CASE REPORT

Unexpected Intrauterine Fetal Death in Parvovirus B19 Fetal

Infection
Enrico Silingardi, MD,* Anna Laura Santunione, MD,* Francesco Rivasi, MD, Bernard Gasser, MD,
Silvia Zago, MD, and Lorella Garagnani, PhD,
Abstract: Parvovirus B19 infection during pregnancy can be transmitted to
the fetus through the placenta. The consequences for the health of the fetus
are very variable and can be very serious. They include intrauterine fetal
death (IUFD) and miscarriage, which can lead to medico-forensic questions.
For the most part, cases of IUFD take place during the second trimester of
gestation and present an anatomopathologic picture characteristic of fetal
infection with hydrops, placental edema, serous effusion, and erythroblasto-
sis with nuclear inclusions. Endocardial broelastosis, medullar and thymic
hypoplasia, and hepatic hemosiderosis are frequently present. In the third
trimester, the cases are less frequent, not accompanied by hydrops, and can
depend more on placental compromise than on direct infection of the fetus.
We present 5 cases of IUFD resulting from parvovirus B19 and we discuss
the pathogenetic and anatomopathologic aspects and obstetric liability. In 4
cases, the IUFD took place suddenly, in the absence of symptoms, in women
who had not previously shown any symptom of the viral infection. In one
case, the patient was hospitalized following an ultrasound diagnosis of fetal
hydrops and IUFD took place 5 days after admission. Of these cases 3 were
veried in the second trimester and 2 in the third trimester. Only the cases of
the second trimester and one of the 2 cases of the third trimester presented
the characteristic aspects of fetal infection. The other case of third trimester
was characterized by placental involvement.
Key Words: unexpected intrauterine fetal death, parvovirus B19 infection,
anatomopathologic diagnosis, obstetrical liability
(Am J Forensic Med Pathol 2009;30: 394397)
P
arvovirus B19 (B19) is a nonenveloped, single stranded DNA
virus.
1
It exclusively infects man and shows a marked trophism
for the precursors of erythroid cells.
2
B19 infections show a seasonal trend, having greater fre-
quency in the winter and the beginning of spring. Because the major
part of the infections are found among young children of school age,
the most exposed adults are the parents of children in this age group
and people working in the scholastic community.
2
B19 is usually transmitted through the respiratory tract, but other
possible modalities of transmission are organ and bone marrow trans-
plants as well as blood transfusions and hematic derivatives.
2
Clinical
manifestations are present in only 25% to 50% of the infected subjects
and include, above all, erythema infectiosum (also known as fth
disease), characterized by a cutaneous rash and, in particular in adults,
by arthralgia. In immunocompromised patients, the infection can cause
aplastic crises, whereas immunocompetent patients recover spontane-
ously, leaving them with a permanent immunity.
2
Transplacental transmission from mother to fetus has been doc-
umented.
1
It can take place in any phase of pregnancy,
2
but is more
frequent in the rst 2 trimesters and can have variable consequences. In
fact, it can be asymptomatic both for the pregnant woman and for the
fetus but, in some cases, it can provoke severe fetal complications and,
in rare cases, intrauterine death (IUFD) or miscarriage,
2
with possible
consequences on a medico-forensic level.
We present 5 cases of maternal-fetal infection from B19
followed by IUFD. All the patients had been exposed to infection
from B19 but the absence of symptoms of infection had convinced
physicians not to activate programs monitoring fetal conditions. In
all the cases examined, the investigation pointed out pathologic
signs and laboratory characteristics of B19 infection, in 4 cases as a
direct infection of the fetus and in 1 case as a placental involvement.
METHODS
From 2001 to 2005, we reviewed 5 cases of maternal-fetal
infection from B19 followed by IUFD observed. Three of these
cases took place in the second trimester of pregnancy and the other
2 cases in the third trimester. In 4 cases, the IUFD took place
suddenly in the absence of prodromic clinical manifestations; in 1
case, the patient was hospitalized following an ultrasound diagnosis
of fetal hydrops and IUFD took place 5 days after admission.
All the fetuses, whose degree of development corresponded to
their gestational age, were autopsied and appeared to be in an optimal
state of conservation. Histopathological examinations were carried out
on the encephalon, heart, lungs, liver, spleen, kidneys, thymus, bone
marrow, and placenta, using HE methods, Azan-Mallory for collagen
bers, Weigert for elastic bers, and Perls for hemosiderin. The diag-
nosis was made by the histopathological identication of the typical
nuclear inclusions in cells of erythroid series (erythroblasts) or placental
involvement. Diagnostic conrmation was obtained through research
on B19 DNA, using PCR analysis carried out on histologic sections of
the lung, liver, spleen and placenta.
CASE REPORTS
Case 1
A 38-year-old patient in her 21st week, in good health, who had
a normal pregnancy, was admitted following a casual ultrasound nding
of fetal hydrops and notable placental thickening. The same ultrasound
had documented increase in peak velocity of the middle cerebral artery
due to a condition of anemia and encephalic hypoxia; the amniotic uid
was within the norm. IUFD took place 5 days after admittance.
The fetus was male, weighed 440 g, 25.5 cm in length.
Autopsy showed cutaneous purpura, diffuse hydrops and ascites,
increased liver, and placental volume. Malformations or structural
anomalies were absent. Histology showed erythroid hypoplasia of
the bone marrow, numerous intravascular erythroblasts with eosin-
ophilic nuclear inclusions from B19 in the liver and the kidneys,
Manuscript received June 1, 2007; accepted March 20, 2008.
From the *Department of Legal Medicine, University of Modena and Reggio
Emilia, Modena, Italy; The Department of Pathological Anatomy, University
of Modena and Reggio Emilia, Modena, Italy; Service of Pathologic Anat-
omy, E. Muller Hospital, Mulhouse, France; and Service of Pathological
Anatomy, Ravenna Hospital, Ravenna, Italy.
All gures can be viewed in color at http://amjforensicmedicine.com.
Reprints: Enrico Silingardi, MD, Department of Legal Medicine, University of
Modena and Reggio Emilia, Largo del Pozzo 71, 41100 Modena, Italy.
E-mail: enrico.silingardi@unimore.it.
Copyright 2009 by Lippincott Williams & Wilkins
ISSN: 0195-7910/09/3004-0394
DOI: 10.1097/PAF.0b013e3181c17b2e
Am J Forensic Med Pathol Volume 30, Number 4, December 2009 394 | www.amjforensicmedicine.com
endocardial broelastosis (Fig. 1A), and thymic hypoplasia with
lymphocytic depletion.
Furthermore, there was hepatic hemosiderosis and intense
edema of the chorionic villi.
Case 2
A 29-year-old patient, in good health who had a normal preg-
nancy. IUFD in the absence of symptoms in the 24th week.
The fetus was male, weighed 640 g, 32.5 cm in length. Autopsy
showed cutaneous purpura, diffuse hydrops, bilateral pleural effusion
and ascites, and increase in liver and spleen volume. Malformations or
structural anomalies were absent. Histology showed intravascular
erythroblasts with eosinophilic nuclear inclusions from B19 in various
organs (Figs. 1B, C), evident endocardial broelastosis extending to the
4 cardiac cavities, moderately branched into myocardial interstice,
thymic hypoplasia with lymphocytic depletion, and, in addition, hepatic
hemosiderosis and edema of the chorionic villi.
Case 3
A 35-year-old patient in good health who had had a normal
pregnancy. IUFD in the absence of symptoms in the 28th week.
The fetus was female, weighed 1200 g, 38.5 cm in length.
Autopsy showed diffuse hydrops, very pronounced in the cranial and
thoracoabdominal region, bilateral hydrothorax and ascites, and
modest increase in liver and spleen volume.
Histology showed eosinophilic nuclear inclusions from B19 in
numerous intravascular erythroblasts in liver and spleen. In addition,
there was hepatic hemosiderosis and pronounced placental hydrops.
Case 4
A 28-year-old patient in good health who had had a normal
pregnancy. IUFD in the absence of symptoms at the 21st week.
The fetus was male, weighed 495 g, 25 cm in length. Autopsy
showed diffuse hydrops, hydropericardium, hydrothorax and a mod-
erate ascites, pronounced dilatation of cardiac ventricular chambers
and volumetric increase of the spleen.
Histology showed erythroid hypoplasia of the bone marrow,
intravascular erythroblasts with eosinophilic nuclear inclusions from
B19 at the splenic level, endocardial broelastosis particularly
evident in the right ventricle, thymic hypoplasia with lymphocytic
depletion; in addition, hepatic hemosiderosis and brosis, intense
edema, and erythroblastosis of chorionic villi (Fig. 1D).
Case 5
A 28-year-old patient in good health who had had a normal
pregnancy. At the 31st week, ultrasound showed regular fetal
growth and slightly increased amniotic uid. IUFD at the 39th week.
The fetus was male, weighed 3050 g, 54 cm in length.
Autopsy showed cutaneous purpura, moderate subcutaneous edema,
ascites, hydroceles, and subpleural petechiae.
Histology showed edema and inltration of the polynucleated
cells in the chorionic membranes, appearance of necrosis, calcica-
tion of the villi, and absence of erythroblastosis.
PCR ANALYSIS
Materials
Analysis was carried out to determine the presence of B19
DNA in cases of IUFD using parafn-embedded tissue: fetal lung,
liver, spleen tissue, and placenta.
DNA Extraction
Three 5 m sections from each block were cut with a
microtome. To prevent carryover of contaminating DNA, a fresh
blade was used for each sample and the microtome overlay was
covered with a piece of adhesive tape changed for every sample. The
cut sections were deparafnized by washing twice with xylene and
twice with 100% ethanol. After evaporation of the ethanol, 200 L
of digestion buffer (50 mM Tris pH 8.5, 1 mM EDTA, 0.5% Tween
20 and 200 g of proteinase K per mL) was added and the mixture
was incubated for 3 hours at 56C. Proteinase K was inactivated by
incubating the samples at 95C for 10 minutes.
Polymerase Chain Reaction
For the PCR, 2 different primer sets were used: one set
(primer set A) generating a DNA fragment located on the genoma
part coding for nonstructural proteins and another set (primer set B)
in the structural protein part of the genome.
Primer set A:
1. 5-ACTGGTGGTGCTCTTTACTG-3 (bp 497516)
2. 5-TAACCCCTCTACACACACTG-3 (bp 744725)
Primer set B:
1. 5-CAAAAGCATGTGGAGTGAGG-3 (bp 31873206)
2. 5-CCTTATAATGGTGCTCTGGG-3 (bp 32903271)
Primer sets A and B generate DNA fragments of 248 bp and
104 bp, respectively.
The total reaction volume in PCR was 50 L and the reaction
mixture contained 200 M each of dATP, dCTP, dGTP, and dTTP,
50 mM KCl, 10 mM Tris (pH: 8.3), 2 mM MgCl
2
, 1 g of each
primer for both strands and 1 U of AmpliTaq Gold DNA Polymerase
(Applera Italia). Thirty-two incubation cycles were carried out. The
PCR for both primer sets was conducted with an initial 10 minutes
denaturation step at 94C coupled with a repeating cycle of 1 minute
at 94C, 2 minutes at 55C (reannealing) and 2 minutes at 72C
(primer extension).
Detection of PCR Products
For the analysis of the amplied products of the PCR per-
formed on each primer set, 10 L of reaction solution were analyzed
on 3% agarose gel containing 1 g of ethidium bromide per mL.
Results
The PCRs were positive in overall the tissues examined (Fig. 2).
FIGURE 1. A, Endomyocardial fibroelastosis. Trichromic Azan
4. B, Spleen: erythroblastosis with nuclear inclusions from
B19 (arrows). He 40. C, Kidney: glomerular erythroblasto-
sis with nuclear inclusions from B19 (arrows). He 60. D,
Placental edema and erythroblastosis without nuclear inclu-
sions. He 40.
Am J Forensic Med Pathol Volume 30, Number 4, December 2009 Intrauterine Fetal Death
2009 Lippincott Williams & Wilkins www.amjforensicmedicine.com | 395
DISCUSSION
B19 infection during pregnancy can have very different
clinical pictures and results, ranging from the total absence of
maternal and fetal symptoms to transitory hydrops of the fetus, to
IUFD and miscarriage which constitute the most serious events
3,4
and can raise important medico-forensic questions.
Fifty percent of pregnant women are immunologically sus-
ceptible to contracting B19 infection, but the incidence of maternal
infection varies from 16.7% to 21% of the total number of women
exposed.
35
About 25% of these patients do not present clinical
symptoms.
6
The risk of vertical maternal-fetal transmission through
the placenta is about 30% of the maternal infections
2
and is consid-
ered to be more probable in the rst 2 trimesters, becoming less
frequent as the gestational age progresses. This depends on the fact
that the antigen of blood group P (P-ag), the principal antigen
necessary for maternal-fetal transmission, is present to a lesser
degree at the placental level as the gestational age increases.
7
The
total incidence of important effects on the fetus (hydrops, IUFD) is
between 5% and 10% of the patients infected.
4,8
Nevertheless, there
are a number of studies in which no case of hydrops was reported in
pregnant patients exposed to the infection.
3
The incidence of IUFD
from B19 in North America and Europe has been estimated to be
less than 1 of 1000 pregnancies per year.
9
A large study carried out
by the Society of Perinatal Obstetricians pointed out that IUFD
affects 30% of fetuses with hydrops who are not transfused, and only
6% of those fetuses which are transfused.
10
Between the exposition of a pregnant woman to the infection
and the manifestation of the clinical fetal picture, there is, on the
average, an interval of 6 weeks, at times even a few months, and
infection of the fetus can take place even in the absence of clinical
and laboratory signs of maternal infection.
2
In fact, the infection can
be asymptomatic, and seroconversion can take place even months
after contagion.
11
All this does not make it easy to predict fetal
infection and IUFD.
Fetal infection can cause anemia since the virus determines
cytotoxic apoptosis and the lysis of erythroid precursors and, in this
way, it inhibits erythropoiesis.
9
The presence of the virus in the
erythroid precursors is revealed by the typical nuclear inclusions.
12
The nuclei of the erythroblasts present an intensely margined and
colored chromatin; the center of the nuclei is more luminous and
appears homogeneous and vitreous.
12
Anemia can lead to cardiac insufciency and hydrops, which
can be of varying degrees. Other anatomopathologic aspects
12
cor-
related to fetal infection from B19, such as hepatosplenomegaly,
hemosiderosis, and hepatic brosis from an excess of erythrolysis,
have been described. The placenta can show an increase in weight,
a pallid and edematous appearance due to hydrops, and inamma-
tory inltrates of the villi which can lead to necrosis and calcica-
tion. The heart can be normal or symmetrically enlarged, with
endocardial broelastosis; the thymus can be abnormally small due
to lymphocytic depletion.
12
The characteristics and the extent of the fetal damage vary
according to the trimester of pregnancy in which the contagion takes
place. In the rst trimester, miscarriage has been reported in 3%of cases
but the causal connection with B19 infection remains difcult to
demonstrate.
13
Isolated reports of cases of embryopathy have not been
conrmed.
14
Clinical manifestations of fetal damage are more frequent in
the second trimester.
2
This probably depends on the fact that, in this
phase of the pregnancy, the concentration of P-ag in the placental
trophoblast is still elevated.
9
Furthermore, very intense hematopoi-
esis is prevalently located in the liver, the average life of the
erythrocytes is shortened (4570 days) and fetal growth requires a
rapid increment of 3 to 4 times the erythrocytic mass.
15
In this way,
the fetus is more vulnerable to a condition of erythrocytic damage
induced by the virus. Histopathological examinations reveal the
typical nuclear inclusions in intravascular erythroblasts.
12
Our investigation documented 3 cases of IUFDwhich took place
in the second trimester (cases 1, 2, 4) in which the ndings of major
importance corresponded with a typical anatomopathologic picture,
conrming the specic pathogenesis. In addition, we observed an
endocardial broelastosis of varying degrees in these 3 cases which was
not always accompanied by an increase in cardiac dimension.
IUFD can also take place, but with a lesser frequency, in a
more advanced phase of gestation. In the major part of cases which
take place during the third trimester, hydrops is absent,
16
and, in
many cases, clinical and laboratory signs of a recent maternal
infection are not found.
9,11
According to the prevailing opinion, this
comes from the reduced concentration of placental P-ag and the
normalization of the average erythrocytic life.
2
In this period, the
persistence of the maternal infection can, nevertheless, determine
inammatory and degenerative phenomena in the placenta,
17
whose
dysfunction may be a cause of IUFD, even without fetal infection.
2
In these cases, histopathological examinations of the fetal organs do
not show particular alterations or the typical viral inclusions.
18
A similar typology nds substantial correspondence in case 5
of our collection, in which only ogosis of the chorionic membranes
was found, with the absence of signs of fetal infection.
Our case 3 took place in the beginning phase of the third
trimester and presented signs of fetal infection superimposable with
cases 1, 2, 4, without endocardial broelastosis.
IUFD, above all when it takes place suddenly and unexpect-
edly (an eventuality of which our case histories constitute a signif-
icant example) can raise medico-forensic problems connected to the
diagnosis of the cause of death and to eventual obstetric liability.
In fact, the cases of IUFD from B19 have appeared recently
in the eld of forensic medicine. This is due to increased knowledge
of the pathology which today permits a rapid diagnostic approach,
valid monitoring strategies ad relatively simple therapies, not with-
out risks but effective in many cases. The parents informed that the
pathology can be diagnosed and cured in cases at risk, sometimes do
not accept the unfavorable results calmly and may take legal action.
Naturally, the involvement of forensic pathology in the study
and evaluation of these cases is possible in those countries in which,
by law, the question of medical responsibility for the cases involving
FIGURE 2. PCR. Photo Gel. Samples were analyzed on aga-
rose gel stained with ethidium-bromide for presence of am-
plified B19 DNA specific bands: (16) 248 basepairs, using
primer set A (nonstructural protein part of the genome); (7
12) 104 basepairs, using primer set B (structural protein
part). Samples 1, 3 and 7, 9 were positive with both sets
primer. M molecular weight; 1, 7 placenta; 2, 8
liver; 3 spleen; 4, 10 lung; 5, 11 positive control, 6,
12 negative control.
Silingardi et al Am J Forensic Med Pathol Volume 30, Number 4, December 2009
396 | www.amjforensicmedicine.com 2009 Lippincott Williams & Wilkins
a death is managed by the Judicial Authorities, who charge the forensic
pathologist to carry out necessary verications. Thus, it can happen that
the case is directly entrusted to the forensic pathologist, as happened in
one of our cases; in other cases, if the legal initiative is undertaken at a
later date, the forensic pathologist can be entrusted with this after the
autopsy has been carried out by the hospital pathologist, which is what
happened in the other 4 cases in our series.
We believe that the forensic pathologist should orient his
research in 2 directions. As for the rst point, for medico-forensic
ends, the exact diagnostic denition of the cause of death through a
complete anatomopathologic investigation is important; this, how-
ever, can be very difcult especially if the fetus is macerated.
19
The diagnosis, liable to suspicion on the basis of the autoptic
ndings, namely hydrops, serous effusion and placental thickening,
is initially conrmed by the documentation of typical nuclear inclu-
sions in the intravascular erythroblasts. Denitive conrmation can
come from a search for B19 DNA in the fetal tissues and in the
placenta using PCR, which is the most sensitive method for diag-
nosing fetal infection.
9
The above-mentioned anatomopathologic
and laboratory ndings are convergent and conclusive signs for
diagnosing IUFD from B19.
In cases of IUFD of the third trimester, if there are no signs
of fetal infection, the diagnosis involves the identication of inam-
matory-degenerative placental lesions and PCR.
The second point concerns the obstetrical liability in the
management of clinical cases.
Every patient who is pregnant should be made aware of the
risks coming from exposition to infection from B19. If a patient who
is pregnant is exposed to the infection, the rst thing is to diagnose
the infection which is done using a serologic study of the IgM-IgG
relationship.
9
If the IgGs are positive and the IgMs are negative, the
patient is in condition of immunity which excludes any risk. If the
test is negative for both the IgGs and the IgMs, it has to be repeated
2 to 4 weeks later to evaluate an eventual positivity. If the IgM test,
or both tests, are positive, the patient has an active infection. It then
becomes necessary to inform the patient about the risks to which the
fetus is potentially exposed, and begin monitoring to diagnose fetal
infection early.
6
In these cases, besides the daily counting of the fetal movements
(starting from the end of the second trimester), ultrasound monitoring is
advised, to be continued weekly for a varying amount of time according
to the gestational age up to a maximum of 12 weeks, the time within
which the major part of fetal complications manifested themselves.
6
The most common ultrasound signs are hydrops, effusion towards the
serous cavities, placental edema and polyhydramnios.
6
Doppler ultra-
sound can also allow us to recognize anemia, under the form of an
increase in the peak velocity of the systolic ow of the medial cerebral
artery.
20
Anemia can also be identied with greater precision using an
invasive method (cordocentesis).
6
Early diagnosis is very important because the incidence of
IUFD can be reduced considerably by the timeliness of the diagnosis
and the therapy.
Therapy includes the intravenous administration of immuno-
globulins at a high concentration which can give positive results.
21
The greatest benets can be obtained by a blood transfusion which
corrects the anemia and signicantly reduces mortality.
22
Without
therapy, IUFD takes place in 30% of the total number of cases of
hydrops and in all cases of severe hydrops,
23
whereas intrauterine
hematic transfusion can increase the survival rate to over 80%.
10,23
However, transfusion can add risks in 2% to 5% of cases.
6
Possible
complications of transfusion include hematomas, lacerations and
hemorrhage of the funiculus, infections, breaking of the membranes,
increase in uterine activity and miscarriage which, in turn, are
possible causes of obstetric liability.
If the pregnancy is in a more advanced stage (at least 3234
weeks), the diagnosis of hydrops and fetal anemia can lead to
considering the eventuality of an early delivery.
6
In conclusion, accurate research on the anatomopathologic and
laboratory signs of B19 infection furnishes fundamental elements for
diagnostic judgment. On the one hand, it can explain the nature of the
pathology which caused the IUFD and, on the other hand, it constitutes
the basis for judging the conduct of the obstetricians.
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