Highlight
– National prospective APSU surveillance (1999–2024) identified 586 reported congenital CMV cases, 479 of them definite, but this represents only ~1% of expected cases based on developed-country prevalence estimates.
– The common clinical manifestations included intrauterine growth restriction/small for gestational age, sensorineural hearing loss, microcephaly, hepatic involvement, and thrombocytopenia.
– Newborn dried blood spot (Guthrie card) PCR identified CMV in 91.7% of tested specimens and was the sole basis for classification as definite infection in many cases.
– Since universal neonatal hearing screening (introduced 2004), reported definite cases and the proportion treated with antivirals have risen; however, surveillance remains insufficient to define true prevalence or burden.
Background: disease burden and clinical context
Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of congenital malformations and a major non-genetic cause of childhood sensorineural hearing loss (SNHL) and neurodevelopmental disability. International prevalence estimates in high-resource settings typically range between 0.3–0.7% of live births (3–7 per 1,000), with higher rates in socioeconomically disadvantaged populations. Most infants with cCMV are asymptomatic at birth, but a subset develop clinically overt disease (including central nervous system involvement) or later sequelae such as progressive SNHL.
Early diagnosis can enable audiological surveillance and, for selected symptomatic infants, antiviral treatment (intravenous ganciclovir or oral valganciclovir) that has been shown in randomized trials to improve hearing and developmental outcomes when given for extended courses in infants with CNS disease. Public health strategies to reduce cCMV burden include maternal education about hygiene to reduce primary maternal infection, consideration of maternal screening or antepartum interventions in certain contexts, development of a vaccine, and newborn screening approaches (targeted or universal) to facilitate early detection and intervention.
Study design
The Australian Paediatric Surveillance Unit (APSU) conducted a prospective national observational surveillance program from 1 January 1999 to 1 January 2024. Clinicians reported suspected congenital CMV infections; cases were classified as definite congenital CMV infections based on laboratory confirmation (including Guthrie card dried blood spot PCR evidence). The study measured the number of reported definite cCMV cases across the surveillance period and after introduction of universal neonatal hearing screening (from 1 January 2004), described clinical sequelae recorded at presentation, and reported the proportion of symptomatic definite infants treated with antiviral medications.
Key findings
Case ascertainment and prevalence estimates
During the 25-year surveillance period, 586 congenital CMV cases were reported to APSU (crude rate 8.15 per 100,000 births; 95% CI 7.50–8.83). Of these, 479 (82%) met criteria for definite congenital CMV infection. Importantly, the authors conclude that the number of reported definite cases equates to only ~1% of the number expected in Australia if prevalence mirrored estimates from developed countries. This large discrepancy strongly suggests substantial under-ascertainment in current clinical and surveillance systems.
Clinical presentation and sequelae
Among definite infections the most frequently reported sequelae were:
- Small for gestational age or intrauterine growth restriction: 135 infants (28.2%).
- Neurological conditions: sensorineural deafness in 183 infants (38.2%); microcephaly in 89 (18.6%).
- Hepatic disease: jaundice in 130 (27.1%), hepatomegaly in 75 (15.7%), hepatitis in 85 (14.7%).
- Bone marrow involvement and bleeding diatheses: thrombocytopenia in 139 (29.0%), petechiae/purpura in 89 (18.6%).
These findings align with classical descriptions of symptomatic cCMV and underscore that when diagnosed, many infants present with multisystem disease.
Role of dried blood spot (Guthrie card) testing
Of 168 Guthrie card dried blood spot PCRs performed, 154 (91.7%) were CMV-positive. For 143 infants, a positive Guthrie card PCR provided the sole basis for classifying the infection as definite congenital CMV. This observation highlights the practical utility of retrospective PCR on stored newborn blood spots for confirming congenital infection, and it supports the feasibility of using dried spot testing in targeted or population-level newborn screening strategies.
Temporal trends, hearing screening, and treatment
After the introduction of universal neonatal hearing screening in Australia from 2004 through 2024, 506 cases were reported and 447 (88.3%) were definite cCMV. Among these 447 definite cases, 366 (81.9%) were symptomatic and 116 (32%) of symptomatic infants received antiviral therapy. The absolute number of reported definite cases and the proportion receiving antiviral medications increased over time, suggesting that newborn hearing screening may facilitate case detection and referral for treatment, and that clinician willingness to prescribe antivirals has risen.
Interpretation and clinical implications
Under-ascertainment and public health surveillance gaps
The striking under-ascertainment (reported definitive cases ~1% of expected) indicates that surveillance based on clinician reporting and passive case-finding misses the great majority of congenital CMV infections. Reasons likely include a high background proportion of asymptomatic infants who are never tested, variable testing practices, lack of universal newborn CMV screening, and absence of a centralized reporting system. Given that many infants may develop late-onset or progressive sensorineural hearing loss, failure to detect cCMV early represents a missed opportunity to institute audiological surveillance and, in selected symptomatic infants, antiviral therapy.
Screening strategies: universal versus targeted approaches
Two pragmatic options exist: universal newborn CMV screening (for example, PCR on saliva or dried blood spot) or targeted screening of infants who fail newborn hearing tests. Targeted testing after a failed newborn hearing screen has been proposed as a cost-effective compromise, as it efficiently identifies many infants at highest immediate risk of hearing loss. The APSU data show that the introduction of universal hearing screening coincided with increased case detection, supporting a targeted approach as an interim measure. However, targeted screening will miss asymptomatic infants who later develop hearing loss, whereas universal screening would detect these cases at birth and enable structured follow-up.
Treatment considerations
Randomized and controlled studies have demonstrated that antiviral therapy (notably valganciclovir) given for extended durations can preserve or improve hearing and developmental outcomes in infants with symptomatic congenital CMV affecting the CNS. For example, randomized trials have supported up to 6 months of valganciclovir in symptomatic infants with CNS involvement, with careful monitoring for hematological toxicity. In the APSU cohort, only 32% of symptomatic infants received antivirals, reflecting either limited indications, clinician preference, concerns about toxicity, or delayed diagnosis. Broader and earlier detection could increase opportunities for evidence-based antiviral therapy but must be balanced against potential drug toxicity and the need for monitoring infrastructure.
Feasibility of Guthrie card testing
The high positivity rate of Guthrie card PCRs in tested infants (91.7%) shows that retrospective testing on newborn dried blood spots is a sensitive method for confirming congenital infection. This approach could be leveraged for surveillance and for retrospective case ascertainment in program evaluations. However, for point-of-care newborn screening where timely action is needed, saliva or urine PCR within the first three weeks of life is preferred for diagnostic sensitivity and speed.
Expert commentary, limitations, and generalizability
Strengths of the APSU study include national, long-term prospective surveillance, systematic case classification, and reporting of clinical phenotypes and management. However, as a clinician-report surveillance system, it is vulnerable to underreporting and ascertainment bias toward symptomatic and more severe cases. The observed shortfall compared with expected prevalence almost certainly reflects these limitations rather than a true low incidence of cCMV in Australia.
Generalizability to other high-income countries is plausible with respect to clinical manifestations and the usefulness of newborn screening modalities, but local prevalence and health-system capacity will influence the optimal screening strategy. Consideration of equity is essential: cCMV disproportionately affects socioeconomically disadvantaged and certain ethnic groups in many settings, and targeted prevention and screening should prioritize populations at higher risk.
Practical recommendations and next steps
- Expand and standardize surveillance: integrate newborn CMV testing data (e.g., saliva/DBS PCR) into national registries to capture asymptomatic and symptomatic cases and their long-term outcomes.
- Implement pragmatic screening policies: consider targeted testing of infants who fail newborn hearing screens as an immediate policy step, while evaluating cost-effectiveness and infrastructure needs for universal newborn CMV screening.
- Ensure timely diagnostic pathways: early testing (saliva/urine PCR within 21 days of life) should be available where CMV is suspected to guide treatment decisions.
- Clarify treatment protocols: adopt evidence-based indications for antiviral therapy (e.g., symptomatic infants with CNS disease) with systems for monitoring hematologic toxicity and long-term outcomes.
- Strengthen prevention: emphasize maternal hygiene education, support CMV vaccine development, and consider targeted antenatal counseling for high-risk populations.
Conclusion
The APSU national prospective surveillance data demonstrate that only a small fraction of the expected congenital CMV burden is being detected in Australia, despite increasing case identification and antiviral use since the introduction of newborn hearing screening. These findings support urgent expansion of systematic surveillance, consideration of targeted or universal newborn screening strategies, clear clinical pathways for early diagnosis and antiviral therapy in eligible infants, and strengthened prevention efforts. Better data will enable policymakers and clinicians to align resources with the true clinical and societal burden of congenital CMV.
Funding and clinicaltrials.gov
The APSU study authors report funding and details in the original publication. Relevant clinical trials on neonatal valganciclovir for cCMV have been registered and reported (see Kimberlin et al., NEJM, 2015).
References
1. Egilmezer E, Teutsch SM, Nunez C, Hamilton ST, Bartlett AW, Palasanthiran P, Elliott EJ, Rawlinson WD. Birth prevalence, clinical sequelae, and management of congenital cytomegalovirus infections in Australia, 1999-2023: a national prospective study. Med J Aust. 2025 Sep 11. doi: 10.5694/mja2.70047. Epub ahead of print. PMID: 40936229.
2. Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med. 2015;372(10):933-943.
3. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of congenital cytomegalovirus infection in the United States. Rev Med Virol. 2007;17(5):343–352.
4. Centers for Disease Control and Prevention. Congenital Cytomegalovirus (CMV) — Clinician FAQ. CDC website. Updated resources and guidance: https://www.cdc.gov/cmv/index.html (accessed 2025).
Thumbnail AI image prompt
A tender hospital scene: a newborn in a clear bassinet swaddled in a pale blanket, a Guthrie blood spot card and pipette on a tray nearby; a faint overlay of a PCR amplification curve and a small audiology headset in soft-focus background; neutral clinical colours, gentle lighting, and a hopeful but serious mood.
