Cytomegalovirus in Pregnancy and the Newborn — Questions

A complete answer contrasts vaccine availability, the window of risk and the maternal infections that transmit, then draws the preventive implication.

Congenital rubella. Rubella is vaccine-preventable and near-eliminated wherever coverage is high. Fetal damage follows maternal primary infection in the first trimester, so prevention is achieved by immunising women before pregnancy.

Congenital CMV. CMV has no licensed vaccine, transmits throughout gestation, and follows both primary and non-primary maternal infection. Where rubella is controlled, CMV is now the commonest congenital viral infection.

Implication. Without a vaccine, CMV prevention rests on hygiene counselling of seronegative pregnant women rather than on the pre-pregnancy immunisation that controls rubella.

Treatment is decided by phenotype. Any central nervous system involvement, defined broadly to include abnormal neuroimaging, microcephaly, chorioretinitis or hearing loss, is treated for six months; symptomatic disease without central nervous system involvement is treated for six weeks. The drug of choice is oral valganciclovir at 16 mg/kg per dose twice daily, started before four weeks of age. A randomised trial established that six months preserves hearing and neurodevelopment better than six weeks. Asymptomatic infants with normal hearing are not treated.

Saliva is easy to collect but prone to a false positive from cytomegalovirus in breast milk retained in the mouth, so a positive saliva result is confirmed on urine, which is the specimen of choice, and saliva is collected at least one to two hours after a feed. Virus must be detected within the first three weeks of life to prove congenital infection, because after three weeks acquisition through the birth canal or breast milk can no longer be excluded.

Oral valaciclovir, 8 g a day, started before 16 weeks for a first-trimester or periconceptional primary infection, reduces transmission to the fetus (odds ratio ~0.37) and shifts the balance towards milder, asymptomatic infection. It is continued until a negative amniotic-fluid result. Cytomegalovirus hyperimmune globulin, by contrast, does not work: two randomised trials found no benefit and it has been abandoned. Ganciclovir and valganciclovir are neonatal, not maternal, treatments.

Transmission to the fetus rises steadily through gestation, from ~9% for a periconceptional infection to ~40% in the third trimester, while the severity of damage moves the opposite way: severe neurological injury follows almost only first-trimester infection, and after the first trimester the risk falls sharply and is largely limited to hearing loss. A virus acquired late is therefore more likely to reach the fetus but far less likely to harm it seriously.

Detecting the virus by polymerase chain reaction (PCR) on urine or saliva within the first 21 days of life confirms congenital infection. After 21 days a positive result cannot be separated from the common, benign infection acquired around birth, so the timing of the sample is what makes the diagnosis. A retrospective dried blood spot, the stored newborn screening card, is the fallback when a child presents late.

Neonatal IgG reflects transplacental maternal antibody; maternal IgM does not confirm fetal infection; cord blood is prone to maternal contamination; and culture is slower and less sensitive than PCR.

A primary infection in a seronegative woman carries the highest per-event risk of transmission, but pre-existing immunity does not fully protect, because a seropositive woman can transmit through reactivation or reinfection with a new strain. Because the seroimmune population is so large, about two-thirds of congenital cytomegalovirus arises in already-immune mothers, each pregnancy carrying a low individual risk. Once the fetus is infected, primary versus non-primary infection no longer predicts severity.

In a Gauteng cohort, congenital cytomegalovirus was commoner in HIV-exposed than HIV-unexposed neonates (~5.2% against ~1.4%), and a congenitally infected HIV-exposed neonate carried roughly a twentyfold higher risk of acquiring HIV in utero, independent of maternal CD4 count or treatment duration. A positive cytomegalovirus result in this setting therefore flags a pregnancy at high risk of vertical HIV transmission, rather than confirming infant HIV in itself.

Sensorineural hearing loss is the commonest long-term consequence of congenital CMV and the leading non-genetic cause of childhood hearing loss. It may be present at birth or have delayed, progressive onset over the first few years, so infected infants need audiological follow-up even when they appear normal at birth and even when the infection was asymptomatic.

Cataract and patent ductus arteriosus point to congenital rubella; limb reduction defects suggest varicella; cleft palate is not a CMV sequela.

Amniotic-fluid polymerase chain reaction works because the infected fetus excretes virus in its urine into the amniotic fluid, so two intervals must both be met: at least 6 to 8 weeks after the maternal infection, and from about 17 weeks of gestation, by which time placental transfer and fetal renal excretion have occurred. Under those conditions sensitivity is 90 to 95%; the residual false-negative rate of ~8% falls mainly on fetuses without injury.

A complete answer contrasts the two on transmission rate, on severity once the fetus is infected, and on their relative contribution to the overall burden.

Primary maternal infection. A first infection in pregnancy carries the highest vertical transmission, around 30 to 40% across the trimesters, because the mother has no pre-existing immunity to limit viraemia.

Non-primary infection. Reactivation or reinfection in an already-immune woman transmits far less often, of the order of 1%, because pre-existing maternal immunity is substantially protective.

Severity and the absolute burden. Once the fetus is infected, the type of maternal infection no longer reliably predicts the outcome: symptomatic disease at birth and long-term sequelae are broadly similar either way, and about 10 to 15% of infected infants are symptomatic at birth. Because seropositive women so greatly outnumber those having a first infection, most congenitally infected infants are born to immune mothers despite the low per-pregnancy risk, so non-primary infection contributes a large share of the absolute caseload where seroprevalence is high.

A complete answer explains what avidity measures, how it changes after primary infection, and how that dates the infection.

What avidity measures. Avidity is the strength with which IgG binds its antigen. Antibody from a recent primary infection binds weakly (low avidity) and matures to high avidity over about the following six months as germinal-centre affinity maturation proceeds.

How it dates the infection. Low-avidity CMV IgG in early pregnancy indicates a primary infection within roughly the preceding three to four months, the window of highest risk for fetal transmission. High-avidity IgG indicates a past infection and a much lower risk to the fetus.

Why it matters. Avidity resolves the ambiguity of a positive CMV IgM, which can persist for months or be falsely positive, and so helps avoid unnecessary intervention when the infection is in fact long-standing.