Approximately 20,000 (0.5%) children are born with congenital cytomegalovirus (CMV) infection annually in the United States^{1, 2}, of which 85–90% appear asymptomatic at birth.^{3, 4} The extent to which asymptomatic congenital CMV infection is associated with increased risk of intellectual impairment or low academic achievement throughout childhood is not well established. Several studies have found no differences in intelligence or various cognitive domains among children with asymptomatic congenital CMV infection identified by newborn screening compared to uninfected children.^5–16 The largest study included 159 children with asymptomatic congenital CMV infection and 130 uninfected children between ages 1–13 years, although <20% of all children received assessments at age ≥7 years.⁵ Most other studies followed a small number of children with asymptomatic congenital CMV infection (median: 32, range: 15–60)^{6–11, 16} through ≤5 years of age.^{7, 9, 10, 12, 13, 16} In this study, we examined intelligence, language, and academic achievement among children with asymptomatic congenital CMV infection identified through hospital-based newborn screening and uninfected children followed through age 18 years.

Eighty-nine (97%) of 92 case-patients and 40 (95%) of 42 controls enrolled in the longitudinal study had neurodevelopmental assessments and were included in this analysis. Overall, 20 case-patients and 3 controls were diagnosed with SNHL, at median ages of 16 months (range: 1 month–18 years) and 11 years (range: 9–15), respectively. Eleven case-patients were diagnosed with SNHL by age 2 years, among whom 9 had moderate to profound SNHL (>40 dB) at age 2 years; 2 progressed to those levels later. All 9 case-patients and 3 controls diagnosed with SNHL after age 2 years had SNHL ≤40 dB in the poorer-hearing ear, except one case-patient diagnosed with mild unilateral SNHL at age 5 years, which progressed to severe by age 8 years. Thus, our analyses consisted of comparisons among 78 case-patients with normal hearing, 11 case-patients with SNHL by age 2 years, and 40 controls.

A majority of the children were born to non-Hispanic white mothers, aged 20–40 years, married, who had at least some college education and medium/high socioeconomic status, with no statistically significant differences among the 3 groups, except for health insurance status (Table 1). Median age at last assessment among all 3 groups was 13 years for expressive vocabulary and 17 years for all other measures (Table 2). Median number of measures of full-scale intelligence (including tests at younger ages) was greater among case-patients with normal hearing or with SNHL compared with controls.

In this study, infants with congenital CMV infection who were asymptomatic at birth with normal hearing by age 2 years were not at increased risk for intellectual impairment or low academic achievement compared to uninfected controls throughout adolescence. This confirms findings of smaller studies which found no significant difference in intelligence measures through early or late childhood.^{6, 7, 9–11, 13, 14, 32} Our study included infants identified through hospital-based newborn screening followed through adolescence, and provides new information on intellectual functioning, language and academic achievement of children with asymptomatic congenital CMV infection with and without SNHL compared to a group of uninfected children.

About 85–90% of children with congenital CMV infection are asymptomatic at birth. Findings from our study suggest that the majority of children that would be identified by newborn screening do not appear to be at increased risk of intellectual impairment and, therefore, may not need long-term monitoring for cognitive impairment/disabilities. Although this information could provide reassurance to parents, the psychosocial consequences, including increased parental anxiety, and other family-level impacts of CMV screening (i.e. time and costs incurred for regular monitoring) need to be systematically evaluated.³³ More research is needed to understand the cost-benefit and minimize potential adverse psychosocial consequences of newborn screening for congenital CMV infection.

Although we found no increased risk of intellectual impairment in children with asymptomatic congenital CMV infection, we did observe that children who had asymptomatic congenital CMV infection and developed SNHL by age 2 years had full-scale intelligence and receptive vocabulary scores that were lower than controls. However, their non-verbal intelligence and academic achievement scores in math and reading were not significantly different than controls, suggesting that the full-scale intelligence scores in case-patients with SNHL were an underestimate of their intellectual potential. We are not aware of any study that has assessed the impact of SNHL on intelligence among children with asymptomatic congenital CMV infection. Significant differences in receptive vocabulary scores between case-patients and controls were likely attributable to SNHL rather than asymptomatic congenital CMV infection. Previously, we reported that the prevalence of SNHL among our asymptomatic case-patients nearly doubled from ages 3 months to 24 months.¹⁹ Data from the CMV and Hearing Multicenter Screening Study revealed that nearly half of children with asymptomatic congenital CMV infection who are diagnosed with SNHL within 8 weeks of age are missed by newborn hearing screening.³⁴ Screening of newborns for congenital CMV infection may allow early identification of SNHL in children with asymptomatic congenital CMV infection³⁴ so that they can receive appropriate interventions to minimize delays in their communication, cognition, reading, and social-emotional development.³⁵ However, there is currently no consensus on audiologic monitoring for children with asymptomatic congenital CMV infection.³⁶

In our cohort, we observed trends in intelligence, language and academic achievement that were intriguing. We found a modest increase in full-scale intelligence scores with increasing age in case-patients with either normal hearing or SNHL, and in controls. Trends and mean scores were similar when restricting the analysis to the WISC and WASI, which are administered to children between 6–18 years of age and provide more comparable measures of intelligence. Because intelligence measures are expected to remain unchanged over time, it is possible that the increasing scores with age reflect literacy or cultural gains among children, a phenomenon described as the Flynn effect.³⁷ Previous studies of children with asymptomatic congenital CMV infection have also found slightly higher scores at older ages though the groups under comparison did not necessarily include the same group of children followed over time.^{5, 6} In contrast to the increasing trend in intelligence scores with increasing age, we found that receptive vocabulary scores increased up to age 12.5 years and then decreased, while scores for expressive vocabulary decreased with increasing age. These trends in receptive and expressive vocabulary scores were similar when excluding children who developed SNHL after age 2 years. Furthermore, scores in academic achievement in math, but not in reading, appeared to decrease with increasing age in all 3 groups. It is unclear if the amount of change in test scores that would be explained by age is of clinical importance. Nonetheless, it is possible that other domains of intellectual functioning (e.g. attention) or other factors (e.g., social, environmental) could have influenced children’s expressive vocabulary and academic achievement in math.

Our study had several strengths. Newborns with asymptomatic congenital CMV infection were identified through hospital-based screening, providing an opportunity to assess the full spectrum of outcomes among these children. The uninfected newborns followed as controls had no significant differences in sociodemographic characteristics. Thus, the control group appeared to have been valid for comparisons. The comprehensive neurodevelopmental follow-up with multiple assessments through adolescence was important for understanding variability in scores over time. Finally, the robust analytical approach allowed for examination of trends in scores while controlling for variability within and between groups and imbalances in the number of assessments.

Nonetheless, our study had some limitations. Not all infants with congenital CMV infection identified through newborn screening were enrolled in the study and the number of uninfected children enrolled as controls was relatively small. A majority of children were born to mothers with at least some college education and medium/high socioeconomic status. Thus, the findings may not be generalized to populations with lower education level/socioeconomic status.³⁸ Our sample size was not large enough to include other potential risk factors in the analysis. Our control group had fewer evaluations than our case-patients. Nevertheless, the median age at the last assessment among the 3 groups was similar. We did not assess whether there were differences in specific cognitive domains, such as attention, perception, memory, and executive functioning, though we found no significant differences between case-patients and controls in exploratory analysis (not shown). Finally, data on interventions provided to children identified with asymptomatic infection were not systematically collected or assessed. Interventions provided for case-patients with SNHL may have helped minimize the impact of hearing loss on their intellectual functioning.

Our study suggests that infants with asymptomatic congenital CMV infection identified through newborn screening with normal hearing by age 2 years do not appear to have differences in intelligence quotient, vocabulary or academic achievement scores during childhood or adolescence compared with uninfected children. The implication that children with asymptomatic congenital CMV infection at birth may not need long-term monitoring for cognitive impairment/disabilities based on current evidence is of clinical importance. Further studies are needed to better understand the impact of asymptomatic congenital CMV infection on behavior and specific cognitive domains such as attention, perception, and memory.