Article infectious diseases

Evaluation and Treatment of Fetal Exposure

to Toxoplasmosis
Bridget M. Wild, MD,*
Emily Obringer, MD, Abstract
Elaine Farrell, MD* Symptomatic congenital toxoplasmosis is a rare disease in the United States. However,
prenatal screening is becoming increasingly available, resulting in identication of in-
fants at risk of developing the disease. Infants who are born asymptomatic may still
Author Disclosure develop signicant neurodevelopmental sequelae months or even years after birth if
Drs Wild, Obringer, untreated. Congenital toxoplasmosis is a difcult infection to diagnose. Using one case
as an example, this review attempts to highlight the importance of identifying at-risk
and Farrell have
infants and summarize the most current recommendations with regard to workup and
disclosed no financial treatment of affected infants. Initial evaluation of an infant at risk of congenital toxo-
relationships relevant plasmosis includes complete history and physical examination, lumbar puncture, head
to this article. This computed tomography, complete blood cell count with differential, detailed ophthal-
commentary does not mologic examination, and Toxoplasma gondii polymerase chain reaction and serologic
contain a discussion of testing. Because of the complexity of the laboratory studies involved, expert interpre-
tation is required. Although there is still much to learn about the best approach to the
an unapproved/
identication and treatment of affected infants, we know that early treatment leads to
investigative use of the best neurodevelopmental outcomes.
a commercial product/
device. Objectives After completing this article, readers should be able to:
1. Identify historical risk factors for vertical transmission of Toxoplasma gondii in
a prenatal history.
2. Decide how to best initially evaluate an infant whose mother tested positive for recent
T gondii infection while pregnant.
3. Recognize prenatal treatment options used to prevent parasite transmission or
decrease infant disease burden.
4. Anticipate the likely treatment and follow-up for an infant with suspected congenital
toxoplasmosis by laboratory evaluation or symptoms.

Introduction
Although the American Congress of Obstetricians and Gynecologists does not currently
recommend universal screening of pregnant women for toxoplasmosis, screening by check-
ing maternal titers is available and inexpensive. Some clinicians offer this test routinely to all
women or to women with risk factors. We present a case of fetal exposure to toxoplasmosis
discovered by routine screening as a means to illustrate the present understanding of this
disease, neonatal evaluation, and treatment.

The Case
A 30-year-old, gravida 1, para 0 woman presents to establish routine prenatal care, which
includes screening laboratory tests for congenital infections. She screens positive for Toxo-
plasma gondii. The patient recalls no symptoms. She does not own a cat or handle animals
but has recently traveled to Thailand. She is referred to a maternal fetal medicine specialist
for further testing.
Ultrasonography at 16 weeks gestation reveals a fetus with average growth parameters
and grossly normal anatomy. The results of additional low-avidity IgM testing are positive,
indicating recent maternal toxoplasmosis infection. The patient starts spiramycin therapy

*NorthShore University HealthSystem, Evanston, IL.

Comer Childrens Hospital, Pritzker School of Medicine, University of Chicago, Chicago, IL.

e236 NeoReviews Vol.16 No.4 April 2015

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and continues to receive this therapy for the duration of
the pregnancy. An amniocentesis is performed at 18 weeks
gestation, yielding a negative toxoplasmosis polymerase
chain reaction (PCR) result. She returns for multiple level
II ultrasonograms, all of which produce normal results.
The patient and her husband consult with a neonatolo-
gist at 36 weeks gestation and review the recommended
neonatal evaluation. At 402/7 weeks estimated gestational
age, she presents in spontaneous labor. Because of late de-
celerations on fetal heart rate monitoring, the infant is de-
livered by cesarean section.
A vigorous male infant weighing 2,673 g (second per-
centile) is delivered. His head circumference is 33.5 cm
(12th percentile), and his length is 48.3 cm (eighth per-
centile). The remainder of his examination ndings are
normal. He undergoes the preplanned evaluation. The re-
sults of noncontrast head computed tomography (CT) are
negative for intracranial calcications or hydrocephalus.
Results of a dilated funduscopic examination are negative
for retinitis, deposits, and inltrates. A complete blood
count (CBC) with differential reveals a white blood cell
count of 17,800/mL (17.8  109/L), a hemoglobin level
of 15.7 g/dL (157 g/L), hematocrit of 45% (0.45), and
platelet count of 179 103/mL (179 109/L) with a dif-
ferential of 74% neutrophils, 18% lymphocytes, and 8%
monocytes. Hepatic function tests reveal the following: al-
bumin, 3.3 g/dL (33 g/L); total bilirubin, 8.6 mg/dL
(147.1 mmol/L); direct bilirubin, 0.5 mg/dL (8.6
mmol/L); alkaline phosphatase, 126 U/L; serum glutamic
oxaloacetic transaminase, 77 U/L; and serum glutamic
pyruvic transaminase, 12 U/L. The following evaluations
are sent to the Palo Alto Toxoplasma Serology Laboratory:
maternal serum IgG and IgM T gondii titers (both posi-
tive); placenta T gondii DNA PCR (not detected); neona-
tal serum for T gondii IgG (positive), IgM (negative), and
IgA (negative); neonatal serum T gondii DNA PCR (not
detected); and neonatal cerebrospinal uid T gondii DNA
PCR (not detected).
The infant has an uneventful remaining nursery course
and is discharged 4 days after birth. At follow-up with the
pediatrician, the infant has normal weight gain and growth
in the rst month. He is scheduled to have periodic serum
quantitative immunoglobulin values and T gondii titers
measured through his rst birthday.
Etiology
Toxoplasmosis is caused by the protozoa T gondii. The
denitive host is felines, but a variety of mammals can be-
come infected and serve as intermediate hosts. The par-
asite exists in 3 forms: oocyst, tachyzoite, and bradyzoite.
The oocyst is excreted by infected cats and is commonly
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infectious diseases / toxoplasmosis
found in litter boxes, soil, and contaminated water and plant
products. When ingested by humans and other mammals,
the oocyst transforms into the active tachyzoite, which trav-
els through the bloodstream and lymphatic system to infect
a variety of tissues. As the immune system responds to the
infection, the tachyzoite is sequestered in tissue as the bra-
dyzoite or cyst form. The cyst can persist in tissue for many
years and, if ingested, can revert to the tachyzoite form and
cause disease. Humans become infected through the in-
gestion of oocysts or cysts, which are usually found in
undercooked meat. Primary maternal infection leads to par-
asitemia, and if the tachyzoite crosses the placenta, congen-
ital toxoplasmosis may occur. (1) Rare cases of congenital
disease due to reactivation of latent disease in an immuno-
compromised mother have been reported.
The incidence of congenital toxoplasmosis ranges from
1 in 1,000 live births in some European countries to 1 in
10,000 in the United States. (1) The difference in incidence
is related to risk factors for T gondii exposure. The parasite
is more commonly found in warm, humid locations, where
the oocyst can easily replicate, leading to a high burden of
disease in tropical climates. The incidence is increased in
populations where the consumption of undercooked meats,
particularly lamb and pork, is common. Other risk factors
include exposure to contaminated soil, water, or plant
product and contact with infected cat feces. Vertical trans-
mission increases with gestational age, from 5% in the rst
trimester to 32% in the third trimester. (2)
Findings
Congenital toxoplasmosis is asymptomatic in up to 80%
of patients. (3) When symptoms arise, they can occur at
birth, in early infancy, or in later years. The neonatal and
infantile forms are more severe and often have central ner-
vous system and ocular manifestations. Generally, more se-
vere disease correlates with earlier infection in utero. The
classic triad of neonatal disease includes intracranial calci-
cations, hydrocephalus, and chorioretinitis. However, the
presence of all 3 signs is uncommon, and other abnormal-
ities, such as hepatosplenomegaly, anemia, and cerebrospi-
nal uid changes, may be present. Infants often present
with seizures, hydrocephalus, or eye ndings. Later disease
is usually localized to the eyes, with chorioretinitis being
the most common manifestation. (4)
Evaluation
Evaluation of a neonate suspected of having congenital
toxoplasmosis should include a complete history and
physical examination, lumbar puncture, head CT, CBC
with differential, detailed ophthalmologic examination,
NeoReviews Vol.16 No.4 April 2015 e237
infectious diseases / toxoplasmosis
and T gondii PCR and serologic testing. Characteristic ce-
rebrospinal uid ndings include mononuclear pleocytosis
and high protein content. A head CT is recommended to
evaluate for intracranial calcications. The sensitivity of
head ultrasonography to detect smaller lesions makes it
an unreliable screening tool. Hematologic abnormalities,
such as anemia, thrombocytopenia, and eosinophilia,
may be seen on peripheral blood smear. An ophthalmo-
logic examination, preferably by a pediatric ophthalmolo-
gist experienced with retinal disease, is essential. Ocular
ndings may include retinitis, chorioretinal scarring, cata-
ract, and microphthalmia. Blood, spinal uid, and placenta
samples should be evaluated for T gondii by PCR. Parasi-
temia is found in up to 50% of asymptomatic newborns.
(5) T gondii serologic test results can be difcult to inter-
pret, and consultation with an infectious disease expert is
recommended. The clinician should ensure that samples
are sent to an appropriate reference laboratory. Positive
neonatal T gondii IgM test results essentially conrm
the diagnosis. However, false-positive results related to
cross-contamination with maternal uids have been re-
ported. Additional IgM titers may be considered. IgM will
typically normalize several days after birth if placental leak
was the cause, whereas in congenital disease IgM will re-
main elevated for weeks to months. (6) IgA and IgE sero-
logic test results will also usually be positive when disease is
present. T gondii IgG at birth typically reects maternal
antibodies. If a neonate is not infected, specic IgG levels
will return to normal after several months.
Screening
Screening programs exist in many high-incidence countries
because of the potential severity of congenital infection and
the fact that infected mothers are largely asymptomatic. For
example, in France where the incidence of congenital dis-
ease is approximately 1 in 1,000 live births, there is a man-
datory monthly screening program for all seronegative
pregnant women. (7) In the United States, Massachusetts
and New Hampshire have chosen to include toxoplasma-
specic IgM titers on their newborn screening panel. (8)
The cost-benet ratio of such screening programs in places
with low incidence of disease is a highly debated topic. (7)
Currently, the United States has no standard prenatal or
newborn screening recommendations for toxoplasmosis
and practices vary; (9) however, optional prenatal screening
is becoming increasingly available.
Treatment
Because of the evolving strategies and complexity of pre-
natal diagnosis, no randomized clinical trials exist to
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clearly dene best practices for prenatal maternal treatment
and infant treatment. However, many studies indicate that
maternal treatment with spiramycin from the time of sero-
conversion or low-avidity test (meaning as close to time of
primary infection as possible) reduces the vertical transmis-
sion by as much as 60% and decreases severity of disease in
affected neonates. (7)(8)(10) This drug has been used in
pregnancy for toxoplasmosis since the 1970s and signi-
cantly lowers placental T gondii infestation. (11) Spiramy-
cin is a macrolide antibiotic that concentrates in the
placenta without crossing to fetal circulation. It is not com-
mercially available in the United States but can be pro-
vided at no cost after application to the Food and Drug
Administration for pregnant women with conrmed toxo-
plasmosis. (7) Because it is well tolerated, many affected
women continue to take spiramycin for the duration of
pregnancy unless fetal disease is suspected.
If fetal infection is suspected by imaging or amniocen-
tesis, treatment should be directed at minimizing fetal dis-
ease by initiating pyrimethamine, sulfadiazine, and folinic
acid (PSF). Because of the higher incidence of transmis-
sion after 18 weeks gestation, some specialists empirically
switch affected women to PSF after the 18th week through
the duration of the pregnancy. These drugs cross the pla-
centa to the affected fetus. (7) Gastrointestinal symptoms
are the most common adverse effects, but because of the
risk of bone marrow suppression from the antiprotozoal
pyrimethamine, twice weekly CBCs are required for the
mother through delivery. The combination of spiramycin
and PSF is not superior to spiramycin monotherapy in pre-
venting vertical transmission (2) and is therefore reserved
for cases where fetal infection is suspected.
Asymptomatic neonates with positive amniocentesis re-
sults, postnatal titers, or clinical symptoms should be pre-
scribed PSF as soon as possible to prevent evolution of
neurodevelopmental sequelae. (12) Treatment is contin-
ued at least through the rst year after birth and requires
frequent (12 times per week) laboratory surveillance for
detection of bone marrow suppression and possibly for
hepatitis. (7) Symptomatic infants may be treated longer,
and those with signicant ophthalmologic inammation
may require corticosteroid therapy. (8) Treatment should
be provided in consultation with a toxoplasmosis specialist.
At this time, spiramycin is not the favored treatment in
neonates because it has been associated with QTc prolon-
gation and fatal arrhythmias. (13)
ACKNOWLEDGMENT. The authors would like to ac-
knowledge and thank Dr. Joseph R. Hageman, MD,
for his clinical guidance and mentorship in the writing
process.

American Board of Pediatrics NeonatalPerinatal
Content Specifications
Know the epidemiology, pathogenesis, and
prevention of perinatal infections with
toxoplasmosis.
Know the clinical manifestations,
diagnostic features, management, and
complications of perinatal infections with
toxoplasmosis.
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NeoReviews Vol.16 No.4 April 2015 e239
 Evaluation and Treatment of Fetal Exposure to Toxoplasmosis
Bridget M. Wild, Emily Obringer and Elaine Farrell
NeoReviews 2015;16;e236
DOI: 10.1542/neo.16-4-e236

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 Evaluation and Treatment of Fetal Exposure to Toxoplasmosis
Bridget M. Wild, Emily Obringer and Elaine Farrell
NeoReviews 2015;16;e236
DOI: 10.1542/neo.16-4-e236

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/16/4/e236

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