REVIEW

CURRENTOPINION Parvovirus B19 in pregnancy: prenatal diagnosis

and management of fetal complications

Copyright © Lippincott W

1040-872X � 2012 Wolters Kluwer

a,b c d

Anneke C. Dijkmans , Eveline P. de Jong , Ben A.C. Dijkmans ,Enrico Loprioree, Ann Vossena, Frans J. Walthere, and Dick Oepkesf

Purpose of review

Parvovirus B19 infection is often considered a mild and self-limiting disease of minor clinical importance.This review aims to raise awareness of recently discovered potentially devastating consequences of thisinfection in pregnancy, and provides updated guidelines on diagnosis and management.

Recent findings

In contrast to previous beliefs, parvovirus B19 infection during any stage of pregnancy may not only causefetal death, but may also result in severe and irreversible neurological sequelae in survivors. Improveddiagnostic techniques allow more reliable and earlier diagnosis of fetal disease.

Summary

Clinicians need to be aware of the risk of adverse outcome of parvovirus B19 infection in pregnancy, andsometimes the long interval between exposure and fetal symptoms. Accurate diagnosis using PCR andweekly ultrasound checks ups with Doppler measurement of middle cerebral artery flow velocity up to20 weeks postexposure may improve detection of fetal disease. More timely treatment likely results inimproved outcome.

Keywords

fetal anemia, fetal infection, fetus, hydrops, parvovirus B19, pregnancy

aDepartment of Medical Microbiology, Leiden University Medical Centre,Leiden, bDepartment of Medical Microbiology, HAGA Hospital, TheHague, cDepartment of Paediatrics, Juliana Children’s Hospital, HAGAHospital, The Hague, dDepartment of Rheumatology, VU Amsterdam,Amsterdam, eDivision of Neonatology, Department of Paediatrics andfDivision of Fetal Medicine, Department of Obstetrics, Leiden UniversityMedical Centre, Leiden, The Netherlands

Correspondence to Dick Oepkes, MD, PhD, Maternal-Fetal MedicineSpecialist, Department of Obstetrics, K06-35, Leiden University MedicalCenter, PO Box 9600, 2300 RC Leiden, The Netherlands. Tel: +31 715262872/2896; fax: +31 71 5266741; e-mail: d.oepkes@lumc.nl

Curr Opin Obstet Gynecol 2012, 24:95–101

DOI:10.1097/GCO.0b013e3283505a9d

INTRODUCTION

Human parvovirus B19 was first discovered andreported by Cossart et al. [1,2]. The discovery ofparvovirus B19 (B19V) as causative agent for its mostcommonly known clinical manifestation, erythemainfectiosum, took about a decade [3–5]. Erythemainfectiosum, also known as fifth disease, is a rela-tively benign disease affecting mainly childrenand young adults [4–7]. The characteristic rash isoften described as ‘slapped cheeks’ [8]. During B19Vinfection arthralgia is reported by 10% of childrenand 80% of female adults [9]. In addition, arthritis isa reported complication, and virus particles can beisolated from the synovial fluid [10,11]. Two otherimportant complications of B19V infection resultfrom its potent inhibition of erythropoiesis. Thefirst occurs in patients with preexisting erythro-poietic disorders, in which B19V infection can causea severe aplastic crisis [5,12]. The second majorcomplication of B19V infection, and the focusof this review article, concerns the potentiallydevastating effects for the fetus during maternalinfection.

illiams & Wilkins. Unau

Health | Lippincott Williams & Wilki

EPIDEMIOLOGY

Infection with B19V is common and occurs world-wide. Transmission occurs through respiratorydroplets. In addition, B19V can be transmitted byblood and blood-derived products and can be trans-mitted ‘vertically’ from pregnant woman to fetus[13]. The peak annual incidence occurs during latespring. Moreover, B19V shows an epidemiologicalcycle every 4 years [14]. This explains for instancethe well known, though poorly understood, pattern

thorized reproduction of this article is prohibited.

ns www.co-obgyn.com

C

KEY POINTS

� Using only simple serology may miss or delay thediagnosis of parvovirus B19 infection in pregnancy.

� Clinicians must be aware that severe fetal anemia mayoccur up to 20 weeks after maternal infection, and thusoffer close surveillance during this period.

� Timely diagnosis is essential for timely treatment, whichcan minimize the risks of death or irreversibleneurological sequelae in the fetus.

Prenatal diagnosis

of epidemics every 4 years of hemolytic anemia insickle-cell children in the Caribbean [5]. The preva-lence of IgG antibodies to B19V, evidence of a statusafter infection, in the population ranges from 2 to15% in children 1–5 years old, 15 to 60% in children16–19 years old, 30 to 60% in adults and more than85% in the geriatric population [15]. About 25–45%of women in the childbearing age are estimated notto possess IgG antibodies to B19V, and therefore aresusceptible to infection [16]. The incidence of B19Vinfection during pregnancy is estimated at 1–2% inendemic periods, rising to 10% during epidemicperiods [17,18]. In case of a maternal infection,transmission to the fetus occurs in one third toone half of cases, with a risk of adverse fetal outcomeof about 10% [13,18–21,22

&

,23]. Brkic et al. [24]recently analyzed 176 pregnancies for asympto-matic B19V infection, and found a significantlyhigher prevalence of B19V in second trimesterwomen with symptoms of miscarriage as comparedto uncomplicated controls. The risk of fetal compli-cations is believed to be greatest when infectionoccurs in the first 22 weeks of pregnancy [25]. Ina recent study the highest rate of B19V transmissionand fatal outcome were observed when maternalinfection occurred before 20 weeks of gestation(43 and 25%, respectively) [26

&

].

PATHOGENESIS

The fetus is infected with B19V via transplacentaltransmission, which occurs in an estimated 35% ofinfected pregnant women [26

&

,27]. This so-calledvertical transmission occurs 1–3 weeks aftermaternal infection, suggesting that fetal infectionoccurs during the maternal peak viral load [28]. Fetalinfection may resolve spontaneously without anysequelae, or lead to severe consequences such asnonimmune hydrops fetalis (NIHF) and fetal death.The pathogenesis for fetal complications can beascribed to infection and lysis of erythroid progen-itor cells, making B19V a potent inhibitor of

opyright © Lippincott Williams & Wilkins. Unautho

96 www.co-obgyn.com

erythropoiesis [29]. Several cellular receptors andco-receptors for parvovirus are present in erythroidprogenitor cells and fetal capillary endothelium inthe placenta leading to productive infection [30].Endothelial cells and myocardial cells also expressthese cellular receptors and can therefore be infectedwith B19V [29]. Both direct toxic cell injury by theviral protein NS1 and the induction of apoptosiscontribute to cell death.

MANIFESTATIONS OF FETALINVOLVEMENT

Fetal manifestations associated with B19V infectionare intrauterine fetal death (IUFD), NIHF due tosevere fetal anemia, thrombocytopenia, hyperecho-genic bowel, myocarditis and possibly central nerv-ous system damage. Fetal B19V infection can alsooccur without clinical manifestations [31]. A recentItalian study reported that congenital infectionremains clinically unrecognized in about 60% ofthe fetuses, while in the remaining 40% the infectedfetuses developed anomalies [26

&

]. When maternalB19V infection was asymptomatic, the intervalbetween likely time of maternal infection and fetalmanifestations ranged from 3 to 15 weeks. Interest-ingly, fetal abnormalities became evident on ultra-sound investigations at 17–33 weeks of gestations,irrespective of the gestational age at time ofmaternal infection [26

&

].

Intrauterine fetal death

IUFD associated with B19V infection occurs mostlybetween 20 and 24 weeks of gestation. However,cases of IUFD as early as 10 weeks and as late as41 weeks of gestation have been described [21].Moreover, IUFD can occur without fetal hydropsand erythropoietic suppression [32].

Nonimmune hydrops fetalis

The observed risk of parvovirus-induced NIHF (anaccumulation of excess fluid in at least two bodycompartments of the fetus) ranges from 3.9 to 11.9%[21,26

&

]. NIHF has the highest frequency during thehepatic stage (8–20 weeks of gestation) of hemato-poeitic activity [33]. In this stage of hematopoiesisthe half-life of erythrocytes is shorter compared tothe later bone marrow and splenic hematopoieticstage [20]. Therefore, a fetus at this age is especiallyvulnerable to anemia and subsequent hydrops. Theinterval between B19V infection and developmentof NIHF commonly ranges from 2 to 6 weeks [33].Importantly however, well-documented cases ofintervals of 10–12 weeks have been reported [34]

rized reproduction of this article is prohibited.

Volume 24 � Number 2 � April 2012

Parvovirus B19 infection in pregnancy Dijkmans et al.

and exceptionally, the interval may even be20 weeks [35].

The underlying mechanism responsible for thefetal symptoms of NIHF is severe anemia, whicheventually leads to high output cardiogenic heartfailure. A fetus affected by B19V may show signs ofhydrops on ultrasound investigation, typically theseare ascites, cardiomegaly and pericardial effusion. Inadvanced stages, generalized edema and a thick,hydropic placenta can be found. The latter maybe responsible for a maternal preeclampsia-like syn-drome with swollen legs, hypertension, proteinuriaand maternal anemia, which is called the mirrorsyndrome because maternal signs reflect thosepresent in the fetus, probably because of perfusiondifficulties of the placenta.

Thrombocytopenia

Moderate to severe thrombocytopenia is a commonfinding in hydropic, anemic B19V infected fetuses.The largest published series, by de Haan et al. [36]described platelet counts less than 50�109/l in14/30 (46%) of B19V infected fetuses just beforeintrauterine transfusion (IUT). However, in noneof these cases prenatal bleeding signs were observed.

Neurological manifestations

Although uncommon, several short-term neuro-logical complications following intrauterine B19Vinfection have been reported including encephal-opathy, cerebral migratory abnormalities andneonatal encephalitis [37,38]. The long-term con-sequences are not well known. Only two smallstudies have been reported on the long-term neuro-developmental outcome. Dembinski et al. [39] eval-uated 20 survivors after IUT for B19V and hydropsand report a good neurodevelopmental prognosis inall survivors. However, the lost-to-follow-up ratewas extremely high (35%). In contrast, a study fromour research group reported an increased incidenceof severe neurodevelopmental outcome in 12.5%(2/16) of survivors [40]. We recently updated thislong-term follow-up study and found a similar inci-dence of severe developmental delay (3/28, 11%).The rate of severe neurodevelopmental impairmentappears to be higher compared to the Dutch norma-tive population (2.3%) suggesting that B19V infec-tion may cause cerebral damage to the developingfetal brain. However, cerebral injury may also prim-arily result from severe fetal anemia and hydropsbecause of hypoxic-ischemic injury. To gain furtherinsight in central nervous system damage and intra-uterine B19V, larger studies including cerebral imag-ing and long-term follow-up are urgently required.

Copyright © Lippincott Williams & Wilkins. Unau

1040-872X � 2012 Wolters Kluwer Health | Lippincott Williams & Wilki

DIAGNOSIS OF B19V INFECTION INPREGNANCYClinical suspicion of B19V infection in a pregnantwoman may arise from history of contact withinfected others, often young children, from symp-toms compatible with viral infections or from fetalsymptoms, commonly reduced fetal movementsand hydrops fetalis.

Diagnosis of maternal infection

Physicians must be aware of the clinical manifes-tations of B19V infection and realize that thiscan occur without overt clinical symptoms. Directevidence of infection is obtained by detection ofB19V-DNA using PCR (Fig. 1).

The diagnosis of maternal infection relies onantibody detection. B19V IgM and IgG antibodydetection is mostly performed by enzyme immuneassays. B19V specific IgM antibodies become detect-able in serum 7–10 days after infection, sharplypeak at 10–14 days, and then decline within 2 or3 months [8]. IgG antibodies gradually increasefrom 14 days after infection and reach a plateaulevel after 4 weeks of gradual increase [8]. IgG anti-bodies are supposed to be present for a long period,and probably give lifelong protection to infection. Itis important to realize that there is a window ofapproximately 1 week wherein no antibodies arepresent [41].

The sensitivity of IgM antibody detectionbetween 8 and 12 weeks after maternal infectionis reported to vary from 63 to 70% [42

&

,43], whichimplicates a substantial amount of false negativeresults. In a recent study with 72 pregnancies com-plicated by maternal B19V infections, IgM serologycorrectly diagnosed 94.1% of B19V infections, whileDNA testing correctly diagnosed 96.3% [26

&

]. Inclinical suspect cases PCR analysis will provide asignificant contribution to the accuracy of thematernal diagnosis [44]. On the contrary, lowB19V-DNA levels may persist for longer periodsafter acute infection. Therefore, depending on theclinical suspicion physicians should request for anti-body detection and in doubt also for complemen-tary PCR analysis. To detect maternal infection, weuse the flowchart as described in Fig. 2.

Diagnosis of fetal infection

Several studies have shown that serological diagno-sis of viral B19V infection cannot rely on maternaltesting for B19V infection only [13,41]. Moreover,serological examinations of fetal and neonatalblood samples are highly unreliable because fetuseswill not yet produce an antibody response to B19V

thorized reproduction of this article is prohibited.

ns www.co-obgyn.com 97

C

Clinicalfeatures

Reticulocytes

Dot blot

PCR

Viremia

IgM

7 14 21 28

Days Months

2 4 60

IgG

IgG

IgM

Hemoglobin

Normal valuesHematologicalchanges

B19 DNA

B19 viremia andantibody responses

Fever, chills,headache,

myalgia

Rash andArthralgia

FIGURE 1. Course over time for clinical, serological and virological characteristics of B19V infection in pregnancy.

Prenatal diagnosis

infection. Therefore, examination for fetal B19Vinfection should be confined to DNA detection byPCR, which effectively will confirm or exclude fetalB19V infection. Both fetal cord blood and amnioticfluid samples are suitable for diagnosis [44,45]. Asthe concentrations of viral DNA in amniotic fluidmay be extremely high and persist for the fullduration of the fetal infection, amniocentesis offersa practical opportunity for a reliable diagnosis,although the procedure is only indicated whenthe possible alternative approaches like ultrasoundand maternal diagnosis are inconclusive and a highsuspicion of fetal infection remains [44,45].

Diagnosis of fetal complications

In case of a maternal B19V infection ultrasoundexaminations should be performed to detect fetalcomplications. The primary objective is to detectsigns of fetal anemia and/or NIHF. Fetal anemiacaused by B19V infection can reliably be detectednoninvasively by Doppler measurement of the peaksystolic velocity (PSV) of blood flow in the middlecerebral artery (MCA-PSV) [46].

Hydrops caused by anemia usually manifestsitself first by ascites, together with enlargementand thickening of the fetal heart. Untreated, fluidaccumulation progresses with skin edema, pericar-dial effusion and placental thickening. Pleural

opyright © Lippincott Williams & Wilkins. Unautho

98 www.co-obgyn.com

effusions are late and minimal in anemic hydrops.Amniotic fluid volume may be normal or evendecreased; polyhydramnion is rare [25].

MANAGEMENT OF MATERNAL B19VINFECTION AND PREVENTION OF FETALDEMISE

If maternal infection is confirmed, the fetus shouldbe monitored for the development of hydrops byweekly ultrasound examination including Dopplerassessment of MCA-PSV, at least up to 12 and to besafe probably even until 20 weeks postexposure. Ifthe fetus develops signs of hydrops and/or anemia,urgent referral to a tertiary care center is of utmostimportance. Timely IUT can correct fetal anemiaand may reduce the risk of mortality of B19V infec-tion. In most cases, one transfusion is sufficient forfetal recovery. Following successful transfusion, itmay take weeks for all hydropic signs to disappear. Afew cases of spontaneous resolution of hydrops havebeen described [26

&

]. This has led to the discussionon the optimal time to intervene. Most clinicianschoose to proceed with transfusion when the fetalblood sample shows anemia.

The relevance of B19V associated thrombocyto-penia in the fetus is still unclear. Although intra-uterine platelet transfusion can be performedrelatively safely, the benefits must outweigh any

rized reproduction of this article is prohibited.

Volume 24 � Number 2 � April 2012

Contact with B19V infectedchild

orsuspected maternal B19V

infection.

Determine maternal B19Vserology.

IgG+IgM+

Current activematernal B19V

infection

Follow-up(See figure 3)

Follow-up(See figure 3)

Follow-up(See figure 3)

B19V PCR positive B19V PCR negative

Determine presence ofB19V by PCR

Determine B19V viralload (PCR) and

redetermine B19Vserology after 14 days

Current activematernal B19V

infection

Current activematernal B19V

infection

No current activematernal B19V

infection

No current activematernal B19V

infection.Past immunity due to

IgG+

Reassurance ofparents, no follow-up

for B19V infectionnecessary

Past infection withB19V with current

immunitybut:

Low sensitivity IgM

IgG–IgM+

IgG+IgM–

IgG–IgM–

FIGURE 2. Flowchart for diagnosis of parvovirus B19 infection in pregnancy.

Parvovirus B19 infection in pregnancy Dijkmans et al.

possible complications such as fluid overload andconcomitant cardiac failure in these already com-promised fetuses [36]. We therefore advise againstplatelet transfusions in fetal B19V infection. Inour center we use the flowchart in Fig. 3 for fetalmanagement.

Prevention of maternal exposure is the first stepto forestall fetal B19V infection. It can be discussed

Copyright © Lippincott Williams & Wilkins. Unau

1040-872X � 2012 Wolters Kluwer Health | Lippincott Williams & Wilki

whether it is beneficial to screen women in thechildbearing age on the presence of IgG antibodiesto parvovirus. In the literature a recombinantvaccine is described, which proved to be immuno-genic and safe in human volunteers [47]. Vaccina-tion of nonimmune pregnant woman could be ahighly effective method to prevent fetal infection[17,47], especially in women with high-risk

thorized reproduction of this article is prohibited.

ns www.co-obgyn.com 99

C

Active maternalB19V infection.

Refer to fetal medicine specialistPerform weekly ultrasound for signs of

hydrops fetalis (incl. MCA flow).

No signs of anemia20 weeks post

exposure.Signs of anemia

Stop follow-up

Refer to tertiary carecentre for further

evalution.

MCA flow > 1.5 MoM.

Plan erythrocyte IUT.

Plan neonatal shortterm and long term

follow-up.

FIGURE 3. Flowchart for clinical management ofpregnancies complicated by parvovirus B19 infection.

Prenatal diagnosis

professions, such as healthcare workers, primaryschool teachers or daycare workers. Furthermore itcan be discussed that B19V seronegative pregnantwomen should avoid high-risk populations especi-ally in endemic periods.

CONCLUSION

Parvovirus B19 infection is common in women ofchildbearing age, especially those with young

opyright © Lippincott Williams & Wilkins. Unautho

100 www.co-obgyn.com

children. Maternal infection can occur withoutsymptoms, while putting the fetus at risk for severeanemia, hydrops and death. Simple serology maybe misleading, advanced diagnostic methods maybe needed. Infected pregnant women should befollowed with weekly ultrasound and Doppler todetect fetal infection on time. Single intrauterineblood transfusion if often sufficient to save the fetus,although there is a risk for neurological damagein survivors.

Acknowledgements

None.

Conflicts of interest

The authors have no conflicts of interest to disclose.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:

& of special interest&& of outstanding interest Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 116).

1. Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in humansera. Lancet 1975; 1:72–73.

2. Siegl G, Bates RC, Berns KI, et al. Characteristics and taxonomy of Parvovir-idae. Intervirology 1985; 23:61–73.

3. Anderson LJ. Human parvoviruses. J Infect Dis 1990; 161:603–608.4. Anderson MJ, Lewis E, Kidd IM, et al. An outbreak of erythema infec-

tiosum associated with human parvovirus infection. J Hyg (Lond) 1984;93:85–93.

5. Pattison JR, Jones SE, Hodgson J, et al. Parvovirus infections and hypoplasticcrisis in sickle-cell anaemia. Lancet 1981; 1:664–665.

6. Cohen BJ, Mortimer PP, Pereira MS. Diagnostic assays with monoclonalantibodies for the human serum parvovirus-like virus (SPLV). J Hyg (Lond)1983; 91:113–130.

7. Edwards JM, Kessel I, Gardner SD, et al. A search for a characteristic illness inchildren with serological evidence of viral or toxoplasma infection. J Infect1981; 3:316–323.

8. Anderson MJ, Higgins PG, Davis LR, et al. Experimental parvoviral infection inhumans. J Infect Dis 1985; 152:257–265.

9. Anderson MJ, Pattison JR. The human parvovirus. Brief review. Arch Virol1984; 82:137–148.

10. Dijkmans BA, Breedveld FC, Weiland HT. Acute joint symptoms in a parvo-virus infection. Ned Tijdschr Geneeskd 1986; 130:1702–1705.

11. Dijkmans BA, van Elsacker-Niele AM, Salimans MM, et al. Humanparvovirus B19 DNA in synovial fluid. Arthritis Rheum 1988; 31:279–281.

12. Bell LM, Naides SJ, Stoffman P, et al. Human parvovirus B19 infection amonghospital staff members after contact with infected patients. N Engl J Med1989; 321:485–491.

13. Enders M, Weidner A, Zoellner I, et al. Fetal morbidity and mortality afteracute human parvovirus B19 infection in pregnancy: prospective evaluationof 1018 cases. Prenat Diagn 2004; 24:513–518.

14. Kooistra K, Mesman HJ, de Waal M, et al. Epidemiology of high-levelparvovirus B19 viraemia among Dutch blood donors. Vox Sang 2011;100:261–266.

15. Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Rev 2002;15:485–505.

16. Rohrer C, Gartner B, Sauerbrei A, et al. Seroprevalence of parvovirus B19 inthe German population. Epidemiol Infect 2008; 136:1564–1575.

17. de Jong EP, de Haan TR, Kroes AC, et al. Parvovirus B19 infection inpregnancy. J Clin Virol 2006; 36:1–7.

18. Valeur-Jensen AK, Pedersen CB, Westergaard T, et al. Risk factors forparvovirus B19 infection in pregnancy. JAMA 1999; 281:1099–1105.

19. Prospective study of human parvovirus (B19) infection in pregnancy. PublicHealth Laboratory Service Working Party on Fifth Disease. BMJ 1990;300:1166–1170.

20. Chisaka H, Morita E, Yaegashi N, Sugamura K. Parvovirus B19 and thepathogenesis of anaemia. Rev Med Virol 2003; 13:347–359.

rized reproduction of this article is prohibited.

Volume 24 � Number 2 � April 2012

Parvovirus B19 infection in pregnancy Dijkmans et al.

21. Norbeck O, Papadogiannakis N, Petersson K, et al. Revised clinical pre-sentation of parvovirus B19-associated intrauterine fetal death. Clin Infect Dis2002; 35:1032–1038.

22.&

Enders M, Klingel K, Weidner A, et al. Risk of fetal hydrops and nonhydropiclate intrauterine fetal death after gestational parvovirus B19 infection. J ClinVirol 2010; 49:163–168.

This relatively large observational study shows a 10.6% risk of fetal hydrops inwomen infected between 9 and 20 weeks’ gestation.23. Yaegashi N. Pathogenesis of nonimmune hydrops fetalis caused by intra-

uterine B19 infection. Tohoku J Exp Med 2000; 190:65–82.24. Brkic S, Bogavac MA, Simin N, et al. Unusual high rate of asymptomatic

maternal parvovirus B19 infection associated with severe fetal outcome.J Matern Fetal Neonatal Med 2011; 24:647–649.

25. van Kamp IL, Klumper FJ, Bakkum RS, et al. The severity of immune fetalhydrops is predictive of fetal outcome after intrauterine treatment. Am J ObstetGynecol 2001; 185:668–673.

26.&

Bonvicini F, Puccetti C, Salfi NC, et al. Gestational and fetal outcomes in b19maternal infection: a problem of diagnosis. J Clin Microbiol 2011; 49:3514–3518.

This cohort study showed that neither B19 IgM nor B19 DNA detected all maternalinfections. IgM serology correctly diagnosed 94.1% of the B19 infections, whileDNA testing correctly diagnosed 96.3%. Combining both methods provided thebest sensitivity. B19 vertical transmission was observed in 39% of the pregnan-cies, with an overall 10.2% rate of fetal deaths.27. Bonvicini F, Manaresi E, Gallinella G, et al. Diagnosis of fetal parvovirus B19

infection: value of virological assays in fetal specimens. BJOG 2009;116:813–817.

28. de Haan TR, Beersma MF, Claas EC, et al. Parvovirus B19 infection inpregnancy studied by maternal viral load and immune responses. Fetal DiagnTher 2007; 22:55–62.

29. Broliden K, Tolfvenstam T, Norbeck O. Clinical aspects of parvovirus B19infection. J Intern Med 2006; 260:285–304.

30. Pasquinelli G, Bonvicini F, Foroni L, et al. Placental endothelial cellscan be productively infected by Parvovirus B19. J Clin Virol 2009;44:33–38.

31. Koch WC, Harger JH, Barnstein B, Adler SP. Serologic and virologicevidence for frequent intrauterine transmission of human parvovirus B19 witha primary maternal infection during pregnancy. Pediatr Infect Dis J 1998;17:489–494.

32. Nyman M, Skjoldebrand-Sparre L, Broliden K. Nonhydropic intrauterine fetaldeath more than 5 months after primary parvovirus B19 infection. J PerinatMed 2005; 33:176–178.

33. Yaegashi N, Niinuma T, Chisaka H, et al. The incidence of, and factors leadingto, parvovirus B19-related hydrops fetalis following maternal infection; reportof 10 cases and meta-analysis. J Infect 1998; 37:28–35.

Copyright © Lippincott Williams & Wilkins. Unau

1040-872X � 2012 Wolters Kluwer Health | Lippincott Williams & Wilki

34. Simms RA, Liebling RE, Patel RR, et al. Management and outcome ofpregnancies with parvovirus B19 infection over seven years in a tertiary fetalmedicine unit. Fetal Diagn Ther 2009; 25:373–378.

35. Nunoue T, Kusuhara K, Hara T. Human fetal infection with parvovirus B19:maternal infection time in gestation, viral persistence and fetal prognosis.Pediatr Infect Dis J 2002; 21:1133–1136.

36. de Haan TR, Van den Akker ESA, Porcelijn L, et al. Thrombocytopenia inhydropic fetuses with parvovirus B19 infection: incidence, treatment andcorrelation with fetal B19 viral load. BJOG 2008; 115:76–81.

37. Pistorius LR, Smal J, de Haan TR, et al. Disturbance of cerebral neuronalmigration following congenital parvovirus B19 infection. Fetal Diagn Ther2008; 24:491–494.

38. Isumi H, Nunoue T, Nishida A, Takashima S. Fetal brain infection with humanparvovirus B19. Pediatr Neurol 1999; 21:661–663.

39. Dembinski J, Haverkamp F, Maara H, et al. Neurodevelopmental outcome afterintrauterine red cell transfusion for parvovirus B19-induced fetal hydrops.BJOG 2002; 109:1232–1234.

40. Nagel HT, de Haan TR, Vandenbussche FP, et al. Long-term outcome afterfetal transfusion for hydrops associated with parvovirus B19 infection. ObstetGynecol 2007; 109:42–47.

41. Beersma MF, Claas EC, Sopaheluakan T, Kroes AC. Parvovirus B19 viralloads in relation to VP1 and VP2 antibody responses in diagnostic bloodsamples. J Clin Virol 2005; 34:71–75.

42.&

Bredl S, Plentz A, Wenzel JJ, et al. False-negative serology in patients withacute parvovirus B19 infection. J Clin Virol 2011; 51:115–120.

This analysis of samples from blood donors and patients with suspected parvovirusB19 infections clerly showed the unreliability of simple IgM/IgG evaluation.Antibodies against the capsid proteins VP1 and VP2 may complex with B19V-particles thereby becoming undetectable in diagnostic tests.43. Enders M, Helbig S, Hunjet A, et al. Comparative evaluation of two commer-

cial enzyme immunoassays for serodiagnosis of human parvovirus B19infection. J Virol Methods 2007; 146:409–413.

44. Enders M, Weidner A, Rosenthal T, et al. Improved diagnosis of gestationalparvovirus B19 infection at the time of nonimmune fetal hydrops. J Infect Dis2008; 197:58–62.

45. de Haan TR, Beersma MF, Oepkes D, et al. Parvovirus B19 infection inpregnancy: maternal and fetal viral load measurements related to clinicalparameters. Prenat Diagn 2007; 27:46–50.

46. Delle Chiaie L, Buck G, Grab D, Terinde R. Prediction of fetal anemia withDoppler measurement of the middle cerebral artery peak systolic velocity inpregnancies complicated by maternal blood group alloimmunization orparvovirus B19 infection. Ultrasound Obstet Gynecol 2001; 18:232–236.

47. Ballou WR, Reed JL, Noble W, et al. Safety and immunogenicity of arecombinant parvovirus B19 vaccine formulated with MF59C.1. J InfectDis 2003; 187:675–678.

thorized reproduction of this article is prohibited.

ns www.co-obgyn.com 101