Fruit of the Womb
Fruit of the Womb

Cytomegalovirus (CMV): Primary or Recurrent Infection?

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Perhaps the hardest part of making the diagnosis of CMV infection during pregnancy in mother and baby is simply suspecting that it might be a problem. Certainly, if the woman develops a prolonged (weeks) febrile illness, resembling infectious mononcleosis, and that diagnosis cannot be confirmed by routine testing, then CMV should be high on the differential diagnosis. The ante goes up considerably if the mother is a young teen having her first baby (especially if she conceived shortly after becoming sexually active or changing partners), or if she works, or has another young child, in a high risk setting such as a daycare center.

CMV grows very slowly and the incubation period from the time of exposure to onset of symptoms, or asymptomatic excretion of the virus, is on the order of 4-12 weeks. Serologic testing, which we will discuss in a minute, can often help to confirm a primary infection when it is obtained coincident with maternal symptoms. Virus detection by culture, immunofluorescent techniques, or polymerase chain reaction (PCR), best done by sampling maternal urine, may be positive (and almost always will be for months after a primary infection), but this alone does not tell us if this is a primary symptomatic CMV infection or a recurrent infection accompanying another illness.

Unfortunately, since such a high percentage of primary maternal infections are asymptomatic, or simply confused with another illness, or even written off as normal symptoms of pregnancy, usually the diagnosis is not suspected until the baby is found to be growth restricted or has subtle physical abnormalities, or a thickened placenta, to suggest it has either a chromosomal abnormality or a congenital infection, sometimes months after the maternal exposure. Under these circumstances, maternal serologic testing might not be helpful in establishing either the fetal diagnosis or the diagnosis of a primary maternal infection during pregnancy.

Establishing the presence of fetal infection requires an 'invasive' procedure. Performing a simple amniocentesis, and using any of the techniques noted above for virus detection, can confirm fetal infection with CMV in nearly 100% of cases. (Remember, the amniotic fluid from midtrimester on is mostly fetal urine, and CMV is excreted in large amounts from the kidneys following congenital infection, and often for years afterwards, even in 'asymptomatic' cases). However, unless we have confirmatory maternal serologic information, or symptomatic infection confirmed to be the result of CMV during the pregnancy, we still may not know if the congenital infection is the result of primary or recurrent maternal disease. If the diagnosis of CMV is not suspected until late in pregnancy, or not until after the birth of the baby, detection of CMV in a urine sample taken from the baby within the first two weeks' of life also suffices to confirm congenital infection. CMV is a VERY slow growing virus, so any detection of virus in this time frame most certainly represents intrauterine infection.

Now let's discuss serologic testing because this is where things become even more confusing with CMV. Usually, when we contract a virus infection like the flu, our immune systems react by first producing specific antibodies to the virus of the IgM class. These usually hang around only for no more than 2-4 weeks after the infection has been cleared. Shortly after IgM antibodies begin to be made, our bodies switch to the production of a second class of specific antibodies called IgG. IgG antibodies generally hang around for a long time after the infection is cleared and provide us with a source of 'permanent immunity' to the organism, helping to prevent reinfection, or decrease the severity of a secondary infection, with the same or similar organisms with which the antibodies might 'cross-react.'It is these IgG antibodies that also afford protective immunity to the baby because they can cross the placenta whereas IgM antibodies cannot.

We can use this information to help us to characterize the status of an infection. If neither IgM nor IgG is present, the individual has probably never been exposed to the organism of concern (or is too early in the course of the infection to have mounted any antibody response). If IgM is present and there is no IgG, then the infection is probably a 'primary' infection, indicating first time exposure to the organism, usually very early in its course. If both IgM and IgG are present, this also usually reflects a primary infection, but later in the course of the disease. And, if only IgG is present, then this indicates a state of permanent immunity established from an infection that occurred at some time in the past. In any of the first three circumstances, if an infection with a specific organism is suspected and could be of concern for a pregnancy, it is probably worth repeating the antibody titers in 4-6 weeks. In the case of CMV, IgG antibodies usually can be detected by 1-2 weeks after the onset of symptomatic infections, but because of the long incubation period of CMV, this might be a month or more after actual exposure to the virus. Rising and falling antibody titers can also help to characterize the status of an infection.

With CMV infections, things are a little trickier. The presence of IgM in the absence of IgG and in the presence of symptomatic disease (or a history of recent exposure to a known carrier) is highly presumptive of a true 'primary infection.' Similarly, the findings of both IgM and IgG with a significant rise (four-fold or more) in IgG titers (with or without a fall in IgM titers) on a follow-up screen 4-6 weeks later, usually (but not always in the case of CMV) indicates a recent primary infection. Also useful, the presence of IgG in the absence of IgM, is highly suggestive of a remote exposure to the virus, often greater than 6 months previously.

The rub with serology in classifying CMV infections comes in most often when IgM is present but IgG titers are relatively stable or mildly fluctuating. Unlike most common viral infections, CMV-specific IgM can sometimes persist 6-9 months following its appearance. And to make things even more confusing, IgM has been found to reappear on occasion with reactivation of latent CMV infections. In otherwords, except in the circumstances detailed above, we may not be able to use the presence of IgM in our counseling to tell patients that they have had a primary or recurrent infection during the pregnancy or if the infection might have occurred even prior to the current pregnancy.

Ascertaining the status of a maternal infection as primary or recurrent, when we can do it, helps in counseling the patient. Babies contracting CMV as the result of recurrent infections are much less likely to suffer the severe sequelae associated with congenital CMV. Congenital CMV infections associated with primary maternal infections early in pregnancy and accompanied by growth restriction and detectable abnormalities by fetal ultrasound, generally, have a very poor prognosis, but even then, the outcome is not entirely predictable....
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