Abstract
Introduction
Infection with Toxoplasma gondii is asymptomatic or mild in immunocompetent people and leads to lifelong immunity, but it can have serious consequences in pregnancy. About five per 1000 non-immune pregnant women may acquire toxoplasma infection, with a 10% to 100% risk of transmission to the baby. Risks of transmission to the baby are higher later in pregnancy, but risks of infection causing harm to the baby are greater earlier in pregnancy.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects on mother and baby of treating toxoplasmosis during pregnancy to reduce risk of vertical transmission and treat fetal infection? What are the effects of treating toxoplasmosis in neonates infected with toxoplasmosis prenatally? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found six systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiparasitic drugs in pregnancy, and antiparasitic drugs in neonates.
Key Points
Infection with Toxoplasma gondii is asymptomatic or mild in immunocompetent people, and leads to lifelong immunity, but it can have serious consequences in pregnancy.
About five per 1000 non-immune pregnant women may acquire toxoplasma infection, with a 10% to 100% risk of transmission to the baby.
Infection is usually acquired from undercooked meat, or from fruit and vegetables contaminated with cat faeces.
Fetal infection can cause eye and brain damage, growth retardation, and intrauterine death.
Risks of transmission to the baby are higher later in pregnancy, but risks of infection causing harm to the baby are greater earlier in pregnancy.
Children with subclinical infection at birth may have cognitive, motor, or visual defects that may be difficult to diagnose in early childhood.
We don't know whether treating infected pregnant women with spiramycin, pyrimethamine–sulfonamides, or both reduces the risk of fetal infection, as the few trials we found have produced conflicting results.
It is possible that treatment of infection in pregnancy may save the pregnancy without preventing infection, which could increase the prevalence of congenital disease.
We don't know whether antiparasitic drugs given to neonates who have been infected prenatally are effective, although there is consensus that infected infants should be treated with pyrimethamine and sulfadiazine for 6 to 12 months.
About this condition
Definition
Toxoplasmosis is caused by the parasite Toxoplasma gondii. Infection is asymptomatic or unremarkable in immunocompetent individuals, but leads to a lifelong antibody response. During pregnancy, toxoplasmosis can be transmitted across the placenta and may cause intrauterine death, neonatal growth retardation, mental retardation, ocular defects, and blindness in later life. Congenital toxoplasmosis (confirmed infection of the fetus or newborn) can also present at birth: either as subclinical disease, which may evolve with neurological or ophthalmological disease later in life, or as a disease of varying severity, ranging from mild ocular damage to severe mental retardation.
Incidence/ Prevalence
Reported rates of toxoplasma seroprevalence vary among and within countries, as well as over time. The risk of primary infection is highest in young people, including young women during pregnancy. We found no cohort studies describing annual seroconversion rates in women of childbearing age or incidence of primary infection. One systematic review (search date 1996) identified 15 studies that reported rates of seroconversion in non-immune pregnant women ranging from 2.4/1000 to 16/1000 in Europe and from 2/1000 to 6/1000 in the US. France began screening for congenital toxoplasmosis in 1978; during the period from 1980 to 1995, the seroconversion rate during pregnancy in non-immune women was 4/1000 to 5/1000.
Aetiology/ Risk factors
Toxoplasma infection is usually acquired by ingesting either sporocysts (from unwashed fruit or vegetables contaminated by cat faeces) or tissue cysts (from raw or undercooked meat). The risk of contracting toxoplasma infection varies with eating habits, contact with cats and other pets, and occupational exposure.
Prognosis
One systematic review of studies conducted from 1983 to 1996 found no population-based prospective studies of the natural history of toxoplasma infection during pregnancy. One systematic review (search date 1997; 9 controlled, non-randomised studies) found that untreated toxoplasmosis acquired during pregnancy was associated with infection rates in children of between 10% and 100%. We found two European studies that correlated gestation at time of maternal seroconversion with risk of transmission and severity of disease at birth. Risk of transmission increased with gestational age at maternal seroconversion, reaching 70% to 90% when seroconversion occurred after 30 weeks' gestation. By contrast, the risk of the infant developing clinical disease was highest when maternal seroconversion occurred early in pregnancy. The highest risk of developing early signs of disease (including chorioretinitis and hydrocephaly) was about 10%, recorded when seroconversion occurred between 24 and 30 weeks' gestation. Infants with congenital toxoplasmosis and generalised neurological abnormalities at birth develop mental retardation, growth retardation, blindness or visual defects, seizures, and spasticity. Children with subclinical infection at birth may have cognitive, motor, and visual deficits, which may go undiagnosed for many years. One case control study (845 school children in Brazil) found mental retardation and retinochoroiditis to be significantly associated with positive toxoplasma serology (population-attributable risk 6%–9%).
Aims of intervention
To prevent transmission from mother to child, congenital infection, visual impairment, and neurological impairment in neonates and in later life, with minimum adverse effects.
Outcomes
Incidence of fetal infection (including serological positivity in the newborn); incidence of spontaneous abortion; overt neonatal disease (neurological and visual impairment); adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to June 2013, Embase 1980 to June 2013, and The Cochrane Database of Systematic Reviews, issue 2, 2013 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search run by an information specialist were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and observational studies; and RCTs in any language, which were at least single-blinded, with a minimum of 20 participants. There was no minimum length of follow-up required for included studies, and a maximum of 20% of participants lost to follow-up. We included systematic reviews of RCTs and observational studies, and RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Congenital toxoplasmosis.
| Important outcomes | Incidence of fetal infection, Incidence of spontaneous abortion, Overt neonatal disease (neurological and visual impairment) | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects on mother and baby of treating toxoplasmosis during pregnancy to reduce risk of vertical transmission and treat fetal infection? | |||||||||
| 9 (unclear) | Incidence of fetal infection | Antiparasitic drugs versus no treatment | 2 | –2 | –1 | –1 | 0 | Very low | Quality points deducted for incomplete reporting of results and for poor-quality studies. Consistency point deducted for conflicting results. Directness point deducted for differences in gestation periods |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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