INTRODUCTION — Parvovirus B19 infection is a common childhood illness. Asymptomatic or mild infection occurs most often when B19 affects immunocompetent adults. Rarely, acute infection in pregnancy may lead to fetal loss or hydrops fetalis. The issues surrounding B19 infection during pregnancy are reviewed here.
MICROBIOLOGY/PATHOGENESIS — The Parvoviruses were discovered in 1975 by electron microscopy during evaluation of tests for hepatitis B surface antigen . Parvoviridae are small, nonenveloped deoxyribonucleic acid (DNA) viruses that infect a variety of animals, usually in a species-specific fashion. Human parvovirus B19 is the predominant parvovirus pathogen in humans. (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection", section on 'Virology'.)
Parvovirus B19 has a single-stranded DNA genome containing approximately 5000 nucleotides. It encodes at least two major structural proteins and one nonstructural protein and serves as the template for its own replication.
Parvovirus B19 preferentially infects rapidly dividing cells and is cytotoxic for erythroid progenitor cells [2,3]. B19 also may stimulate a cellular process initiating apoptosis (programmed cell death) . The latter may account for the minimal inflammatory response noted in tissues infected with B19.
EPIDEMIOLOGY — Antibodies to B19 are found in 30 to 60 percent of adults [5-7]. The secondary attack rate for household contacts may be as high as 50 percent; a susceptible individual exposed in a classroom has a 20 to 30 percent risk of infection . (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection".)
Pregnant women lacking antibodies to the virus are as susceptible as any other immunocompetent adult to B19 infection. However, 35 to 53 percent of pregnant women have preexisting IgG to the virus, indicating immunity from a prior infection [9,10].
The incidence of acute B19 infection in pregnancy is 3.3 to 3.8 percent [9,10]; this risk varies among different occupational groups. In one study, for example, the highest infection rates occurred in schoolteachers (16 percent), followed by day care workers and homemakers (9 percent each) . A systematic review evaluating the seroprevalence among day care workers also suggested that they are a particularly vulnerable population; both seroprevalence (relative risk [RR] 1.12) and seroconversion rates (RR 2.63) were higher among day care educators who worked with children than the general population . (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection", section on 'Transmission and risk factors for infection'.)
CLINICAL FEATURES — Parvovirus B19 causes erythema infectiosum (EI), also known as fifth disease. It is a common childhood illness characterized by a "slapped cheek" appearance on the face and a "lace-like" erythematous rash on the trunk and extremities. Although adults can develop a rash, it is not as common as in children, and the "slapped cheek" appearance is rare.
Children and adults also may experience one to four days of systemic symptoms prior to the appearance of the rash. Arthropathy affecting the joints of the hands, wrists, knees, and ankles can occur, most commonly in adults. Joint symptoms also can precede the development of a rash in adults. Arthropathy typically lasts one to two weeks. The clinical course in immunocompetent children and adults, including pregnant women, generally is self-limited. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
Individuals with an underlying chronic anemia such as sickle cell anemia or thalassemia may experience a transient, generally self-limited, aplastic crisis caused by B19. In addition, individuals with acquired or inherited immunodeficiencies are at risk for chronic parvovirus B19 infection, which may require therapy. (See "Treatment and prevention of parvovirus B19 infection".)
Infectivity — B19 viremia begins approximately six days after exposure and lasts for one week in immunocompetent individuals. An infected person is contagious before the onset of symptoms; B19 can be detected in blood and secretions as early as 5 to 10 days after exposure [13,14]. Patients with normal immune systems probably are not infectious after the onset of B19-associated rash, arthralgias, or arthritis.
Individuals with B19 IgG generally are considered immune to recurrent infection. However, in a study of five seropositive volunteers inoculated with B19, one became viremic, suggesting that reinfection is possible .
Maternal-fetal effects — B19 infection during pregnancy may be associated with fetal loss or hydrops fetalis. However, there do not appear to be long-term developmental sequelae of infection in children who do not develop hydrops fetalis.
Fetal loss — The initial reports linking B19 and poor fetal outcome suggested that the risk of stillbirth or fetal loss was greater than 30 percent [15,16]. Many subsequent, larger prospective studies have more accurately established lower rates of fetal loss (table 1). The largest prospective study of B19 infection in pregnant women included 1018 women with acute infection based upon serological studies . Major findings from this report were:
●Fetal death occurred in 6.3 percent of pregnancies (64/1018) and was limited to B19 infections diagnosed in the first one-half of pregnancy. The fetal death rate in women diagnosed with first trimester infection was 13 percent (34/256 first trimester infections), decreasing to 9 percent (30/322) for infections diagnosed at 13 to 20 weeks of gestation, and 0 (0/439) after 20 weeks.
●There were six stillbirths (ie, fetal death ≥22 weeks of gestation). Four were attributed to B19 infection prior to 20 weeks of gestation and occurred at 22 to 24 weeks; the other two stillbirths were diagnosed at 39 and 40 weeks and appeared to be unrelated to B19.
A summary of the available data suggests that the risk of fetal loss in pregnancies infected before and after 20 weeks of gestation is 11 percent and <1 percent, respectively [17,18]. In a subsequent case control study, a positive parvovirus IgM test during the first trimester was more common among 2918 women with fetal loss prior to 22 weeks compared with 8429 matched controls with live births (0.8 versus 0.5 percent, respectively; OR 1.71, 95% CI 1.02-2.86) . Nevertheless, the estimated contribution of parvovirus infection to the overall burden of fetal losses was low (0.1 up to 0.8 percent during epidemics).
A separate question is what percent of third trimester stillbirths are attributable to B19? Three studies suggest that the prevalence of parvovirus B19 infection in late trimester fetal deaths is very low [20-22]. In a study from Sweden, fetal loss this late in pregnancy occurred in 93 of 33,759 deliveries . Polymerase chain reaction (PCR) on placental tissue revealed B19 DNA in seven of these cases. Thus, of the 0.3 percent of cases of intrauterine fetal death in the third trimester in this study, 7.5 percent were associated with evidence of B19 infection, an exceedingly small number.
In another study from this same group, nested PCR was positive in 7 of 57 cases (15 percent) of intrauterine fetal death at ≥22 weeks gestation compared to 0 of 53 term pregnancies . Although the overall numbers are still small in a population of 14,147 deliveries, the authors suggest that this sensitive test be applied in the evaluation of intrauterine fetal loss in the late second and third trimesters. A separate study investigating the etiologies of stillbirths found a higher incidence of trisomy karyotype in parvovirus-infected fetuses . These findings suggest that infants with chromosomal abnormalities may be more susceptible to parvovirus infection, and that such chromosomal abnormalities may be responsible for some of the morbidity attributed to parvovirus.
Transient effusions — Maternal parvovirus infection has been associated with transient isolated fetal pleural or pericardial effusions that resolve spontaneously before term . These effusions are thought to result from direct pleural or myocardial inflammation.
Fetal hydrops — In addition to causing fetal loss, B19 is cytotoxic to fetal red blood cell precursors and may cause anemia and hydrops fetalis [25-28]. Hydrops fetalis refers to abnormal accumulation of fluid in the fetal soft tissues and serous cavities. Case reports have suggested that enlarged nuchal lucency on ultrasound may also represent early hydrops [29,30]. The specific ultrasound findings of nonimmune hydrops fetalis are discussed elsewhere. (See "Nonimmune hydrops fetalis", section on 'Fetal findings'.)
The risk of anemia and fetal hydrops appears to be greater when women are infected during the first half of pregnancy [17,31,32]. As an example, in a large series of pregnant women with acute parvovirus B19 infection, hydrops occurred in 3.9 percent (40 of 1018) of pregnancies and was more common when infection was diagnosed at ≤32 weeks of gestation (4.4 versus 0.8 percent after 32 weeks) . The median interval between diagnosis of maternal infection and hydrops was three weeks; 50 percent of cases occurred two to five weeks after maternal infection and 93 percent occurred within eight weeks of maternal diagnosis.
The risk of fetal loss is higher when parvovirus B19 infection is complicated by hydrops , which can lead rapidly to fetal death within a few days to weeks. However, hydrops can also resolve spontaneously with an apparently normal infant at delivery, although the rate of spontaneous resolution is uncertain [34,35]. In one systematic review of fetal parvovirus B19 infection that included 314 cases with hydrops, spontaneous resolution was reported in 5 percent . Among cases of severe hydrops, spontaneous resolution is probably a rare event. In a report of 40 cases of hydrops, 23 were considered severe (hemoglobin less than 4.7 mmol/L or a large amount of ascites and at least one of: pleural effusions, skin edema of more than 5 mm, hydropic placenta, pericardial effusion, cardiomegaly, poor ventricular contractility, or polyhydramnios or oligohydramnios ) . Thirteen of these 23 fetuses underwent intrauterine transfusions, with 11 survivors. Death occurred in all 10 fetuses with severe hydrops that did not receive intrauterine transfusion.
The hydrops and fetal death are thought to result from severe B19-associated anemia. The severity of the anemia probably results from three factors:
●Reduced survival of fetal red blood cells
●The need to meet the red cell demands of an expanding intravascular volume
●Inability of the immature immune system of some fetuses to control the infection.
Hemoglobin levels of 2 g/dL or lower have been reported and presumably lead to high-output congestive heart failure. B19 also can infect myocardial cells ; thus, myocardial injury may contribute to the hydrops and fetal death in some cases .
Severe thrombocytopenia has been observed in 36 of 97 (37 percent) parvovirus-infected fetuses with hydrops [38,39]. Severe thrombocytopenia can lead to exsanguination at the time of intrauterine red cell transfusion; for this reason, the platelet count should be determined and platelets should be available for transfusion at the time of any fetal procedures. (See "Intrauterine fetal transfusion of red cells".)
Children who survive fetal hydrops caused by parvovirus may have an increased risk of neurodevelopmental impairments [33,40]. In one study, 28 Dutch children who had received intrauterine transfusion for fetal hydrops were evaluated at a median of five years old . Three had severe and two had mild cognitive developmental delays, and another child had fine motor impairment. These rates are higher than those historically seen in the Dutch population. In contrast, an earlier study of 20 children surviving fetal hydrops in Germany did not show an excess of developmental delay . The discrepancy in findings may be due to differences in the follow-up rate of hydrops survivors and cognitive testing methodology.
Neonatal and developmental considerations — Parvovirus appears to be teratogenic in fetal animals, causing cerebellar hypoplasia and ataxia in cats and anencephaly, microcephaly, facial defects, and ectopic hearts in hamsters. Despite case reports suggesting a link between B19 infection during pregnancy and fetal malformations [42,43], epidemiologic studies do not support this association .
Case reports describe congenital abnormalities in four human newborn infants with parvovirus infection including ocular anomalies (eg, microphthalmia; dysplastic changes of the sclera, choroid, cornea and retina; and degeneration of the lens), hydrocephalus, cleft lip or palate, webbed joints, musculoskeletal anomalies, hepatocellular damage, myocarditis, congenital cardiomyopathy, and myositis [42,43,45,46]. Congenital parvovirus infection also has been reported in two premature infants whose illness was associated with placentomegaly, edema, angioedema, hepatomegaly, anemia, thrombocytopenia, respiratory insufficiency and other non-specific features shared by life-threatening congenital infections [47,48].
Despite the above associations, most intrauterine parvovirus infections do not have an adverse outcome [10,49,50] and the bulk of the available data suggest that parvovirus B19 is not a teratogen  (see "Clinical manifestations and diagnosis of parvovirus B19 infection"). Long-term studies of offspring of B19-infected pregnant women also are encouraging. Although data are limited, developmental delays are no more frequent in offspring of actively infected mothers compared to uninfected mothers [41,52].
DIAGNOSIS — During pregnancy, the laboratory diagnosis of maternal parvovirus B19 infection relies primarily on IgG and IgM antibody testing, although polymerase chain reaction assays may also be helpful in certain situations. Parvovirus B19 is difficult to culture.
Maternal parvovirus infection — IgM antibody capture radioimmunoassay and enzyme-linked immunosorbent assay (ELISA) are sensitive tests, detecting between 80 and 90 percent of patients with clinical B19 infection .
●Circulating IgM antibodies can be detected approximately 10 days after exposure and just prior to the onset of symptoms; they may persist for three months or longer [54,55].
●B19 IgG antibodies are detected several days after IgM and usually persist for years; they are a marker of past infection.
However, reliance on a negative IgM serologic result alone can be misleading in a patient with a significant exposure history, because in some instances maternal IgM levels may be below the detection limit. In such cases, polymerase chain reaction can be useful. In a study utilizing serum samples from 101 pregnant women with confirmed B19-induced fetal hydrops, 15 percent of the patients who were seronegative for B19 IgM antibodies had evidence of viremia by maternal B19 DNA testing. (See 'Approach to the patient exposed to B19' below.)
Fetal parvovirus infection — Polymerase chain reaction is a sensitive method to detect small amounts of B19 DNA. Use of this technique on amniotic fluid is particularly helpful when attempting to determine the cause of hydrops and is the method of choice to make the diagnosis of fetal parvovirus infection [56-58]. Another option is to obtain fetal blood for B19 IgM; however, percutaneous fetal blood sampling, the method used to obtain fetal blood, carries a 1 percent fetal loss rate.
Other methods — Other techniques such as electron microscopy, detection of viral DNA, and probe hybridization assays for nucleic acids are available but typically are not necessary to detect acute maternal infection. (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection".)
APPROACH TO THE PATIENT EXPOSED TO B19 — Pregnant women who are exposed to or have symptoms of parvovirus infection should have serologic testing for IgG and IgM antibodies.
The discussion below gives guidance in diagnostic evaluation of the patient with possible parvovirus infection. Detailed information regarding diagnostic testing for parvovirus is available elsewhere. (See "Virology, epidemiology, and pathogenesis of parvovirus B19 infection".)
Past infection — A positive IgG antibody and a negative IgM indicate maternal immunity; thus, the fetus is protected from infection.
Acute infection — A positive IgM antibody is consistent with acute parvovirus infection. The significance of this will depend on when testing is done relative to the stage of pregnancy:
●Women who are diagnosed with acute infection in the first half of pregnancy should be counseled that there is no proven risk of parvovirus-induced congenital anomalies, but there is a risk for fetal loss. The only potentially effective intervention is intrauterine fetal transfusion for treatment of severe fetal anemia; however, this procedure is not feasible before about 20 weeks of gestation due to limited visualization and the small size of the relevant anatomic structures. (See "Intrauterine fetal transfusion of red cells".)
●Women who are diagnosed with acute infection beyond 20 weeks gestation should receive periodic ultrasounds (weekly beginning as early as 22 weeks) to look for signs of fetal hydrops (eg, scalp edema, ascites, polyhydramnios, cardiomegaly).
Although serial ultrasounds commonly are performed, the risk of hydrops is low, and some have questioned the advantage of monitoring because the benefits of therapeutic intervention are not clear (see below). There is also controversy about how long to continue ultrasound monitoring. There have been cases of hydrops reported more than eight weeks after the initial maternal infection , suggesting that ultrasound be performed for at least eight weeks after an acute infection.
Susceptible host — A pregnant woman who is negative for both IgG and IgM parvovirus antibody is susceptible to infection, especially if she has contact with small children and there are parvovirus cases in the community. Management of this patient will depend on history of potential parvovirus exposure:
No history of exposure — Ideally, susceptible pregnant women should avoid contact with B19. However, there is no proven benefit to removal of seronegative women from high-risk employment (eg, school teacher or day care center employee) for the duration of pregnancy . However, careful hand washing and avoiding sharing food or drinks is likely to at least partially prevent the spread of B19. (See "Treatment and prevention of parvovirus B19 infection".)
Recent history of exposure — If a pregnant patient has a history of recent parvovirus exposure and initial serologies are negative, we suggest sending serum parvovirus B19 polymerase chain reaction (PCR) to evaluate for infection. If PCR is not available, we repeat serologies in four weeks after exposure to identify the patients who may have been in the process of developing IgM antibodies .
In a study of serum samples collected at the time of invasive prenatal diagnosis from 101 pregnant females with confirmed B19-induced fetal hydrops, only 77 percent of the females had positive IgM serologies, underscoring the problem of false-negative serologies in acute infection . Of the 24 samples that were tested by PCR, all were positive for parvovirus B19.
MANAGEMENT OF ANEMIA AND HYDROPS — Mild to moderate anemia generally is well tolerated by the fetus and resolves without sequelae. Severe anemia, although uncommon, can lead to hydrops fetalis and death. Because parvovirus-induced anemia is a transient process, determination of fetal hemoglobin is not necessary unless severe anemia is suggested by sonographic signs, such as fetal skin edema, ascites, or pleural or pericardial effusions. Doppler assessment of the fetal middle cerebral artery (MCA) peak systolic velocity (PSV) and ductus venosus velocity are accurate tools for the determination of fetal anemia and a noninvasive alternative to cord blood sampling [63-65]. Amniocentesis to determine change in optical density of amniotic fluid at 450 nm on the spectral absorption curve (delta OD450) probably is not useful for evaluating the degree of anemia since red blood cell destruction with production of bilirubin is not the primary cause of the anemia.
When severe anemia is suspected because of an elevated Doppler MCA PSV or signs of hydrops, the fetus requires close monitoring and assessment of fetal hematocrit by percutaneous umbilical vein sampling. Intrauterine fetal blood transfusion usually is performed if severe anemia is confirmed. As discussed above, severe thrombocytopenia can lead to exsanguination at the time of intrauterine red cell transfusion; for this reason, the platelet count should be determined and platelets should be available for transfusion at the time of any fetal procedures. (See "Fetal blood sampling" and "RhD alloimmunization in pregnancy: Overview".)
Intrauterine blood transfusion — Intrauterine transfusion of RBCs is indicated to prevent fetal death from severe anemia. The procedure is generally limited to fetuses between 18 and 35 weeks of gestation because of technical limitations before 18 weeks and excessive fetal risk compared with delivery after 35 weeks. Intrauterine transfusion is discussed in detail elsewhere. (See "Intrauterine fetal transfusion of red cells".)
The efficacy of intrauterine transfusion in parvovirus infection is suggested by a review of 14 studies and case reports of 705 fetal parvovirus B19 infections . Fetal transfusion for hydrops improved the survival rate (82 versus 55 percent without transfusion). Two included studies are detailed below:
●In one retrospective series of 38 hydropic fetuses, an apparently normal infant was delivered more often following intrauterine blood transfusions than in untreated pregnancies (9 of 12 versus 13 of 26, p<0.05 controlling for gestational age and severity of hydrops by ultrasound) . The survival rate decreased with increasing severity of hydrops on ultrasonography, and the fetuses died a median of 4.5 days after the first abnormal ultrasound examination.
●In the large survey of obstetricians, the outcome of 467 cases of hydrops was improved in cases of intrauterine transfusion with death in 27 of 164 fetuses (16 percent) who received intrauterine transfusion and in 138 of 296 fetuses (47 percent) who did not .
Immune globulin — Intravenous immune globulin (IVIG) has been used to treat acute parvovirus in immunodeficient adults and human immunodeficiency virus (HIV)-infected children. However, there is only one case report on its use as a fetal therapy . Given the limited available data, the use of IVIG during pregnancy currently is not recommended.
Delivery room and postnatal management of the hydropic infant — Whenever possible, the management of a woman with a hydropic infant should be undertaken in a tertiary care facility staffed by individuals experienced in the care of sick neonates. As with all high-risk births, delivery of a hydropic infant mandates coordinated efforts by the obstetrician, perinatologist, and neonatal team to optimize pregnancy outcome.
Resuscitation of such infants frequently is difficult and advance preparation is advisable. The majority of hydropic infants require respiratory assistance and mechanical ventilation. Ventilation may be compromised by pulmonary hypoplasia, pulmonary edema, air leaks, or by the accumulation of pleural or peritoneal fluid. Abdominal paracentesis and thoracocentesis of fetal ascites and pleural effusions may be needed either just prior to delivery or immediately after to facilitate resuscitation.
Postnatal management depends upon the gestational age of the infant, other associated conditions (eg, respiratory distress syndrome), and illness severity. Infants with severe anemia and cardiovascular instability may benefit from an isovolumetric or partial exchange transfusion with packed red blood cells. (See "Nonimmune hydrops fetalis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Avoiding infections in pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Parvovirus B19 is a small non-enveloped DNA virus that frequently infects humans, with antibodies to B19 found in 30 to 60 percent of adults. The incidence of B19 infection during pregnancy is 3.3 to 3.8 percent. (See 'Microbiology/pathogenesis' above and 'Epidemiology' above.)
●Parvovirus B19 causes erythema infectiosum, also known as fifth disease, characterized by self-limited fever and rash, and in adults, arthropathy. Viremia begins approximately six days after exposure and lasts for one week in immunocompetent individuals, who are usually infectious from the onset of viremia until the appearance of B19 associated rash or arthropathy. (See 'Clinical features' above and 'Infectivity' above.)
●Most intrauterine parvovirus infections do not have an adverse outcome, and developmental delays are no more frequent in offspring of actively infected mothers compared with uninfected mothers. Rarely, infection with parvovirus B19 during pregnancy can lead to fetal loss and hydrops fetalis. The overall incidence of these complications is low and concentrated among infections that occur during the first half of pregnancy. (See 'Maternal-fetal effects' above.)
●During pregnancy, the laboratory diagnosis of maternal parvovirus B19 infection relies primarily on IgG and IgM antibody testing to determine pre-existing immunity, acute infection, or susceptibility. Polymerase chain reaction (PCR) testing on amniotic fluid is the method of choice to make the fetal diagnosis. (See 'Diagnosis' above and "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnosis'.)
●Pregnant women who are exposed to or have symptoms of parvovirus infection should have serologic testing for IgG and IgM antibodies. A positive parvovirus IgM is consistent with acute infection. Women diagnosed with acute infection during the first half of pregnancy should be counseled that there is no proven risk of parvovirus-induced congenital anomalies, but there is a risk for fetal loss. Women who are diagnosed with acute infection beyond 20 weeks gestation should receive weekly ultrasounds to evaluate for fetal hydrops for at least eight weeks. (See 'Approach to the patient exposed to B19' above.)
●If a pregnant woman with a recent parvovirus exposure is negative for both IgG and IgM, PCR testing of her plasma for maternal parvovirus B19 DNA may be more sensitive and should be performed. (See 'Susceptible host' above.)
●When severe anemia is suspected on ultrasound findings, the fetus requires close monitoring and assessment of fetal hematocrit by percutaneous umbilical vein sampling. Intrauterine transfusion of RBCs is indicated to prevent fetal death from severe anemia. (See 'Intrauterine blood transfusion' above and "Intrauterine fetal transfusion of red cells".)
●Management of the birth of a hydropic infant should be undertaken at a tertiary care facility with experience in neonatal critical care. Drainage of fetal ascites or pleural effusions may be necessary perinatally to facilitate resuscitation. Postnatally, hydropic infants generally require mechanical ventilation. (See 'Delivery room and postnatal management of the hydropic infant' above and "Postnatal care of hydrops fetalis", section on 'Management'.)