Human parvovirus B19

REVIEW
The Obstetrician
8 Gynaecologist

2003;5:4-9 infection and pregnancy

Khaled MK Ismail, Mark D Kilby
Keywords
fetal anaemia, It is estimated that human parvovirus B19 infection affects 1600-2200
h u m a n pa rvovi r us, pregnant mothers each year in England and Wales. Vertical
hydrops fetalis, (transplacental) transmission occurs in approximately one-third of
intrauterine these maternal infections. In contrast t o the relatively mild clinical
transfusion,
nonimmune
effects of human parvovirus B19 in the mother, fetal infection via
hydrops. haematogenous transplacental spread can be severe and sometimes
fatal. The infection causes a wide range of clinical syndromes. These
varying clinical presentations are described, with the aim of increasing
the diagnostic awareness of readers of possible exposures to human
parvovirus B19 infection during pregnancy and providing an up-to-
date management protocol.

lytic infection of erythroid progenitor cells from

Introduction human bone marrow.’ Intranuclear viral
Human Parvovirus B19 was first discovered by particles typical of human parvovirus B19 have
chance in 1975 at the Central Public Health also been discovered in fetal myoblasts.’
Laboratory during routine screening for hepatitis
B of asymptomatic blood donors from the South
Epidemioloqy
London Blood Transfusion Centre.’ For some
years it remained an orphan virus with no
apparent associated disease. However, in 1981 it
Distribution
was shown to be the causal agent of transient
aplastic crisis (TAC) in patients with sickle-cell Large-scale serological testing for human
anaemia and was later associated with the parvovirus B19 in the UK indicates that
common childhood exanthem, erythema infection occurs throughout the year, although
infectiosum (also known as fifth disease or there is a peak in late spring and early summer
Author details ‘slapped cheek’ syndrome).**’ The first case months. All age groups are affected but it is
reports of human parvovirus B19 adversely most common in younger school-age children.
affecting the fetus appeared in early 1980~.‘*~There are periods of increased activity every
More recently, interest has focused on the effects three to four years, followed by periods of
of persistent human parvovirus B19 infection in relatively lower incidence. Recent epidemic
severely immunocompromised individuals as a years in the UK have been 1989-90, 1993-94
cause of intractable anaemia.6 and 1997-98.

Kholed MK Isinoil MO MRCOG. Human parvovirus B19 belongs to the The outcome for fetuses infected by human
Clinical Lecturer in Obstetrics and parvovirus genus of the family Parvoviridae, parvovirus B19 and who showed ultrasono-
Gynaecology.Academic Unit of
Obstetrics and Gynaecology, Keele which comprises the smallest and the simplest graphic signs of the infection (ascites, hydrops
University School of Medicine, City of the known DNA viruses. I t has a diameter of fetalis or elevated middle cerebral artery peak
General Hospital. North
Staffordshire NHS Trust, UK. 23 nm and contains a single stranded DNA systolic velocities) has been reviewed. Eleven
genome (5.5 kb).The viruses in the parvovirus cases were identified between October 1996 and
genus are species-specific and thus human January 2000 in the Fetal Medicine Centre at
Mark 0 Kilby MD MRCOG,
parvovirus B 19 is the only known pathogenic Birmingham Women’s Hospital; 8 of these
Professor of Fetal Medicine. parvovirus in humans. Parvoviruses can replicate presented in 1998. Therefore, it seems that the
Department of Fetal Medicine,
autonomously but only in dividing cells in the last epidemic has been reflected in this study
Division of Reproductiveand Child
Health, BirminghamWomen‘s S-phase of mitosis (a feature relevant in cases of (unpublished data), as is concordant with data
Hospital, Edgbaston,
Birmingham E l 5 2TG. UK.
fetal B19 infection). I t has been shown to from the Public Health Laboratory Service
email: m.d.kilbyObham.ac.uk replicate in, inhibit colony fortnation and cause Communicable Disease Surveillance Centre.
(correspondingauthor)

4 .__________.
0 2003 Royal College of Obstetricians and Gynaecologists
 presentations will be reviewed in order to raise REVIEW
Transmission and incubation the diagnostic awareness of likely exposures
period The Obstetrician
among pregnant women and of symptoms of the
& Gynaecologist
Transmission is believed to be through respiratory infection occurring in the woman herself.
secretions. In studies with human volunteers,
2003;5:4-9
serum and respiratory secretions become positive Erythema infect i o sum
for human parvovirus B19 at 5-10 days after
intranasal inoculation. However, the rash does not Erythema infectiosum (fifth disease) usually
occur until 17-18 days after inoculation and after presents as a mild childhood illness characterised
the confirmed disappearance of the virus from by fever and facial rash (‘slapped-cheek’
serum and respiratory secretions for at least one to appearance) and a reticulate o r lace-like rash on
five days. Thus, patients presenting with clinical the trunk and extremities. Erythema infectiosum
features of infection are probably past the period of is distributed worldwide and most commonly
maximuni infectiousness. encountered in children younger than 14 years.
T h e illness is less infectious than measles or
T h e transmissibility of the virus is found to be chickenpox, although surveys show that 60% of
approximately 50-90% among susceptible adults have serologic evidence of prior infection.6
household contacts. In school outbreaks, 1 0 4 0 % In adults, the clinical presentation is more
of students may develop erythema infectiosum variable and diffuse: fever, malaise and,
and 20-30‘%, of susceptible staff develop uncommonly, post-infectious arthralgia and
serological evidence of B19 infection. Other arthritis-like symptoms may be present.
mechanisms o f transmission include the Approximately 20% of human parvovirus B19
parenteral route (by transfusion of infected blood infections, confirmed serologically, may be
products) and vertical transmission from mother asympt~matic.~
to fetus. The latter route will be discussed in
more detail.
Transient aplastic crisis
The healthcare professionals to whom women Sickle-cell disease was the first haemolytic
may turn for advice should be aware that anaemia in which transient aplastic crisis was
epidemics of fifth disease pose an increased risk of shown to be associated with human parvovirus
fetal loss to susceptible pregnant women. Blanket B 19. Subsequently, transient aplastic crisis in
decisions on exclusion from work or transfer to a people with other hereditary anaemias
lower risk area are, however, inappropriate. First, (spherocytosis, thalassaemia, pyruvate kinase
serological determination of susceptibility to deficiency) and autoimmune haemolytic
human parvovirus B 19 may be undertaken; anaemia has also been associated with human
women with hunian parvovirus B 19 imniuno- parvovirus B19, as the causal agent.
globulin G (IgG) but no inimuno-globulin M
(IgM) can then be reassured. Aniong patients Other clinical presentations
thought to be susceptible to infection, decisions
should then be made on individual basis. Women “Chronic anaemia” can be a feature of persistent
should be made aware that the risk of acquiring B19 infection in severely immunocompromised
infection in the workplace might be similar to that individuals and has been suggested as a candidate
in the community. For this reason, routine agent in several autoimmune
exclusion from the classroom of susceptible
pregnant teachers who are less than 20 weeks of
Groups ‘at increased susceptibility’
gestation should not be adopted as policy, since it of infection
is not likely to reduce the risk of infection.
However, if there is an outbreak in the school then In a study of seroconversions among susceptible
consideration may be given to excluding school and hospital employees during an
susceptible pregnant employees from the epidemic period, the most important single
classroom until they are more than 20 weeks of factor for seroconversion was daily contact with
gestation.An outbreak would be defined as two or children, either at home or in primary school
more cases in the same class with onset date within settings.” Daily occupational contact with
three weeks or three or more cases in the scliool or school-age children was associated with a five-
rrrtrsery with onset dates within three weeks. times increased likelihood of seroconversion. In
contrast, the rate o f serconversion among
hospital staff was low. T h e annual seroconversion
CI in ica I features rate for susceptible primary school employees
Human parvovirus B19 causes a wide range of was 5.2% compared with 2.4% among other
clinical syndromes. These varying clinical school employees and 0 . 0 4 5 % among hospital

5
 REVIEW employees. Having school children at home was polymerase chain reaction in placental and fetal
almost as important, with seroconversion rates of tissue was more successful in making the
T h e Obstetrician 3.3-5.6%. Parous women may be at greater risk diagnosis than immunohistochernistry and
& Gynaecologist than nulliparous women for the same reason. histology alone. The presence of B19 DNA in
pregnancy losses (second and third trimesters)
2003;5:4-9 was relatively common and in many cases these
Infection in pregnancy
babies were not hydropic.I6 Such conclusions are
Analysis of the results of a serological survey, of great interest but are controversial.
stratified by age, suggests that, on average, slightly
less than 1% of susceptible adults are infected
Nonimmune fetal hydrops
each year. It was estimated from this that
1600-2200 mothers are 'infected' in pregnancy Nonimmune fetal hydrops is the most frequent
each year in England and Wales; that is, one pathological finding in fetuses infected with
infection in every 400 pregnancies." During an human parvovirus B19. I t is estimated to affect
epidemic year there may be two or three times 3% of pregnancies in which B19 infection
more cases than in an average year. In an occurred at 9-20 weeks of gestation.l'The virus
epidemic year for human parvovirus B19 in binds to its cellular receptor, the P-antigen, and
England and Wales, 310 laboratory-confirmed has a tropism for immature erythrocytes in the
infections in pregnancy were reported to the bone marrow and in extramedullary sites,
Public Health Laboratory Service Communi- inhibiting their multiplication." In the fetus, as
cable Disease Surveillance Centre. This in chronic haemolytic anaemia, there is
represents at most 10% of the 3000-6000 shortened red-cell lifespan of 45-70 days.
infections that are estimated to occur." This Moreover, the fetal red-cell mass increases about
demonstrates the extent to which B19 infection 34-fold between the third and sixth months of
is underdiagnosed. gestation; this setting is therefore ideal for an
agent whose intracellular replication depends on
rapidly dividing cells. Virally induced red-cell
Fetal effects
maturation arrest at this time of increased
Human parvovirus B19 has a predilection for demand causes an aplastic crisis with resultant
rapidly dividing cells; the intense viraemia severe anaemia and cardiac failure. The presence
provides ample opportunity for vertical of inflammatory changes in the placenta and
(transplacental) transmission, which is estimated myocardium of hydropic fetuses due to
to occur in 30% of infections." In contrast to the parvovirus infection indicates that hydrops in
relatively mild clinical effects of infection in the these specific cases may not be due to anaemia
mother, fetal infection via haematogenous Indeed, the associated findings of
transplacental spread can be severe and myocardial contractile failure using fetal
sometimes fatal. echocardiography and elevated cardiac enzymes
in fetal blood are described and indicate the
presence of a myocarditis.
Fetal loss
In a prospective study of human parvovirus B19 In fetal medicine centres, such a diagnosis is
infection in pregnancy, the risk of fetal death due considered in babies presenting with
to B19 in an infected pregnancy was estimated nonimmune hydrops fetalis (or isolated ascites),
to be 9%, with the highest risk in the second usually with significantly increased middle
trimester." Applying this fetal death rate to the cerebral artery Doppler velocity indices,
estimated number of infections suggests that indicative of fetal anaemia. Fetal blood sampling
150-200 fetal deaths are caused by B19 in usually demonstrates profound anaemia and
England and Wales each year." often an associated pancytopenia. The presence
of a significant reticulocytosis (greater than 20%)
In a prospective study of women experiencing in fetal blood indicates that, in many cases, the
third-trimester intrauterine fetal death, 7.5% of fetal haemoglobin had probably reached its nadir
these deaths had detectable human parvovirus and likely to rise in response to recovering
B19 DNA in the placental tissues. Because there erythropoiesis. However, the decision to treat an
was no other explanation for these losses, the anaemic fetus in utero will depend upon the
authors concluded that these might have been gestational age at presentation, the degree of fetal
caused by B19 infe~ti0n.I~ This group has gone anaemia present and the associated reticylocyte
on to investigate the detection of human count.
parvovirus B19 in fetal material from pregnancy
losses across gestation. These data indicated that In a review of cases of hydrops fetalis in the West
detection of human parvovirus B19 DNA using Midlands Region, UK, between September

6
1996 and March 1999, human parvovirus B19 serum and in respiratory secretions by REVIEW
infection was the most frequently identified polymerase chain reaction, before the IgM
The Obstetrician
cause of noninimune hydrops. However, 87.5% response develops. However, both viraemia and
& Gynaecologist
of these severely affected pregnancies had a viral excretion are transitory phenomena and
successful Although hydrops due to antibody assay is the recommended method of
2003;5:4-9
U19 infection can resolve spontaneously in up investigation.
to 34%) of cases, there are no clinical or
ultrasound criteria to specifically help the
Fetal diagnosis
obstetrician to identify those that will resolve
spontaneo~sly.~~’~ If maternal infection is confirmed, the fetus
should be followed up by serial ultrasound scans
for the early detection of fetal hydrops. The
Diagnosis and management in
pregnancy period for which serial ultrasound
preqnancv
scans should be performed after a confirmed
Diagnosis of a recent human parvovirus B19 maternal infection is controversial. In a postal
infection might be required in certain clinical survey conducted by Rodis et al.,” the views of
scenarios. These include: 541 members of the Society of Perinatal
a pregnant woman presenting with a rash Obstetricians regarding the management of
human parvovirus B 19 infection in pregnancy
-
illness and/or acute arthropathy
were reviewed. Eight percent of the respondents
maternal exposure (especially before 20
followed-up their patients for 2-5 weeks, 48%
weeks of gestation) to definite human
for 6-8 weeks, 17% for 9-1 1 weeks and 24% for
parvovirus B19-related infection or to a rash
12 weeks.There is some evidence that elevated
- illness of unknown cause
as part of the investigation of intrauterine
maternal serum alpha-fetoprotein (MSAFP) may
be a marker for fetal human parvovirus B19
fetal death and stillbirth
infection.” Interestingly, the association between
investigation of the cause of noninimune
hydrops and B19 infection was first recognised
fetal hydrops fetalis or ascites.
in a patient undergoing an evaluation for
elevated MSAFP
Maternal diagnosis
In cases of unexplained nonimmune hydrops,
A careful history can provide aetiological clues human parvovirus B19 IgM and viral DNA are
and may be important in devising appropriate used to identify fetuses infected with B19. The
advice on prevention. Because of the important appropriate serological tests on the mother
differential diagnosis between human parvovirus would include human parvovirus B19-specific
B19 and rubella, it is important to measure both IgM and IgC. Fetal complications associated
B19 and rubella antibodies. Recent infection with B19 can occur two or more months after
can be diagnosed by detection of human maternal infection, when IgM has fallen to
parvovirus B19 IgM, either by antibody capture concentrations difficult to detect with currently
radioimmunoassay (RIA) or by enzyme-linked available assays. This may account for the
inimunosorbent assays (ELISA). These methods inability to detect IgM-specific antibodies in
detect human parvovirus B19 IgM in both fetal and maternal sera simultaneously in
approximately 90% of cases by the third day after these pregnancies.
the onset of symptoms.” Titres start to decline
3 0 4 0 days after onset but low levels can persist Pregnant women with acute B19 infection
for up to six months in some subjects. For the should be treated symptomatically. If, on follow-
purpose of timing infection in relation to up, fetal hydrops is detected, referral to a tertiary
conception, the serological findings should be fetal medicine centre is prudent. Delivery and
related to the clinical history of exposure or of extrauterine therapy can be considered if the
symptoms. An exposed antenatal patient who is gestational age permits. Otherwise, a fetal blood
seronegative a t the first test should have the sample should be taken to confirm fetal anaemia
human parvovirus B 19 IgM measured again 2-3 and intrauterine transfision to correct it is
weeks later, depending on the timing of the advised.** Conservative management and
exposure (Figure 1). reassessment may be appropriate (if fetal
reticulocyte counts are high) as the fetal hydrops
Human parvovirus B19 IgC can be detected by and anaemia may resolve spontaneously. Thus,
RIA or ELISA. I t is usually present by the the obstetrician (preferably a fetal medicine
seventh day of illness and persists for life. Its subspecialist) must carefully weigh the risks of
presence appears to convey lasting immunity to the available forms of intervention against the
further infection. B19 DNA can be detected in condition and prognosis of the fetus.

7
 REVIEW
The Obstetrician
& Gynaecologist If, after counselling the pregnant woman, a decision is made to investigate

2003;514-9 I

Seropositive Take serum if rash appears or

at 21 days after contact.
Test for IgG and IgM

IgG tve IgG -ve IgM +ve

IgM -ve IgM -ve

Figure 1 Flowchart for the

management of pregnant
women at less than 20
weeks of gestation in
contact with a suspected
or confirmed case of
human parvovirus B19 No risk Need to follow-up future rash contacts Refer to specialist
infection (contact: in the
same room for a fOllOw-Up by
significant period of time ultrasound to detect
(15 minutes or more) or fetal hydrops and
face-to-face contact
during the period from intrauterine transfusion
seven days before the if necessary
appearance of a rash to
the date of appearance of
the rash)

T h e investigation of an unexplained pregnancy Conclusion

loss or stillbirth should include maternal B19
antibody estimations. If human parvovirus B l 9 At present, there is n o role for a routine antenatal
IgM is not detected, it may be possible to screening programme for human parvovirus I3 19
demonstrate seroconversion by measuring B 19 and infection in pregnancy is not an indication
IgC in paired sera if any stored blood is available for therapeutic termination. Women, particularly
from earlier in the pregnancy. Antibodies may those working in close contact with young
also be measured in the fetus or stillbirth. Fetal children, should be given information about
tissues or products o f conception can b e human parvovirus B19 infection in pregnancy.
examined for human parvovirus B19 D N A by This information should not only be given in
dot hybridisation, even if formalin fixed. antenatal clinics but also in preconception and
Immune electron microscopy can also be used to family planning clinics. Human parvovirus B 19
detect B19 virions in a variety of fetal tissues. is an important cause o f nonimniune hydrops. A
Characteristic intranuclear inclusions of significant proportion of these fetuses might
parvovirus-like particles can be detected in fetal recover spontaneously. However, there are n o
tissues by light and by electron microscopy. T h e clinical or ultrasonographic criteria to predict
prospective collection o f such data indicate that this. Therefore it is prudent to refer pregnancies
a n increasing number of'apparently unexplained complicated by nonininiune hydrops to fetal
pregnancy losses' are associated with human medicine centres with facilities for intrauterine
parvovirus B19 infection.16 transfusion.

8
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