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.
doi:10.1016/j.ajog.2004.07.031 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 c2 tests.
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 16. Daffos F, Mirlesse V, Hohlfeld P, Jacquemard F, Thulliez P, medications without charge to medically indigent pa- Forestier F. Toxoplasmosis in pregnancy. Lancet 1994;344:541.
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