Congenital Toxoplasmosis
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Synonyms and keywords: Congenital Toxoplasmosis

# Overview
Toxoplasmosis is a part of TORCH group of infections caused by protozoan parasite, Toxoplasma gondii. In United States 89% of women in the childbearing age are susceptible to have an acute infection and are at risk for transmitting the parasite to the baby, if an acute infection occurs during the gestational period. Motile tachyzoites cross the placenta, and the frequency their transmission via the placenta is inversely related to the period of gestation. The severity of the disease is dependent on the timing of infection during the gestational period--earlier the infection more severe the disease. Infection in the first trimester results in miscarriage, still born or new born with severe neurological deficits. Newborns with infection acquired later in the pregnancy are asymptomatic at birth but develop neurological manifestations in the first or second decade. Prenatal screening and establishment of the timing of infection using serological tests plays a key role in the management of congenital toxoplasmosis. Amniotic fluid PCR is useful to confirm the infection in the fetus. Medical therapy for acute infection in the mother with no fetal infection,  spiramycin throughout the pregnancy is recommended. In pregnant women with a confirmed fetal infection pyrimethamine, sulfadiazine and leucovorin is recommended. Education on  prevention of T.gondii infection is recommended to all pregnant women to minimize the risk of infection.

# Historical Perspective
- In 1908, Nicolle and Manceaux described the parasite in the blood, spleen and liver of a North African rodentgundi (Ctenodactylus gundi) and named it Leishmania gondii.
- In 1909, Nicolle and Manceaux renamed the parasite as T.gondii.
- In 1937, Sabin & Olitsky described that toxoplasma was an obligate intracellular parasite and could be passed onto laboratory animals by intracranial,  subcutaneous, intraperitoneal inoculation of brain homogenates (The slurry of tissues and cells which results when cell structure has been mechanically disrupted). They have also suggested that ingestion of toxoplasma contaminated tissue can result in toxoplasmosis.
- In 1937 to 1940, Wolf and Cowen have described necrotic and granulomatous lesions on autopsy of a 3 day old infant's brain infected with toxoplasma. They have also reported that the mothers were asymptomatic but carried antibodies against toxoplasma and the possibility of congenital transmission was expressed.
- In 1940, Pinkerton and Weinman reported the first fatal case of toxoplasmosis in an adult.
- In 1948, Sabin and Feldman developed a serological test to identify infected individuals by using antibodies specific to toxoplasma, called the Sabin Feldman Dye test. The serological test when used in large population studies showed a high proportion of humans and domestic animals carried antibodies against toxoplasma.
- In 1965, Desmonts described that ingestion of under-cooked and uncooked meat plays a role in the pathogenesis of toxoplasmosis.
- In 1970, Dubley described the life cycle of the parasite and established that the cats are the definitive hosts and any warm blooded animal can be an intermediate host.

# Classification
There is no classification for congenital toxoplasmosis.

# Pathophysiology

## Pathogenesis

### Infective stages of the Parasite
The three infective stages of T. gondii include:
- Tachyzoite: It is the rapidly dividing and invasive form and can invade any vertebrate cell type
- Bradyzoite: These are the result of conversion from tachyzoites, they are slowly diving form and are present as tissue cysts, which can remain in the host throughout the lifetime in the muscles.
- Sporozoite: It is the environmental form present in the oocysts

### Mechanism of cell Invasion
- The initial step of invasion is attachment of the tachyzoite to the host cell membrane. A set of proteins help in the adherence and penetration of the host cell membrane, these proteins also enhance the growth and virulence of the parasite.
- In the host cell the parasite forms a vacuole where it divides for 6 to 9 cycles after which the parasites are released into the circulation.  It is an active process dependent on the increase in intracellular calcium stores.

### Pathogenesis of Vertical Transmission
- Acute infection with tachyzoites in the blood stream during pregnancy,  a possibility of transplacental infection is present.
- The tachyzoites colonize in the placenta and can cross the barrier to reach the fetus in 30% of cases leading to the disease.
- The frequency of transmission of the tachyzoites to the fetus is related to the gestational age, with low transmission rates in the first trimester (10-15%) and highest transmission rates in the third trimester (60-90%). However the disease is more severe if the infection is acquired early in the pregnancy.
- The factors influencing the transfer of tachyzoites to the fetus is not well understood.

## Gross Pathology
- T.gondii has tropism for central nervous system and mostly affects the brain and eye. Areas of necrosis and granulomatous lesions in the brain can be demonstrated on autopsy.

## Microscopic Pathology
- In patients with congenital toxoplasmosis, microscopy of the lesions demonstrate periaqueductal and periventricular vasculitis with necrosis.
- Fetal tissue and placenta can demonstrate  t.gondii cysts with the Wright-Giemsa stain and also with immunoperoxidase staining using t.gondiispecific antibodies.

# Causes
Congenital Toxoplasmosis is caused by a coccidian parasite Toxoplasma gondii.

# Differentiating Toxoplasmosis from other Diseases
The most important congenital infections, which can be transmitted vertically from mother to fetus are the TORCH infections. These infections have overlapping features and hence, must be differentiated from Congenital toxoplasmosis  :

# Epidemiology, Demographics

## Prevalence
- It is estimated that 25 to 30% of the world's population is infected with toxoplasma.
- In United States 89% of women in the childbearing age are susceptible to have an acute infection and at risk for transmitting the parasite to the baby if the primary infection occurs during the gestational period.
- In United States the age adjusted seroprevalence rate is 22.5%. There is significant variation in the distribution with highest prevalence reported in the North-eastern states and lowest in the western states.
- In countries such as North America, Northern Europe and in Sahelian countries of Africa low seroprevalences of 10% to 30% are observed. In countries of Central and Southern Europe, tropical African countries and Latin America the seroprevalence is around 30 to 50%. This shows the variation within the countries and as well as between the countries.

## Incidence
- Congenital toxoplasmosis affects 500 to 4000 new borns every year.
- In United States, toxoplasmosis affects 1.1 million people every year.

## Race
- The prevalence of toxoplasmosis is higher in non-Hispanic black population and Mexican Americans than non-Hispanic white population.

## Age
- A decreasing trend in prevalence is reported in the population of U.S born persons aged between 12 to 49 years; with 14% between the years 1988 to 1994, and 9% in the years 1999 to 2004. This trend is attributed to the improvement of hygienic conditions, changes in farming systems, the consumption of frozen meat, and the feeding of cats with sterilized food.
- The similar decreasing trend of seroprevalence is been reported in France and Netherlands.

## Developing Countries
- In countries with poor hygienic measures and using unfiltered surface water for consumption reported higher seroprevalence rates. In these countries the childhood population is at a higher risk of acquiring the infection, the mean age is reported to be 15 years.

# Risk Factors
The major risk factors for acquiring the infection is consuming raw meat and ingestion of food contaminated with toxoplasma oocysts excreted in cat feces.
The risk factors which predispose pregnant women for primary infection include: 
- Consumption of raw oysters and clams
- Eating undercooked meat which includes pork, beef and lamb
- Drinking unpasteurized goats milk
- Exposure to kitten litter
- Working with meat
- Low socioeconomic status
- Poor Hygiene
- Drinking unfiltered water
- Immunocompromised state

# Screening
- Majority of the countries do not follow standard screening for the detection of toxoplasma infection during the antenatal period.
- In countries such as France, Austria, Brazil standard screening is followed during the antenatal period for detecton of  toxoplasmosis .
- Women are tested for antibodies aganist toxoplasma on their first antenatal visit, and if they are seropositive they are followed up periodically in every trimester to examine the trends in IgG titer levels.
- Women who seroconvert during gestation, fetal testing by amniocentesis and fetal blood sampling is recommended to identify the infection status in the fetus.

# Natural History, Complications, Prognosis

## Natural History
Congenital toxoplasmosis is due to transplacental transmission of infective tachyzoites to the developing fetus. The severity of clinical manifestation is dependent on the timing of the infection during gestation. Early gestational infection results in a miscarriage, still birth or a new born with neurological abnormalities. Late gestational infection is asymptomatic in majority of children at birth but they develop neurological abnormalities and vision changes in the 1st or 2nd decade.

## Complications
If left untreated congenital toxoplasmosis results in mental retardation, seizures, motor difficulties, severe vision loss, hydrocephalus or microcephalus and hearing loss.

## Prognosis
Prognosis of congenital toxoplasmosis is dependent on the severity of the disease. Severe infection causes death at an early age, asymptomatic infection at birth will present in the 1st or 2nd decade with progressive chorioretinitis with poor prognosis.

# Diagnosis
The presence of intracranial calcification, hydrocephalus and chorioretinitis is the classic traid of congenital toxoplasmosis.

## History and Symptoms
The severity of manifestations in the newborn are dependent on the fetal age when the infection occurred and the trimester of pregnancy the mother gets infected. The disease is severe in mothers who acquire infection in the first trimester.

### Symptoms in the Mother
- Acute infection of toxoplasma in an asymptomatic women can be easily missed as they present with flu like symptoms, lymph node swelling in the neck and rarely with a skin rash.
- Early gestational infection results in a miscarriage or a still birth.

### Symptoms in newborn
The clinical manifestations in the newborn are dependent on the month of gestation the infection has occurred - earlier the infection more severe the disease.
Infection in early pregnancy : Neuro-ocular symptoms are typical presenting features in congenital toxoplasmosis, symptoms include:
- Involvement of the CNS can present with psycho-motor retardation and seizures.
- Chorioretinitis presents with impaired vision.
- Obstruction in the ventricles results in accumulation of CSF, causing enlargement of the head and increased intracranial pressure symptoms such as vomiting, headache, confusion and double vision.
- Yellowish discolouration of skin
- Focal neurological deficits and learning disabilities
- Feeding difficulties
- Hearing impairment
- Skin rash
- Fever
Infection later in the pregnancy: Majority of the infected newborns remain asymptomatic at birth.
- Children develop psycho-motor retardation and chorioretinitis later in life.
- Loss of vision is a common symptom and is seen in 95% of infants due to chorioretinitis.

## Physical Examination
Typical examination findings in toxoplasmosis include chorioretinitis, hydrocephalus and developmental delay. The presence of following physical examination findings are suggestive of congenital toxoplamosis:

## Laboratory Findings

### Prenatal Diagnosis
- During the period of gestation toxoplasma infection is diagnosed by the presence of parasite in the amniotic fluid or in the fetal tissue by DNA amplification, microscopy or by isolation of the organism.
- The most commonly used diagnostic test is the PCR of the amniotic fluid and a positive test is diagnostic of congenital toxoplasmosis.

### Postnatal Diagnosis
The most commonly used diagnostic investigation for early detection is the serological detection of antibodies (IgG, IgM and IgA) in the serum of the infant. A combination of all the antibodies (IgG, IgM, IgA) is done as the maternal IgG can cross the placenta and give false positive result.
- In the postnatal period the gold standard for diagnosis of congenital toxoplasmosis is the presence of Toxoplasma IgG by 12months of age.
- During the postnatal period the standard to rule out diagnosis is the the absence of toxoplasma IgG at 12months of age in the absence of treatment.

## Imaging Studies

### Ultrasound
- In toxoplasma seropositive pregnant women with negative amniotic fluid PCR and a high degree of suspicion fetal ultrasound is done to rule out hydrocephalus, intracranial calcification, and intrauterine growth retardation.

### Principles and various methods used for the diagnosis of congenital toxoplasmosis:
Table adopted from Laboratory Diagnosis of Congenital Toxoplasmosis

## Interpretation of Serological Tests
Table adopted from Management of Toxoplasma gondii Infection during Pregnancy

## Approach to a patient when Antenatal Screening findings are documented
Screening programs benefit the clinicians with information regarding maternal serological and amniotic fluid PCR test results, precise gestational age at which the mother was infected, and detailed anti-toxoplasma treatment history which play a vital role in the management of congenital toxoplasmosis.
Table adopted from Laboratory Diagnosis of Congenital Toxoplasmosis

## Approach to the patient with no documentation of Antenatal Screening
Table adopted from Laboratory Diagnosis of Congenital Toxoplasmosis

# Treatment

## Medical Therapy
The principle for medical therapy of congenital toxoplasmosis is based on the timing of diagnosis.
- Pregnant women with active toxoplasma infection: Spiramycin should be initiated and identification of infection status in the fetus by amniocentesis and fetal blood sampling should be done.
- Pregnant women with excluded fetal infection: Spiramycin should be continued throughout the pregnancy. It is administered orally at a dosage of 1.0 g (or 3 million U) every 8 h (total dosage of 3 g or 9 million U per day).
- Pregnant women with confirmed fetal infection: Pyrimethamine, sulfadiazine, and folinic acid should be given throughout the pregnancy and it is shown to decrease infection of the placenta, neurological sequalae and ocular symptoms. However, it does not reduce the rate of transmission and the regimen is contraindicated in the first trimester of pregnancy due to the teratogenic effect.
- Infants with established infection: Low or high dose pyrimethamine with sulfadiazine throughout the first year of life, showed better outcomes compared to untreated infants. 

### Follow Up
- Infants with congenital toxoplasmosis should be followed up regularly to examine for presence of motor abnormalities, cognitive outcomes, vision impairment, formation of new eye lesions, and hearing loss.
- Systemic corticosteroids are recommended for reducing the inflammation from chorioretinitis.

## Management of HIV Positive Pregnant Women
- HIV positive patients are at a higher risk for reactivation of toxoplasmosis and transmission to fetus.
- Data is inconclusive on the effectiveness of the standard treatment regimen.
- In toxoplasma seropositive pregnant women with CD4 cell count of less than 200 cells/mm 3 should receive trimethoprim-sufamethoxazole(80mg/400mg), one tablet a day as a prophylaxis.
- In toxoplasma seropositive pregnant women with CD4 greater than 200cells/mm3 spiramycin is suggested for the duration of pregnancy.

## Surgical Therapy
There are no surgical management measures for the treatment of congenital toxoplasmosis.

# Prevention

## Primary Prevention
Prevention is the best way to reduce the transmission of disease. The following are recommended by the CDC to reduce the risk of transmission of toxoplasma from the environment.
- Avoid drinking untreated drinking water.
- Wear gloves when gardening and during any contact with soil or sand because it might be contaminated with cat feces that contain Toxoplasma.
- Wash hands with soap and warm water after gardening or contact with soil or sand.
- Teach children the importance of washing hands to prevent infection.
- Keep outdoor sandboxes covered.
- Feed cats only canned or dried commercial food or well-cooked table food, not raw or undercooked meats.
- Change the litter box daily if you own a cat. The toxoplasma parasite does not become infectious until 1 to 5 days after it is shed in a cat's feces.
- If you are pregnant or immunocompromised: Avoid changing cat litter if possible. If no one else can perform the task, wear disposable gloves and wash your hands with soap and warm water afterwards.
- Keep cats indoors.
- Do not adopt or handle stray cats, especially kittens. Do not get a new cat while you are pregnant.

## Reducing the risk of transmission from meat
To prevent risk of toxoplasmosis from food:
- Cook food to safe temperatures. A food thermometer should be used to measure the internal temperature of cooked meat. Do not sample meat until it is cooked.
- For Whole Cuts of Meat (excluding poultry): Cook to at least 145 F (63 C) as measured with a food thermometer placed in the thickest part of the meat, then allow the meat to rest- for three minutes before carving or consuming.
- For Ground Meat (excluding poultry): Cook to at least 160 F (71 C); ground meats do not require a rest time.
- For All Poultry (whole cuts and ground): Cook to at least 165 F (74 C), and for whole poultry allow the meat to rest for three minutes before carving or consuming.

## Secondary Prevention
- Countries such as France and Austria recommend prenatal screening for toxoplasma, by antibody measurement in the pregnant mother to establish the status of infection. 
- Pregnant women with acute infection are treated with spiramycin, it is shown to reduce the transplacental transmission by 60%.