Human Parvovirus B19 in pregnancy

S F Wong王紹宏, C B Chow周鎮邦, L C Ho何樓章

HK Pract 2003;25:263-269

Summary

Parvovirus B19 infection in pregnant women is associated with hydrops foetalis and increased foetal loss. Some of the foetal losses can be reduced by intra-uterine transfusion. General practitioners and obstetricians caring for pregnant women should be aware of this virus and the usual clinical features of women contracting this disease during pregnancy. This review article outlines the appropriate management protocol for human Parvovirus B19 complicating pregnancy..

摘要

懷孕婦女受到微小病毒B19感染可以引致嬰兒水腫及死亡。接受宮內輸血可以減少嬰兒死亡。照顧孕婦的全科及婦產科醫生應對此種病毒及其臨床病徵有所認識。本回顧文章並概述了合適的診治方案。

Introduction

Since the discovery of human Parvovirus B19 infection in 1983,¹ there has been good evidence that such infection during pregnancy can result in foetal death.² It has been shown that up to 25% of non-immune foetal hydrops in anatomically normal foetuses detected during pregnancy are due to this infection.³ A recent report has suggested that human Parvovirus B19 infection in pregnancy might be the cause of some third-trimester stillbirths.⁴

General practitioners and obstetricians caring for pregnant women should be aware of this virus and the usual clinical features of women contracting this disease during pregnancy. Some of the foetal loss secondary to Parvovirus infection can be reduced by intrauterine transfusion.⁵ Unfortunately, in a prospective review of over 600 pregnant women exposed to Parvovirus, it was shown that 33% of women with the infection were asymptomatic.⁶

The purpose of this article is to offer a narrative review of the published data and evaluate the management of women exposed to, or infected with, Parvovirus infection during pregnancy. In this review article we outline the clinical features of Parvovirus infection, the management protocol during pregnancy and the appropriate screening programme.

Parvovirus B19 infection

Human Parvovirus B19 is the only member of the Parvovirus family that is pathogenic in humans. Parvovirus B19 is a small non-enveloped single-stranded DNA virus measuring between 18 to 26nm. The virus binds to P-antigen on the cell surface and is incorporated into the human genome. This leads to viral replication and subsequent cell lysis. P-antigen is commonly expressed on erythrocytes and erythroblasts. However, P-antigen is also present on megakaryocytes, placental cells, foetal liver and heart cells.

The infection is normally transmitted through respiratory secretions and is highly contagious. Viraemia develops 7 days after inoculation and persists for up to 4 days. A macular rash usually appears 16 days after inoculation, or 5 days after disappearance of the virus from the circulation.

Figure 1: Picture of a child with erythema infectiosum, showing bright red malar eruption or slapped cheek syndrome

Parvovirus B19 infection is a common childhood disease with peak incidence at 5-10 years of age. The symptoms of erythema infectiosum in children include fever and "influenza-like" symptoms followed by a biphasic rash. A bright red malar eruption (slapped cheek syndrome) is followed by maculopapular rash on the extremities and trunk (Figure 1). In adults, arthralgia is more common. A study on 618 women exposed to Parvovirus B19 infection during pregnancy showed that in women with proven infections, 46% had arthralgia; 38% had rash and 19% had fever.⁶ Up to 33% of women with Parvovirus infection did not have any symptoms. Aplastic crisis can occur in susceptible individuals, especially patients with chronic haemolytic anaemia such as sickle cell anaemia, thalassaemia, pyruvate kinase deficiency and hereditary spherocytosis.

During pregnancy, maternal infection can result in trans-placental infection. This infection can cause miscarriage, foetal death and foetal hydrops. Studies have shown a foetal loss rate of about 5-10%.⁵ A few case reports of persistent aplastic anaemia after birth have been described in foetuses exposed to in-utero Parvovirus infection.

Background immunity and risk of seroconversion

Various reports on background immunity have been published from the United States, Europe, Middle East and Hong Kong. These studies showed that 35-65% of pregnant women had Parvovirus IgG antibodies before pregnancy.^7,8 These women are immune to future Parvovirus B19 infection. The background immunity varies between countries, and different age groups; highest being among women with children.^7,8

Valeur-Jensen et al (1999) investigated the risk of seroconversion during pregnancy. They studied 30,946 serum specimens obtained in the first trimester and found that 10,824 (35%) women did not have immunity to Parvovirus.⁸ Dried blood spots of the babies for 95 % of these women (9221) were analysed and the seroconversion rate was assessed. A seroconversion rate of 1.5% (95% confidence interval 0.2-1.9%) was reported during the endemic period. The seroconversion rate increased to 13% during an outbreak of Parvovirus infection (95% confidence interval 8.7-23.1%).

Valeur-Jensen et al (1999) also assessed the risk of acute infection and associated risk factors.⁸ The risk of acute infection during pregnancy was related to the number of children in the household and occupation of the women. The odds ratio of acute infection was 7.5 (95% CI 3.8-14.9) if the women had 3 or more children. The risk also increased in women with children aged 6-7 years (Odds ratio of 4.1, 95% CI = 1.9-8.7). For nursery school teachers, the odds ratio of acute infection was 3.1 (95% CI = 1.6-5.9). Other factors reported to be significantly associated with increased risk of acute B19 infection in pregnancy during a Parvovirus epidemic included serious medical diseases and having a stressful job.

For women exposed to erythema infectiosum, the risk of infection depends on the type of exposure. Up to 50% of women exposed to their own children with Parvovirus infection will seroconvert. Exposure at childcare centres or at schools will cause 30% of women to seroconvert. The lowest risk of seroconversion (20%) is among women exposed in the community.

Figure 2: Flow chart showing the outcome of human Parvovirus B infection, especially on pregnant women and their unborn foetuses

Foetal risk

Figure 2 shows the possible outcomes among women who contracted human Parvovirus B19 during pregnancy. The maternal to foetal transmission rate of Parvovirus is estimated to be 33%. Foetal loss rate of 5-10% has been reported from large prospective studies on women with acute Parvovirus infection in pregnancy.² The incidence of foetal hydrops reported in retrospective studies ranged from 1-3%.⁹ Lower incidence of foetal hydrops (0.6%) was reported in prospective studies.^2,8 It must be borne in mind that in retrospective studies, women with abnormal outcomes were more likely to be included. Foetal loss rate also varied among women exposed at different gestations. Exposure in the first and early second trimesters (<20 weeks) is associated with the highest loss rate.⁹ Although hydrops foetalis has also been reported in the first trimester, it occurs more commonly in the second trimester. Women exposed during the third trimester do not usually present with foetal hydrops. This may be due to improved placental function and increased transport of maternal Parvovirus IgG antibodies into the foetus, hence reducing the risk of significant foetal infection. Nevertheless, Parvovirus infection in the third trimester of pregnancy may not be totally benign, and may still be associated with stillbirth.⁴

The overall risk of foetal hydrops in women with acute Parvovirus infection is 1-3%. This usually occurs 3-6 weeks after maternal infection, although a case of hydrops foetalis has been reported 12 weeks after acute maternal Parvovirus infection. The mechanism of foetal hydrops is mainly cardiogenic heart failure secondary to severe anaemia. There have been a few case reports of foetal hydrops in foetuses with mild anaemia. These were thought to be due to viral myocarditis. Viral particles have indeed been detected in cardiac tissue by electron microscopy and in-situ hybridisation techniques.

The outcome of foetal hydrops depends on the gestation at detection, severity of hydrops, and whether any treatment has been given. Summarising the findings in the literature,^5,9 approximately one third of foetal hydrops will resolve spontaneously, the majority of these belonging to those with mild features of hydrops. Another third of all reported cases die in-utero. The other third will have intra-uterine transfusion performed with reported foetal loss rate of less than 20%. Fairley et al (1995) compared the outcome of foetal hydrops with and without intra-uterine transfusion.⁵ They found that with intra-uterine blood transfusion, the odds ratio of intra-uterine death was 0.14 (95% CI = 0.02-0.96) after adjusting for the severity of hydrops and gestation.

Parvoviruses are potent teratogens in the animal kingdom. However, teratogenic effect has not been clearly established in human studies. Another prospective study found that there was no increase in the congenital anomaly rate among babies exposed to Parvovirus infection before birth.¹⁰ A study with a ten year follow-up of children exposed to Parvovirus infection in-utero did not find any increase in long-term sequelae.⁵

Prevention

Unfortunately, avoiding exposure to Parvovirus is not practical because most patients with Parvovirus infection have non-specific symptoms or are asymptomatic. Symptomatic patients are infectious before their clinical illnesses. Gillespie et al compared the infection rates between non-pregnant schoolteachers who did not leave the workplace during an outbreak and pregnant schoolteachers who did.¹¹ They did not find any difference in infection rates between these two groups of women, so there may not be any justification for pregnant women to leave the workplace during an outbreak of erythema infectiosum.

Passive immunity may be considered once a susceptible pregnant woman becomes exposed to Parvovirus infection. Commercially available intravenous immunoglubulin, being a pooled product, virtually always contains Parvovirus IgG antibodies. Reports on the use of intravenous immunoglobulin in pregnancy showed that it appeared to be effective in modifying the clinical course of the disease.¹² Commercially available intravenous immunoglobulin has also been used to treat persistent infection. The small risk of transmission of infective diseases such as hepatitis C, and anaphylactic reactions has to be weighed against the small risk of foetal loss.

Currently, there is no available vaccine against human Parvovirus B19, although vaccination for Parvovirus infection has been widely used in the poultry industry. Human Parvovirus B19 vaccine is currently being developed. Theoretically, once such a vaccine becomes commercially available, it can be administered to susceptible adult women before or during pregnancy. It can also be administered to all children, eliminating them as vectors for transmission of the virus to pregnant women. The cost-effectiveness of such a vaccination programme needs to be assessed before it can be recommended. Another approach is to vaccinate susceptible women during an outbreak of erythema infectiosum. Thus, before human Parvovirus B19 vaccine is available, routine screening among pregnant women is not recommended.

Management of human Parvovirus B19 in pregnancy

An appropriate approach to prevent foetal loss due to Parvovirus B19 is to increase the awareness of all health care workers regarding this disease and its effect on the foetus. General practitioners treating family members with erythema infectiosum should explore the possibility of pregnancy in other family members. Those cases with direct exposure to this disease should be screened for Parvovirus infection. When attending pregnant women presenting with arthralgia or rash, specific questions regarding possible contact with children with erythema infectiosum should be explored. Appropriate investigations as outlined below should be performed for those in whom there is high suspicion of Parvovirus infection.

Serological testing for Parvovirus IgG and IgM should be performed in pregnant women documented to have been exposed to the infection. Testing for Parvovirus IgG antibody can be performed using retrieved serum taken at the first antenatal booking visit. Women who already have anti-Parvovirus IgG are immune to further infection. For women without Parvovirus IgG antibodies, blood tests should be performed to test for the presence of Parvovirus IgM antibodies. A second blood test in 1-2 weeks is required for women without Parvovirus IgG or IgM antibodies. The presence of Parvovirus IgM antibodies in a recent sample indicates acute infection.

Pregnant women proven to have recent acute Parvovirus B19 infection should be referred to foetal medicine units for counselling and assessment. Serial weekly ultrasound scans for at least 8 weeks should be offered. Serial scanning for up to 12 weeks may be needed because there are a few case reports of foetal hydrops up to 12 weeks after acute maternal infection.

Ultrasound scan assessment in these cases should include assessment for early signs of foetal anaemia, such as increase in cardiac size, middle cerebral arterial peak flow, and/or liver size.^13,14 Features of foetal hydrops such as ascites, pleural effusion or skin oedema should also be carefully sought. These types of monitoring should preferably be performed in a tertiary foetal medicine unit. If the foetus does develop hydrops foetalis, cordocentesis and intra-uterine blood transfusion should be offered for cases with moderate or severe anaemia. Cord blood should be collected for Parvovirus polymerase chain reaction assay for confirmation of infection (Figure 3).

Figure 3: Flow chart of the management of pregnant women suspected to have or exposed to Parvovirus B19 infection

The management of mild foetal hydrops is more controversial, as mild foetal hydrops may be due to viral myocarditis, unrelated to anaemia. Many would advise conservative management of the foetuses with mild foetal hydrops with daily ultrasound monitoring.⁶ If the condition worsens, cordocentesis should still be offered. Whether the assessment of middle cerebral artery peak flow can help to differentiate moderately anaemic foetuses from those with viral myocarditis needs to be evaluated.¹³

Intra-uterine blood transfusion, if performed, should preferably be accompanied by platelet transfusion because in the majority of affected pregnancies, mild to moderate foetal thrombocytopenia is also present. After initial cordocentesis, the pregnancy should be monitored regularly to assess the response as well as the need and timing for subsequent intra-uterine transfusions.

Conclusion

Human Parvovirus B19 infection in pregnancy is associated with foetal loss. Serological testing should be offered to women who are exposed to the infection, or suspected of having Parvovirus B19 infection. Women with proven acute infection during pregnancy should be monitored with serial ultrasound scans. Intra-uterine blood transfusion appears to be able to reduce the mortality rate of hydrops foetalis due to human Parvovirus B19 infection.

Key messages

1. Human Parvovirus B19 is a benign viral disease of children, usually presenting as facial rash, fever and "flu-like" symptoms.
2. In adults, it causes rash and arthralgia but up to 30% are asymptomatic.
3. There will be a substantial risk to the first- and second-trimester foetuses with up to 15% foetal loss rate. However, Parvovirus infection does not have a teratogenic effect on surviving foetuses.
4. Currently, there is no commercial vaccine available and the disease cannot be prevented.
5. To prevent foetal losses, screening for pregnant women who have been exposed to or contracted human Parvovirus B19 is advisable.
6. Booking serum should be screened for anti-Parvovirus IgG. (Figure 3)
7. For women with no anti-Parvovirus IgG (35%), anti-Parvovirus IgG and IgM should be checked and repeated 2 weeks later. Presence of IgM or recently detectable IgG indicates recent infection.
8. All pregnant women with documented Parvovirus infection during first- and second-trimester should be referred to Foetal Medicine Unit for monitoring of their foetuses.
9. Serial ultrasound monitoring should be performed on these women on weekly basis, looking for early sign of foetal anaemia.
10. Timely intra-uterine transfusion has been shown to reduce foetal loss rate.