Lessons derived from a 3-year congenital cytomegalovirus screening programme in Israel: a prospective population-based cohort study - 11/12/25

Doi : 10.1016/S1473-3099(25)00620-6

Smadar Eventov Friedman, ProfMD ^a,^b,^{*
Contributed equally}, Noa Ofek Shlomai, MD ^a,^b,^{*
Contributed equally}, Esther Oiknine-Djian, PhD ^b,^c,^d,^{*
Contributed equally}, Tal Sido, BSc ^c, Oren Gordon, MD ^b,^e, Sraya Greenberger, BSc ^c, Hadar Horowitz, BSc ^c, Lior Merav, BSc ^c,^f,^g, Stav David Mehaber, BSc ^b,^c,^d, Orit Caplan, MSc ^c, Miriam Geal-Dor, PhD ^h,ⁱ, Natalia Simanovsky, MD ^j, Diana Averbuch, MD ^b,^e, Colin Kunzweiler, PhD ^k, Yosefa Hefter, MD ^l, John Diaz-Decaro, PhD ^k, Ora Paltiel, ProfMD ^b,^m, Moran Yassour, PhD ^f,^g,^{^{†
These authors jointly supervised this work}}, Dana G Wolf, ProfMD ^b,^c,^d,^{^{†
These authors jointly supervised this work},}⁎
^a Department of Neonatology, Hadassah and Hebrew University Medical Center, Jerusalem, Israel
^b Faculty of Medicine, Hebrew University, Jerusalem, Israel
^c Clinical Virology Unit, Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew University Medical Center, Hebrew University Faculty of Medicine, Jerusalem, Israel
^d Lautenberg Center for General and Tumor Immunology, Jerusalem, Israel
^e Pediatric Infectious Diseases, Pediatric Division, Hadassah Hebrew University Medical Center, Jerusalem, Israel
^f School of Computer Science and Engineering, Hebrew University of Jerusalem, Jerusalem, Israel
^g Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
^h Speech and Hearing Center, Hadassah Hebrew University Medical Center, Jerusalem, Israel
ⁱ Department of Communication Disorders, Jerusalem Multidisciplinary College, Jerusalem, Israel
^j Pediatric Radiology Unit, Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel
^k Moderna Therapeutics, Cambridge, MA, USA
^l Medison Pharma, Petah Tikva, Israel
^m Braun School of Public Health and Community Medicine, Hadassah Medical Organization, Jerusalem, Israel

^*Correspondence to: Prof Dana G Wolf, Clinical Virology Unit, Department of Clinical Microbiology and Infectious Diseases, Hadassah Hebrew University Medical Center, Hebrew University Faculty of Medicine, Jerusalem 91120, IsraelClinical Virology UnitDepartment of Clinical Microbiology and Infectious DiseasesHadassah Hebrew University Medical CenterHebrew University Faculty of MedicineJerusalem91120Israel

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Thursday 11 December 2025

Summary

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.