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Lessons derived from a 3-year congenital cytomegalovirus screening programme in Israel: a prospective
Smadar Eventov Friedman1, Noa Ofek Shlomai1, Esther Oiknine-Djian2
1Department of Neonatology, Hadassah and Hebrew University Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Insights
Universal screening for congenital cytomegalovirus (cCMV) using pooled saliva testing is feasible and identifies many infants missed by targeted approaches. This method enables early diagnosis and treatment, improving outcomes for newborns with cCMV.
Area of Science:
- Public Health
- Virology
- Neonatal Screening
Background:
- Congenital cytomegalovirus (cCMV) is a primary cause of pediatric neurological and hearing impairments.
- No standardized public health screening strategy currently exists for cCMV.
- A novel saliva-pooling method was developed to assess universal cCMV screening outcomes.
Purpose of the Study:
- To evaluate the performance and feasibility of pooled-saliva testing for cCMV over time.
- To determine the actual prevalence of cCMV and identify infants missed by expanded-targeted screening.
- To attribute cCMV and its sequelae to primary or non-primary maternal infection.
Main Methods:
- A prospective study involving 48,556 newborns screened via pooled-saliva real-time PCR (rtPCR).
- Confirmatory urine rtPCR for infants with positive saliva tests.
- Comparison of universal screening detection rates against expanded-targeted strategies.
Main Results:
- 176 newborns (3.6/1000) tested positive for cCMV.
- Pooled testing demonstrated 5.82 efficiency with minimal sensitivity loss.
- 57% of cCMV cases would have been missed by expanded-targeted screening, including symptomatic infants.
Conclusions:
- Pooled-saliva testing is a sensitive and feasible method for universal cCMV screening.
- Universal screening facilitates early diagnosis and treatment, informing public health guidelines.
- Further cost-benefit analyses are recommended for widespread implementation.
Background:
Congenital cytomegalovirus (cCMV) is a leading cause of paediatric neurological and hearing deficits, yet there is currently no uniform public health strategy for cCMV screening. We investigated key outcomes of a 3-year universal cCMV screening programme using our newly developed saliva-pooling setup. The study objectives were to: assess the performance and feasibility of the pooled-saliva testing over time; determine the true burden of cCMV and the fraction of infants with cCMV missed by expanded-targeted screening; and define the attribution of cCMV and cCMV-related sequelae to primary or non-primary maternal infection.
Methods:
A prospective study was conducted in two hospitals in Jerusalem, Israel (from April 1, 2022, to March 31, 2025). All newborns whose parents provided written informed consent were screened for cCMV in pooled-saliva real-time PCR (rtPCR) testing as part of a routine newborn screening policy. Infants with positive saliva tests had confirmatory urine rtPCR tests. Pooling efficiency (number of samples tested per single rtPCR) and loss of sensitivity (pool cycle threshold [Ct] vs individual positive sample Ct) were calculated. Detection by universal screening was compared with the expanded-targeted screening strategy, focusing on infants with failed hearing screen, clinically suspected cCMV, or a history of maternal infection. Infants with cCMV were evaluated at birth and at 1 year. Maternal CMV infection type was defined by prenatal serology.
Findings:
Overall, 48 556 infants (94·7% of all live newborns) were screened for cCMV with the use of the pooled approach. cCMV was identified in 176 newborns, with a birth prevalence of 3·6 per 1000 (95% CI 3·1-4·2). The pooling efficiency was 5·82 (95% CI 5·69-5·95), with 3·7 Ct loss of sensitivity. 100 (57%) of 176 infants with cCMV identified by universal screening would have been missed by expanded-targeted screening. Of these, eight (8%) were classified as moderately to severely symptomatic and three (3%) as asymptomatic with sensorineural hearing loss, and 11 (11%) received valganciclovir. 84 (53%) of 158 cCMV cases with maternal infection type available were born to mothers with non-primary infection and 74 (47%) to mothers with primary infection; these infants exhibited similar rates of moderate-to-severe symptoms, sensorineural hearing loss, and 1-year hearing or developmental sequelae.
Interpretation:
The study demonstrated the benefits and feasibility of pooled-saliva testing, which is a sensitive approach to screening for cCMV that could enable the implementation of universal cCMV screening in diverse settings; however, further cost-benefit analyses are needed. Beyond the clinical implications of universal screening for cCMV, including enabling early diagnosis and treatment, data derived from universal screening could serve to inform public health guidelines.
Funding:
Israel Science Foundation and Moderna Therapeutics.
