Elsevier

The Lancet

Volume 369, Issue 9556, 13–19 January 2007, Pages 115-122
The Lancet

Articles
Effectiveness of prenatal treatment for congenital toxoplasmosis: a meta-analysis of individual patients' data

https://doi.org/10.1016/S0140-6736(07)60072-5Get rights and content

Summary

Background

Despite three decades of prenatal screening for congenital toxoplasmosis in some European countries, uncertainty remains about the effectiveness of prenatal treatment.

Methods

We did a systematic review of cohort studies based on universal screening for congenital toxoplasmosis. We did a meta-analysis using individual patients' data to assess the effect of timing and type of prenatal treatment on mother-to-child transmission of infection and clinical manifestations before age 1 year. Analyses were adjusted for gestational age at maternal seroconversion and other covariates.

Findings

We included 26 cohorts in the review. In 1438 treated mothers identified by prenatal screening, we found weak evidence that treatment started within 3 weeks of seroconversion reduced mother-to-child transmission compared with treatment started after 8 or more weeks (adjusted odds ratio [OR] 0·48, 95% CI 0·28–0·80; p=0·05). In 550 infected liveborn infants identified by prenatal or neonatal screening, we found no evidence that prenatal treatment significantly reduced the risk of clinical manifestations (adjusted OR for treated vs not treated 1·11, 95% CI 0·61–2·02). Increasing gestational age at seroconversion was strongly associated with increased risk of mother-to-child transmission (OR 1·15, 95% CI 1·12–1·17) and decreased risk of intracranial lesions (0·91, 0·87–0·95), but not with eye lesions (0·97, 0·93–1·00).

Interpretation

We found weak evidence for an association between early treatment and reduced risk of congenital toxoplasmosis. Further evidence from observational studies is unlikely to change these results and would not distinguish whether the association is due to treatment or to biases caused by confounding. Only a large randomised controlled clinical trial would provide clinicians and patients with valid evidence of the potential benefit of prenatal treatment.

Introduction

Toxoplasma gondii is a common parasitic infection acquired by ingestion of oocysts excreted by cats and contaminating soil or water, or by eating tissue cysts that remain viable in undercooked meat of infected animals.1, 2 Mother-to-child transmission of the parasite occurs only when infection is acquired for the first time during pregnancy. The risk of transmission rises steeply with gestational age at maternal infection.3 Overall, about a third of infected mothers give birth to an infant with toxoplasmosis.3, 4 Most children with congenital toxoplasmosis are developmentally normal5 but up to 4% die or have evidence of permanent neurological damage or bilateral visual impairment during the first years of life.6, 7

Toxoplasma infection in pregnancy is usually asymptomatic and can only be detected by serological testing. Prenatal testing for toxoplasmosis is routinely offered in many European countries so that infected mothers can be treated with antibiotics to reduce the risk of mother-to-child transmission and, if fetal infection has occurred, to reduce impairment in the child.8 No consensus exists about the most effective screening strategy or the best type of treatment. Uncertainty about the benefits of prenatal treatment9 and concerns about adverse treatment effects and the infrastructure and costs needed to implement prenatal screening have led to diverse policies including no screening, neonatal screening6, 10, 11 and prenatal screening with monthly or 3-monthly re-testing schedules.4, 8, 12, 13 In countries where prenatal screening is done, recommendations for treatment can differ. In most centres, including those in France, spiramycin is prescribed immediately after diagnosis of maternal infection and changed to a pyrimethamine-sulphonamide combination if fetal infection is diagnosed or if infection is acquired in late pregnancy.4 By contrast, in Austria, mothers are initially treated with pyrimethamine-sulphonamide (after 15 weeks of gestation), and changed to spiramycin if fetal diagnosis is negative.4

So far, two systematic reviews have evaluated the effect of prenatal treatment on mother-to-child transmission.9, 14 No randomised controlled trials were found and we know of no subsequent trial. Meta-analysis of the effect of prenatal treatment was not possible in these reviews because of differences between studies in analytical methods and the way aggregate data were presented. However, new observational data have been published since then: three analyses of retrospective cohort studies12, 13, 15, 16 and the results of a large prospective multicentre cohort study.4, 7 None of these studies reported a significant effect of treatment on mother-to-child transmission but none could exclude clinically important effects. The findings for the effect of prenatal treatment on the risk of clinical manifestations of congenital toxoplasmosis (intracranial and ocular lesions) have been inconsistent.7, 12, 13, 16

Our aim was to estimate the effects of timing and different types of prenatal treatment on the risk of congenital toxoplasmosis and its clinical manifestations during infancy, with a systematic review using individual patients' data to undertake a meta-analysis.

Section snippets

Study selection

Any cohort study of women identified during pregnancy by universal screening for T gondii infection was eligible for inclusion if the following data had been recorded. For the analysis of mother-to-child transmission: sample dates for the last negative and first positive specific antibody tests; date prenatal treatment was started; date of birth or last menstrual period; and congenital infection status on the basis of specific antibody tests beyond 11 months postnatal age. Exact dates for

Results

We found no randomised controlled trials in our search. 26 observational cohorts were included in the review, including a total of 1745 infected mothers and 691 infected liveborn infants. Three cohorts from the same study12 had relevant data but the investigators declined to participate (96 mothers, 43 infected infants). Investigators for four further studies,23, 24, 25, 26 accounting for 288 mothers and 49 infected infants, did not respond (figure 1). Studies of prenatal screening varied from

Discussion

We found weak evidence for an increased risk of mother-to-child transmission the later prenatal treatment was started after maternal seroconversion. This result might be due to a true protective effect of early treatment, or to confounding caused by selective treatment of mothers at high risk of fetal infection whose infection was diagnosed late—ie, outside the standard monthly or 3-monthly re-testing schedule. We found no evidence that prenatal treatment significantly reduced the risk of

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