Cytomegalovirus (CMV) Neonatal Pathway

Disclaimer These guidelines have been produced to guide clinical decision making for the medical, nursing and allied health staff of Perth Children’s Hospital. They are not strict protocols, and they do not replace the judgement of a senior clinician. Clinical common sense should be applied at all times. These clinical guidelines should never be relied on as a substitute for proper assessment with respect to the particular circumstances of each case and the needs of each patient. Clinicians should also consider the local skill level available and their local area policies before following any guideline.  Read the full CAHS clinical disclaimer.

Aim

To provide a pathway for the assessment, management and follow-up of neonates at risk of, or diagnosed with, congenital cytomegalovirus (CMV) infection and postnatal CMV infection.

Risk

Process

Congenital CMV

Testing

• Universal screening for congenital CMV is not offered, targeted testing should be performed on high-risk infants.

Who to test

• Neonates:
  • with clinical suspicion of congenital CMV (cCMV)
    • including thrombocytopenia, petechiae, hepatomegaly, splenomegaly, hepatitis, microcephaly, unexplained intrauterine growth restriction (IUGR), chorioretinitis, seizures or indicative central nervous system (CNS) radiological abnormalities
    • sensorineural hearing loss (SNHL) (based on either failed newborn hearing screening and/or subsequent auditory brainstem response testing)
  • born to a mother with confirmed CMV infection during (or just prior to) pregnancy
  • with a positive CMV PCR on amniocentesis. These neonates are considered to have congenital CMV, and confirmatory neonatal testing should be performed.

How and when to test

Ideally testing should be performed as early as practical in order to allow for timely decisions to be made around treatment and follow-up:

• For infants under 3 weeks of age CMV PCR testing can be performed using a single urine (preferred) or saliva sample. This testing is sensitive and specific for congenital CMV (and more sensitive than dried blood spot testing)^1,2.
  • Urine for this purpose can be collected using a bag sample (minimum 1 mL urine sample required)
  • Saliva should be taken at least one hour after the last feed using a sterile swab, the tip of which is then placed in a viral transport media.
• For infants older than 3 weeks of age CMV PCR can be performed using the initial newborn screening blood sample (dried blood spot ‘Guthrie’ card)² by contacting the WA Newborn Screening Program (phone 6383 4171 or email wanbs@health.wa.gov.au) and completing a “Consent for further testing on a stored blood sample” form, which will need to be signed by the infant’s parents.
  • Urine / saliva CMV PCR in infants older than 3 weeks of age cannot differentiate congenital from postnatal infection.

Any infant with a positive CMV PCR on saliva should have repeat sampling of urine and saliva to confirm CMV.

Congenital CMV is diagnosed if:

• positive CMV PCR on amniocentesis, or
• positive CMV PCR on urine or saliva (confirmed as above) (under 3 weeks of age), or
• positive CMV PCR on newborn screening blood spot (any age).

These infants require a thorough clinical assessment, baseline investigations and follow-up arranged as outlined (diagnosis and management of infants with post-natal CMV infection is discussed separately below).

Clinical assessment

• Growth parameters (length, weight, head circumference).
• Physical examination including neurological examination, abdominal examination (jaundice, hepatosplenomegaly) skin examination (petechiae).
• Hearing assessment (either through newborn hearing screening and / or formal hearing assessment by paediatric audiologists using auditory brainstem response testing (ABR).

Investigations

• Bloods: Full Blood Count (FBC), Liver Function Tests (LFT), conjugated bilirubin +/- CMV viral load (EDTA 2 mL).
• Imaging: early Magnetic Resonance Imaging (MRI) brain to assess for CNS involvement (ideally prior to 4 weeks of age where possible). MRI is more sensitive for intracerebral calcification than head ultrasound (US). Where MRI is not possible, consider US or Computerised Tomography (CT) brain. MRI scans of the brain can now be done without general anaesthesia using a “feed and wrap” technique.
• Ophthalmology: early assessment for chorioretinitis.

Treatment

Discuss all cases considered for treatment with the Infectious Diseases (ID) fellow / Consultant or the Clinical Microbiologist on call through Perth Children’s Hospital (PCH) / King Edward Memorial Hospital (KEMH) switchboard.

Who

• Symptomatic cCMV disease: consider treatment in neonates with moderate to severe manifestations^3,4 defined as:
  • CNS involvement
    • microcephaly, radiographic changes indicative of CMV CNS disease, chorioretinitis +/- confirmed SNHL.
  And / or
  • multiple manifestations attributable to cCMV
    • thrombocytopaenia, petechiae, hepatomegaly, splenomegaly, IUGR, hepatitis.

• Symptomatic cCMV with isolated SNHL: discuss with ID team and Ear Nose and Throat (ENT) team.
  Recommendations regarding the treatment of children with cCMV and isolated SNHL differ between consensus guidelines^3,4. Some observational data suggest a potential benefit⁵, however definitive data from randomised clinical trials is still lacking in this group⁶. Patients with isolated SNHL may be candidates for either hearing aids or cochlear implantation depending upon the severity of hearing loss. Early review with ENT is recommended.
• Mildly symptomatic cCMV disease (one or two transient manifestations, e.g. isolated thrombocytopenia, thrombocytopaenia transaminitis): treatment is not routinely recommended.
• Asymptomatic cCMV infection: treatment is not routinely recommended.

The potential benefits and side effects of treatment should be discussed with the patient’s family ideally by the ID / Microbiology team and the Neonatology team (for Neonatal Intensive Care Unit (NICU) patients).

Treatment should not commence without informed parental consent, which needs to be documented in the patient’s medical record.

When and how

• For KEMH patients refer to the Congenital CMV Checklist MR429.00 (CAHS Neonatology Form).
• Patients should be assessed urgently in the ID outpatient clinic at PCH prior to commencing therapy (or discussed with the ID / Microbiology team for NICU patients).
• Treatment should be commenced within the first month of life^1,2.
• Treat with oral valganciclovir twice daily (or ganciclovir – Neonatal Medication Monograph, initially if extreme prematurity or unable to tolerate / absorb oral medications) for a total duration of 6 months. Refer also to Valganciclovir Monograph – Paediatric - ChAMP monograph.
• All infants commenced on antivirals should have monthly follow-up with the ID team at PCH.

Follow-up

All infants with cCMV regardless of treatment status should be referred for the following:

• Audiology: Follow-up at least 6 monthly up to 3 years of age, then annually thereafter until 10 years old for hearing assessments and/or speech pathology assessments.
• Development:
  • Initial paediatric developmental review at 9-12 months:
    • for >32/40 gestation - through the PCH developmental clinic (through eReferrals - Paediatric Medicine (PAE) - specify on referral that “this child has complex medical needs with ongoing follow up at PCH”).
    • for <32/40 gestation and born / admitted at KEMH - KEMH developmental follow up.
  • Consider Ages and Stages Questionnaire (ASQ) at 6 months and 12 months. (Refer to Ages and Stages Questionnaires guideline - Child and Adolescent Community Health Clinical Nursing Manual).
  • Consider early referral to Child Development Services – Eligibility and referrals / Early Intervention Clinic if concerns identified.
• Ophthalmology: early assessment for chorioretinitis and follow-up thereafter as determined by the ophthalmologist.

Infants with cCMV on valganciclovir require:

• ID review: Early review at 1-2 weeks, then 2-4 weekly thereafter to monitor compliance, side effects and complications, increase valganciclovir dose with growth and coordinate follow-up.
• Neutrophil count (FBC): At least weekly for 2-3 weeks, then monthly thereafter.
• Liver Function Test (LFT) and renal function (UEC): At least monthly throughout therapy.
• Other follow-up as above: paediatrics, audiology and ophthalmology.

CMV viral load testing is not routinely required after commencing therapy, except if there are acute septic features or if there are specific concerns about absorption. CMV viral loads are expected to rebound after ceasing therapy, confirmation of this by viral load testing is not warranted.

Postnatally acquired CMV infection

• Infants can acquire CMV infection perinatally via exposure to maternal genital secretions or postnatally via blood transfusion, contact with siblings or most commonly through breastfeeding.
• Postnatal CMV disease is rare in full-term infants however those born at <32 weeks gestation or with very low birth weight <1500 grams are at higher risk of symptomatic disease. Manifestations include hepatitis, thrombocytopaenia, neutropenia, respiratory distress syndrome and sepsis-like syndrome.
• Where postnatal CMV disease is suspected, a urine (preferred) or saliva sample should be collected for PCR testing. A CMV viral load (EDTA tube 2 mL minimum) should also be requested. In patients where differentiation between congenital and postnatal CMV infection is required consider CMV PCR testing on initial newborn screening blood sample as above.
• Treatment (IV ganciclovir / oral valganciclovir) should be reserved for cases of severe disease in discussion with the ID team.
• A low risk of mild neurological and cognitive sequelae in premature infants infected postnatally has been reported although this finding has not been consistent across studies. In contrast to cCMV, postnatally acquired CMV infection has not been definitively associated with SNHL. Developmental follow-up can be considered on a case-by-case basis.
• Overall the risk of severe disease and/or subsequent sequelae in postnatal CMV infection is low and outweighed by the benefits of breastfeeding⁷.
  • This is reflected in the American Academy of Paediatrics 2012 policy statement which recommends breast milk as the enteral feed of choice for preterm infants in CMV seropositive mothers⁸.
• Infants with suspected T cell immunodeficiency are at high risk of severe manifestations of postnatal CMV disease and breastfeeding should be avoided.

References

1. Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, Sánchez PJ, Bernstein DI, Tolan Jr RW, Novak Z, Chowdhury N. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. New England Journal of Medicine. 2011 Jun 2;364(22):2111-8.
2. Wang L, Xu X, Zhang H, Qian J, Zhu J. Dried blood spots PCR assays to screen congenital cytomegalovirus infection: a meta-analysis. Virol J. 2015;12:60. Published 2015 Apr 14. doi:10.1186/s12985-015-0281-9.
3. Rawlinson WD, Boppana SB, Fowler KB, Kimberlin DW, Lazzarotto T, Alain S, Daly K, Doutré S, Gibson L, Giles ML, Greenlee J. Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. The Lancet Infectious Diseases. 2017 Jun 1;17(6):e177-88.
4. Luck, S. E., Wieringa, J. W., Blázquez-Gamero, D., Henneke, P., Schuster, K., Butler, K., Capretti, M. G., Cilleruelo, M. J., Curtis, N., Garofoli, F., Heath, P., Iosifidis, E., Klein, N., Lombardi, G., Lyall, H., Nieminen, T., Pajkrt, D., Papaevangelou, V., Posfay-Barbe, K., Puhakka, L., … ESPID Congenital CMV Group Meeting, Leipzig 2015 (2017). Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management. The Pediatric Infectious Disease Journal, 36(12), 1205–1213.
5. Pasternak Y, Ziv L, Attias J, Amir J, Bilavsky E. Valganciclovir is beneficial in children with congenital cytomegalovirus and isolated hearing loss. The Journal of Pediatrics. 2018 Aug 1;199:166-70.
6. Ross, S., Long, S. S., & Kimberlin, D. W. (2018). Closer to Universal Newborn Screening for Congenital Cytomegalovirus Infection but Far Away from Antiviral Therapy in All Infected Infants. The Journal of Pediatrics, 199, 7–9.
7. Kurath S, Halwachs‐Baumann G, Müller W, Resch B. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clinical Microbiology and Infection. 2010 Aug 1;16(8):1172-8.
8. Lanzieri TM, Dollard SC, Josephson CD, Schmid DS, Bialek SR. Breast milk–acquired cytomegalovirus infection and disease in VLBW and premature infants. Pediatrics. 2013 Jun 1;131(6):e1937-45.
9. Australian Society for Infectious Diseases: Management of Perinatal Infections 2014.
10. Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR. Valganciclovir for symptomatic congenital cytomegalovirus disease. New England Journal of Medicine. 2015 Mar 5;372(10):933-43.
11. Boppana SB, Ross SA, Fowler KB. Congenital cytomegalovirus infection: clinical outcome. Clinical Infectious Diseases. 2013 Dec 15;57(suppl 4):S178-81.

Approved by:	Medication Safety Committee	Date:	July 2023
Endorsed by:	Drugs and Therapeutics Committee	Date:	July 2023
		Review date:	July 2026

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