Cytomegalovirus (CMV) infection, the most common congenital infection, affects approximately 1% of all live births [1-3]. Congenital CMV infection is usually transmitted to the fetus in utero, whereas perinatal infection occurs during the intrapartum period or immediately after birth [1]. The diagnosis of congenital CMV infection is established by isolating the virus from urine, saliva, or tissue during the first 3 weeks of life [1]. Only about 1-15% of neonates with congenital CMV infection have symptoms at birth [4]; approximately 90% of infected newborns show no overt signs of infection. Thus, congenital CMV infection is easily overlooked [1, 4]. Subsequently, 10-20% of asymptomatic newborns develop late sequelae, particularly sensorineural hearing loss (SNHL) and neurodevelopmental disorders [4, 5].

Thrombocytopenia is an important prognostic factor in patients with CMV infection. Rivera et al. reported that CMV-induced neonatal thrombocytopenia is associated with symptoms at birth [6]. Benoist et al. demonstrated that the presence of abnormalities on prenatal ultrasound examination and thrombocytopenia appear to be strong, independent prenatal predictors of a poor outcome [3]. Petechiae are usually, but not always, present in patients with thrombocytopenia, and platelet counts in the first few weeks of life range from 2,000 to 125,000/µL [7]. Therefore, thrombocytopenia may be overlooked in the neonatal period, and it may persist or worsen after the neonatal period. However, little data are available on the association between congenital or perinatal CMV infection and thrombocytopenia during early infancy.

Therefore, we evaluated the clinical manifestations and neurodevelopmental outcomes of CMV-induced thrombocytopenia in infants aged younger than 6 months.

CMV is the most common cause of intrauterine infection, affecting 0.5-2.4% of live births; perinatal infection may occur from exposure to genital secretions at the time of delivery or from infected breast milk or close contact with an infected person [1, 3]. Currently, routine screening for CMV infection is not recommended in neonates because the overall risk of symptomatic CMV infection is low (0.2%) and because several limitations are imposed in screening all pregnant women: the positive predictive value is low, fetal diagnosis requires invasive amniocentesis, and the only available intervention at present is abortion [1, 5].

Few studies have reported on cases of asymptomatic CMV infection after the neonatal period. Although 85-90% of children with congenital CMV infection are asymptomatic during the neonatal period, some may subsequently develop symptomatic disease [4]. In fact, 10-20% of children with congenital CMV, either symptomatic or asymptomatic during the neonatal period, exhibit neurological deficits when followed up, which indicates that close follow-up evaluation, particularly of any neurological deficits, is warranted [4, 9]. None of the patients in this study had apparent clinical manifestations of CMV infection at birth, but they later developed thrombocytopenia, which was the chief reason for hospital admission.

The presence of IgM at birth is highly suggestive of a congenital infection, although its absence does not rule out the possibility of congenital infection. Typically, the diagnosis of congenital CMV infection is based on testing positive for IgM at 2-3 weeks of age; however, only 70% of patients who test positive for IgM are clinically significant cases of CMV infection. Direct demonstration of the virus' presence is needed for the diagnosis in neonates [4, 10]. However, patients with primary and secondary infection continue to test positive for IgM antibody for 6-18 months; hence, the IgM antibody test is useful in infants suspected of having CMV infection [5].

The major symptoms of CMV infection include intrauterine growth retardation, jaundice with direct hyperbilirubinemia, hepatosplenomegaly, petechiae or purpura, thrombocytopenia, and pneumonia. SNHL and ocular involvement are important late sequelae.

Petechiae are usually, but not always, accompanied by thrombocytopenia, and the platelet counts during the first few weeks of life range from 2,000 to 125,000/µL [1]. The thrombocytopenia usually resolves during the second week of life, but may persist and require treatment with repeated platelet transfusions. While several studies have reported on thrombocytopenia associated with CMV infection, the role of CMV infection in typical acute, self-limited, or persistent idiopathic immune thrombocytopenia (ITP) in children remains unclear. Several hypotheses exist to explain how CMV infection causes thrombocytopenia: direct cytotoxicity of CMV on hematopoietic cells, immune-mediated destruction of infected cells, or impaired bone marrow stromal function by CMV [11, 12]. In addition, CMV infection may induce nonspecific autoantibodies that cause antibody-mediated platelet destruction [13]. No apparent correlation exists between CMV clearance and the resolution of thrombocytopenia [11].

Evans syndrome has rarely been described in association with CMV infection; one report described 3 of 28 pediatric patients presenting with thrombocytopenia (11%) as being positive for CMV in the urine, using the shell vial assay [11]. Of these, 2 patients were diagnosed with ITP, and 1 patient had Evans syndrome [11]. One patient in our series had Evans syndrome; he had abnormal findings on brain MRI scans but no otologic or ophthalmologic manifestations.

Except for the patient with an initial platelet count 105,000/µL, all patients with CMV-induced thrombocytopenia in this study were treated with intravenous immunoglobulin; their platelet counts normalized within 3 months of the diagnosis, which is compatible with a diagnosis of the acute form of ITP. However, reports have described infants with CMV infection who experienced disease progression to chronic ITP, even with intravenous immunoglobulin therapy [14]. Therefore, long-term follow-up of our patients is needed to completely rule out chronic disease.

In cases of SNHL, the follow-up period is extremely important. A previous study reported that only 59% of the patients with SNHL diagnosed at 72 months of age had been correctly diagnosed at 12 months [15-17]. In addition, approximately half the cases with hearing loss due to congenital CMV infection were reported to be late-onset or progressive and therefore could not be detected at birth via newborn hearing screening tests [17, 18]. In our series, 1 patient developed unilateral SNHL. This patient, who is currently 2 years old, is undergoing regular follow-up evaluation. Ocular involvement with chorioretinitis is common in patients with CMV infection, and retinal scars, optic atrophy, and central vision loss have also been described [1, 4, 15]. In this study, however, no patients had ocular involvement.

We speculate that the CMV infections in our patients were acquired as congenital infections during late pregnancy or as perinatal infections. First, the patients did not have clinical signs of infection during early pregnancy, such as intrauterine growth retardation or microcephaly; however, they had signs of late infection, such as hepatitis, petechiae, and thrombocytopenia. Second, IgM persists for a long period, and 4 of 6 patients in our series were positive for CMV PCR and CMV pp65 Ag, which indicated recently acquired infection [8, 15, 19]. CMV infection during late pregnancy has a higher rate of neonatal infection but a lower rate of symptomatic manifestation than that during early pregnancy [20]. The transplacental infection rate during the first and second trimesters is around 45%, and the rate increases to 58-78% during the third trimester. Since neuronal growth and migration is completed before 26 weeks of gestation, transplacental infection during the third trimester is less frequently associated with symptomatic neurodevelopmental manifestations as compared to earlier infections [20, 21]. If the CMV infections in our series of patients were congenital infections, recurrent infection would have been more likely than primary infection, since all the patients were asymptomatic at birth and positive for CMV IgG but had no symptoms at admission other than those related to thrombocytopenia [22].

In conclusion, this study showed that thrombocytopenia can be the main clinical manifestation of otherwise asymptomatic CMV infection after the neonatal period. CMV infection needs to be considered in infants between 1 and 6 months old with thrombocytopenia, and close follow-up is needed to detect neurodevelopmental sequelae.

Patient 1 shows normal auditory brainstem response (ABR) on the right side (up to 25 dB) and minimal response on the left side.

Brain MRI of Patient 2 shows multiple small nodular T1-high and gradient echo-dark signal intensity lesions in the right occipital lobe (arrow). This finding is compatible with a calcified inflammatory granuloma as a sequela of previous CMV infection. Also note the subdural effusion and right frontotemporal convexity (arrowheads).

(A) Brain images of Patient 4 during the neonatal period. Red arrows point to the small nodular T2-weighted GRE-dark signal intensity lesion in the caudo-thalamic notch on the MRI scan (left) and left germinal matrix hemorrhage on brain sonogram (right). (B) Brain MRI scan of the patient obtained at the diagnosis of thrombocytopenia showed a small nodular T2-weighted axial GRE-(left) and coronal FSE (right)-dark signal intensity lesion in the caudo-thalamic notch (red arrows).

Table 1 Comparisons of patients with thrombocytopenia according to CMV status.

Table 2 Summary of test results in patients with CMV infection in infancy.

Table 3 Clinical manifestations of the patients.