Toxoplasmosis and Pregnancy

Published on January 2017 | Categories: Documents | Downloads: 24 | Comments: 0 | Views: 165
of 21
Download PDF   Embed   Report



Toxoplasmosis and pregnancy
All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Mar 2015. | This topic last updated: Nov
20, 2013.
INTRODUCTION — Toxoplasma gondii is a ubiquitous protozoan parasite that
infects humans in various settings. The parasite is mainly acquired during
childhood and adolescence [1]. In industrially developed, temperate climate
countries, the prevalence of infection has declined over the last 30 years
[1], with 10 to 50 percent of adults aged 15 to 45 years displaying
serological evidence of past infection [2]. Much higher rates of infection (up
to 80 percent) are found in the tropics in communities exposed to
contaminated soil, undercooked meat, or unfiltered water [3-5].
Once a person is infected, the parasite lies dormant in neural and muscle
tissue and will never be eliminated. Studies based in Europe and North
America suggest that the large majority of immunocompetent humans are
able to limit the spread of the parasite and the associated tissue damage,
ensuring that it remains in its dormant form [3]. Inflammation of the retina
and choroid (retinochoroiditis) is the most frequent, permanent
manifestation of toxoplasmic infection. In Europe and North America, up to 1
percent of infected individuals eventually develop such lesions [6-9].
Evidence has been accumulating over the last 15 years that these findings
are not applicable to parts of Latin America, where clinical manifestations of
infection are much more common and more severe, probably because of the
predominance of more diverse and more virulent parasite genotypes
[10,11]. Toxoplasma gondii strains in Europe and North America belong to
three distinct clonal lineages, type I, type II, and type III [12]. A comparison
of European and Brazilian cohort studies of newborns identified by universal
screening showed that eye lesions were larger and more numerous and
more likely to impair vision in Brazilian cohorts [13].
In contrast to Europe and North America, acquisition of toxoplasmosis during
childhood or adulthood in Brazil accounts for high levels of eye disease. In
parts of Brazil, up to 20 percent of the population has toxoplasmic
retinochoroiditis, resulting in high levels of visual impairment [14-17].
Toxoplasmosis is a leading cause of blindness in South America [18], but not
in Europe or North America [19,20]. A detailed discussion of toxoplasmosis
in nonpregnant individuals can be found separately.
When toxoplasmic infection is acquired for the first time during pregnancy,
infection can be transmitted to the fetus, resulting in congenital
toxoplasmosis and associated neurological and ocular manifestations.
Continued parasite proliferation and tissue destruction can occur within the
fetal brain even after a marked maternal immune response, including
maternal IgG production [21].

This topic will focus on maternal infection and its effect on the fetus. Other
aspects of toxoplasmosis infection are reviewed separately.
●(See "Diagnostic assays for toxoplasmosis infection".)
●(See "Toxoplasmosis in immunocompetent hosts".)
●(See "Toxoplasmosis in HIV-infected patients".)
●(See "Congenital toxoplasmosis: Clinical features and diagnosis".)
●(See "Congenital toxoplasmosis: Treatment, outcome, and prevention".)
SOURCES OF INFECTION — Toxoplasma gondii is an obligate intracellular
parasite that exists in three forms: the oocyst, which is shed only in cat
feces; the tachyzoite (a rapidly dividing form observed in the acute phase of
infection); and the bradyzoite (a slow growing form observed within tissue
cysts) [3]. During a primary infection, a cat can shed millions of oocysts
daily from its alimentary canal for a period of one to three weeks. These
oocysts become infective one to five days later and may remain infectious
for over a year, especially in warm, humid environments. Cats typically
develop immunity after a primary infection; therefore, recurrent infection
with passage of oocysts is unlikely.
In developed temperate climate countries, the main source of maternal
infection is thought to be ingestion of bradyzoites contained in undercooked
or cured meat or meat products. Maternal ingestion of oocysts from contact
with contaminated soil or water or eating soil-contaminated fruit or
vegetables is also a major source of infection [3-5,22-26]. Food animals
(pigs, chickens, lambs, goats) become infected by the same routes, resulting
in meat containing tissue cysts [27].
PATHOGENESIS — Maternal toxoplasmosis infection is acquired orally. Fetal
infection results from transmission of parasites via the placenta following
primary maternal infection [3]. It is likely that transmission occurs in most
cases during the parasitemic phase in the days after infection and before
the development of a serologic response. The risk of transmitting infection
to the fetus increases steeply with the gestational age at seroconversion
To survive and multiply, the tachyzoite invades host cells, especially in the
brain and muscle, where it forms tissue cysts which can remain dormant for
years. In immunocompetent animal models, tissue cysts can be formed
within a week of infection [29,30]. It is not known how long this process
takes in the relatively immunologically immature fetus. The transition from
acute infective tachyzoite form, which is responsible for cell damage, to the
dormant bradyzoite form contained in tissue cysts impenetrable to
antibiotics has important implications for the therapeutic "window of

Incidence — The incidence of maternal infection during pregnancy ranges
from 1 to 8 per 1000 susceptible pregnancies, with the highest reported
rates in France [31].
Clinical manifestations — Acute infection in the mother is usually
asymptomatic. When symptoms of infection occur, they are nonspecific,
such as fatigue, fever, headache, malaise, and myalgia. Lymphadenopathy
is a more specific sign of the disease. In a prospective European cohort
study, lymphadenopathy was noted in 7 percent of 1144 infected pregnant
women before diagnosis of infection [32]. (See "Toxoplasmosis in
immunocompetent hosts", section on 'Clinical manifestations' and
"Infectious mononucleosis in adults and adolescents".)
Screening and diagnosis — Pregnant women who experience a
mononucleosis-like illness, but who have a negative heterophile test, should
be tested for toxoplasmosis as part of their diagnostic evaluation (see
"Infectious mononucleosis in adults and adolescents", section on 'Clinical
manifestations'). Maternal infection during pregnancy is most accurately
diagnosed when based on a minimum of two blood samples at least two
weeks apart showing seroconversion from negative to positive toxoplasmaspecific IgM or IgG. (See "Toxoplasmosis in immunocompetent hosts",
section on 'Diagnosis' and "Diagnostic assays for toxoplasmosis infection".)
Serial testing of susceptible asymptomatic women is usually feasible only as
part of a prenatal screening program. Monthly or three monthly retesting
schedules operate in parts of Europe [32,33]. The more frequently a woman
is retested, the greater the chance of detecting infection early, when
treatment is more likely to be effective. However, the costs of frequent
testing and the chances of false positive results increase as the frequency of
retesting increases [31,34]. Thus, women may undergo invasive prenatal
investigations and be treated unnecessarily. These potential harms have to
be weighed against potential benefits of treatment, which have been found
only for rare, serious neurological sequelae of congenital toxoplasmosis
[35,36]. Randomized controlled trials are needed to determine if these
benefits outweigh the harms of screening. We agree with recommendations
of national societies in the United States, Canada and the United Kingdom
against routine universal screening for toxoplasmosis in pregnancy
[31,37,38]. Issues related to immunosuppressed or human
immunodeficiency virus (HIV)-positive are discussed separately. (See
"Toxoplasmosis in HIV-infected patients".)
In the United States, clinicians are usually faced with the need to interpret a
positive IgM or IgA or low IgG avidity test result from a single sample. None
of these tests reliably predict recent infection [32,39,40]. Although the IgM
response lasts a median of 10 to 13 months, depending on the type of test
used, there is substantial variation in duration between individuals, and
about one-quarter of infected women have a persistent IgM response lasting

years [40]. For women whose first prenatal test at 13 weeks of gestation
was IgM and IgG positive, the probability that their infection occurred after
conception is 1 to 3 percent, depending on the test used [40]. Although high
IgG avidity is a hallmark of latent infection, low avidity is not diagnostic of
acute infection; low IgG avidity can persist for years in some women [4143].
The usefulness of a rising IgG titer has never been adequately evaluated
and is subject to error because of lack of reproducibility in many laboratories
when specimens are analyzed on different days. However, the combination
of a positive IgM and negative IgG result, with both tests becoming positive
two weeks later, thereby ruling out a nonspecific IgM response, is evidence
of infection occurring about two weeks before the first positive IgM result
[44,45]. In the United States, serological diagnosis of acute infection should
be confirmed by a reference laboratory, such as the Palo Alto Medical
Foundation Research Institute's (PAMFRI) Toxoplasma Serology Laboratory
(TSL, 650-853-4828).
FETAL INFECTION — The risk of fetal infection increases steeply with
advancing gestational age at the time of maternal seroconversion [28]. A
meta-analysis of all available cohorts estimated the risk of transmission to
be 15 percent when the mother seroconverted at 13 weeks, 44 percent at
26 weeks, and 71 percent at 36 weeks [28]. Although these figures are
based on women who were mostly treated during pregnancy, they are likely
to be generalizable to untreated women, as there is no clear evidence that
prenatal treatment administered in screening programs reduces the risk of
mother to child transmission of toxoplasmosis (see 'Rationale for prenatal
treatment' below).
Immunocompetent women infected prior to conception virtually never
transmit toxoplasmosis to the fetus, although rare exceptions have been
reported [46-52]. Immunocompromised women (eg, women with acquired
immunodeficiency syndromes [AIDS] or taking immunosuppressive
medications) may have parasitemia during pregnancy despite
preconceptional infection; their infants are at risk of congenital infection
Congenital toxoplasmosis secondary to reinfection is a rare event; this
phenomenon has been reported in approximately six women over the past
three decades [54]. One well-documented case demonstrated that prior
immunity to toxoplasma did not protect against reinfection with an atypical
strain [54]. (See "Toxoplasmosis in HIV-infected patients".)
Fetal sequelae — Fetal ultrasound can be useful to provide diagnostic
information, although findings are nonspecific. The most common
intracranial sonographic findings in fetal toxoplasmosis are intracranial
hyperechogenic foci or calcifications and ventricular dilatation, which are
poor prognostic signs [35,55-57]. Cerebral ventricular dilatation is generally
bilateral and symmetrical. In one series of 32 proven infected cases,

evolution was always very rapid over a period of a few days [55]. In a
European prospective cohort study [58], abnormal sonographic findings of
intracranial calcification or ventricular dilatation were found in 7 percent
(14/218) of infected fetuses; however, as reported in other studies, such
lesions appear only after 21 weeks of gestation [35,55]. Abnormal findings
involving areas other than the brain (eg, ascites) are less specific for
toxoplasmosis. Intrahepatic densities, increased thickness and hyperdensity
of the placenta, ascites, and, rarely, pericardial and pleural effusions have
also been observed [55]. Serial ultrasound is useful if late termination is
being actively considered.
Intrauterine growth restriction and microcephaly are not characteristic of
congenital toxoplasmosis [55,59]. Stillbirth appears to be a rare
complication; a prospective European cohort study of 1208 infected women
found the risk of stillbirth among 448 women infected during the first
trimester was no higher than that in the general obstetrical population
matched for age [59]. An observed association between early maternal
infection and preterm delivery may be due to obstetric intervention, rather
than the disease itself [59].
Diagnosis — The main purpose of prenatal diagnosis of fetal infection is to
help decide whether to change prenatal treatment from spiramycin to a
pyrimethamine-sulfonamide combination (see 'Rationale for prenatal
treatment' below). As prenatal diagnosis requires amniocentesis, which is an
invasive test with a small but well-established risk of miscarriage, clinicians
need to ensure that women are sufficiently informed to enable them to
weigh the potential benefits and risks when deciding whether to undergo
prenatal diagnosis. (See "Diagnostic amniocentesis".) Although there have
been no randomized controlled trials comparing types of treatment, none of
the comparative cohort studies have provided any evidence that a
pyrimethamine-sulfonamide combination is more effective than spiramycin
for any outcomes related to congenital toxoplasmosis in humans [4,28].
In some women, prenatal diagnosis is important to aid in their decision as to
whether to terminate the pregnancy. Exclusion of fetal infection by prenatal
diagnosis can also prevent unnecessary postnatal treatment in children
without clinical signs of toxoplasmosis and at low risk of congenital infection
Polymerase chain reaction (PCR) for T. gondii DNA in amniotic fluid is the
best method for diagnosing fetal infection, but accuracy varies among
laboratories and techniques and sensitivity is lower in early (<18 weeks of
gestation) than in late pregnancy [39,58,60]. Real time PCR appears to be
more sensitive than conventional PCR, but not commercially available [6164]. The sensitivity of real time PCR testing was illustrated by a prospective
French study of real time PCR for T. gondii that reported sensitivity and
specificity of 92.2 and 100 percent, respectively; sensitivity was not affected
by gestational age at the time of maternal seroconversion [64]. Four of the
51 infected children had negative amniotic fluid PCR results; maternal

seroconversion occurred at 13, 20, 28, and 32 weeks of gestation in these
The four false negative tests were performed five to nine weeks after
maternal seroconversion, thus, timing of amniocentesis was unlikely to be a
factor. Furthermore, at least one study has reported no association between
a positive amniocentesis and time since seroconversion, thereby challenging
the rationale for past recommendations that amniocentesis be delayed until
four weeks after seroconversion [58].
Mouse inoculation of amniotic fluid, used in some European centers to
diagnose fetal infection, is hard to justify, given the high cost, limited
sensitivity, and the fact that results take four to six weeks [58].
Cordocentesis has not been widely used for more than a decade because of
the risk of fetal loss [28].
Some clinicians recommend fetal ultrasound to detect fetal abnormalities
suggestive of infection in women with negative amniotic fluid testing, in
case of a false negative PCR result [65]. However, this strategy subjects a
very large number of uninfected fetuses to unnecessary repeated
After delivery, placental findings of toxoplasmosis include (picture 1):
granulomatous villitis, cysts, plasma cell deciduitis, villous sclerosis, and
chorionic vascular thromboses. Free trophozoites may be observed in villous
stroma, amniotic epithelium, chorion, and Wharton's jelly.
RATIONALE FOR PRENATAL TREATMENT — The approach to management of
toxoplasmosis during pregnancy was largely based upon the experience of
Desmonts and Couvreur, who reported nearly 40 years ago that prenatal
treatment with spiramycin was associated with a reduced risk of congenital
infection [66]. Their findings were flawed because they did not take into
account the fact that the treated women in their study seroconverted in
early pregnancy, and, therefore, were at low risk of fetal infection, whereas
the untreated women mostly seroconverted in late pregnancy and were at
high risk of fetal infection [67]. Their findings have since been refuted by a
series of cohort studies [28,32,68,69].
Whether any treatment reduces the risk of mother to child transmission
remains controversial, as no randomized controlled trials evaluating this
issue have been performed. The most robust evidence comes from a
systematic review and individual patient data meta-analysis at single
patient level of 20 European cohort studies (1438 women) in which universal
screening for toxoplasmosis in pregnancy was performed [28]. The analysis
assessed the effect of timing and type of prenatal treatment on mother-tochild transmission of infection and clinical manifestations before age one
year. Prenatal regimens included spiramycin alone, spiramycin followed by
pyrimethamine-sulfonamides, and pyrimethamine-sulfonamides alone.

The authors found weak evidence that treatment started within three weeks
of seroconversion reduced mother-to-child transmission compared with
treatment started after eight or more weeks (OR 0.48, 95% CI 0.28-0.80; p
= 0.05), but they could not distinguish whether this was a real benefit of
treatment or a bias due to late detection and inclusion in the cohort of
women at increased risk of fetal infection. Only one in five women were
treated within three weeks of seroconversion, despite the fact that most (76
percent) were identified in France, where a regimen of monthly retesting is
mandated by law. Thus, even if early treatment is effective, it will be difficult
to identify and treat women so quickly after seroconversion.
In addition, the authors found no statistically significant evidence that early
treatment reduced the risk of intracranial lesions detected after birth, or of
retinochoroiditis detected during infancy [28]. Two other large cohort studies
also found no evidence that prenatal treatment reduced the risk of
retinochoroiditis up to school age [70,71]. However, there is clear evidence
of a reduction in serious neurological sequelae or postnatal death in children
with congenital toxoplasmosis whose mothers were treated during
pregnancy. In a European study involving 293 infected fetuses, 8 percent
had serious neurological sequelae [35]. The authors estimated that prenatal
treatment reduced the risk of serious neurological sequelae or death by
three-quarters. They also estimated that, to prevent one case of serious
neurological sequelae or death after maternal infection at 10 weeks of
pregnancy, it would be necessary to treat three fetuses with confirmed
infection. To prevent one case of serious neurological sequelae or death
after maternal infection at 30 weeks of pregnancy, 18 fetuses would need to
be treated.
There is fairly strong evidence, again from cohort studies, that treatment
with a pyrimethamine-sulfonamide combination is no more effective than
spiramycin alone for reducing the risk of clinical manifestations in the
infected infant [28,35,68,70,72]. Nevertheless, pyrimethamine-sulfonamide
combinations are widely recommended, based on evidence that levels of
spiramycin in fetal blood samples are about half those found in maternal
serum, and may be insufficient for treating fetal infection [3,73]. However,
this issue remains controversial, given the difficulty in measuring blood
levels of spiramycin and the extent of variation in blood levels between
women [74].
The lack of evidence that pyrimethamine-sulfonamide combinations are
more effective than other drugs is important and undermines the rationale
for prenatal diagnosis. Clinicians and women need to be aware that we
simply do not know whether changing treatment from spiramycin to a
pyrimethamine-sulfonamide combination if the fetus is infected is beneficial.
Adverse drug effects are more common with pyrimethamine-sulfonamide
combinations than with spiramycin. A European multicenter cohort study
found adverse effects requiring treatment cessation in 3.4 percent (11/322)
of women prescribed pyrimethamine-sulfonamide compared with 1.7

percent (13/780) of women prescribed spiramycin alone [32]. A prospective
study of 48 children with congenital toxoplasmosis identified by neonatal
screening found that 7 experienced adverse reactions leading to treatment
cessation; 6 of the 7 patients with adverse reactions had neutropenia [75].
In summary, there is evidence that prenatal treatment reduces serious
neurological sequelae of congenital toxoplasmosis, but no evidence of any
effect on ocular disease, vision, or mother-to-child transmission of infection.
Randomized controlled trials are required to determine whether the benefits
of prenatal treatment justify the potential harms and costs of prenatal
screening. However, if toxoplasmosis is identified through testing because of
maternal symptoms or a high risk of exposure to infection, then treatment is
justified, though uncertainty remains about the type of treatment and
TREATMENT REGIMENS — Despite the lack of evidence of treatment efficacy,
prenatal treatment is usually offered to pregnant women who are diagnosed
with toxoplasmosis. The uncertainty about treatment effectiveness, risk of
adverse effects, and the high probability that the child will not be impaired
should be discussed with women when deciding whether or not to treat.
Spiramycin — Pregnant women who become infected during pregnancy are
generally treated immediately with spiramycin (1 g orally every eight hours
without food), which is a macrolide antibiotic similar to erythromycin. It is
concentrated in the placenta, where it is thought to treat placental infection
and thus helps to prevent transmission to the fetus, at least theoretically
[3,76]. The drug is licensed in Europe and Canada, and is available in the
United States for use in pregnancy from Rhone-Poulenc (Montreal, Quebec)
if an Investigational New Drug (IND) number is obtained from the US Food
and Drug Administration (FDA) ("compassionate use" pathway).
Pyrimethamine and sulfadiazine — Pyrimethamine is a folic acid antagonist
which can cause dose-related bone marrow suppression with resultant
anemia, leukopenia, and thrombocytopenia. It is teratogenic in animals
when given in large doses [3]. Sulfadiazine, another folic acid antagonist,
works synergistically with pyrimethamine against T. gondii tachyzoites, and
can also cause bone marrow suppression and reversible acute renal failure.
Due to the potential toxicity of these drugs, their use during pregnancy
should only be considered if fetal infection has been documented, although
there is no clinical evidence that these drugs are more effective than
spiramycin [3,28,68,70,72]. There are no direct maternal benefits from
these drugs.
Various dosing regimens have been proposed but, even in France, where
prenatal screening has operated for 30 years, treatment regimens vary
●A three-week course of pyrimethamine (50 mg once per day orally or 25
mg twice per day) and sulfadiazine (3 g/day orally divided into two to three

doses), alternating with a three-week course of spiramycin (1 g orally three
times per day) until delivery.
●Pyrimethamine (25 mg once per day orally) and sulfadiazine (4 g/day
orally divided into two to four doses) administered continuously until term.
Leucovorin calcium (folinic acid, 10 to 25 mg/day orally) is added during
pyrimethamine and sulfadiazine administration to prevent bone marrow
suppression. Monitoring of complete blood counts and platelet counts should
be performed weekly, and treatment discontinued, if a significantly
abnormal result is reported.
Other — Azithromycin has been used successfully to treat T. gondii in both
an animal model and in humans with acquired immunodeficiency syndromes
(AIDS) [3,62,63,78]. (See "Toxoplasmosis in HIV-infected patients".) It is a
Category B drug that has been used safely for treatment of Chlamydia
trachomatis infections in pregnancy. Large clinical trials are necessary to
determine whether this agent, or perhaps clarithromycin, is an effective
alternative to spiramycin to prevent in utero infection with T. gondii [3].
Pyrimethamine (100 mg loading dose orally followed by 25 to 50 mg/day)
combined with azithromycin (500 mg per day) has been found to have
equivalent effects to the combination with sulfonamide in a randomized
controlled trial of adult patients with toxoplasmic retinochoroiditis [79].
Women intolerant of pyrimethamine may consider trimethoprimsulfamethoxazole [80] or clindamycin [81,82]. However, the safety and
efficacy of these drugs for treating in-utero toxoplasmosis infection are
TERMINATION OF PREGNANCY — A small proportion of women have their
pregnancies terminated because of toxoplasmosis. Within the prenatal
screening program in France, termination is discouraged unless there is
definite evidence of fetal infection based on polymerase chain reaction
(PCR) performed in a reference laboratory and evidence of intracranial
abnormalities on fetal ultrasound. The rationale for this approach is that
most infected babies have a good prognosis and, on average, do not differ
in their development at three to four years from uninfected children
[77,83,84]. However, fetuses with ultrasound evidence of intracranial lesions
are thought to be at high risk of serious neurological sequelae or postnatal
death. It is not clear whether prenatal treatment reduces these risks once
intracranial lesions are apparent [35]. In France, approximately 1.4 percent
(17/1208) of infected women undergo termination and just over half of
these pregnancies have proven fetal infection [32,58].
NEONATAL MANAGEMENT AND OUTCOME — Toxoplasma infection in the
newborn is discussed in detail separately. (See "Congenital toxoplasmosis:
Clinical features and diagnosis" and "Congenital toxoplasmosis: Treatment,
outcome, and prevention".)

PREVENTION — Prevention of primary infection is based upon avoidance of
sources of infection. While access to reliable information on sources of
infection is undoubtedly important, systematic reviews have found no high
quality evidence that such information changes women's behavior during
pregnancy [85,86]. Evidence from case control studies of risk factors in
Europe has identified the following principal sources of infection:
●Travel to less developed countries is a major risk factor, especially to
South America, where more virulent parasite genotypes predominate [5,22].
●Women should avoid drinking unfiltered water in any setting [4,5,87].
●Avoid ingesting soil by observing strict hand hygiene after touching soil.
Fruit and vegetables should be washed before eating [22,24].
●Raw or undercooked meat is an important source of infection. Cutting
boards, knives, counters and the sink should be washed after food
preparation. Avoid mucous membrane contact when handling uncooked
meat. Women should also avoid tasting meat while cooking [4,5,22,24].
●Meat should be cooked to 152ºF (66ºC) or higher, or frozen for 24 hours in
a household freezer (at less than -12ºC), both of which are lethal to
tachyzoites and bradyzoites [88]. Meat farmed in strict indoor conditions is
less likely to be contaminated than outdoor reared meat [5]. There is weak
evidence that meat that has been smoked or cured in brine is not safe. The
risk of infection is likely to be increased when cured products involve meat
from more than one animal and limited drying and curing, as in some local
production methods [5,23,89].
●There is some evidence that shellfish can be infected with toxoplasma
cysts [90].
●Owning a cat is only weakly associated with acute infection. This is
probably because cats only excrete oocysts for three weeks of their life, and
people are just as likely to be exposed to oocysts excreted by someone
else's cat. Nevertheless, it seems sensible for pregnant women with cats to
ask someone else to change the litter box daily (fresh cat feces are not
infectious) [5,22,24].
Hand washing is the single most important measure to reduce transmission
of microorganisms from one site to another on the same patient. Thus,
handwashing is important after activities such as preparing food or
Timing pregnancy after maternal infection — There are limited data on
which to base a recommendation for how long to delay pregnancy after an
acute toxoplasmosis infection. Although a delay of six months has been
suggested [38], parasitemia is very short lived and it is likely that
encystment occurs rapidly in women with adequate immune function, thus
immunocompetent women who become pregnant at least three months

after an acute infection are unlikely to transmit the infection to the fetus. In
a study of parasitemia after acute infection, none of the 54 patients had
positive blood polymerase chain reaction (PCR) results by 21 to 25 weeks
from onset of lymphadenopathy [91] and data from the Systematic Review
on Congenital Toxoplasmosis (SYROCOT) study suggested congenital
infection occurs within three weeks of maternal infection [28].
Reactivation of latent toxoplasmosis during pregnancy could occur in human
immunodeficiency virus (HIV)-infected pregnant women, particularly in
those who are severely immunocompromised. In the European Collaborative
Study, a large prospective study of children born to HIV-infected women,
451 children recruited to the study were born to mothers with antiToxoplasma IgG antibody and none of these children had clinical evidence of
congenital toxoplasmosis [92]. Congenital infection was excluded
serologically in a subgroup of 71 children. These findings indicate a very low
risk of maternal-fetal transmission of the parasite, with a statistical upper
limit of approximately 4 percent [93]. However, most of the women in the
study were asymptomatic, and the risk of transmission may be higher in
severely immunocompromised HIV-infected women. Management of HIV
infected women is discussed separately. (See "Toxoplasmosis in HIV-infected
patients" and "Prenatal evaluation and intrapartum management of the HIVinfected patient in resource-rich settings".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient
education materials, “The Basics” and “Beyond the Basics.” The Basics
patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated,
and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and
are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient information: Avoiding infections in pregnancy
(The Basics)")
●Beyond the Basics topics (see "Patient information: Avoiding infections in
pregnancy (Beyond the Basics)")
General principles

●The main sources of maternal toxoplasmosis infection are ingestion of
contaminated undercooked or cured meat or meat products, soilcontaminated fruit or vegetables, or contaminated unfiltered water. (See
'Sources of infection' above.)
●Serological diagnosis of acute maternal infection should be confirmed by a
reference laboratory. (See 'Screening and diagnosis' above.)
●For women planning pregnancy or who are pregnant, we recommend
avoidance of risky behaviors, such as eating raw or undercooked meat or
drinking unfiltered water (Grade 1C). Public health interventions include
provision of clean filtered water and promoting greater awareness of the
sources of infection. (See 'Prevention' above.)
●Despite the lack of evidence of cost effectiveness, prenatal treatment is
usually offered to pregnant women with toxoplasmosis. Pregnant women
who become infected during pregnancy are generally treated immediately
with spiramycin to prevent maternal-fetal transmission. For women with
proven fetal infection who choose to be treated, pyrimethamine plus
sulfadiazine is more widely used than spiramycin or azithromycin, but there
is no evidence of improved effectiveness and it is associated with more
serious adverse effects. (See 'Treatment regimens' above.)
For toxoplasmosis strains circulating outside of South America
●Maternal toxoplasmosis infection is usually asymptomatic, but may be
manifested by nonspecific symptoms. In most cases, the most serious
consequence of maternal infection is transmission to the fetus. (See 'Clinical
manifestations' above and 'Fetal sequelae' above.)
●The risk of vertical transmission increases with increasing gestational age
at maternal infection. Conversely, the risks of intracranial lesions and
serious neurodevelopmental sequelae decrease with increasing gestational
age at maternal infection. Rarely, fetal infection leads to stillbirth or
neonatal death. (See 'Fetal sequelae' above.)
●Maternal infection during pregnancy is most accurately diagnosed when
based on a minimum of two blood samples at least two weeks apart
showing seroconversion from negative to positive toxoplasma-specific IgM or
IgG. Polymerase chain reaction (PCR) for T. gondii DNA in amniotic fluid is
the best method for diagnosing fetal infection, but is not sensitive when
women seroconvert in the first trimester. Sonography of an infected fetus
may show intracranial calcification or ventricular dilatation after 21 weeks of
gestation. (See 'Screening and diagnosis' above and 'Diagnosis' above.)
●We suggest not performing routine universal prenatal screening for
toxoplasmosis in women at low risk of infection, given there is insufficient
evidence that the benefits of prenatal treatment outweigh the potential
harms and costs (Grade 2C). However, testing is clinically indicated to
diagnose infection in women with symptoms of toxoplasmosis or at high risk

of recent exposure. In such cases, prenatal treatment is justified to reduce
the risk of serious neurological sequelae or postnatal death, although
information on the low risk of serious adverse outcome and the risk of
adverse drug effects should be shared with women when deciding whether
or not to treat. (See 'Diagnosis' above and 'Rationale for prenatal treatment'
For toxoplasmosis strains circulating in South America
●Infection acquired during pregnancy in South America carries a much
higher risk of serious sequelae for the fetus than does infection acquired in
Europe or North America. (See 'Prevention' above.)
●Although evidence is lacking for the effectiveness of treatment for these
more virulent strains, we suggest treating women who are tested for clinical
indications and acquired infection in South America (Grade 2C). (See
'Rationale for prenatal treatment' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
Welton, NJ, Ades, AE. A model of toxoplasmosis incidence in the UK:
evidence synthesis and consistency of evidence. JRSS (C) Applied Statistics
2005; 54:385.
Gilbert RE. Congenital toxoplasmosis: Scientific background, clinical
management and control. In: Epidemiology of infection in pregnant women,
1st ed, Petersen E, Amboise-Thomas P (Eds), Springer-Verlag, Paris 2000.
Remington JS, McLeod R, Thulliez P, Desmonts G. Toxoplasmosis. In:
Infectious Disease of the Fetus adn Newborn Infant, 6th ed, Remington JS,
Klein J, Wilson CB, Baker CJ (Eds), Elsevier Saunders, Philadelphia 2006.
Bahia-Oliveira LM, Jones JL, Azevedo-Silva J, et al. Highly endemic,
waterborne toxoplasmosis in north Rio de Janeiro state, Brazil. Emerg Infect
Dis 2003; 9:55.
Cook AJ, Gilbert RE, Buffolano W, et al. Sources of toxoplasma infection in
pregnant women: European multicentre case-control study. European
Research Network on Congenital Toxoplasmosis. BMJ 2000; 321:142.
Burnett AJ, Shortt SG, Isaac-Renton J, et al. Multiple cases of acquired
toxoplasmosis retinitis presenting in an outbreak. Ophthalmology 1998;
Perkins ES. Ocular toxoplasmosis. Br J Ophthalmol 1973; 57:1.
Gilbert RE, Stanford MR. Is ocular toxoplasmosis caused by prenatal or
postnatal infection? Br J Ophthalmol 2000; 84:224.

Gilbert RE, Dunn DT, Lightman S, et al. Incidence of symptomatic
toxoplasma eye disease: aetiology and public health implications. Epidemiol
Infect 1999; 123:283.
Wendte JM, Miller MA, Lambourn DM, et al. Self-mating in the definitive host
potentiates clonal outbreaks of the apicomplexan parasites Sarcocystis
neurona and Toxoplasma gondii. PLoS Genet 2010; 6:e1001261.
Frazão-Teixeira E, Sundar N, Dubey JP, et al. Multi-locus DNA sequencing of
Toxoplasma gondii isolated from Brazilian pigs identifies genetically
divergent strains. Vet Parasitol 2011; 175:33.
Minot S, Melo MB, Li F, et al. Admixture and recombination among
Toxoplasma gondii lineages explain global genome diversity. Proc Natl Acad
Sci U S A 2012; 109:13458.
Gilbert RE, Freeman K, Lago EG, et al. Ocular sequelae of congenital
toxoplasmosis in Brazil compared with Europe. PLoS Negl Trop Dis 2008;
Silveira C, Belfort R Jr, Muccioli C, et al. A follow-up study of Toxoplasma
gondii infection in southern Brazil. Am J Ophthalmol 2001; 131:351.
Glasner PD, Silveira C, Kruszon-Moran D, et al. An unusually high prevalence
of ocular toxoplasmosis in southern Brazil. Am J Ophthalmol 1992; 114:136.
Portela RW, Bethony J, Costa MI, et al. A multihousehold study reveals a
positive correlation between age, severity of ocular toxoplasmosis, and
levels of glycoinositolphospholipid-specific immunoglobulin A. J Infect Dis
2004; 190:175.
de Amorim Garcia CA, Oréfice F, de Oliveira Lyra C, et al. Socioeconomic
conditions as determining factors in the prevalence of systemic and ocular
toxoplasmosis in Northeastern Brazil. Ophthalmic Epidemiol 2004; 11:301.
de Carvalho KM, Minguini N, Moreira Filho DC, Kara-José N. Characteristics of
a pediatric low-vision population. J Pediatr Ophthalmol Strabismus 1998;
de Boer J, Wulffraat N, Rothova A. Visual loss in uveitis of childhood. Br J
Ophthalmol 2003; 87:879.
Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness:
a literature survey. Br J Ophthalmol 1996; 80:844.
Ferguson DJ, Bowker C, Jeffery KJ, et al. Congenital toxoplasmosis: continued
parasite proliferation in the fetal brain despite maternal immunological
control in other tissues. Clin Infect Dis 2013; 56:204.

Kapperud G, Jenum PA, Stray-Pedersen B, et al. Risk factors for Toxoplasma
gondii infection in pregnancy. Results of a prospective case-control study in
Norway. Am J Epidemiol 1996; 144:405.
Buffolano W, Gilbert RE, Holland FJ, et al. Risk factors for recent toxoplasma
infection in pregnant women in Naples. Epidemiol Infect 1996; 116:347.
Baril L, Ancelle T, Goulet V, et al. Risk factors for Toxoplasma infection in
pregnancy: a case-control study in France. Scand J Infect Dis 1999; 31:305.
de Moura L, Bahia-Oliveira LM, Wada MY, et al. Waterborne toxoplasmosis,
Brazil, from field to gene. Emerg Infect Dis 2006; 12:326.
Boyer K, Hill D, Mui E, et al. Unrecognized ingestion of Toxoplasma gondii
oocysts leads to congenital toxoplasmosis and causes epidemics in North
America. Clin Infect Dis 2011; 53:1081.
Hill DE, Dubey JP. Toxoplasma gondii prevalence in farm animals in the
United States. Int J Parasitol 2013; 43:107.
SYROCOT (Systematic Review on Congenital Toxoplasmosis) study group,
Thiébaut R, Leproust S, et al. Effectiveness of prenatal treatment for
congenital toxoplasmosis: a meta-analysis of individual patients' data.
Lancet 2007; 369:115.
Denkers EY, Gazzinelli RT. Regulation and function of T-cell-mediated
immunity during Toxoplasma gondii infection. Clin Microbiol Rev 1998;
Lüder CG, Gross U. Toxoplasmosis: from clinics to basic science. Parasitol
Today 1998; 14:43.
Gilbert RE, Peckham CS. Congenital toxoplasmosis in the United Kingdom: to
screen or not to screen? J Med Screen 2002; 9:135.
Gilbert R, Gras L, European Multicentre Study on Congenital Toxoplasmosis.
Effect of timing and type of treatment on the risk of mother to child
transmission of Toxoplasma gondii. BJOG 2003; 110:112.
Wallon M, Peyron F, Cornu C, et al. Congenital toxoplasma infection: monthly
prenatal screening decreases transmission rate and improves clinical
outcome at age 3 years. Clin Infect Dis 2013; 56:1223.
Binquet C, Wallon M, Quantin C, et al. [Evaluation of prevention strategies
for congenital toxoplasmosis: a critical review of medico-economic studies].
Rev Epidemiol Sante Publique 2002; 50:475.
Cortina-Borja M, Tan HK, Wallon M, et al. Prenatal treatment for serious
neurological sequelae of congenital toxoplasmosis: an observational
prospective cohort study. PLoS Med 2010; 7.

McLeod R, Boyer K, Karrison T, et al. Outcome of treatment for congenital
toxoplasmosis, 1981-2004: the National Collaborative Chicago-Based,
Congenital Toxoplasmosis Study. Clin Infect Dis 2006; 42:1383.
American Academy of Pediatrics and The American College of Obstetricians
and Gyneclogists. Guidelines for Perinatal Care. Seventh edition. 2012. page
Paquet C, Yudin MH, Society of Obstetricians and Gynaecologists of Canada.
Toxoplasmosis in pregnancy: prevention, screening, and treatment. J Obstet
Gynaecol Can 2013; 35:78.
Montoya JG, Remington JS. Management of Toxoplasma gondii infection
during pregnancy. Clin Infect Dis 2008; 47:554.
Gras L, Gilbert RE, Wallon M, et al. Duration of the IgM response in women
acquiring Toxoplasma gondii during pregnancy: implications for clinical
practice and cross-sectional incidence studies. Epidemiol Infect 2004;
Lefevre-Pettazzoni M, Le Cam S, Wallon M, Peyron F. Delayed maturation of
immunoglobulin G avidity: implication for the diagnosis of toxoplasmosis in
pregnant women. Eur J Clin Microbiol Infect Dis 2006; 25:687.
Meroni V, Genco F, Tinelli C, et al. Spiramycin treatment of Toxoplasma
gondii infection in pregnant women impairs the production and the avidity
maturation of T. gondii-specific immunoglobulin G antibodies. Clin Vaccine
Immunol 2009; 16:1517.
Villard O, Breit L, Cimon B, et al. Comparison of four commercially available
avidity tests for Toxoplasma gondii-specific IgG antibodies. Clin Vaccine
Immunol 2013; 20:197.
Gras L, Wallon M, Pollak A, et al. Association between prenatal treatment
and clinical manifestations of congenital toxoplasmosis in infancy: a cohort
study in 13 European centres. Acta Paediatr 2005; 94:1721.
Dunn D, Wallon M, Peyron F, et al. Mother-to-child transmission of
toxoplasmosis: risk estimates for clinical counselling. Lancet 1999;
Gavinet MF, Robert F, Firtion G, et al. Congenital toxoplasmosis due to
maternal reinfection during pregnancy. J Clin Microbiol 1997; 35:1276.
Hennequin C, Dureau P, N'Guyen L, et al. Congenital toxoplasmosis acquired
from an immune woman. Pediatr Infect Dis J 1997; 16:75.
Vogel N, Kirisits M, Michael E, et al. Congenital toxoplasmosis transmitted
from an immunologically competent mother infected before conception. Clin
Infect Dis 1996; 23:1055.

Boumahni B, Randrianivo H, Flodrops H, et al. [Maternal toxoplasmosis
before conception and chorioretinitis in twin sisters]. J Gynecol Obstet Biol
Reprod (Paris) 2004; 33:248.
Chemla C, Villena I, Aubert D, et al. Preconception seroconversion and
maternal seronegativity at delivery do not rule out the risk of congenital
toxoplasmosis. Clin Diagn Lab Immunol 2002; 9:489.
Villena I, Chemla C, Quereux C, et al. Prenatal diagnosis of congenital
toxoplasmosis transmitted by an immunocompetent woman infected before
conception. Reims Toxoplasmosis Group. Prenat Diagn 1998; 18:1079.
Pons JC, Sigrand C, Grangeot-Keros L, et al. [Congenital toxoplasmosis:
transmission to the fetus of a pre-pregnancy maternal infection]. Presse Med
1995; 24:179.
Desmonts G, Couvreur J, Thulliez P. [Congenital toxoplasmosis. 5 cases of
mother-to-child transmission of pre-pregnancy infection]. Presse Med 1990;
Elbez-Rubinstein A, Ajzenberg D, Dardé ML, et al. Congenital toxoplasmosis
and reinfection during pregnancy: case report, strain characterization,
experimental model of reinfection, and review. J Infect Dis 2009; 199:280.
Hohlfeld P, MacAleese J, Capella-Pavlovski M, et al. Fetal toxoplasmosis:
ultrasonographic signs. Ultrasound Obstet Gynecol 1991; 1:241.
Malinger G, Werner H, Rodriguez Leonel JC, et al. Prenatal brain imaging in
congenital toxoplasmosis. Prenat Diagn 2011; 31:881.
Becker LE. Infections of the developing brain. AJNR Am J Neuroradiol 1992;
Thalib L, Gras L, Romand S, et al. Prediction of congenital toxoplasmosis by
polymerase chain reaction analysis of amniotic fluid. BJOG 2005; 112:567.
Freeman K, Oakley L, Pollak A, et al. Association between congenital
toxoplasmosis and preterm birth, low birthweight and small for gestational
age birth. BJOG 2005; 112:31.
Foulon W, Pinon JM, Stray-Pedersen B, et al. Prenatal diagnosis of congenital
toxoplasmosis: a multicenter evaluation of different diagnostic parameters.
Am J Obstet Gynecol 1999; 181:843.
Romand S, Chosson M, Franck J, et al. Usefulness of quantitative polymerase
chain reaction in amniotic fluid as early prognostic marker of fetal infection
with Toxoplasma gondii. Am J Obstet Gynecol 2004; 190:797.
Brenier-Pinchart MP, Morand-Bui V, Fricker-Hidalgo H, et al. Adapting a
conventional PCR assay for Toxoplasma gondii detection to real-time

quantitative PCR including a competitive internal control. Parasite 2007;
Bretagne S, Costa JM. Towards a nucleic acid-based diagnosis in clinical
parasitology and mycology. Clin Chim Acta 2006; 363:221.
Wallon M, Franck J, Thulliez P, et al. Accuracy of real-time polymerase chain
reaction for Toxoplasma gondii in amniotic fluid. Obstet Gynecol 2010;
Gay-Andrieu F, Marty P, Pialat J, et al. Fetal toxoplasmosis and negative
amniocentesis: necessity of an ultrasound follow-up. Prenat Diagn 2003;
Desmonts G, Couvreur J. Congenital toxoplasmosis. A prospective study of
378 pregnancies. N Engl J Med 1974; 290:1110.
Thiébaut R, Leroy V, Alioum A, et al. Biases in observational studies of the
effect of prenatal treatment for congenital toxoplasmosis. Eur J Obstet
Gynecol Reprod Biol 2006; 124:3.
Foulon W, Villena I, Stray-Pedersen B, et al. Treatment of toxoplasmosis
during pregnancy: a multicenter study of impact on fetal transmission and
children's sequelae at age 1 year. Am J Obstet Gynecol 1999; 180:410.
Gilbert RE, Gras L, Wallon M, et al. Effect of prenatal treatment on mother to
child transmission of Toxoplasma gondii: retrospective cohort study of 554
mother-child pairs in Lyon, France. Int J Epidemiol 2001; 30:1303.
Freeman K, Tan HK, Prusa A, et al. Predictors of retinochoroiditis in children
with congenital toxoplasmosis: European, prospective cohort study.
Pediatrics 2008; 121:e1215.
Binquet C, Wallon M, Quantin C, et al. Prognostic factors for the long-term
development of ocular lesions in 327 children with congenital toxoplasmosis.
Epidemiol Infect 2003; 131:1157.
Gras L, Gilbert RE, Ades AE, Dunn DT. Effect of prenatal treatment on the
risk of intracranial and ocular lesions in children with congenital
toxoplasmosis. Int J Epidemiol 2001; 30:1309.
Forestier F, Daffos F, Rainaut M, et al. [Fetomaternal therapeutic follow-up of
spiramycin during pregnancy]. Arch Fr Pediatr 1987; 44:539.
Gratzl R, Sodeck G, Platzer P, et al. Treatment of toxoplasmosis in
pregnancy: concentrations of spiramycin and neospiramycin in maternal
serum and amniotic fluid. Eur J Clin Microbiol Infect Dis 2002; 21:12.
Schmidt DR, Hogh B, Andersen O, et al. Treatment of infants with congenital
toxoplasmosis: tolerability and plasma concentrations of sulfadiazine and
pyrimethamine. Eur J Pediatr 2006; 165:19.

Couvreur J, Desmonts G, Thulliez P. Prophylaxis of congenital toxoplasmosis.
Effects of spiramycin on placental infection. J Antimicrob Chemother 1988;
22 Suppl B:193.
Binquet C, Wallon M, Metral P, et al. [Toxoplasmosis seroconversion in
pregnant women. The differing attitudes in France]. Presse Med 2004;
Godofsky EW. Treatment of presumed cerebral toxoplasmosis with
azithromycin. N Engl J Med 1994; 330:575.
Bosch-Driessen LH, Verbraak FD, Suttorp-Schulten MS, et al. A prospective,
randomized trial of pyrimethamine and azithromycin vs pyrimethamine and
sulfadiazine for the treatment of ocular toxoplasmosis. Am J Ophthalmol
2002; 134:34.
Derouin F, Jacqz-Aigrain E, Thulliez P, et al. Cotrimoxazole for prenatal
treatment of congenital toxoplasmosis? Parasitol Today 2000; 16:254.
Nahum GG, Uhl K, Kennedy DL. Antibiotic use in pregnancy and lactation:
what is and is not known about teratogenic and toxic risks. Obstet Gynecol
2006; 107:1120.
Katlama C, De Wit S, O'Doherty E, et al. Pyrimethamine-clindamycin vs.
pyrimethamine-sulfadiazine as acute and long-term therapy for toxoplasmic
encephalitis in patients with AIDS. Clin Infect Dis 1996; 22:268.
Berrebi A, Kobuch WE, Bessieres MH, et al. Termination of pregnancy for
maternal toxoplasmosis. Lancet 1994; 344:36.
Freeman K, Salt A, Prusa A, et al. Association between congenital
toxoplasmosis and parent-reported developmental outcomes, concerns, and
impairments, in 3 year old children. BMC Pediatr 2005; 5:23.
Gollub EL, Leroy V, Gilbert R, et al. Effectiveness of health education on
Toxoplasma-related knowledge, behaviour, and risk of seroconversion in
pregnancy. Eur J Obstet Gynecol Reprod Biol 2008; 136:137.
Di Mario S, Basevi V, Gagliotti C, et al. Prenatal education for congenital
toxoplasmosis. Cochrane Database Syst Rev 2013; 2:CD006171.
Dubey JP. Toxoplasmosis - a waterborne zoonosis. Vet Parasitol 2004; 126:57.
Dubey JP. Strategies to reduce transmission of Toxoplasma gondii to animals
and humans. Vet Parasitol 1996; 64:65.
Warnekulasuriya MR, Johnson JD, Holliman RE. Detection of Toxoplasma
gondii in cured meats. Int J Food Microbiol 1998; 45:211.
Fayer R, Dubey JP, Lindsay DS. Zoonotic protozoa: from land to sea. Trends
Parasitol 2004; 20:531.

Guy EC, Joynson DH. Potential of the polymerase chain reaction in the
diagnosis of active Toxoplasma infection by detection of parasite in blood. J
Infect Dis 1995; 172:319.
Low incidence of congenital toxoplasmosis in children born to women
infected with human immunodeficiency virus. European Collaborative Study
and Research Network on Congenital Toxoplasmosis. Eur J Obstet Gynecol
Reprod Biol 1996; 68:93.
Dunn D, Newell ML, Gilbert R. Low risk of congenital toxoplasmosis in
children born to women infected with human immunodeficiency virus.
Pediatr Infect Dis J 1997; 16:84.
Topic 6756 Version 13.0
Toxoplasmosis of the placenta

(A) Granulomatous villitis (B) Trophozoites.
Courtesy of Drucilla J Roberts, MD.

Graphic 52889 Version 2.0
Print Options:




Disclosures: Ruth Gilbert, MD Nothing to disclose. Eskild Petersen, MD,
DMSc, DTM&H Nothing to disclose. Charles J Lockwood, MD, MHCM
Consultant/Advisory Boards: Celula [Aneuploidy screening (Prenatal and
cancer DNA screening tests in development)]. Equity Ownership/Stock
Options: Celula [Aneuploidy screening (Prenatal and cancer DNA screening
tests in development)]. Peter F Weller, MD, FACP Grant/Research/Clinical
Trial Support: NIH [EGPA (Mepolizumab)]. Consultant/Advisory Boards: GSK
[EGPA (Mepolizumab)]. Vanessa A Barss, MD, FACOG Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial
group. When found, these are addressed by vetting through a multi-level
review process, and through requirements for references to be provided to
support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Sponsor Documents

Or use your account on


Forgot your password?

Or register your new account on


Lost your password? Please enter your email address. You will receive a link to create a new password.

Back to log-in