American Journal of Obstetrics and Gynecology (2005) 192, 564e71

www.ajog.org

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,e

Douglas Mack, PhD,b Jack Remington, MD,g Shawn Withers, RN,h Paul Meier, PhD,i

Rima 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

KEY WORDSCongenital

toxoplasmosisToxoplasma gondii

Maternal screeningRisk factor

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 oftreatment 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/undercooked

meat 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 programs

might 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.

� 2005 Elsevier Inc. All rights reserved.

Supported by National Institutes of Health, grants No. R01

AI27530 and TMP R01 AI 27530 and the Hyatt Foundation.

* Reprint requests: Rima McLeod, MD, Department of Ophthal-

mology and Visual Sciences, The University of Chicago, MC2114

Room S208, 5841 S Maryland, Chicago, IL 60637.

E-mail: rmcleod@midway.uchicago.edu

0002-9378/$ - see front matter � 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ajog.2004.07.031

Congenital toxoplasmosis is a disease that affects anestimated 500 to 5000 newborn infants in the UnitedStates each year.1 Most infected infants have noapparent physical abnormalities at birth, but, withouttreatment, most of the infected infants will havesignificant morbidity that is related to chorioretinitis,hydrocephalus, or neurologic damage by the end of

Boyer et al 565

adolescence.2-8 Treatment of infected infants in the firstyear of life substantially improves outcomes,9-14 andtreatment of a mother with acute Toxoplasma gondiiinfection during pregnancy can prevent vertical trans-mission or initiate treatment of the congenitally infectedfetus.9,15-21 Therefore, strategies for early recognition ofmaternal or infant infection and the institution ofeffective treatment could have a substantial impact onthe incidence and morbidity that are associated with thiscongenital infection.9-23

In theChicagoCollaborative Treatment Trial, we havefollowedup a cohort of infantswhowere referred to us forcongenital toxoplasmosis over the past 20 years.9-14

In the present study, we have analyzed the mother’shistory of exposure to potential vehicles of transmissionof T gondii and the history of illness that is compatiblewith acquired toxoplasmosis during gestation. Thisanalysis defines the potential for prevention of congenitaltoxoplasmosis through educational efforts, obstetric man-agement of illness during pregnancy, selective maternalscreening, or universal maternal or neonatal screening.

Material and methods

Between 1983 and 1998, a total of 131 infants andchildren were referred to the Chicago CollaborativeTreatment Trial with laboratory-confirmed congenitaltoxoplasmosis.9-23 Of the 131 patients, 122 patients werereferred as infants within the first months of life. Allstudies that involve the Collaborative Treatment Trialparticipants are approved by the University of Chica-go’s Institutional Review Board in accordance withNational Institutes of Health guidelines.

In the course of multidisciplinary evaluations of theseinfants, demographic data were acquired, and motherswere questioned regarding their possible exposure torecognized vehicles of transmission of T gondii and theirhistory of compatible illness during pregnancy. Specif-ically, demographic data were acquired with regard tomaternal residence, maternal age, maternal race/ethnic-ity, family’s Hollingshead index (a measure of socioeco-nomic status),24 and method of payment for care. Ageand race/ethnicity distributions were compared withthose of the general US population using c2 tests.Mothers were questioned regarding their exposure tocats. Specifically, they were asked whether they owneda cat, had emptied a litter pan, had gardened, hadexposure to sand boxes, or had any combination of theabove. Mothers were also questioned regarding theirpossibility of exposure to raw meat, specifically whetherthey had a history of preparation of foods with rawmeat, had eaten any dishes that contained raw orundercooked meat, or had consumed any other rawfoods (such as unpasteurized milk or raw eggs). Thenature of exposure during pregnancy and the trimester

in which it may have occurred were questioned specif-ically. Mothers were also asked about the occurrence ofany illness during pregnancy that was compatible withinfection and were queried specifically regarding fever ornight sweats, flu-like illness or myalgia, headache, orlymphadenopathy.

For referred children, congenital infection was con-firmed with standard laboratory tests in a referencelaboratory (J. Remington, Toxoplasma Serology Labo-ratory, Palo Alto)11 that included the Sabin-Feldmandye test, immunoglobulin M, immunoglobulin A, andimmunoglobulin E enzyme-linked immunosorbent as-says or immunosorbent agglutination assays (ISAGA);subinoculation or polymerase chain reaction (PCR) ofblood, amniotic fluid, or cerebrospinal fluid, or com-patible findings in infants who were born of acutelyinfected mothers when other diagnoses were excluded.11

Maternal infection with T gondii was documented withserologic tests that included the Sabin-Feldman dye test,immunoglobulin M, immunoglobulin A, or immuno-globulin E enzyme-linked immunosorbent assay orISAGA, and the differential agglutination test.25,26

Results

Demographic parameters

Hollingshead indicesCongenital toxoplasmosis was found to affect infantswho were born to families of all socioeconomic classes(Table I), although our population had a higher thanpredicted proportion of Hollingshead indices 1 and 2.

Payment for careThe method of payment for medical care and type ofhealth insurance in referred families was comparable tothat of the US population as a whole (Table I).

Hometown sizeOne half the families were from urban settings, approx-imately one quarter each from suburban or ruralhometowns (Table I).

Maternal age and ethnicityThe median maternal age was 25 to 29 years (Table II).Ethnicities are shown in Table III, with an over-representation of Asian/Pacific Islander subjects and anunderrepresentation of African American subjects. Agedifferences were not statistically significant compared tothe general US population, but racial differences were.

Risk factors

Although 75% of women who were delivered of an infantwith congenital toxoplasmosis could recall a conceivableexposure, only 39% of the women specifically recalled

566 Boyer et al

Table I Hollingshead indices,* methods of payment for care, and hometown size for 131 families with infants with congenitaltoxoplasmosis in the National Collaborative Treatment Trial (1981-1998)

Socioeconomicstatus score N (%) Type of insurance N (%) Hometown size N (%)

1 32 (26) Insured/health maintenanceorganization

77 (61)y Urban 63 (48)

2 32 (26)3 21 (17) Public aid 41 (33) Suburban 32 (25)4 21 (17)5 17 (15) Self-pay 8 (6)z Rural 35 (27)Unknownx 8 Unknown 5 Unknown 1

* The Hollingshead index includes factors, such as education and income, that are used to calculate a socioeconomic status score; a socioeconomic

status score of 1 is the highest.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.

exposure to cat litter or raw meat dishes (Table IV).Surprisingly, 25% of the women could not identify anypossible exposure to cats or any ingestion of evenundercooked meat.

Compatible clinical illness

Although 48% of the mothers noted an illness thatmight have included toxoplasmosis as a cause, only27% of the women recalled fever or night sweats, andonly 23% of the women recalled lymphadenopathy(Table V). Fifty-two percent of the mothers could notrecall an infectious illness of any kind during pregnancy.

Overall, 60 mothers (48%) recognized signs andsymptoms that were considered typical of toxoplasmosisor had known, specific risk factors (Table VI).

Prenatal serologic testing

Only 10 women (8%) had serologic tests for toxoplas-mosis before delivery of their infant. Of these 10 women,3 women were American expatriates living in Francewho were tested during their pregnancies as a componentof routine obstetric care. Interestingly, all 3 of these

Table II Maternal age for 131 women who were delivered ofinfants with congenital toxoplasmosis

Age (y) N (%)Percentage in theUnited States*

15-19 16 (13) 12.320-24 23 (18) 24.525-29 38 (30) 27.530-34 29 (23) 22.635-39 15 (12) 10.840-44 4 (3) 2.1Unknown 6 d

All comparisons were P O .05.

* 1998 National Center for Health Statistics: http://www.cdc.gov/

nchs.data/nvs48_3.pdf.

women also recalled compatible symptoms (eg, lymph-adenopathy, malaise, myalgia, fever, chills, or ‘‘flu-like’’illness), but screening occurred as part of the standardpractice 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 onprenatal ultrasound scans in both her twins; 3 womenwere tested only because their physicians were lookingfor the cause of compatible illness and/or identified riskfactors, and 3 women were tested because their physi-cians used routine screening practices.

Comment

This study addresses whether a report of exposure toepidemiologic risk factors or etiologic investigation ofa compatible illness during pregnancy would lead to theidentification of most or all women who are at risk fortransmitting T gondii to their unborn babies. If theidentification of most such women could identify mostinfected infants, then serologic screening would not be

Table III Maternal race/ethnicity for 131 women withinfants with congenital toxoplasmosis

Race/ethnicity N (%)Percentage inUnited States* P value

White 96 (73) 72.2 O .05Hispanicy 20 (15) 10.9 O .05Asian/PacificIslander

11 (8) 3.7 .003

African American 3 (2) 12.5 ! .001Native American 1 (1) 0.7 O .05

* 1998 census data for US population: http://www.census.gov/

population/estimates/nation/intfile3-1.txt.y Hispanic ethnicity includes women of any race.

Boyer et al 567

needed. Simply obtaining a careful history would lead toappropriate testing and management. Our data demon-strate that a careful history would identify, at most, 48%of mothers who have acquired toxoplasmosis duringpregnancy. Thus, only serologic screening would haveidentified the rest.

Implications of our findings for prevention witheducation are clear. Even if education about the risksof toxoplasmosis became a component of standardobstetric practice, only approximately one half of thewomen had risk factors that might have been recognizedand thus could have been eliminated by education. Ourobservation that only 8% of women in our study werescreened for toxoplasmosis during pregnancy is consis-tent with the relatively infrequent screening of pregnantwomen in the United States for this disease. In Franceand Austria, where educational measures have beenincorporated into routine obstetric care, reductions inrates of infection by 50% have been reported.7,9 Thus,other measures appear to be necessary to prevent oridentify a higher proportion of cases of this congenitaldisease.

Our study is retrospective, because we elicited histo-ries only from women whose infants already had beendiagnosed with congenital toxoplasmosis. In manyinstances, the babies had substantial handicaps, andtheir mothers were knowledgeable about toxoplasmosisand understandably actively seeking explanations fortheir infection.11 Thus, the bias in ascertainment of riskbehaviors and compatible illness in our experience is infavor of the identification of a higher proportion of

Table IV Recognized maternal risk factors for 131 womenwith infants with congenital toxoplasmosis

Variable N (%)

Cat exposureAny cat exposure 80 (65)Own cat 36 (29)Emptied litter pan 18 (15)Garden/sandbox 33 (27)Unknown 8No cat exposure 43 (35)

Maternal raw or undercooked meat exposureAny raw meat exposure 62 (50)Preparation with raw meat 45 (37)Ate raw or undercooked meat 38 (31)Ate raw meat dishes 15 (12)Ate raw milk or eggs 11 (9)Unknown 8No raw meat exposure 61 (50)

Combined risk factorsAny cat or raw meat exposure 91 (75)No cat or raw meat exposure 31 (25)Cat litter or raw meat dishes 47 (39)No cat litter or raw meat dishes 75 (61)

mothers with risk factors. It is likely that the proportionof these women who reported risk exposures or com-patible illnesses, if queried prospectively, would havebeen considerably lower. The degree to which USpopulations of pregnant women are aware of the risksof exposure to cats and cat excrement and of consumingraw or undercooked meat was not addressed specificallyin our study and deserves further investigation. Thereare no means for determining percentages of womenwith similar symptoms and risk factors in a demograph-ically comparable, concomitant control group duringthe past 20 years. This type of control group, establishedprospectively, might have helped identify whether anyfactor was seen more commonly in the mothers in ourstudies or whether nothing in the history was distinctive.However, this information was not available and doesnot effect the conclusion of this work.

In the course of the study, several additional obser-vations and demographic factors were noted. First, theproportion of African American women with infantswho were infected with toxoplasmosis in the study wasquite low, representing only 2% of the total, whereas theproportion of African American women in the USpopulation is 12% (P! .001). Whether this low prev-alence is due to different exposure rates, to poorer

Table V Maternal illness during pregnancy in 131 motherswith congenitally infected infants

Illness N (%)

Fever or night sweats 33 (27)Flu-like illness or myalgia 32 (26)Headache 14 (11)Lymphadenopathy 29 (23)Unknown 8Any infectious illness 60 (48)No maternal illness 63 (52)

Table VI Summary epidemiologic factors of maternal expo-sure and illness history

Factor Percentage

Any exposure to cats 65Any exposure to undercooked oruncooked meat

50

Any exposure to cats or undercooked oruncooked meat

75

Specific exposure to cat litter oruncooked meat

39

Unexplained febrile illness or lymphadenopathyduring pregnancy

48

Exposure to cat litter, uncooked meat, ortoxoplasmosis-like illnessduring pregnancy

48

568 Boyer et al

quality of primary health care for African Americanwomen and infants, or possibly to a genetically based,increased resistance to the transmission of the diseaseremains to be determined. If the lower than expectedproportion of African American infants is due to poorerquality of health care, systematic screening would helpto remedy the problem of differential access to properdiagnosis and health care. Second, despite reportingnonspecific symptoms of infection to their physicians(such as prolonged fever or lymphadenopathy), many ofthe women indicated that toxoplasmosis was seldomconsidered as a possible explanation of the symptoms.This observation points out the importance of greaterrecognition by obstetricians of the pediatric implicationsof maternal infection and infectious symptoms duringpregnancy.27

Other new epidemiologic observations have beenmade recently and suggest the possibility of additionalmodes of transmission of T gondii in North America. Ahigh number of sea otters have died off the coast ofCalifornia since 1995, and investigators have found thatT gondii infection is 1 of the causes.28 The suggestedepidemiologic factor is that the otters ingest Toxoplasmaoocysts in sea water, where oocysts can persist up to 6months, concentrated in mussels or other shellfish.Researchers hypothesize that oocysts infect shellfishthrough cat excrement in litter that people discard intotoilets or watershed areas, which then arrive in coastalwaters where otters live. Similarly, a large communityepidemic of toxoplasmosis took place in Victoria,British Columbia, in 1995.29 No conventional trans-mission vehicle was identified, but case-control studiesshowed significant associations between acute infectionand residence in the distribution system of one reservoirthat supplied unfiltered water to greater Victoria. Arecent study from Brazil, where toxoplasmosis is hyper-endemic, also supports the hypothesis of transmissionby unfiltered drinking water.30 In our study, we did notask about the consumption of shellfish31 or sources ofwater consumption in our inquiries about possible riskfactors.

There have been economic analyses, Cochran Data-base reviews, and metareviews concerning screeningprograms for toxoplasmosis and their outcomes.1,9,32-40

Some of these have assigned equal value to well-performed studies and to dissimilar cohorts in studiesthat sometimes are designed, controlled, performed, orinterpreted inadequately. Some of these analyses havenoted the absence of perfectly designed and performedprospective, placebo-controlled, randomized studieswith long follow-up, which included economic analyses,that clearly document savings in costs and efficacy ofnewborn infant or maternal screening.33-36 Some au-thors who reviewed these available data have concludedthat, in the absence of better prospective studies, it maybe too costly or unwarranted to perform universal

screening or even testing and treatment at all, even toprevent suffering, health careerelated costs, loss ofproductivity, and limitation in quality of life that areassociated with untreated congenital toxoplasmosis.36

Some authors have commented that such screeningcould cause anxiety because of false-positive test resultsor unnecessary pregnancy terminations caused by sero-logic testing that was not confirmed in a high-qualityreference laboratory or to counseling that was sub-optimal.34 In contrast, other analyses have concludedthat screening, in conjunction with careful confirmationin a high-quality reference laboratory and knowledge-able and caring counseling is important to facilitateidentification and treatment.19,20,32,37-43 We criticallyreviewed these analyses and the concerns they raise.We conclude that there is rigorous and careful work thatindicates that systematic detection of this infection inpregnant women and the treatment of the infected fetus,as described,9,37-40 results in improved outcomes foraffected children. Careful confirmation of serologictesting in a high-quality, reliable reference laboratoryand knowledgeable and empathetic medical care andcounseling are essential parts of this process.

From our analysis of the risk factors and illnesses inmothers of congenitally infected children, we concludethat the most effective way to prevent or detect a higherproportion of infants with this congenital infection is bysystematic serologic screening. It is difficult to imaginethat any informed mother or father would choose not toinclude this screening in their prenatal care, consideringthat almost all untreated infants who are infected with Tgondii in utero experience ophthalmologic and/or neu-rologic disease4-6 and that treatment of the fetus andinfant clearly reduces these risks.11-21

An implication of our data is that education ofpregnant women concerning risk factors for acquiringToxoplasma during gestation would be useful in theprevention of congenital toxoplasmosis. Also, althoughuncommon,9 the recognition of signs and symptoms ofthis infection by obstetricians is important for pre-vention. Another implication of our findings is thatonly systematic serologic screening would detect a sub-stantial proportion of mothers who are infected duringgestation and those fetuses and infants with congenitaltoxoplasmosis. For many of these mothers, risk factorsand signs or symptoms were not identified. Thus, ourapproach to prevention also is to include serologicscreening to prevent congenital toxoplasmosis. Delaysin treatment have been shown to result in more severeclinical manifestations. Therefore, our approach to howfrequent serologic screening is performed, withoutlimitation of resources, includes preconception testingof women and the identification of women who areinfected acutely during pregnancy with an initial test forToxoplasma infection at the first prenatal visit in the firsttrimester. Thereafter, monthly testing of seronegative

Boyer et al 569

women to identify seroconversion and testing of new-born infants to identify congenital infection should beperformed. We recognize that this optimal approachmay not be economically feasible at this time in theUnited States, where seroprevalence is relatively low,resources are limited, and automated testing proceduresare not widely available. In this country, testing sero-negative pregnant women once each trimester (eg, at 8-10, 18-20, and 28-30 weeks’ gestation)32 and all newborninfants might be considered.40 However, it should berecalled that the best outcomes derive from monthlyscreening approaches.9,36,39

T gondiiespecific immunoglobulin G and M assaysare used for screening pregnant women and newborninfants. Acute infection in the mother should be con-firmed by a Toxoplasma serologic reference laboratory(eg, in the United States: www.pamf.org/serology).Toxoplasma-specific immunoglobulin A, differential ag-glutination test, and avidity assays are used to documentthe timing of the acquisition of an infection duringgestation more precisely. The avidity assay is an impor-tant, recently developed test that can be used in the first12 to 16 weeks of gestation (based on the test kit used) toaccurately date the acquisition of infection beforeconception.41,42 High avidity of Toxoplasma-specificantibody in a single serum that has Toxoplasma-specificimmunoglobulin G and M antibodies and that has beenobtained in the first 12 or 16 weeks of gestation indicatesthat infection has occurred before conception andtherefore is not likely to threaten the fetus.

This approach to the diagnosis and treatment ofwomen who are suspected or proved to have acquiredthe infection during gestation also includes fetal ultra-sound scans and amniocentesis with PCR on theamniotic fluid at 18 weeks of gestation or thereafter todetermine whether the fetus is infected. Whereas thespecificity of PCR testing on amniotic fluid approaches100%, the sensitivity is significantly less.43 Thus, a neg-ative PCR does not rule out infection in the fetusdefinitively. If the PCR is negative, spiramycin is usedto attempt to reduce the transplacental transmission ofT gondii to the fetus. When infection is acquired by thepregnant woman before mid gestation and there is nofetal infection that is documented by amniocentesis orsuggested by fetal ultrasound scans, spiramycin iscontinued until term. If the fetus is determined to beinfected, the administration of pyrimethamine andsulfadiazine to the mother provides treatment for thefetus as well. Dosages of these medicines for thepregnant woman are pyrimethamine (50 mg per day)and sulfadiazine (2 g, twice daily) with leucovorin (10mg per day) for its marrow-protective effects. Pyrimeth-amine is not administered before 12 weeks of gestation.

Management of the pregnant woman who becomesinfected later in gestation is controversial. Some physi-cians use the same approach as described earlier to

differentiate the exposed and infected fetus. However,because the likelihood of transplacental transmissionand an infected fetus is very high late in gestation, otherphysicians treat all such mothers and their infants withpyrimethamine, sulfadiazine, and leucovorin.

Our approach to newborn infants who are born tomothers who are suspected or proved to have acquiredthe infection during gestation is to evaluate the infantclinically and serologically, with an attempt to isolate theparasite from placental tissue.9 The results of that testingare used to determine whether the treatment of the infantshould be initiated or continued. Testing for immuno-globulin M antibodies by a sensitive method like theimmunoglobulin M ISAGA test and immunoglobulin Aantibodies by enzyme-linked immunosorbent assay mustbe performed. Serologic testing and subinoculation ofthe placenta for the infant are performed by a Toxo-plasma serologic reference laboratory. Treatment inutero reduces clinical manifestations, the ability toisolate the parasite from the placenta, and the serologicmarkers of infection in the newborn infant. The infectedinfant is treated throughout the first year of life.

Analyses of cost and efficacy of screening programsare important in public health policy decision making.Rigorous analyses clearly are needed. However, con-genital toxoplasmosis eventually has devastating clinicalconsequences for nearly all infected infants.4-6 Early andaggressive antimicrobial therapy has a clear benefit.11-21

The disease occurs with an incidence that is comparableto or higher than a number of genetic and metabolicdiseases (eg, phenylketonuria, congenital hypothyroid-ism, and congenital adrenal hyperplasia) for whichneonatal screening is mandated by law in most states.44

The data herein support the conclusion that ‘‘the timehas come’’ to screen for acute acquired Toxoplasmainfection in pregnant women and congenital toxoplas-mosis in infants to prevent the potentially devastatingoutcomes from untreated disease.25,32

Acknowledgments

We thank the patients with congenital toxoplasmo-sis and their families for their generous cooperation;the physicians and other participants in the ChicagoCollaborative Toxoplasmosis Treatment Study Group(Ilona Buscher, Audrey Cameron, Esther Castro, DianaChamot, Barbara Danis, Peter Heydemann, MD, JoyceHopkins, PhD, Lara Kallal, Kristin Kasza, MS, Mi-chael Kipp, MD, Michael Kirisits, PhD, James McAu-ley, MD, Marilyn Mets, MD, Sanford Meyers, MD,Ernest Mui, Gwen Noble, MD, Dushyant Patel, MD,Jeanne Perkins, PhD, Linda Pfiffner, MD, Peter Rabiah,MD, Laszlo Stein, MD (deceased), Mark Stein, PhD,Andrew Suth, PhD, Marie Weissbord, PhD, HuiYuanZhang, MD); the airlines and hotels that providedcomplimentary transportation to and accommodations

570 Boyer et al

in Chicago; the pharmaceutical companies that providedmedications without charge to medically indigent pa-tients; Pam Stipeck-Biek, Dorothy Gibbons, MariePaul, Nannette Cannon, and Meg Davis for theirtechnical assistance in Dr Jack Remington’s laboratory;Dr Theodore Karrison for his assistance in initial studydesign, helpful discussions, and assistance with statisti-cal analyses; Drs Jacques Couvreur, George Desmonts,and Philippe Thulliez for their insight, helpful sugges-tions, and advice; and Judy Darbro for her assistance inpreparation of the manuscript.

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