Abstract. – Objectives:Congenital toxo-plasmosis is a particular manifestation of Toxo-plasma gondii infection, which may present as a mild or severe neonatal disease. This pathology remains a difficult challenge in terms of therapy for the pediatrician and gynecologist. In this arti-cle we have set ourselves the objective to pro-vide an overview of the main aspects of the dis-ease, with particular attention to the treatment, based on the information in the literature.
Results: Two kinds of treatment are currently available: prenatal and postnatal. When pregnant women seroconvert, spiramycin is administered in order to prevent the mother-to-child transmis-sion. When the fetal infection is confirmed the as-sociation of pyrimethamine and sulfadiazine is prescribed. After birth the specific therapy is based on the administration of pyrimethamine and sulfadiazine. However, to date, there is not strong evidence on the effectiveness of treat-ment, whether prenatal or postnatal.
Conclusions: The studies undertaken so far have not given satisfactory answers. Double-blind randomized controlled trials would be re-quired, but for obvious ethical reasons they can-not be achieved.
Congenital toxoplasmosis, Pyrimethamine, Sulfadi-azine, Spiramycine, Randomized controlled trial.
Toxoplasmosis is an important zoonotic para-sitic disease worldwide. Toxoplasma gondii (T. gondii) is a coccidian protozoan that multiplies only in living cells. Its life cycle includes sexual reproduction in the definitive host, the cat, and asexual division in intermediate hosts which in-clude man, birds and rodents1.
The human infection may be acquired by inges-tion of oocysts excreted by cats and contaminating soil or water, or by eating tissue cysts that remain viable in undercooked meat of infected animals2,3 and it may generate devastating damage in fetuses, newborns and immunocompromised patients.
Congenital toxoplasmosis treatment
D. SERRANTI, D. BUONSENSO, P. VALENTINI
Department of Pediatrics, Catholic University of the Sacred Heart, Rome (Italy)
Most human infections with this protozoon are asymptomatic, although a minority may present malaise, low grade fever and lymphadenopathy. The immunocompromised patient can face a se-vere, life-threatening infection.
Mother-to-child transmission of the parasite occurs only when infection is acquired for the first time during pregnancy. Infection may be transmitted to the fetus transplacentally or during vaginal delivery.
Congenital toxoplasmosis (CT) may present as a mild or severe neonatal disease. There is a wide variety of manifestations of congenital infection, ranging from fetal hydrops and perinatal death to small size for gestational age, prematurity, periph-eral retinal scars, persistent jaundice, mild throm-bocytopenia, cerebro-spinal fluid (CSF) pleocyto-sis, and the characteristic triad of chorioretinitis, hydrocephalus, and cerebral calcifications. Reti-nal disease, which may be unilateral, follows a re-lapsing and remitting course into adult life, often with severe impairment of vision4.
There are considerable geographic differences in prevalence rates. In Europe the prevalence of infec-tion is higher in France (54.3%)5than elsewhere in the continent (46%), probably attributed to a pref-erence for consumption of undercooked meat6.
One recent French study, based on serology data collected during national perinatal surveys conducted between 1995 and 2003 to estimate toxoplasmosis prevalence, indicates that although it decreased over time, toxoplasmosis prevalence remained higher than 43.8%7.
Cultural habits regarding food are probably the major cause of the differences in frequency of T. gondiiinfection from one country to another, from one region to another in the same country, and from one ethnic group to another in the same region.
The mother-to-child transmission rates rise from 7% in the first trimester, to 24% in the sec-ond, to 59% in the third, while the incidence of severe fetal infection falls from 75% to a negligi-ble risk in late pregnancy8,9.
IgG – IgM – Seronegative patient
IgG + (< 200 UI) IgM – Previous infection
IgG + IgM + IgA + IgG avidity < 15% Acute infection
IgG + (> 300 UI) IgM + IgA – Probably recent infection
IgG + (< 300 UI) IgM + IgA – IgM chronic carrier
IgG + (> 300 UI) IgM – IgA – IgG avidity > 30% Probably reinfection
IgG – IgM + IgA – Natural IgM
Table I.Criteria for evaluation of maternal serology.
These are the criteria for the serological evaluation and diagnosis of primary maternal infection during pregnancy, proposed by the European Research Network on Congenital Toxoplasmosis, based on probability of infection.
Where maternal toxoplasmosis is suspected, appropriate assays for testing maternal serum samples include the latex agglutination test or the direct agglutination test followed by referral, where indicated, to a reference laboratory for the dye test, indirect haemagglutination test, ELISA for IgG and IgM, the immunosorbent agglutina-tion assay (ISAGA) for IgM and IgA, the en-zyme-linked immunofiltration assay (ELIFA) or immunoblotting (IB) for the detection of IgG or IgM. A positive result requires that a repeated maternal serum sample be requested to confirm identification and results of the previous sample.
For the serological evaluation and diagnosis of primary maternal infection during pregnancy we can use the “case definition”, proposed by the Eu-ropean Research Network on Congenital Toxoplas-mosis,based on probability of infection (Table I)10.
Other useful diagnostic tools to determine the infection of the fetus are the polymerase chain reaction (PCR) and ultrasound. The amplification of T. gondii DNA in amniotic fluid should be done at 18 weeks of gestation or later. If done at the 18th week, this test has an overall sensitivity of 64%, a negative predictive value of 88%, and a specificity and positive predictive value of 100%11. Its sensitivity and specificity for amniot-ic fluid obtained before 18 weeks of gestation have not been studied. In addition, the procedure done early in gestation is associated with a high-er risk to the fetus and is likely less useful.
Concerning the ultrasound, this procedure is rec-ommended for women with suspected or diag-nosed acute infection acquired during or shortly before gestation. It may reveal the presence of fetal abnormalities, including hydrocephalus, brain or hepatic calcifications, splenomegaly, and ascites.
After the birth, diagnosis of CT in the postna-tal period is problematic. Current assays often fail to detect IgM in the neonatal serum and pas-sively acquired IgG makes interpretation of
rou-tine serology difficult. Following identification of a toxoplasma-positive serum in the primary labo-ratory, that serum and antenatal booking and cur-rent sera from the mother should be investigated at one of the reference laboratories. When mater-nal infection cannot be excluded, serial serum specimens from the infant should be tested until toxoplasma antibodies disappear.
To treat CT two types of regimen are avail-able: prenatal and postnatal. The first is aimed at preventing the infection of the fetus and, in case of documented infection, hasten the treatment before birth, while the second is designed to treat the infection and to prevent the sequelae.
With the advent of prenatal diagnosis, attempts are being made to treat the infection during the gestational period. The aim of this approach is to decrease the risk of mother-to-child transmission of the infection and possibly anticipate its treat-ment before birth.
The key drugs which are administered are: Spiramycin – a macrolide antibiotic, with an an-tibacterial spectrum comparable to that of ery-thromycin; Pyrimethamine – a substituted phenylpyrimidine antimalarial drug; and Sulfadi-azine – a sulfonamide antibiotic.
Once it has been established that the mother’s serological test results are consistent with a re-cently acquired infection and that acquisition of the infection during the first 18 weeks of gesta-tion or shortly before concepgesta-tion cannot be ex-cluded, a treatment with spiramycin should be administered in order to prevent vertical trans-mission of the parasite.
If fetal infection is confirmed by a positive re-sult of PCR on amniotic fluid at 18 weeks of ges-tation or later, treatment with pyrimethamine, sul-fadiazine, and folinic acid is recommended12.
Af-Medication Dosage Duration of therapy Pregnant woman with Spiramycin 1 g (3 million U) every 8 h Spiramycin treatment should
suspected or documented (for a total of 3 g or 9 million be continued until delivery in infection (< 18th week U per day) women with low suspicion
of gestation) of fetal infection or those
with documented negative results of amniotic fluid PCR and negative findings on ultrasounds at follow-up Pregnant women with Pyrimethamine Loading dose: 100 mg per Until birth
confirmed infection day in two divided doses for (>18th week of gestation) 2 days, then 50 mg per day
Sulfadiazine Loading dose: 75 mg/kg per Until birth day in two divided doses
(maximum 4 g per day) for 2 days, then 100 mg/kg per day in two divided doses (maximum 4 g per day)
Leucovorin 10-20 mg daily During and for 1 wk after pyrimethamine therapy Table II.Guidelines for treatment of T. gondiiinfection in the pregnant women.
Medication Dosage Duration of therapy
Pyrimethamine Loading dose: 2 mg/kg per day for 2 days, 1 year then 1 mg/kg per day for 2 or 6 month,
then this dose every Monday, Wednesday, Friday.
Sulfadiazinne 100 mg/kg per day in two divided doses. 1 year
Leucovorin 10 mg three times weekly During and for 1 wk after pyrimethamine therapy Table III.Guidelines for treatment of CT in the infant.
The table is adapted from information appearing in: Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med 1988; 31: 271-275.
The table is adapted from information appearing in: Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med 1988; 31: 271-275.
ter the eighteenth week of gestation, it’s necessary to administer the combination pyrimethamine-sul-fadiazine immediately, because the rate of mother-to-child transmission is so high as to render unuse-ful the use of spiramycin (Table II).
Obviously it’s important to take account of pos-sible side effects of pyrimethamine. It inhibits the dihydrofolate reductase, which is important in the synthesis of folic acid, thus producing reversible and usually gradual bone marrow depression.
In fact, during this period of drugs administra-tion, the mother is carefully monitored for devel-opment of hematologic toxicity. If significant toxicity appears, despite treatment with folinic acid, the drug combination is discontinued until the hematologic abnormalities are corrected and the drug regimen is then restarted.
Although this treatment is in use for a long time and many studies have been conducted over the years, our knowledge on its efficacy is not entirely clear. Concerning spiramycin, the results of obser-vational studies showed the potential of this antibi-otic to prevent vertical transmission of the para-site13,14. Moreover, it may reduce the severity of in-fection in a fetus because it delays transmission to a later time in gestation, when transmission is asso-ciated with less severe manifestations of infection.
Instead, the combination of pyrimethamine and sulfadiazine is highly active against T. gondiiand is widely used as a treatment to reduce the risk of clinical manifestation in infected children15.
Currently the debate about the effectiveness of this treatment is becoming more heated. Many stud-ies have set themselves the goal of finding strong
every case of CT, symptomatic or not, even though there are no sufficient data to evaluate properly treatment in the asymptomatic infected infant. That treatment of such infants should be undertaken with the aim of preventing the late untoward sequelae.
Another important consideration is that the agents which can be recommended for specific therapy at present are beneficial against the tachyzoite form, but none has been shown to ef-fectively eradicate the encysted form, especially from Central Nervous System and from eye.
The specific postnatal therapy is based on the same two drugs also essential in the prenatal: pyrimethamine and sulfadiazine.
The simultaneous use of both drugs is 8-fold more active than either pyrimethamine or sulfadi-azine alone, and has been the “gold standard” to which other antimicrobial agents, alone and in combination, have been compared22.
This regimen, described more accurately in the Table III, has been associated with resolution of signs of active CT, usually within the first weeks after initiation of therapy23. We must, however, keep in mind the pyrimethamine toxic effects, which had already talked about. This is why all patients treated with this drug should have a pe-ripheral blood cell and platelet count twice each week and moreover folinic acid (in the form of leucovorin calcium) administration, as described in Table III.
Two recent studies have been published to support this type of treatment. The first evaluated the outcomes of treatment in 120 infants with CT between 1981 and 2004. It affirmed that treat-ment of infants without substantial neurologic disease at birth with pyrimethamine and sulfadi-azine for 1 year resulted in normal cognitive, neurologic, and auditory outcomes for all pa-tients. Treatment of infants who had moderate or severe neurologic disease at birth resulted in nor-mal neurologic and cognitive outcomes for >72% of the patients, and none had sensorineural hear-ing loss. 91% percent of children without sub-stantial neurologic disease and 64% of those with moderate or severe neurologic disease at birth did not develop new eye lesions. So it seems clear in this study24that almost all of these out-comes are markedly better than outout-comes report-ed for children who were untreatreport-ed or treatreport-ed for 1 month in earlier decades.
Similar results have been obtained in a prospec-tive longitudinal observation of a cohort of 132 children, treated during their first year of life with evidence that could solve this gordian knot.
Proba-bly, the most comprehensive overview of the com-plex situation, we are talking about, is provided by the work of SYROCOT study group in 200716. It’s a systematic review and individual data meta-analysis of 20 European cohort studies, in which universal screening for toxoplasmosis in pregnancy was per-formed. In 1438 treated mothers identified by pre-natal screening, the European researchers 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. In 550 infected liveborn infants identified by prenatal or neonatal screening, they found no evidence that prenatal treatment signifi-cantly reduced the risk of clinical manifestations. Moreover, they found weak evidence for an associ-ation between early treatment and reduced risk of CT. Analyzing the data from this study it is obvious that there is a need to change the way of approach to evaluating the effectiveness of treatment. Indeed, the evidence obtained from observational studies is not suitable to make this kind of assessment.
Moreover, the lack of appropriate knowledge and clear data, has led to consider other drugs as possible candidates for prenatal treatment. Indeed, we must not forget that spiramycin is unable to eradicate existing fetal infection and administration of the combination pyrimethamine-sulfadiazine is not without risks (potential toxicity and terato-genicity). In fact an ideal drug would show an effi-cient penetration and concentration in the placenta, should be effective against different stages of the parasite and not having any kind of fetal toxicity.
Examples include atovaquone or fluoro-quinolones that have shown activity against T. gondii in vivo and in vitro, but that cannot be used during pregnancy because the potential harmful effects on the embryo and fetus have not been well evaluated17,18.
Others are azithromycin, that showed to be capa-ble to inhibit the vertical transmission of T. gondii in mice model of CT19, or thiolactomycin analogues that demonstrated anti-T. gondii in vitroactivity20.
Finally we must emphasize that encouraging results were observed using spiramycin-cotri-moxazole association, primarily for its safety and also because it showed effects on reducing the mother-to-child transmission rate and on prevent-ing the risk of clinical sequelae21.
Concerning the postnatal treatment, it’s rec-ommended to administer specific therapy in
It was also impossible to perform therapeutic maneuvers to change the survival of the patient (hospitalization in intensive care units or shunt procedures), as the current ones. Then, only well-conducted randomized trials evaluating new treatment regimens or strategies will allow a col-lection of data which could be more significant. The potential for bias and unmeasured confound-ing factors in cohort studies, coupled with the moderate treatment effects expected, limits the value of information from observational studies. Confounding factors can only be avoided by ran-domization and biases can only be avoided by high quality, standardized procedures31. The ideal approach would be double-blind randomized controlled trials.
However, it’s realistically impossible to achieve this kind of studies for obvious ethical reasons. It would be unlikely that a mother aware of current treatment, even if of dubious effectiveness, could accept the risk of receiving a placebo or not being treated.
Thus, although methodologically not correct, comparison with historical data of CT studies in pre-treatment era, remains the only option that can be followed.
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pyrimethamine, sulfadiazine and leucovorin, and evaluated for chorioretinal involvement25.
Although, as the prenatal, concerning the post-natal treatment, it was developed many years ago and the studies to determine its effectiveness can-not yet give us satisfactory answers. The debate is still open on which drugs are the best, what kind of regimen should be adopted, and finally what the ideal duration of treatment should be. This be-comes evident if we observe the different regimens adopted by the various centers of CT treatment. The main cause of this situation is the lack of ade-quate evidence. In fact, studies conducted until now have several limitations: first, the comparison with historical studies, rather than appropriate con-trol groups. This limits their validity.
So, the general opinion is that children born with symptomatic T. gondiiinfection should be treated, but the benefit of treatment in children without symptoms at birth is presently under intense discus-sion, because there is a lack of evidence.
Moreover, opinions regarding postnatal treat-ment vary considerably in terms of drugs and regimens.
New drugs suitable for treatment of CT have been studied, although there are still insufficient data enabling usage.
The most promising drug in the treatment of T. gondii is atovaquone, already proposed for toxo-plasmosis during pregnancy, which has potent in vitro activity against the tachizoite and the cyst forms26,27. Other studies about atovaquone in animal models have also reported significantly increased survival and reduction in brain cyst burden28,29.
The same can be said for azithromycin, that has also been found to have a partial effect on T. gondiitissue cysts30.
After having completed this overview on treat-ment of CT, in agreetreat-ment with other Authors, many questions are still to be solved, regarding the management of patients (both for mother and child) and the choice of a specific therapy.
Available studies are either observational stud-ies of groups of referred patients or observational studies with historical controls accrued over many years, often decades. In fact we have to keep in mind that in the past, diagnosis of disease and patient care were different: for example, pre-natal diagnosis or ultrasound were not available.
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