Donna Chriss-Price, RT, RDMS, Sandra K. Lawrence, MD^¶, Philippe Jeanty, MD, PhD^#

Address correspondence to Donna Chriss-Price, RT, RDMS, Dept. of Ultrasound/OB-GYN, Centennial Hospital of Nashville. ¶Dept. of Radiology, Vanderbilt University, # ^{Women’s Health Alliance, Nashville, TN}

Synonyms: Cytomegalovirus (CMV) disease, cytomegalic inclusion disease, "blue muffin" syndrome, TORCH syndrome.

Definition: Cytomegalic inclusion disease is caused by a species-specific double-stranded DNA herpes group virus, which causes an inapparent infection or a "mononucleosis-type" illness in young healthy adults, a chronic disease in older adults, and mild to severe congenital infections.

Incidence: An estimated 0.2-2.4% of worldwide live-born infants acquire the virus perinatally¹. Only 10% of these will demonstrate classic signs of illness at birth².

Pathogenesis: Cytomegalovirus preferentially invades the salivary glands and, in infants, the germinal matrix, but can infect other organ cells with development of characteristic cytoplasmic or nuclear inclusion bodies. Timing of the maternal infection and fetal development with hematogenous transplacental transmission is felt to play a critical role in the pathogenesis³, as disruption from the inclusion viral material may cause cell damage versus cell death and subsequent sequelae.

Differential diagnosis: Many viral prenatal infections including mumps, Ebstein-Barr virus, varicella, or TORCH etiologies (toxoplasmosis, rubella, cytomegalovirus, herpes virus) can clinically mimic congenital cytomegalic inclusion disease. Erythroblastosis fetalis due to Rh incompatibility or ABO incompatibility may present similar findings clinically. Extensive differential diagnoses of splenomegaly are in Table 1.

Prognosis: Neonatal symptomatology of microcephaly, intracranial abnormalities, and seizures are poor prognostic signs². Previous longitudinal studies have indicated that the majority of symptomatic infants have permanent visual, motor, or intellectual disabilities^4-7.

Associated anomalies: Hepatomegaly, splenomegaly, microcephaly, hydrocephaly, hydrops fetalis, intracranial calcifications, cardiovascular defects, gastrointestinal and musculoskeletal defects, ocular lesions, petechiae, neurosensory hearing loss, poor intellectual development, IUGR, and ascites.

MESH Cytomegalovirus inclusion disease BDE 0381 POS 3220 ICD9 771.1 CDC 771.100 

There are rare case reports^8-12 and one small series of antenatal sonographic findings with confirmed fetal cytomegalovirus infection. Only one case report has described both hepatomegaly and splenomegaly in a cytomegalovirus infected fetus with intrauterine growth retardation (IUGR). We describe a case of isolated splenomegaly detected by sonography in a 36-week gestation fetus, which had antenatal laboratory confirmation of prenatal cytomegalovirus infection.

A 23-year-old G₂P₁ Caucasian woman (0 negative, Rh+) was referred for prenatal ultrasound at 22 weeks gestation by EGA for a routine anomaly screen. Her last menstrual periods were unknown. The patient had a normal triple screen at 16-17 weeks gestation. At this time, the amniotic fluid was considered low-normal and the fetus presented no evidence of anomaly. The measurements were consistent with a 20-week size. Three weeks later, a follow-up scan was performed. The biometry and measurements were consistent with 3 weeks growth. The fluid volume had increased to the 50^th percentile. The stomach was not seen at this time, and it was thought to be empty. Two weeks later, the ultrasound demonstrated a normal fetal stomach position and amniotic fluid. Seven weeks later, growth retardation was suspected, as the maternal abdomen size failed to increase appropriately. The ultrasound examination now revealed a small fetal chest with a normal heart. The amniotic fluid was low-normal (AFI: 25^th percentile) for 36/37 week gestation.

The biometry of the fetus confirmed growth retardation with measurements of 32/33 week size and splenomegaly. The spleen measured 6x5x2 cm, reaching the fetal umbilicus (fig. 1). A viral infection was suggested.

Blood analysis was negative for HIV. A TORCH profile verified an acute maternal cytomegalovirus infection. The lab values were as follows: toxo IGM: 0.2 Index (Negative results < 0.5 Index), toxo IGG: 0.1 IU/ml (Negative < 6 IU/ml), cytomegalovirus IGM: 1.0 Index (Negative < 0.500 Index), cytomegalovirus IGG: 250 AU/ml (Negative < 15 AU/ml), rubella: 57 (Negative >10 IU/ml). The patient spontaneously went into labor 4 days later.

The male newborn had an Apgar of 8 at 1 minute and 9 at 5 minutes. He weighed 2220g (5^th percentile). The neonate presented with congenital deafness, splenomegaly, microcephaly, and petechiae: culture and TORCH titers were positive for cytomegalovirus. The cord blood typed A-negative. A Coombs test was negative, which ruled out ABO incompatibility. The normal antenatal intracranial findings were confirmed with a normal study of neonatal head. The infant was fitted with bilateral hearing aids and will be monitored closely over the next few developing years.

Incidence

Cytomegalovirus antibodies are identified in 44% to 100% of the adult population². In the United States, pregnancy is often complicated by infection with cytomegalovirus¹³. The occurrence of maternal cytomegalovirus differs with maternal age, parity, socioeconomic status, and stage of gestation. Day care workers, dialysis technicians, and nursery hospital personnel are at the highest risk. Most primary and nearly all recurrent maternal cytomegalovirus infections are asymptomatic in the mother.

With the change in society lifestyle and more children in day-care, there is an increasing incidence of cytomegalovirus infection in the United States¹⁷ . More than 9000 infants demonstrate sequelae from the 30,000 to 40,000 cytomegalovirus congenitally infected infants born in the United States each year¹⁸. Cytomegalovirus has become the most frequent cause of perinatal viral infection and is responsible for 3000 new cases of mental retardation each year¹⁹. Cytomegalovirus is the primary cause of congenital viral deafness²⁰.

Prenatal infection

Congenital infection usually occurs in a fetus of a mother with primary infection, with timing of the maternal infection and fetal stage of development considered a critical factor¹⁴, as there is a 40-50% risk of giving birth to a clinically symptomatic infected neonate¹⁵. Cytomegalovirus transmission has been occasionally reported in consecutive pregnancies in women who are seropositive, but such infants are rarely adversely affected¹⁵ , as maternal antibody prior to conception provides substantial protection¹⁵. Worldwide estimates that 0.2-2.4% of liveborn infants acquire the virus perinatally¹; of these, only 10% will demonstrate classic signs of illness at birth². An additional 5-15% of asymptomatic congenitally infected infants will demonstrate late sequelae of deafness, neurodevelopmental delay, and/or chorioretinitis.

Prenatal diagnosis

In a study in Brussels, Belgium (1985 to 1992), 52 women at risk for congenital cytomegalovirus infection were investigated using ultrasound examinations, amniocentesis, and fetal blood sampling. Other nonspecific blood testing was done such as white blood cell count, hemoglobin, hematocrit, platelets, and gamma-glutamyl transferase determination. With results of all testing, antenatal diagnosis of cytomegalovirus was made in 13 of 16 fetuses¹⁷. The ultrasound findings in the literature are isolated case reports, and a few small series of cytomegalovirus infected fetuses were reviewed. Drose et al reported the largest series of ten fetal cytomegalovirus confirmed-infection patients⁸. The amniotic fluid was normal in one, decreased in six, and increased in three⁸. The placenta was enlarged in only 50%⁸. Antenatal ultrasound findings included (Table 1) hydrocephalus (3), periventricular calcifications (2), inhomogeneous brain parenchyma (2), microcephaly (1), ascites (3), bilateral pleural effusions (1), growth retardation (2), cardiomegaly (2), septal abnormalities (2), and multiple cystic areas in the pelvis (1)⁸. Microcephaly, periventricular calcifications, cerebral ventriculomegaly, and IUGR have been noted in other reports^{3,8,9,10, 16,21,22}. Polyhydramnios and placental enlargement were previously described by Price et al²⁴. A fetal abdominal echogenic mass has been described in several separate case reports^{8,11,12,16,21, 24,25,26,}. A single case report had previously noted splenomegaly and IUGR but with associated microcephaly and hepatomegaly⁹. Antenatal ascites^8,11,21,24 and/or hydrops fetalis^19,20 is a poor prognostic indicator with 100% fetal demise.

The differential diagnosis of splenomegaly in an infant or fetus presents a puzzling diagnostic dilemma. The differential diagnosis of splenomegaly in a fetus has not been established. However, the differential for an enlarged spleen in an infant is similar to an adult (Table 2), with the exception of no reported cases of lymphoma, multiple myeloma, rheumatoid arthritis, or Felty"s syndrome. With most etiologies presenting as a neonate or infant, it is conceivable that a very early presentation of some of the disorders could occur in the fetus.

Splenomegaly is usually secondary to systemic illness, signifying an abnormality of the lymphoid, reticuloendothelial, or vascular components of the spleen. The most common cause of splenomegaly is infection, but other categories include hematologic, metabolic, vascular, neoplastic, congestive states and miscellaneous disorders.

In our case, without evidence of splenic infarction, mass lesion, portal or splenic vein thrombosis, cavernous transformation of the portal vein, or other organ abnormalities, the suspected etiology was primarily splenic lymphoid hyperplasia from an infectious agent, hemolytic disease of the newborn with compensatory hematopoietic recruitment, or leukemia.

Less likely considerations included other lymphohematogenous disorders, storage diseases, reticuloendithelioses, and lupus erythematous syndrome. Initial blood analysis demonstrated no lymphohematogenous disorders or erythroblastosis fetalis. Seronegative titers to HIV, toxoplasmosis, herpes simplex virus, rubella, hepatitis with seropositive confirmation of cytomegalovirus from urine and blood established the diagnosis.

Associated anomalies

The associated anomalies with cytomegalovirus cover a wide range of systems. Congenital cytomegalic inclusion disease is classically associated with periventricular calcifications, petechiae, splenomegaly, hepatomegaly, prematurity, hydrocephaly, intrauterine growth retardation, jaundice, microcephaly, chorioretinitis, deafness, and intellectual developmental delay^2,18.

Presentation in the newborn

Clinical presentation of petechiae, jaundice, splenomegaly, and neurosensory hearing loss are typical congenital cytomegalovirus sequelae.

Comments

Early detection of IUGR with subsequent sonographic follow-up evaluation allowed detection of the isolated splenomegaly in our case. Ultrasound abnormalities in isolation may not suggest a definitive diagnosis but does alert the physician to the possibility of a prenatal congenital disease or disorder and the need for further evaluation. As more information is accrued, detection of fetal splenomegaly in utero may represent a sign of early infection and provide predictive value of multi-organ involvement. From review of previous case reports, antenatal ascites and/or hydrops fetalis is a poor prognostic indicator. Since prenatal diagnosis of fetal cytomegalovirus infection has been reported using amniotic fluid analysis, cordocentesis, and fetal blood analysis^{16,20,22,28,29,30,31,32} after an active maternal infection is documented, sonographic evaluation of the fetus is an important fetal screen modality21. If further trials with dosage and administration of ganciclovir in neonates is successful in ameliorating the sequelae of cytomegalovirus infection, early sonographic detection of abnormalities and appropriate follow-up studies will play a role in fetal management.