Download Congenital toxoplasmosis treatment

European Review for Medical and Pharmacological Sciences
2011; 15: 193-198
Congenital toxoplasmosis treatment
D. SERRANTI, D. BUONSENSO, P. VALENTINI
Department of Pediatrics, Catholic University of the Sacred Heart, Rome (Italy)
Abstract. – Objectives: Congenital toxoplasmosis is a particular manifestation of Toxoplasma 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 article we have set ourselves the objective to provide an overview of the main aspects of the disease, 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 transmission. When the fetal infection is confirmed the association 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 treatment, whether prenatal or postnatal.
Conclusions: The studies undertaken so far
have not given satisfactory answers. Doubleblind randomized controlled trials would be required, but for obvious ethical reasons they cannot be achieved.
Key Words:
Congenital toxoplasmosis, Pyrimethamine, Sulfadiazine, Spiramycine, Randomized controlled trial.
Introduction
Toxoplasmosis is an important zoonotic parasitic 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 include man, birds and rodents1.
The human infection may be 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 animals2,3
and it may generate devastating damage in fetuses,
newborns and immunocompromised patients.
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 severe, 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, peripheral retinal scars, persistent jaundice, mild thrombocytopenia, cerebro-spinal fluid (CSF) pleocytosis, and the characteristic triad of chorioretinitis,
hydrocephalus, and cerebral calcifications. Retinal disease, which may be unilateral, follows a relapsing and remitting course into adult life, often
with severe impairment of vision4.
Epidemiology
There are considerable geographic differences in
prevalence rates. In Europe the prevalence of infection is higher in France (54.3%)5 than elsewhere in
the continent (46%), probably attributed to a preference 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.
gondii infection 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 second, to 59% in the third, while the incidence of
severe fetal infection falls from 75% to a negligible risk in late pregnancy8,9.
Corresponding Author: Piero Valentini, MD; e-mail: [email protected]
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D. Serranti, D. Buonsenso, P. Valentini
Diagnosis
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 agglutination assay (ISAGA) for IgM and IgA, the enzyme-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 European Research Network on Congenital Toxoplasmosis, 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 amniotic fluid obtained before 18 weeks of gestation
have not been studied. In addition, the procedure
done early in gestation is associated with a higher risk to the fetus and is likely less useful.
Concerning the ultrasound, this procedure is recommended for women with suspected or diagnosed 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 postnatal period is problematic. Current assays often
fail to detect IgM in the neonatal serum and passively acquired IgG makes interpretation of rou-
tine serology difficult. Following identification of
a toxoplasma-positive serum in the primary laboratory, that serum and antenatal booking and current sera from the mother should be investigated
at one of the reference laboratories. When maternal infection cannot be excluded, serial serum
specimens from the infant should be tested until
toxoplasma antibodies disappear.
Treatment
To treat CT two types of regimen are available: 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.
Prenatal Treatment
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 treatment before birth.
The key drugs which are administered are:
Spiramycin – a macrolide antibiotic, with an antibacterial spectrum comparable to that of erythromycin; Pyrimethamine – a substituted
phenylpyrimidine antimalarial drug; and Sulfadiazine – a sulfonamide antibiotic.
Once it has been established that the mother’s
serological test results are consistent with a recently acquired infection and that acquisition of
the infection during the first 18 weeks of gestation or shortly before conception cannot be excluded, a treatment with spiramycin should be
administered in order to prevent vertical transmission of the parasite.
If fetal infection is confirmed by a positive result of PCR on amniotic fluid at 18 weeks of gestation or later, treatment with pyrimethamine, sulfadiazine, and folinic acid is recommended12. Af-
Table I. Criteria for evaluation of maternal serology.
IgG –
IgG + (< 200 UI)
IgG +
IgG + (> 300 UI)
IgG + (< 300 UI)
IgG + (> 300 UI)
IgG –
IgM –
IgM –
IgM +
IgM +
IgM +
IgM –
IgM +
IgA +
IgA –
IgA –
IgA –
IgA –
IgG avidity < 15%
IgG avidity > 30%
Seronegative patient
Previous infection
Acute infection
Probably recent infection
IgM chronic carrier
Probably reinfection
Natural IgM
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.
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Congenital toxoplasmosis treatment
Table II. Guidelines for treatment of T. gondii infection in the pregnant women.
Medication
Dosage
Pregnant woman with
suspected or documented
infection (< 18th week
of gestation)
Spiramycin
1 g (3 million U) every 8 h
(for a total of 3 g or 9 million
U per day)
Pregnant women with
confirmed infection
(>18th week of gestation)
Pyrimethamine
Loading dose: 100 mg per
day in two divided doses for
2 days, then 50 mg per day
Loading dose: 75 mg/kg per
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)
10-20 mg daily
Sulfadiazine
Leucovorin
Duration of therapy
Spiramycin treatment should
be continued until delivery in
women with low suspicion
of fetal infection or those
with documented negative
results of amniotic fluid
PCR and negative findings
on ultrasounds at follow-up
Until birth
Until birth
During and for 1 wk after
pyrimethamine therapy
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-sulfadiazine immediately, because the rate of motherto-child transmission is so high as to render unuseful the use of spiramycin (Table II).
Obviously it’s important to take account of possible 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 administration, the mother is carefully monitored for development 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 observational studies showed the potential of this antibiotic to prevent vertical transmission of the parasite13,14. Moreover, it may reduce the severity of infection in a fetus because it delays transmission to
a later time in gestation, when transmission is associated with less severe manifestations of infection.
Instead, the combination of pyrimethamine and
sulfadiazine is highly active against T. gondii and 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 studies have set themselves the goal of finding strong
Table III. Guidelines for treatment of CT in the infant.
Medication
Pyrimethamine
Sulfadiazinne
Leucovorin
Dosage
Loading dose: 2 mg/kg per day for 2 days,
then 1 mg/kg per day for 2 or 6 month,
then this dose every Monday, Wednesday, Friday.
100 mg/kg per day in two divided doses.
10 mg three times weekly
Duration of therapy
1 year
1 year
During and for 1 wk after
pyrimethamine therapy
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.
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D. Serranti, D. Buonsenso, P. Valentini
evidence that could solve this gordian knot. Probably, the most comprehensive overview of the complex 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 performed. In 1438 treated mothers identified by prenatal 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 significantly reduced the risk of clinical manifestations.
Moreover, they found weak evidence for an association 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 teratogenicity). In fact an ideal drug would show an efficient 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 fluoroquinolones 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 capable to inhibit the vertical transmission of T. gondii
in mice model of CT19, or thiolactomycin analogues
that demonstrated anti-T. gondii in vitro activity20.
Finally we must emphasize that encouraging
results were observed using spiramycin-cotrimoxazole association, primarily for its safety and
also because it showed effects on reducing the
mother-to-child transmission rate and on preventing the risk of clinical sequelae21.
Postnatal Treatment
Concerning the postnatal treatment, it’s recommended to administer specific therapy in
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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 effectively 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 sulfadiazine 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 peripheral 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 treatment of infants without substantial neurologic
disease at birth with pyrimethamine and sulfadiazine for 1 year resulted in normal cognitive,
neurologic, and auditory outcomes for all patients. Treatment of infants who had moderate or
severe neurologic disease at birth resulted in normal neurologic and cognitive outcomes for >72%
of the patients, and none had sensorineural hearing loss. 91% percent of children without substantial 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 study24 that almost all of these outcomes are markedly better than outcomes reported for children who were untreated or treated for
1 month in earlier decades.
Similar results have been obtained in a prospective longitudinal observation of a cohort of 132
children, treated during their first year of life with
Congenital toxoplasmosis treatment
pyrimethamine, sulfadiazine and leucovorin, and
evaluated for chorioretinal involvement25.
Although, as the prenatal, concerning the postnatal treatment, it was developed many years ago
and the studies to determine its effectiveness cannot 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 becomes 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 adequate evidence. In fact, studies conducted until
now have several limitations: first, the comparison
with historical studies, rather than appropriate control groups. This limits their validity.
So, the general opinion is that children born with
symptomatic T. gondii infection should be treated,
but the benefit of treatment in children without
symptoms at birth is presently under intense discussion, because there is a lack of evidence.
Moreover, opinions regarding postnatal treatment 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 toxoplasmosis 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.
gondii tissue cysts30.
Conclusions
After having completed this overview on treatment of CT, in agreement 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 studies 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, prenatal diagnosis or ultrasound were not available.
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 wellconducted randomized trials evaluating new
treatment regimens or strategies will allow a collection of data which could be more significant.
The potential for bias and unmeasured confounding 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 randomization 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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