Hooi Kuan Tan

Ocular Sequelae of Congenital Toxoplasmosis in Brazil Compared with Europe

Background Toxoplasmic retinochoroiditis appears to be more severe in Brazil, where it is a leading cause of blindness, than in Europe, but direct comparisons are lacking. Evidence is accumulating that more virulent genotypes of Toxoplasma gondii predominate in South America. Methods We compared prospective cohorts of children with congenital toxoplasmosis identified by universal neonatal screening in Brazil and neonatal or prenatal screening in Europe between 1992 and 2003, using the same protocol in both continents. Results Three hundred and eleven (311) children had congenital toxoplasmosis: 30 in Brazil and 281 in Europe, where 71 were identified by neonatal screening. Median follow up was 4.1 years in Europe and 3.7 years in Brazil. Relatively more children had retinochoroiditis during the first year in Brazil than in Europe (15/30; 50% versus 29/281; 10%) and the risk of lesions by 4 years of age was much higher: the hazard ratio for Brazil versus Europe was 5.36 (95%CI: 3.17, 9.08). Children in Brazil had larger lesions, which were more likely to be multiple and to affect the posterior pole (p<0.0001). In Brazil, visual impairment (<6/12 Snellen) was predicted for most affected eyes (87%, 27/31), but not in Europe (29%; 20/69, p<0.0001). The size of newly detected lesions decreased with age (p = 0.0007). Conclusions T. gondii causes more severe ocular disease in congenitally infected children in Brazil compared with Europe. The marked differences in the frequency, size and multiplicity of retinochoroidal lesions may be due to infection with more virulent genotypes of the parasite that predominate in Brazil but are rarely found in Europe.

Genetic and Epigenetic Factors at COL2A1 and ABCA4 Influence Clinical Outcome in Congenital Toxoplasmosis

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 mothers 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.

Prenatal Treatment for Serious Neurological Sequelae of Congenital Toxoplasmosis: An Observational Prospective Cohort Study

An observational study by Ruth Gilbert and colleagues finds that prenatal treatment of congenital toxoplasmosis could substantially reduce the proportion of infected fetuses that develop serious neurological sequelae.

Supplementation with antioxidants and folinic acid for children with Down’s syndrome: randomised controlled trial

Objectives To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down’s syndrome. Design Randomised controlled trial with two by two factorial design. Setting Children living in the Midlands, Greater London, and the south west of England. Participants 156 infants aged under 7 months with trisomy 21. Intervention Daily oral supplementation with antioxidants (selenium 10 μg, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo. Main outcome measures Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months. Results Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval −2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, −1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results. Conclusions This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down’s syndrome. Trial registration Clinical trials NCT00378456.

Screening for congenital toxoplasmosis: accuracy of immunoglobulin M and immunoglobulin A tests after birth.

Objectives: To determine the accuracy of postnatal screening for toxoplasma-specific immunoglobulin (Ig) M and IgA. Setting: Ten centres in three European countries. Methods: We compared results of the first postnatal IgM or IgA test in infants with infected mothers identified by prenatal screening with the reference standard for congenital infection status of specific IgG status at one year of age. Results: In all, 170 infected and 822 uninfected infants were analysed. Overall, IgM or IgA testing detected only 52–55% of infected infants. Sensitivity was highest between one and two weeks after birth and declined thereafter. Specificity was highest from four weeks after birth. For IgM, but not IgA, sensitivity was statistically significantly lower if the mother seroconverted in the first and second trimesters of pregnancy (29% and 34%, respectively) than the third (71%). Prenatal treatment with pyrimethamine–sulphonamide did not significantly reduce IgM or IgA sensitivity. Sensitivity was lowest for the immunofluorescence (IF) IgM test (10%) and the enzyme-linked immunosorbent assay (ELISA) IgM test (29%), but similar for the immunosorbent agglutination assay (ISAGA) IgM (54%), ISAGA IgA (58%) and ELISA IgA (52%) tests. Specificity was significantly lower for the ISAGA IgA test (91%) than for the ISAGA IgM (96%), IF IgM (100%), and ELISA IgA tests (98%). Conclusions: Poor performance of IgM and IgA tests in the newborn, particularly if the mother seroconverted in early pregnancy, casts doubt on the value of neonatal screening in industrialized countries where the risk of clinical manifestations during childhood is low. More accurate diagnostic tests are needed for newborns identified by prenatal screening.

Predictors of Retinochoroiditis in Children With Congenital Toxoplasmosis: European, Prospective Cohort Study

OBJECTIVE. By school age, 20% of children infected with congenital toxoplasmosis will have ≥1 retinochoroidal lesion. We determined which children are most at risk and whether prenatal treatment reduces the risk of retinochoroiditis to help clinicians decide about treatment and follow-up. PATIENTS AND METHODS. We prospectively studied a cohort of children with congenital toxoplasmosis identified by prenatal or neonatal screening in 6 European countries. We determined the effects of prenatal treatment and prognostic markers soon after birth on the age at first detection of retinochoroiditis. RESULTS. Of 281 children with congenital toxoplasmosis, 50 developed ocular disease, and 17 had recurrent retinochoroiditis during a median follow-up of 4.1 years. Prenatal treatment had no significant effect on the age at first or subsequent lesions. Delayed start of postnatal treatment did not increase retinochoroiditis, but the analysis lacked power. Older gestational age at maternal seroconversion was weakly associated with a reduced risk of retinochoroiditis. The presence of nonocular clinical manifestations of congenital toxoplasmosis at birth strongly predicted retinochoroiditis. For 92% (230 of 249) of children with no retinochoroiditis detected before 4 months of age, the probability of retinochoroiditis by 4 years was low, whether clinical manifestations were present or not 8.0%. CONCLUSIONS. Prenatal treatment did not significantly reduce the risk of retinochoroiditis in this European cohort. If children have no retinochoroiditis in early infancy, the low risk of subsequent ocular disease may not justify postnatal treatment and repeated ophthalmic assessments during childhood. Controlled trials are needed to address the lack of evidence for the effectiveness of postnatal treatment.

Symptomatic toxoplasma infection due to congenital and postnatally acquired infection

Aims: To determine the incidence and severity of symptomatic toxoplasma infection presenting during childhood due to congenital or postnatally acquired infection. Methods: Between 2002 and 2004, newly diagnosed children (<16 years) with signs or symptoms of congenital or ocular toxoplasmosis were reported by clinicians to the British Paediatric and Ophthalmic Surveillance Units or by toxoplasma referral laboratories. Confirmed cases were estimated to have a greater than 50% probability of congenital and/or ocular toxoplasmosis, based on clinical and serological findings. Results: Thirty eight children had confirmed toxoplasma infection. Twenty two (58%) were classified with congenital infection (cumulative incidence for England and Wales 3.4/100 000 live births; 95% CI 2.4 to 4.8), of whom 2 (9%) were stillborn, 7 (32%) live births had intracranial abnormalities and/or developmental delay (5 of whom had retinochoroiditis), and 10 (45%) had retinochoroiditis with no other abnormalities reported. A further 16 (42%) children were classified as infected after birth; all had retinochoroiditis. Conclusions: The low burden of symptomatic congenital toxoplasmosis combined with the lack of evidence of an effective treatment support current policy not to offer prenatal or neonatal screening for toxoplasma infection. Primary prevention strategies need to address acquisition of infection in childhood which accounts for half the ocular disease due to toxoplasma infection in children in the UK and Ireland.

Association between congenital toxoplasmosis and parent-reported developmental outcomes, concerns, and impairments, in 3 year old children

BackgroundInformation is lacking on the effects of congenital toxoplasmosis on development, behavior, and impairment in later childhood, as well as on parental concerns and anxiety. This information is important for counselling parents about the prognosis for an infected child and for policy decisions on screening.MethodsWe prospectively studied a cohort of children identified by screening for toxoplasmosis in pregnant women or neonates between 1996 and 2000 in ten European centers. At 3 years of age, parents of children with and without congenital toxoplasmosis were surveyed about their childs development, behavior, and impairment, and about parental concerns and anxiety, using a postal questionnaire.ResultsParents of 178/223 (80%) infected, and 527/821 (64%) uninfected children responded. We found no evidence that impaired development or behavior were more common in infected children, or that any potential effect of congenital toxoplasmosis was masked by prenatal treatment. Parents of infected children were significantly more anxious and reported more visual problems in their children.ConclusionOn average, children aged three to four years with congenital toxoplasmosis identified by screening and treated during infancy in this European setting had risks of abnormal development and behavior similar to uninfected children. Parental anxiety about infected children needs to be addressed by clinicians. Future studies with longer follow up and clinician-administered assessments may be better able to detect any subtle differences in child outcomes.

Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis

BackgroundWe aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres.MethodsProspective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks.ResultsThe questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres.ConclusionDifferences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies.