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Published: 23 October 2015

The obstetrician, congenital cytomegalovirus, clinical and diagnostic approaches to the pregnant woman

Antonia W Shand

Clinical and Population Perinatal Health Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065, Australia

Sydney Medical School Northern, University of Sydney, Australia

Department of Maternal Fetal Medicine, Royal Hospital for Women, Randwick, NSW 2031, Australia

Tel: +61 2 9382 6098
Fax: +61 2 9382 6038
Email: Antonia.shand@sydney.edu.au

There is low awareness of congenital cytomegalovirus (CMV) in Australia. Routine pregnancy serological screening for CMV is not recommended, but all pregnant women should be given advice about CMV prevention. Obstetricians may be asked to see a pregnant woman when serology suggests CMV infection or when features of fetal infection are present on ultrasound. If maternal CMV infection is confirmed, the timing of infection (pre-pregnancy or gestation of pregnancy), must be determined to predict the fetal risks. In addition, it is important to establish whether maternal infection is primary or reactivation. If there is fetal infection, ultrasound can be used to attempt to establish whether the fetus may have been affected. Serial serology, CMV IgG avidity, maternal viraemia (using serum PCR), amniotic fluid CMV PCR, serial fetal ultrasounds, and possibly fetal MRI (magnetic resonance imaging) are investigations that may be useful to predict neonatal outcomes. Timely and accurate counselling is important to optimise maternal and neonatal management.

Primary maternal CMV infection in the first trimester of pregnancy has the greatest risk of adverse fetal and infant outcomes1. These include hearing loss, adverse neurodevelopmental outcomes and in severe cases, fetal death2. In first trimester CMV infection, approximately 35% of fetuses will develop CMV infection3,4. Of these, only 25% will have an adverse outcome due to the infection4,5. Thus, it is estimated 10% of women with a primary CMV infection in early pregnancy will have a fetus or infant with an adverse outcome3. The rate of fetal infection increases with gestation, but the rate of fetal and infant adverse outcomes decreases with gestation6. The rates of adverse outcomes with peri-conception CMV are lower still than in the first trimester4. Furthermore, the risks of fetal infection and adverse outcomes are lower with CMV reactivation or re-infection, than with primary infection7.

Routine serologic CMV screening in pregnancy is not recommended in Australia8,9. The potential benefits of routine screening are outweighed by the harms10. Screening women at high risk of acquiring CMV infection, ideally pre-pregnancy, may be considered8. In addition, CMV serology testing may be indicated in women with signs or symptoms of infection. However, regardless of serological status, pregnant women should be given advice about how CMV is spread and how to reduce exposure to saliva and urine that might contain CMV: this includes advice about handwashing after contact with body fluids, and avoiding sharing food and eating utensils11.

Most women with CMV infection are asymptomatic4. In my practice, I see asymptomatic pregnant women who have had ad hoc screening and are CMV IgG positive and/or IgM positive. The differential diagnosis includes pre-pregnancy infection, primary infection (peri-conception or in pregnancy), reactivation/reinfection, or less commonly false positive serology. CMV IgM is a sensitive marker of primary infection, however only 50% of CMV positive individuals have primary infection, as CMV IgM may persist for long periods of time7,12. Primary CMV infection can be diagnosed by IgG seroconversion. Antenatal booking serology is kept for 1 year. CMV IgG avidity may be useful to determine timing of CMV infection, especially if no other sample serology is available for comparison7. High avidity during the first trimester excludes primary infection within the preceding 3–4 months7. Low avidity suggests infection within the previous 3 months. Change in avidity may also be used to predict timing of infection13. Maternal CMV viraemia using polymerase chain reaction (PCR) may be also useful to establish the time of infection14.

Once the diagnosis of primary maternal CMV in pregnancy, or periconception is established, determining fetal infection will assist in predicting infant outcomes. Amniotic fluid CMV PCR is the most accurate method of detection of fetal CMV infection15. Ideally an amniocentesis should be performed after 20–22 weeks gestation, and a minimum of 6 weeks after the primary infection16. A negative result before then may be falsely reassuring, and a repeat amniocentesis with a small risk of miscarriage (0.5%), may be required. If the amniotic fluid CMV PCR is negative, the risk of the fetus being infected at birth is small (8%), and the risk of an abnormal outcome is low (~0.5%)3.

Fetal ultrasound can be used to predict adverse fetal/ neonatal outcomes of fetal CMV infection. The ultrasound features of congenital CMV are non-specific, but include microcephaly, echogenic bowel, intrauterine growth restriction, hydrops fetalis, cerebral ventriculomegaly, brain calcifications and an enlarged placenta5,17,18. The risk of adverse fetal/ neonatal outcomes when there are ultrasound abnormalities and proven fetal infection is ~46%3. This risk is significantly reduced to 13%, when there are no ultrasound abnormalities3. However, if there are no ultrasound abnormalities, ongoing ultrasound surveillance is recommended, as ultrasound evidence of CMV damage may develop later15. MRI may give additional information in cases of confirmed fetal infection, especially if the fetal ultrasound shows no abnormality5.

Women who have possible or proven CMV infection in pregnancy should be counselled by experienced clinicians10,19. The role of maternal therapy to prevent adverse fetal and neonatal effects of CMV infection is uncertain20. Ongoing research into the role of CMV hyperimmune globulin is in progress21. Termination of pregnancy may be an option for some women, particularly if there is fetal infection and/or ultrasound evidence of fetal sequelae. The availability and timing of termination of pregnancy varies, as laws differ between states and territories in Australia22. A previous study has found that 17% of women with a CMV diagnosis in the first trimester will terminate the pregnancy, before undergoing an amniocentesis22. If fetal or maternal CMV in pregnancy has been diagnosed and the pregnancy continues, neonatal investigation is recommended. Clinical examination and neonatal saliva PCR are the initial methods of choice23, and placental examination may be useful. When neonatal CMV infection is detected, neonatal surveillance for hearing loss and long-term outcomes is recommended to reduce the risk of adverse sequelae24. The role of antiviral therapies is less certain20.

It is well recognised that CMV infection may persist25. The optimal time to avoid pregnancy after CMV infection is not known. However postponing pregnancy for a period of 6–12 months may be advisable after primary CMV infection, as periconception infection is also associated with fetal effects4,26.


Biography

Dr Antonia Shand MBChB, FRANZCOG, DDU, CMFM, M. Med (Clin. Epi.) is a Maternal-Fetal Medicine subspecialist at the Royal Hospital for Women in Sydney. She went to medical school in Otago, New Zealand and completed her obstetric and maternal fetal medicine subspecialty training in Sydney and in Perth. She also works in the Clinical Population and Perinatal Health research group at the Kolling Institute of medical research at the University of Sydney. Her clinical and research interests include infection in pregnancy as well as complicated pregnancies.

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