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We report two cases of congenital toxoplasmosis following maternal primary infection occurring late during pregnancy. These congenital infections are often asymptomatic at birth and can be recognized only by an appropriate serological screening program performed in mothers after delivery.
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.
The aim of this comparative study was to investigate the clinical usefulness of the measurement of Toxoplasma gondii IgG avidity in the postnatal diagnosis of congenital toxoplasmosis. IgG avidity values in serum samples from infants with congenital infection were compared with those in samples from uninfected infants, all born to mothers with toxoplasmosis acquired during gestation. This analysis revealed that IgG avidity values soon after birth reflected maternal values in the large majority of the samples. Low or borderline IgG avidity values were systematically found in the cohort of congenitally infected subjects. After birth, IgG avidity values slowly increased over time for up to 2 years in congenitally infected subjects. On the contrary, IgG avidity values in the uninfected infants remained stable over time. The presence of low IgG avidity in a newborn can be considered a marker of maternal seroconversion in the second or third trimester of gestation and, as a consequence, an indicator of risk for congenital toxoplasmosis. An IgG avidity assay can be easily carried out with antibodies eluted from dried blood spots (Guthrie cards), providing an opportunity to retrospectively evaluate the risk of congenital infection in special clinical circumstances, for example when suspicion of congenital infection arises during late infancy.
BACKGROUND: A pilot neonatal screening programme revealed a high (approximately 1 per 4800 live births) prevalence of congenital toxoplasmosis (CT) in the State of Rio Grande do Sul, Brazil. The purpose of this paper was to estimate in a larger prospective study the prevalence of CT in the country. METHODS: At the beginning of the study, an in-house indirect enzyme immunoassay (EIA) was used, to be later replaced with a commercial capture IgM fluorometric enzyme immunoassay (FEIA). Both methods detect specific anti-Toxoplasma gondii IgM-class antibodies eluted from dried blood spots. RESULTS: Of the total of 140,914 samples received from all over the country, 47 cases were identified and confirmed as CT. This finding suggests a prevalence of 1 per 3000 live births. Of the 47 patients, only eight (17%) had clinical manifestations: two had intracranial calcifications, four had retinal scars, one had an intracranial calcification and retinal scars, and one had hepatosplenomegaly with lymphoadenopathy. The testing was paid for by the patients' families who volunteered for the study and gave their informed consent. CONCLUSION: The 3-year prospective study using sensitive detection methods, reliable confirmation, and feedback from clinicians showed that CT has an extraordinarily high prevalence in Brazil, in fact the highest ever reported in the world. Although the long-term efficacy of treatment of CT has not been well documented, in view of the availability of reliable diagnostics, confirmation and monitoring, functional logistics, and networking for screening, the insidious nature of the sequelae and the very high prevalence of the disease, neonatal screening for CT should be considered an alternative to no screening at all.
PROBLEM: The evidence supporting an additional benefit of a combined regimen of pyrimethamine-sulfonamides compared with spiramycin alone in the secondary prevention of congenital toxoplasmosis was critically evaluated. METHOD OF STUDY: We reviewed the series of cases published in the English literature on antiparasitic treatment of acute toxoplasmosis infection in pregnancy, using spiramycin until fetal infection is documented, then using cycles of spiramycin alternated with combined pyrimethamine-sulfonamide therapy. We then compared the occurrence of overt disease among infected offspring (both severe, represented by ophthalmologic or cerebral abnormalities, and mild occurrences, represented by asymptomatic intracranial calcifications and retinal scars without visual impairment) between the published case series and our consecutive series of cases treated during a 10-year period (January 1986-December 1995) with spiramycin alone. RESULTS: The prevalence of fetal infection in our series was 7.8% (12/154), similar to that reported after alternated regimens (7.0%). The rate of overt disease among infected fetuses is not different after treatment with alternated regimens than after continuous antibiotic spiramycin therapy [23% (19/82) vs. 10% (1/10); relative risk, 2.3; 95% confidence interval, 0.4, 47.0]. The pharmacokinetics of the drugs used may account for this finding. CONCLUSION: The treatment of acute toxoplasmosis in pregnancy with an alternated antibiotic regimen of pyrimethamine-sulfonamide is not more efficacious at preventing overt neonatal disease than treatment with continuous spiramycin alone.
Pregnant mice infected with Toxoplasma by the vaginal route have been found to transmit toxoplasmosis to the placentas and fetuses in utero. The microorganism entered the blood stream of the mother from primary foci of infection in the vaginal wall and produced disseminated lesions in the labyrinth of the allantoic placenta at the same time as other peripheral maternal tissues were involved. Placental lesions were observed in mice infected with Toxoplasma by vagina between the 3rd and the 9th day of pregnancy. They consisted of microscopic foci of degeneration, without inflammation, in the syncytial trophoblast, and parasites undergoing multiplication were readily identified in them. Here Toxoplasma gained access to the fetal circulation. Following the vaginal instillation of Toxoplasma on the 8th day of pregnancy, subinoculation of test animals revealed the parasites in the maternal peripheral and placental blood on the 13th day and later, while the first histopathologic changes in the placenta were found on the 17th day. Toxoplasma could be demonstrated in suspensions of fetal tissues on and after the 17th day by the injection of normal test animals. However, no lesions of toxoplasmosis, or Toxoplasma, were found in histologic sections of fetuses 11 to 21 days old removed at autopsy from vaginally infected mothers. It is concluded that before birth the parasites were confined to the fetal blood. The experiments provide the first direct histological demonstration of placental toxoplasmosis. The possible bearing of the experimental disease on human placental and fetal toxoplasmosis is briefly considered. It is probable that a maternal parasitemia during the latter part of pregnancy, whatever the portal of entry may be, is an essential factor in the pathogenesis of human congenital toxoplasmosis and that this occurs shortly after exposure to Toxoplasma rather than in a later chronic stage of the infection. The suggestion is offered that some instances of spontaneous abortion or fetal death in man, as in the mouse, may be due to inapparent toxoplasmosis.
Secreted (TSA) and water lysed antigens (WLA) derived from cell culture of the RH strain of Toxoplasma gondii have been used to induce antigen-specific mitogenesis of lymphocytes from children with congenital toxoplasmosis. Responsiveness to WLA was variable, with all patients giving false negative results. Responses to TSA, however, were highly specific, with no false negatives. This increased specificity was not due to an increased response to TSA (P less than 0.001), but a lower TSA response by the lymphocytes of the uninfected subjects (P greater than 0.1), compared with WLA in both cases. Preliminary studies have shown that while WLA induces high levels of non-specific immunity, such as natural killing, TSA is able to induce specific killing of Toxoplasma in vitro through the action of activated macrophages; this may partially explain the increased specificity of TSA in the lymphocyte transformation test.
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We report a case of congenital acquired immunodeficiency syndrome (AIDS) with congenital opportunistic toxoplasmosis. The thymic histopathology was that seen in childhood AIDS cases and not that seen in primary congenital toxoplasmosis. The toxoplasma infection was selectively localized to the brain and the serum titers were paradoxically low as reported in most adult cases of AIDS with secondary infection by the parasite. These findings strongly suggest that the infection by the human immunodeficiency virus (HIV) preceded the toxoplasma infection in the fetus.
No doubt, toxoplasmosis is a prevalent infection in all the Arab countries. However, the incidence differs from one country to another and even within the same country. Congenital toxoplasmosis is the most important form of the infection. In the present study, some 78 premature infants with different clinical pictures were examined for Toxoplasma IgG (by IHAT and ELISA) and Toxoplasma IgM (by ELISA). The results showed Toxoplasma IgG ranging between 32.1% (IHAT) and 46.2% (ELISA) while IgM (ELISA) was 23.1%. The highest positivity rate was among those suffering jaundice and the lowest was among those suffering fever of unknown origin. Protection of women particularly pregnant ones, from Toxoplasma infection is a must.
The main objective of this work was to improve the early serologic diagnosis of toxoplasmosis in children at risk of congenital infection by using recombinant antigens. Serum samples from 104 infants born to mothers with primary Toxoplasma gondii infection acquired during pregnancy, of which 35 were congenitally infected and 22 had clinical silent toxoplasmosis at birth, were included. Immunoglobulin M (IgM), IgG, and IgG subtype antibodies against epitopes carried by fragments of T. gondii MIC2, MIC3, MIC4, M2AP, AMA1, and SAG1 gene products were measured by performing parallel enzyme immunoassays (Rec-ELISAs). Recombinant antigens preferentially reacted with IgG antibodies from infected infants compared to uninfected subjects (P < 0.0001), indicating that sera from infected children recognized a more diverse repertoire of antigens than sera transferred over the placenta from the mothers. Using two serial samples collected within 3 months of life, it was possible to demonstrate a neosynthesis of specific anti-MIC2 and anti-SAG1 immunoglobulin G, mainly of the IgG2 subtype, in 13 out of 20 infants with congenital toxoplasmosis. IgM antibodies in 97% of infected infants reacted with at least one of the recombinant antigens, confirming the diagnosis of congenital infection as soon as 2 months after birth (P < 0.0001). The use of recombinant antigens is effective in distinguishing T. gondii-infected from uninfected infants and shows that assays based on recombinant antigens improve the diagnosis of newborns with congenital toxoplasmosis.
Pyrimethamine levels in sera, cerebrospinal fluid (CSF), and ventricular fluid were measured by using reversed-phase high-pressure liquid chromatography. The specimens were from 37 infants receiving pyrimethamine for treatment of suspect or proven congenital toxoplasmosis. Pyrimethamine half-life in serum was 64 +/- 12 h when determined by study of terminal-phase kinetics of samples obtained from nine babies. This half-life was significantly different (P = 0.008) from the pyrimethamine half-life (33 +/- 12 h) determined by terminal-phase kinetics for two babies of the same age taking phenobarbital. Serum pyrimethamine levels at various intervals after dosages of pyrimethamine were also lower for infants receiving phenobarbital. Levels measured in sera from babies taking the same dose of pyrimethamine throughout their first year of life did not appear to vary significantly over time or at different ages (P greater than 0.05). Mean +/- standard deviation serum levels 4 h after a pyrimethamine dose were 1.297 +/- 0.54 micrograms/ml for babies taking 1 mg of pyrimethamine per kg of body weight daily and 0.7 +/- 0.26 microgram/ml for babies taking 1 mg/kg each Monday, Wednesday, and Friday. Levels in CSF were approximately 10 to 25% of concomitant levels in serum. Serum folate levels for infants who took 0.64 to 1.7 mg leukovorin per kg ranged from 33 to 663 ng/ml. To determine whether the levels of pyrimethamine in serum and CSF of treated infants were in a range that affected the most virulent, rapidly replicating, and standard laboratory strain of Toxoplasma gondii, effects of various concentrations of pyrimethamine and sulfadiazine on replication of T. gondii in vitro were assessed. The levels of the antimicrobial agents effective in vitro were in the range of levels of pyrimethamine achieved in sera and CSF. Although folinic acid could inhibit the therapeutic effect of pyrimethamine and sulfadiazine in vitro, inhibition was noted only at levels (> or = 4,800 ng/ml) that were considerably higher than the folate levels found in the treated infants' sera.
Electron immunocytochemistry, using rabbit polyclonal anti-Toxoplasma IgG as the primary layer in immunogold staining, was used to assess the distribution of Toxoplasma antigen within, and in relation to, intact tissue cysts in brain tissue from mice with congenital toxoplasmosis. Toxoplasma antigen was widely distributed in the matrix of the cyst, being most concentrated in the proximity of the inner surface of the parasitophorous vacuole membrane (PVM). Relatively little Toxoplasma antigen was detected directly associated with cystozoites. Small amounts of antigen were detected within the host cell components exterior to the PVM and in the host neuropil immediately adjacent to the tissue cyst.
We report seven cases of subclinical congenital toxoplasmosis secondary to maternal primary infections. Mothers were infected between two and four weeks prior to delivery. The diagnostic criteria of congenital infections included: IgM antibody (Ab) (1 case); IgM and IgA Ab (1 case); a real IgG seroconversion in the neonatal and postnatal samples (3 cases); persistence of IgG Ab beyond 6 months post-delivery (2 cases). A treatment was initiated, including a combination of pyrimethamine + sulfadiazine (6 cases); trimethoprim + sulfamethoxazole (1 case). This retrospective study suggests that it is important to screen the non-immune pregnant women until delivery. We confirmed the usefulness of a combination of isotypes of antibodies for the accurate assessment of congenital infection. Finally, infected infants have to be treated and monitored clinically and immunologically during the first year of life.
In a study involving 14 laboratories supported by the European Community Biomed 2 program, we evaluated immunologic methods for the postnatal diagnosis of congenital toxoplasmosis (CT). Among babies born to mothers who seroconverted to positivity for toxoplasmosis during pregnancy, we analyzed 55 babies with CT on the basis of persistent anti-Toxoplasma immunoglobulin G (IgG) at 1 year of life and 50 control babies without anti-Toxoplasma IgG at 1 year of life in the absence of curative treatment with pyrimethamine-sulfonamides. We tested in-house methods such as the enzyme-linked immunofiltration assay (ELIFA) or Immunoblotting (IB) for the detection of IgG or IgM; these methods allowed comparison of the immunologic profiles of the mothers and the infants. We compared ELIFA and IB with a commercial enzyme immunoassay (EIA) or in-house immunosorbent agglutination assay (ISAGA) for the detection of IgM or IgA. The performances of combinations of methods were also assessed. A cumulative sensitivity of 98% during a 1-year follow-up was obtained with the ELIFA plus ISAGA combination. Only one case of CT was missed by the ELIFA plus ISAGA combination, whereas three cases were missed by the IB plus ISAGA combination, even though 48% of patients with CT were treated with pyrimethamine-sulfonamides, which are known to inhibit antibody neosynthesis. A similar performance was obtained with either ELIFA or IB in combination with EIA. The difference in performance between ELIFA plus ISAGA and IB plus ISAGA was not statistically significant (P = 0.31), and we conclude that both combinations of tests can be used for the diagnosis of CT in newborns.
A programme for the prevention of congenital toxoplasmosis in Slovenia involving the screening of pregnant women for Toxoplasma infection is presented. Of 21,270 pregnant women screened for toxoplasmosis between, 1996 and the end of 1999, 13,987 (66%) were seronegative, 7,151 (34%) seropositive and 132 had primary infection; approximately 9/1,000 women were at risk of acquiring the primary infection. One hundred live-born infants of primary infected women were available for follow-up. Nine infected but asymptomatic children were born to mothers who were screened and treated in time and two congenitally infected babies were born to mothers in whom infection was detected too late in pregnancy and who therefore received no adequate treatment. It is suggested that the results obtained in this study outweigh the cost of screening for toxoplasmosis in pregnancy. Pregnant women should always be tested at the beginning of pregnancy and, in cases of seronegativity, should be re-tested in the second and third trimesters of the pregnancy. Toxoplasma primary infected pregnant women and neonates should be treated as soon as possible. However, long-term follow-up of children born to primary infected women would be necessary for an accurate evaluation of the effectiveness of the screening because of the possibility of late onset of symptoms.
We describe a neonate with congenital ocular toxoplasmosis that presented as isolated, acute bilateral retinochoroiditis. Although toxoplasmic retinochoroiditis is not rare, it is quite unusual to diagnose congenital toxoplasmosis based on isolated bilateral retinochoroiditis in an otherwise healthy neonate. Bilateral retinochoroiditis can be caused by syphilis, herpes virus, cytomegalovirus, and toxoplasmosis. Because specific treatments now exist for these conditions, it is important to establish proper diagnosis so that treatment can be initiated promptly. The differential diagnosis, work-up, and management of retinochoroiditis in the newborn is presented and discussed.
All pregnant women followed during the period 1982-87 were screened for toxoplasmosis, and 35 patients had documented seroconversion or doubtful toxoplasmosis titers. One patient opted for pregnancy termination. The remaining were followed with a protocol that included serial ultrasound examinations and prophylactic antibiotic treatment of the mother and neonate. No fetal abnormalities related to congenital toxoplasmosis were found. All the infants had negative toxoplasmosis test titers at birth; at follow-up only one was found to have developed a subclinical infection, at 2 months of age. Our data suggest that antiparasitic treatment during pregnancy for those at risk for Toxoplasma infection may reduce the transmission rate.