Congenital CMV Guidelines

Management of Congenital CMV

Introduction

The purpose of this guideline is to provide guidance for obstetricians, midwives, neonatal staff and paediatricians on the diagnosis and management of infants with congenital cytomegalovirus (CMV) infection.

This guideline is based on the European Expert Consensus Statement on Diagnosis and Management of Congenital CMV (PIDJ 2017), the Royal College of Obstetricians Scientific Impact Paper (2018) and the published literature.

Scope & Purpose

This guideline is relevant to pregnant women and infants being cared for within Wessex, for whom a diagnosis of active CMV is suspected or confirmed in pregnancy or congenital CMV infection is suspected or confirmed in the infant.

Aims

This guideline aims to describe the process for timely diagnosis and appropriate management of pregnant women with active CMV infection and the diagnosis and management of infants suspected or confirmed to have congenital CMV infection.

Implementation

Guideline to inform investigation and management of congenital CMV across Wessex. Guideline to be reviewed by Infectious Diseases Team every 3 years.

Abbreviations

cCMV = congenital cytomegalovirus
CNS = central nervous system
FBC = full blood count
Ig = immunoglobulin
IUGR = intrauterine growth retardation
LFTs = liver function tests
MRI= magnetic resonance imaging
PCR = polymerase chain reaction
PID= Paediatric Infectious Diseases team
SNHL = sensorineural hearing loss
U&Es = urea and electrolytes
USS = ultrasound

Flowchart 1: Diagnosis of Congenital CMV in the Antenatal Period

Flow Chart 1: Notes

a) The most common ultrasound features of CMV include:

Brain abnormalities: ventriculomegaly, microcephaly, white matter abnormalities, brain cysts, calcification.
Extra-brain abnormalities: echogenic bowel, IUGR, oligo/anhydramnios, polyhydramnios, ascites, placentomegaly

b) CMV serology can be complex to interpret. Discuss with virologist on case by case basis. CMV serology is most useful in the diagnosis of primary infection. Primary infection is diagnosed in the following circumstances:

The appearance of CMV IgG in a woman who was previously seronegative,
The detection of CMV IgM antibody with low IgG avidity.

In mothers with ultrasound features suggestive of fetal CMV infection whose current serology is IgM negative but IgG positive, testing should be repeated in the booking samples to ensure that there was not an early pregnancy infection where IgM has now disappeared. CMV serology is less helpful in secondary CMV infection (re-infection or re-activation). A rise in IgG levels does not conﬁrm secondary infection as this may be due to nonspeciﬁc polyclonal stimulation of the immune system. CMV PCR and IgG avidity may provide additional useful information. In practice, the best way of assessing the outcome of a possible maternal secondary CMV infection (whether reinfection or reactivation) is by invasive testing (amniocentesis for CMV PCR and, less commonly, fetal blood collection for CMV IgM, IgG and PCR).

c) The risk of acquisition of CMV may be reduced by taking simple hygiene precautions. These include:

Avoiding sharing any food, drink, cutlery or dummies that have been in the mouth of young children,
Kissing children on the forehead and not on the mouth,
Washing hands after contact with urine or salvia of young children.

Information can be found on the NHS choices website (https://www.nhs.uk/conditions/cytomegalovirus-cmv/) or CMV Action website (cmvaction.org.uk)

d) A positive CMV IgM result may be found for several reasons, including acute CMV infection and therefore may not be diagnostic of recent CMV infection for several reasons:

IgM can persist for months after the primary CMV infection (so may represent infection prior to pregnancy)
There may be cross-reactivity with IgM due to another viral infection, e.g. Epstein–Barr virus
IgM may be detected as a result of nonspeciﬁc polyclonal stimulation of the immune system

e) Avidity indicates the strength with which IgG binds to antigen. Avidity is low in the first weeks following acute infection and increases after 12 weeks post infection. A high avidity index would therefore indicate that CMV infection was acquired more than 3 months previously. The avidity index is highest where infection has occurred a significant period of time beforehand.

f) Fetal urination is reliably established by 20 weeks gestation. Aminocentesis prior to this point, may have a positive CMV PCR prior to this, however a negative CMV PCR does not reliably rule out fetal infection before 20 weeks (newer studies suggest fetal urination may be established by 16 weeks). Amniocentesis should be done > 6 weeks post maternal CMV infection.

g) There are no treatment options which are recommended for use in pregnancy, however, valaciclovir 8g/day may be considered on a case by case basis, if parents opt to continue pregnancy and fully understand the potential risks and benefits.

Flowchart 2: Diagnosis & Management of Congenital CMV after Birth

a) Urine for CMV PCR does not need to be sterile. Cotton wool in nappy or bag urine is acceptable.

b) Saliva should be collected a minimum of 1 hour post a breast feed to avoid false positive results. The swab (green topped swab) should be placed next to the buccal mucosa and left for 1 minute to ensure that the swab is soaked with saliva. A positive CMV PCR result from a salivary swab should be checked on a urine sample.

c) The sensitivity of CMV PCR from the Guthrie card varies between laboratories but is usually 80-95%. Therefore, a negative result cannot fully rule out congenital acquisition of CMV.

d) Minor abnormalities include: clinically insignificant or transient findings, such as petechiae, mild hepatomegaly or splenomegaly or biochemical/hematologic abnormalities (such as thrombocytopenia, anaemia, leucopenia, borderline raised liver enzyme abnormalities or conjugated hyperbilirubinemia) or Small for Gestational Age (SGA, defined as weight for gestational age <2 standard deviations) without microcephaly.

Flowchart 3: Follow up of Infants with Congenital CMV Infection

Background

Congenital CMV is the most common congenital infection worldwide, affecting an estimated 3 to 6 in every 1000 infants born in high income countries. In a hospital with 5,000 deliveries per year, we would expect 15-30 infants to be born each year who have congenital CMV infection. However, CMV is often not diagnosed in the neonatal period, meaning that infants do not have the opportunity to benefit from treatment or from hearing, visual or neurodevelopmental screening which might allow earlier intervention.

Only 10-15% of neonates with congenital CMV present with symptoms at birth such as: petechiae, hepatomegaly, splenomegaly, hepatitis and / or neurological signs such as microcephaly, chorioretinitis and intracranial calcification (equates to around 1 - 5 infants per year in units delivering 5,000 infants per year). Around half of these infants develop permanent sequelae (around 3 infants in hospitals above), but higher proportions of infants who present with neurological presentations at birth have long-term impairments.

Of the 90% of infants who do not have symptoms at birth, 14% will development impairments, most commonly sensorineural hearing loss (SNHL). This equates to a further 2 – 4 infants per year in units delivering 5,000 infants)

Diagnosis & Treatment of CMV Infection in the Antenatal Period

Flow chart 1 provides guidance regarding indications for testing and interpretation of CMV serology, results should be discussed with a virologist. Following identification of recent CMV infection, women should be referred to the Wessex Fetal medicine centre for further investigation and management.

Diagnosis & Management of CMV in the Postnatal Period

Clinical examination

Infants suspected of having cCMV, should have a full examination for symptoms and signs of cCMV. Clinically detectable features which may be found on physical examination are detailed in table 1, section A. Other abnormalities consistent with cCMV which may have identified incidentally or as a result of screening are detailed in table 1.

Table 1: Features of Congenital CMV (adapted from Luck 2017 PIDJ)

Diagnosis of Congenital CMV

When and who to test?

Routine screening of all neonates is not currently recommended. Targeted testing should be performed whenever there is suspicion of cCMV disease. Indications for testing include:

Antenatal ultrasound or MRI imaging consistent with cCMV disease (see flow chart 1)
Newborns whose mothers had suspected or confirmed acute CMV infection during pregnancy
Newborns with signs or symptoms consistent with cCMV disease (table 1)
Infants & children with confirmed sensorineural hearing loss

Congenital CMV infection should be confirmed at birth following testing on amniotic fluid for CMV PCR, since both false positive and negative results can occur.

Individual hospitals may choose to test all infants who have ‘no clear response’ on the newborn hearing screening test to expediate a diagnosis of cCMV, other units will only test once SNHL is confirmed by formal audiological testing. It is essential that CMV is included in the aetiological investigations for SNHL and optimal that this should occur with the first month of life to ensure that infants can benefit from treatment where indicated.

Individual neonatal units may choose to test all premature infants (<30 weeks gestational age within the first few days of life to distinguish between congenital and postnatal acquisition of CMV. Other units may choose to store samples and only test those for whom there is a clinical indication to do so). The majority of units do not test all extremely preterm infants.

What samples to test?

Samples should be tested as soon as cCMV is considered, it is essential that they are taken within the first 21 days of life for a diagnosis of cCMV to be made. Samples collected post 21 days could be due to postnatal acquisition of infection.
Newborn infants with congenital CMV shed high quantities of virus in the urine and saliva and the diagnostic sensitivity of these samples is higher than that of blood. PCR testing has replaced viral culture as the diagnostic method of choice.

Urine: A single sample of urine is sufficient to make the diagnosis of cCMV as it has an excellent sensitivity and specificity (100% and 99% respectively, de Vries, J Clin Virol,2012). The sample may be collected by any method and a sterile sample is not required (cotton wool and bag samples are acceptable).
Saliva: CMV PCR testing of saliva is an alternative, with equivalent specificity, however a positive test should be confirmed with a urine sample as false positives can occur due to contamination with breast milk containing CMV (viral load usually low in false positive samples). Saliva samples should be collected before a breast feed (minimum 1 hour post feed). A green-topped swab with viral transport medium should be used. The swab should be left next to the buccal mucosa for 1 minute to ensure it is soaked with saliva. Two samples should be sent to the virology laboratory.
Dried blood spots: PCR testing of dried blood spots can be done to make a retrospective diagnosis of cCMV in infants > 21 days of age. The sensitivity is variable and depends on the methodology employed, a meta-analysis shows sensitivity of 84% and specificity of 99% (Wang, 2015). A positive test therefore reliably confirms a diagnosis of cCMV, however a negative result does not exclude cCMV.

Screening for other features of cCMV

Following a diagnosis of congenital CMV, further tests should be performed to evaluate the extent to which an infant is affected by CMV.

Blood tests should be performed including a full blood count (FBC), to detect neutropenia and thrombocytopenia, and liver function test (LFTs), to detect abnormal liver enzymes. These blood tests also serve as a baseline before treatment, if indicated, is commenced - valganciclovir and ganciclovir can also cause neutropenia, thrombocytopenia and transaminitis. In addition, renal function should be performed to ensure normal function prior to commencing treatment. A baseline quantitative CMV PCR should be collected.

A cranial USS should be performed by an operator experienced in scanning. If cranial USS abnormalities are detected or there are clinical concerns, a cranial MRI should be performed. Under three months of age, a ‘feed and wrap’ MRI is likely to be possible, after this time a general anaesthetic will be required, therefore this should be performed as soon as possible where indicated.

A newborn hearing screen will be performed for all infants, however where a diagnosis of cCMV has been made, referral for formal auditory assessment and follow-up should be made irrespective of the results of the newborn hearing screening.

All infants diagnosed with cCMV should be referred for formal ophthalmic assessment.

A lumbar puncture is not routinely required in infants diagnosed with cCMV. It is not required for diagnosis or prognosis, however if it is performed as part of a sepsis assessment, it may demonstrate abnormal indices and CMV PCR may be positive.

Treatment

Treatment of congenital CMV is normally only started for moderate-severely affected infants. Treatment should be initiated after discussion with Paediatric Infectious Diseases team (see flow chart 2). Treatment is usually only commenced within the first month of life and to date there is no evidence to support treatment after this time. Infants and children over the age of 4 months to 4 years of age might be eligible for treatment as part of research studies, discuss with paediatric infectious diseases team (07824417993).

Oral valganciclovir should be started in enterally fed infants at 16mg/kg twice daily. The dose should be adjusted if side effects are experienced, discuss dose adjustment with PID team.

The most common side effects are: Neutropenia (1 in 5), anaemia (1 in 50), thrombocytopenia (1 in 100), transaminitis (rare), renal impairment (rare).

Unquantified risks:

Roche, the manufacturer of Valcyte have carried out a (unpublished) study which has shown that in adult, Valcyte can inhibit spermatogenesis. This was reversible, however they have stated that male infertility is an identified risk.
Animal studies have shown that there is a theoretical risk of gonadotoxicity and carcinogenicity.52,53 Although this has not been shown in humans (apart from the study above) to date, parents should be counselled about these potential risks, particularly when considering treatment in groups of infants in which benefit has not been clearly shown. No adverse long-term effects have been documented in a small cohort of babies treated in early neonatal studies and followed up to puberty (NCT00031421, unpublished data).

Monitoring on treatment

The following blood tests should be done prior to initiation of treatment at 2 and 4 weeks after starting treatment and then monthly for a total of 6 months (FBC, U&Es, LFTs).

Intravenous (IV) ganciclovir should be the initial treatment for infants who are not yet enterally fed. Once enterally fed, oral valganciclovir should be substituted. Side effects are more common with IV ganciclovir, so blood monitoring should occur weekly.

Urine CMV viral load and therapeutic drug monitoring not routinely required - as directed by Paediatic Infectious Disease (PID) team

Contact number of Paediatric Infectious Diseases Consultant: 07824417993

Follow Up

All infants diagnosed with congenital CMV should receive follow-up, irrespective of whether they have clinical symptoms or signs or whether they receive treatment.

All infants should be offered the opportunity to be seen in the congenital infection clinic by the Paediatric Infectious Diseases team following diagnosis. For some infants, it be more appropriate to be seen locally with PID advice.

Infants NOT treated: Paediatric ID clinic review following diagnosis (or General Paediatrics with PID input), minimum follow-up 2 years.

Infants treated: Paediatric ID clinic at diagnosis, then as required 6-12 monthly

Local follow-up monthly for 6 months, then annually. Minimum follow-up 2 years, those infants with more complex problems will need longer follow-up.

Development should be monitored by the general paediatrician, with formal neurodevelopmental assessment at 12 months of age. If clinical concerns are raised, a formal assessment should be done earlier. Where provision exists, neurodevelopmental assessment performed according to the standardised neurodevelopmental follow-up protocol for preterm infants and at risk newborns, with Neonatal Neurodevelopment protocol, with assessments at 3, 12, 24, 48 months corrected gestational age.

Audiology assessment should be performed every 3-6 months in the first year, then every 6 months until 3 years of age, then every 12 months until age 6 years.

A formal ophthalmological assessment should be made at diagnosis and then as indicated by Ophthalmology, ideally with annual follow-up until the age of 5 years (Jin, 2017, PIDJ).

Parents should be provided with details of CMV Action charity (cmvaction.org.uk) for information and support.

Infection Control

Children with congenital CMV will excrete the virus in their urine and saliva, often for prolonged periods of time. Many healthy young children first acquire CMV infection in the first 3 years of life and also excrete the virus. Therefore, children with congenital CMV should not be treated any differently in nursey or childcare settings than their peers. All those looking after young children should take basic hygiene precautions, these would also reduce their risk of acquiring CMV, for example, not sharing any food, drinks, cutlery after it has been in a child’s mouth, kissing on forehead and not on mouth, washing hands after contact with urine or saliva.

In the healthcare setting (paediatric, neonatal or renal units), healthcare professionals who may be pregnant are not at increased risk of catching CMV compared to the general population, because these measures would be taken routinely.

References

de Vries JJ, van der Eijk AA, Wolthers KC, Rusman LG, Pas SD, Molenkamp R et al. Real-time PCR versus viral culture on urine as a gold standard in the diagnosis of congenital cytomegalovirus infection. J Clin Virol2012; 53(2):167-170.

Jin, H. D., Demmler-Harrison, G. J., Coats, D. K., Paysse, E. A., Bhatt, A., Edmond, J. C., et al. (2017). Long-term Visual and Ocular Sequelae in Patients With Congenital Cytomegalovirus Infection. The Pediatric Infectious Disease Journal, 36(9), 877–882.

Khalil, A., Heath, P. T., Jones, C. E., Soe, A., & Ville, Y. (2018). Congenital Cytomegalovirus Infection: Update on Treatment: Scientific Impact Paper No. 56. BJOG, 125(1), e1–e11

Luck, S. E., Wieringa, J. W., Blázquez-Gamero, D., Henneke, P., Schuster, K., Butler, K., et al. (2017). Congenital Cytomegalovirus. The Pediatric Infectious Disease Journal, 36(12), 1205–1213

Shah, T., Luck, S., Sharland, M., Kadambari, S., Heath, P., & Lyall, H. (2016). Fifteen-minute consultation: diagnosis and management of congenital CMV. Archives of Disease in Childhood - Education & Practice Edition, 101(5), 232–235

Wang, L., Xu, X., Zhang, H., Qian, J., & Zhu, J. (2015). Dried blood spots PCR assays to screen congenital cytomegalovirus infection: a meta-analysis. Virology Journal, 12(1), 355–11

Document Version:
1.0

Lead Author:
Dr Chrissie Jones, Associate Professor & Paediatric ID consultant, UHS & UoS

Approving Network:
Wessex ID/Immunology Network

Date of Approval:
05/2024

Review Date:
05/2027

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