CADTH Health Technology Review

Newborn Screening for Congenital Cytomegalovirus

Rapid Review

What Is the Issue?

• Congenital cytomegalovirus (cCMV) is estimated to affect between 0.2% and 2.4% of newborns worldwide, and may cause long-term effects, including hearing loss and neurodevelopmental disability.

• Newborn screening for cCMV can identify affected neonates and provide an opportunity for early treatment, which may reduce any long-term effects from infection.

• We wanted to know if universal newborn screening is a clinically effective and cost-effective intervention for identifying and managing cCMV.

What Did We Do?

• We identified and summarized published literature comparing the clinical effectiveness and cost-effectiveness of universal newborn screening with either targeted newborn screening or no screening for congenital cytomegalovirus in neonates. We also identified and summarized published, evidence-based guidelines that make recommendations concerning the use of newborn screening for congenital cytomegalovirus to help inform decisions considering the use of this intervention.

• An information specialist searched for peer-reviewed and grey literature sources published between January 1, 2014, and March 19, 2024. The search was limited to English-language documents. One reviewer screened articles for eligibility based on predefined criteria, critically appraised the included studies, and narratively summarized the findings.

What Did We Find?

• Evidence from 1 prospective cohort study in the US found that, compared to universal newborn screening for cCMV, targeted newborn screening failed to identify a significant proportion of neonates who developed hearing loss associated with infection.

• Three cost-effectiveness evaluations concluded that universal newborn screening for cCMV was cost-effective when compared to targeted newborn screening or no screening. None of these analyses were specific to the Canadian context.

• While 1 of 3 evidence-based guidelines identified by this review makes a recommendation favouring universal newborn screening for cCMV, 2 evidence-based guidelines recommend against the implementation of universal newborn screening for cCMV (including 1 from the Canadian context), generally citing a lack of sufficient clinical evidence.

What Does This Mean?

• The included cost-effectiveness studies and evidence-based guidelines in this report emphasize that limited clinical evidence is currently available to inform decision-making concerning newborn screening for cCMV.

• Jurisdictions where universal newborn screening for cCMV has been implemented provide an opportunity for clinical research to support and inform future decision-making.

• The current limitation of available clinical data describing newborn screening for cCMV will require decision-makers to draw from a broader set of inputs and sources than those available from empirical studies.

Context and Policy Issues

What Is cCMV?

Cytomegalovirus (CMV) is a common herpesvirus that infects most adults, but often goes unnoticed and/or is asymptomatic.¹ During pregnancy, maternal antibodies do not fully protect the fetus from CMV infection, which can result in transmission to the fetus and congenital cytomegalovirus (cCMV) infection at birth.¹ CMV is reported to be the largest contributor to congenital infection in the world, with a range of 0.2% to 2.4% of newborns affected.^2-5 Neonates with symptomatic cCMV may present with rash, jaundice, small for gestational age, and/or neurologic findings (e.g., encephalitis), and are at risk of long-term and permanent sequelae, including sensorineural hearing loss (SNHL), developmental delay, and intellectual and learning disabilities.^1-4,6 Mortality is estimated to occur in one-third of neonates with a severe presentation of the disease.^1,2 While most neonates with cCMV will not have symptoms, it is estimated that 10% to 20% of neonates who are asymptomatic may develop long-term sequelae, including SNHL.^2-5

How Is cCMV Managed?

There is no vaccine or preventive medical intervention to protect from cCMV infection.^2,4,7 However, there is some evidence to demonstrate a beneficial long-term effect of antiviral medication for preventing SNHL and other neurodevelopmental sequelae.² Treatment with an antiviral medication should begin in the first month after birth for neonates with cCMV to ensure optimal benefit.² Nonetheless, antiviral medication is generally limited to neonates with moderate to severe symptoms of cCMV, and may not be available to other neonates with cCMV, who are at risk for long-term sequelae, as well.² Consequently, detection of cCMV must occur within the first 3 weeks after birth — not only to allow an opportunity for the potentially effective treatment of cCMV, but also to distinguish the infection as congenital versus acquired after birth, as the latter is expected to pose less of a risk to the infant.^1,2,4,5,8,9

What Is Newborn Screening for cCMV?

There are generally 2 approaches to newborn screening (NBS) for cCMV: universal screening for all neonates and targeted screening for neonates believed to be at risk of having cCMV.² Targeted screening may rely on clinical suspicion of cCMV infection in neonates who are symptomatic or on a newborn hearing screen, with neonates who demonstrate a risk of impaired hearing referred for cCMV testing. Prenatal screening may also be performed,² but was not the focus of this report.

While universal NBS infrastructure is in place for multiple metabolic, inherited, and other conditions in many jurisdictions, most existing NBS programs use dried blood spots (DBSs), making this method of screening desirable for the addition of cCMV.³ However, previous studies have demonstrated that DBSs are unlikely to be ideal samples for the detection of cCMV, as the viral load in DBSs may not be detectable at birth.^2,3,10 Urine is generally considered to be the optimal sample for detection of cCMV.^2,5,11 Saliva samples may also be used, and are more easily obtainable than urine samples, but generally have lower specificity, introducing a higher risk of false-positive results.² However, either urine or saliva sample collection for NBS will demand significant changes and impacts to existing NBS programs that are likely to be challenging and costly.^3,8,10 While research is under way and ongoing to investigate methods for improved test performance of DBS, a feasible and effective DBS method currently requires further investigation.^3,10,11 Nonetheless, several jurisdictions in Canada and the US — including Saskatchewan, Ontario, and Minnesota — have begun universal NBS programs that use DBSs.^4,12

Why Is It Important to Do This Review?

Given the public health burden of cCMV for neonates, approaches to NBS for cCMV have been considered for years; however, the optimal approach to NBS for cCMV remains uncertain and continues to be debated.^4-6 To support and inform Canadian health care policy and decision-making for the detection and management of cCMV, this report aims to identify and summarize clinical effectiveness and cost-effectiveness evidence comparing universal NBS for cCMV with either targeted screening or no screening, and to identify and summarize the evidence-based guidelines that make recommendations concerning NBS for cCMV.

Research Questions

1. What is the clinical utility of universal NBS versus targeted or no newborn screening for cCMV?

2. What is the cost-effectiveness of universal NBS versus targeted or no newborn screening for cCMV?

3. What are the evidence-based guidelines regarding NBS for cCMV?

Methods

Literature Search Methods

An information specialist conducted a focused literature search on key resources, including MEDLINE, the Cochrane Database of Systematic Reviews, the International HTA Database, and the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevance. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The focused search concepts (limiting to focused MeSH headings and concepts appearing in the title and keywords only) were cytomegalovirus, screening, and newborns. No study design filters were applied to limit retrieval. The search was completed on March 19, 2024, and limited to English-language documents published since January 1, 2014.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the eligibility criteria presented in Table 1.

Table 1: Eligibility Criteria

ICER = incremental cost-effectiveness ratio; NA = not applicable; QALY = quality-adjusted life-year.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, were duplicate publications, or were published before 2014. Guidelines with unclear methodologies were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: the Downs and Black checklist¹³ for nonrandomized studies, the Drummond checklist¹⁴ for economic evaluations, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument¹⁵ for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

This report included and summarized 7 publications that met the eligibility criteria.^16-22 These comprised 1 nonrandomized study,¹⁹ 3 economic evaluations,^17,18,22 and 3 evidence-based guidelines.^16,20,21 Appendix 1 presents the PRISMA²³ flow chart of the study selection.

To support and inform consideration of cCMV NBS programs for decision-makers, in addition to the eligible studies identified in this report, studies that described noncomparative assessments of NBS programs (i.e., ineligible comparator), or did not describe the features of clinical utility (i.e., ineligible outcomes), but were otherwise relevant to the research questions (i.e., universal NBS and/or targeted cCMV NBS programs) were summarized by abstract only. Description of these ineligible studies was limited to the past 5 years of publication. A tabulated summary of the abstracts from these studies is presented in Appendix 5.

Summary of Study Characteristics

This report summarizes the characteristics and findings from 1 prospective cohort study,¹⁹ 3 cost-effectiveness evaluations,^17,18,22 and 3 evidence-based guidelines.^16,20,21

Additional details regarding the characteristics of the included publications are provided in Appendix 2.

Study Design

The prospective cohort study was published in 2017 and was conducted across 7 sites, with data collected between 2007 and 2012.¹⁹

The 3 cost-effectiveness studies used lifetime horizons in their models.^17,18,22 While 2 of the cost-effectiveness studies described a public health payer perspective,^18,22 1 did not describe the perspective used in the study.¹⁷ All 3 cost-effectiveness studies used decision-tree and/or Markov modelling, using clinical and cost inputs from referenced, published, and governmental data sources.^17,18,22 Key model assumptions included appropriate diagnosis and treatment for all study participants.^17,18,22

One of the evidence-based guidelines was developed by the Institut national d'excellence en santé et en services sociaux (INESSS),¹⁶ another by the International Congenital Cytomegalovirus Recommendations Group,²⁰ and another by the UK National Screening Committee.²¹ The 3 evidence-based guidelines reported reviews of available evidence, synthesis, and critical appraisal of eligible studies, with an explicit link from the evidence to the relevant recommendations that were developed.^16,20,21 One of the guidelines was reported as an updated review of the evidence for a previous version of the guideline that was published in 2012.²¹ One guideline provided a description of the quality of evidence informing the recommendations (i.e., ranging from levels 1 to 3),²⁰ whereas 2 did not.^16,21 None of the evidence-based guidelines explicitly described a strength for the recommendations of relevance to this report.^16,20,21

Country of Origin

The prospective cohort study was conducted in the US.¹⁹ The economic evaluations were conducted in Japan,¹⁷ China,¹⁸ and the US.²² Of the evidence-based guidelines, 1 was developed in the Canadian province of Quebec,¹⁶ another in the UK,²¹ and the third was developed by an international group, with no country of origin reported (though experts were invited from Europe, the US, and Australia to develop the guidance, and the group was convened in Australia).²⁰

Patient Population

All of the included studies and evidence-based guidelines described neonates as the population of interest.^16-22

Interventions and Comparators

The prospective cohort study described NBS for cCMV and compared universal versus targeted approaches.¹⁹ The 3 cost-effectiveness studies reported data comparing universal NBS for cCMV to targeted screening or no screening.^17,18,22 Three of the studies described NBS programs using saliva samples,^18,19,22 2 described NBS programs using urine samples,^17,18 and 1 described a NBS program using DBS.¹⁹ The timing of screening was described variably, with the prospective cohort indicating NBS occurred while neonates were in the newborn nursery (though no quantitative time frame was reported).¹⁹ Two of the cost-effectiveness studies reported that NBS occurred within the first 3 weeks after birth,^17,22 while 1 cost-effectiveness study reported that NBS occurred after birth (with no quantitative time frame reported).¹⁸

The prospective cohort study exposed all neonates in the cohort to both a universal cCMV NBS program using saliva and DBS samples, as well as a targeted screening program using newborn hearing screening (NHS) with Auditory Brainstem Response to detect risk for SNHL at birth.¹⁹ Neonates with a diagnosis of cCMV, and those who failed the NHS, were referred for audiologic assessment.¹⁹

The evidence-based guidelines describe NBS for cCMV, with 1 evidence-based guideline focusing on the use of DBS¹⁶ and 2 describing NBS without a focus on sample type.^20,21 The timing of NBS is not addressed in the evidence-based guidelines.^16,20,21

Outcomes

The prospective cohort and cost-effectiveness studies focused on the role of NBS for cCMV in the reduction of hearing loss (HL).^16,19-21 Additional features of clinical utility (i.e., number needed to screen, time to diagnosis, time to treatment, morbidity other than HL, mortality, and quality of life) were not addressed by the clinical effectiveness or cost-effectiveness studies.^16,19-21

The prospective cohort study reported on cases of cCMV detected by the universal NBS program (diagnoses only, with no data describing screening results), symptoms associated with cCMV, the findings of NHS (i.e., pass or fail), and the findings of audiologic assessment between 3 and 8 weeks of life for all neonates who were either diagnosed with cCMV and/or who failed the NHS.¹⁹

The cost-effectiveness studies reported on incremental costs of universal NBS as compared to targeted or no screening.^17,18,22 Two of the studies reported costs in US dollars^18,22 and 1 study reported costs in Japanese yen (¥) (valued at approximately 0.006 US dollars as of April 17, 2024²⁴).¹⁷ Two of the cost-effectiveness studies reported on incremental quality-adjusted life-years and calculated incremental cost-effectiveness ratios (ICERs),^17,18 while 1 did not.²² Though neither of the cost-effectiveness studies that reported ICERs characterized cost-effectiveness in terms of a willingness-to-pay threshold, both described the ICERs expressed as gross domestic product (GDP) per capita for the respective countries in which the studies were conducted.^17,18 The cost-effectiveness of the ICERs was interpreted in accordance with thresholds established by the WHO (i.e., an ICER of less than 3 times the GDP per capita indicates cost-effectiveness, whereas an ICER that is greater than 3 is considered not to be cost-effective).^17,18 Clinical inputs to the cost-effectiveness models included cases of cCMV identified, costs of screening and treatment for cCMV and/or HL, and costs saved with reduced morbidity caused by cCMV-associated HL.^17,18,22 All 3 cost-effectiveness studies reported the findings from one-way sensitivity analyses.^17,18,22

The 3 evidence-based guidelines considered features of clinical utility of NBS for cCMV (primarily as it concerned cCMV-associated HL, with some consideration of developmental delay) and cost (for screening and diagnosis, treatment, and reduced HL) outcomes in the development of their recommendations.^16,20,21 Additional considerations included populational, organizational, sociocultural,¹⁶ and health system.²¹

Summary of Critical Appraisal

Overall, a key limitation of the included studies and guidelines summarized in this report was a focus on cCMV-associated HL as an outcome of NBS screening strategies, with limited information describing a broader set of relevant clinical utility outcomes (e.g., morbidity from neurodevelopmental and other possible sequelae, as well as impacts to quality of life).^16-22

Prospective Cohort Study

The prospective cohort study was well reported, with a description of the characteristics of the population, intervention, comparator, and outcomes.¹⁹ The main findings were clearly reported, including estimates of random variability.¹⁹ The study’s external validity appeared robust, with a large cohort from multiple study sites, including study participants and health care that were likely to be representative of the population.¹⁹ Follow-up of the cohort was consistent across the universal and targeted screening approaches, and compliance with screening, diagnostic testing, and treatment was also consistent.¹⁹ Losses to follow-up were minimal.¹⁹ These study features, which demonstrated internal and external validity of the study methods, provide confidence in the findings of the study.

The limitations of the prospective cohort study included a lack of randomization and/or blinding;¹⁹ however, these limitations are a consistent feature of studies describing and comparing NBS programs, given the characteristics of the intervention. Furthermore, in this study, all neonates were exposed to both universal and targeted screening approaches,¹⁹ which rendered the value of randomization and/or blinding less important to establishing internal validity.

Cost-Effectiveness Evaluations

The 3 cost-effectiveness studies were generally well reported, and included sources and references to data used for the model inputs.^17,18,22 The key features of the cost-effectiveness analyses were described, including currency and price data, the time horizons over which the outcomes were considered (which were lifetime horizons, thus appropriate to the research questions), primary outcomes, model structures, and discount rates applied.^17,18,22 These study features are essential for informing an assessment of the utility of the findings generated.

While 2 of the cost-effectiveness studies included some description of the viewpoint from which the analyses were conducted,^18,22 1 did not,¹⁷ which limited the extent to which the costs and benefits included in the model could be ascertained as relevant. Similarly, while 2 of the studies described productivity costs,^17,22 1 did not,¹⁸ which limited the interpretation of the cost-effectiveness findings reported, as any sequelae from cCMV may have downstream consequences that could impact the productivity of affected neonates and their families. None of the cost-effectiveness studies reported detailed data describing the characteristics of patients or studies from which data were drawn to inform the model estimates; however, estimated rates of cCMV diagnosis in the study populations were reported.^17,18,22 Notably, the estimated rates of cCMV in 2 of the cost-effectiveness studies (i.e., the studies conducted in the Japanese and Chinese contexts)^17,18 appeared to be lower than in the third (i.e., the study conducted in a US context),²² and also appeared to be lower than that found in the prospective cohort study that was included in this report (also conducted in the US).¹⁹ This variability in the estimated prevalence of cCMV across the cost-effectiveness study populations may have impacted the inputs used to estimate cost-effectiveness (e.g., costs of diagnosis and treatment, and cost savings of long-term sequelae avoided). Nonetheless, it is known that the presence of cCMV does vary widely across various populations,^2,25 and must therefore be accounted for in modelled data.

While all of the cost-effectiveness studies reported on sensitivity analyses, no explicit justification for the selection of variables used in these analyses was reported,^17,18,22 and 1 study did not clearly describe the methods used to inform the sensitivity analyses.²² A clear and detailed description of sensitivity analyses is essential to consider uncertainty in the model estimates and inform interpretation around the robustness and meaningfulness of the findings.¹⁴

Whereas 2 of the studies were clear about the limitations of their studies, and the associated caveats around interpretation of their findings,^17,18 1 did not provide an explicit acknowledgement of these caveats,²² which limited the interpretation concerning how the findings may be used in a decision-making context. Nonetheless, all 3 author groups conceded that the available clinical evidence was limited, which consequently limited the interpretation of their findings.^17,18,22 Generally, all 3 cost-effectiveness studies made assumptions of health care that characterized ideal scenarios (e.g., that diagnosis and treatment was always appropriate and effective), which may not reflect real-world experience and could potentially inflate cost-effectiveness estimates.^17,18,22

Evidence-Based Guidelines

The scope and purpose are generally well reported by the 3 included evidence-based guidelines.^16,20,21 Stakeholder involvement and appropriate input into the development of the recommendations are clear in 1 of the guidelines.^21,26,27 While expert involvement from relevant professional groups was apparent for all of the included evidence-based guidelines,^{16,20,21,26,27} it was not clear whether members of the public (including those affected) were consulted, nor who the target users of the recommendations were for 2 of the guidelines.^16,20 These details are important when considering the utility of the recommendations (i.e., considerations of input from the public and those affected are essential elements of a robust recommendation for screening, and identification of target users is important for understanding the scope and purpose of the guideline).

Rigour of development is generally apparent for all of the 3 evidence-based guidelines, with all describing a consultation of the evidence by literature review (either systematic or with unclear methods).^16,20,21 However, the strengths and limitations of the body of evidence are not clearly reported for 2 of the evidence-based guidelines (i.e., whereas critical appraisal for individual studies is reported, an assessment of the totality of the evidence considered is not).^16,21 Similarly, external review is not clear for 2 of the guidelines,^16,21 and a procedure for updating the recommendations is not clear for 2 of the guidelines.^16,20

Presentation of the recommendations is generally clear for the 3 evidence-based guidelines.^16,20,21 However, 1 guideline does not provide a clear and unambiguous recommendation in its wording; rather, indicating that universal NBS for cCMV should be considered (as opposed to providing a recommendation concerning whether it should or should not be adopted).²⁰ This limits the utility of the recommendation, as it does not provide clear guidance concerning implementation. The applicability of the recommendations is generally not clearly reported in the 3 included evidence-based guidelines, with little to no guidance provided concerning how to implement the recommendations.^16,20,21 Nonetheless, 1 of the guidelines described consideration of resource implications in the development of its relevant recommendation.¹⁶

A demonstration of editorial independence is clear for 1 of the evidence-based guidelines;²⁰ nonetheless, 2 of the guidelines do not clearly describe whether the recommendations may have been influenced by the views of any funders,^16,21 and 1 of the guidelines did not report potential conflicts of interest for guideline development group members.²¹

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Summary of Findings

Of the studies included in this review, 1 addressed clinical utility, 3 described cost-effectiveness, and 3 evidence-based guidelines stated recommendations relevant to universal NBS for cCMV.

Appendix 4 presents the main study findings.

Comparative Clinical Utility of Universal Newborn Screening for cCMV

Universal Versus Targeted NBS for cCMV

The prospective cohort study identified 443 cases of cCMV from 99,945 neonates (0.4%) who underwent universal NBS (i.e., only diagnosed cases were reported; numbers of cCMV screen positive results were not reported). Of the 443 neonates diagnosed with cCMV, 40 (9%) exhibited symptoms at birth and 35 (7.9%; 95% confidence interval [CI], 5.6 to 10.8) were later diagnosed with SNHL.¹⁹

Of the 443 neonates diagnosed with cCMV, 31 (7.0%; 95% CI, 4.8 to 9.8) did not pass the NHS. Of these 31 neonates, 20 were diagnosed with SNHL between 3 and 8 weeks of life and 11 were not. In addition to these neonates, 15 neonates with cCMV who passed the NHS were identified as having SNHL by the audiologic assessment between 3 and 8 weeks of life.¹⁹

Consequently, among the 35 neonates diagnosed with both cCMV and SNHL, 20 (57%) were identified by both universal NBS and targeted NBS programs, whereas 15 (43%) were not identified by targeted NHSs alone. Neonates with cCMV who exhibited symptoms at birth had a statistically significantly higher rate of SNHL (38%; 95% CI, 23.6 to 54.4) as compared to those who were asymptomatic (4.7%; 95% CI, 2.9 to 7.3).

Study authors concluded that, while a targeted NBS approach to cCMV identifies most of the neonates who are later found to be affected by SNHL as a consequence of cCMV, a substantial proportion of cCMV-associated SNHL cases were missed by the targeted NBS approach.¹⁹ The study authors urge that approaches to cCMV be improved to more effectively identify neonates who are at risk of cCMV-associated SNHL.¹⁹

Universal Versus No NBS for cCMV

No studies comparing the clinical utility of universal NBS versus no NBS for cCMV were identified; therefore, no summary of the evidence could be provided.

Comparative Cost-Effectiveness of Universal Newborn Screening for cCMV

Universal Versus Targeted NBS for cCMV

Of the 2 cost-effectiveness studies that reported ICERs, both reported that universal NBS for cCMV was cost-effective as compared to targeted NBS for cCMV (i.e., ICERs were less than 3, as expressed by GDP per capita).^17,18 The Japanese study reported an ICER of ¥2,966,296,¹⁷ and the Chinese analysis generated an ICER of US$2,963.¹⁸ The third cost-effectiveness study also concluded that universal NBS for cCMV was more cost-effective than targeted NBS for cCMV (assuming all neonates identified with cCMV receive treatment with valganciclovir regardless of symptoms, and including projected loss-of-productivity costs), reporting an estimated saving of US$10.66 per newborn screened using a universal NBS strategy.²²

The findings from the sensitivity analyses demonstrated that the prevalence or incidence of cCMV, the cost of the CMV screening test, the rate of development of SNHL, and the cost of antiviral treatment were the most influential variables with regard to cost-effectiveness.^17,18,22 In the Japanese study, the most influential variable was the cost of the screening test, with ICERs ranging from ¥520,872 to ¥9,940,633 at various estimated costs for the screening test.¹⁷ In the Chinese study, the prevalence of cCMV was reported as the most influential variable, with ICERs ranging from US$1,390 to 9,011, depending on the prevalence estimates used.¹⁸ In the US cost-effectiveness analyses, only the cost of antiviral therapy was subjected to sensitivity analysis; though, the findings of these analyses were not reported for the comparison between universal NBS versus targeted NBS for cCMV.²²

Universal Versus No NBS for cCMV

Of the 2 cost-effectiveness studies that reported ICERs, both reported that universal NBS for cCMV was cost-effective as compared to no NBS for cCMV (i.e., ICERs were less than 3, as expressed by GDP per capita).^17,18 The Japanese study reported an ICER of ¥2,175,121,¹⁷ and the Chinese analysis reported and ICER of US$2,087.¹⁸ The third cost-effectiveness study also concluded that universal NBS for cCMV was more cost-effective than no NBS for cCMV (again, assuming all neonates identified with cCMV receive treatment with valganciclovir regardless of symptoms, and including projected loss-of-productivity costs), generating an estimated cost saving of US$37.97 per newborn screened.²²

The findings from the sensitivity analyses in the Japanese cost-effectiveness study were not reported for the comparison between universal NBS for cCMV screening and no NBS.¹⁷ In the Chinese cost-effectiveness comparison between universal NBS for cCMV and no screening, sensitivity analyses again demonstrated that it was the estimated prevalence of cCMV in the population that was the most influential variable to cost-effectiveness, with ICERs ranging from US$932 to US$6,532.¹⁸ In the US cost-effectiveness analyses, the variable estimated costs of antiviral therapy produced an estimated range of cost savings between US$14.60 and US$61.34 per newborn screened using a universal NBS strategy for cCMV as compared to no NBS.²²

Evidence-Based Recommendations Regarding the Use of Newborn Screening for cCMV

Of the 3 evidence-based guidelines included in this report,^16,20,21 2 make recommendations against the use of universal NBS for cCMV^16,21 and 1 makes a recommendation in favour of universal NBS for cCMV.²⁰

The most recent evidence-based guideline included in this report (published in 2024 in Canada’s province of Quebec) recommends that universal NBS for cCMV not be added to the provincial newborn DBS program.¹⁶ The limited availability of appropriate evidence is indicated as 1 reason for the recommendation against universal NBS for cCMV.¹⁶ The quality of the studies reviewed was critically appraised; however, the quality of the evidence base is not graded or systematically characterized, and there is no strength of the recommendation provided.¹⁶

The other guideline recommending against universal NBS for cCMV was published in 2017 in the UK and reports an updated review of the evidence from a previous guideline that recommended against universal NBS for cCMV (published in 2012); similarly, the updated review concludes that the evidence remains insufficient to support universal NBS for cCMV.²¹ Again, the authors report critical appraisal of studies reviewed but do not describe the quality of the evidence base overall.²¹ Similarly, no strength of the recommendation is reported.²¹

The International Congenital Cytomegalovirus Recommendations Group published its guidance in 2017 and recommends that universal NBS for cCMV be considered.²⁰ While no strength of the recommendation is indicated, the quality of the evidence supporting the recommendation was characterized as moderate (i.e., from nonrandomized studies).²⁰ Notably, the recommendation does not clearly favour implementation of NBS for cCMV; rather “consideration” of NBS for cCMV,²⁰ which may be interpreted as less clear than a recommendation supporting implementation. Unlike the other 2 evidence-based guidelines, the authors of this guideline do not describe concerns around the implementation of NBS for cCMV, such as costs, impacts to health systems, uncertainty around which neonates will most benefit from treatment, and potential harms of screening (e.g., false-positive screen results). In supporting statements, the group indicates that additional, high-quality (i.e., prospective) studies may further inform recommendations concerning universal or targeted NBS for cCMV.²⁰

Limitations

This review identified 1 prospective cohort study,¹⁹ 3 cost-effectiveness evaluations,^17,18,22 and 3 evidence-based guidelines^16,20,21 describing NBS for cCMV. Overall, the studies identified were limited in their coverage of relevant clinical outcomes, with HL being the focus of the findings (other outcomes of relevance to clinical utility were not described, including the number needed to screen, time to diagnosis, time to treatment, morbidity, mortality, and quality of life). This limits the findings of this report from describing a broader set of sequelae that are known to affect neonates with cCMV through infancy, childhood, and beyond, including developmental delays, learning difficulties, cerebral palsy, and visual impairments.⁴

Comparative evidence describing the clinical utility of universal NBS for cCMV was limited, with findings from 1 study published in the US in 2017 identified and summarized in this report.¹⁹ Some of the limitations of the study included no description of the precise timing of NBS and limited data describing long-term outcomes (i.e., findings from audiological assessments between 3 and 8 weeks were described).¹⁹ The effects of cCMV on other outcomes across a longer time frame were not described and remain unclear, limiting the interpretation of clinical utility in this report.

The 3 cost-effectiveness studies modelled data from Japan,¹⁷ China,¹⁸ and the US,²² which may have limited relevance to the Canadian context. The assumptions and variables used in the models may not be relevant in Canada, such as costs of screening and treatment. Furthermore, the cost-effectiveness models made assumptions concerning the effectiveness of screening and treatment that may not be characteristic of the care and outcomes experienced in real-world settings (e.g., the long-term effectiveness of antiviral treatments for the reduction of cCMV-associated HL remains unclear).⁵ This limits the generalizability of the findings from these studies.

Finally, the 3 evidence-based guidelines identified in this review make conflicting recommendations concerning the implementation of universal NBS for cCMV. While 1 guideline recommends in favour of universal NBS for cCMV,²⁰ 2 guidelines recommend against the implementation of universal NBS for cCMV.^16,21 In addition, the recommendation in favour of universal NBS for cCMV is not clear, with guidance that favours consideration of universal NBS as opposed to clear guidance in favour of implementing NBS for cCMV.²⁰ All of the guidelines make reference to the paucity of available clinical evidence to inform recommendations concerning the use of universal NBS for cCMV.^16,20,21 Limited available clinical evidence was also identified in this report, which constrains the interpretation of its findings.

Conclusions and Implications for Decision- or Policy-Making

This report summarized and described 7 sources describing the comparative clinical utility and cost-effectiveness of universal NBS for cCMV, as well as evidence-based guidelines regarding NBS for cCMV.^16-22 Of these, 1 prospective cohort study reported on the comparative clinical utility of universal NBS versus targeted NBS for cCMV,¹⁹ 3 economic evaluations reported on the comparative cost-effectiveness of universal versus targeted or no NBS for cCMV,^17,18,22 and 3 evidence-based guidelines make recommendations concerning universal NBS for cCMV.^16,20,21

Overall, the limited clinical utility evidence and cost-effectiveness findings appear to be supportive of a universal approach to NBS for cCMV, as is also acknowledged by the authors of these studies.^17-19,22 Specifically, a considerable proportion of neonates with cCMV and associated SNHL who were missed by targeted NHS were identified by a universal approach to NBS.¹⁹ Similarly, the 3 cost-effectiveness studies all reported a benefit of universal as compared to targeted NBS or no NBS for cCMV under a range of assumptions (though, all 3 papers also acknowledge a lack of available clinical evidence as a limitation of their work).^17,18,22 The potential benefits of universal NBS for cCMV, including clinical and cost benefits (i.e., the opportunity for early treatment and potential reduction of long-term sequalae), as well as the opportunity for families to have a diagnosis for their affected infant(s), are widely acknowledged in the broader literature, as well.^4,6,7,10,11 Nonetheless, 2 of the 3 evidence-based guidelines identified in this review are not supportive of the implementation of universal NBS for cCMV, generally citing the limited availability of meaningful and high-quality clinical evidence.^16,20,21

This current lack of clinical evidence describing key considerations for NBS for cCMV is likewise acknowledged in the broader literature,^1,2 and was also observed in this review, which consequently limits the findings of this report. Some of the key areas for clinical research that are yet needed to inform decision-making concerning universal NBS for cCMV include the effectiveness of screening and therapy for cCMV.^1,2,8 While NBS programs that currently use DBS present an opportune infrastructure that may allow for the addition of cCMV screening, the limitations of DBS test performance for cCMV remain a barrier, with additional research needed to understand and develop this technology.^1,4 In addition, the effectiveness of antiviral treatments for reducing cCMV-associated sequelae remains unclear, which similarly constitutes a barrier to establishing the utility and value of a universal NBS program for cCMV.^2,5,8 The potential for overtreatment with antiviral medications has also been raised as a concern around universal NBS for cCMV.⁴ Importantly, research that includes long-term evaluation of the clinical utility of NBS for cCMV — and considers a range of outcomes broader than HL alone — is still needed.^1,5 Another key consideration is health system readiness to manage the increased numbers of affected neonates that will be identified by a universal NBS program for cCMV — particularly given the unanswered questions concerning treatment and its effectiveness (particularly among neonates with cCMV who are asymptomatic).⁷

Jurisdictions where universal NBS for cCMV have been implemented¹² offer the opportunity to support research that may elucidate these key considerations and inform evidence-based decision-making.⁴ The evidence-based guideline included in this review from INESSS highlights the importance of evidence generated by these recently established universal NBS programs to inform guidance and decision-making for other jurisdictions.¹⁶ As these universal NBS programs are able to generate and accrue data, there is opportunity to increase an understanding of the clinical utility of NBS for cCMV through evaluation and reporting,⁴ which can support and inform other jurisdictions in considering best approaches to NBS for cCMV — though, an imperative is needed to generate and report the necessary data to inform a more robust clinical evidence base for the universal NBS of cCMV.

Given the currently available clinical effectiveness and cost-effectiveness evidence, as well as available guidelines describing NBS for cCMV, deliberation and decision-making around the implementation of universal NBS for cCMV may also benefit from extra evidentiary sources; for example, clinical and public health expertise, as well as public (including families and those who may have been affected by cCMV), health payer, and other stakeholder input.

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Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Note that this appendix has not been copy-edited.

Table 2: Characteristics of Included Primary Clinical Study

ABR = auditory brainstem response; cCMV = congenital cytomegalovirus; DBS = dried blood spot; NBS = newborn screening; NHS = newborn hearing screening; NIDCD = National Institute on Deafness and Other Communication Disorders; NIH = National Institutes of Health; NR = not reported

Table 3: Characteristics of Included Economic Evaluations

cCMV = congenital cytomegalovirus; CMV = cytomegalovirus; CEA = cost effectiveness analysis; DBS = dried blood spot; NBS = newborn screening; NHS = newborn hearing screening; NIH = National Institutes of Health; NR = not reported; PCR = polymerase chain reaction; SNHL = sensorineural hearing loss

Table 4: Characteristics of Included Evidence-Based Guidelines

cCMV = congenital cytomegalovirus; CDP = Comité délibératif permanent-Approches diagnostiques et dépistage; DBS = dried blood spot; INESSS = Institut national d'excellence en santé et services sociaux; NBS = newborn screening; NR = not reported

Appendix 3: Critical Appraisal of Included Publications

Note that this appendix has not been copy-edited.

Table 5: Strengths and Limitations of Clinical Study Using the Downs and Black Checklist¹³

HL = hearing loss; NBS = newborn screening

Table 6: Strengths and Limitations of Economic Evaluations Using the Drummond Checklist¹⁴

HL = hearing loss

Table 7: Strengths and Limitations of Evidence-Based Guidelines Using AGREE II¹⁵

AGREE II = Appraisal of Guidelines for Research and Evaluation II; INESS = Institut national d'excellence en santé et services sociaux; NSC = National Screening Committee.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 8: Summary of Findings by Outcome — Comparative Clinical Utility of Concurrent Universal Versus Targeted NBS for cCMV

cCMV = congenital cytomegalovirus; CMV = cytomegalovirus; NHS = newborn hearing screening; NR = not reported; SNHL = sensorineural hearing loss

Table 9: Summary of Findings by Outcome — Comparative Cost-Effectiveness of Universal Versus Targeted or No NBS for cCMV

cCMV = congenital cytomegalovirus; cCMVi = congenital cytomegalovirus infection; GDP = gross domestic product; HL = hearing loss; JPY = Japanese Yen; NR = not reported; PCR = polymerase chain reaction; SNHL = sensorineural hearing loss; USD = US dollar(s)

Table 10: Summary of Recommendations in Included Evidence-Based Guidelines

cCMV = congenital cytomegalovirus; CDP = Comité délibératif permanent-Approches diagnostiques et dépistage; cCMV = congenital cytomegalovirus; INESS = Institut national d'excellence en santé et services sociaux; NR = not reported; PCR = polymerase chain reaction

Appendix 5: Ineligible Studies With Relevance to the Research Questions

Table 11: Summary of Abstracts — Studies Comparing NBS Programs for cCMV

bVL = birth viral load; cCMV = congenital cytomegalovirus; CI = confidence interval; CMV = cytomegalovirus; DBS = dried blood spot; HL = hearing loss; NBS = newborn screening; NHS = newborn hearing screening; NPA = negative percent agreement; NPV = negative predictive value; NR = not reported; PCR = polymerase chain reaction; PPA = positive percent agreement; PPV = positive predictive value; RT = real time; SGA = small for gestational age; SNHL = sensorineural hearing loss.

Note: This table has not been copy-edited.

^aWhile the study describes the intervention targeted to premature neonates as ‘universal’, it has been characterized in this report as a targeted strategy (i.e., targeted to premature neonates only; not universal to all neonates).

^bCurrently NR

^cThe time frame over which the cost estimate applies was not reported.

Table 12: Summary of Abstracts — Studies Not Comparing NBS Programs

cCMV = congenital cytomegalovirus; CCMVI = congenital cytomegalovirus infection; CI = confidence interval; CMV = cytomegalovirus; DBS = dried blood spot; DTA = diagnostic test accuracy; HL = hearing loss; NBS = newborn screening; NHS = newborn hearing screening; NPA = negative percent agreement; NR = not reported; NS = not statistically significant; PCR = polymerase chain reaction; PPA = positive percent agreement; SGA = small for gestational age; VGVC = valganciclovir.

Note: This table has not been copy-edited.

Appendix 6: References of Potential Interest

Systematic Reviews

Ineligible Systematic Review (No Study Selection Criteria Reported)

Hilditch C, Liersch B, Spurrier N, Callander EJ, Cooper C, Keir AK. Does screening for congenital cytomegalovirus at birth improve longer term hearing outcomes? Arch Dis Child. 2018 Oct;103(10):988-992. PubMed

Guidelines and Recommendations

Guidance With No Apparent Link to Evidence

2022.Congenital Cytomegalovirus Screening Guidelines. Tallahassee (FL): Florida Department of Health, Florida Newborn Hearing Screening (NBHS) Program; 2022: https://floridanewbornscreening.com/wp-content/uploads/CMV-Screening-Guidelines-FINAL.pdf. Accessed 2024 Mar 27.

Relevant Position and Other Statements With No Explicit Recommendation(s) Regarding NBS

Position Statement on Universal Congenital Cytomegalovirus Screening in Canadian Newborns. Toronto (ON): Canadian Infant Hearing Task Force; 2022: https://canadianaudiology.ca/wp-content/uploads/2022/04/SAC_cCMV-Position-statement_EN.pdf. Accessed 2024 Mar 27.

Barton M, Forrester AM, McDonald J, Canadian Paediatric Society Infectious Diseases and Immunization Committee. Update on congenital cytomegalovirus infection: Prenatal prevention, newborn diagnosis, and management. Ottawa (ON): Canadian Paediatric Society; 2020: https://cps.ca/en/documents/position/update-on-congenital-cytomegalovirus-infection-prenatal-prevention-newborn-diagnosis-and-management. Accessed 2024 Mar 27.

Review Articles

Commentary on 1 of The Cost-Effectiveness Assessments Included in This Report

Hilditch C, Keir AK. Cost-effectiveness of universal and targeted newborn screening for congenital cytomegalovirus infection. Acta Paediatr. 2018 May;107(5):906. PubMed