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ORIGINAL RESEARCH |
From the Division of Obstetrics and Gynecology, Karolinska Institutet, Danderyd Hospital, Danderyd, Sweden; and Departments of Clinical Virology and Obstetrics and Gynecology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
Address reprint requests to: Kristina Broliden, MD, PhD, Karolinska Institutet, Huddinge University Hospital, Department of Clinical Virology, F68, Stockholm, S-141 86, Sweden; E-mail: kristina.broliden{at}viruslab.hs.sll.se.
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ABSTRACT |
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METHODS: Placental tissues from first-trimester fetal losses were examined for presence of B19 DNA by polymerase chain reaction in a prospective study during 30 months. For comparison, placental tissues from second-trimester fetal losses, as well as from full-term normal pregnancies, were also studied.
RESULTS: B19 DNA was detected by polymerase chain reaction in one of 36 (3%) placental tissues from first-trimester fetal losses. In second-trimester fetal losses, eight of 64 (12%) samples were B19 DNA positive. None of the 53 placental tissues from full-term normal pregnancies were B19 DNA positive. In first-trimester fetal losses, maternal serum from the B19 DNA-positive sample was B19 immunoglobulin (Ig)G positive but B19 IgM negative. In second-trimester fetal losses, six of six tested B19 DNA-positive samples were both B19 IgG and IgM positive.
CONCLUSION: The frequency of first-trimester fetal loss associated with parvovirus B19 infection was low, 3%, during a nonepidemic period in Sweden, as measured by B19 DNA-specific polymerase chain reaction in placental tissue.
Parvovirus B19 is the etiologic agent of the common childhood disease erythema infectiosum (Fifth disease).1 No convincing evidence has been presented regarding the role of primary B19 infection for congenital abnormalities. Infection with the virus was, however, shown to be associated with fetal death.2 The virus is also known to cause fetal hydrops in nonimmune mothers, with the highest incidence occurring during the second trimester, sometimes fatal in outcome.3 Whereas several studies from early second trimester are reported,4 only a few case reports describe the role of B19 infection in first-trimester fetal losses (less than 14 gestational weeks).5–9 Thus, no prospective studies using sensitive techniques for detection of B19 DNA, such as nested polymerase chain reaction (PCR), have been reported for first-trimester fetal losses. By using such techniques, a recent report has shown that B19 infection is associated with third-trimester fetal death in about 7% of subjects.10
Detection of B19 DNA by PCR in placenta, amniotic fluid, cord blood, or fetal tissues at autopsy has proven useful for routine diagnostic purposes and is a necessary complement to serology in fetal complications, including intrauterine death.11 In the present study, we evaluated the presence of B19 DNA in placental tissue to understand if B19 would be associated with early pregnancy loss. For comparison, placental tissues from second-trimester fetal losses, as well as from full-term normal pregnancies, were included.
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MATERIALS AND METHODS |
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Specific B19 immunoglobulin (Ig)G in serum was detected using enzyme-linked immunosorbent assay (Biotrin International, Dublin, Ireland), and B19 IgM was detected using an indirect immunofluorescence test (Biotrin International). Before PCR amplification, frozen tissues were thawed and sections homogenized in a sterile mortar, followed by heat treatment (95C for 10 minutes) and centrifugation (14,000 revolutions per minute for 10 minutes). Two uL of the supernatant were used as a template in the PCR. Nested PCR was performed, as described earlier,13 with primers corresponding to the NS-1 gene. To eliminate sample-to-sample contamination, all procedures were performed in geographically separated facilities for sample preparation, reagent preparation, amplification, and detection using sterile materials and aerosol-resistant pipette tips.
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RESULTS |
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). The positive tissue was from a 35-year-old woman who suffered spontaneous abortion at gestational week 10. No clinical signs of infection were noted before the incident, and maternal serum at the time of abortion was found B19 IgG positive but B19 IgM negative. No serologic signs of acute infection, as determined by presence of B19 IgM, were noted in maternal sera from the placental B19 DNA-negative samples. The prevalence of B19 IgG among the B19 DNA-negative samples was 85%.
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). Maternal sera from all these samples (except two, where serum was not available) tested B19 IgG and IgM positive, indicating an acute or recent infection. All B19 DNA-negative samples were found B19 IgM negative, whereas 87% were B19 IgG positive. Placental tissues from 53 normal pregnancies at term were tested using the same procedure.12 Of these 53 tissues, none were found B19 DNA positive. |
DISCUSSION |
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A B19 DNA-positive placenta may not always represent fetal infection because it can be contaminated by viremic maternal blood. Therefore, PCR should be performed directly on fetal tissues to confirm the diagnosis of B19 infection as a possible cause of fetal death. This was not done in the first-trimester abortion cases in our study because the fetuses did not undergo autopsy. However, by using the same technique and sample conditions, none of the 53 placental tissues from normal pregnancies at term were B19 DNA positive.12 Furthermore, in cases from the second and third trimester, there was a good correlation in the presence of B19 DNA in placental tissues as compared with fetal tissues.10,12
The incidence of adverse fetal outcome after intrauterine B19 infection is unknown. Different studies have used diverse criteria and methods to define congenital infection. Their results have also been influenced by seasonal and geographic variations of viral spread, as well as the gestational age of their subjects. It is clear, however, that the majority of infants born to B19-infected mothers are delivered at term and are then asymptomatic.17–19 In a prospective evaluation of pregnant women exposed to parvovirus B19, 50% were found immune. Of the nonimmune women, 17% later contracted a B19 infection.19 In one study, an increase of fetal loss by 9% during the first 20 weeks’ gestation was found in B19-infected women, with the largest excess concentrated at 9–16 weeks, whereas cases after week 20 were rare.18 Furthermore, women with serologically confirmed B19 infection showed a significantly higher second-trimester fetal loss rate (11.8%) than a control group.18 Still, the rate of fetal mortality caused by B19 infection has not been determined.
B19 infects immature erythroblasts and thereby arrests red blood cell production. Destruction of erythroid lineage cells may partly be caused by apoptosis induced by the nonstructural protein of B19.20 The infected fetus may be especially vulnerable to this because of its high erythrocyte turnover rate and its immature immune system. The resulting anemia may lead to congestive heart failure and fetal hydrops. Because of the overwhelming B19-induced anemia leading to high output cardiac failure, smaller fetuses might die relatively quickly. Larger fetuses, however, may have a larger hematologic reserve, which allows time for the development of hydrops. Other mechanisms of fetal death from B19 infection may include placental edema and obstruction of venous return caused by ascites.3 Additionally, the virus can directly infect fetal cardiac cells,21,22 causing clinical complications.23,24 Direct infection of endothelial cells may cause vascular damage in fetuses,25 and, finally, hypoxic damage to the capillary bed may produce increased capillary permeability, leading to fetal complications.
Maternal B19 infection is often atypical or asymptomatic, which contributes to diagnostic difficulties. Our first-trimester B19 DNA-positive sample showed no clinical signs of recent or ongoing infection, which is consistent with data from late pregnancies where none of the women experiencing B19-associated fetal deaths could recall any recent signs of infection.10,12 The rash, usually seen in children, is much less frequent in adults, whereas joint problems are more common. There are also limitations to the use of maternal serology in diagnosing B19 infections during pregnancy. IgM titers may have already dropped to undetectable levels by the time fetal symptoms appear,6 and development of IgG may be delayed.10,11 Furthermore, one study found that serologic responses to B19 in infants can be a variable: only a few infants in whom PCR of viral DNA confirmed a congenital B19 infection demonstrated a positive B19 IgM response in cord blood, and only two of nine infants infected during the first 14 weeks of pregnancy were IgM positive at delivery, whereas all four infected in the last trimester had B19 IgM in cord blood.14 IgM antibodies appear in the middle of pregnancy, which makes diagnostic tests of specific IgM in the fetus less sensitive.4 Infants exposed to the virus earlier in gestation are less likely to produce an IgM response either because the fetal immune system is immature or because passively acquired maternal antibodies may prevent the production of viral-specific IgM, perhaps even inducing a state of tolerance. It was, therefore, of particular importance to clarify the B19 incidence in early pregnancy using detection of the viral genome by PCR.
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Footnotes |
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Received June 5, 2001. Received in revised form November 26, 2001. Accepted December 26, 2001.
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REFERENCES |
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This article has been cited by other articles:
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  M. S. Amstey and K. Broliden Detection of Human Parvovirus B19 Infection in First-Trimester Fetal Loss Obstet. Gynecol., October 1, 2002; 100(4): 831 - 832. [Full Text] [PDF]
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