To x o p l a s m o s i s ,

Parvovirus, and
Cytomegalovirus
i n P re g n a n c y
Deborah M. Feldman, MDa, Diane Timms, DO
b
,
Adam F. Borgida, MDa,*

KEYWORDS
 Toxoplasmosis  Parvovirus  Cytomegalovirus
 Diagnosis  Management

TOXOPLASMOSIS

Toxoplasmosis is caused by the Toxoplasma gondii protozoan, an obligate intracel-

lular parasite. The organism can infect any warm-blooded animal or may be found
in soil, but its definitive host is the cat family. The organism completes its sexual cycle
in feline intestinal epithelial cells and oocysts are shed in the feces for several weeks
after the reproductive cycle is completed.1 Three routes of infection have been iden-
tified. Oocysts may be ingested from contaminated cat feces, water, or fruits and
vegetables as well as gardening in contaminated soil. Tissue cysts are ingested in
infected raw or undercooked meat. In a study of 148 patients including 76 pregnant
women with recently acquired infection, age 50 years or more, male sex, Midwest
region, working with meat, having 3 or more kittens, eating locally produced cured,
dried, or smoked meat, rare lamb, raw ground beef, and unpasteurized goat’s milk
were found to be associated with infection.2 A third route of infection is via vertical
transmission. Vertical transmission from a pregnant woman to her fetus can cause
congenital toxoplasmosis, with consequences including stillbirth, chorioretinitis, deaf-
ness, microcephaly, and developmental delay.3,4
The true prevalence of toxoplasmosis is unknown because it is not a reportable
disease in the United States; however, it was estimated by the fourth National Health

a
Prenatal Testing Center, Division of Maternal Fetal Medicine, Department of Obstetrics and
Gynecology, University of Connecticut School of Medicine, Hartford Hospital, 85 Jefferson
Street, #625, Hartford, CT 06102, USA
b
Maternal Fetal Medicine, UConn Health Center, Department of Obstetrics and Gynecology,
University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT
06030, USA
* Corresponding author.
E-mail address: [email protected]

Clin Lab Med 30 (2010) 709–720

doi:10.1016/j.cll.2010.04.009 labmed.theclinics.com
0272-2712/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
710 Feldman et al

and Nutrition Examination Survey (NHANES) performed from 1999 to 2000.1 Of 4234
people tested for immunoglobulin (Ig) G antibodies to Toxoplasma, 15.8% were posi-
tive. Of 2221 women aged 12 49 years, 14.9% were seropositive, leaving 85% of
women of child-bearing age susceptible to infection. The rate of congenital toxoplas-
mosis has been reported to be as high as 10 per 10,000. In a more recent study of
635,000 infants in the New England Regional Newborn Screening Program, it was
found to be 1 per 10,000 live births.3 With approximately 4 million live births in the
United States annually, it can be estimated that between 400 and 4000 infants will
be born with congenital toxoplasmosis.
Vertical transmission of infection to the fetus is most likely to occur with a primary
infection during the pregnancy. However, immunocompromised women with chronic
infection may also transmit the disease.5 More than 90% of pregnant women who
acquire a primary infection are asymptomatic, as are 85% of neonates born with
congenital toxoplasmosis.6 Transmission is rare in early pregnancy and increases
with duration of pregnancy. Transmission frequency in the first trimester is approxi-
mately 15%, 30% in the second trimester, and 60% in the third trimester.6 Exposure
to infection acquired in the first trimester causes more severe congenital toxoplas-
mosis, with fetuses exposed in the third trimester most likely to be asymptomatic.
These infants require treatment to prevent manifestations later in life. Transmission
can be decreased by antenatal treatment, and appropriate therapy should be initiated
for suspected fetal infection.

Diagnosis
Diagnosis can be made by testing maternal serum for antibodies. Initial testing should
measure IgG and IgM antibodies. If both are negative, infection has not occurred. A
negative IgM result with a positive IgG during the first or second trimester often indi-
cates an infection that predated the pregnancy; this is also likely in the third trimester
but the infection could have occurred early in pregnancy with the IgM level decreased
to undetectable levels.7 A positive IgM result with or without IgG to Toxoplasma
requires further testing to determine the status of the infection. IgM antibodies may
represent false-positive results or chronic or past infection, as they can persist for 1
year or more.8
Up to 60% of patients positive for IgM in the community have results inconsistent
with recent infection on confirmatory testing at the reference laboratory.9 Therefore,
confirmation is important before consideration of elective termination of pregnancy.
In 1 study, confirmatory testing decreased the rate of abortion from 17.2% to 0.4%.9
Confirmatory testing consists of the Toxoplasma serologic profile (TSP), performed
at reference laboratories such as the Toxoplasma Serology Laboratory of the Palo Alto
Medical Foundation. The panel of tests available includes the Sabin-Feldman test, the
differential agglutination (AC/HS) test, IgG avidity, and enzyme-linked immunosorbent
assay (ELISA) for IgM, IgE, and IgA.
ELISA is used to qualitatively determine the presence or absence of antibodies by
adding serum to a well containing T gondii antigen bound to an enzyme. A fluorescent
substrate is then added that will fluoresce if antigen-antibody linking has occurred.10
The presence of IgA and IgE on ELISA implies recent infection.
The IgG avidity test measures the strength of antigen-antibody binding, which
increases with duration of infection. Avidity is determined by diluting the substrates
in an immunoassay with urea and comparing the ratio of antibody titer in an untreated
well with that of the urea-treated well.11 High avidity requires at least 3 months to
develop, and so helps to rule out acute infection.
 Toxoplasmosis, Parvovirus, and CMV in Pregnancy 711

Ultrasound can be used to detect certain fetal manifestations of infection. Findings

suggestive of congenital toxoplasmosis include unilateral or bilateral ventriculome-
galy, ascites, intracranial or intrahepatic calcifications, hepatomegaly, and spleno-
megaly.7 In the absence of abnormalities, monthly ultrasonographic monitoring
should continue throughout the pregnancy.
Amniocentesis can be offered for polymerase chain reaction (PCR) testing of the
amniotic fluid. The procedure should be performed after 18 weeks’s gestation and 4
or more weeks after the estimated date of infection. Amplification of the B1 gene of
the parasite is used to assess for the presence of infection. In a study performed at
3 centers in France, overall sensitivity was 64% with a negative predictive value of
98.8%. There were no false-positives, yielding a specificity of 100%, as well as a posi-
tive predictive value of 100%.12 The sensitivity of PCR diagnosis was highest when
maternal infection occurred between 17 and 21 weeks. Although other studies have
suggested a higher sensitivity,13,14 a negative PCR result does not rule out congenital
disease and adequate treatment and follow-up are still indicated for these patients.

Treatment
Vertical transmission of newly acquired infection during early pregnancy at 18 weeks
or more can be prevented by administration of oral spiramycin, 1 g every 8 hours. This
macrolide antibiotic does not cross the placenta, so is not appropriate for fetal treat-
ment. In the absence of signs of fetal infection, spiramycin should be continued until
delivery. The drug is not commercially available in the United States, but can be
obtained at no cost from the Food and Drug Administration or the reference laborato-
ries that perform confirmatory testing.6 Spiramycin does not seem to have any fetal
effects, however a small percentage of women may develop gastrointestinal side
effects.6,15
If seroconversion occurs after 18 weeks or fetal infection is confirmed by PCR or
ultrasound findings, treatment should be initiated. Pyrimethamine 50 mg twice daily
for 2 days followed by 50 mg per day, sulfadiazine 75 mg/kg per day in 2 divided doses
for 2 days followed by 50 mg/kg twice daily, and folinic acid 10 to 20 mg per day, may
prevent congenital infection at later gestational ages and also treat the fetus.6 Pyri-
methamine is a folic acid anatagonist that is teratogenic early in pregnancy, therefore
its use in the first trimester should be avoided. It is not associated with hyperbilirubi-
nemia, but may cause bone marrow depression.16 Folinic acid may help prevent
hematologic toxicity.
Immunocompromised women with chronic infection may rarely transmit the parasite
to the fetus, resulting in congenital infection. This includes women with AIDS as well as
those on immunosuppressive treatment. Vertical transmission may occur in up to 4%
of cases, particularly when the CD4 count is less than 100/mm3.17 The risk of transmis-
sion is low when the CD4 count is greater than 200/mm3. Consideration should be
given to screening all immunosuppressed women for evidence of a history of infection
to establish an early diagnosis of reactivation. Seropositive women with low CD4
counts should receive trimethoprim-sulfamethoxazole to prevent reactivation of Toxo-
plasma. Because of reports of congenital toxoplasmosis in mild or moderately immu-
nosuppressed women, it is recommended that women infected with human
immunodeficiency virus with CD4 counts less than 200/mm3 or immunocompromised
women not infected with HIV be treated with spiramycin for the duration of pregnancy.6

Prevention
In a recent survey of pregnant women in the United States, only 48% of respondents
had heard of toxoplasmosis but 60% were aware that Toxoplasma is shed in the feces
712 Feldman et al

of cats and can be contracted by changing cat litter. Only 30% knew of the association
with raw or undercooked meat.18 A 2009 survey of obstetricians practicing in the
United States showed that 87.7% counsel patients about how to prevent toxoplas-
mosis and why, with 78% of counseling occurring only at the first prenatal visit.19
The rate of primary infection may be decreased by as much as 63% to 92% by coun-
seling pregnant woman on how to avoid infection.20
Secondary prevention strategies to prevent fetal infection in women who contract
the disease are in place in many countries with a higher incidence of toxoplasmosis
than the United States, including France and Austria. In these countries, all women
are screened for antibodies to Toxoplasma on initiation of prenatal care. Seronegative
women are rechecked monthly to allow for intervention if a new infection is detected.
In the United States, several states have instituted newborn serologic screening for
Toxoplasma IgM. However, this does not allow for prenatal intervention, and may
miss neonates infected early in gestation or late in the third trimester.5

PARVOVIRUS

Parvovirus B19 is a small, single-stranded DNA virus that infects only humans. It most
commonly presents as erythema infectiosum, or fifth disease, a common viral exan-
them in children. Typically the disease is characterized by fever and an erythematous
rash on the cheeks. It is self-limited and symptoms resolve within 7 to 10 days. Immu-
nity after the disease is life-long, and at least 50% of adults are immune from exposure
to the virus during childhood. Clinical manifestations for those adults who are suscep-
tible to the virus include malaise, a reticular rash, and joint pain/swelling that may last
from days to months. Approximately 20% to 30% of patients have no symptoms at
all.21
Transmission of parvovirus B19 occurs most commonly through spread of respira-
tory droplets. The incubation period is 5 to 10 days after exposure and before any
symptoms. By the time a rash is present, respiratory secretions and serum are usually
free of the virus and the patient is no longer contagious.22
Because parvovirus B19 preferentially infects rapidly dividing cells and is cytotoxic
for erythroid progenitor cells, there is concern about the effect of fetal transmission
from an infected mother. Among the first reported association between parvovirus
B19 and fetal nonimmune hydrops was a case series published in the mid to late
1980s after an outbreak of the virus in a Connecticut community in 1986.23 Since
then, several hundred publications have reported the potential risks and outcomes,
and management plans for parvovirus in pregnancy have been outlined.

Diagnosis of Maternal Infection

Maternal serology using ELISA, Western blot, or radioimmunoassay is the most
common method of detecting the presence of IgG and IgM immunoglobulins, which
are both produced in response to infection with parvovirus B19. The sensitivity of
these assays to detect IgG and IgM is generally around 70% to 80%.24 The IgM-
specific antibody is usually present by the third to fifth day after symptoms present,
and may persist for several weeks to months. Positive IgM antibody indicates acute
infection. The presence of IgG antibodies is noted approximately 7 days after the
onset of symptoms and lasts indefinitely. In the absence of IgM antibodies, a positive
IgG indicates an old infection and therefore immunity. Cases of recurrent or persistent
parvovirus are extremely rare. The prevalence of IgG antibodies to the virus increases
with age, with 2% to 10% rates of seropositivity in preschool-age children to 60% in
adolescents and adults.25
 Toxoplasmosis, Parvovirus, and CMV in Pregnancy 713

Diagnosis of Fetal Infection

Ultrasound is the primary tool for diagnosing congenital parvovirus B19 infection.
Because of the affinity of the virus for erythroid stem cells, infected fetuses may
become profoundly anemic. In addition, the virus can attack the myocardium, causing
a cardiomyopathy, as well as direct hepatic injury that may impair protein synthesis
and lower colloid oncotic pressure. All of these effects may lead to hydrops fetalis,
which is readily diagnosed with ultrasound (Fig. 1). Hydrops occurs in up to 10% of
pregnancies in which parvovirus infection is documented before 20 weeks. The risk
for hydrops lowers significantly if infection occurs in the late second or third trimester.
Infection early in the first trimester is associated with a higher risk for spontaneous
abortion than in uninfected pregnancies.26 Fetal parvovirus B19 infection can also
be diagnosed using PCR of amniotic fluid or in fetal/placental tissue after a fetal
demise.26,27

Management of Parvovirus B19 Infection During Pregnancy

Following exposure to parvovirus B19, the pregnant patient should be tested for the
presence of IgG and IgM antibodies. If immunity is documented by the presence of
IgG and the absence of IgM antibodies, the patient can be reassured that her fetus
is not at risk for prenatal infection. If IgG and IgM antibodies are undetectable, this indi-
cates that the patient is susceptible to infection and titers should be repeated in 3 to 4
weeks. If they remain negative, the patient remains susceptible to the disease without
evidence of infection. Continued hand-washing and avoidance of possible sources of
infection are recommended. There is no vaccine or known medical treatment of the
virus, so routine screening and avoidance of work among school teachers or daycare
providers is recommended.
Should the patient have evidence of seroconversion with positive titers of IgG and
IgM antibodies, ultrasound surveillance of the fetus should be initiated. Attention
should be focused on the presence of ascites, pleural or pericardial effusions, or scalp
edema. In addition, more recent evidence supports the use of middle cerebral artery
(MCA) Doppler to evaluate for fetal anemia (Fig. 2), as this may be detected before
fetal hydrops.28,29 The incubation period for congenital infection may be longer than
in adults, and reports of fetal hydrops have been made as long as 8 to 10 weeks after
exposure. Therefore, we recommend weekly ultrasounds for approximately 10 weeks
after exposure to the virus. If no hydrops or evidence of anemia has been

Fig. 1. Fetal hydrops diagnosed by ascites and pleural effusions in a fetus with known parvo-
virus B19 infection.
714 Feldman et al

Fig. 2. MCA-peak systolic velocity to screen for fetal anemia after acute parvovirus B19
infection.

demonstrated by then, the likelihood of its development is small.30 Few cases of fetal
death in the absence of hydrops have been attributed to parvovirus B19.
If there is evidence of fetal hydrops or anemia by an increased peak systolic velocity
through the MCA, a cordocentesis should be performed when technically possible.
Although the disease is often self-limited and there have been cases of spontaneous
resolution of hydrops reported,10 an in utero blood transfusion is indicated in cases of
severe anemia. This is best performed intravascularly through the umbilical vein using
ultrasound guidance.31,32
Neonatal Outcomes after Parvovirus Infection
There have been few data published on the long-term outcomes of fetuses
requiring in utero blood transfusion because of parvovirus B19 infection. Barring
any complications related to the procedure itself, most fetuses do well after intra-
vascular transfusion even if they are profoundly anemic before the procedure.
Results regarding the neurodevelopment of these infants after birth are slightly
conflicting. Most studies suggest normal neurologic outcomes after appropriate
therapy. One small retrospective study reported a higher rate of delayed psycho-
motor development in children aged 6 to 8 years who had undergone intrauterine
transfusion for parvovirus B19 infection, suggesting a potential effect of the virus
on the central nervous system.33 A larger controlled study suggested a similar rate
of developmental delay among infants born to mothers with acute parvovirus
infection during pregnancy compared with controls.34

CYTOMEGALOVIRUS

Human cytomegalovirus (CMV) is an enveloped DNA herpes virus. It has numerous

characteristics of a herpes virus including the ability to cause congenital infection.
The seroprevalence of CMV is approximately 50% in adults in industrialized countries.
Approximately 0.6% to 0.7% of infants born in the United States are congenitally
infected making it the most common cause of infection-related congenital handi-
caps.35 Vertical transmission of CMV depends on numerous factors including type
 Toxoplasmosis, Parvovirus, and CMV in Pregnancy 715

and timing of infection. Treatment of congenital CMV infection is an active area of

research, and the Institute of Medicine has rated the development of a CMV vaccine
a high priority.36
CMV infection is typically asymptomatic in immunocompetent adults. Less than 5%
of pregnant women with a primary CMV infection are symptomatic, making the diag-
nosis of infection in pregnancy difficult.37 CMV infection is known to cause neurologic
sequelae in newborns; however, prediction of vertical transmission can be difficult.
Neurologic handicap is possible after either primary or recurrent infection. However,
after primary infections with CMV, about one-third of newborns acquire a CMV infec-
tion but only approximately 1% to 2% of newborns acquire CMV after a recurrent
infection.35,38 Up to 90% of infants who are symptomatic at birth will have serious
long-term handicaps including hearing loss, visual impairment, mental retardation,
and/or mild cognitive impairment.39 In contrast, asymptomatic newborns are at
much less risk for serious long-term impairment, in the range of 5% to 15%.38,40
The timing in gestation has also been described as an important risk factor for vertical
transmission. Third trimester infection seems to have a higher rate of vertical transmis-
sion, but the incidence of symptomatic newborns with these late infections is much
less than first trimester vertical transmission.41 In contrast, the rate of vertical trans-
mission after maternal infection early in pregnancy is low, but in cases of congenital
infection, the rate of severe disease is much higher.42,43

Maternal Infection
Acute maternal infection to CMV can be considered if a woman has seroconversion of
CMV IgG during her pregnancy. In this situation, her nonimmune status would have to
have been previously established. Another possible indicator of acute maternal infec-
tion is CMV IgG and/or IgM antibodies. However, CMV IgM antibodies can persist for
more than 6 months making it difficult to determine the precise timing of infection.44 In
addition, there has been concern about the accuracy of commercially available CMV
antibody test kits.45 CMV IgM may also be present with reinfection and false-positive
results have been reported from other viral infections.45,46
When there is a question of acute maternal CMV infection, IgG avidity testing may
be the most reliable way to confirm the diagnosis. Low avidity IgG antibodies are
present in acute or recent primary CMV infections.47 If testing is performed at 16 to
18 weeks’s gestation, anti-CMV IgG avidity testing has been reported to have
a 100% sensitivity for newborn infection.48 If high avidity CMV IgG is detected by
16 weeks, a recent infection can be ruled out.

Fetal Infection
If acute maternal infection is suspected in pregnancy, fetal infection can then be inves-
tigated. Historically, fetal blood sampling was performed by cordocentesis to deter-
mine fetal immune status. Because the fetus may not be immunocompetent in early
gestation, fetal immune status may not be helpful until late in pregnancy. There is
also concern about the safety and availability of cordocentesis.49 Amniocentesis,
which is much safer than cordocentesis, can obtain amniotic fluid for detection of
CMV by PCR. PCR of amniotic fluid has a reported sensitivity and specificity of
more than 90% for vertical transmission of CMV.50,51 Viral culture or CMV early antigen
testing has also been performed to confirm vertical transmission, but the speed and
accuracy of PCR have made it the standard diagnostic test for fetal infection of CMV.
As mentioned earlier, fetal infection may be suspected during pregnancy from ultra-
sound findings suspicious for CMV infection. These findings include early onset intra-
uterine growth restriction, microcephaly, ventriculomegaly, liver calcifications,
716 Feldman et al

echogenic bowel, and fetal hydrops (Fig. 3). Unfortunately, only about 5% to 25% of
infected newborns have ultrasound evidence of congenital infection.52 However, if
fetal anomalies are detected, it would infer a more severely affected newborn.53 Any
ultrasound findings suspicious for congenital CMV infection should prompt a serologic
and/or invasive diagnostic evaluation to determine if an acute infection is present.
Amniocentesis with CMV PCR has been reported to be most accurate for diagnosing
fetal infection when performed after 20 weeks’s gestation making this the ideal time for
the procedure.54,55
Treatment
Once fetal CMV infection has been confirmed, no standard therapy for in utero treat-
ment has been established. A recent nonrandomized trial of CMV hyperimmune glob-
ulin was promising for treatment of acute fetal CMV infection. Women who received
CMV hyperimmune globulin during pregnancy had only a 3% incidence of a symptom-
atic newborn at birth and 2 years of age, whereas untreated women had a 50% inci-
dence.56 There are no specific antiviral regimens for fetal treatment of CMV infection
but postnatal treatment of severely affected newborns has been reported with ganci-
clovir and valganciclovir with varying degrees of efficacy.47,57 Pregnancy termination
remains an option for pregnancies with CMV infection, but this should be reserved for
cases with documented acute fetal infection after a thorough diagnostic evaluation
and extensive counseling.
Routine screening for CMV infection in pregnancy is controversial and will remain so
until an efficacious treatment of acute fetal infection is established. A recent study
evaluated 3 screening strategies and showed that universal screening could be cost
effective if treatment of CMV in pregnancy could achieve at least a 47% reduction
in disease.58 Until then, education on prevention with good hygiene makes most sense
for women known to be at risk for primary CMV infection.

SUMMARY

There are many infections that may be asymptomatic or cause only mild clinical symp-
toms in an immunocompetent adult, but cause much more significant consequences
in a developing fetus. Depending on the gestational age of infection, there is wide vari-
ation in the pregnancy outcomes of women who acquire toxoplasmosis, parvovirus, or
CMV during pregnancy. Most fetal outcomes are favorable even for those with

Fig. 3. Echogenic bowel noted in the abdomen of a fetus with early CMV infection.
 Toxoplasmosis, Parvovirus, and CMV in Pregnancy 717

documented infection during pregnancy. However, there remains much anxiety

among patients who develop these infections. With proper screening, maternal and
fetal testing, and treatment where appropriate, these patients can be provided with
the best possible pregnancy outcome.

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