Perinatal Viral Infections
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Many viral infections are associated with significant maternal and fetal consequences if acquired during pregnancy. In the United States, some the most commonly encountered infections with subsequent perinatal effects include cytomegalovirus (CMV), parvovirus B19 (fifth disease), varicella zoster virus (VZV). The purpose of this document is to describe these infections, their mode of transmission, and their maternal and fetal effects. Guidelines for counseling about and management of these infections during pregnancy are also discussed.
In general, perinatal infections have more severe fetal consequences when they occur early in gestation, because first-trimester infections may disrupt organogenesis. Second and third trimester infections can cause neurologic impairment or growth restriction. In utero infection may be associated with certain ultrasound findings, including intrauterine growth restriction, intracranial or intrahepatic calcifications, hydrocephalus, microcephaly, isolated ascites, pericardial or pleural effusions, or nonimmune hydrops, although congenital infections also can be asymptomatic.
I. Cytomegalovirus (CMV)
Cytomegalovirus (CMV) is a double-stranded DNA herpes virus that is transmitted by contact with infected blood, saliva, or urine, or by sexual contact. The incubation period of CMV is 28-60 days, with mean of 40 days. Infection induces an immunoglobulin M (IgM) antibody response that disappears within 30-60 days. Primary CMV infection in adults generally is asymptomatic. Occasionally, patients experience mononucleosis like syndrome, with leukocytosis, lymphocytosis, abnormal liver function tests, fever, malaise, myalgias and chills. Viremia can be detected 2-3 weeks following primary infection. After the initial infection, CMV remains latent in host cells; recurrent infection can occur following reactivation of latent virus. In rare cases, recurrent CMV infection can occur by infection with a new strain of virus (1).
Prevalence of both primary and recurrent infection in pregnant women varies regionally from 0.7% to 4% for primary infection and up to 13.5% for recurrent infection. Vertical transmission of CMV may occur as a result of transplacental infection after primary or recurrent CMV infection, exposure to contaminated genital tract secretions at delivery, or breastfeeding. CMV infection acquired as a result of exposure to infected cervical secretions or breast milk is typically asymptomatic and is not associated with severe neonatal sequelae.
The majority of adult CMV infections are asymptomatic, which makes diagnosis of primary infection difficult. It is detected by culture or polymerase chain reaction (PCR) of infected blood, urine, saliva, cervical secretions, or breast milk. Diagnosis of CMV infection in adults usually is confirmed by serologic testing. Serum samples collected 3-4 weeks apart, tested in parallel for anti-CMV IgG, are essentially for the diagnosis of primary infection. Seroconversion from negative to positive or a significant increase (greater than four-fold, eg, from 1:4 to 1:16) in anti -CMV IgG titers is the evidence of infection. The presence of CMV specific IgM is a useful but not completely reliable indication of a primary infection. IgM titers may not be positive during an acute infection, or they may persist for months after the primary infection (2). A small proportion of women with recurrent infection will demonstrate anti-CMV IgM. The reported sensitivity of CMV IgM serologic assays ranges from 50% to 90%.
Effect on Fetus and Newborn:
Cytomegalovirus is the most common congenital infection, occurring in 0.2-2.2% of all neonates, and is the leading cause of congenital hearing loss. With primary maternal CMV infection, the risk of transmission to the fetus is 30-40%. Of those infected in utero following a primary infection, 10% will have signs and symptoms of CMV infection at birth and develop sequelae. Approximately 30% of severely infected infants die, and 80% of survivors have severe neurologic morbidity. The incidence of severe fetal infection is much lower after recurrent maternal infection than after primary infection. Most infants with congenital CMV are symptomatic at birth. Clinical findings of symptomatic congenital CMV infection include jaundice, petechiae, thrombocytopenia, hepatosplenomegaly, growth restriction, and nonimmune hydrops (3).
Diagnosis of fetal infection: congenital CMV may be suspected prenatally after a documented maternal primary infection or, more typically, after detection of ultrasound findings suggestive of infection. These include abdominal and liver calcifications, calcification of the lateral border of the lateral ventricles, hydrops, echogenic bowel, ascites, hepatosplenomegaly, and ventriculomegaly. Fetuses that demonstrate abnormalities, particularly if they involve the central nervous system, generally have a much poorer prognosis. Cytomegalovirus can be detected in the amniotic fluid of infected fetuses by either culture or PCR. The sensitivity of CMV culture ranges from 50% to 69%, compared with a sensitivity of 77-100% for PCR. Detection of anti-CMV IgM in fetal blood is suggestive of the infection and testing for fetal thrombocytopenia or abnormal liver function has been suggested as a method to diagnose congenital CMV. Although these tests are promising, neither amniotic fluid culture nor PCR can detect all cases of congenital CMV infection.
Treatment for maternal, fetal and congenital neonatal infections with CMV:
Currently, no therapies are available for the treatment of maternal or fetal CMV infection. Antiviral treatment with ganciclovir or foscarnet is approved only for treatment of CMV retinitis in patients with HIV/AIDS. Ganciclovir and CMV hyper-immune gamma globulin have shown promise for the treatment of neonates with congenital CMV infection. The effectiveness of treatment in the prevention of long-term neurologic sequelae has not been proven. A live attenuated vaccine using the Towne 125 strain has been developed, and appears to be safe, somewhat protective and economically beneficial (4). There is reluctance to embrace vaccination because of concerns about the ability of the vaccine strain to reactivate and potentially infect the host, the potential for viral shedding from the cervix or breast milk, and the possible oncogenic potential of vaccine virus. However, the science in this area is advancing rapidly, and new treatment options may become available.
Counseling of women at high risk of CMV:
Factors associated with an increased risk of CMV infection include history of abnormal cervical cytology, lower socioeconomic status, birth outside North America, first pregnancy at younger than 15 years, and infection with other sexually transmitted diseases. The greatest impact obstetricians and gynecologists can have on reducing CMV disease by educating patients about preventive measures. Counseling should cover careful handling of potentially infected articles, such as diapers, and thorough hand-washing when around young children or immunocompromised individuals, explaining that careful attention to hygiene is effective in helping to prevent transmission. In addition, women should be counseled, when appropriate, about the avoidance of high-risk behaviors, such as intravenous drug use and sharing of needles. Condom use should be encouraged as a method of contraception.
Currently, routine serologic testing for CMV during pregnancy is not recommended. Maternal IgM antibody screening is limited for differentiating primary from recurrent infection, which makes it difficult to use such results in counseling patients about fetal risk. In addition, maternal immunity does not eliminate the possibility of fetal infection. Although the virus is not contagious, some groups of women are at higher risk for the acquisition of CMV infection. The women with young children or those who work with young children should be advised that the risk of infection can be reduced significantly by safe-handling techniques, such as the use of latex gloves and rigorous hand-washing after handling diapers or after exposure to respiratory secretions (5).
II. Parvovirus B19 (Fifth Disease):
Parvovirus B 19 is a single-stranded DNA virus that causes the childhood exanthem erythema infectiosum, also known as fifth disease. The most common symptoms of parvovirus B19 infection are a reticular rash on the trunk and peripheral arthropathy (painful joints), although about 33% of infections are symptomatic. Another manifestation of parvovirus B19 infection is transient aplastic crisis, which is more common in those with an underlying hemoglobinopathy. Most infections are mild; most individuals recover completely from parvovirus B19 infection and require only supportive care. Transmission of parvovirus B19 most commonly occurs through respiratory secretions and hand-to-mouth contact. The infected person generally is infectious 5-10 days after the exposure prior to the onset of the rash or other symptoms and is no longer infectious with the onset of rash. Both IgM and IgG are produced in response to infection. The IgM response, which persists for 1 to several months, is indicative of a recent infection; IgG antibodies persist indefinitely and in the absence of IgM, indicate prior infection and immunity. The risk of maternal infection of parvovirus B19 varies with the level of exposure to the infected individual. Exposure to a household member infected with parvovirus B19 is associated with an approximate 50% risk of seroconversion. The risk of transmission in a child care setting or classroom is lower, ranging from approximately 20% to 50%.
Recent maternal infection with parvovirus B19 constitutes a low risk for fetal morbidity, although some cases have been associated with adverse fetal effects. Transplacental transmission has been reported to be as high as 33%, and fetal infection with parvovirus B19 has been associated with spontaneous abortion, hydrops, and stillbirth (6). Long term development appears to be normal in fetuses with congenital parvovirus B19 infection that do not succumb to the disease.
Diagnosis of Maternal Parvovirus B19 infection:
Maternal serology is the most commonly used test to diagnose acute infection with parvovirus B19. Enzyme-linked immunosorbent assay (ELISA), radioimmunoassay, and Western blot tests can measure the antibody to parvovirus B19. The sensitivity of IgM and IgG assays is generally 79%. Identification of parvovirus-specific IgM in maternal serum is diagnostic of a primary infection, although a laboratory with experience should measure titers, because false-positive results can occur. Previous exposure and infection with parvovirus B19 is indicated by the presence of anti-parvovirus B19 IgG in the absence of IgM and has not been associated with adverse perinatal outcome.
Parvovirus B19 can be identified by direct visualization of viral particles in infected tissues or serum by electron microscopy or by identification of characteristic intranuclear inclusions within erythroblasts (7).
Diagnosis of Fetal Parvovirus B19 infection:
Diagnosis of fetal parvovirus B19 infection can be accomplished by isolation of viral particles in abortuses or placental specimens. Polymerase chain reaction also has been used to detect parvovirus B19 in fetal specimens, including autopsy tissue, serum, amniotic fluid and placenta. IgM antibodies appear in the fetal circulation after 22 weeks of gestation, limiting the usefulness of such tests. Ultrasonography has been the mainstay for diagnosing fetal parvovirus infection. Severely infected fetuses typically have evidence of hydrops fetalis. Serial ultrasound examinations for up to 10 weeks after maternal infection are indicated. If the fetus shows no signs of hydrops fetalis, additional tests are necessary.
After documented exposure to parvovirus B19, the woman should have serologic testing to determine if she is immune with evidence of anti-parvovirus IgG. If non-immune, the test should be repeated in 3-4 weeks and paired samples tested to document whether the woman is seropositive for parvovirus. If seroconversion does not occur, the fetus should be monitored for 10 weeks by serial ultrasound examination to evaluate for presence of hydrops fetalis, placentomegaly, and growth disturbances. However, if hydrops fetalis develops, percutaneous umbilical blood sampling should be performed to determine the fetal hematocrit, leukocyte and platelet count, and viral DNA in preparation for supportive care using transfusion. Intrauterine transfusion should be considered if anemia is present.
When outbreak of parvovirus B19 infection occur in situations in which prolonged, close-contact exposure occurs, as in schools, homes, or child care centers, options for prevention of transmission are limited. Exposure cannot be eliminated by identifying and excluding persons with acute parvovirus B19 infection; up to 20% are symptomatic, and those with infection are infectious before they develop symptoms. Exclusion of pregnant women from the workplace during endemic periods is controversial, and a policy routinely exclude members of high-risk groups from work during an outbreak of parvovirus B19 is not recommended.
III Varicella Zoster Virus (VZV)
Varicella zoster virus (VZV) is a DNA herpesvirus that is highly contagious and is transmitted by respiratory droplets or close contact. The attack rate among susceptible contacts is 60-90% after exposure. The incubation period after infection is 10-20 days, with a mean of 14 days. The period of infectivity begins 48 hours before the rash appears and lasts until the vesicles crust over. The primary infection causes chickenpox, which is characterized by fever, malaise, and a maculopapular pruritic rash that becomes vesicular. After the primary infection, VZV remains dormant in sensory ganglia and can be reactivated to cause a vesicular erythematous skin rash known as herpes zoster. The antibody to VZV develops within a few days after the onset of infection, and prior infection with VZV confers lifelong immunity.
Varicella infection is uncommon in pregnancy, occurring in 0.4-0.7 per 1,000 patients, because of the high prevalence of natural immunity. Pregnancy complicated by maternal varicella infection is associated with untoward maternal, fetal and neonatal effects. The disease usually is benign and self limiting in children; however, varicella national mortality data indicate that although less than 5% of varicella cases occur among adults 20 years of age or older, that group contributes to 55% of varicella related deaths (8). Severe complications, such as encephalitis and pneumonia, are more common in adults than in children; VZV pneumonia in pregnancy is a risk factor for maternal mortality.
In pregnancy, varicella may be transmitted across the placenta, resulting in congenital or neonatal chickenpox. The risk of congenital varicella syndrome is limited to exposure during the first 20 weeks of pregnancy, occurs uncommonly up to 2%, and is characterized by skin scarring, limb hypoplasia, chorioretinitis, and microcephaly. Neonatal VZV infection is associated with a high neonatal death rate when maternal disease develops from 5 days before delivery up to 48 hours postpartum as a result of the relative immaturity of the neonatal immune system and the lack of protective maternal antibody.
Diagnosis of Maternal Infection:
Usually, this diagnosis is based on clinical findings, and laboratory testing is not needed, especially if a rash occurs after known exposure. If laboratory diagnosis is required, the VZV antigen can be demonstrated within skin lesions or vesicular fluid by immunofluorescence. Varicella infection also can be documented by the detection of the fluorescence antibody to the membrane antigen or of the VZV antibody by ELISA.
Diagnosis of Fetal Infection:
The risk of congenital varicella syndrome is small; however, the outcome for the affected infant is serious enough that a reliable method of prenatal diagnosis would be valuable. Fetal varicella can be suspected by the presence of ultrasonographic abnormalities. Ultrasound findings suggestive of congenital varicella include hydrops, hyperechogenic foci in the liver and bowel, cardiac malformations, limb deformities, microcephaly, and intrauterine growth restriction. Although the sensitivity of ultrasonography is unknown, it is the preferred method of diagnosis of congenital VZV. However, not all fetuses with congenital VZV that have ultrasound abnormalities do poorly.
Treatment of Maternal, Fetal and Congenital Neonatal Infections with Varicella:
Oral acyclovir, if instituted within 24 hours of the rash, has been shown to reduce the duration of new lesion formation and the total number of new lesions and to improve constitutional symptoms in children, adolescents and adults. Oral acyclovir appears to be safe and can be prescribed for pregnant women if lesions develop. Maternal varicella complicated by pneumonia should be treated with intravenous acyclovir, because intravenous acyclovir may reduce maternal morbidity and mortality associated with varicella pneumonia.
Maternal treatment with acyclovir has not been shown to ameliorate or prevent the fetal effects of congenital varicella syndrome. Varicella-zoster immune globulin (VZIG) should be given to infants born to women who develop varicella between 5 days before and 2 days after delivery, although this does not universally prevent neonatal varicella. Infants who develop varicella within the first 2 weeks of life should be treated with intravenous acyclovir (9).
Nonpregnant women of childbearing age should be questioned about previous infection with varicella preconceptionally and offered vaccination if no report of chickenpox is elicited. Varicella vaccine has been available since March 1995 and is approved for use in healthy susceptible persons 12 months or older. Conception should be delayed until 1 month after the second vaccination dose is given. Among women who do not recall a history of varicella, 70-90% has detectable antibodies.
Antenatal VZV screening of all pregnant women with negative or indeterminate varicella histories is not believed to be cost-effective. Patients known to be nonimmune to VZV should be counseled to avoid contact with individuals who have chickenpox. If exposure does occur, prophylactic intervention with ZVIG early in the incubation period can prevent or attenuate the disease manifestations of VZV in susceptible contacts at high risk from this infection. Although VZIG is effective in reducing the severity of maternal varicella when administered up to 72 hours after exposure, it should be given as soon as possible. Maternal administration of VZIG does not prevent fetal infection (10).
Vaccine Prevention of Maternal Cytomegalovirus (CMV) Infection:
Congenital infection with CMV is an important cause of hearing, cognitive, and motor impairments in newborns. In this phase 2, placebo-controlled, randomized, double-blind trial, evaluation of a vaccine consisting of recombinant CMV envelope glycoprotein B with MF59 adjuvant, as compared with placebo was done (11). Three doses of the CMV vaccine or placebo were given at 0, 1, and 6 months to CMV-seronegative women within 1 year after they had given birth. Testing for CMV infection in the women in quarterly tests during a 42-month period, was evaluated using an essay for IgG antibiotics against CME proteins other than glycoprotein B. infection was confirmed by virus culture or immunoblotting. The primary end point was the time until the detection of CMV infection. Kaplan-Meier analysis showed that the vaccine group was more likely to remain uninfected during a 42-month period than the placebo group (P=0.02). Vaccine efficacy was 50% (95% confidence interval, 7 to 73) on the basis of infection rates per 100 person-years. One congenital infection among infants of the subjects occurred in the vaccine group, and three infections occurred in the placebo group, in this study. There were more local reactions (pain, erythema, induration, and warmth) and systemic reactions (chills, arthralgias, and myalgias) in the vaccine group than in the placebo group. CMV glycoprotein B vaccine has the potential to decrease incident cases of maternal and congenital CMV infection.
Cytomegalovirus (CMV) is a common cause of congenital viral infection and occurs in approximately 1% of all newborns. Approximately 10% of infected liveborn neonates have symptomatic disease at birth and 10-15% of asymptomatic newborns develop late sequelae, including sensoneural hearing loss and neurodevelopment disorders. However, little is known about the relationship between gestational age at the primary maternal infection and the outcome of the fetal infection. Late fetal infection (in third trimester) after fetal development is complete probably does not lead to neonatal sequelae (12). Although this is small study, it is encouraging because authors carefully monitored the patients from the time of conception until birth, monitoring them for the precise time that infection occurred, suggesting that third-trimester infection probably is not potentially damaging to the fetus. Among pregnant women with a young child in day care, approximately one-third will be exposed to CMV during pregnancy by their child (13). This information, we believe, should be helpful in counseling such patients.
Routine serologic screening of all pregnant women for CMV is not recommended. Pregnant women should be counseled about methods to prevent acquisition of CMV. Pregnant women exposed to parvovirus B19 should have serologic screening performed to determine if they are at risk for seroconversion. Pregnant women who have acute parvovirus B19 infection during pregnancy should be monitored with serial ultrasound examinations for at least 10 weeks following infection for the presence of hydrops fetalis. Fetuses with evidence of hydrops should undergo fetal blood sampling and transfusion as needed. Pregnant women who are seronegative for VZV and exposed to chickenpox should receive VZIG. Pregnant women who develop chickenpox should be treated with oral acyclovir to minimize maternal symptoms; if pneumonia develops, they should be treated with intravenous acyclovir. Nonpregnant women of reproductive age who have no history of varicella infection should be offered varicella vaccine.
- World Health Organization
Vaccine-preventable diseases and vaccines (pdf)
- Centers for Disease Control and Prevention (CDC)
Varicella, Zoster, and Varicella Vaccines (ppt slides)
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- ACOG Practice Bulletin. Perinatal viral and parasitic infections. Number 20; September 2000
- Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2006;55(RR-11):1-36 (Level III)
- Pass RF, Zhang C, Evans A et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009;360:1191-1199
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