INTRODUCTION

Human cytomegalovirus is the leading cause of congenital viral infections. The frequency of congenital cytomegalovirus infection in the United States and Europe ranges from 0.2 to 2.4% live births (1, 2). During the neonatal period and early infancy, only 5-10% of children with prenatally acquired infection present such symptoms as spleno- and hepatomegaly, intensive or prolonged jaundice, pneumonia, microcephaly, petechiae. Despite being infected, the remaining children are clinically asymptomatic or mildly effected. Nonetheless, many months or years later, children in both groups may develop late sequelae of congenital infection – this occurs in up to 90% of those with symptomatic infection, and in about 20% children with silent infections (1). Even asymptomatic and subclinical CMV infections can affect intellectual and cognitive development, including speech, especially if hearing impairment ensues (1, 3, 4).

AIM

Assessment of intellectual development of 6-year-old children following asymptomatic or mildly symptomatic congenital cytomegalovirus infection in infancy.

MATERIAL AND METHODS

This investigation was a longitudinal cohort study. In the year 2000, a total of 1895 neonates aged 3 to 5 days were preliminarily enrolled into the study by sampling urine for the presence of DNA-CMV. Among the tested neonates 38 were positive. In the whole group specific serological tests (IgG and IgM) were performed, as well as specialized clinical evaluation during the neonatal and early infancy period (evaluation I). The second clinical assessment was performed at the age of 12-18 months (evaluation II) (5), and the final comprehensive clinical evaluation (evaluation III) at the age of 6-6.5 years.

The following investigations were performed:

• Anti-CMV IgG and IgM antibodies in serum were determined by a microparticle enzyme immunoassay using AxSYM system and commercially available kits (Abbott Laboratories). CMV DNA load in urine was analyzed by semi-automated quantitative CMV DNA assay (Cobas Amplicor CMV Monitor, Roche Diagnostic System) according to slightly modified manufacturer’s instructions.

• The concentrations of unconjugated and direct bilirubin, numbers of platelets, percent of neutrophils in peripheral blood smears and serum aminotransferases activity were determined.

• Ultrasound (USG) examinations of the brain and abdomen were performed and, depending on the clinical condition, also electroencephalography (EEG) and computer tomography (CT) of the brain.

• Comprehensive clinical evaluation included paediatric, neurological, audiological (Auditory Brain Stem Response – ABR), ophthalmologic (anterior segment and eye fundus) and rehabilitative aspects. Psychological tests included: Terman-Merill IQ Scale, the Bender-Kopitz test and the Dole Scale.

Specialised examinations and laboratory tests were performed at different departments of the Institute. The local Bioethics Commission approved the study and the mothers gave informed consent for participation of their children in the study.

RESULTS

In the analysed group of six-year-old children only 5 (13%) children were found to have mild organ abnormalities of the central nervous system and the sense of hearing. During the last visit EEG abnormalities (in one child seizures were observed) were found in 3 children, mainly in those with abnormal neuroimaging in infancy. Two of the children have mild bilateral sensorineural hearing impairment. None of the children were found to have hepatosplenomegaly nor elevated aminotransferases activity or neutropenia during the last visit. The clinical symptoms observed during the neonatal period and infancy were also mild. There were changes in muscle tonus (especially hypotonia) in about 25% of the studied children which normalized. The most frequent findings by paediatric examination in infancy was discrete peripheral lymph nodes enlargement and hepato/hepatosplenomegaly accompanied by elevated aminotransferases activity with hiperbilirubinaemia and neutropenia (5).

Psychological evaluation during the last visit showed:

• In terms of cognitive development, all children indicated normal mental development. IQ values were from 88 to 114, i.e. in the average range. In the Bender-Koppitz test, 3 children (8%) had a total score of 3 or less, indicating poor visual-motor integration, 12 (32%) children showed significant abnormalities in speech development – the vast majority of these problems were misarticulation of sounds (11 children – 29%), one child stuttered (3%).

• In terms of emotional and social functioning, all had a normal level of maturity. Nonetheless, 14 (37%) children exhibited excessive emotional sensitivity-anxiety, weeping, nervousness, a tendency to withdraw, sleep disorders, 3 (8%) were hyperactive, 3 (8%) had nocturnal enuresis, and 1 (3%), nervous ticks.

Based on a comprehensive assessment by a psychologist, 6 (16%) children may have problems with school maturity.

DISCUSSION

The late sequelae of symptomatic cytomegaloviruus infection have been described by numerous authors (1, 2, 3, 4). Most often they include psychomotor and mental retardation, hearing impairment, epilepsy, and various forms of cerebral palsy. The impact of congenital but mild or asymptomatic infection on future development of the children has been less frequently studied (1).

Data in the literature show, that following even asymptomatic cytomegalovirus infection, hearing impairment may develop later in life (even in adolescence) or be progressive; the percent of affected children among those with asymptomatic infection ranges from 10% to 25%. It is believed that following asymptomatic or mildly symptomatic congenital infection, the vast majority of children do not show any abnormalities in terms of intellectual and physical development (4, 6). In the opinion of some researchers, asymptomatic congenital cytomegalovirus infection does not significantly affect intellectual development if hearing impairment does not ensue (7), whereas others show that asymptomatic cytomegalovirus infection can be a risk factor for learning difficulties (8, 9). In our group most of the children examined by a psychologist were found to have normal cognitive and emotional development and social adaptation. The IQ of the entire group was on an average level. Six children were, however, considered to be at risk for problems with school maturity, which is 18% of the studied group. Also noteworthy is the significant percentage (37%) of children with increased emotional liability as well as significant problems with speech development (32%). The occurrence of such problems, especially with speech development, is corroborated by Zhang et al. (10). There is less information, however, about the emotional disturbances in children which we found in the analysed group. Although authors who have conducted long-term follow-up of children with asymptomatic congenital CMV infection and compared them with a control group of healthy children show that most of the affected children develop normally intellectually and cognitively, they also point out that these children may have learning difficulties. This pertains in particular to those children with progressive hearing impairment that may become apparent even as late as adolescence (1, 7, 8). When comparing children with asymptomatic congenital infection with healthy children in terms of school maturity Saigal et al. (11) pointed to the important role of the home environment in stimulating the children’s proper development and behavior.

CONCLUSION

In view of the possibility of late sequelae, especially those affecting intellectual development and hearing impairment, long-term follow-up of children with congenital cytomegalovirus infection, including patients with a mild clinical course, is neccessary.

..............................................................................................................................................................

REFERENCES

1.     Nelson Ch.T., Demmler G.J.: Cytomegalovirus infection in the pregnant mother, fetus and newborn infant. Clin. Perinatol., 1997, 24, 151-160.

2.     Ross S.A., Boppana S.B.: Congenital cytomegalovirus infection: outcome and diagnosis. Semin. Pediatr. Infect. Dis., 2005, 16, 44-49.

3.     Leung A.K., Sauve R.S., Davies H.D.: Congenital cytomegalovirus infection. J. Natl. Med. Assoc., 2003, 95, 213-218.

4.     Peckham C.S.: Cytomegalovirus infection: congenital and neonatal disease: Scand. J. Infect. Dis. Suppl., 1991, 80, 82-87.

5.     Milewska-Bobula B., Idzik M., Żebrowska J., Dunin-Wąsowicz D., Kassur-Siemieńska B., Hautz W. et al.: Diagnosis of congenital cytomegalovirus (CMV) infection by detection of DNA-CMV in newborn’s urine. Int. Proc. Perinatal. Medicine, 2004, 323-327.

6.     Iwasaki S., Yamashita M., Maeda M., Misawa K., Mineta H.: Audiological outcome of infants with congenital cytomegalovirus infection in a prospective study. Audiol. Neurootol., 2007, 12, 31-36.

7.     Conboy T.J., Pass R.F., Stagno S., Britt W.J., Alford C.A., McFarland C.E. et al.: Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection. Pediatrics, 1986, 77, 801-806.

8.     Hanshaw J.B., Scheiner A.P., Moxley A.W., Gaev L., Abel V., Scheiner B.: School failure and deafness after “silent” congenital cytomegalovirus infection. N. Engl. J. Med., 1976, 295, 468-470.

9.     Ivarsson S.A., Lenmark B., Svanberg L.: Ten-year clinical, developmental and intellectual follow-up of children with congenital cytomegalovirus infection without neurologic symptoms at one year of age. Pediatrics, 1997, 99, 800-803.

10.     Zhang X.W., Li F., Yu X.W., Shi X.W., Shi J., Zhang J.P.: Physical and intellectual development in children with asymptomatic congenital cytomegalovirus infection: a longitudinal cohort study in Qinba mountain area, China. J. Clin. Virol., 2007, 40, 180-185.

11.     Saigal S., Lunyk O., Larke R.P., Chernesky M.A.: The outcome in children with congenital cytomegalovirus infection. A longitudinal follow-up study. Am. J. Dis. Child., 1982, 136, 896-901.

..............................................................................................................................................................

Corresponding address:

Bogumiła Milewska-Bobula
Klinika Niemowlęca IPCZD
Al. Dzieci Polskich 20, 04-730 Warszawa
tel. +48(22) 815-74-64
b.milewska@czd.pl