Original Title: Pertinence de l’ajout du dépistage universel de l’infection congénitale au cytomégalovirus (CMV) au programme québécois de dépistage néonatal

Authors' objectives: The cytomegalovirus (CMV) is a common virus that belongs to the herpesvirus family (lat. herpesviridae) and has the ability to establish lifelong latency. When a pregnant woman is infected, there is a risk that her baby will be affected by a congenital CMV (cCMV) infection. Worldwide birth prevalence is 0.67%. This is significantly higher in lowand middle-income countries (1.42%) than in high-income countries (0.48%). Although several clinical trials are presently underway, no vaccine to prevent CMV infection and congenital infections in newborns is currently approved. About 75 to 80% of children with cCMV infection have a good prognosis, with no apparent sequelae of the disease. The severity of long-term adverse effects varies considerably, ranging from minimal deficits to major neurodevelopmental complications in a minority of newborns. Hearing problems are the most common sequelae. Currently in Québec, clinical suspicion identifies only a very small proportion of infected infants. The Ministère de la Santé et des Services sociaux mandated the Institut national d’excellence en santé et en services sociaux to assess the relevance of adding newborn screening for cCMV infection to Québec newborn screening program.

Authors' results and conclusions: (#1 DISEASE ETIOLOGY AND NATURAL HISTORY ARE COMPLEX AND ONLY PARTIALLY UNDERSTOOD): The specific mechanisms of cCMV pathogenesis are not fully understood, and there is considerable phenotypic variation among infected newborns; • CMV is a common virus and the prevalence of cCMV at birth is approximately 0.5% (1 case per 200 births) in Canada; • Sensorineural hearing loss, central nervous system involvement and thrombocytopenia are the most common clinical presentations; • About 85 to 90% of cases are asymptomatic at birth. (#2 DISEASE SEVERITY AND PROGNOSIS ARE VARIABLE): cCMV affects the fetus more severely when infection occurs before the third trimester, whether this is a result of primary infection or reactivation or reinfection in the mother; • At least 75% of affected children will have a good prognosis, with no apparent sequelae of the infection; • The severity of long-term adverse effects varies considerably, with sequelae being mainly associated with hearing disorders of various degrees; • Epidemiological evidence linking CMV to cerebral palsy and retinitis is of sufficient quality, but is limited in quality for some neurodevelopmental disorders, ocular problems and vestibular conditions; • cCMV causes death in a small proportion of infected newborns. (#3 THE CCMV NEONATAL SCREENING TEST CAN BE EFFECTIVELY PERFORMED): The polymerase chain reaction (PCR) test on saliva is the most widely studied and shows good performance; • The performance of a PCR test on dried blood samples collected at birth would be sub-optimal, but optimization processes are underway for this procedure. (#4 THERE IS LIMITED EVIDENCE OF EFFECTIVENESS): There is no evidence demonstrating that universal newborn screening is effective in reducing morbidity and mortality; • Evidence of effectiveness of treatment against cCMV is limited to modest effects on deafness and on some components of neurological development, in children with clinical symptoms related to the central nervous system and moderate to severe impairment in the neonatal stage; (#5 UNIVERSAL CCMV SCREENING COULD HAVE ADVERSE EFFECTS): • This screening test presents risks of anxiety linked to the detection of false positives (via saliva) and benign cases; • The use of a dried blood test would lead to false negatives and thus the test results could be falsely reassuring; • Screening could lead to overdiagnosis, since it is not possible to accurately estimate the number of benign cases, who cannot be identified a priori and will remain asymptomatic for their entire lives. (#6 THERE ARE ETHICAL ISSUES RELATED TO THIS INFECTION AND ITS SCREENING): #6.1 Universal newborn screening for cCMV could reduce inequity: – for populations of vulnerable newborns (very low birth weight, small for gestational age or uninfected babies exposed to human immunodeficiency virus through their mothers), all of whom having higher cCMV prevalence rates than those of newborns in the general population; – based on the type of disease, since the comparators, i.e. clinical identification and targeted CMV screening for newborns who fail a hearing test, identify only a small proportion of affected infants. #6.2 Universal newborn screening for cCMV could increase inequity: – by stigmatizing particular populations at greater risk of infection based on ethnic origin or low income; – since not all patients identified by the test would have equal access to pharmacological treatment which is recommended only at birth for certain types of symptomatic cases. (#7 UNIVERSAL NEWBORN SCREENING FOR CCMV WOULD PUT PRESSURE ON THE HEALTHCARE SYSTEM AND REQUIRE ORGANIZATIONAL CHANGES TO THE CARE PATHWAY): The existing newborn screening program uses the dried blood sample taken at birth for the majority of diseases tested in Québec; IX • If saliva testing were to be introduced, major organizational changes to the program would be required for sample collection, processing and storage; • The implementation of universal screening could lead to the diagnosis of nearly 400 newborns annually by paediatric infectious diseases specialists at the reference centres, who would all require multidisciplinary follow-up in the setting of limited personnel when it comes to all the healthcare professionals implicated. (#8 LITERATURE ON THE COST-EFFECTIVENESS OF NEWBORN SCREENING IS LIMITED): The results of a single American study with several limitations are partially transferable to the Québec context; • According to this study: – neonatal screening for cCMV would generally be associated with savings, or would be essentially costneutral from the perspective of public spending, and would therefore appear to be cost-effective; – universal screening would offer greater net savings and a better opportunity to provide directed care than targeted screening. (#9 VERY FEW PROGRAMS HAVE IMPLEMENTED UNIVERSAL NEWBORN CCMV SCREENING): To date, two Canadian provinces and one U.S. state have implemented universal newborn screening for CMV, and only one favourable position from learned societies has been published.

Authors' recommendations: The relevance of adding cCMV screening to the Québec newborn screening program was discussed with experts from the advisory committee and the Comité délibératif permanent – Approches diagnostiques et dépistage (CDP). Perspectives and issues raised during consultations with the advisory committee were shared with members of the CDP and integrated into their deliberation. The CDP members raised several arguments against screening, the main ones being the lack of evidence of its effectiveness, the absence of reliable markers to discern the severity of cases and the risk of overdiagnosis (absence of health gains) for most of the asymptomatic children detected. In addition, the blood test that would be favoured by the Québec newborn screening program currently shows sub-optimal performance, and no program that has implemented universal CMV screening has yet published results. Finally, the addition of such screening would have significant organizational impact. In light of all the scientific, contextual and experiential data collected, the findings and the deliberative process conducted: INESSS does not recommend adding universal screening for congenital cytomegalovirus infection to the blood testing platform of the Québec newborn screening program. However, the following points are noted: • INESSS emphasizes that it is essential for healthcare professionals to be properly informed about CMV, and that in order to reduce prevalence of the infection, priority should be given to educating pregnant women and the general population about measures to be taken to limit such infections and the potential effects of this disease on newborns. • INESSS remains open to a re-evaluation when there is evidence in the literature on the performance of programs that use dried blood samples, on the effectiveness of universal screening or on the effectiveness of treatment in a wider range of patients.

Authors' methods: A rapid review2, that is, a thorough and transparent synthesis of the literature, was conducted to document the parameters of interest, including test performance, effectiveness, screening safety (the clinical dimension) and cost-effectiveness (the economic dimension). A narrative review of the scientific literature was also conducted to document the populational, organizational, and sociocultural dimensions. Scientific and grey literature were identified in several databases and other sources, with no restrictions on study design. Contextual and experiential data were collected from an advisory committee of professionals working in the field.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/pertinence-de-lajout-du-depistage-universel-de-linfection-congenitale-au-cytomegalovirus-cmv-au-programme-quebecois-de-depistage-neonatal.html

Year Published: 2024

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/pertinence-de-lajout-du-depistage-universel-de-linfection-congenitale-au-cytomegalovirus-cmv-au-programme-quebecois-de-depistage-neonatal.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)