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CMV - An infection in pregnancy that can be devastating

6/9/2019

 
At the weekly Neonatal Unit Multidisciplinary Team Meeting the Microbiologist was asked about a baby with Cytomegalovirus infection. The baby had been born at term but was very small, below the 3rd centile. Other than the size of the baby there were no other concerns during the pregnancy. The baby had looked otherwise well and was behaving normally. A number of tests had been done to look for a reason why the baby might be small and a urine sample had tested positive for Cytomegalovirus DNA by PCR.
 
The Neonatologists wanted to know what they should do next and the MDT members looked at the Microbiologist expectantly, who started to feel somewhat uncomfortable under all those stares…
​What is Cytomegalovirus?
Cytomegalovirus (CMV) is a Human Herpes Virus (HHV); in fact it is HHV5 or the fifth HHV discovered. It is a double-stranded DNA virus. Like the other HHV (Herpes Simplex Virus 1 & 2 (cold sores and genital herpes), Varicella Zoster Virus, Epstein-Barr Virus, HHV6, HHV7 and Kaposi Sarcoma Virus) CMV causes a latent infection with virus persisting in body tissues from where it can reactivate if the patient’s immune system becomes compromised.
 
CMV is often described as a “kissing contacts” infection in that close personal contact is usually required to spread the infection, usually via droplets from the upper respiratory tract… hence the risk of catching CMV when kissing someone with CMV! In the UK it is estimated that 60-80% of the population has been infected with CMV by the age of 18 years.
 
Congenital infection is one that occurs due to exposure to the infecting microorganism in utero i.e. before birth. In order for the foetus to become infected the virus has to cross the placenta and the risk of this occurring differs at different stages of pregnancy. With primary maternal infection (not reactivation of latent infection) the rates of transfer are:
  • First trimester – 37%
  • Second trimester – 40%
  • Third trimester – 65%
 
If you already have CMV you will not necessarily reactivate it in pregnancy and it is not known how many reactivations actually occur in pregnancy. The risk of infection following reactivation is very low, around 0.15-2%, as maternal antibody provides protection to the baby as well as the mother. However acquiring CMV (primary CMV) in pregnancy carries the highest risk of congenital CMV; but remember most women have already had CMV before they become pregnant and so the overall risk to the foetus is low.
 
How does congenital CMV present?
It is estimated that the rate of congenital CMV is around 0.6% live births in developed countries, but most of these infections are not diagnosed because 90% of the babies are asymptomatic at birth. The symptoms and signs of possible CMV that might be present at birth include:
  • Petechiae (bruising)*
  • Early jaundice <2 days (all babies become jaundiced to some degree but from day 2 to day 7 as they breakdown foetal haemoglobin and produce adult haemoglobin)
  • Hepatosplenomegaly*
  • Intra-uterine growth retardation (IUGR)  
  • Thrombocytopenia (low platelet count)*
  • Microcephaly (small head)*
  • Intracranial calcifications (calcified brain tissue seen on ultrasound)
  • Polymicrogyria and ventriculomegaly (brain abnormalities)*
  • Sensorineural hearing loss (unilateral or bilateral)
  • Chorioretinitis (inflammation in the eye)
  • Seizures*
* Indicators of possible life-threatening infection
Congenital CMV
Click for larger image
Sensorineural hearing loss (hearing loss due to damage to the ear structure for detecting sound and the nerves that then communicate with the brain) is the most common feature of congenital CMV infection, occurring in up to 50% of symptomatic infants. The virus replicates in the organ of Corti in the ear causing progressive damage and worsening hearing loss. It is thought that in utero infection leads to “tolerance” whereby the newborn baby’s immune system fails to recognise the CMV DNA as foreign and therefore the body does not launch an immune response. The virus just continues to replicate and damage progresses.

The overall mortality rate is 5% in symptomatic newborns, although 50-60% of the survivors have long term neurological problems such as hearing loss, cerebral palsy, intellectual disability, vision impairment, and seizures.
​

Of the asymptomatic babies 15-25% develop neurological problems, in particular hearing loss, by the age of 3 years.
Congenital CMV
Click for larger image
​How is congenital CMV diagnosed?
If a mother is diagnosed with CMV in pregnancy it is normal practice to offer amniocentesis to see if the foetus has also been infected. If CMV DNA is detected by PCR in amniotic fluid then the foetus has been infected because the only way for CMV to get into the amniotic fluid is for the foetus to pee it out into the amniotic sack. Amniocentesis to look for CMV can only be relied upon 6-8 weeks after maternal infection as it takes this long for virus to get into the amniotic fluid. Whilst this can occur before 21 weeks gestation a negative test at this time does not exclude infection and it is therefore often better to wait until 21 weeks to do the test or repeat a negative test at 21 weeks.
 
With primary infection the risk of amniocentesis is much lower that the risk of having a child with congenital CMV. If CMV is reactivated in pregnancy then it is important to remember that the complication rate, including the risk of spontaneous foetal loss, due to amniocentesis is 0.1%, so not much lower than the risk of congenital CMV from reactivation itself and this can make decision making difficult.
 
Once the baby has been born congenital CMV is usually diagnosed by testing a urine sample for CMV DNA by PCR. If the baby is <3 weeks old then any CMV in urine confirms the diagnosis. From 3 weeks to 1 year CMV in urine is still likely to be congenital but post-natal infection cannot be ruled out, and after 1 year it is impossible to say. If a baby presents after 3 weeks it is usual practice to get parental consent to retrieve the newborn screening Guthrie card from storage (dried blood spot taken shortly after birth to screen for diseases such as cystic fibrosis, hypothyroidism, phenylketonuria, etc.) and test this for CMV DNA by PCR. A negative Guthrie card doesn’t rule out the diagnosis as the baby may not be viraemic (virus in blood) but a positive test is diagnostic for congenital CMV.
 
How is congenital CMV treated?
The treatment of congenital Cytomegalovirus infection is controversial and as of yet there is no clear evidence of the best way to manage these babies. The difficulty is finding a balance between preventing harm by treating the virus and causing harm with the treatment in asymptomatic babies even when they have a positive result.
Risk
of not treating
  • 15-25% develop neurological abnormalities​
Risk of treating
  • Bone marrow toxicity - neutropaenia (25-60% with IV Ganciclovir, 20% with Valganciclovir), thrombocytopaenia in 6% - usually returns to normal on stopping treatment but may recur with restarting treatment
  • Liver failure (% unknown)
  • Renal failure <1%
  • 6 weeks in hospital on IV Ganciclovir
  • IV device related complications e.g. infection, scarring
  • Possible viral resistance to treatment
Perhaps the table above shows why at present the school of thought is that the risk of damage from the treatment is thought to be too high compared to no treatment for asymptomatic babies.

The current best practice is to only treat babies who are symptomatic whilst accepting that some babies may already have unknown/unseen permanent damage caused by the virus whilst the baby was in utero. The evidence shows that IV Ganciclovir or oral Valganciclovir given to symptomatic babies can prevent further neurological damage and may even aid recovery of function in others. At present no treatment is offered to asymptomatic babies or to treat in utero infection.
​

Treatment should be started as soon as the diagnosis is made in a symptomatic baby; treatment works best if started within the first 30 days of life.
Life-threatening infection*
IV Ganciclovir for 6 weeks
THEN
PO Valganciclovir for up to 6 months
Non-life-threatening infection
PO Valganciclovir for 6 months
​Long-term follow up of children with congenital CMV
All babies with congenital CMV, irrespective of whether they are symptomatic or not, should be followed up by an experienced Paediatrician. Hearing tests should be performed every 6 months until 3 years of age and then annually until 18 years of age. Eye assessments should be performed yearly or more frequently if abnormalities are detected. Regular dental check-ups are required to detect abnormal tooth development and developmental and neurological function should be monitored frequently.
 
So a decision was made to not start treatment and to follow-up our asymptomatic baby. Hearing and eye assessments were arranged and the plan was to see the baby in clinic a couple of weeks after discharge to make sure the baby remained well.
 
Many in the NNU MDT looked a little stunned having not expected the possibility of such a devastating diagnosis; we hope our baby continues to be one of the normal asymptomatic positive test babies…

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    Blog Author:

    David Garner
    Consultant Microbiologist
    Surrey, UK

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