Objective
Maternal toxoplasmosis infection acquired during pregnancy carries significant risk of fetal damage. We aimed to assess the long-term outcome of children and young adults with congenital toxoplasmosis diagnosed and treated in utero.
Study Design
This was a 20 year prospective study (1985-2005). All mothers received spiramycin, alone or associated with pyrimethamine-sulfadoxine, and underwent amniocentesis and monthly ultrasound screening. Infected children were followed every 3-6 months.
Results
Of 666 liveborn children (676 mothers), 112 (17%) had congenital toxoplasmosis. Among these, 107 were followed up for 12-250 months: 79 were asymptomatic (74%) and 28 had chorioretinitis (26%). Only 1 child had a serious neurological involvement.
Conclusion
The percentage of chorioretinitis in treated children depends on length of follow-up, but this complication occurs mainly before the age of 5 years and almost always before the age of 10 years. Visual impairment was infrequently severe, and outcome appears consistently good. Long-term follow-up is recommended to monitor ocular and neurological prognosis, whatever the practical difficulties.
Congenital toxoplasmosis is particularly important during 2 periods of pregnancy. First, early (first trimester) maternal toxoplasmosis infection affects pregnancy in less than 5% of cases, but may cause severe fetoplacental infections that generally lead to a miscarriage or, in a few continuing pregnancies, to major fetal lesions, mainly of the central nervous system (CNS). Second, later maternal infection is associated with progressively increasing incidence and decreasing severity of congenital toxoplasmosis.
For Editors’ Commentary, see Table of Contents
See Journal Club article, page 597
The incidence of congenital toxoplasmosis rises to 60-80% in late pregnancy with fetal lesions that mainly consist of toxoplasmic chorioretinitis. These lesions may also appear later during childhood or early adulthood and occasionally jeopardize visual function.
Fetal damage caused by toxoplasmosis is detectable by ultrasound screening only when severe CNS anomalies are present, and termination of pregnancy is then proposed. However, toxoplasmic chorioretinitis, which occurs mainly after late maternal infection, is commonly isolated and thus not accessible to prenatal diagnosis. The diagnosis of toxoplasmic chorioretinitis can be established only by ocular fundus examinations, which are carried out at birth and regularly throughout the postnatal follow-up period.
We present the long-term outcome of children with toxoplasmosis infection acquired in utero. Long-term follow-up is very difficult to achieve, but is indispensable to assess the true prognosis of congenital toxoplasmosis detected prenatally and treated pre- and postnatally.
Materials and Methods
Patients and study design
This prospective study was carried out over 20 years, from 1985 to 2005, in the Federation of Obstetric Gynecology (Toulouse, France). All women who presented confirmed seroconversion for Toxoplasma gondii during their pregnancy were included in the study. In France, seronegative patients undergo monthly serological tests throughout their pregnancy. Infection is detected by the appearance of specific G immunoglobulins (IgG) in a previously seronegative patient or by marked elevation of specific IgG in the presence of specific immunoglobulin M (IgM).
All women were followed up by the same practitioner, and as soon as seroconversion was detected they were treated with 9 × 10 6 SI units per day of spiramycin. All patients were immediately referred to our center as soon as toxoplasmosis seroconversion was diagnosed and were treated once it was confirmed.
Ultrasound screening was performed monthly. The visualization of major abnormalities on ultrasound (such as hydrocephalus and severe intrauterine growth restriction) was considered an indication for termination of the pregnancy in the centers following up these patients. In other cases, the patient was referred to our tertiary reference center for specialized management. Amniocentesis was performed 1 month after the presumed time of maternal infection. Sixty milliliters of amniotic fluid was obtained under ultrasound guidance to test for T gondii by polymerase chain reaction (PCR) and mouse inoculation. Two 7 mL samples of amniotic fluid were used for molecular diagnosis and a 20 mL sample for the mouse inoculation. After diagnosis, excess fluid was centrifuged and pellets were stored at –80°C.
Laboratory procedures
After centrifugation of 7 mL of amniotic fluid, deoxyribonucleic acid (DNA) was extracted in duplicate. The initial target for T gondii genomic amplification was the B1 gene repeated approximately 30 times (Genbank accession no. AF179871 ). A newer sequence, repeated 200-300 times, has been used since June 2003 (Genbank accession no. AF146527 ). We initially used conventional PCR and began Southern blotting in 1994, followed by PCR enzyme-linked immunosorbent assay (ELISA; from December 1995 to February 2002), with digoxigenin (DIG) labeling (PCR ELISA DIG labeling and DIG detection; Boehringer Mannheim, Mannheim, Germany).
In February 2002, we switched to real-time PCR on Light-cycler (Roche Molecular Biochemicals, Roche Diagnostics, Meylan, France). Uracil-DNA-glycosylase was used as soon as the PCR was completed to prevent contamination from previous reactions. Female Swiss Webster mice were inoculated.
Before 1994, fetal blood as well as amniotic fluid was sampled because PCR techniques were not yet routinely available. These samples were used to test for specific IgM, culture on human fibroblasts, and mouse inoculations. When the results were positive, confirming fetal infection by the parasite, the patient was treated as soon as possible and until term with pyrimethamine-sulfadoxine and folinic acid.
Not all our patients received treatment with pyrimethamine-sulfadoxine for several reasons: Before 1989, in France this combination was not authorized during pregnancy, some patients did not accept treatment with this combination, and patients in whom fetal infection was not confirmed by antenatal testing continued to receive spiramycin alone.
At birth, the newborns routinely had a full clinical examination, transfontanellar ultrasound, ocular fundus examination, and serological and parasitological tests. The placenta and cord blood also underwent serological and parasitological study. Clinical and serological follow-up of the children continued for 12-18 months. Congenital toxoplasmosis was confirmed if specific antibodies were still present after the age of 18 months. However, for the children of mothers whose antenatal diagnosis was positive, we included the newborns who were followed up for 12 months only without waiting for possible disappearance of their antibodies at 18 months because we were certain of their infection.
Children with a negative prenatal diagnosis, who very probably were not infected, received clinical and ophthalmological follow-up every 3 months until the disappearance of their antibodies. Children whose prenatal diagnosis had shown infection received clinical and ophthalmological follow-up monthly for the first year, every 2 months for the second year, and every 3 months for the third year. After this time, follow-up was at the discretion of the physicians, who usually saw the children every 3-6 months according to the evolution of the antibodies and the development or otherwise of chorioretinitis.
Prenatal treatment
Once their seroconversion was known, all mothers were treated with 9 × 10 6 SI units per day of spiramycin. For those mothers whose antenatal diagnosis was positive, this treatment was immediately replaced by pyrimethamine 50 mg per week and sulfadoxine 1000 mg per week, to which folinic acid 50 mg per week was added.
Postnatal treatment
Newborns with a negative prenatal diagnosis were not treated immediately after birth. On the other hand, newborns with a positive prenatal diagnosis were treated immediately after birth with pyrimethamine 6.25 mg and sulfadoxine 125 mg every 15 days until they reached a weight of 10 kg. They were then treated until the age of 2 years with the same treatment combination at a dose of 12.5 and 250 mg, respectively, every 15 days. This treatment was combined with folinic acid 50 mg every 15 days. Because this treatment could induce anemia or leukopenia during the first few months, complete blood counts were performed once a month for the first 6 months, and if the hemoglobin level and the polymorphonuclear leukocyte count were normal, the blood count was repeated once every 2 months until the age of 2 years.
All the children, with and without chorioretinitis, were followed up regularly, and their psychomotor development was monitored, specifically their language acquisition, academic retardation, growth retardation (height and weight), auditory outcomes, and ocular lesions.
We saw these children regularly and recorded at each visit the onset of abnormalities related to toxoplasmosis according to their age. Their management did not change during the follow-up period.
Statistical analysis
Statistical analysis was conducted with Statview version 5.0 software (SAS Institute Inc, Cary, NC). Data are presented as percentages, ratios, or means ± SD. Comparisons used the χ 2 test. P < .05 was considered to be statistically significant.
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