Congenital toxoplasmosis

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 thousand non-immune pregnant women may acquire toxoplasma infection, with a 10–100% 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? What are the effects of treating toxoplasmosis in neonates exposed to toxoplasmosis prenatally? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2007 (BMJ 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 four 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, antiparasitic drugs in neonates. over time. The risk of primary infection is highest in young people, including young women during found no cohort studies describing annual seroconversion rates in women of of


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 nor 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 2.4-16/1000 in Europe and from 2-6/1000 in the USA. [1] France began screening for congenital toxoplasmosis in 1978, and during the period 1980-1995 the seroconversion rate during pregnancy in non-immune women was 4-5/1000. [2]

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 1983-1996 found no population-based prospective studies of the natural history of toxoplasma infection during pregnancy. [1] 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 10-100%. [3] We found two European studies that correlated gestation at time of maternal seroconversion with risk of transmission and severity of disease at birth. [4] [5] Risk of transmission increased with gestational age at maternal seroconversion, reaching 70-90% when seroconversion occurred after 30 weeks' gestation. In 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. [5] 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%). [6]

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 spontaneous abortion, fetal infection, and overt neonatal disease (neurological and visual impairment); serological positivity in the newborn; adverse effects of treatment. Additional searches were carreid out using these websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study-design criteria for inclusion in this review were: published systematic reviews (including RCTs and observational studies) and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 5 ).

Incidence of infection
Compared with no treatment We don't know whether treating infected mothers with spiramycin, pyrimethamine-sulphonamides, or a combination of these antiparasitics is more effective at reducing the incidence of fetal infection (very low-quality evidence).

Congenital toxoplasmosis Infectious diseases
Benefits: Antiparasitic drugs versus no treatment: We found three systematic reviews and one study of case series on antiparasitic treatment compared with no treatment. [3] [7] [8] [9] The first review (search date 1997) found no RCTs. [3] It identified nine small cohort studies comparing treatments (spiramycin alone, pyrimethamine-sulphonamides, or a combination of the two treatments) versus no treatment. [7] Five of the studies identified by the review found that treating mothers significantly reduced fetal infection rates compared with no treatment (P less than 0.01), and the other four found no significant reduction in fetal infection. The second review (search date 1997) had stricter inclusion criteria and identified no RCTs or observational studies of significant quality. [7] The third review (search date 2005) found no RCTs. [8] The review identified 26 observational cohorts (1438 mothers identified by prenatal screening) comparing spiramycin, pyrimethamine-sulfadiazine alone, or in combination with no treatment, during pregnancy. The review found that mothers treated within 3 weeks of seroconversion were significantly less likely to transmit the infection to their children compared with mothers who started treatment after 8 or more weeks (OR; 0.48, 95% CI 0.28 to 0.80; P = 0.05).The study of case series of women treated with spiramycin or spiramycin plus pyrimethamine-sulphonamide found no evidence of a difference in outcomes (fetal infection, overt neonatal disease). [9] Comparing data from these studies was difficult owing to different followup periods.

Harms:
Spiramycin and pyrimethamine-sulphonamides are reportedly well tolerated and non-teratogenic. [10] Sulpha drugs are known to carry a risk of kernicterus in the newborn, and should be avoided if possible in the third trimester; there is also a risk of bone marrow suppression, which can be reduced through concomitant use of folic acid. [10] Comment: We found that the quality of evidence was poor. Studies included in the second systematic review were small and did not account for differences in gestation. Only two studies provided information about the control group, and congenital infection was common in the treatment groups. [3] One decision analysis on screening and treatment for intrauterine toxoplasma infection has suggested that treatment may save the pregnancy without preventing infection in the neonate. [11] This may lead to an increase in congenital disease. Drug regimens of co-trimoxazole (trimethoprim plus sulfamethoxazole), atovaquone, or fluoroquinolones, which are either used or being tested for secondary prophylaxis of toxoplasmosis in immunocompromised people (particularly those with HIV infection), have not been studied in pregnancy because their reproductive toxicity has not been properly documented. Finally, optimal duration of follow-up is not established, although the longer the children are observed the higher the incidence of sequelae.
QUESTION What are the effects of treating toxoplasmosis in neonates exposed to toxoplasmosis prenatally? We found no direct information about antiparasitic drugs for the treatment of congenital toxoplasmosis in newborns. There is consensus that infected infants should be treated with pyrimethamine and sulfadiazine for 6-12 months.

OPTION
For GRADE evaluation of interventions for congenital toxoplasmosis, see table, p 5 .

Benefits:
Antiparasitic drugs versus no treatment: We found no systematic review or RCTs assessing antiparasitic drugs for treating toxoplasmosis in neonates.

Harms:
Antiparasitic drugs versus no treatment: We found no RCTs.

Comment: Clinical guide:
We found a lack of quality evidence on treatment of neonates diagnosed with congenital toxoplasmsosis. Current recommendations are based on clinical experience rather than evidence. There is consensus that infected infants should be treated with pyrimethamine and sulfadiazine for 6 to 12 months. [12] GLOSSARY Kernicterus Cerebral toxicity caused by high levels of bilirubin in the neonate is known as kernicterus. Clinical effects include vomiting, lethargy, fever, and fits. Very low-quality evidence Any estimate of effect is very uncertain.

SUBSTANTIVE CHANGES
Antiparasitic drugs in neonates New option for which we identified no systematic review or RCTs. Categorised as Unknown effectiveness.