Congenital – Neonates
Commonest congenital infection in developed world – 0.3% of births. Assoc
with STIs, breast feeding and childcare. About 40% of pregnant women
seronegative. Primary maternal CMV transmits in 40%, of which 10% symptomatic.
Symptomatic babies have 30% mortality, and 90% morbidity. Even asymptomatic
babies have 5-15% long term sequlae esp deafness. Virus is found in all body
fluids so spread by close contact. Survives in fomites for several hours, but no
apparent increase in risk in health care environments cf nurseries. Transmission
usually occurs during primary infection, but possible in maternal reactivation
(but disease is less aggressive) – an important issue if a vaccine is ever
considered. Gestation at time of infection not very important (cf toxo, rubella,
CMV positive mothers nearly all secrete CMV DNA in breast milk, even if other
body fluids are negative! Main cause of postnatally acquired CMV – usually
asymptomatic in term babies but can be severe in preterms. See Prevention,
Causes anaemia, thrombocytopaenia, petechiae, hepatosplenomegaly, pneumonitis. Can cause a sepsis-like syndrome. Also chorioretinitis, enteritis (even NEC type picture), conjugated jaundice, and/or aseptic meningitis. Later, abnormal teeth, deafness (about 12% of all cases, can be progressive but sometimes improves, major economic impact), cerebral palsy. CNS involvement can lead to abnormal tone and (rarely) seizures. Whether postnatal infection can also cause late effects is uncertain.(Pediatr 2003;143:16-25, PMID 12915819 )
CT to look for intracranial calcifications (more sensitive than USS),
opthalmology. Urine/blood PCR, culture of urine and surface swabs. IgG will
usually be maternal, as usual; IgM is only 70% sensitive and sometimes gives
false positives (in adults, can persist or reappear during reactivation). The
presence of low/moderate avidity anti-CMV antibody indicates primary infection,
and persists for about 20 weeks.
USS is vaguely prognostic: (n=57) at least 1 sequela developed in all
neonates with symptoms who had abnormal US results, whereas none of the neonates
with symptoms who had normal US results had long-term sequelae. Unusual to get
asymptomatic babies with abnormal scans. In the population without symptoms,
sensorineural hearing loss developed in 3 of 37 (8.1%) neonates with normal US
results, so NPV isn’t great. (J Pediatrics Volume 150, Issue
2 , February 2007, Pages 157-161)
Guthrie PCR testing has been looked at, but sensitivity only about 70% cf
Ganciclovir gives mixed results, many studies have been uncontrolled and
small. Not curative: appears that viruria always returns. Drug is carcinogenic,
mutagenic, causes infertility, needs central line, 6/52 course, causes
neutropenia in 63% so line infection is a big problem. For sepsis-like syndrome,
treatment with Ganciclovir is worthwhile until oral valganciclovir can be
tolerated. For less severe infections, the risk:benefit balance of treatment is
less clear. Kimberlin RCT (n=100) chose patients with:
- intracranial calcification
- or abnormal CSF
Patients received 12mg/kg/d of Ganciclovir for 6 weeks. At 1 year, just 26%
of untreated controls had normal hearing in their best ear. 50% of the
ganciclovir group had improved hearing or maintained normal hearing cf 26% of
controls (not significant). 21% of the ganciclovir group had deterioration cf
68% of controls (p=0.002). Interim results at 6 months were similar. These
figures are for hearing in the best ear.
In conclusion, in a fairly small study, ganciclovir appears to help prevent
hearing deterioration for at least a year, and may also help recovery of hearing
impairment. The number needed to treat (NNT) is 1.91 to prevent 1 case of
hearing deterioration at 6/12, and 3.66 at 1 year. There are, however, some
problems with Kimberlin’s trial.
- The intervention requires a central line, and ganciclovir causes
neutropenia. Grade 3 or 4 neutropenia was seen in 64% of treated patients,
although this led to discontinuation of treatment in only 4 out of the 29
patients on ganciclovir.
- 3 patients had catheter infections.
- There were 3 deaths in the ganciclovir group and 6 in the control group.
None of the deaths was considered to be related to therapy.
- It should also be noted that there was an extremely high drop out rate (58%)
due to a combination of factors including difficulties with transport, and
access to BSER testing. This drop out rate could potentially lead to
- There was little evidence of other benefit to treatment. There was no
difference in resolution of hepatosplenomegaly or retinitis. There was better
weight gain and head growth at 6 weeks but this was not sustained at 1 year. A
subsequent conference abstract looked at developmental delay using the Denver
developmental evaluation and found significantly less delay at 12 months but
neither this study nor any other longer term neurological outcome data appear to
have been published, perhaps surprisingly.(Oliver et
al, Pediatric Academic Societies 2006)
Valganciclovir is a prodrug of ganciclovir. It is an oral preparation.
Pharmacokinetic studies have found that a dose of 16mg/kg produces a similar
AUC12 (area under the concentration-time curve over a 12 hour period) to that
obtained with ganciclovir. Neutropenia was still seen but was less common,
perhaps because of the dosing strategy and drug level monitoring.
It is an attractive alternative to ganciclovir but there is currently no
evidence to show any long term benefit. A current UK placebo controlled study
aims to compare 6 weeks and 6 months of valganciclovir (16mg/kg). A randomized
comparison with ganciclovir has not been attempted, perhaps due to fears of a
high drop out rate.
How to counsel parents
Given the limited evidence and the complex nature of the interventions, a
full discussion should be had with the parents and a treatment plan drawn up
with their explicit consent.
Issues to consider are:
- How severe is the infection? Microcephaly, petechiae, IUGR, cranial USS
abnormalities are all indicators of a poor outcome. Viral load predicts
asymptomatic babies at high risk of deafness.(Arch Dis Child
2008 PMID 18039747) This may increase the perceived need for
intervention, or alternatively make intervention seem more hopeless.
- How do the parents feel about the potential for deafness or other
disability? Deafness is not inevitable, and may not be the most significant
issue for that child. Different individuals have differing attitudes about the
seriousness of potential disabilities.
- Can parents accept an experimental treatment? Neither ganciclovir or
valganciclovir are used routinely, and the evidence in their favour is limited.
At the same time there is no long term safety data.
- If treatment is considered, does the lack of evidence for valganciclovir
compensate for its ease of use and better side effect profile? An initial course
of ganciclovir followed by valganciclovir is another option, particularly if
access or side effects are problematic.
Postnatal infection is known to occur, ie initial screening of the baby is
negative, but blood PCR turns positive after 10 days, or urine after 3 weeks of
age. Breast feeding is the most likely mechanism, given that blood products for
transfusions are generally CMV negative or leucodepleted. CMV can be found in
the breast milk of most seropositive mothers, even though it does not appear in
maternal urine/blood, so it appears to be local reactivation in the breast!
There also appear to be factors in the milk that inhibit CMV (hence virolactia
is not the same as DNAlactia!).
The rate of postnatal infection varies widely between studies (6-55%), as
does the rate of symptomatic infection (0-75%). (Hamprecht K,
J Clin Virol 2008;41:198�205.) The mean age at seroconversion is 77 days;
appears to be related to maternal IgG level, and whether virus can actually be
cultured from milk or not.(PIDJ 2004 PMID 15361725) In
term babies postnatal infection is rarely symptomatic, but in preterm babies a
spectrum of disease is seen, with some developing a sepsis syndrome, others just
transient neutropenia, thrombocytopenia, and cholestasis. The severity appears
to relate to gestation and birth weight (inversely related, with the highest
risk in birthweights below 1000g and gestation below 30 weeks).(Maschmann J, Clin Infect Dis 2001;33:1998�2003). Evidence to
date does not support any long term sequelae of postnatal infection, in term or
preterm babies. Luck S, Arch Dis Child 2009;94:F58-F64 PMID
18838466 Freeze-thawing and pasteurization are quite effective at
eliminating CMV from breast milk (Holder pasteurization, ie for 30 min at
62.5�C, is probably more effective) and the UK association for milk banking
(UKAMB) recommends a sequence of alternate freezing and pasteurization – but
immunological qualities of breast milk are affected, and cases of severe
infection have still been described.(Hamprecht K, J Clin
Whether the breastmilk of all seropositive mothers should be treated before
being given to preterm babies is unclear. Austria and France currently support
pasteurization. If risk factors for symptomatic infection could be identified,
then a selective policy might be the best way forward.
Prevention in utero has been tried. IVIG should theoretically work if
sufficient seropositives in donating population but a RCT of its use
preventively did not show significant benefit. CMV hyperimmune globulin has been
given to Italian women with CMV in amnio, only 1 of 31 had an infant with
symptomatic CMV at birth, as compared with 7 of 14 women who did not receive
hyperimmune globulin (50 percent). Appears to be safe, and also to prevent
disease in women with primary infection. Not strictly an RCT, and surprisingly
high rate of CMV disease in primary infection. N Engl J Med.
2005 Sep 29;353(13):1350-62
See Euro Cong CMV initiative, who have a
register of cases and are looking at whether viral load will help predict which
babies do badly.