Cytomegalovirus in Pregnancy
1. What every clinician should know
Clinical features and incidence
Cytomegalovirus (CMV) has a high seroprevalence, with 58.3% of American women of reproductive age testing positive, and near universal exposure by middle age.The prevalence in Mexican Americans and non-Hispanic blacks is higher, even when adjusting for other characteristics. Estimates suggest that approximately 520,000 women of childbearing age experience a primary CMV infection every year.
Although prevalence is high, there remain a large population of women susceptible to primary CMV infection during pregnancy. Human CMV is the most common viral intrauterine infection that causes congenital malformations. In addition, congenital CMV is the leading cause of sensorineural hearing loss and the leading infectious cause of brain damage in children.
The rate of primary CMV infection during pregnancy ranges between 1-4% of seronegative women. A large population-based study of infants showed that the birth prevalence of CMV infection is 0.5%. Approximately 35,000 infants are born infected with CMV and about 8,000 experience sequalae annually in the United States.
CMV infection can have a devastating impact when transmitted to the fetus during the course of pregnancy. Intrauterine infection occurs in approximately 30-40% of women with primary infection. The likelihood of maternal infection does not vary by trimester, but the earlier the fetus is exposed to the infection, the more likely that there will be subsequent sequalae. The actual timing of transmission can happen weeks to months after maternal infection. Approximately 11% of infants will exhibit symptoms of CMV infection shortly after delivery.
Over 90% of women infected with CMV during pregnancy do not have symptoms. Of those women who do experience symptoms, those symptoms include asthenia, myalgia and a flu-like syndrome consisting of fever and other symptoms. Laboratory abnormalities include an increased number of lymphocytes as well as an increase in aliver enzymes. Laboratory abnormalities are much more common in primary infections.
In women infected with HIV or those receiving immunosuppressive medications, CMV can present with varying degrees of severity and in some cases can be life threatening.
Given that most women are asymptomatic from their infection, one way to detect that the fetus has been exposed to CMV is because of ultrasound findings. A fetus infected with CMV can have a large variety of findings, the most common include: growth restriction, intracerebral calcifications, hepatosplenomegaly, ascites, hyperechoic fetal bowel, amniotic fluid abnormalities, hydrops, an enlarged placenta, microcephaly and cerebral ventriculomegaly.
Prevention measures aimed at halting maternal infection would be ideal. There is currently no approved vaccine for CMV but there are ongoing trials. Hygiene measures have been examined as a means of prevention. One possible way to decrease the risk of infection is to encourage handwashing in women who are in contact with small children, especially those who work in a daycare center.
Transmission of CMV can occur from direct or indirect person-to-person contact, including sexual contact. There is a large reservoir of CMV in the population at any given time. CMV is spread through contact of infected bodily fluids, such as saliva, urine, nasopharyngeal secretions, semen, breast milk, tissue, cervical and vaginal secretions, and blood.
Most congenital infections are thought to be related to exposure to saliva of young children. CMV can infect the placenta and then be transmitted to the fetus, where it infects and replicates in many tissues.
The degree of organ involvement that occurs in the infected individual is dependent on the amount of viral replication and dissemination. Higher levels lead to more organ damage. In general central nervous system (CNS) involvement is limited to intrauterine transmission. Even very immunocompromised adults tend not to develop CNS symptoms. Some of these findings are based on the gestational age when the fetus is infected. The earlier the entry of CMV into the CNS, the more significant the structural damage.
Hearing loss is one of the most common long-term effects of the virus and its severity can range from mild to profound. It can be either unilateral or bilateral and it can progress after delivery. The mechanism of damage is unknown. Another predictor of the severity of infection may include the maternal immunity that is passed to the fetus. Women who have immunity to CMV from naturally acquired infections have about a 60% lower relative risk of delivering an infant with CMV infection than women who were initially seronegative.
CMV transmission can occur with either a primary maternal infection, reactivation or reinfection. Recurrence occurs when there is a case of congenital CMV in a woman who has had a past infection. This can include reactivation of an endogenous latent virus, persistent active infection or reinfection with a new strain. The rate of congenital infection from recurrent CMV was shown to be 1.9% in one study. Clinical evidence of disease is usually less in a fetus infected from a recurrent maternal infection but can still be significant
2. Diagnosis and differential diagnosis
The initial laboratory evaluation that should occur when there is a concern for maternal CMV exposure or infection includes serology, typically serum CMV IgM and IgG. IgM assays have excellent specificity (95%) and sensitivity (100%). In pregnant women, CMV IgM peaks during the first 1 to 3 months in a primary infection but can persist from 18-39 weeks. Only 75-90% of women with acute infection develop CMV IgM. Fewer than 10% of women who are IgM positive will transmit the infection to the fetus. CMV-specific IgM may not indicate a primary infection since it can also be produced during reactivation and reinfection. It can also occur as a false positive with intercurrent infections.
A primary CMV infection is diagnosed when there is conversion of the IgG from negative to positive in the setting of IgM on serum screens separated by a several weeks.
In the absence of serial serology, it is impossible to differentiate a primary from a recurrent infection. In this circumstance, CMV-specific IgG can be tested using an antigen avidity test. This test can help to differentiate between primary and non-primary infections. In primary infection, the IgG avidity is low. Over time, the avidity of the antibody increases. In pregnant women, low-avidity IgG can persist for up to 17 weeks. The antibody usually is fully mature approximately 25 weeks after symptom onset.
Moderate to high avidity before the 18th week of gestation can identify nearly all women who will have an affected fetus, however the assays vary in quality and have a range of sensitivities and specificities. Between 21-23 weeks there is an estimated 91% negative predictive value. After 20 weeks the sensitivity is reduced to around 62.5%.
Once a woman is diagnosed with CMV infection (either primary or recurrent), the amniotic fluid can be evaluated to determine whether the fetus is infected. This can be done with quantitative PCR testing or shell vial culture of amniotic fluid. However, there are flaws to such testing. There is an increased risk of a false-negative result if the fluid is obtained less than 6-8 weeks since infection. The sensitivity of the testing is not optimal and the gestational age also impacts sensitivity. Testing prior to 21 weeks only has a 30-45% sensitivity, the sensitivity after 21 weeks is only 74%. The reason for the difference in sensitivity for gestational age is likely due to fetal excretion of CMV through urination into amniotic fluid. Fetal diuresis begins to occur after 20 weeks.
Other screening tests to evaluate maternal infection are from samples of maternal urine or saliva. CMV shedding can occur in both primary and non-primary infections. Urinary shedding has a poor correlation with intrauterine infections as does saliva shedding. There are low positive prediction rates rates for congenital CMV and fetal injury when the mother has CMV detected in her saliva or urine during the first (29.2%) or second (57.1%) trimester.
Evaluation for fetal infection can also be done via percutaneous umbilical cord blood sampling (PUBS) but is not recommended because this test is no more sensitive or specific than amniocentesis and carries greater risks. Abnormal fetal liver function tests or abnormal fetal hematologic indices are signs of severe disease. IgM antibodies and direct viral markers can be detected after 20 weeks but have a low sensitivity and can miss nearly 15-20% of cases.
The decision to evaluate a woman for CMV infection is often based on ultrasound findings. These findings can include intrauterine growth restriction, oligohydramnios, polyhydramnios, hyperechoic bowel, brain calicification, ventriculomegaly, hydrops, placental enlargement and pleural effusions.
Ultrasound findings suggestive of congenital CMV infection are only seen in approximately 10-15% of infected fetuses. A normal ultrasound can only exclude about 50% of neonates with symptomatic infection. Hyperechoic bowel and ventriculomegaly are the most common findings but are also associated with many other causes. Ultrasound changes may not be seen until later in the pregnancy, even when there was a normal ultrasound earlier in the pregnancy.
The severity of the insult is greater if microcephaly or IUGR are seen. Microcephaly is defined by head circumference (HC) less than the 3rd percentile and has been found in 53% of fetuses. The most specific predictor of future cognitive impairment in infected infants is microcephaly.
Patients with symptomatic CMV should be given medication for relief of symptoms, such as acetominophen for fever. Antiviral medications are not routinely recommended.
Counseling regarding pregnancy outcomes should include the option of termination depending on the gestational age.
There are preliminary data to suggest that antepartum CMV-specific hyperimmune globulin therapy may reduce the neonatal complications from congenital CMV transmission. A study by Nigro et al. evaluated the benefit of treatment with hyperimmune globulin in women with primary CMV infection. This was not a randomized trial and there were only a small number of patients treated. The authors that CMV-specific hyperimmune globulin seemed to reduce the risk of congenital CMV disease. There are ongoing trials to address whether hyperimmune globulin prevents transmission. However, at this time, there is insufficient evidence to support treatment of a pregnant woman with a recent diagnosis of CMV.
Ultrasound examination in the third trimester to evaluate for growth abnormalities should be considered among women with known primary or congenital infection. Delivery timing should be for usual obstetric indications. Neonates should be tested by urine or saliva for congenital infection at birth. More detailed neonatal testing including head ultrasound or blood testing can be reserved for clinical indications.
4. Prognosis and outcome
Nearly 90% of infants with congenital CMV have no early clinical manifestations, but 10-15% of these will develop developmental abnormalities, usually within the first 2 years of life. The most significant abnormality is hearing loss which can occur in at least 20% of infected infants by five years of age. Intellectual impairment and chorioretinitis are uncommon.
Mortality rates in the most severely affected infants may range from 10-30% with most deaths occurring in the neonatal period. The most common presenting signs at birth are hepatosplenomegaly, petechiae and jaundice. The time of occurrence and the duration of time during which the neonate is jaundiced can vary. Petechiae usually are not present at time of birth but develop within a few hours of delivery and may be transient and disappear after 48 hours or may persist for weeks after delivery.
CMV can affect the CNS and is perhaps the most important consequence of fetal infection. The infection shows focal encephalitis and periependymitis which eventually leads to gliosis and calcification. The ear can also be infected and cause hearing loss while the eyes can become infected and cause chorioretinitis, cataract formation, colobomas and optic neuritis. Chorioretinitis has been reported in 14% of infected infants.
Involvement of the liver is frequent in congenital CMV infections, with elevated levels of serum transaminases and hepatic involvement in the neonate. Usually these resolve and there is no permanent liver damage. Thrombocytopenia, anemia and extramedullary hematopoiesis are common but usually resolve by the end of the first year of life without permanent impact. The kidneys, thyroid, adrenal cortex, anterior pituitatry, lungs and the GI tract can all become infected but there are no long term sequelae from the infection.
There was no difference in symptomatic neonates born to mothers with first trimester infection versus those infected after the first trimester. There were no statistically significant differences in frequency of petechiae, hepatosplenomegaly, jaundice or abnormal neurologic findings in the newborn despite timing of maternal infection. There was a trend toward greater severity of disease in those infected during the first trimester. The rate of CNS findings was higher in fetuses infected in the first trimester but it was not a significant difference.
Deafness is the most common detriment occurring in congenital CMV infection, with a frequency of 33-58% in those diagnosed at birth compared to 7.4-21% who were asymptomatic at birth.
5. What is the evidence for specific management and treatment recommendations
Nigro, G, Anceschi, MM, Cosmi, EV. “Clinical manifestations and abnormal laboratory findings in pregnant women with primary cytomegalovirus infection”. BJOG. vol. 110. 2003. pp. 572-7.
Boppana, SB, Rivera, LB, Fowler, KB, Mach, M, Britt, WJ. “Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity”. NEJM. vol. 344. 2001. pp. 1366-71. (This study demonstrates that women with with demonstrated CMV infection prior to pregnancy can still become infected with an new strain of CMV which can cause a symptomatic congenital infection.)
Foulon, I, Naessens, A, Foulon, W, Casteels, A, Gordts, F. “A 10-year prospective study of sensorineural hearing loss in children with congential cytomegalovirus infection”. J Pediatr. vol. 153. 2008. pp. 84-8. (This study focuses on hearing loss in neonates and infants with known CMV infection. They do a detailed analysis examining the timing of presentation of symptoms as well as the type of CMV infection with which the mother is diagnosed.)
Grangeot-Keros, L, Mayaux, MJ, Lebon, P, Freymuth, F, Eugene, G, Stricker, R, Dussaix, E. “Value of cytomegalovirus (CMV) IgG avidity andex for the diagnosis of primary CMV infection in pregnant women”. JID. vol. 175. 1997. pp. 944-6. (This study evaluated the diagnostic value of the avidity index (AI) for CMV to determine if it is an accurate test to differentiate between women with a primary infection and those with a non-primary infection. They found that an AI greater than 65% is highly suggestive of a non-primary infection.)
Guerra, B, Simonazzi, G, Puccetti, C, Lanari, M, Farina, A, Lazzarotto, T, Rizzo, N. “Ultrasound prediction of symptomatic congenital cytomegalovirus infection”. Am J Obstet Gynecol. vol. 198. 2008. pp. 380.e1-380.e7. (This is a retrospective cohort study evaluating sonograms of fetals of mothers with CMV primary infection. They found a poor sensitivity for the prediction of neonatal CMV and symptomatic neonatal CMV with ultrasound. They also looked at the time of detection of fetal abnormalities in pregnancy and most cases were diagnosed between 20-22 weeks but over 1/3 were discovered between 27-33 weeks. The different types of ultrasound abnormalities and the frequency of these findings are discussed.)
Nigro, G, Anceschi, MM, Cosmi, EV. “Clinical manifestations and abnormal laboratory findings in pregnant women with primary cytomegalovirus infection”. BJOG. vol. 110. 2003. pp. 572-7. (This study evaluated the signs and symptoms of CMV infection in pregnant women and outlined the different manifestations that can be present as well as the likelihood of these symptoms )
Nigro, G, Adler, SP, La Torre, R, Best, AM. “Passive immunization during pregnancy for congenital cytomegalovirus infection”. NEJM. vol. 353. 2005. pp. 1350-62. (This study evaluated the use of CMV-specific hyperimmune globulin in women who were diagnosed with a primary CMV infection. This was not a randomized trial and the number of patients included was small. The study found a significant difference in the rate of infants with CMV disease with a lower rate in patients who were treated. The authors propose that based on their findings that a controlled trial of CMV-specific hyperimmune globulin should be performed.)
Stagno, S, Pass, RF, Cloud, G, Britt, WJ, Henderson, RE, Walton, PD, Veren, DA, Page, F, Alford, CA. “Primary cytomegalovirus in pregnancy: incidence, transmission to fetus, and clinical outcome”. JAMA. vol. 256. 1986. pp. 1904-8. (This was a landmark article which outlined the epidemiology of CMV in pregnancy.)
Staras, SA, Dollard, SC, Radford, KW, Flanders, WD, Pass, RF, Cannon, MJ. “Seroprevalence of cytomegalovirus infection in the United States, 1988-1994”. Clinical Infectious Diseases. vol. 43. 2006. pp. 1143-51. (Serum samples were tested for CMV-specific immunoglobulin G in the third National Health and Nutrition Examination Survey. This led to the ability to estimate the number of women at risk for CMV infection in pregnancy.)
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