Prenatal treatment for serious neurological sequelae of congenital toxoplasmosis: an observational prospective cohort study.

BACKGROUND: The effectiveness of prenatal treatment to prevent serious neurological sequelae (SNSD) of congenital toxoplasmosis is not known. METHODS AND FINDINGS: Congenital toxoplasmosis was prospectively identified by universal prenatal or neonatal screening in 14 European centres and children were followed for a median of 4 years. We evaluated determinants of postnatal death or SNSD defined by one or more of functional neurological abnormalities, severe bilateral visual impairment, or pregnancy termination for confirmed congenital toxoplasmosis. Two-thirds of the cohort received prenatal treatment (189/293; 65%). 23/293 (8%) fetuses developed SNSD of which nine were pregnancy terminations. Prenatal treatment reduced the risk of SNSD. The odds ratio for prenatal treatment, adjusted for gestational age at maternal seroconversion, was 0.24 (95% Bayesian credible intervals 0.07-0.71). This effect was robust to most sensitivity analyses. The number of infected fetuses needed to be treated to prevent one case of SNSD was three (95% Bayesian credible intervals 2-15) after maternal seroconversion at 10 weeks, and 18 (9-75) at 30 weeks of gestation. Pyrimethamine-sulphonamide treatment did not reduce SNSD compared with spiramycin alone (adjusted odds ratio 0.78, 0.21-2.95). The proportion of live-born infants with intracranial lesions detected postnatally who developed SNSD was 31.0% (17.0%-38.1%). CONCLUSION: The finding that prenatal treatment reduced the risk of SNSD in infected fetuses should be interpreted with caution because of the low number of SNSD cases and uncertainty about the timing of maternal seroconversion. As these are observational data, policy decisions about screening require further evidence from a randomized trial of prenatal screening and from cost-effectiveness analyses that take into account the incidence and prevalence of maternal infection. Please see later in the article for the Editors' Summary.

Recovery of anti-Toxoplasma gondii immunoglobulin M in stored guthrie card blood spots.

Retrospective testing of neonatal Guthrie card blood spots for specific immunoglobulin M (IgM) can distinguish congenital toxoplasmosis from acquired toxoplasmosis. We determined whether storage temperature reduced IgM detection, using filter paper blood samples "spiked" with anti-Toxoplasma IgM. After 300 days, IgM detection deteriorated with storage at room temperature but not at temperatures of 4 degrees C or lower.

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 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.

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 > or = 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.

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 mug, 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.

Inequalities in provision of the Disability Living Allowance for Down syndrome.

OBJECTIVES: To assess factors associated with granting of the Disability Living Allowance (DLA) for Down syndrome. DESIGN: Cross-sectional survey. SETTING: Families with a child with Down syndrome enrolled in a community-based trial of vitamin supplementation. PARTICIPANTS: 156 children with trisomy 21 (59% male, 20% non-white) were enrolled before 7 months of age and 138 completed follow-up. MAIN OUTCOME MEASURES: Before the child was 2 years old, we surveyed parents about applications for the DLA and socioeconomic factors, and assessed the child's development. RESULTS: Application for the DLA was not associated with ethnicity or speaking English. Significantly fewer ethnic minority parents (OR = 0.10; 95% CI 0.03 to 0.35; 69% vs 96%, risk difference 27%) and parents with English as a second language (OR = 0.15: 95% CI 0.04 to 0.62; 67% vs 93%, risk difference 26%) were granted the DLA. Amongst those granted the DLA, ethnic minority families were significantly less likely to be granted a higher monetary award (OR = 0.19; 95% CI 0.06 to 0.55). Severity of disability, reflected by quartile of Griffiths Developmental Quotient or the presence of severe cardiac disease requiring surgery, was not associated with application, granting or level of the DLA award. CONCLUSIONS: Although all children with Down syndrome meet some of the criteria for the DLA, only 80% were receiving this benefit. The decision to award the DLA and the monetary level of the award favoured white, English speaking parents and was not related to severity of disability. Routine monitoring of awards by ethnicity and language spoken is needed. TRIAL REGISTRATION NUMBER: NCT00378456.

Risk of visual impairment in children with congenital toxoplasmic retinochoroiditis.

PURPOSE: Reliable information is needed to counsel parents of children with congenital toxoplasmosis regarding the long-term risk of visual impairment resulting from ocular toxoplasmosis. DESIGN: Prospective cohort study of children with congenital toxoplasmosis identified by prenatal or neonatal screening. METHODS: After three years of age, ophthalmologists reported the site of retinochoroidal lesions and visual acuity and parents reported visual impairment. An ophthalmologist predicted the child's vision based on the last retinal diagram. Selection biases were minimized by prospective enrollment and data collection, high rates of follow-up, and exclusion of referred cases. RESULTS: Two hundred and eighty-one of 284 infected children who underwent ophthalmic examinations were followed up to a median age of 4.8 years. One in six children (49/281; 17%) had at least one retinochoroidal lesion, two-thirds of whom (32/49; 65%) had a lesion at the posterior pole. In children with retinochoroiditis who had visual acuity measured after 3 years of age, 94% (31/33) had normal vision in the best eye (6/12 Snellen or better), as did 91% of those with a posterior pole lesion (21/23). Analyses based on affected eyes showed that 42% (29/69) had a posterior pole lesion, of which just more than half (15/29, 52%) had normal vision, as did 84% (16/19) of eyes with a peripheral lesion alone. Vision predicted by the ophthalmologist was moderately sensitive (59%) but overestimated impairment associated with posterior pole lesions. Of 44 children with information on acuity, four (9%) had bilateral visual impairment worse than 6/12 Snellen. CONCLUSIONS: Severe bilateral impairment occurred in 9% of children with congenital toxoplasmic retinochoroiditis. Half the children with a posterior pole lesion and one in six of those with peripheral lesions alone were visually impaired in the affected eye.

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.

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

BACKGROUND: Information 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. METHODS: We 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 child's development, behavior, and impairment, and about parental concerns and anxiety, using a postal questionnaire. RESULTS: Parents 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. CONCLUSION: On 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.