Toxoplasmosis (Congenital)

Congenital toxoplasmosis results from transplacental transmission of Toxoplasma gondii during primary maternal infection in pregnancy. 70–90% of infected neonates are asymptomatic at birth, but up to 90% develop late sequelae (chorioretinitis, neurodevelopmental delay, hearing loss) without treatment. [1-2] The classic triad of chorioretinitis, hydrocephalus, and intracranial calcifications is rare but highly suggestive. [3]

1. History

• Maternal history is paramount: Ask about seroconversion during pregnancy, timing of infection relative to gestational age, and whether prenatal treatment was administered [4-5]
• Exposure risks: consumption of raw/undercooked meat, contact with cat feces, gardening without gloves, contaminated water [2]
• Timing of maternal infection determines severity vs. transmission rate:
  • First trimester: low transmission (~10–15%) but highest severity if infected [6-7]
  • Third trimester: high transmission (>60%) but lower severity [2]
• Prior maternal serostatus: infection acquired >3 months before conception carries essentially zero congenital transmission risk [8]
• Prenatal screening results (IgG/IgM), amniocentesis PCR results, prenatal ultrasound findings [5]

2. Alarm Features

• Hydrocephalus (progressive head enlargement, bulging fontanelle, sunsetting eyes) [3-4]
• Seizures at birth or in the neonatal period [1][4]
• Severe thrombocytopenia with petechiae/purpura [1]
• Severe jaundice with hemolysis and pancytopenia [9]
• Microcephaly suggesting severe early gestational infection [10]
• Signs of generalized systemic disease: hepatosplenomegaly, ascites, diffuse rash [1-2]
• Active chorioretinitis threatening the macula [3]
• CSF protein >1,000 mg/dL (indicates severe CNS involvement, warrants corticosteroids) [1]

3. Medications

Preferred neonatal treatment (12-month course): [1]

• Pyrimethamine: loading dose 2 mg/kg/day PO × 2 days → 1 mg/kg/day × 2–6 months → 1 mg/kg 3 times weekly
• Sulfadiazine: 50 mg/kg PO twice daily
• Leucovorin (folinic acid): 10 mg PO or IM with each dose of pyrimethamine (to prevent hematologic toxicity)

Alternatives:

• If pyrimethamine unavailable: TMP-SMX (age-appropriate dosing) may substitute [1][11]
• Sulfonamide-intolerant: clindamycin 5–7.5 mg/kg/dose QID with pyrimethamine + leucovorin [1]
• Azithromycin has been used in case reports with good response [9]
• Corticosteroids (prednisone 1 mg/kg/day or dexamethasone) for CSF protein >1,000 mg/dL or significant mass effect; discontinue as soon as possible [1]

Prenatal treatment:

• <14 weeks gestation: spiramycin (not commercially available in the US; requires FDA assistance) [2][5]
• ≥14 weeks gestation: pyrimethamine + sulfadiazine + leucovorin [5]
• Prenatal treatment reduces infection risk (RR 0.34) and clinical manifestations (RR 0.30) [12]

Contraindications/Cautions:

• Pyrimethamine is teratogenic; requires CBC monitoring at least weekly while on daily dosing [1][13]
• Warn caregivers about signs of bone marrow suppression: sore throat, pallor, purpura, glossitis [13]

4. Diet

• Not directly applicable to the neonate
• Maternal prevention is key: avoid raw/undercooked meat, unpasteurized dairy, unwashed produce [2]
• Ensure adequate maternal nutrition during breastfeeding (breastfeeding is not contraindicated in toxoplasmosis)

5. Review of Systems

• Neurologic: seizures, abnormal tone (hyper- or hypotonia), poor feeding, irritability, lethargy, abnormal head circumference trajectory [4]
• Ophthalmologic: strabismus, nystagmus, leukocoria (white pupillary reflex) [3]
• Hematologic: pallor, petechiae, bruising [1]
• GI/Hepatic: jaundice, abdominal distension, hepatosplenomegaly [1-2]
• General: fever, rash (maculopapular), failure to thrive, generalized lymphadenopathy [1]
• Auditory: sensorineural hearing loss (may present later) [4]

6. Collateral History and Family History

• Maternal serologic history: pre-pregnancy IgG status, seroconversion timing, IgG avidity results [14-15]
• Maternal treatment during pregnancy and duration [12][16]
• Prenatal ultrasound findings (ventriculomegaly, calcifications, ascites, placental thickening) [3]
• Amniocentesis PCR results if performed [5]
• Cat ownership, dietary habits, travel to endemic regions, gardening exposure [2]
• Family history is not a significant factor (not a hereditary condition), but maternal HIV status is critical as it increases risk of reactivation and severity [1]

7. Risk Factors

• Primary maternal infection during pregnancy (not reactivation in immunocompetent hosts) [2][7]
• Maternal seronegative status at conception [2]
• Geographic region: higher prevalence in France, Brazil, parts of Africa [7][12]
• Consumption of raw/undercooked meat (especially lamb, pork, venison) [2]
• Contact with cat feces or contaminated soil [2]
• Lack of prenatal screening programs [11][16]
• Maternal HIV/immunosuppression: risk of reactivation and congenital transmission [1]
• Later gestational age at infection → higher transmission rate; earlier gestational age → more severe disease [4][6]

8. Differential Diagnosis

No signs of congenital toxoplasmosis are pathognomonic; the presentation overlaps with other TORCH infections: [3]

• Congenital CMV: most common congenital infection; periventricular calcifications (vs. diffuse/scattered in toxoplasmosis), sensorineural hearing loss, petechiae, hepatosplenomegaly
• Congenital rubella: cataracts, cardiac defects (PDA), sensorineural hearing loss, "blueberry muffin" rash
• Congenital syphilis: hepatosplenomegaly, snuffles, osteochondritis, mucocutaneous lesions, positive RPR/VDRL
• Congenital HSV: vesicular skin lesions, encephalitis, DIC, liver failure
• Congenital Zika: severe microcephaly, arthrogryposis, subcortical calcifications
• Congenital lymphocytic choriomeningitis virus (LCMV): hydrocephalus, chorioretinitis, periventricular calcifications
• Neonatal sepsis: may mimic systemic toxoplasmosis with hepatosplenomegaly, jaundice, thrombocytopenia

Key distinguishing feature: Intracranial calcifications in toxoplasmosis are typically diffuse/scattered throughout the parenchyma, whereas CMV calcifications tend to be periventricular. [1][10]

9. Past Medical History

• Prenatal care records: frequency and results of serologic screening [11]
• Maternal treatment history (spiramycin vs. pyrimethamine-sulfadiazine, timing of initiation) [12][16]
• Prenatal imaging findings [3]
• Birth history: gestational age, birth weight, APGAR scores
• Prior pregnancies affected by toxoplasmosis (rare if immunocompetent, as prior infection confers immunity) [7]
• Maternal HIV status and CD4 count [1]

10. Physical Exam

• Head circumference: macro- or microcephaly; bulging fontanelle (hydrocephalus) [4]
• Neurologic: tone abnormalities, seizure activity, developmental reflexes, sunsetting sign [4]
• Eyes: fundoscopic exam for chorioretinitis (white retinal lesions with minimal hemorrhage), strabismus [1][3]
• Skin: maculopapular rash, petechiae, jaundice [1]
• Abdomen: hepatosplenomegaly, ascites [1-2]
• Lymph nodes: generalized lymphadenopathy [1]
• Vital signs: fever may be present in systemic disease

11. Lab Studies

Serologic diagnosis: [1][15]

• Toxoplasma-specific IgM (neonatal serum): positive in ~60–77% of infected neonates at birth
• Toxoplasma-specific IgA: may be more sensitive than IgM in some assays, though 20–30% of infected neonates will be missed by IgA/IgM alone [1]
• Toxoplasma-specific IgG: persistence beyond 12 months of age confirms congenital infection (maternal IgG crosses placenta and wanes by ~6–12 months)
• Compared immunological profile (CIP)/Western blot: detects neosynthesized IgG/IgM; 98% sensitivity in first 10 days of life [17]
• IgG avidity testing (maternal): low avidity suggests recent infection [14-15]

PCR: [1]

• T. gondii DNA PCR on CSF, blood (buffy coat), urine, placental tissue
• Reference laboratory testing recommended (e.g., Palo Alto Medical Foundation Toxoplasma Serology Laboratory) [15]

Additional labs:

• CBC with differential: anemia, thrombocytopenia, neutropenia [1]
• LFTs, bilirubin (direct and indirect) [9]
• CSF analysis: protein, cell count, glucose, PCR [1]
• Reticulocyte count if hemolysis suspected [9]

Monitoring on treatment: Weekly CBC while on daily pyrimethamine; at least monthly on less-than-daily dosing [1]

12. Imaging

• Head CT (non-contrast): first-line for detecting intracranial calcifications (diffuse, scattered throughout parenchyma) and hydrocephalus [1]
• Brain MRI: more sensitive for parenchymal lesions, white matter abnormalities, and basal ganglia involvement; better characterization of ventriculomegaly [1]
• Prenatal ultrasound findings that may have been noted: intracranial calcifications, ventricular dilatation, hepatic enlargement, ascites, increased placental thickness [3]
• Imaging is mandatory in all suspected cases to assess for hydrocephalus and calcifications [1][18]

13. Special Tests

• Comprehensive ophthalmologic examination (dilated fundoscopy): mandatory at diagnosis and serially throughout childhood [1][19]
• Auditory brainstem response (ABR): screen for sensorineural hearing loss [1]
• Neurodevelopmental assessment: baseline and serial evaluations [4]
• Lumbar puncture: CSF protein, cell count, T. gondii PCR [1]
• Parasite isolation: mouse inoculation or tissue culture from CSF, blood, placenta, urine (reference lab) [1]
• Amniocentesis PCR (prenatal, ≥18 weeks gestation): sensitivity ~65–90% for fetal infection [5-6]

14. ECG

• Not routinely indicated unless clinical suspicion for myocarditis/cardiomyopathy, which is a rare manifestation of disseminated toxoplasmosis [1]
• If suspected: ECG may show conduction abnormalities, ST changes, or arrhythmias; echocardiography is more informative

15. Assessment

Severity stratification: [4][10][20]

• Subclinical (majority at birth): normal exam, identified only by screening; still at high risk for late sequelae without treatment
• Mild/moderate: isolated chorioretinitis or scattered calcifications without hydrocephalus
• Severe: hydrocephalus, extensive calcifications, microcephaly, seizures, generalized systemic disease

Key prognostic factors: [4]

• Gestational age at maternal infection (earlier = more severe)
• Whether prenatal treatment was administered (4-fold lower risk of clinical features at birth with treatment) [16]
• Timing of postnatal treatment initiation (treatment within first 2 months is protective against new retinochoroidal lesions) [21]
• Parasite genotype virulence (Type I and atypical strains in South America tend to be more virulent) [4]

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 in the National Collaborative Chicago-Based Study. [20]

16. Treatment Plan

Initial stabilization:

• Assess for and manage hydrocephalus (neurosurgical consultation for CSF shunting or endoscopic third ventriculostomy if symptomatic) [22]
• Manage seizures with anticonvulsants as needed [1]
• Treat severe jaundice/hemolysis (phototherapy, exchange transfusion if indicated) [9]

Pharmacologic treatment: [1-2]

• Pyrimethamine + sulfadiazine + leucovorin × 12 months (see dosing in Medications section above)
• Corticosteroids if CSF protein >1,000 mg/dL or significant mass effect; taper as soon as clinically feasible [1]

Monitoring during treatment:

• Weekly CBC while on daily pyrimethamine; monthly on thrice-weekly dosing [1]
• Serial ophthalmologic exams [19]
• Serial head imaging to monitor hydrocephalus/calcifications
• Neurodevelopmental assessments

Surgical:

• Child's Nervous System[22]

17. Disposition

• Admit all symptomatic neonates for initial workup, treatment initiation, and monitoring
• Admit if hydrocephalus, seizures, severe jaundice, significant cytopenias, or hemodynamic instability
• Asymptomatic neonates identified by screening may be managed outpatient with close follow-up after initial workup (including LP, head imaging, ophthalmologic exam) is completed [23]
• Infectious disease consultation is recommended for all confirmed or suspected cases [1]
• Neurosurgery consultation for hydrocephalus [22]
• Ophthalmology consultation for all cases [1]

18. Follow Up / Return Precautions

Follow-up schedule:

• Weekly CBC during daily pyrimethamine therapy [1]
• Ophthalmologic exams: at diagnosis, then every 3 months during the first year, then at least annually; retinochoroiditis can develop well into adulthood with peak incidences at 7 and 12 years of age [19][24]
• Audiology: at diagnosis and periodically (sensorineural hearing loss may be delayed) [4]
• Neurodevelopmental monitoring: serial assessments through childhood [20]
• Serologic follow-up: IgG levels monitored to confirm congenital infection (persistence beyond 12 months) or resolution (decline of passively transferred maternal antibody) [1]

Return precautions (counsel caregivers):

• Increasing head circumference, bulging fontanelle, vomiting, irritability, lethargy (worsening hydrocephalus)
• New seizure activity
• Pallor, petechiae, fever, sore throat (pyrimethamine-related bone marrow suppression) [13]
• Visual changes or strabismus (new chorioretinitis)
• Poor feeding, developmental regression

Expected course: With 12 months of treatment, >72% of infants even with moderate-to-severe neurologic disease at birth achieve normal cognitive outcomes; 91% of those without substantial neurologic disease do not develop new eye lesions. [20] However, lifelong ophthalmologic surveillance is warranted given the risk of late retinochoroiditis. [19][24]

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