MANUSCRIPT CITATION

Gantt S, Dionne F, Kozak FK, et al. Cost-effectiveness of Universal and Targeted Newborn Screening for Congenital Cytomegalovirus Infection. JAMA Pediatrics. 2016; 170(12):1173-1180. PMID:27723885

REVIEWED BY

Cathie Hilditch and Amy Keir

Healthy Mothers, Babies and Children’s Theme, South Australian Health and Medical Institute, North Adelaide, South Australia

Robinson Research Institute and the Adelaide Medical School, the University of Adelaide, Adelaide, South Australia

TYPE OF INVESTIGATION

Economics of healthcare or interventions

QUESTION

Is targeted or universal screening for congenital CMV infection in newborn infants cost-effective when compared to not screening for congenital CMV?

METHODS

• Design: Economic modelling study using rates and outcomes from prospective cohort studies of newborn cCMV screening in the USA and early hearing program data.
  • Costs: Laboratory testing, treatment, interventions and ongoing surveillance costs were taken from Medicaid data and published estimates.
  • Benefits: Assumed to come from provision of antiviral therapy to affected newborns to reduce hearing loss as well as from earlier identification of hearing loss with onset beyond the newborn period.
• Allocation: not applicable
• Blinding: not applicable
• Follow-up period: All hearing loss due to cCMV was assumed to occur by 6 years of age.
• Setting: USA
• Patients:
  • Targeted group: infants <21 days of age who had failed their primary (newborn) hearing screen
  • Universal group: all infants <21 days of age
  • Nil inclusion or exclusion criteria
• Intervention
  • Universal screening for cCMV with salivary CMV PCR in all infants <21 days of age or targeted screening for cCMV in infants <21 days of age who failed their primary (newborn) hearing screening test.
• Comparison
  • No screening for cCMV
• Outcomes:
  • Incremental costs for identifying one congenital CMV infection, one case of CMV-related hearing loss, and preventing one cochlear implant
  • Incremental reduction in cases of severe to profound hearing loss
  • Differences in cost per infant screened by universal of targeted strategies under different assumptions around the effectiveness of antiviral treatment
• Time:
  • Analysis undertaken from July 2014 to March 2016
• Analysis and Sample Size: Cost-effective analysis performed under a variety of different assumptions including:
  • Cost of screening at $USD10 to 50 per infant (oral swab, salivary CMV PCR analysis and confirmatory urine PCR analysis for any infant with a positive screen)
  • Costs of medical evaluations including testing, increased audiological surveillance, early intervention programs, hearing aids, antiviral treatments were included in the modelling
  • Infants with confirmed cCMV all underwent a medical evaluation
  • Infants with a failed hearing screen had a fast-tracked audiological evaluation within the first month of age to guide antiviral treatment
  • Infants with asymptomatic cCMV had audiological testing every 6 months until 6 years of age or when hearing loss was identified; this was assumed to lead to hearing loss being identified 24 months earlier
  • It was assumed that antiviral treatment would improve hearing outcomes in approximately half of the symptomatic infants with cCMV when commenced within 4 weeks of age
  • Modelling included antiviral treatment for infants with symptomatic cCMV compared to infants with cCMV with isolated hearing loss at birth
• Patient follow-up: not applicable

MAIN RESULTS

In this cost-effectiveness study comparing universal and targeted cCMV screening with no screening both universal and targeted cCMV screening were both found to be cost-effective.  Universal screening resulted in larger net savings than targeted screening, despite having higher screening costs, and allowed for more opportunity for surveillance, in particular for later onset hearing loss.  The calculated costs of identifying cases of cCMV and cCMV-related hearing loss are shown in Table 1.  The estimated reduction in numbers of children with severe-profound hearing loss and mean savings with each screening strategy are shown in Table 2.  Net savings from universal screening were estimated to be greater than those from targeted screening, although screening costs were higher.  Both screening programs were more cost-effective if antiviral therapy was given and assumed effective for all infants with symptomatic cCMV, including those with isolated hearing loss at birth.

CONCLUSION

Newborn screening for cCMV appears to be cost-effective under a number of different assumptions in a highly resourced healthcare setting.

COMMENTARY

Congenital CMV is the most common intra-uterine infection in highly resourced countries, occurring in 0.4 to 0.64% of all births.(1, 2) The true impact of the disease is likely to be higher, as up to 90% of infected infants are asymptomatic at birth. Up to a quarter of all childhood sensorineural hearing loss (SNHL) is attributed to cCMV infection, making CMV the biggest non-genetic cause in children. Many of these children with hearing loss related to cCMV will pass their newborn hearing screen and develop later onset hearing loss. The opportunity to identify infants at birth with hearing loss related to cCMV and provide treatment with the potential to improve outcomes is lost without, at a minimum, targeted cCMV screening program. Without universal cCMV screening, children with cCMV who will go on to develop hearing loss, but pass their newborn hearing screen, will miss the opportunity for early intervention.  Improved speech, language and educational outcomes are all possible if hearing loss is identified as early as possible.(3)

Introduction of either targeted or universal cCMV screening has the potential to improve outcomes for children with cCMV. The authors propose that the disease meets the criteria for a screening program, including cCMV being an important health problem, the availability of a highly specific and sensitivity screening test in the salivary CMV PCR (4), and the availability of suitable treatments (5, 6) and interventions. Evidence regarding the efficacy and timing of antiviral treatment for symptomatic congenital CMV is growing.(5) The resources for diagnosis, treatment and ongoing surveillance of asymptomatic infants, likely required to at least 6 years of age, is the limiting factor for most healthcare systems, even highly resourced ones.

Introducing a screening program for cCMV would allow for population-based estimates of prevalence, and provide an opportunity to perform high-quality clinical interventional trials and observational research in this area. Screening for cCMV at birth would allow for identification of asymptomatic newborns with cCMV, who would previously have gone undiagnosed and provide potentially early treatment and ongoing neurodevelopmental monitoring, including hearing surveillance. There is evidence that antiviral therapy reduces hearing deterioration and improves neurocognitive outcomes in newborns with cCMV if started within the first month of birth (5).

Up until now, there has been no widely available cost-effectiveness modelling using both a targeted and universal cCMV screening approach to allow for invaluable comparisons. This well-designed cost-effectiveness study by Gantt et al (7) provides key support for the healthcare system benefits, in particular cost savings, for either a targeted or universal approach to screening for cCMV. The study is limited by its applicability to the healthcare system in the USA only but the authors’ approach could be applied to other highly resourced settings. A significant limitation of the analysis is the assumption that salivary PCR testing can be absorbed into U.S. newborn screening programs at no additional cost for infrastructure or personnel. However, the potential benefits described by this study, in particular those provided by universal screening, when loss of productivity costs are taken into account, make it the most attractive form of screening, compared to targeted screening. This study is an important step towards advocating for further investigation of the feasibility of screening for cCMV in newborn infants to improve important outcomes, in particular around hearing.

REFERENCES

1. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Reviews in medical virology 2007; 17 4:253-76.
2. Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med 2011; 364 22:2111-8.
3. Goderis J, Keymeulen A, Smets K, Van Hoecke H, De Leenheer E, Boudewyns A, et al. Hearing in Children with Congenital Cytomegalovirus Infection: Results of a Longitudinal Study. J Pediatr 2016; 172:110-5 e2.
4. Ross SA, Ahmed A, Palmer AL, Michaels MG, Sanchez PJ, Bernstein DI, et al. Detection of congenital cytomegalovirus infection by real-time polymerase chain reaction analysis of saliva or urine specimens. J Infect Dis 2014; 210 9:1415-8.
5. Kimberlin DW, Jester PM, Sanchez PJ, Ahmed A, Arav-Boger R, Michaels MG, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med 2015; 372 10:933-43.
6. Kimberlin DW, Lin CY, Sanchez PJ, Demmler GJ, Dankner W, Shelton M, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003; 143 1:16-25.
7. Gantt S, Dionne F, Kozak FK, Goshen O, Goldfarb DM, Park AH, et al. Cost-effectiveness of Universal and Targeted Newborn Screening for Congenital Cytomegalovirus Infection. JAMA pediatrics 2016; 170 12:1173-80.