Nonneurologic symptoms at birth
a. Petechiae (most common nonneurologic symptom) b. Thrombocytopenia
c. Purpura d. Ecchymoses e. Splenomegaly
f. Hepatomegaly g. Jaundice
h. Intrauterine growth retardation i. Chorioretinitis
j. Pneumonitis k. Anemia
l. Nonimmune hydrops 4. Neurologic symptoms at birth
a. Hypotonia b. Lethargy c. Jitteriness d. Split sutures
e. Immature primitive reflexes f. Feeding difficulties
g. Microcephaly: the most specific predictor of mental retardation and major motor disability
h. Seizures 5. Eye manifestations
a. Chorioretinitis resulting in a chorioretinal scar b. Corneal opacities
c. Bilateral anterior polar cataracts
d. Optic nerve hypoplasia and optic nerve coloboma e. Cyclopia and anophthalmia
6. Later neurologic symptoms a. Sensorineural hearing loss b. Learning disability c. Mental retardation d. Cerebral palsy
7. Prognosis
a. Neonatal clinical abnormalities expected to resolve spontaneously within weeks, except for those involv- ing the CNS and hearing
b. A leading cause of mental retardation and sensory impairment (50–90% of symptomatic newborns) and sensorineural hearing loss (7–15% of asymptomatic infants)
c. An important cause of cerebral palsy and retinal damage 8. Maternal primary CMV infection
a. Asymptomatic: vast majority of pregnant women b. Symptomatic (mononucleosis-like syndrome) in
approximately 10% of infected pregnant patients i. Fever
ii. Fatigue/malaise iii. Myalgia
iv. Pharyngitis v. Cough vi. Nausea vii. Headache
DIAGNOSTIC INVESTIGATIONS
1. Children with symptomatic congenital CMV infection a. Cytomegalic inclusion bodies in the urine
b. Elevated alanine aminotransferase (ALT >80 IU/mL) c. Thrombocytopenia (<100,000/mcL)
d. Conjugated hyperbilirubinemia (direct bilirubin
>2 mg/dL) e. Anemia
f. Elevated CSF protein (>120 mg/dL)
g. Abnormal CT scan (most common neurologic sign and the most sensitive predictor for mental retardation)
i. White matter lucencies ii. Ventriculomegaly
iii. Intracranial calcifications (usually periventricular) iv. Destructive encephalopathy
v. Brain atrophy
vi. Neuronal migration disorders 2. Evidence of infection with CMV
a. 4-fold rise in antiCMV IgG titers b. Seroconversion from negative to positive
c. Sensitivity of the CMV IgM assays (50–90%). The IgM titers may not become positive during acute infection
3. Viral isolation
a. The most sensitive method to diagnose CMV infection b. Culture of CMV from virtually all body fluids, including saliva and urine of the newborn, semen, and cervicovaginal secretions
c. Detection of CMV within the first 3 weeks of life:
considered proof of congenital CMV infection 4. Identification of CMV DNA through PCR (sensitivity of
75–100%)
GENETIC COUNSELING
1. Recurrence risk
a. Preconceptional immunity to CMV provides substan- tial protection against intrauterine transmission and severe fetal infection
b. Presence of maternal humoral antibody: conferring no fetal protection in subsequent reinfection or reactivation 2. Prenatal diagnosis
a. Prenatal ultrasonography
i. Intrauterine growth retardation ii. Microcephaly
iii. Ventriculomegaly
iv. Periventricular calcifications v. Intrahepatic calcifications vi. Nonimmune hydrops vii. Fetal Ascites viii. Pericardial effusion
ix. Hepatosplenomegaly x. Echogenic bowel xi. Cardiomegaly xii. Oligohydramnios xiii. Placentomegaly
b. Prenatal diagnosis of congenital CMV infection by combined detection of CMV-DNA and CMV-IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA and IgM antibodies (sensitivity of 100%)
c. Negative results of CMV culture or PCR in the amniotic fluid cannot formally exclude intra-uterine infection d. Prenatal diagnosis of CMV infection remains a ‘long-
standing problem still seeking a solution’ as long as no assistance (treatment or prevention) can be offered to the pregnant women
3. Management a. Prevention
i. Complicated because both primary and second- ary maternal infections give rise to disease in the offspring and absence of characteristic symp- toms in CMV-infected mothers excludes clinical recognition of at-risk pregnancies
ii. Routine screening of pregnant patients for CMV status: not currently recommended because no effective antiviral therapy is available during gestation and also there is no means to predict the outcome in an infected fetus
iii. Risk to CMV infection for women in high-risk environments (day-care centers, nurseries, ele- mentary schools, or health care facilities) iv. Strict hygiene practices for seronegative women
to reduce the risk for the infection
b. No pharmaceutic regimens available for treatment of maternal and fetal CMV infections. Treatment with antiviral agents (ganciclovir, foscarnet) is limited to severe infections (CMV retinitis) in immunocom- romised patients and not currently used in pregnancy c. A live attenuated CMV vaccine
i. Live vaccines may bear a serious risk when transmittable to the fetus
ii. Concerns for reactivation (reinfection), viral shed- ding in breast milk and cervix, and oncogenesis
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Fig. 1. A neonate with blue berry muffin skin lesions (generalized purpura) due to cytomegalovirus infection. He died 20 hours after birth. CMV inclusions were noted in kidneys, lungs, liver, pancreas, thyroid, brain and eyes, and also in the urine. Photomicrograph of the kidney shows many tubular epithelial cells containing large cytome- galic inclusion bodies.
Fig. 2. Photomicrograph of the kidney (macerated fetus, 16 weeks ges- tation). Even though the tissue is macerated, many cytomegalic inclu- sion bodies are demonstrable. Coronal section of the brain (frontal lobe) showing ventricular hemorrhage and focal encephalomalacia (chalky white discoloration) due to cytomegalovirus infection.
Fig. 3. Photomicrograph of premature lung of a different patient showing a single large cytomegalic inclusion body.
Fig. 4. One cytomegalic inclusion body in the urine sediment in another patient.
Fig. 8. An adult with congenital CMV infection showing mental retar- dation and intracranial calcifications by CT scan.
Fig. 5. A macerated stillborn with hydrops fetalis from congenital CMV infection.
Fig. 6. An infant with CNS involvement and chorioretinitis from con- genital CMV infection.
Fig. 7. Skull radiographs of another patient with congenital CMV infection showing microcephaly and typical intracranial ventricular subependymal calcifications.
