Introduction

Congenital Cytomegalovirus (CCMV) is the most common cause of congenital infection and is worldwide in distribution; incidence ranges from about 0.2 to 2.5% of live births and around 40,000–80,000 infants with CCMV are born each year in the US [5, 7, 9, 11, 16, 17, 24, 26]. It is caused by Human Cytomegalovirus (HCMV), a ubiquitous virus and like other viruses in the Herpes virus family share properties of latency and reactivation [7, 9, 17]. Cytomegalovirus (CMV) can be vertically transmitted transplacentally and can lead to severe fetal injury, resulting in fetal loss and of those born with CCMV, 10 to 15% will have symptoms at birth and the rest are asymptomatic CCMV (ACCMV) [6, 21].

CCMV is a major cause of central nervous system (CNS) damage leading to sensorineural hearing loss (SNHL), mental retardation and cerebral palsy. In SCCMV, the mortality in the early neonatal period is 30% and the morbidity is devastating, due to its potential to cause cerebral palsy, cognitive impairment (50–80%), SNHL (30–60%), visual impairment (20–35%), neuro-developmental, behavioral and neuromuscular disorders (30–60%) [6, 19, 21, 23]. Treatment of neonates with CCMV infection also remains controversial especially as most of the injury has occurred during fetal life and neuronal damage is irreversible. But as there is significant mortality, progressive injury and long-term neurological sequelae, treatment may be considered in some patients with severe SCCMV infection [3, 14, 15, 22, 25, 27]. The prevalence of congenital CMV and the severity of adverse neurological outcome in this group of infants make this a major public health problem. Because of the paucity of information, we have undertaken a study of SCCMV, to document the diversity of the clinical presentation, describe the range of sequelae and severity of the adverse outcomes.

Methods

Patient population

Patients with congenital CMV were identified through the Congenital Infections Clinic, the Cytomegalovirus Registry and a search of the databases at The Hospital for Sick Children, Toronto, which serves as a regional referral hospital to a region having approximately 70,000 births per year. Infants were included if they had definite SCCMV infection which is defined as CMV detected in urine, saliva, secretions or tissue obtained within the first three weeks of life in a newborn with any clinical manifestations of an intrauterine infection and were registered in the database from 1987–2000. CMV was detected by shell vial rapid detection of early antigen fluorescent foci technique (DEAFF) [26]. This study had approval of the institutional ethics and research review board.

Data collection

Baseline data obtained included demographic information, maternal, perinatal and neonatal history, clinical information from history, physical examination laboratory, neuro-imaging and neuro-physiological findings. More than 50 variables were collected from patient records. Outcome data included hearing and vision test results, results of developmental and clinical tests, neurological, intellectual, motor function evaluation including Bayley (Psychological Corp, San Antonio, TX, USA) and other tests of cognitive function, and functional level as described in the activities of daily living (ADL) and growth parameters at 1 year, 2 years and, if available, at 5 years of age. Definitions are provided in the Appendix.

The primary outcome was neurodevelopmental and classified as normal or adverse outcome groups. The adverse outcome group was defined as one or more of the following: death, moderate or severe cerebral palsy, moderate or severe developmental delay (Bayley score of <2SD for age (<70) or untestable), blindness or deafness at 2 years of age. Outcome data at later ages are also obtained to obtain a spectrum of severity and also to capture minimal disabilities.

Data description and analysis

The clinical, laboratory, neuro-physiological, imaging and outcome data were computed and the data were described using means, medians and standard deviations for continuous variables and percentages for categorical variables. The demographic and clinical characteristics were compared based on their different outcome variables. Fisher’s exact or Chi square tests were used to determine significant differences between potential categorical risk factors and outcomes. Univariate and bivariate associations were explored using logistic regression on the variables of potential continuous risk factors to assess their relationship to outcomes. All analyses were performed using the SAS statistical software package (SAS institute, Cary, NC, USA).

Results

Of the 104 patients identified as SCCMV, 42 infants were included. Exclusions were due to misdiagnosis of possible SCCMV, where the diagnosis was not within three weeks of life or difficulty in proving the CMV infection was congenital and not postnatally acquired and when they were asymptomatic. The male:female ratio was 1:1.4. Three patients (7%) died and one child was lost to follow-up. Causes of death were pneumonia and respiratory failure, cyanotic congenital heart disease and unknown in a severely impaired older infant who died at home and occurred at ages 2 weeks, 1 month and 6 months, respectively. The clinical characteristics of this cohort are summarised in Table 1. The mean maternal age was 29.2 years±5.4. There were 9 (21%) preterm infants. Hepatosplenomegaly, petechia and microcephaly were the most common initial presenting features. Ophthalmologic findings included cataract in 7% (3/42), corneal opacity in 7% (3/42), retinal hemorrhage in 5% (2/42), retinal scars in 8% (3/38) and Peters’ anomaly in 2% (1/42). Other anomalies included Pierre Robin sequence in 2% (1/42), inguinal hernias in 7% (3/42), pneumonitis in 7% (3/42), hypothyroidism, in 2% (1/38), dental enamel defects in 11% (4/38), persistent pulmonary hypertension in 2% (1/42), ventricular septal defect in 5% (2/42), Fallot’s tetralogy in 2% (1/42) and complex cyanotic congenital heart disease in 2% (1/42). Abnormalities on imaging included cerebral atrophy, hydrocephalus, pachygyria, periventricular white matter defects, polymicrogyria, lissencephaly, ventriculomegaly, intracranial calcifications, cerebellar asymmetry and hypoplasia and absence of the corpus callosum. Outcomes and severity of neurological deficits are summarised in Table 2. The mean duration of follow-up was 4.3 years±2.3 (Range: 2–13 years). Among those with hearing loss, it was bilateral and moderate to severe (>50 db) in 17/38 (46%). There were 16/38 (43%) patients who had hearing aids and two with cochlear implants and 6 patients who were bedridden or wheelchair bound.

Table 1 Clinical characteristics of SCCMV
Full size table
Table 2 Outcome and neurological deficits in SCCMV infection
Full size table

Table 3 summarizes the associations of adverse outcomes with initial presenting signs. Univariate analysis did not show any statistically significant association between the potential risk factors and outcome variables. However bivariate association did show statistically significant associations and there was a significant risk of adverse outcome if there was abnormal BAER (OR 8.7), abnormal head ultrasound (OR 8.5) or abnormal brain CT scan (OR 21.0) at presentation.

Table 3 Bivariate association of adverse outcome and initial presenting signs
Full size table

Discussion

The common clinical presentations of SCCMV in our cohort include intrauterine growth retardation (IUGR), purpura, jaundice, hepatosplenomegaly, microcephaly, hearing impairment and thrombocytopenia. Reticuloendothelial system signs like hepatosplenomegaly, anaemia, petechiae and lymphadenopathy are transient and differences in incidence are due to the difference in the timing of examination. Similarly, incidence of microcephaly varies (20–50%) if HC was recorded at birth or early in presentation rather than later [1, 6, 13, 26, 19]. It is generally presumed that infants born with SCCMV infection have a poor prognosis as up to 90% of symptomatic infants will have neurological sequelae and the mortality rate can range from 2–30% [6, 19, 26]. A bimodal distribution of intelligence and developmental scores, with one profoundly affected group having a mean IQ of 29 and the other a mean IQ of 92 has also been reported [8].

The mortality of 7% represents in-hospital mortality, but as loss to follow-up was small, it would not be expected to increase significantly and 71% of this cohort had 1 or more adverse outcome. The reasons for these differences in reported outcomes include variation in choice and timing of endpoints use of either motor assessment or cognitive assessment. Infants referred to tertiary centers, as in our study, are a highly selected population and severely affected infants are more likely to be included. Prospective ascertainment and follow-up of infants also suffers from selection bias as universal screening is not generally performed.

The present study extends the findings of other cohort studies which are limited by follow-up periods to 1 or 2 years or single follow-up visits or lack of detailed evaluations [2, 4, 6, 8, 19]. Long term follow-up is essential as some of the major neurological deficits improve with time and other deficits like cognitive, learning disabilities, dyslexia, hyperactivity-inattention syndromes and behavioral difficulties become apparent as children grow older, at school age or later. SNHL not identified by early testing can be found at a later age and pre-existent SNHL can worsen suggesting progressive neural damage. Our series shows that early SNHL was seen in 38% and later loss detected in a further 18%. This compares with an earlier study, which detected early SNHL at birth in 5.2% of all infected children, including ACCMV, but late-onset disease at 6 years in 15.4% of children [10]. The risk factors for an adverse outcome included abnormalities on neuroimaging and BAER at presentation.

Infection in utero can occur in 35–40% of cases after primary infection and it is also more severe but CCMV occurs in 1–2% of pregnant women with previous infection due to chronic infection, reactivation or reinfection with a new strain. Although controversial, there are groups advocating pre-conceptional screening, so that the sero-negative pregnant woman can be monitored closely for sero-conversion and for amniotic fluid HCMV [7, 12, 17].

To prognosticate, retrospectively, in SCCMV it is helpful in determining the sero-status of mothers during pregnancy from stored blood samples, but in view of the length of time spread it was not possible in this cohort. Ganciclovir has now been shown to prevent hearing deterioration at 6 months of age when treatment was started in the neonatal period and continued for at least 6 weeks but the need for intravenous access, prolonged duration, costs and adverse effects need to be considered [14, 25]. From a public health perspective, it is imperative that we focus on prevention of CCMV and, apart from hygiene and the detection of pre-conceptional immunity, an effective vaccine is the most important element. The cost and burden of SCCMV can be reduced markedly only if a safe and effective vaccine is developed. Currently, work is being done on recombinant Towne strains, gB glycoprotein, Vactor and DNA vaccines [12, 18, 20].

In this cohort of SCCMV, we have identified a diverse presentation with very severe neurological outcome and some children who have progressive deficits. This study consequently reinforces the need for all children with CCMV to have long term follow up at least till their school years, when more comprehensive assessments can be done. The major challenge for primary care physicians will be to ensure this long term follow up.