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Summary Table

Feature	Detail
Risk Factors	Exposure to cat feces (litter box), ingestion of undercooked/raw meat (lamb, pork, venison), contaminated water, gardening in contaminated soil, recent immigration from high-prevalence regions (France, Latin America, Sub-Saharan Africa)
Etiology	*Toxoplasma gondii*, an obligate intracellular protozoan parasite; definitive host is the cat (Felidae family)
Patient Presentation	Most pregnant women are asymptomatic; if symptomatic, presents with painless cervical lymphadenopathy, low-grade fever, malaise, myalgia
Classic Physical Exam	Nontender posterior cervical lymphadenopathy in the mother; in the neonate: chorioretinitis, hydrocephalus, and intracranial calcifications (classic triad of congenital toxoplasmosis)
Key Diagnostic Results	Maternal: Toxoplasma-specific IgM and IgG serology followed by IgG avidity testing to determine timing of infection; Fetal: amniocentesis with *PCR for T. gondii* DNA** in amniotic fluid; Neonatal imaging: diffuse (scattered) intracranial calcifications on CT
Management	Maternal seroconversion before 18 weeks: spiramycin (to reduce vertical transmission); Confirmed fetal infection or seroconversion after 18 weeks: pyrimethamine + sulfadiazine + leucovorin (folinic acid)
Keywords	"Cat litter," "undercooked meat," "ring-enhancing lesions" (in immunocompromised), "blueberry muffin rash," "chorioretinitis," "intracranial calcifications (diffuse/scattered)," "hydrocephalus"

1. Pathophysiology

Toxoplasma gondii is an obligate intracellular parasite with a complex life cycle. The definitive host is the domestic cat, which sheds oocysts in its feces. Humans become infected through three primary routes: ingestion of oocysts from contaminated soil, water, or cat litter; ingestion of tissue cysts (bradyzoites) in undercooked or raw meat; or vertical transmission from mother to fetus across the placenta.

Once ingested, the parasite invades intestinal epithelial cells and transforms into tachyzoites, the rapidly dividing, actively invasive form. Tachyzoites disseminate hematogenously and can cross biological barriers, including the placenta and the blood-brain barrier. In immunocompetent individuals, the cell-mediated immune response (primarily CD4+ T-cells and interferon-gamma) controls the infection, forcing the tachyzoites to convert into bradyzoites that encyst in tissues (brain, skeletal muscle, myocardium) and remain dormant for the host's lifetime.

In pregnancy, the critical concern is transplacental transmission. The risk of vertical transmission increases with gestational age: approximately 10-15% in the first trimester, rising to 60-70% by the third trimester. However, the severity of fetal disease is inversely proportional to gestational age at transmission. This is the single most tested concept. First-trimester infection leads to the most devastating congenital disease (spontaneous abortion, severe neurologic damage) because organogenesis is still occurring and the fetal immune system is profoundly immature. Third-trimester infection transmits more readily but tends to produce subclinical disease or mild manifestations at birth.

The fetal brain and eyes are preferentially targeted because tachyzoites have tropism for neural tissue. Invasion of the retina causes chorioretinitis (the most common manifestation of congenital toxoplasmosis). Inflammation of the ependymal lining and cerebral aqueduct leads to obstructive hydrocephalus. Necrosis and subsequent calcification of destroyed brain parenchyma produce the characteristic diffuse intracranial calcifications seen on imaging.

2. Classification and Clinical Manifestation

Maternal Infection

Presentation	Features
Asymptomatic (80-90%)	No clinical signs; detected only through routine serologic screening
Symptomatic (acute)	Nontender cervical or generalized lymphadenopathy, low-grade fever, fatigue, myalgia, headache; rarely hepatosplenomegaly or atypical lymphocytosis (can mimic infectious mononucleosis)

Congenital Toxoplasmosis

Category	Timing of Maternal Infection	Clinical Features
Severe (Classic Triad)	First trimester	Chorioretinitis + hydrocephalus + diffuse intracranial calcifications; seizures, microcephaly or macrocephaly, intellectual disability, spontaneous abortion or stillbirth
Moderate	Second trimester	Chorioretinitis, intracranial calcifications, hepatosplenomegaly, jaundice, thrombocytopenia, anemia
Mild / Subclinical	Third trimester	Mostly normal at birth; may develop late-onset chorioretinitis, learning disabilities, or sensorineural hearing loss months to years later
Generalized (disseminated neonatal)	Any trimester	Hepatosplenomegaly, jaundice, maculopapular rash ("blueberry muffin" appearance if extramedullary hematopoiesis), pneumonitis, myocarditis, thrombocytopenia

Key teaching point: The "blueberry muffin rash" is not unique to toxoplasmosis. It also appears in rubella, CMV, and other congenital TORCH infections. It represents dermal erythropoiesis (extramedullary hematopoiesis in the skin) due to severe fetal anemia and is therefore a shared finding, not a discriminator.

Intracranial Calcification Patterns

Infection	Calcification Pattern
Congenital Toxoplasmosis	Diffuse, scattered throughout the brain parenchyma
Congenital CMV	Periventricular (surrounding the ventricles)

This distinction is a classic exam differentiator between the two most common congenital infections causing intracranial calcifications.

3. Diagnostic Workup

Test	Role	Key Finding
Toxoplasma IgG and IgM serology	Best initial test (maternal screening)	IgM positive suggests recent or acute infection; IgG positive confirms exposure
IgG avidity testing	Timing of infection	High avidity = infection occurred >12-16 weeks ago (rules out recent acquisition); Low avidity = recent infection (within past 12-16 weeks)
Amniocentesis with PCR	Confirmatory test for fetal infection (gold standard)	Detection of T. gondii DNA in amniotic fluid
Fetal ultrasound	Screening for fetal complications	Hydrocephalus, intracranial calcifications, hepatomegaly, ascites, placental thickening
Neonatal head CT	Postnatal confirmation	Diffuse intracranial calcifications, ventriculomegaly

Serologic Interpretation

The first step in evaluating a pregnant woman with suspected toxoplasmosis is Toxoplasma-specific IgG and IgM antibody testing. Interpretation depends on the pattern:

IgG negative, IgM negative: The patient is seronegative and susceptible. She has never been infected and should receive counseling on prevention (avoid cat litter, cook meat thoroughly, wash produce).
IgG positive, IgM negative: This indicates prior (remote) infection, meaning immunity was established before pregnancy. There is essentially no risk to the fetus because dormant bradyzoites do not cross the placenta in immunocompetent hosts.
IgG positive, IgM positive: This is the problematic result. IgM can persist for months to over a year after acute infection, so a positive IgM does not necessarily mean the infection is recent. This is where IgG avidity testing becomes essential.
IgG negative, IgM positive: May represent very early seroconversion (IgG has not yet risen) or a false-positive IgM. Repeat testing in 2-3 weeks is required.

IgG Avidity Testing

This is the key concept that test-writers exploit. IgG avidity measures the strength of the bond between IgG antibodies and the antigen. In the early weeks following infection, the immune system produces low-avidity IgG (weak binding). Over 12-16 weeks, affinity maturation produces high-avidity IgG (strong binding). Therefore, high avidity in the first trimester effectively excludes an infection acquired during early pregnancy, which is reassuring. Low avidity suggests recent infection and warrants further investigation with amniocentesis.

Amniocentesis with PCR

When serologic testing suggests recent maternal infection, the next step is amniocentesis with PCR for T. gondii DNA in amniotic fluid. This should be performed no earlier than 18 weeks of gestation and at least 4 weeks after suspected maternal infection to allow adequate sensitivity (the parasite needs time to reach the amniotic fluid via fetal urination). PCR has high specificity (approaching 100%) but sensitivity ranges from 65-92%, so a negative result does not completely exclude fetal infection.

Fetal ultrasound is performed concurrently to evaluate for structural abnormalities (ventriculomegaly, echogenic foci in the brain, hepatomegaly, ascites, growth restriction).

4. Management and Treatment

Clinical Scenario	Treatment	Details
Maternal seroconversion, fetal infection NOT confirmed, <18 weeks	Spiramycin	1 g (3 million IU) orally every 8 hours, continued until delivery or until fetal infection is confirmed/excluded
Confirmed fetal infection (positive amniotic fluid PCR) OR seroconversion at ≥18 weeks	Pyrimethamine + Sulfadiazine + Leucovorin	Pyrimethamine 50 mg orally every 12 hours for 2 days (loading), then 50 mg daily; Sulfadiazine 75 mg/kg loading dose (max 4 g), then 50 mg/kg every 12 hours (max 4 g/day); Leucovorin (folinic acid) 10-25 mg daily throughout treatment
Confirmed congenital toxoplasmosis in neonate	Pyrimethamine + Sulfadiazine + Leucovorin	12 months of treatment; pyrimethamine 1 mg/kg daily for first 6 months, then every other day for 6 months; sulfadiazine 50 mg/kg twice daily; leucovorin 10 mg three times weekly
Active chorioretinitis in neonate	Add corticosteroids	Prednisone 1 mg/kg/day until resolution of active inflammation threatening vision

Spiramycin is a macrolide antibiotic that concentrates in the placenta. It reduces the rate of vertical transmission by approximately 60% but does not treat established fetal infection because it does not cross the placenta in therapeutic concentrations. It is the drug of choice when maternal seroconversion is detected early (before 18 weeks) and fetal infection has not yet been confirmed.

Once fetal infection is confirmed by amniocentesis PCR, or if seroconversion occurs at or after 18 weeks gestation (when the risk of transmission is high enough to warrant empiric treatment), the regimen is switched to pyrimethamine + sulfadiazine + leucovorin. Pyrimethamine inhibits dihydrofolate reductase, and sulfadiazine inhibits dihydropteroate synthase. Together they synergistically block sequential steps in the folate synthesis pathway of the parasite. Because pyrimethamine also suppresses human bone marrow folate metabolism, leucovorin (folinic acid, NOT folic acid) must always be co-administered to prevent dose-limiting hematologic toxicity (pancytopenia, megaloblastic anemia). Weekly complete blood counts are mandatory during treatment.

Pyrimethamine is teratogenic and contraindicated in the first trimester due to its antifolate mechanism. This is why spiramycin is used as the bridge therapy during early pregnancy.

For infected neonates, treatment continues for a full 12 months regardless of whether the infant is symptomatic at birth, because untreated subclinical infection frequently progresses to chorioretinitis and neurologic sequelae later in life. Corticosteroids are added only when there is active chorioretinitis threatening the macula or when CSF protein is markedly elevated (>1 g/dL), indicating intense CNS inflammation.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Looks Similar	Key Discriminator
Congenital CMV	Also causes intracranial calcifications, microcephaly, hepatosplenomegaly, chorioretinitis, blueberry muffin rash, SNHL	CMV calcifications are periventricular; toxoplasmosis calcifications are diffuse/scattered. CMV is the most common congenital infection overall and the leading infectious cause of sensorineural hearing loss.
Congenital Rubella	Causes cataracts, hearing loss, cardiac defects, blueberry muffin rash	Rubella triad: cataracts + sensorineural deafness + PDA (cardiac). Rubella does NOT typically cause intracranial calcifications or hydrocephalus.
Congenital Syphilis	Can present with hepatosplenomegaly, rash, osteochondritis, snuffles	Syphilis causes osteochondritis/periostitis on radiograph, rhinitis ("snuffles"), and a maculopapular rash involving palms and soles. No intracranial calcifications. Diagnosed with RPR/VDRL confirmed by FTA-ABS.
Infectious Mononucleosis (maternal)	Maternal lymphadenopathy, fatigue, atypical lymphocytes on smear	EBV causes posterior cervical lymphadenopathy with pharyngitis and a positive heterophile (monospot) test. No risk of congenital transmission.
Lymphoma	Persistent, painless lymphadenopathy in reproductive-age woman	Constitutional B-symptoms (drenching night sweats, weight loss >10%, fever), and diagnosis requires lymph node biopsy showing Reed-Sternberg cells (Hodgkin) or monoclonal populations.
Congenital Herpes (HSV)	Neonatal encephalitis, skin vesicles, chorioretinitis	HSV is acquired during passage through the birth canal (peripartum), NOT transplacentally. Presents with grouped vesicles, temporal lobe predilection on imaging, and diagnosed by viral PCR of CSF or vesicle fluid.

6. Traps and High-Yield Pearls

The single most common trap in exam questions on this topic is confusing the calcification pattern. When a vignette describes a neonate with intracranial calcifications, the test-writer expects you to immediately ask: are they diffuse or periventricular? Diffuse calcifications point to toxoplasmosis; periventricular calcifications point to CMV. Students who do not make this distinction will pick the wrong TORCH infection.

A second frequent trap involves the IgG avidity test. A vignette may present a pregnant woman with both IgG and IgM positivity and then offer treatment options. The correct next step is NOT to start treatment immediately. The answer is to order IgG avidity testing to determine whether the infection was acquired recently or before conception. High avidity in the first trimester is reassuring and prevents unnecessary treatment and invasive testing.

Another tested concept is the inverse relationship between transmission risk and disease severity by gestational age. Test-writers may describe a third-trimester infection and ask about expected fetal outcomes. The answer is that while transmission is very likely, the disease is usually mild or subclinical. Conversely, first-trimester infections transmit less frequently but cause devastating disease when they do.

Students also confuse leucovorin (folinic acid) with folic acid. Only leucovorin bypasses the dihydrofolate reductase block caused by pyrimethamine. Giving folic acid instead would be ineffective and would also antagonize the antiparasitic action of the drug.

Finally, remember that spiramycin prevents transmission but does not treat the fetus, and pyrimethamine is contraindicated in the first trimester. Questions testing the switch from spiramycin to pyrimethamine-sulfadiazine hinge on whether fetal infection has been confirmed and the gestational age at the time of diagnosis.

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