Universal Newborn Screening for Congenital Cytomegalovirus Infection – From Infant to Maternal Infection: A Prospective Multicenter Study

Abstract

Introduction:Most infants at risk for cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) are unrecognized because of the absence of a universal neonatal CMV screening. The search of CMV-DNA by molecular methods in salivary swabs was demonstrated to be a reliable approach. This study describes the results obtained by carrying out a universal screening for congenital CMV (cCMV) infection including all live-born newborns in three Italian sites, as well as the therapeutic interventions and clinical outcome of the CMV-infected neonates. Moreover, CMV maternal infection's characteristics were evaluated.MethodsTo confirm or exclude cCMV infection, a CMV-DNA-positive result on a first salivary swab was followed by repeated saliva and urine samples collected within 21 days of age. Breast milk samples were also collected. The search of CMV-DNA was performed with a single automated quantitative commercial real-time PCR assay, regardless of the type of samples used.ResultsA total of 3,151 newborns were enrolled; 21 (0.66%) of them were congenitally infected (median saliva viral load at screening, 6.65 [range, 5.03–7.17] log10 IU/ml). Very low/low viral load in screening saliva samples (median value, 1.87 [range, 1.14–2.59] log10 IU/ml) was associated with false-positive results (n = 54; 1.7%). CMV-DNA was detected in almost half of the breast milk samples of mother–infant pairs with a false-positive result, suggesting that contamination from breast milk may not be the only explanation in the study population. cCMV infection confirmation with the search of CMV-DNA in a urine sample proved to be the gold standard strategy, since false-positive results were observed in 4/54 (7.5%) of the repeated saliva samples. Symptomatic cCMV infection was observed in 3/21 (14.3%) infants; notably, one (4.7%) developed moderate unilateral SNHL at 5 months after birth. Finally, two symptomatic cCMV infections were associated with primary maternal infection acquired in the first trimester of gestation; one newborn with severe cCMV symptoms was born to a mother with no CMV checkups in pregnancy.ConclusionWithout universal neonatal CMV screening, some infected infants who develop late neurological sequelae may not be recognized and, consequently, they are not able to benefit early from instrumental and therapeutic interventions to limit and/or treat CMV disease.

Useful Clinical Criteria for Identifying Neonates with Congenital Cytomegalovirus Infection at Birth in the Context of an Expanded Targeted Screening Program

“…Importantly, our incidence rate of 1.17% is close to the 1.08% figure recently reported by Chiereghin and colleagues in a research study assessing the feasibility and clinical validity of a universal newborn cCMV screening program at their center located in Northern Italy [15]. Similar detection rates between expanded and universal cCMV screening programs have also been reported by studies conducted in the United State and Israel [14,27], further supporting the clinical relevance of an expanded targeted screening.…”

“…In our study, screening was performed by CMV DNA identification on saliva samples [16]. In case of positivity, a urine sample was assessed for confirmatory purposes [15]. In some cases, particularly those born during the initial months after protocol implementation, testing was performed only on urine samples.…”

“…Although several studies have suggested the potential benefits of a universal newborn screening for cCMV to detect all infants at risk of sequelae, there is still an ongoing debate about the feasibility of such a program [9][10][11][12][13][14][15][16].…”

Droplet Digital PCR (ddPCR) Does Not Enhance the Sensitivity of Detection of Cytomegalovirus (CMV) DNA in Newborn Dried Blood Spots Evaluated in the Context of Newborn Congenital CMV (cCMV) Screening

“…A novel urine collection kit using filter paper demonstrated that this may be a promising approach for newborn screening for cCMV [ 31 ]. Future studies on newborn screening using both saliva [ 32 , 33 ] and urine collected on filter paper cards could hold promise in enhancing cCMV screening programs, and these merit additional study, but the established infrastructure for processing newborn DBS cards that exists in state newborn screening programs in the USA justifies adoption of universal cCMV using DBS PCR at the current time, challenges in sensitivity notwithstanding, as is now standard practice in Minnesota.…”

Prevalence of asymptomatic cytomegalovirus (CMV) infection in newborns in northeast Florida

“…In order to treat infants with potential congenital CMV infection, it becomes necessary to identify those who are infected ( 23 ). The only way to identify neonates who are asymptomatically infected with CMV during gestation is through universal screening for CMV infection at birth ( 24 ).…”