American Journal of Obstetrics and Gynecology (2005) 192, 564e71
Risk factors for Toxoplasma gondii infection in mothersof infants with congenital toxoplasmosis: Implicationsfor prenatal management and screening
Kenneth M. Boyer, MD,a Ellen Holfels, BS,b Nancy Roizen, MD,c Charles Swisher, MD,eDouglas Mack, PhD,b Jack Remington, MD,g Shawn Withers, RN,h Paul Meier, PhD,iRima McLeod, MD,b,d,* the Toxoplasmosis Study Groupa-i
Rush University Medical Center, Chicago, Ill,a University of Chicago, Chicago, Ill,b SUNY Upstate MedicalUniversity, Syracuse, NY,c Michael Reese Hospital, Chicago, Ill,d Children’s Memorial Hospital and NorthwesternUniversity, Chicago, Ill,e Illinois Institute of Technology, Chicago, Ill,f Stanford University, Stanford, Calif,g CermakHealth Services of Cook County, Chicago, Ill,h and Columbia University, New York, NYi
Received for publication March 25, 2004; revised June 23, 2004; accepted July 19, 2004
Objective: The purpose of this study was to determine whether demographic characteristics,
history of exposure to recognized transmission vehicles, or illness that was compatible with acute
toxoplasmosis during gestation identified most mothers of infants with congenital toxoplasmosis.
Study design: Mothers of 131 infants and children who were referred to a national study of
treatment for congenital toxoplasmosis were characterized demographically and questioned
concerning exposure to recognized risk factors or illness.
Results: No broad demographic features identified populations that were at risk. Only 48% ofmothers recognized epidemiologic risk factors (direct or indirect exposure to raw/undercookedmeat or to cat excrement) or gestational illnesses that were compatible with acute acquiredtoxoplasmosis during pregnancy.
Conclusion: Maternal risk factors or compatible illnesses were recognized in retrospect by fewerthan one half of North American mothers of infants with toxoplasmosis. Educational programsmight have prevented acquisition of Toxoplasma gondii by those mothers who had clear exposurerisks. However, only systematic serologic screening of all pregnant women at prenatal visits or of allnewborn infants at birth would prevent or detect a higher proportion of these congenital infections.
Ó 2005 Elsevier Inc. All rights reserved.
Congenital toxoplasmosis is a disease that aﬀects an
estimated 500 to 5000 newborn infants in the United
Supported by National Institutes of Health, grants No. R01
States each year.Most infected infants have no
AI27530 and TMP R01 AI 27530 and the Hyatt Foundation.
apparent physical abnormalities at birth, but, without
* Reprint requests: Rima McLeod, MD, Department of Ophthal-
treatment, most of the infected infants will have
mology and Visual Sciences, The University of Chicago, MC2114
signiﬁcant morbidity that is related to chorioretinitis,
Room S208, 5841 S Maryland, Chicago, IL 60637.
hydrocephalus, or neurologic damage by the end of
0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
adolescTreatment of infected infants in the ﬁrst
in which it may have occurred were questioned specif-
year of life substantially improves outcomes,and
ically. Mothers were also asked about the occurrence of
treatment of a mother with acute Toxoplasma gondii
any illness during pregnancy that was compatible with
infection during pregnancy can prevent vertical trans-
infection and were queried speciﬁcally regarding fever or
mission or initiate treatment of the congenitally infected
night sweats, ﬂu-like illness or myalgia, headache, or
fetus.Therefore, strategies for early recognition of
maternal or infant infection and the institution of
For referred children, congenital infection was con-
eﬀective treatment could have a substantial impact on
ﬁrmed with standard laboratory tests in a reference
the incidence and morbidity that are associated with this
laboratory (J. Remington, Toxoplasma Serology Labo-
ratory, Palo Altthat included the Sabin-Feldman
In the Chicago Collaborative Treatment Trial, we have
dye test, immunoglobulin M, immunoglobulin A, and
followed up a cohort of infants who were referred to us for
immunoglobulin E enzyme-linked immunosorbent as-
congenital toxoplasmosis over the past 20 years.
says or immunosorbent agglutination assays (ISAGA);
In the present study, we have analyzed the mother’s
subinoculation or polymerase chain reaction (PCR) of
history of exposure to potential vehicles of transmission
blood, amniotic ﬂuid, or cerebrospinal ﬂuid, or com-
of T gondii and the history of illness that is compatible
patible ﬁndings in infants who were born of acutely
with acquired toxoplasmosis during gestation. This
infected mothers when other diagnoses were exclud
analysis deﬁnes the potential for prevention of congenital
Maternal infection with T gondii was documented with
toxoplasmosis through educational eﬀorts, obstetric man-
serologic tests that included the Sabin-Feldman dye test,
agement of illness during pregnancy, selective maternal
immunoglobulin M, immunoglobulin A, or immuno-
screening, or universal maternal or neonatal screening.
globulin E enzyme-linked immunosorbent assay orISAGA, and the diﬀerential agglutination test.
Between 1983 and 1998, a total of 131 infants andchildren were referred to the Chicago Collaborative
Treatment Trial with laboratory-conﬁrmed congenitaltoxoplasmosis.Of the 131 patients, 122 patients were
referred as infants within the ﬁrst months of life. All
Congenital toxoplasmosis was found to aﬀect infants
studies that involve the Collaborative Treatment Trial
who were born to families of all socioeconomic classes
participants are approved by the University of Chica-
although our population had a higher than
go’s Institutional Review Board in accordance with
predicted proportion of Hollingshead indices 1 and 2.
National Institutes of Health guidelines.
In the course of multidisciplinary evaluations of these
infants, demographic data were acquired, and mothers
The method of payment for medical care and type of
were questioned regarding their possible exposure to
health insurance in referred families was comparable to
recognized vehicles of transmission of T gondii and their
history of compatible illness during pregnancy. Specif-
ically, demographic data were acquired with regard to
One half the families were from urban settings, approx-
maternal residence, maternal age, maternal race/ethnic-
imately one quarter each from suburban or rural
ity, family’s Hollingshead index (a measure of socioeco-
nomic status),and method of payment for care. Ageand race/ethnicity distributions were compared with
those of the general US population using c
The median maternal age was 25 to 29 years (
Mothers were questioned regarding their exposure to
cats. Speciﬁcally, they were asked whether they owned
representation of Asian/Paciﬁc Islander subjects and an
a cat, had emptied a litter pan, had gardened, had
underrepresentation of African American subjects. Age
exposure to sand boxes, or had any combination of the
diﬀerences were not statistically signiﬁcant compared to
above. Mothers were also questioned regarding their
the general US population, but racial diﬀerences were.
possibility of exposure to raw meat, speciﬁcally whetherthey had a history of preparation of foods with raw
meat, had eaten any dishes that contained raw orundercooked meat, or had consumed any other raw
Although 75% of women who were delivered of an infant
foods (such as unpasteurized milk or raw eggs). The
with congenital toxoplasmosis could recall a conceivable
nature of exposure during pregnancy and the trimester
exposure, only 39% of the women speciﬁcally recalled
Hollingshead indices,methods of payment for care, and hometown size for 131 families with infants with congenital
toxoplasmosis in the National Collaborative Treatment Trial (1981-1998)
* The Hollingshead index includes factors, such as education and income, that are used to calculate a socioeconomic status score; a socioeconomic
y 70% in the United States.
z 16% in the United States.
x Unknown for reasons such as the child was adopted, and this information about birth parents was not available to us.
Maternal age for 131 women who were delivered of
Maternal race/ethnicity for 131 women with
* 1998 National Center for Health Statistics:
y Hispanic ethnicity includes women of any race.
exposure to cat litter or raw meat dishes (
women also recalled compatible symptoms (eg, lymph-
Surprisingly, 25% of the women could not identify any
adenopathy, malaise, myalgia, fever, chills, or ‘‘ﬂu-like’’
possible exposure to cats or any ingestion of even
illness), but screening occurred as part of the standard
practice of care in France and not because of theirsymptoms. Of the remaining 7 women, all had compat-
ible illness and/or identiﬁed risk factors; however, 1woman was tested because of ascites that was noted on
Although 48% of the mothers noted an illness that
prenatal ultrasound scans in both her twins; 3 women
might have included toxoplasmosis as a cause, only
were tested only because their physicians were looking
27% of the women recalled fever or night sweats, and
for the cause of compatible illness and/or identiﬁed risk
only 23% of the women recalled lymphadenopathy
factors, and 3 women were tested because their physi-
(Fifty-two percent of the mothers could not
cians used routine screening practices.
recall an infectious illness of any kind during pregnancy.
Overall, 60 mothers (48%) recognized signs and
symptoms that were considered typical of toxoplasmosis
This study addresses whether a report of exposure toepidemiologic risk factors or etiologic investigation of
Only 10 women (8%) had serologic tests for toxoplas-
a compatible illness during pregnancy would lead to the
mosis before delivery of their infant. Of these 10 women,
identiﬁcation of most or all women who are at risk for
3 women were American expatriates living in France
transmitting T gondii to their unborn babies. If the
who were tested during their pregnancies as a component
identiﬁcation of most such women could identify most
of routine obstetric care. Interestingly, all 3 of these
infected infants, then serologic screening would not be
Recognized maternal risk factors for 131 women
Maternal illness during pregnancy in 131 mothers
with infants with congenital toxoplasmosis
Maternal raw or undercooked meat exposure
Summary epidemiologic factors of maternal expo-
Unexplained febrile illness or lymphadenopathy
needed. Simply obtaining a careful history would lead to
appropriate testing and management. Our data demon-
Exposure to cat litter, uncooked meat, or
strate that a careful history would identify, at most, 48%
of mothers who have acquired toxoplasmosis during
pregnancy. Thus, only serologic screening would haveidentiﬁed the rest.
Implications of our ﬁndings for prevention with
mothers with risk factors. It is likely that the proportion
education are clear. Even if education about the risks
of these women who reported risk exposures or com-
of toxoplasmosis became a component of standard
patible illnesses, if queried prospectively, would have
obstetric practice, only approximately one half of the
been considerably lower. The degree to which US
women had risk factors that might have been recognized
populations of pregnant women are aware of the risks
and thus could have been eliminated by education. Our
of exposure to cats and cat excrement and of consuming
observation that only 8% of women in our study were
raw or undercooked meat was not addressed speciﬁcally
screened for toxoplasmosis during pregnancy is consis-
in our study and deserves further investigation. There
tent with the relatively infrequent screening of pregnant
are no means for determining percentages of women
women in the United States for this disease. In France
with similar symptoms and risk factors in a demograph-
and Austria, where educational measures have been
ically comparable, concomitant control group during
incorporated into routine obstetric care, reductions in
the past 20 years. This type of control group, established
rates of infection by 50% have been reported.Thus,
prospectively, might have helped identify whether any
other measures appear to be necessary to prevent or
factor was seen more commonly in the mothers in our
identify a higher proportion of cases of this congenital
studies or whether nothing in the history was distinctive.
However, this information was not available and does
Our study is retrospective, because we elicited histo-
not eﬀect the conclusion of this work.
ries only from women whose infants already had been
In the course of the study, several additional obser-
diagnosed with congenital toxoplasmosis. In many
vations and demographic factors were noted. First, the
instances, the babies had substantial handicaps, and
proportion of African American women with infants
their mothers were knowledgeable about toxoplasmosis
who were infected with toxoplasmosis in the study was
and understandably actively seeking explanations for
quite low, representing only 2% of the total, whereas the
their infection.Thus, the bias in ascertainment of risk
proportion of African American women in the US
behaviors and compatible illness in our experience is in
population is 12% (P ! .001). Whether this low prev-
favor of the identiﬁcation of a higher proportion of
alence is due to diﬀerent exposure rates, to poorer
quality of primary health care for African American
screening or even testing and treatment at all, even to
women and infants, or possibly to a genetically based,
prevent suﬀering, health careerelated costs, loss of
increased resistance to the transmission of the disease
productivity, and limitation in quality of life that are
remains to be determined. If the lower than expected
associated with untreated congenital toxoplasmosis.
proportion of African American infants is due to poorer
Some authors have commented that such screening
quality of health care, systematic screening would help
could cause anxiety because of false-positive test results
to remedy the problem of diﬀerential access to proper
or unnecessary pregnancy terminations caused by sero-
diagnosis and health care. Second, despite reporting
logic testing that was not conﬁrmed in a high-quality
nonspeciﬁc symptoms of infection to their physicians
reference laboratory or to counseling that was sub-
(such as prolonged fever or lymphadenopathy), many of
optimal.In contrast, other analyses have concluded
the women indicated that toxoplasmosis was seldom
that screening, in conjunction with careful conﬁrmation
considered as a possible explanation of the symptoms.
in a high-quality reference laboratory and knowledge-
This observation points out the importance of greater
able and caring counseling is important to facilitate
recognition by obstetricians of the pediatric implications
of maternal infection and infectious symptoms during
reviewed these analyses and the concerns they raise.
We conclude that there is rigorous and careful work that
Other new epidemiologic observations have been
indicates that systematic detection of this infection in
made recently and suggest the possibility of additional
pregnant women and the treatment of the infected fetus,
modes of transmission of T gondii in North America. A
as describedresults in improved outcomes for
high number of sea otters have died oﬀ the coast of
aﬀected children. Careful conﬁrmation of serologic
California since 1995, and investigators have found that
testing in a high-quality, reliable reference laboratory
T gondii infection is 1 of the causes.The suggested
and knowledgeable and empathetic medical care and
epidemiologic factor is that the otters ingest Toxoplasma
counseling are essential parts of this process.
oocysts in sea water, where oocysts can persist up to 6
From our analysis of the risk factors and illnesses in
months, concentrated in mussels or other shellﬁsh.
mothers of congenitally infected children, we conclude
Researchers hypothesize that oocysts infect shellﬁsh
that the most eﬀective way to prevent or detect a higher
through cat excrement in litter that people discard into
proportion of infants with this congenital infection is by
toilets or watershed areas, which then arrive in coastal
systematic serologic screening. It is diﬃcult to imagine
waters where otters live. Similarly, a large community
that any informed mother or father would choose not to
epidemic of toxoplasmosis took place in Victoria,
include this screening in their prenatal care, considering
British Columbia, in 1995.No conventional trans-
that almost all untreated infants who are infected with T
mission vehicle was identiﬁed, but case-control studies
gondii in utero experience ophthalmologic and/or neu-
showed signiﬁcant associations between acute infection
rologic diseaseand that treatment of the fetus and
and residence in the distribution system of one reservoir
that supplied unﬁltered water to greater Victoria. A
An implication of our data is that education of
recent study from Brazil, where toxoplasmosis is hyper-
pregnant women concerning risk factors for acquiring
endemic, also supports the hypothesis of transmission
Toxoplasma during gestation would be useful in the
by unﬁltered drinking water.In our study, we did not
prevention of congenital toxoplasmosis. Also, although
ask about the consumption of or sources of
uncommonthe recognition of signs and symptoms of
water consumption in our inquiries about possible risk
this infection by obstetricians is important for pre-
vention. Another implication of our ﬁndings is that
There have been economic analyses, Cochran Data-
only systematic serologic screening would detect a sub-
base reviews, and metareviews concerning screening
stantial proportion of mothers who are infected during
programs for toxoplasmosis and their outcomes
gestation and those fetuses and infants with congenital
Some of these have assigned equal value to well-
toxoplasmosis. For many of these mothers, risk factors
performed studies and to dissimilar cohorts in studies
and signs or symptoms were not identiﬁed. Thus, our
that sometimes are designed, controlled, performed, or
approach to prevention also is to include serologic
interpreted inadequately. Some of these analyses have
screening to prevent congenital toxoplasmosis. Delays
noted the absence of perfectly designed and performed
in treatment have been shown to result in more severe
prospective, placebo-controlled, randomized studies
clinical manifestations. Therefore, our approach to how
with long follow-up, which included economic analyses,
frequent serologic screening is performed, without
that clearly document savings in costs and eﬃcacy of
limitation of resources, includes preconception testing
newborn infant or maternal screening.Some au-
of women and the identiﬁcation of women who are
thors who reviewed these available data have concluded
infected acutely during pregnancy with an initial test for
that, in the absence of better prospective studies, it may
Toxoplasma infection at the ﬁrst prenatal visit in the ﬁrst
be too costly or unwarranted to perform universal
trimester. Thereafter, monthly testing of seronegative
women to identify seroconversion and testing of new-
diﬀerentiate the exposed and infected fetus. However,
born infants to identify congenital infection should be
because the likelihood of transplacental transmission
performed. We recognize that this optimal approach
and an infected fetus is very high late in gestation, other
may not be economically feasible at this time in the
physicians treat all such mothers and their infants with
United States, where seroprevalence is relatively low,
pyrimethamine, sulfadiazine, and leucovorin.
resources are limited, and automated testing procedures
Our approach to newborn infants who are born to
are not widely available. In this country, testing sero-
mothers who are suspected or proved to have acquired
negative pregnant women once each trimester (eg, at 8-
the infection during gestation is to evaluate the infant
10, 18-20, and 28-30 weeks’ gestaand all newborn
clinically and serologically, with an attempt to isolate the
infants might be considerHowever, it should be
parasite from placental tissue.The results of that testing
recalled that the best outcomes derive from monthly
are used to determine whether the treatment of the infant
should be initiated or continued. Testing for immuno-
T gondiiespeciﬁc immunoglobulin G and M assays
globulin M antibodies by a sensitive method like the
are used for screening pregnant women and newborn
immunoglobulin M ISAGA test and immunoglobulin A
infants. Acute infection in the mother should be con-
antibodies by enzyme-linked immunosorbent assay must
ﬁrmed by a Toxoplasma serologic reference laboratory
be performed. Serologic testing and subinoculation of
the placenta for the infant are performed by a Toxo-
Toxoplasma-speciﬁc immunoglobulin A, diﬀerential ag-
plasma serologic reference laboratory. Treatment in
glutination test, and avidity assays are used to document
utero reduces clinical manifestations, the ability to
the timing of the acquisition of an infection during
isolate the parasite from the placenta, and the serologic
gestation more precisely. The avidity assay is an impor-
markers of infection in the newborn infant. The infected
tant, recently developed test that can be used in the ﬁrst
infant is treated throughout the ﬁrst year of life.
12 to 16 weeks of gestation (based on the test kit used) to
Analyses of cost and eﬃcacy of screening programs
accurately date the acquisition of infection before
are important in public health policy decision making.
conception.High avidity of Toxoplasma-speciﬁc
Rigorous analyses clearly are needed. However, con-
antibody in a single serum that has Toxoplasma-speciﬁc
genital toxoplasmosis eventually has devastating clinical
immunoglobulin G and M antibodies and that has been
consequences for nearly all infected infants.Early and
obtained in the ﬁrst 12 or 16 weeks of gestation indicates
aggressive antimicrobial therapy has a clear beneﬁt.
that infection has occurred before conception and
The disease occurs with an incidence that is comparable
therefore is not likely to threaten the fetus.
to or higher than a number of genetic and metabolic
This approach to the diagnosis and treatment of
diseases (eg, phenylketonuria, congenital hypothyroid-
women who are suspected or proved to have acquired
ism, and congenital adrenal hyperplasia) for which
the infection during gestation also includes fetal ultra-
neonatal screening is mandated by law in most states.
sound scans and amniocentesis with PCR on the
The data herein support the conclusion that ‘‘the time
amniotic ﬂuid at 18 weeks of gestation or thereafter to
has come’’ to screen for acute acquired Toxoplasma
determine whether the fetus is infected. Whereas the
infection in pregnant women and congenital toxoplas-
speciﬁcity of PCR testing on amniotic ﬂuid approaches
mosis in infants to prevent the potentially devastating
100%, the sensitivity is signiﬁcantly Thus, a neg-
ative PCR does not rule out infection in the fetusdeﬁnitively. If the PCR is negative, spiramycin is used
to attempt to reduce the transplacental transmission ofT gondii to the fetus. When infection is acquired by the
We thank the patients with congenital toxoplasmo-
pregnant woman before mid gestation and there is no
sis and their families for their generous cooperation;
fetal infection that is documented by amniocentesis or
the physicians and other participants in the Chicago
suggested by fetal ultrasound scans, spiramycin is
Collaborative Toxoplasmosis Treatment Study Group
continued until term. If the fetus is determined to be
(Ilona Buscher, Audrey Cameron, Esther Castro, Diana
infected, the administration of pyrimethamine and
Chamot, Barbara Danis, Peter Heydemann, MD, Joyce
sulfadiazine to the mother provides treatment for the
Hopkins, PhD, Lara Kallal, Kristin Kasza, MS, Mi-
fetus as well. Dosages of these medicines for the
chael Kipp, MD, Michael Kirisits, PhD, James McAu-
pregnant woman are pyrimethamine (50 mg per day)
ley, MD, Marilyn Mets, MD, Sanford Meyers, MD,
and sulfadiazine (2 g, twice daily) with leucovorin (10
Ernest Mui, Gwen Noble, MD, Dushyant Patel, MD,
mg per day) for its marrow-protective eﬀects. Pyrimeth-
Jeanne Perkins, PhD, Linda Pﬁﬀner, MD, Peter Rabiah,
amine is not administered before 12 weeks of gestation.
MD, Laszlo Stein, MD (deceased), Mark Stein, PhD,
Management of the pregnant woman who becomes
Andrew Suth, PhD, Marie Weissbord, PhD, HuiYuan
infected later in gestation is controversial. Some physi-
Zhang, MD); the airlines and hotels that provided
cians use the same approach as described earlier to
complimentary transportation to and accommodations
in Chicago; the pharmaceutical companies that provided
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