Unexpected Intrauterine Fetal Death in Parvovirus.20

8/12/2019 Unexpected Intrauterine Fetal Death in Parvovirus.20

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CASE REPORT

Unexpected Intrauterine Fetal Death in Parvovirus B19 FetalInfection

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 fibroelastosis, 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

verified 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 Pathol2009;30: 394397)

Parvovirus B19 (B19) is a nonenveloped, single stranded DNAvirus.1 It exclusively infects man and shows a marked trophismfor 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 majorpart of the infections are found among young children of school age,the most exposed adults are the parents of children in this age groupand people working in the scholastic community.2

B19 is usually transmitted through the respiratory tract, but otherpossible modalities of transmission are organ and bone marrow trans-

plants as well as blood transfusions and hematic derivatives.2 Clinicalmanifestations are present in only 25% to 50% of the infected subjectsand include, above all, erythema infectiosum (also known as fifthdisease), characterized by a cutaneous rash and, in particular in adults,

by arthralgia. In immunocompromised patients, the infection can causeaplastic 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 morefrequent in the first 2 trimesters and can have variable consequences. Infact, it can be asymptomatic both for the pregnant woman and for thefetus but, in some cases, it can provoke severe fetal complications and,in rare cases, intrauterine death (IUFD) or miscarriage,2 with possibleconsequences on a medico-forensic level.

We present 5 cases of maternal-fetal infection from B19followed by IUFD. All the patients had been exposed to infectionfrom B19 but the absence of symptoms of infection had convincedphysicians not to activate programs monitoring fetal conditions. Inall the cases examined, the investigation pointed out pathologicsigns and laboratory characteristics of B19 infection, in 4 cases as adirect infection of the fetus and in 1 case as a placental involvement.

METHODSFrom 2001 to 2005, we reviewed 5 cases of maternal-fetal

infection from B19 followed by IUFD observed. Three of thesecases took place in the second trimester of pregnancy and the other2 cases in the third trimester. In 4 cases, the IUFD took place

suddenly in the absence of prodromic clinical manifestations; in 1case, the patient was hospitalized following an ultrasound diagnosisof fetal hydrops and IUFD took place 5 days after admission.

All the fetuses, whose degree of development corresponded totheir gestational age, were autopsied and appeared to be in an optimalstate of conservation. Histopathological examinations were carried outon the encephalon, heart, lungs, liver, spleen, kidneys, thymus, bonemarrow, and placenta, using HE methods, Azan-Mallory for collagenfibers, Weigert for elastic fibers, and Perls for hemosiderin. The diag-nosis was made by the histopathological identification of the typicalnuclear inclusions in cells of erythroid series (erythroblasts) or placentalinvolvement. Diagnostic confirmation was obtained through researchon B19 DNA, using PCR analysis carried out on histologic sections ofthe lung, liver, spleen and placenta.

CASE REPORTS

Case 1A 38-year-old patient in her 21st week, in good health, who had

a normal pregnancy, was admitted following a casual ultrasound findingof fetal hydrops and notable placental thickening. The same ultrasoundhad documented increase in peak velocity of the middle cerebral arterydue to a condition of anemia and encephalic hypoxia; the amniotic fluidwas 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 ofthe 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, Universityof Modena and Reggio Emilia, Modena, Italy; Service of Pathologic Anat-omy, E. Muller Hospital, Mulhouse, France; and Service of PathologicalAnatomy, Ravenna Hospital, Ravenna, Italy.

All figures 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: [email protected].

Copyright 2009 by Lippincott Williams & WilkinsISSN: 0195-7910/09/3004-0394DOI: 10.1097/PAF.0b013e3181c17b2e

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endocardial fibroelastosis (Fig. 1A), and thymic hypoplasia withlymphocytic depletion.

Furthermore, there was hepatic hemosiderosis and intenseedema of the chorionic villi.

Case 2A 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. Autopsyshowed cutaneous purpura, diffuse hydrops, bilateral pleural effusionand ascites, and increase in liver and spleen volume. Malformations orstructural anomalies were absent. Histology showed intravascularerythroblasts with eosinophilic nuclear inclusions from B19 in variousorgans (Figs. 1B, C), evident endocardial fibroelastosis extending to the4 cardiac cavities, moderately branched into myocardial interstice,thymic hypoplasia with lymphocytic depletion, and, in addition, hepatichemosiderosis and edema of the chorionic villi.

Case 3A 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 andthoracoabdominal region, bilateral hydrothorax and ascites, andmodest increase in liver and spleen volume.

Histology showed eosinophilic nuclear inclusions from B19 innumerous intravascular erythroblasts in liver and spleen. In addition,there was hepatic hemosiderosis and pronounced placental hydrops.


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 chambersand volumetric increase of the spleen.

Histology showed erythroid hypoplasia of the bone marrow,intravascular erythroblasts with eosinophilic nuclear inclusions fromB19 at the splenic level, endocardial fibroelastosis particularly

evident in the right ventricle, thymic hypoplasia with lymphocyticdepletion; in addition, hepatic hemosiderosis and fibrosis, intenseedema, and erythroblastosis of chorionic villi (Fig. 1D).


pregnancy. At the 31st week, ultrasound showed regular fetal

growth and slightly increased amniotic fluid. 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 infiltration of the polynucleatedcells in the chorionic membranes, appearance of necrosis, calcifica-tion of the villi, and absence of erythroblastosis.

PCR ANALYSIS

MaterialsAnalysis was carried out to determine the presence of B19

DNA in cases of IUFD using paraffin-embedded tissue: fetal lung,liver, spleen tissue, and placenta.

DNA ExtractionThree 5 m sections from each block were cut with a

microtome. To prevent carryover of contaminating DNA, a freshblade was used for each sample and the microtome overlay wascovered with a piece of adhesive tape changed for every sample. Thecut sections were deparaffinized by washing twice with xylene andtwice with 100% ethanol. After evaporation of the ethanol, 200 Lof digestion buffer (50 mM Tris pH 8.5, 1 mM EDTA, 0.5% Tween20 and 200 g of proteinase K per mL) was added and the mixturewas incubated for 3 hours at 56C. Proteinase K was inactivated byincubating 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 genomapart 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 and104 bp, respectively.

The total reaction volume in PCR was 50 L and the reactionmixture contained 200 M each of dATP, dCTP, dGTP, and dTTP,50 mM KCl, 10 mM Tris (pH: 8.3), 2 mM MgCl2, 1 g of eachprimer for both strands and 1 U of AmpliTaq Gold DNA Polymerase(Applera Italia). Thirty-two incubation cycles were carried out. ThePCR for both primer sets was conducted with an initial 10 minutesdenaturation step at 94C coupled with a repeating cycle of 1 minuteat 94C, 2 minutes at 55C (reannealing) and 2 minutes at 72C(primer extension).

Detection of PCR ProductsFor the analysis of the amplified products of the PCR per-

formed on each primer set, 10 L of reaction solution were analyzedon 3% agarose gel containing 1 g of ethidium bromide per mL.

ResultsThe PCRs were positive in overall the tissues examined (Fig. 2).

FIGURE 1.A, Endomyocardial fibroelastosis. Trichromic Azan4. B, Spleen: erythroblastosis with nuclear inclusions fromB19 (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.

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DISCUSSIONB19 infection during pregnancy can have very different

clinical pictures and results, ranging from the total absence ofmaternal and fetal symptoms to transitory hydrops of the fetus, toIUFD and miscarriage which constitute the most serious events3,4

and can raise important medico-forensic questions.Fifty percent of pregnant women are immunologically sus-

ceptible to contracting B19 infection, but the incidence of maternalinfection varies from 16.7% to 21% of the total number of womenexposed.35 About 25% of these patients do not present clinical

symptoms.

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The risk of vertical maternal-fetal transmission throughthe placenta is about 30% of the maternal infections2 and is consid-ered to be more probable in the first 2 trimesters, becoming lessfrequent as the gestational age progresses. This depends on the factthat the antigen of blood group P (P-ag), the principal antigennecessary for maternal-fetal transmission, is present to a lesserdegree at the placental level as the gestational age increases.7 Thetotal incidence of important effects on the fetus (hydrops, IUFD) isbetween 5% and 10% of the patients infected.4,8 Nevertheless, thereare a number of studies in which no case of hydrops was reported inpregnant patients exposed to the infection.3 The incidence of IUFDfrom B19 in North America and Europe has been estimated to beless than 1 of 1000 pregnancies per year.9 A large study carried outby the Society of Perinatal Obstetricians pointed out that IUFD

affects 30% of fetuses with hydrops who are not transfused, and only6% of those fetuses which are transfused.10

Between the exposition of a pregnant woman to the infectionand the manifestation of the clinical fetal picture, there is, on theaverage, an interval of 6 weeks, at times even a few months, andinfection of the fetus can take place even in the absence of clinicaland laboratory signs of maternal infection.2 In fact, the infection canbe asymptomatic, and seroconversion can take place even monthsafter contagion.11 All this does not make it easy to predict fetalinfection and IUFD.

Fetal infection can cause anemia since the virus determinescytotoxic apoptosis and the lysis of erythroid precursors and, in thisway, it inhibits erythropoiesis.9 The presence of the virus in theerythroid precursors is revealed by the typical nuclear inclusions.12

The nuclei of the erythroblasts present an intensely margined andcolored chromatin; the center of the nuclei is more luminous andappears homogeneous and vitreous.12

Anemia can lead to cardiac insufficiency and hydrops, whichcan be of varying degrees. Other anatomopathologic aspects12 cor-related to fetal infection from B19, such as hepatosplenomegaly,hemosiderosis, and hepatic fibrosis 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 inflamma-

tory infiltrates of the villi which can lead to necrosis and calcifica-tion. The heart can be normal or symmetrically enlarged, withendocardial fibroelastosis; the thymus can be abnormally small dueto lymphocytic depletion.12

The characteristics and the extent of the fetal damage varyaccording to the trimester of pregnancy in which the contagion takesplace. In the first trimester, miscarriage has been reported in 3% of casesbut the causal connection with B19 infection remains difficult todemonstrate.13 Isolated reports of cases of embryopathy have not beenconfirmed.14

Clinical manifestations of fetal damage are more frequent inthe second trimester.2 This probably depends on the fact that, in thisphase of the pregnancy, the concentration of P-ag in the placentaltrophoblast is still elevated.9 Furthermore, very intense hematopoi-

esis is prevalently located in the liver, the average life of theerythrocytes is shortened (4570 days) and fetal growth requires arapid increment of 3 to 4 times the erythrocytic mass. 15 In this way,the fetus is more vulnerable to a condition of erythrocytic damageinduced by the virus. Histopathological examinations reveal thetypical nuclear inclusions in intravascular erythroblasts.12

Our investigation documented 3 cases of IUFD which took placein the second trimester (cases 1, 2, 4) in which the findings of majorimportance corresponded with a typical anatomopathologic picture,confirming the specific pathogenesis. In addition, we observed anendocardial fibroelastosis of varying degrees in these 3 cases which wasnot always accompanied by an increase in cardiac dimension.

IUFD can also take place, but with a lesser frequency, in amore advanced phase of gestation. In the major part of cases which

take place during the third trimester, hydrops is absent,16 and, inmany cases, clinical and laboratory signs of a recent maternalinfection are not found.9,11 According to the prevailing opinion, thiscomes from the reduced concentration of placental P-ag and thenormalization of the average erythrocytic life.2 In this period, thepersistence of the maternal infection can, nevertheless, determineinflammatory and degenerative phenomena in the placenta,17 whosedysfunction may be a cause of IUFD, even without fetal infection.2

In these cases, histopathological examinations of the fetal organs donot show particular alterations or the typical viral inclusions.18

A similar typology finds substantial correspondence in case 5of our collection, in which only flogosis of the chorionic membraneswas found, with the absence of signs of fetal infection.

Our case 3 took place in the beginning phase of the thirdtrimester and presented signs of fetal infection superimposable withcases 1, 2, 4, without endocardial fibroelastosis.

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 thediagnosis of the cause of death and to eventual obstetric liability.

In fact, the cases of IUFD from B19 have appeared recentlyin the field of forensic medicine. This is due to increased knowledgeof 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 thepathology can be diagnosed and cured in cases at risk, sometimes donot accept the unfavorable results calmly and may take legal action.

Naturally, the involvement of forensic pathology in the studyand 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, usingprimer set A (nonstructural protein part of the genome); (712) 104 basepairs, using primer set B (structural proteinpart). Samples 1, 3 and 7, 9 were positive with both setsprimer. M molecular weight; 1, 7 placenta; 2, 8 liver; 3 spleen; 4, 10 lung; 5, 11 positive control, 6,12 negative control.

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a death is managed by the Judicial Authorities, who charge the forensicpathologist to carry out necessary verifications. Thus, it can happen thatthe case is directly entrusted to the forensic pathologist, as happened inone of our cases; in other cases, if the legal initiative is undertaken at alater date, the forensic pathologist can be entrusted with this after theautopsy 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 hisresearch in 2 directions. As for the first point, for medico-forensicends, the exact diagnostic definition of the cause of death through acomplete anatomopathologic investigation is important; this, how-ever, can be very difficult especially if the fetus is macerated. 19

The diagnosis, liable to suspicion on the basis of the autopticfindings, namely hydrops, serous effusion and placental thickening,is initially confirmed by the documentation of typical nuclear inclu-sions in the intravascular erythroblasts. Definitive confirmation cancome from a search for B19 DNA in the fetal tissues and in theplacenta using PCR, which is the most sensitive method for diag-nosing fetal infection.9 The above-mentioned anatomopathologicand laboratory findings 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 identification of inflam-matory-degenerative placental lesions and PCR.

The second point concerns the obstetrical liability in themanagement of clinical cases.

Every patient who is pregnant should be made aware of therisks coming from exposition to infection from B19. If a patient whois pregnant is exposed to the infection, the first thing is to diagnosethe infection which is done using a serologic study of the IgM-IgGrelationship.9 If the IgGs are positive and the IgMs are negative, thepatient is in condition of immunity which excludes any risk. If thetest is negative for both the IgGs and the IgMs, it has to be repeated2 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 thenbecomes necessary to inform the patient about the risks to which thefetus is potentially exposed, and begin monitoring to diagnose fetalinfection early.6

In these cases, besides the daily counting of the fetal movements(starting from the end of the second trimester), ultrasound monitoring isadvised, to be continued weekly for a varying amount of time accordingto the gestational age up to a maximum of 12 weeks, the time withinwhich the major part of fetal complications manifested themselves.6

The most common ultrasound signs are hydrops, effusion towards theserous cavities, placental edema and polyhydramnios.6 Doppler ultra-sound can also allow us to recognize anemia, under the form of anincrease in the peak velocity of the systolic flow of the medial cerebralartery.20 Anemia can also be identified with greater precision using an

invasive method (cordocentesis).6

Early diagnosis is very important because the incidence ofIUFD can be reduced considerably by the timeliness of the diagnosisand the therapy.

Therapy includes the intravenous administration of immuno-globulins at a high concentration which can give positive results.21

The greatest benefits can be obtained by a blood transfusion whichcorrects the anemia and significantly reduces mortality.22 Withouttherapy, IUFD takes place in 30% of the total number of cases ofhydrops and in all cases of severe hydrops,23 whereas intrauterinehematic transfusion can increase the survival rate to over 80%.10,23

However, transfusion can add risks in 2% to 5% of cases.6 Possiblecomplications of transfusion include hematomas, lacerations andhemorrhage of the funiculus, infections, breaking of the membranes,

increase in uterine activity and miscarriage which, in turn, arepossible causes of obstetric liability.

If the pregnancy is in a more advanced stage (at least 3234weeks), the diagnosis of hydrops and fetal anemia can lead toconsidering the eventuality of an early delivery.6

In conclusion, accurate research on the anatomopathologic and

laboratory signs of B19 infection furnishes fundamental elements fordiagnostic judgment. On the one hand, it can explain the nature of thepathology which caused the IUFD and, on the other hand, it constitutesthe basis for judging the conduct of the obstetricians.

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Unexpected Intrauterine Fetal Death in Parvovirus.20