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Background: Congenital toxoplasmosis is a treatable, preventable disease, but untreated causes death, prematurity, loss of sight, cognition and motor function, and substantial costs worldwide., Objectives: We asked whether high performance of an Immunochromatographic-test (ICT) could enable accurate, rapid diagnosis/treatment, establishing new, improved care-paradigms at point-of-care and clinical laboratory., Methods: Data were obtained in 12 studies/analyses addressing: 1-feasibility/efficacy; 2-false-positives; 3-acceptability; 4-pink/black-line/all studies; 5-time/cost; 6-Quick-Information/Limit-of-detection; 7, 8-acute;-chronic; 9-epidemiology; 10-ADBio; 11,12-Commentary/Cases/Chronology., Findings: ICT was compared with gold-standard or predicate-tests. Overall, ICT performance for 1093 blood/4967 sera was 99.2%/97.5% sensitive and 99.0%/99.7% specific. However, in clinical trial, FDA-cleared-predicate tests initially caused practical, costly problems due to false-positive-IgM results. For 58 persons, 3/43 seronegative and 2/15 chronically infected persons had false positive IgM predicate tests. This caused substantial anxiety, concerns, and required costly, delayed confirmation in reference centers. Absence of false positive ICT results contributes to solutions: Lyon and Paris France and USA Reference laboratories frequently receive sera with erroneously positive local laboratory IgM results impeding patient care. Therefore, thirty-two such sera referred to Lyon's Reference laboratory were ICT-tested. We collated these with other earlier/ongoing results: 132 of 137 USA or French persons had false-positive local laboratory IgM results identified correctly as negative by ICT. Five false positive ICT results in Tunisia and Marseille, France, emphasize need to confirm positive ICT results with Sabin-Feldman-Dye-test or western blot. Separate studies demonstrated high performance in detecting acute infections, meeting FDA, CLIA, WHO REASSURED, CEMark criteria and patient and physician satisfaction with monthly-gestational-ICT-screening., Conclusions/significance: This novel paradigm using ICT identifies likely false positives or raises suspicion that a result is truly positive, rapidly needing prompt follow up and treatment. Thus, ICT enables well-accepted gestational screening programs that facilitate rapid treatment saving lives, sight, cognition and motor function. This reduces anxiety, delays, work, and cost at point-of-care and clinical laboratories., Trial Registration: NCT04474132, https://clinicaltrials.gov/study/NCT04474132 ClinicalTrials.gov., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: DL and RP are/were affiliated with LDBIO Diagnostics, DL is the scientist and CEO share holder and RP was the R&D Director Scientist until January 13, 2023. A patent application was submitted by DL with the scientists at the University of Chicago and in Lyon, France in August 2018. This application is pending review in the United States in accordance with US Bayh Dole Laws. This is for the development of the whole blood point of care test and the practical clinical utility of the ICT to guide treatment for gestational infection to prevent congenital toxoplasmosis. This is to insure its continued high-quality performance and reproducibility of the results described herein. It is pending in review at the US patent office. All other authors have declared no conflict of interest., (Copyright: © 2024 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Congenital toxoplasmosis (CT) can be accompanied by serious organ manifestations, particularly retinochoroiditis, and may occur throughout life. We aimed to monitor long-term ocular prognosis in a large French cohort of patients with CT and its changes over time in the context of mandatory prenatal screening (since 1992) and incidence decrease since 2008., Methods: Patients with CT diagnosed between 1987 and 2021 were prospectively included and followed for up to 35 years. The effect of the period of conception on the risk of first retinochoroiditis has been tested using a flexible extension of the Cox model. Incidence rates of retinochoroiditis were estimated., Results: A total of 646 infected live born children were followed for a median of 12 years (range, 0.5-35); 187 patients (29%) had at least 1 ocular lesion (first at a median age of 5 years; range, 0-26 years) with peaks at 7 and 12 years. Early maternal infection and the presence of nonocular signs at birth were associated with a higher risk of retinochoroiditis, whereas delayed diagnosis of CT (after birth versus before or at birth) was associated with a lower risk (13% decrease for each additional month after birth; P = .01). A period effect for the risk of developing retinochoroiditis in patients born after 2008 was not detected., Conclusions: Despite prenatal screening and prolonged perinatal treatment, retinochoroiditis is not a rare event in French patients with CT and can occur well into adulthood, with peak incidences at 7 and 12 years of age. It rarely causes severe damage but warrants regular follow-up into adulthood., (Copyright © 2024 by the American Academy of Pediatrics.)

The burden of congenital toxoplasmosis has become small in France today, in particular as a result of timely therapy for pregnant women, fetuses and newborns. Thus, the French screening and prevention program has been evaluated and recently confirmed despite a decline over time in the incidence of toxoplasmosis. Serological diagnosis of maternal seroconversion is usually simple but can be difficult when the first trimester test shows the presence of IgM, requiring referral to an expert laboratory. Woman with confirmed seroconversion should be referred quickly to an expert center, which will decide with her on treatment and antenatal diagnosis. Although the level of proof is moderate, there is a body of evidence in favor of active prophylactic prenatal treatment started as early as possible (ideally within 3 weeks of seroconversion) to reduce the risk of maternal-fetal transmission, as well as symptoms in children. The recommended therapies to prevent maternal-fetal transmission are: (1) spiramycin in case of maternal infection before 14 gestational weeks; (2) pyrimethamine and sulfadiazine (P-S) with folinic acid in case of maternal infection at 14 WG or more. Amniocentesis is recommended to guide prenatal and neonatal care. If fetal infection is diagnosed by PCR on amniotic fluid, therapy with P-S should be initiated as early as possible or continued in order reduce the risk of damage to the brain or eyes. Further research is required to validate new approaches to preventing congenital toxoplasmosis., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: Congenital Toxoplasmosis (CT) can have severe consequences. France, Austria, and Slovenia have prenatal screening programs whereas some other countries are considering universal screening to reduce congenital transmission and severity of infection in children. The efficiency of such programs is debated increasingly as seroprevalence among pregnant women and incidence of congenital toxoplasmosis show a steady decrease. In addition, uncertainty remains regarding the effectiveness of pre- and postnatal treatments., Method: To identify cost-effective strategies, prenatal and neonatal screenings were compared using a decision-analytic model based on French guidelines and current knowledge of long-term evolution of the disease in treated children. Epidemiological data were extracted from the scientific literature and clinical data from the French Lyon cohort. Strategies were compared at one year of age, when infection can be definitively evaluated, and at 15 years of age, after which validated outcome data become scarce. The analysis was performed from the French Health Insurance System perspective and included direct medical costs for pregnant women and their children., Results: The 1-year Incremental Cost-Effectiveness Ratio showed that prenatal screening would require investing €14,826 to avoid one adverse event (liveborn with CT, fetal loss, neonatal death or pregnancy termination) compared to neonatal screening. Extra investment increased up to €21,472 when considering the 15-year endpoint., Conclusions: Prenatal screening is cost-effective as compared to neonatal screening in moderate prevalence areas with predominant Type II strains. In addition, prenatal screening, by providing closer follow-up of women at risk increases the number of occasions for education avoiding toxoplasmosis., Competing Interests: The authors have declared that no competing interests exist.

Globally, congenital toxoplasmosis remains a significant cause of morbidity and mortality, and outbreaks of infection with T. gondii represent a significant, emerging public health burden, especially in the developing world. This parasite is a threat to public health. Disease often is not recognized and is inadequately managed. Herein, we analyze the status of congenital toxoplasmosis in Morocco, Colombia, the United States, and France. We identify the unique challenges faced by each nation in the implementation of optimal approaches to congenital toxoplasmosis as a public health problem. We suggest that developed and developing countries use a multipronged approach, modeling their public health management protocols after those in France. We conclude that education, screening, appropriate treatment, and the development of novel modalities will be required to intervene successfully in caring for individuals with this infection. Gestational screening has been demonstrated to be cost-effective, morbidity-sparing, and life-saving. Recognition of the value and promise of public health interventions to prevent human suffering from this emerging infection will facilitate better patient and societal outcomes.

Background: The treatment of newborns and infants with congenital toxoplasmosis is standard practice. Some observational studies have examined safety in newborns, but most of these failed to provide sufficient details for a provisional assessment of causality. The aim of this study was to evaluate the clinical and biological adverse effects of the combination of sulfadoxine-pyrimethamine., Methods: Sixty-five children treated for 1 year with a combination of sulfadoxine-pyrimethamine (1 dose every 10 days) for congenital toxoplasmosis were followed up to evaluate abnormal hematological values and potential adverse events using a standardized method of causality assessment., Results: Nine patients (13.8%) presented at least 1 adverse clinical event that was nonspecific, such as diarrhea on the day of drug administration, vomiting and agitation. In 1 patient, erythema appeared at the end of the treatment and resolved within 10 days. None of these events was attributed to the treatment. Six patients (9.2%) developed an adverse hematological event (neutropenia, n = 3; eosinophilia, n = 2 and both anemia and eosinophilia, n = 1) that was considered to be possibly related to the sulfadoxine-pyrimethamine combination. Four treatments were temporarily interrupted, and toxicity was observed after readministration of treatment in 1 case only. However, none of these adverse events was life threatening., Conclusions: According to our results and previously published data, the combination of sulfadoxine-pyrimethamine seems to be well tolerated. However, the sample size of our study was too small to rule out the risk of less frequent, but nevertheless severe, reactions and, in particular, of hypersensitivity reactions.

The diagnosis of congenital toxoplasmosis relies mainly on serology. When results are doubtful, pediatricians have difficulties with respect to treatment. We report interferon-γ responses after the stimulation of blood by Toxoplasma gondii antigen in 17 infected infants and 80 infants free of infection. Sensitivity and specificity were 93.75% (95% confidence interval: 67%-99%) and 98.75% (95% confidence interval: 92%-99%), respectively.

Infants born to mothers who seroconverted for toxoplasmosis during pregnancy are at risk of sequelae. In the case of a negative work-up at birth, congenital infection can be ruled out only by monitoring the disappearance of maternal immunoglobulin G (IgG) transmitted through the placenta, which can be achieved by regular blood sampling during the first year. To alleviate the discomfort of this follow-up, we developed an indirect enzyme-linked immunosorbent assay to detect specific IgG diffusing passively from the blood through the gingival epithelium by collecting oral fluid on microsponges. To assess the feasibility of the test, 212 patients were first enrolled. Levels of specific IgG in oral fluid were significantly higher in seropositive (n = 195) than in seronegative (n = 17) patients (mean optical densities, 1.145 ± 0.99 versus 0.092 ± 0.127; P < 0.0001). In a population of 93 patients <15 months of age born to mothers who displayed toxoplasmic infection during pregnancy, 70 were free of congenital infection and were followed up until their serology turned negative, and 23 were congenitally infected. The same patterns of IgG were observed in the oral fluid and sera in each group. Using a cutoff of 0.04 (optical density value), the sensitivity and specificity of the test were 67.9% and 80.3%, respectively, and the probability of not having a congenital infection when the test on oral fluid was negative was 99%. Although the performance of the test needs to be improved, oral fluid sampling appears to be a promising tool for monitoring infants with suspected congenital toxoplasmosis., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Congenital toxoplasmosis (CT) can elicit severe damage to several organs, especially the eye, and may be manifested at birth or later. We assessed the long-term ocular prognosis in a cohort of congenitally infected children treated according to a standardized protocol and monitored for up to 22 years., Methods: This prospective study included confirmed cases of CT, which were identified by obligatory antenatal screening at the Lyon (France) reference center between 1987 and 2008. Data obtained through ocular examinations were recorded on a standardized form and confirmed by an independent external committee. Risk factors for retinochoroiditis were identified by using a multivariable Cox model and a flexible model that accounted for changes in the factor effects during follow-up., Results: A total of 477 of 485 infected live-born children were followed for a median of 10.5 years (75th percentile: 15.0 years). During the follow-up, 142 patients (29.8%) manifested at least 1 ocular lesion. Lesions were unilateral in 98 individuals (69.0%) and caused no vision loss in 80.6%. Lesions were first manifested at a median age of 3.1 (0.0-20.7) years. In 48 (33.8%) of the children, recurrences or new ocular lesions occurred up to 12 years after the appearance of the first lesion. Early maternal infection and confirmation of CT in children, prematurity, and nonocular CT lesions at baseline were associated with a higher risk of retinochoroiditis., Conclusions: Although the consequences of CT are rarely severe in treated children, regular postnatal monitoring is nevertheless justified because of the lifelong persisting risk of new ocular manifestations.

Introduction: Ocular lesions of congenital toxoplasmosis may occur and relapse unpredictably even a long time after birth. There is no consensus concerning the necessity or timing of ophthalmologic follow-up for these patients. We surveyed adults with congenital toxoplasmosis followed regularly since birth, in order to learn their perceptions of this follow-up. The goal of this study was to provide doctors with patient-reported information on how they perceived the long-term monitoring of their disease., Methods: Enrolled patients were given a two-question questionnaire addressing the way they perceived the long-term follow-up and their attitudes toward continuing it. Eligible patients had to be 18 years or older and to have undergone ophthalmologic follow-ups, including funduscopy, every year since birth. The last ophthalmologic examination had to be within one year of the patient's inclusion in the study., Results: Of the 102 patients finally included in the study, 98% stated that the follow-up was useful and 92% reassuring. Among the 11% of patients who found the follow-ups frightening, the proportion of patients with low visual acuity and low score on the visual function test was significantly higher than among the others. All patients except two wished to continue with regular follow-up., Conclusion: Without general agreement or guidelines on how patients with congenital toxoplasmosis should be monitored, the patient's wishes are important in making a decision. Our study brought out a clear fact; the majority of patients found long-term follow-up useful and reassuring and wished to continue., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Background: Toxoplasma infection during pregnancy exposes the fetus to risks of congenital infection and sequelae that depend heavily on gestational age (GA) at time of infection. Accurate risk estimates by GA are necessary to counsel parents and improve clinical decisions., Methods: We analyzed data from pregnant women diagnosed with acute Toxoplasma infection in Lyon (France) from 1987 to 2008 and assessed how the risks of congenital toxoplasmosis and of clinical signs at age 3 years vary depending on GA at the time of maternal infection., Results: Among 2048 mother-infant pairs, 93.2% of mothers received prenatal treatment and 513 (24.7%) fetuses were infected. Because of a significant reduction in risk since 1992 when monthly screening was introduced (59.4% vs 46.6% at 26 GA weeks; P = .038), probabilities of infection were estimated on the basis of maternal infections diagnosed after mid-1992 (n = 1624). Probabilities of congenital infection were <10% for maternal infections before 12 weeks of gestation, rose to 20.0% at 19 weeks, and then continued increasing to 52.3% and almost 70% at 28 and 39 GA weeks, respectively. Because of a significant reduction in risk of clinical signs of congenital toxoplasmosis in infected children born from mothers diagnosed after 1995 when polymerase chain reaction testing on amniotic fluid was initiated (87/794 vs 46/1150; P = .012), probabilities of clinical signs at 3 years were estimated based on 1015 maternal infections diagnosed after 1995 including 207 infected children, with symptoms in 46 (22.2%)., Conclusions: These analyses demonstrated that introduction of monthly prenatal screening and improvement in antenatal diagnosis were associated with a significant reduction in the rate of congenital infection and a better outcome at 3 years of age in infected children. Our updated estimates will improve individual management and counseling in areas where genotype II Toxoplasma is predominant.

This retrospective study proposes a new reading of immunoblotting (IB) in the diagnosis of congenital toxoplasmosis. Our findings demonstrate that a three-IgM-band association at 75, 90, and 100 kDa called the IgM triplet increases the sensitivity to 95.8% when combined with prenatal and serological neonatal tests.

This review defines the concepts of maternal-fetal (congenital) and vertical transmissions (mother-to-child) of pathogens and specifies the human parasites susceptible to be congenitally transferred. It highlights the epidemiological features of this transmission mode for the three main congenital parasitic infections due to Toxoplasma gondii, Trypanosoma cruzi and Plasmodium sp. Information on the possible maternal-fetal routes of transmission, the placental responses to infection and timing of parasite transmission are synthesized and compared. The factors susceptible to be involved in parasite transmission and development of congenital parasitic diseases, such as the parasite genotypes, the maternal co-infections and parasitic load, the immunological features of pregnant women and the capacity of some fetuses/neonates to overcome their immunological immaturity to mount an immune response against the transmitted parasites are also discussed and compared. Analysis of clinical data indicates that parasitic congenital infections are often asymptomatic, whereas symptomatic newborns generally display non-specific symptoms. The long-term consequences of congenital infections are also mentioned, such as the imprinting of neonatal immune system and the possible trans-generational transmission. The detection of infection in pregnant women is mainly based on standard serological or parasitological investigations. Amniocentesis and cordocentesis can be used for the detection of some fetal infections. The neonatal infection can be assessed using parasitological, molecular or immunological methods; the place of PCR in such neonatal diagnosis is discussed. When such laboratory diagnosis is not possible at birth or in the first weeks of life, standard serological investigations can also be performed 8-10 months after birth, to avoid detection of maternal transmitted antibodies. The specific aspects of treatment of T. gondii, T. cruzi and Plasmodium congenital infections are mentioned. The possibilities of primary and secondary prophylaxes, as well as the available WHO corresponding recommendations are also presented., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In France, children with confirmed congenital toxoplasmosis receive a treatment for a period of 12 to 24 months. Such prolonged treatment may generate potentially severe risks, in particular hematologic and cutaneous. Our objective is to compare the effectiveness of two therapeutic strategies on the prevention of retinochoroiditis by a randomized, non-inferiority, open-label, parallel study including 486 children, 3 to 6 months of age with a non-severe form of congenital toxoplasmosis. Following randomization, pyrimethamine-sulphonamide treatment is initiated for a period of three months, followed by a treatment with Fansidar(®) for 9 months, or therapeutic abstention. Follow-up visits during a two-year period will include an examination of the eye, a blood test, and questionnaires to evaluate the children's quality of life and their parents' anxiety. Confirming the non-inferiority of the effectiveness of a short-term treatment will improve the quality of life of parents and children., (© 2011 Société Française de Pharmacologie et de Thérapeutique.)

Background: Long-term evolution of congenital toxoplasmosis is not documented. We assessed the outcome of treated congenital toxoplasmosis in a cohort of adult individuals who had undergone ante- and postnatal treatment to provide information for pediatricians and parents on the evolution of the disease., Methods: We conducted a questionnaire study on 126 adults with congenital toxoplasmosis (mean age: 22.2 years; age range: 18-31 years) monitored regularly until the time of inclusion. The main outcome measures were quality of life (Psychological General Well-Being Index) and visual function (VF14 questionnaire), and the outcomes were correlated with disease-specific factors., Results: Of the 102 patients (80.9%) who were finally included in the study, 12 (11.8%) presented neurologic effects and 60 (58.8%) manifested ocular lesions; in the latter category, 13 individuals (12.7%) had reduced visual function. The overall global quality-of-life score (74.7 ± 14.2) was close to the expected normal range for the general population (73.7 ± 15.3). Overall, visual function was only slightly impaired (M = 97.3; 95% confidence interval, 95.8-98.8). Although disease-independent critical life circumstances were associated with a reduced Psychological General Well-Being Index, this index was not influenced by any of the clinical characteristics of congenital toxoplasmosis. Neurologic pathologies, reduced visual acuity, foveal location of the retinal lesion, and squinting contributed to decreased visual function at follow-up., Conclusions: Our data reveal that treated congenital toxoplasmosis has little effect on the quality of life and visual function of the affected individuals. These encouraging findings may help to alleviate the anxiety of affected individuals and their parents.

Background: The results of the ante- and neonatal diagnostic tests for congenital toxoplasmosis influence the decision to treat the newborn immediately after birth. Here, we estimate the positive and negative likelihood ratios (LRs) and the probabilities of congenital infection according to PCR and IgM-IgA tests results., Methods: The study concerned 767 children born between 1996 and 2002 and followed-up for 1-year at Croix-Rousse hospital, Lyon, France. The LRs and the post-test probabilities were estimated conditionally on gestational age at maternal infection using a logistic regression approach., Results: For the PCR and the IgM-IgA tests, the positive LRs were high. In children with one positive test when only one test was done, the probability of infection reached 90% when the maternal infection occurred at 18-weeks gestation or later. This probability was close to 100% when the 2 tests were positive, whatever the gestational age. The negative LRs of the 2 tests moved closer to 0 at later gestational ages. However, when the tests were negative, the probability of infection remained greater or equal to 10%, except in early maternal infection. When the 2 tests were discordant, the probability of infection was about 50% in early maternal infection., Conclusion: Providing reliable probabilities of congenital infection, the PCR and IgM-IgA tests guide clinical management and counseling of parents.

Objective: To provide clinicians with information about the accuracy of real-time polymerase chain reaction (PCR) analysis of amniotic fluid for the prenatal diagnosis of congenital Toxoplasma infection., Methods: This was a prospective cohort study of women with Toxoplasma infection identified by prenatal screening in three centers routinely carrying out real-time PCR for the detection of Toxoplasma gondii in amniotic fluid. The data available were gestational age at maternal infection, types and dates of maternal treatment, results of amniocentesis and neonatal work-up and definitive infectious status of the child. We estimated sensitivity, specificity and positive and negative predictive values both overall and per trimester of pregnancy at the time of maternal infection., Results: Polymerase chain reaction analysis was carried out on amniotic fluid for 261 of the 377 patients included (69%). It was accurate with the exception of four negative results in children who were infected. Overall sensitivity and negative predictive value were 92.2% (95% confidence interval [CI] 81-98%) and 98.1% (95% CI 95-99.5%), respectively. There was no significant association with the trimester of pregnancy during which maternal infection occurred. Specificity and positive predictive values of 100% were obtained for all trimesters., Conclusion: Real-time PCR analysis significantly improves the detection of T. gondii on amniotic fluid. It provides an accurate tool to predict fetal infection and to decide on appropriate treatment and surveillance. However, postnatal follow-up remains necessary in the first year of life to fully exclude infection in children for whom PCR results were negative., Level of Evidence: III.

Congenital toxoplasmosis in newborns is generally subclinical, but infected infants are at risk of developing ocular lesions. Diagnosis at birth relies mainly on serological tests. Cell-mediated immunity plays the major role in resistance to infection but is not routinely investigated for diagnostic purposes. Here, we describe a simple test based on the gamma interferon (IFN-gamma) response after stimulation of whole blood by crude parasitic antigens. One milliliter of heparinized blood was centrifuged; plasma was kept for routine serological tests, and pellets were resuspended in culture medium. After 24 h of culture in the presence of crude Toxoplasma gondii antigen, the cells were centrifuged and the supernatant was assayed for IFN-gamma. For 62 infants under 1 year of age born to mothers who were infected during pregnancy, the sensitivity and specificity of the test were 94% (with positive results for 16 of 17 infected infants) and 98% (with negative results for 44 of 45 uninfected infants), respectively. The false-negative result was for a treated baby who gave positive results after the withdrawal of treatment. The false positive was obtained for a 3-month-old baby. For a cohort of 124 congenitally infected patients between 1 and 30 years of age, the sensitivity of the assay was 100%. We present a simple test based on IFN-gamma secretion to assess cell-mediated immunity in toxoplasmosis. As only 1 ml of blood is required to investigate humoral and cellular immunity, our assay is well adapted for the study of congenital toxoplasmosis in infants. Using purified antigens or recombinant peptides may improve the test performance.

Monthly serological testing is mandatory in France for pregnant women not immune to toxoplasmosis. We assessed for the first time the adherence to this national programme, using data from antenatal tests for Toxoplasma antibodies collected by the Union of Health Insurance Services in the French Rhone-Alpes region.

In 2008, we have celebrated the centenary of the discovery of Toxoplasma gondii.Although this ubiquitous protozoan can generate devastating damage in foetuses and newborns, its treatment is the only field in which we have made little progress, despite a huge body of research, and has not yet been validated. Pregnant women who seroconvert are generally given spiramycine in order to reduce the risk of vertical transmission. However, to date, we have no evidence of the efficacy of this treatment because no randomized controlled trials have as yet been conducted. When foetal contamination is demonstrated, pyrimethamine, in association with sulfadoxine or sulfadiazine, is normally prescribed, but the effectiveness of this treatment remains to be shown. With regard to postnatal treatment, opinions vary considerably in terms of drugs, regimens and length of therapy. Similarly, we do not have clear evidence to support routine antibiotic treatment of acute ocular toxoplasmosis. We must be aware that pregnant women and newborns are currently being given empirically potentially toxic drugs that have no proven benefit. We must make progress in this field through well-designed collaborative studies and by drawing the attention of policy makers to this disastrous and unsustainable situation.

Background: Primary Toxoplasma gondii infection during pregnancy can be transmitted to the fetus. At birth, infected infants may have intracranial calcification, hydrocephalus, and retinochoroiditis, and new ocular lesions can occur at any age after birth. Not all children who acquire infection in utero develop these clinical signs of disease. Whilst severity of disease is influenced by trimester in which infection is acquired by the mother, other factors including genetic predisposition may contribute., Methods and Findings: In 457 mother-child pairs from Europe, and 149 child/parent trios from North America, we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4. Polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci showed unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers. Modeling suggested either an effect of mother's genotype, or parent-of-origin effects. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting., Conclusions: These associations between clinical outcomes of congenital toxoplasmosis and polymorphisms at ABCA4 and COL2A1 provide novel insight into the molecular pathways that can be affected by congenital infection with this parasite.

Background: Retinochoroiditis is the main complication of congenital toxoplasmosis. Its risk factors have rarely been investigated and were the object of this study., Methods: A retrospective study was conducted on 300 infants with congenital toxoplasmosis born between July 1, 1996 and December 31, 2002 and treated with pyrimethamine and sulfonamide for at least 12 months. Results of eye tests were collected up to 24 months. Risk factors associated with first retinochoroiditis were identified by univariate then multivariate analyses (Cox model)., Results: One hundred forty-nine boys and 151 girls were included. Maternal infection dated from the first trimester in 34 cases, the second in 97 cases, and the last in 169 cases. At birth, 22 infants had cerebral calcifications. During the first 2 years of life, first retinochoroiditis was diagnosed in 36 infants (12%). In multivariate analysis, 3 factors were significantly associated with first retinochoroiditis before the age of 2 years: a delay of >8 weeks between maternal seroconversion and first treatment [hazard ratio, 2.54; 95% confidence interval (CI), 1.14-5.65], female gender (hazard ratio, 2.02; 95% CI, 1.01-4.1), and cerebral calcifications at birth (hazard ratio, 4.3; 95% CI, 1.9-10). There was no correlation between gestational age at the time of maternal infection and risk for retinochoroiditis., Conclusions: A delay of >8 weeks between maternal seroconversion and the beginning of treatment, female gender, and especially cerebral calcifications are risk factors for retinochoroiditis during the first 2 years of life in infants treated for congenital toxoplasmosis.

Background: Retinochoroiditis is the most common ocular manifestation of congenital toxoplasmosis, but other associated ophthalmological pathologies can also occur. The aim of this study was to determine the nature of the latter in treated cases of the disease and to assess their impact on visual function., Methods: Four hundred and thirty consecutive children with serologically confirmed congenital toxoplasmosis were included in this study. Data were prospectively collected using standardized ophthalmological assessment forms. The presence of retinochoroiditis and of associated pathologies was ascertained, and their impact on visual function was assessed., Results: After a median follow-up of 12 years [range 0.6-26 years], 130 children manifested retinochoroiditis. We detected 22 foci of retinochoroiditis at birth and 264 additional ones during the follow-up period. Of these, 48 (17%) were active when first diagnosed. Twenty-five of the 130 children (19%) had other associated ocular pathologies. Of these, 21 (16%) had a strabismus, which was due to macular lesions in 86% of the cases; 7 (5.4%) presented with unilateral microphthalmia, and 4 (3%) with cataracts. Most of these events were detected after the onset of retinochoroiditis. None of the children presented with ocular involvement in the absence of chorioretinal lesions. Macular lesions occurred more frequently in children with associated pathologies (p<0.0001), and associated pathologies were likewise more common in individuals with macular lesions (p=0.0003). Visual impairment occurred in 31/130 cases, and in all but 3 of these eyes it was due not to an associated pathology but to macular retinochoroiditis., Conclusions: At the end of the follow-up period, ocular involvement existed in 30% of the treated children with congenital toxoplasmosis. Associated eye pathologies were manifested less frequently than anticipated. They may occur later in life and are an indirect marker of the severity of congenital toxoplasmosis, but they do not have a direct impact on visual acuity. The overall functional prognosis of congenital toxoplasmosis is better than would be expected on the basis of literature findings, with only 2 of the 130 children suffering bilateral visual impairment.

Factors that regulate the pathogenesis of Toxoplasma gondii in humans are poorly understood. When acquired during pregnancy, toxoplasmosis can be disastrous, leading to fetal loss or conversely to subclinical disease. In congenitally infected infants, evolution is highly unpredictable. Genotype based virulence patterns have been described in mice, but in humans this classification does not correlate with the gravity of the disease. Mutations on DHFR-TS loci have recently been reported to confer T. gondii fitness cost. In this study, we investigated the relationship between the virulence of the parasite, as measured by clinical outcome in the fetus or newborn, fitness, as measured by parasitic load in amniotic fluid, and allelic polymorphism in DHFR. Six cases of severe congenital toxoplasmosis and 23 cases of mild congenital infections were included in the study. Quantitative PCR was performed to evaluate total T. gondii DNA load in amniotic fluid and detection of mutations was carried out with a LightCycler using hybridisation probes. Parasitic load was significantly higher in severe infections than in mild diseases. Among isolates from severe or non-severe cases of congenital toxoplasmosis, no polymorphism could be detected at loci 36, 83 or 245 of the DHFR gene. The virulent RH strain presented the same melting temperature as the non-virulent PRU strain for codons 36, 83 and 245. Only mutated clones, M2M3 and M2M4 with allelic replacement at these positions, displayed different profiles allowing a clear distinction between wild and mutant types. We concluded that the DHFR gene mutations we investigated do not regulate T. gondii fitness in humans.

Objective: Retinochoroiditis is the most frequent consequence of congenital toxoplasmosis. Early diagnosis and treatment are believed to reduce the risk of visual impairment. We report on the clinical evolution of ocular lesions and final visual function in a prospective cohort of congenitally infected children who were identified during monthly maternal prenatal screening., Methods: The study included 327 congenitally infected children who were monitored for up to 14 years at the Croix Rousse Hospital in Lyon, France. Data on date of maternal infection; time and type of therapy; antenatal, neonatal, and postnatal work-ups; and ocular status were analyzed., Results: All mothers but 52 had been treated. Pyrimethamine and sulfadiazine was given in utero to 38% of children and after birth to 72% of newborns. Fansidar was given for an average duration of 337 days in all but 2 children. After a median follow-up of 6 years, 79 (24%) children had at least 1 retinochoroidal lesion. In 23 (29%) of them, at least 1 new event had been diagnosed up to 10 years after detection of the first lesions: reactivation of an existing lesion (1 case), new lesion in a previously healthy location (19 cases), or both (3 cases). Fifty-five children had lesions in 1 eye; of the 45 children for whom final visual acuity data were available, 31 (69%) had normal vision. Twenty-four children had lesions in both eyes; of the 21 for whom final visual acuity data were available, 11 had normal vision in both eyes. None had bilateral visual impairment., Conclusions: Clinicians, parents, and elder children with congenital infection should be informed that late-onset retinal lesions and relapse can occur many years after birth but that the overall ocular prognosis of congenital toxoplasmosis is satisfactory when infection is identified early and treated accordingly.

Objective: Our purpose was to evaluate Toxoplasma gondii concentration in amniotic fluid (AF) samples as a prognostic marker of congenital toxoplasmosis., Study Design: A retrospective study was carried out in 88 consecutive AF samples from 86 pregnant women, which were found positive by prospective polymerase chain reaction (PCR) testing. Parasite AF concentrations were estimated by real-time quantitative PCR and analyzed in relation to the clinical outcome of infected fetuses during pregnancy and at birth, taking into account the gestational age at maternal infection., Results: A significant negative linear regression was observed between gestational age at maternal infection and T gondii DNA loads in AF. After adjusting for time at maternal seroconversion by multivariate analysis, higher parasite concentrations were significantly associated with a severe outcome of congenital infection (odds ratio [OR]=15.38/log (parasites/mL AF) [95% CI=2.45-97.7])., Conclusion: PCR quantification of T gondii in AF can be highly contributive for early prognosis of congenital toxoplasmosis. Maternal infections acquired before 20 weeks with a parasite load greater than 100/mL of AF have the highest risk of severe fetal outcome.

The aim of this study was to identify the high-risk factors associated with the development of ocular lesions in a large cohort of children with congenital toxoplasmosis (CT), irrespective of their gestational age at the time of maternal infection. Children were managed according to a standardized protocol and monitored for up to 14 years at the Croix-Rousse Hospital, Lyon, France. Cox model and a flexible regression, spline-based method were used for the analysis. During a median follow-up time of 6 years, 79 of the 327 children (24%) had at least one retinochoroidal lesion. No bilateral impairment of visual acuity was observed. The risk of a child developing ocular disease was higher not only when mothers were infected early during pregnancy, which was expected, but also when CT was diagnosed prior to or at the time of birth, when non-ocular manifestations were present at baseline and when birth was premature.

Background: The combined influence of congenital toxoplasmosis and twin pregnancy on the duration of gestation has not been previously examined. Similarly little is known about the influence of genetic factors on the clinical course of this disease. The present study addresses these issues., Patients and Methods: Fourteen consecutive twin pairs born of mothers with Toxoplasma seroconversion during pregnancy were monitored after birth and during childhood, and the relevant data were compared with those already documented for similar cases., Results: The presumed time of gestation at which women became infected was earlier in noninfected than in infected twins (P = 0.007). Congenital infection did not influence the duration of pregnancy either in our own cases [36.2 +/- 4.3 weeks for noninfected children and 37.4 +/- 1.8 weeks for infected ones (P = 0.45)] or in previously published ones [35.4 +/- 3.6 weeks (P = 0.69)]. The infection status was identical for monozygotic twins (with one exception) but different for dizygotic ones (19 of 20 vs.35 of 45 cases). The clinical course through childhood corresponded more closely for monozygotic twins than for dizygotic ones [17 of 20 vs.20 of 45 cases (P = 0.007)]., Conclusion: Twin pregnancy is not a risk factor either for premature birth or for Toxoplasma infection in contaminated twins. The closely corresponding infection status between monozygotic twins highlights the crucial role played by the placenta in disease transmission. However, the substantial proportion of discrepant clinical courses suggests that other, as yet unknown, factors may be involved.

Prenatal diagnosis of congenital toxoplasmosis relies on the PCR test on amniotic fluid and ultrasound follow-up of the fetus. We report two cases of toxoplasma infection during the first trimester of gestation with a discrepant diagnosis of fetal infection. PCR performed more than four weeks after the estimated date of contamination was negative. Ultrasound follow-up was normal up to the third trimester when major hydrocephalus was detected, leading to pregnancy termination. In both cases, post-mortem examination revealed a diffuse infection with severe brain lesions. These observations confirm the necessity to continue a monthly ultrasound follow-up, even if amniocentesis is negative, in case of fetal toxoplasma infection in pregnancy., (Copyright 2003 John Wiley & Sons, Ltd.)

The aim of this study was to determine the frequency of anergy to Toxoplasma gondii in congenitally infected newborns and immunocompetent infected individuals. Specific anergy to Toxoplasma has been reported previously, especially in cases of congenital toxoplasmosis. Whole blood from 592 immunocompetent patients with suspected toxoplasmosis was cultured in the presence of soluble Toxoplasma antigen for 7 days. Activated T lymphocytes were detected by flow cytometry. In patients over 1 year of age, the percentage of soluble Toxoplasma antigen-stimulated T cells expressing the interleukin-2 receptor CD25 was higher in infected patients than in uninfected subjects (40.0+/-18.3% vs. 1.8+/-2.0%, P<0.0001). No differences were detected between seroconverters, i.e. those with recent rises in IgM and IgG antibodies, and those with acquired or congenital toxoplasmosis. Similar results were observed when congenitally infected ( n=38) and uninfected ( n=89) children under 1 year of age were compared (17.6+/-9.2% vs. 3.0+/-4.9%, P<0.0001). The sensitivity and specificity values of CD25 detection for diagnosis of congenital toxoplasmosis in infants were 95% and 89%, respectively, at a threshold value of 7% above control culture. The results show that specific cellular immunity is detectable in virtually all Toxoplasma-infected patients, including newborns. Detection of CD25 constitutes a simple, sensitive and specific test for diagnosis of congenital toxoplasmosis.

Background: Congenital toxoplasmosis (CT) may lead to serious neurological or sensory consequences. A serological screening of women at risk of acquiring toxoplasmosis became mandatory in France, first during the visit before wedding (1978), then during the visit for pregnancy declaration (1985) and at last with a monthly follow-up during pregnancy since 1992. The efficacy and the profitability of the program was never assessed, in spite of the modification of the epidemiological context. However medico-economical studies were conducted in countries in which no prevention program for CT was available to determine the interest of an antenatal screening similar to the French one or of other prevention strategies., Methods: Eight studies comparing at least two strategies were selected. Methodologies used in those studies were analyzed by two independent readers with the help of a standardized scale. A score was calculated for each study., Results: Each study analyzed suffered from methodological limitations, in particular concerning the estimation of antenatal treatment efficacy, which could lead to invalidate their conclusion. The most reliable studies in regard to methodological guidelines, that is with the higher score, concluded that antenatal screening was not contributive. However, they could not be transposed directly in the present French situation, because of the difference of the epidemiological and economical context., Conclusions: Given the difficulty to obtain a clear conclusion, it seems necessary to perform a rigorous decision analysis to identify the more effective and acceptable program in terms of human and financial costs for preventing congenital toxoplasmosis.

Objective: To assess the consequences for the fetus of maternal toxoplasma infection acquired during the first 8 weeks of gestation and to set guidelines on how to manage these maternal infections., Methods: Data were prospectively analyzed on 360 pregnancies followed-up in our department due to a toxoplasma infection during the 8 first weeks of pregnancy. Estimates of the risk of fetal infection were based on all cases, including those which could not be followed up until infection was ruled out or confirmed. Severity of infection was estimated based on ultrasound findings during pregnancy, neonatal and long-term postnatal clinical, neurological and ophthalmologic work up., Results: Out of the 360 included women, 336 gave birth to a live born child: 7 (2%) were infected, 302 (90%) were free of infection and follow-up was insufficient to conclude about the 27 (8%) remaining infants. The estimated risk of fetal infection ranged between 2 and 10% based on live born children and between 3 and 14% when the 24 interrupted pregnancies were included. At their last clinical evaluation at 70 months of age, all 7 children, including the 2 who had inactive peripheral eye lesions and the one who had a unique intracranial calcification were free of any ophthalmologic or neurological impairment., Conclusion: Our study confirms that in the event of a maternal infection during the first 8 weeks of pregnancy the risk of fetal infection is low and results mainly in a spontaneous termination of pregnancy. Future parents should be assured that conversely to a common opinion, the prognosis of congenital toxoplasmosis in live-born children is good. For these early maternal infections as for those acquired later, we recommend immediate treatment with spiramycin, monthly ultrasound surveillance, amniocentesis and treatment with pyrimethamine and sulphamides if the PCR is positive. Abortion should be restricted to cases with ultrasound lesions

Background: The aim of prenatal serological screening for toxoplasmosis is to identify and treat maternal infection as soon as possible in order to prevent transmission of the parasite to the fetus. However, despite widespread provision of prenatal toxoplasma screening across Europe, the effectiveness of prenatal treatment is uncertain. The study aimed to determine the effect of the timing and type of prenatal treatment on mother to child transmission of Toxoplasma gondii., Method: A cohort of 554 infected pregnant women were identified in Lyon, France between 1987 and 1995 and their children were followed to determine congenital infection status. We determined the effect of prenatal treatment on transmission by examining the effect of the delay between maternal seroconversion and start of treatment. We also compared the effect of the type of treatment and no treatment on the risk of mother to child transmission. Analyses were adjusted for gestation at maternal seroconversion., Results: Compared to treatment within 4 weeks from seroconversion, the adjusted odds ratios (OR) for mother to child transmission after a treatment delay of 4-7 weeks was 1.29 (95% CI : 0.61, 2.73) and after more than 8 weeks, 1.44 (95% CI : 0.60, 3.31). The adjusted OR associated with spiramycin alone compared with pyrimethamine-sulfadiazine treatment was 0.91 (95% CI : 0.45, 1.84) and the OR for no treatment compared with pyrimethamine-sulfadiazine treatment was 1.06 (95% CI : 0.37, 3.03)., Conclusions: The authors hypothesize that the absence of an effect of prenatal treatment is due to transmission before the start of treatment.

Monthly serological screening of non immune pregnant women, required by law in France, is sometimes interrupted before delivery. As a consequence, late maternal infections resulting in a high risk of vertical transmission with potentially severe late sequelae are not detected.

Unlabelled: Although serological rebound is common in infants with congenital toxoplasmosis, clinical recommendations for management, in particular the need for additional treatment, vary. The goals of our retrospective cohort study in 133 consecutive children with congenital toxoplasmosis were to estimate the incidence and duration of the rebounds, identify predictive factors, assess the long-term risk of eye lesions and the need for treatment. We first estimated the incidence and duration of rebounds and identified predictive factors using an univariate analysis and a Cox model modified to include time-dependent variables. Two cohort studies were then conducted to compare the incidence density of secondary eye lesions in children who had a rebound versus no rebound, and among children who had a rebound after initial therapy, in those who received an additional course of treatment and in those who did not. Of the 133 children, 93 (70%) had at least one rebound during a mean follow-up of 95 months. Of those with one rebound diagnosed after initial treatment, 33 received an additional 3-month course of pyrimethamine/sulphadoxine and 48 were not treated. Intracranial calcification at birth was associated with an increased relative risk (RR) of rebound (RR = 2.601; P = 0.03), and treatment with pyrimethamine/sulphadoxine between 2 and 12 months of age with a decreased risk (RR = 0.3; P = 0.0845), whereas age of pregnancy at maternal infection, type of treatment during pregnancy and sex were not found to be predictive factors. There was no difference in incidence densities of secondary eye lesions in children without rebound (7/3,367 child-months) compared to those with at least one rebound (22/9,609 child-months) (RR = 1.10; 95% CI: 0.47-2.58), and, among the 81 children who had one rebound diagnosed after initial treatment, in those who received an additional course of treatment and in those who did not (RR = 0.72; 95% CI: 0.30-1.72)., Conclusion: serological rebound is common in children with congenital toxoplasmosis but, due to the risk and constraints, an additional course of treatment and more ophthalmological surveillance than currently practiced do not seem warranted.

Toxoplasmosis infection during pregnancy can cause stillbirths, severe mental retardations or ocular disorders that can also occur later in life and have a potential to relapse. As the disease is generally asymptomatic, diagnosis relies on serological tests. Primary prevention intends to prevent the infection of the fetus, while secondary prevention aims at reducing the severity of sequelae. Preventive attitudes regarding congenital toxoplasmosis differ according to countries. In Austria and France, a nationwide programme based on the screening of seronegative pregnant women and the treatment of all seroconversions has been implemented. The UK and Norway have rejected such a screening due to the lack of evidence of its efficacy. A review of published studies showed that no randomised controlled trials have been conducted. The only available data come from retrospective studies and are methodologically flawed. The impact of chemotherapy on primary and secondary prevention still needs to be assessed. This lack of evidence results in conflicting attitudes that increase the anxiety already raised in pregnant women and doctors by the occurrence of a maternal toxoplasmosis during pregnancy. Before making any change in preventative strategy, it is of utmost importance to increase our knowledge on treatment efficacy through proper randomised trials of existing drugs and of new potentially active compounds.

We compared the relative risks of mother-to-child transmission of Toxoplasma gondii and clinical manifestations due to congenital toxoplasmosis associated with intensive prenatal treatment in Lyon and Austria, short term treatment in 51% of Dutch women, and no treatment in Danish women. For each cohort, relative risks were standardized for gestation at seroconversion. In total, 856 mother-child pairs were studied: 549 in Lyon, 133 in Austria, 123 in Denmark and 51 in The Netherlands. The relative risk for mother-to-child transmission compared to Lyon was 1.24 (95% CI: 0.88, 1.59) in Austria; 0.59 (0.41, 0.81) in Denmark; and 0.65 (0.37, 1.01) in The Netherlands. Relative risks for clinical manifestations compared with Lyon (adjusted for follow-up to age 3 years) were: Austria 0.19 (0.04, 0.51); Denmark 0.60 (0.13, 1.08); and The Netherlands 1.46 (0.51, 2.72). There was no clear evidence that the risk of transmission or of clinical manifestations was lowest in centres with the most intensive prenatal treatment.

Objectives: Toxoplasmosis serology may become temporarily negative in children with congenital toxoplasmosis, leading to a risk of misdiagnosis and inadequate surveillance. The purpose of our work was to better understand the time course of toxoplasmosis serology which has not been studied specifically and to propose practical recommendations., Patients and Methods: We conducted a prospective study in 217 children born with congenital toxoplasmosis between January 1988 and December 1997. Clinical, ophthalmological and serology data were collected every three months during their first year of life then every six months until three years of age and every year thereafter for all patients. Negative serology was defined as the absence of IgG at indirect immunofluorescence and ELISA (enzyme linked immunosorbent assay) and by the absence of IgM at ISAGA (immunosorbent agglutination assay)., Results: During the mean follow-up of 66 +/- 33 months (range 12-126 months), 33 children (15%) presented a period where the toxoplasmosis serology (ELISA and indirect immunofluorescence) was negative for a transient period reaching a mean 5 months. The dye test was performed in 25 of these children and was negative in 6 (24%). Among the negative conversions observed at routine testing, 73% occurred in children taking pyrimethamine/sulfadoxin therapy and the others occurred a mean 11.7 months after interruption of treatment. There was a positive association between maternal treatment and transient seronegativity in the cases where the maternal contamination had occurred during the first 2 trimesters of pregnancy. The serology became positive again in 30 of the 33 children (91%) and in 22 children there was a rebound. At last follow-up, the 3 other children still had negative serology (mean duration 35 months, range 3-62 months)., Conclusion: Transient negative toxoplasmosis serology is a frequent phenomenon in children with congenital toxoplasmosis. Although the underlying pathophysiological mechanism remains unknown, it is crucial to avoid questioning the initial diagnosis of congenital toxoplasmosis and to continue regular routine monitoring.

Objective: To evaluate sensitivity, specificity, and predictive values of a prenatal amniotic fluid (AF) polymerase chain reaction (PCR) test for diagnosis of congenital toxoplasmosis., Methods: A multicenter prospective study was done on 271 women with proved primary Toxoplasma infection during pregnancy and who had amniocentesis for prenatal diagnosis by PCR. Live-born infants were eligible for analysis only if a serologic follow-up could assess a definitive infection status., Results: Of the 270 evaluable cases, 75 were congenitally infected, 48 of whom had a positive PCR at prenatal diagnosis. Overall sensitivity of PCR on AF was estimated at 64% (95% confidence interval [CI] 53.1%, 74.9%), negative predictive value of 87.8% (95% CI 83.5%, 92.1%), whereas specificity and positive predictive value were 100% (95% CIs 98%, 100% and 92.3%, 100%, respectively). Among cases with congenital toxoplasmosis, there were no significant differences between those with positive or negative PCR with regard to median gestational age at maternal infection, interval between maternal infection and amniocentesis, or duration of treatment before amniocentesis. However, sensitivity of PCR was found to be significantly higher for maternal infections that occurred between 17 and 21 weeks' gestation (P <.02)., Conclusion: A negative PCR of AF cannot rule out congenital infection. In this case, continuation of treatment with spiramycin combined with ultrasonographic follow-up and postnatal follow-up are warranted. Our results also suggest presumptive treatment combining pyrimethamine and sulfonamides in case of maternal infection occurring late in pregnancy.

Serological rebounds occur frequently in patients with congenital toxoplasmosis, but remain poorly understood. A link between Th1 and Th2 cytokines and the pathophysiology of infectious diseases has been reported. Production of interferon-gamma (IFN-gamma) and IL-4 in supernatants of whole blood after in vitro specific Toxoplasma gondii stimulation and serum-specific IgE levels were studied in 31 congenitally infected children. IFN-gamma was produced at higher levels by lymphocytes from children with stable congenital toxoplasmosis (n = 18) than from children showing serological rebound (n = 13) (P < 0.04). Conversely, supernatants from children with serological rebound showed higher levels of IL-4 than those from children with stable congenital toxoplasmosis (P < 0.03). The polarized Th2 response was confirmed by a greater (IL-4:IFN-gamma) x 100 ratio (P < 0.0001) and production of T. gondii-specific IgE in six out of 13 children showing serological rebound. These results suggest a role of Th2 cytokines in destabilization of congenital toxoplasmosis and perhaps in local reactivation of the parasite.

Unlabelled: Recommendations vary on the best combination of tests to use for the diagnosis of subclinical congenital toxoplasmosis at birth. The diagnostic accuracy of IgM and IgA tests was assessed in the context of routine clinical practice on 233 newborns with congenital toxoplasmosis and 661 healthy controls. IgM/IgA sensibility and specificity were compared in cord and postnatal samples. Both tests were considerably more specific in neonatal blood (IgM: 98%; IgA: 100%) than in cordblood (IgM: 85%; IgA: 88%). Sensitivity for IgM and IgA was not significantly different in neonatal blood (61% and 60%, respectively) and cord blood (67% and 54%, respectively). Combining IgM and IgA increased the overall sensitivity to 73% without any significant loss in specificity (98%). The influence of the date of maternal infection on the sensitivity and negative predictive value was also clearly demonstrated., Conclusion: Because of their relatively low cost compared to more sophisticated methods, IgM and IgA tests should remain the main method for the routine diagnosis of congenital toxoplasmosis although follow up is essential to identify the Ca. 25% of infected children who are missed at birth on the basis of these tests.

Background: Women who acquire toxoplasmosis infection during pregnancy (in most cases detected through serological screening) require counselling about the risk of congenital infection and its clinical sequelae. Reliable estimates of risk are not currently available. We undertook an analysis of data from women referred to the toxoplasmosis reference laboratory, Lyon, France, between 1987 and 1995., Methods: Information was collected from clinical notes kept at the laboratory and, where necessary, from the relevant obstetrician or paediatrician via telephone. Methods were developed to derive estimates of the risk of congenital toxoplasmosis by exact duration of gestation at maternal seroconversion., Findings: We analysed obstetric and paediatric data on 603 confirmed maternal toxoplasmosis infections. At least 564 women received antiparasitic drugs according to a standard protocol. Congenital infection status was ascertained in 554 cases, and infected children were followed-up for a median of 54 months. The overall maternal-fetal transmission rate was 29% (95% CI 25-33), which masked a sharp increase in risk with duration of gestation from 6% at 13 weeks to 72% at 36 weeks. However, fetuses infected in early pregnancy were much more likely to show clinical signs of infection. These effects counterbalance, and women who seroconverted at 24-30 weeks of gestation carried the highest risk (10%) of having a congenitally infected child with early clinical signs who was thus at risk of long-term complications., Interpretation: This information will assist the clinical counselling of pregnant women diagnosed with acute toxoplasmosis and may guide individual decisions on investigative and therapeutic options. Further studies are required to determine the long-term risks of clinical symptoms and disability due to congenital toxoplasmosis.

Patients with congenital toxoplasmosis occasionally show rises in serum antibodies to Toxoplasma gondii (serological rebound), but the underlying cause remains unclear. The acute or chronic presence of available antigen often causes the appearance, in the peripheral blood, of cells actively secreting specific antibody. We have evaluated the capacity of circulating blood cells from 91 children born to T. gondii-infected mothers to actively synthesize anti-T. gondii antibodies according to their serological status. Supernatants from 7-day cultures of peripheral blood mononuclear cells were evaluated for antibody by cytofluorimetry. Only 1 of 49 subjects with low and stable serum antibody titers produced specific antibodies on cultures, while 9 of 22 subjects with recent rebound were positive. One of the positive children alone showed clinical signs of parasite activity. These observations suggest that rebound may be associated with production of available parasite antigens, possibly associated with reactivation. Differentiation from other causes, such as polyclonal B cell stimulation, would improve our ability to detect clinically significant reactivation and to prevent complications., (Copyright 1998 Academic Press.)

Background: Because of routine screening and treatment of pregnant women for Toxoplasma infection in France, most neonates born to mothers who seroconverted during pregnancy are either not infected or asymptomatic. Early diagnosis relies mainly on radiologic, ophthalmologic and biologic tests. Cerebrospinal fluid (CSF) cytochemical evaluation is one of several tests performed in parallel to increase the overall sensitivity of the diagnostic evaluation. Our goal was to assess the value of cytochemical examination and to confirm whether using a portion of available CSF for this analysis is legitimate., Methods: The individual performance of each of the two cytochemical tests and their combined value when used in parallel were assessed. These findings were then compared with the anti-Toxoplasma IgM and IgA serum titers and the clinical, ophthalmologic and radiologic findings at birth., Results: CSF cytochemical analysis was possible in only 52% of the 233 children in the study. Our results in 112 children indicated poor sensitivity estimates. There was no significant change in the posttest probability of infection compared with the pretest estimation of risk in cases of a negative finding. After a mean follow-up of 80 months there was no evidence that CSF cytochemistry helped predict the risk of sequelae., Conclusion: In our setting cytochemical examination did not significantly contribute to the diagnosis of congenital infection at birth. Because of the limited quantity of CSF available, we suggest the use of other methods with higher yield.

Decision analysis seemed the appropriate method to bring out the interest of toxoplasmosis serology in children born from mothers who seroconverted during pregnancy. In particular it provides the possibility to choose between IgA serology, recently introduced in hospital practice, and IgM serology that is the reference test. We study a series of 96 children suspected of having congenital toxoplasmosis who were followed up until the age of one. A decision analysis is thereafter conducted by synthesizing data about clinical efficacy with the RBNCN ratio that is the net benefit of treating an affected person divided by the net cost of treating an unaffected person; these costs and benefits are clinical. The effectiveness of the treatment (sulphonamides in most cases) was not quantified. Therefore, we used the fact that the RBNCN ratio is equal to the number of healthy children likely to be treated unnecessarily in order not to leave untreated a contaminated child. Although data available in the literature and data from our study still remain insufficient to draw a final conclusion, IgA antibodies are significantly more sensitive than IgM antibodies (p < 0.01). Conversely, IgA antibodies are significantly less specific than IgM antibodies (p < 0.001). The sensitivity analysis shows that the IgA test is preferred to the IgM test if the mother is contaminated during the third trimester. On the other hand, for low prevalences, as observed in the first trimester, the IgM serology is more useful.