117: Parvovirus B19 Infection

Human parvovirus B19 (PB19) is a small, single-stranded, nonenveloped DNA virus.

Infection with PB19 is common worldwide. Infection occurs mostly among school-aged children where the major manifestation is erythema infectiosum (fifth disease). The prevalence of immunoglobulin G (IgG) antibodies directed against PB19 ranges from 15 to 60% in children 6–19 years old. About 35–45% of women of childbearing age do not possess protective IgG antibodies against PB19 and therefore are susceptible to primary infection. The incidence of acute PB19 infection in pregnancy is 3.3–3.8%. Annual seroconversion rates in pregnant women in the United States range from 1 to 1.5%.

The only known natural host cell of PB19 is the human erythroid progenitor cell. PB19 is a potent inhibitor of hematopoiesis. The cellular receptor for PB19 is globoside or P-antigen, which is found on erythrocyte progenitor cells, synovium, placental tissue, fetal myocardium, and endothelial cells. The B19-associated red blood cell aplasia is related to caspase-10–mediated apoptosis of erythrocyte precursors. Infection with PB19 is usually acquired through respiratory droplets, but the virus can also be transmitted by blood or blood products and vertically from mother to fetus. In children and adults, viremia develops 2 days after exposure and reaches its peak at ∼1 week. During the phase of viral replication and shedding, the patient is generally asymptomatic. When the typical rash (characterized by a “slapped cheek” appearance on the face and a “lace-like” erythematous rash on the trunk and extremities) or arthralgias develop, the patient is no longer infectious to others. Symptoms during pregnancy are nonspecific and include a flulike syndrome with a low-grade fever, sore throat, generalized malaise, and headache. Pregnant women rarely develop the characteristic “slapped cheek.” The fetus may become infected during the maternal viremic stage. Because of active erythropoiesis in the fetus with a shortened red-cell life span, marked fetal anemia, high-output cardiac failure, and fetal hydrops may develop. Myocarditis, and less often fetal hepatic infection, may contribute to fetal cardiac failure. Teratogenicity from PB19 has been described in case reports; also, one recent study found high prevalence of trisomy in pregnancy loss ascribable to PB19/erythrovirus infection. Despite that, PB19 is considered nonteratogenic based on large epidemiologic studies.

The risk of acquiring PB19 infection during pregnancy is highest in schoolteachers, day care workers, and women who have school-aged children at home.

1. During pregnancy. The mother may report a history of exposure to a child with erythema infectiosum. More commonly, the mother does not recall such exposure and the diagnosis is made based on ultrasound findings. Fortunately, most maternal infections are associated with normal pregnancy outcomes. The overall risk of adverse outcomes after primary infection is probably <10% despite transplacental transmission rate of 33–50%. Adverse outcomes include the following:

   1. Fetal death. Infection in the first trimester may result in fetal loss or miscarriage. A large prospective study of PB19 infection in pregnant women reported fetal death in 6.3% of pregnancies (up to 10.2% in other smaller studies). All deaths were limited to PB19 infections diagnosed in the first half of pregnancy (13% for first trimester infections, 9% for infections diagnosed between 13 and 20 weeks of gestation). Fetal death in the third trimester is exceedingly rare (<1%) and those fetuses (stillborn) are usually nonhydropic.

   2. Nonimmune hydrops fetalis. The observed risk of PB19-induced hydrops fetalis is ∼4% after maternal infection throughout pregnancy, with a maximum of ∼10% when infection occurs between 9 and 20 weeks' gestation. The median interval between diagnosis of maternal infection and hydrops is 3 weeks. Hydrops can progress rapidly to fetal death (days to weeks) or can resolve spontaneously with an apparently normal infant at delivery. The spontaneous resolution is estimated at 34%. Severe thrombocytopenia can develop in 37% of parvovirus-infected fetuses with hydrops. This can lead to significant blood loss and exsanguination at the time of periumbilical blood sampling (PUBS) or other fetal procedures; for this reason, the platelet count should be determined and platelets should be available for transfusion if needed.

2. Neonatal period. The newborn infant may present with anemia and thrombocytopenia, especially if maternal infection occurred in the third trimester. Few cases of encephalopathy, meningitis, and severe central nervous system abnormalities following intrauterine PB19 infection have been reported.

1. Laboratory studies

   1. Serologic tests. PB19 IgG and IgM antibodies are first ordered when PB19 infection is suspected. PB19-specific IgM antibodies become detectable in maternal serum within 7–10 days after infection, sharply peak at 10–14 days, and then rapidly decrease within 2 or 3 months. IgG antibodies rise considerably more slowly and reach a plateau at 4 weeks after infection. Measurement of maternal IgM is highly sensitive and specific. However, at the time of clinically overt hydrops fetalis, IgM levels may already have become low or (rarely) even undetectable. In contrast to maternal testing, serologic examination of fetal and neonatal blood samples is highly unreliable.

   2. Polymerase chain reaction (PCR) to detect PB19 DNA is extremely sensitive. This method is especially useful in patients lacking an adequate antibody-mediated immune response, in immunocompromised or immunosuppressed individuals, and in fetuses. Using standard procedures, detection of PB19-specific IgM in fetal blood has a sensitivity of 29% compared with almost 100% for PCR. However, low viral DNA levels may persist for years after acute infection, and therefore low-positive PCR results do not prove recent infection.

2. Ultrasound and Doppler velocimetry are very useful noninvasive measures to monitor the pregnant woman who is exposed to PB19. Ultrasound is used to monitor for hydrops and fluid accumulation in fetal body cavities. Doppler velocimetry is used to detect blood flow pattern in the fetal middle cerebral artery (MCA). An increase in the MCA peak systolic velocity (MCA-PSV) is a very sensitive measure of fetal anemia.

Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F.

1. Monitoring of the exposed pregnant woman. Women who have been exposed or symptomatic should be assessed by determining their PB19 IgG and IgM status. Blood PCR is recommended when the fetus is hydropic. If the woman is immune to PB19 (IgG positive, IgM negative), she can be reassured that recent exposure will not result in adverse consequences in her pregnancy. If there is no immunity to the virus and seroconversion has not taken place after 2 weeks, the woman is not infected but remains at risk. If the woman has been infected with PB19 (IgM positive), the fetus should be monitored for the development of hydrops fetalis by ultrasound examination and Doppler assessment of MCA-PSV, preferably weekly until 8–10 weeks postexposure.

2. Intrauterine blood transfusion (IUT). If the fetus subsequently develops hydrops and/or anemia (increase in MCA-PSV), PUBS and IUT (PUBS-IUT) should be considered. PUBS-IUT is an invasive procedure and carries a complication rate of 2–5% but can be lifesaving. It should be considered only for fetuses that are symptomatic. In most cases, one transfusion is sufficient for fetal recovery. When preparing for fetal transfusion, both packed red blood cells (PRBCs) and platelets must be available because some fetuses have severe thrombocytopenia in addition to anemia. Platelet transfusion may help if the fetus develops a hemorrhagic complication secondary to the procedure.

3. Packed red blood cell (PRBC) transfusion. PRBC transfusion may be indicated for the symptomatic anemic newborn patient.

4. Intravenous immune globulin (IVIG). IVIG has been used to treat acute B19 infection in immunodeficient adults and human immunodeficiency virus (HIV)-infected children with aplastic crisis. However, there is only 1 case report on its use during pregnancy. Given these limited data, the use of IVIG cannot be recommended.

5. Antiviral agents. No antiviral agents are effective against PB19.

Mortality with parvovirus-related fetal hydrops is better than the generally reported mortality for nonimmune fetal hydrops (50–98%). With treatment, the long-term prognosis is good. Apparently, there is no increase in the frequency of developmental delays in children with exposure in utero to PB19.