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2007-02-27-12 Parvovirus B19 infection, hydrocephalus © Dudarewicz

Parvovirus B19 infection, hydrocephalus

Lech Dudarewicz, MD, Lucjusz Jakubowski, MD, PhD, Wanda Hawula, MSc., Magdalena Kozlowska, MSc.

Polish Mother"s Memorial Hospital, Department of Genetics, Lodz, Poland



Parvovirus B19 (B19V), a single-strand DNA virus is the only Parvovirus replicating in man. The name B19 has replaced "HPV" (human parvovirus) in order to avoid confusion with the human papillomavirus. B19 is associated with erythema infectiosum and other hematologic, rheumatologic, and neurologic conditions, including polyarthropathy and aplastic anemia in postnatal patients. Prenatal infection is the most common cause of hydrops in the developed world; nevertheless manifestations other than fetal anemia, hydrops or placentomegaly are uncommon. Erythema infectiosum was named fifth disease because it was the fifth of 6 classic exanthematous diseases of childhood to be described.

Some data showed a possible relationship between B19 infection and rheumatoid arthritis. However, later studies did not support evidence of rheumatoid arthritis. Furthermore, the seroprevalence of B19 in patients with seropositive RA is the same as that in healthy subjects.

B19 infection has been also reported in association with idiopathic thrombocytopenia purpura, Henoch-Schönlein purpura, and pseudoappendicitis. Such cases are probably very rare.


Congenital parvovirus infection. Fifth disease.

Case report

We present a case of hydrocephaly in a 24-week-old fetus. A 27-year-old primigravida with unremarkable family and environmental history and negative anamnesis relating to infectious diseases was scanned at 24+4 weeks of gestational age, with biometric measurements of the fetus in agreement with the menstrual age (except the head measurements). Scanning revealed macrocephaly (the head perimeter corresponded to 27 weeks) with markedly dilated lateral ventricles, with atrial width of 23-25 mm, with fluttering of the falx, dilated third ventricle and hypoplastic cerebellum (transverse diameter equivalent to 21 weeks) with probable herniation of the cerebellar tonsils into the foramen magnum. The choroid plexus were dangling and hyperechoic. There was mild subependymal hyperechogenicity. The minimum thickness of the cerebral cortex was about 6 mm and maximum about 9 mm. The posterior fontanelle was markedly bulging out. There was a mild splenomegaly and a mild hepatomegaly, with normal echo-structure of the spleen. Minor protosystolic tricuspid regurgitation was observed. The anatomy of the heart was normal and there was no pericardial effusion. There was some hyperechogenicity of the bowel, but neither shadowing, nor ascites or marked dilatation of the bowel was noted. The waveform of the middle cerebral artery was not obtained. The sex of the baby was male. The hands of the fetus were normal, there was normal motion of fingers and thumbs, particularly the thumbs were not adducted. The patient was serologically negative for Toxoplasmosis and CMV and was found positive for Anti parvovirus B19 IgM and IgG. The baby died in utero one week after the presentation and the autopsy confirmed the findings, additionally suggesting myocarditis, although there were some autolytic lesions as the baby was born after an extended period following intrauterine death.

Images 1, 2. 24+4 weeks of pregnancy: 2D images showing transverse plane through fetal skull with marked hydrocephalus (left); and visible cavum septi pellucidi (right, arrow).


Images 3, 4. 24+4 weeks of pregnancy: 2D images showing transverse plane through fetal skull at the level of cerebellum (left) showing mild hypoplasia of cerebellum (transcereberal diameter equivalent to 21st week of pregnancy); and transverse plane of the skull at the level of the bulged occipital fontanel (right).


Images 5, 6. 24+4 weeks of pregnancy: 2D images showing transverse plane through fetal skull at the level of of the bulged occipital fontanel.


Images 7, 8. 24+4 weeks of pregnancy: 2D sagittal plane of the fetal skull showing macrocephaly (left); and sagittal plane through fetal trunk showing striking hepatomegaly (right).


Images 9, 10. 24+4 weeks of pregnancy: 2D images showing transverse plane through fetal abdomen showing hepatomegaly and splenomegaly (left); and four-chamber view of the heart showing minor protosystolic tricuspid regurgitation during Doppler investigation (right).


Video 1, 2. 24+4 weeks of pregnancy: 2D ultrasonography of the skull showing bulging of the occipital fontanel (left); and marked hydrocephalus (right).

Video 3, 4. 24+4 weeks of pregnancy: 2D ultrasonography showing sagittal plane through fetal trunk with striking hepatomegaly and hyperechoic bowel (left); transverse plane through fetal skull showing hydrocephalus with and of the skull showing bulging of the occipital fontanel; and marked hydrocephalus with fluttering of the falx (right).




As far as the frequency is considered, most infections result from epidemics, but sporadic cases also occur quite frequently. Approximately 60% of the population is seropositive for anti-HPV B19 immunoglobulin G by age of 20. The incidence reaches peak in winter and spring. Subclinical infections are common.

Approximately half of childbearing women are B19 seropositive, so they are immune and have low risk to the fetus in case of exposure. Following the control of congenital rubella by pre-pubertal and child vaccination, parvovirus B19 infection has emerged as probably the leading cause of viral embryopathy. In the United States B19V infection is perceived as the most common etiology of hydrops fetalis.


Parvovirus B19 infection


B19V enters susceptible cells by means of the P blood antigen receptor. After the viral particle enters the cell, viral DNA enters the nucleus. The 3" end of the DNA strand folds back on itself, forming a hairpin-like structure that behaves as a self-primer effecting viral DNA replication. The virus attacks mainly erythrocyte precursors, in which it replicates and causes destruction of the contaminated cells. As a result aplastic anemia arises. Occasionally, the virus infects neutrophils. Probably it does not invade other blood cells or blood cells precursors in vivo. Although B19V infection may manifest with pancytopenia, it is not considered to cause real aplastic anemia. Aplastic anemia is mainly observed in patients with underlying hematological disorders (thalassemias, sickle cell disease) or immunodeficiencies. The hematocrit in these patients may decline as fast as 10-15% per day during acute infection. There is evidence that Parvovirus B19 may infect other cell types, and the infection may be associated with myocarditis, vasculitis, glomerulonephritis, rheumatoid arthritis or encephalitis, although the exact role of the B19 virus is not known in such cases. Splenomegaly may be present in infected patients.
Fetal disease resulting from vertical transmission may produce severe anemia with consequential heart failure and hydrops. Hydrops results in fewer than 10% of primary infections of the mother particularly when infection occurs before 20 week"s gestation.
Hydrops fetalis is probably primarily a consequence of anemia, which results in heart failure. The fetus is particularly susceptible to anemia from B19 infection because fetal red blood cells are short lived and while no reticulocytes are produced as the result of infection, circulating red blood cells are used up relatively quickly. Also the immune response of the fetus to foreign antigens is not effective or absent, which leads to chronic infection. Reports of myocardial inflammation and detection of B19 DNA in myocardial fibers raise the possibility of a direct effect on myocardium. Placentomegaly with vasculitis within the villi is also described. Thus, hydrops and fetal demise are due to other causes in addition to anemia, like myocarditis and vasculitis.

Sonographic findings

In fetuses by far the most common sign of severe B19 fetal infection is hydrops. Placentomegaly is the second most frequent symptom. Other abnormalities (rare) associated with B19 infection that may be detected by ultrasound are CNS lesions (e.g. ventriculomegaly, cerebral atrophy), hepatosplenomegaly and abnormal umbilical artery Doppler findings.
Fetal lesions, which are occasionally attributed to B19V infection, include hydrocephalus, calcifications of spleen, endocardial fibroelastosis, meconium peritonitis, and even prenatal stroke (Craze JL, et. al 1998, Schild RL, et al. 1998, Towbin JA, et al. 1994, Suchet I, et al. 2000, Barton LL, et al. 1997, Morey AL, et al. 1992).

For example severe CNS lesions were detected in three infants with serologically proven maternal infection during pregnancy. Neuroimaging studies in those infants showed ventriculomegaly, hydrocephalus, periventricular calcifications, cerebral atrophy or cortical dysplasia. One of those infants died and B19 specific sequences were detected in the brain tissue by PCR. (Conry JA, et al. 1993). In another report autopsy revealed multinucleated giant cells and small calcifications around the vessels, predominantly in the white matter and B19 DNA was found in the brain and liver (Isumi H, et al. 1999).

Differential diagnosis

Other causes of fetal hydrops, heart problems, chromosomal abnormalities, cytomegalovirus, syphilis.

Associated anomalies

There is little evidence to suggest that B19 infection increases the risk of congenital malformation in humans. The most often detected, although rare abnormalities are related to the CNS, myocarditis, hepatosplenomegaly and GI. Abnormalities of other organ systems described in infants or fetuses with evidence of B19 infection represent most probably accidental coincidence.


Recent reports state from 1% up to 9% risk of fetal death in pregnancies with active HPV infection, with the risk of fetal demise greater in earlier pregnancy, while the overall risk of fetal infection is about 30%.


Maternal parvovirus infection during pregnancy continues to be unrecognized or misdiagnosed as it presents as a flu-like viral illness or is asymptomatic. Additionally there is a long interval (up to 12 weeks) between maternal infection and fetal involvement or demise. Most cases are presumably diagnosed if fetal hydrops is present.

If a pregnant woman is exposed to B19V, IgG and IgM serology should be obtained. Definitive diagnosis of B19 infection relies on the detection of B19 IgM or viral DNA. IgM is detectable within three days of onset of symptoms of viremia, and IgG is present several days later. The level of IgM begins to decrease at about one month and is often undetectable by 2-3 months, while IgG persists for years and perhaps for life. B19 serology can be determined using ELISA or RIA. Results of IgM testing can be difficult to interpret and to some extent relies on operator’s skill. B19 DNA can be detected by PCR, which is the most sensitive diagnostic modality can detect B19 sequences not only in serum or amniotic fluid but even in paraffin-embedded tissues. Electron microscopy can also identify viral particles.

  • Positive IgG and negative IgM indicate infection in the past, with probably low risk to the fetus.

  • Positive IgG and IgM indicate infection in the last 3 months, with possible risk to the fetus.

  • Negative IgG and positive IgM indicate acute infection with high risk to fetus.

  • Negative IgG and IgM indicate that the mother is not immune and that no evidence of acute infection exists, serology should be repeated in 3 weeks, appearance of IgM indicates acute infection.

PCR testing for B19 in amniotic fluid/fetal serum provides the most definitive diagnosis of fetal infection, but serological methods are also sensitive and more rapid.

No antiviral therapy is available to treat parvovirus B19 (B19V) infections; although postnatally in aplastic crisis associated with B19 infection IVIG (Intra Venous Immune Globulin) has been shown to be effective in resolution of viremia and improvement in red cell indices.

Fetuses with severe B19-induced anemia have been treated by intrauterine blood transfusions. Spontaneous resolution of fetal hydrops without intervention has also been documented. Therapeutic abortion of a fetus infected with B-19 virus is not indicated.

Older studies suggested that fetal blood sampling should be used to evaluate fetal hematological parameters and thus determine the volume of red blood cells that must be transferred. Newer studies suggest timing of the optimum moment for fetal transfusion based on middle cerebral artery velocimetry. Fetuses with severe hydrops appear to tolerate intrauterine transfusions less well, so it is an important question to start intrauterine transfusions before the onset of hydrops. (Schild RL, et al. 1999).

In some cases improvement of fetal hydrops or cardiac dysfunction was observed after use of digitalis. A recombinant vaccine to prevent B19 infection and complications in high-risk patients is in preparation.



Craze JL, Salisbury AJ, Pike MG. Prenatal stroke associated with maternal parvovirus infection. Dev Med Child Neurol 1996;38:84-85.


Schild RL, Plath H, Thomas P Fetal parvovirus B19 infection and meconium peritonitis. Fetal Diagn Ther 1998;13:15-18.


Towbin JA, Griffin LD, Martin AB Intrauterine adenoviral myocarditis presenting as nonimmune hydrops fetalis: diagnosis by polymerase chain reaction. Pediatr Infect Dis J 1994;13:144-150.


Suchet I, Ens W, Suchet R. Parvovirus B19 Infection in utero – natural history and spectrum of sonographic manifestations in 7 cases. Can Assoc Radiol J 2000;51:198-204)

Barton LL, Lax D, Shehab ZM Congenital cardiomyopathy associated with human parvovirus B19 infection. Am Heart J 1997;133:131-133.


Morey AL, Keeling JW, Porter HJ Clinical and histological features of parvovirus B19 infection in the human fetus. Br J Obstet Gynaecol 1992;99:566-574.


Conry JA, Torok T, Andrews PI. Perinatal encephalopathy secondary to in utero human parvovirus B19 (HPV) infection (abstract 736 S). Neurology 1993;43 (Suppl.):A346.


Isumi H, Nunoue T, Nishida A, Takashima S. Fetal brain infections with human parvovirus B19 . Pediatr. Neurol. 1999;21:661-663.


Schild RL, Bald R, Plath H Intrauterine management of fetal parvovirus B19 infection. Ultrasound Obstet Gynecol 1999;13:161-166.


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