Parvovirus B19 Infection in Pregnancy

1. What every clinician should know

Clinical features and incidence

Parvovirus B19 is a single-stranded DNA virus, and the only parvovirus that causes human disease. It is a viral infection predominantly seen in school age children. By reproductive age, only 40% of women are susceptible to the virus, with an annual seroconversion rate of 1-2%. Transmission occurs primarily through respiratory droplets by person-to-person contact. The incubation period is 4-14 days. Parvovirus follows seasonal variation, with higher prevalence in temperate climates in late winter to early spring. Patients with erythema infectiosum are infectious before the onset of the rash and remain infectious for 1-2 days after the rash develops.

Infection with Parvovirus B19 ranges from asymptomatic or sub-clinical infection, to a biphasic illness. The most common childhood presentation is erythema infectiosum, or “fifth disease.” This typically presents with an initial non-specific prodromal phase, which may include fever, headache and mild gastrointestinal symptoms. This is followed by the classic slapped-cheek rash, which is facial erythema with surrounding pallor. The rash may then spread to the trunk and limbs, and as the rash fades it produces a lacy reticular appearance.

Adults are asymptomatic in 20-30% of cases. The remainder of cases present with mild flu-like symptoms that are often followed by the development of a mild lace-like rash on the trunk and extremities. The typical slapped-cheek seen in childhood illness is not usually seen in adult disease. However, adults may develop symmetric polyarthralgias and arthritis that can persist for several weeks. This may be the only clinical evidence of disease. The arthralgia typically involves the small joints of the hands and feet. Patients with chronic hemolytic disease, such as sickle-cell disease, may progress to transient aplastic crisis. While the aplastic crisis is self-limited, this is the most severe presentation of Parvovirus B19 infection. This may be accompanied by thrombocytopenia and neutropenia.

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In pregnancy, maternal infection results in vertical transmission to the fetus in approximately a third of cases. The majority of pregnancies affected with parvovirus do not result in adverse fetal outcomes. However, fetal infection has been associated with abortion, fetal death and non-immune hydrops. The fetal loss rate is reported to be as high as 15%, however, this rate has recently been debated as an overestimation. Fetal infection at less than 20 weeks gestational age is associated with an increased risk of fetal death and hydrops; Parvovirus B19 is the most common infectious etiology of non-immune fetal hydrops, with an observed rate up to 10% for those infected before 20 weeks gestational age.

Who is at risk

Women seronegative for Parvovirus B19 are at risk for developing the disease. There is no chronic phase nor is there reactivation disease so a prior seropositive pregnant woman is not at risk for maternal or fetal complications during the pregnancy. Women with young children, day care workers and school teachers are all considered high risk exposure groups. Patients with chronic hemolytic disease have the greatest risk for serious complications.

2. Diagnosis and differential diagnosis

A. Establishing the diagnosis

Maternal infection may be suspected based upon symptomatology. More commonly, however, maternal testing is initiated after exposure to an infected individual. When maternal infection or exposure is suspected, a serologic assay for Parvovirus B19 specific antibodies should be performed. lgM develops within days of infection and persists for 2-3 months, whereas lgG develops several days later. The presence of lgG without the presence of lgM indicates prior maternal infection and immunity. The mother may be reassured in this instance that there is no risk of fetal infection. No further testing is necessary in this situation.

The absence of both lgG and lgM indicates no prior infection and a susceptible patient. This combination also may occur in early acute infection prior to antibody formation, and retesting should be performed in 1-3 weeks. If retesting remains negative for both lgG and lgM, no infection is present; however, the mother remains susceptible. If lgM becomes positive on retesting, recent Parvovirus B19 infection has occurred and further evaluation is required.

Parvovirus B19 replicates within the erythroid precursors, inducing cytotoxic apoptosis and inhibiting erythropoiesis. This results in fetal anemia as well as possible multiple fetal organ failure. Myocarditis, in association with marked fetal anemia, may contribute to fetal cardiac failure and subsequent hydrops fetalis. Thus maternal Parvovirus B19 infection requires fetal evaluation. An ultrasound is performed and fetal infection suspected if there is evidence of non-immune fetal hydrops, an accumulation of excess fluid in at least two body compartments.(Figure 1)

Figure 1.

Ascites in a 19 week fetus with non-immune hydrops fetalis resulting from Parvovirus B19 infection (Image courtesy of Dr. Jodi Dashe).

MCA Doppler should also be performed at the time of ultrasonography to predict fetal anemia. (Figure 2) If fetal infection is suspected, an amniocentesis or periumbilical blood sampling (PUBS) should be performed and amniotic fluid or fetal blood sent for DNA amplification for Parvovirus B19. This is the diagnostic test of choice for fetal Parvovirus B19 infection. Fetal serologies are not recommended for the diagnosis of fetal infection, as the immature fetus is relatively immunocompromised and unable to form an appropriate immunologic response to the infection.

Figure 2.

Abnormal MCA Doppler of 112 cm/sec in a 23 week fetus with Parvovirus B19 infection, confirming fetal anemia (Image courtesy of Dr. Jodi Dashe).

B. Differential diagnosis

If a pregnancy is noted to have fetal hydrops on routine ultrasound with or without previous history of maternal illness, laboratory studies for the determination of the cause of immune and non-immune hydrops should be undertaken. While the differential may be extensive, certain studies can be initially undertaken. This includes maternal blood type and antibody determination and maternal serologies for rubella, CMV and toxoplasmosis. Amniocentesis can be performed for nucleic acid amplification testing for CMV and toxoplasmosis.

3. Management

Maternal Parvovirus B19 infection is managed with symptomatic therapy. There is no specific antiviral treatment. High dose intravenous immunoglobulin is occasionally used for treating persistent aplastic anemia associated with Parvovirus B 19 infection – consultation with infectious disease or hematology specialists is recommended in this uncommon situation.

The vast majority of fetal hydrops due to parvovirus occurs within 10 weeks of infection. In a woman with serologic evidence of recent infection, serial sonography should be performed every 2 weeks to evaluate for fetal hydrops, placentomegaly and growth disturbances. Hydrops caused by anemia usually manifests initially with ascites, with enlargement of the fetal heart. MCA dopplers are performed to determine the presence of fetal anemia. If no evidence of hydrops or anemia is present after 10 weeks of monitoring, no further testing is necessary. If fetal infection is diagnosed near term, consideration should be given to delivery. This should take place at a tertiary care center with appropriate neonatal resuscitation capabilities.

When fetal hydrops or fetal anemia is identified by non-invasive testing in a patient with a diagnosis of Parvovirus B19, a cordocentesis is recommended to confirm infection using DNA amplification techniques and to assess the degree of anemia. Depending upon gestational age at the time of cordocentesis, intrauterine transfusion may be performed. Transfusion of fetuses with severe hydrops has been shown to reduce the risk of fetal death. Resolution of hydrops is typically seen in 6-12 weeks, and most fetuses only require one transfusion as fetal hematopoiesis resumes once the infection resolves.

Following fetal transfusion, follow-up ultrasound and MCA Dopplers should be performed to monitor the fetus’ response to the transfusion. Weekly monitoring is reasonable until the anemia resolves. There can be an association with severe fetal anemia and fetal thrombocytopenia, with one study reporting 7 of 8 hydropic fetuses also having thrombocytopenia at the time of cordocentesis.

Because of this association, it may be reasonable to have compatible platelets available at the time of fetal blood sampling and transfusion. If there is no improvement in the fetal condition, repeat intrauterine transfusion can be considered. The timing of repeat transfusion is not firmly established; however, worsening MCA dopplers and suspicion of worsening fetal anemia and hydrops can be used as markers.

Currently, there is no approved vaccine for Parvovirus B19. The risk of infection with casual contact is approximately 5%, and up to 50% for frequent contact, such as in the home. There is no evidence that workers at schools or day-care centers need to avoid infected children, as infectivity is greatest piror to clinical symptoms. Infected children do not need to be isolated.

4. Complications

A. Maternal and fetal complications

Maternal complications from Parvovirus B19 are uncommon. This is usually a self-limited viral infection. Women with sickle cell disease, hereditary spherocytosis or severe nutritional anemias may develop a transient but often profound aplastic anemia. Nephritis, meningoencephalitis, hepatitis and myocarditis have been reported but are rare. Fetal complications from Parvovirus B19 are detailed above.

B. Complications arising from treatment

The main complication that may arise as a consequence of treating the fetal sequelae of Parvovirus B19 infection is that associated with the periumbilical blood sampling procedure itself. PUBS has an overall fetal loss rate of 1-5% depending on operator experience, with most centers reporting loss rates of 1-2%.

5. Prognosis and outcome

A. Maternal and fetal/neonatal outcomes

In fetuses infected with parvovirus, intrauterine transfusion has been shown to decrease mortality. In one series, 84% of those fetuses with severe hydrops who received a transfusion survived, compared with no survivors in the group who did not receive a transfusion.

Few studies have examined long-term neurological outcomes of children who received intrauterine transfusions. No neurologic sequelae were evident on standard neurodevelopmental testing in 20 survivors who received intrauterine transfusion when followed for a mean of 52 months. However, in a recent review of 25 intrauterine transfusions, 32% of survivors demonstrated abnormal neurodevelopment. Three of the children had mild neurodevelopmental delay, while two children had severe delay. The degree of delay was not related to the degree of fetal anemia, leading to the hypothesis that the infection itself may have induced neural damage.

In regards to long-term morbidity and mortality, 1095 children exposed to maternal Parvovirus B19 infection during pregnancy were followed into childhood. No association was found with long term morbidity and mortality and maternal Parvovirus B19 infection during the pregnancy in the absence of hydrops fetalis.

B. Impact on long term health

Infection with Parvovirus B19 produces lifelong immunity to the disease. A woman with a prior pregnancy complicated by Parvovirus B19 will now have lgG specific for parvovirus. Her subsequent pregnancies are not at risk for infection.

6. What is the evidence for specific management and treatment recommendations

Enders, M, Weidner, A, Zoellner, I. “Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1,018 cases”. Prenat Diagn. vol. 24. 2004. pp. 513-8. (A prospective observational study of 1,018 cases of labratory confirmed acute pavovirus B19 infection demonstrating the morbidity and mortality associated with intrauterine infection and the benefit of timely intrauterine transfusion.)

Sarfraz, A, Samuelsen, S, Bruu, A-L. “Maternal human parvovirus B19 infection and the risk of fetal death and low birth weight: a case-control study within 35,940 pregnant women”. BJOG. vol. 116. 2009. pp. 1492-8. (A case-control study of 281 women with a fetal death analyzing the association of parvovirus specific IgG or IgM with fetal death.)

Enders, M, Schalasta, G, Baisch, c. “Human parvovirus B19 infection during pregnancy – value of modern molecular and serological diagnosis”. J Clinic Virol. vol. 35. 2006. pp. 400-6. (A study of currently available molecular and serological methods to investigate the reliability of diagnosis of primary parvovirus B19 infection and the ability to pinpoint the time of infection during pregnancy.)

Al-Buhtori, M, Moore, L, Benbow, EW, Cooper, RJ. “Viral detection in hydrops hetalis, spontaneous abortion, and unexplained fetal death in utero”. J Med Virol. vol. 83. 2011. pp. 679-84. (An examination of the occurance of viral infection in fetal death by examining tissues for the presence of DNA of several viruses.)

Lamont, R, Sobel, J, Vaisbuch, E. “Parvovirus B19 infection in human pregnancy”. BJOG. vol. 118. 2011. pp. 175-86. (A review of parvovirus B19 in pregnancy, including epiemiology, presentation, diagnosis and management.)

De Jong, EP, Walther, FJ, Kroes, ACM. “Parvovirus B19 infection in pregnancy: new insights and management”. Prenat Diagn. vol. 31. 2011. pp. 419-25. (A review of the virology, pathology, epidemiology, clinical presentation and management of parvovirus B19 in pregnancy.)

“Public Health Laboratory Service Working Party on Fifth Disease. Prospective study of human parvovirus (B19) infection in pregnancy”. BMJ. vol. 300. 1990. pp. 1166-70. (A prospective study of 190 women with serologically confirmed parvovirus B19 infection in pregnancy to determine fetal infection rate and pregnancy outcomes.)

Nagel, HT, de Haan, TR, Vandenbussche, FP. “Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection”. Obstet Gynecol. vol. 109. 2007. pp. 42-7. (An evaluation of the neurodevelopmental status of 16 surviving children who underwent intrauterine transfusion for hydrops associated with parvovirus B19 infection.)

Fairley, CK, Smoleniec, JS, Caul, OE. “Observational study of effect of intrauterine transfusions on outcome of fetal hydrops after parvovirus B19 infection”. Lancet. vol. 346. 1995. pp. 1335-7. (An observational study of the clincal effect of intrauterine transfusion on the outcome of fetal hydrops due to parvovirus B19 infection.)

Simms, RA, Liebling, RE, Patel, RR. “Management and outcome of pregnancies with parvovirus B19 infection over seven years in a tertiary fetal medicine unit”. Fetal Diagn Ther. vol. 25. 2009. pp. 373-8. (A study of 47 pregnancies with parvovirus B19 infection to determine the rates of fetal anemia and pregnancy outcome.)

Lassen, J, Bager, P, Wohlfahrt, J. “Parvovirus B19 infection in pregnancy and subsequent morbidity and mortality in offspring”. Int J Epidemiol. vol. 42. 2013. pp. 1070-6. (A study of 1095 exposed to maternal parvovirus B19 infection during pregnancy and subsequent childhood morbidity and mortality.)