TABLE 9

Laboratory, Radiographic, and Clinical Evaluation of Fetuses and Infants With Suspected CT, According to the PAMF-TSL

Fetus
 1. Maternal Toxoplasma serology and amniocentesis at or after 18 weeks of gestation for AF Toxoplasma PCR
2. Fetal ultrasound every month until delivery
Newborn infant
Laboratory workup
  • Peripheral blood for Toxoplasma IgG, IgM, and IgA (if IgA also available at commercial laboratory) can be sent to commercial laboratories as soon as possible after birth. However, testing of infants with suspected congenital toxoplasmosis should be performed at a toxoplasmosis reference laboratory, where the Toxoplasma IgG dye test, the Toxoplasma IgM ISAGA, and the Toxoplasma IgA ELISA (and also additional testing with Toxoplasma PCR in blood/urine/CSF) are performed.
  • Neonatal testing should be performed at a reference laboratory for toxoplasmosis. The more sensitive Toxoplasma IgM ISAGA test (performed only in reference laboratories) should be ordered. Negative Toxoplasma IgM ELISA at commercial hospital-based, clinic-based, or any other nonreference laboratories cannot exclude the diagnosis of CT, even in the absence of positive Toxoplasma IgA results.
 • Toxoplasma IgG
  • Neonatal Toxoplasma IgG antibodies should be tested in parallel with maternal Toxoplasma IgG antibodies. Without maternal serologic test results, appropriate interpretation of neonatal serologic test results may be tenuous unless the infant is found to be completely seronegative for Toxoplasma IgG, IgM ISAGA, and IgA (provided that the infant and the mother were capable of producing immunoglobulins).
 • Toxoplasma IgM (ISAGA)
  • Whenever a Toxoplasma IgM ISAGA test result is positive, reasons for false-positive test results should be considered (eg, caused by blood product transfusion or IVIg infusion), and the test should be repeated at least 7 days after last transfusion.
  • Moreover, if there is concern for false-positive Toxoplasma IgM results because of possible contamination of infant’s blood with maternal blood during labor, the test should be repeated at least 5 days after birth (half-life of Toxoplasma IgM antibodies is ∼5 days).183
 • Toxoplasma IgA
  • Whenever a Toxoplasma IgA test result is positive, reasons for possible false-positive test results should be considered (eg, caused by blood product transfusion or IVIg infusion), and the test should be repeated at least 7 days after last transfusion.
  • Moreover, if there is concern for false-positive Toxoplasma IgA results because of possible contamination of infant’s blood with maternal blood during labor, the test should be repeated at least 10 days after birth (half-life of Toxoplasma IgA antibodies is ∼10 days).183
 • If maternal serologic test result was suggestive of an acute primary infection acquired very late in gestation, initially negative Toxoplasma IgM and IgA results at birth could also be attributable to delayed production of those antibodies, and repeat testing 2 to 4 weeks after birth and every 4 weeks thereafter until 3 months of age might be considered in such cases.
 • Toxoplasma PCR
  • Peripheral blood Toxoplasma PCR, urine Toxoplasma PCR, and CSF Toxoplasma PCR should be performed when there is strong suspicion of CT, as soon as possible after birth.
  • Specifically, CSF Toxoplasma PCR should be considered in the following casesa:
   a. infants with positive Toxoplasma IgM ISAGA and/or IgA ELISA;
   b. infants born to mothers with confirmed acute T gondii infection during pregnancy who had a positive Toxoplasma AF PCR and/or abnormal fetal ultrasonographic findings suggestive of CT independently whether antepartum treatment was received; and
   c. infants born to mothers with confirmed recently acquired T gondii infection during pregnancy, particularly those who likely had acquired the infection in the second or third trimester (even if AF PCR and/or fetal ultrasonography were negative) and had not received any antepartum anti-Toxoplasma treatment.
 • CSF Toxoplasma PCR could be deferred in infants with low suspicion of CT, such as asymptomatic infants at birth whose mothers were diagnosed in the first trimester of pregnancy, had received antepartum treatment (spiramycin), had negative Toxoplasma AF PCR, and had normal monthly fetal ultrasonography results and the infants were asymptomatic and had negative Toxoplasma IgM ISAGA and IgA ELISA results at birth.
 • CSF analysis (CSF cell count, differential, protein, and glucose).
 • Complete blood count and liver function tests
Clinical evaluation
 • Detailed physical examination
  If CT has been confirmed:
   o at birth (along with detailed maternal clinical history); every 2–3 months afterward during the first year of life and every 4–6 months after the first year
  If CT has not been confirmed but also has not been ruled out:
   o detailed physical examination at birth and every 2–3 months afterward during the first year of life and every 4–6 months after the first year (while continuing serologic testing every 4–6 weeks to document appropriate decrease in Toxoplasma IgG titers, according to the half-life of IgG, ∼30 days, until complete disappearance)
 • Pediatric neurologic evaluation
  If CT has been confirmed:
   • at birth and every 2–3 months afterward during the first year of life and every 4–6 months after the first year
  If CT has not been confirmed but also has not been ruled out:
   • neurologic evaluation at birth and every 2–3 months afterward during the first year of life and every 4–6 months after the first year of life (while continuing serologic testing every 4–6 weeks to document appropriate decrease in the Toxoplasma IgG titers, according to the half-life of IgG, ∼30 days, until complete disappearance)
 • Pediatric ophthalmologic examination
 If CT has been confirmed:
  • during the first year of life if CT: ophthalmologic evaluation at birth and every 3–4 months (preferably by a retinal specialist)
  • during the second year of life: ophthalmologic evaluation every 4–6 months
  • during the third year of life if CT: ophthalmologic evaluation every 6 months
      Even if evidence of chorioretinitis has not been found in the initial ophthalmologic evaluation, close serial ophthalmologic follow-up is still indicated for infants with suspicion of CT.b
      If evidence of active Toxoplasma chorioretinitis has been found, closer follow-up might be indicated.
 If CT has not been confirmed but also has not been ruled out:
  • ophthalmologic evaluation at birth and every 2–3 months afterward during the first year of life and every 4–6 months after the first year (while continuing serologic testing every 4–6 weeks to document appropriate decrease in Toxoplasma IgG titers, according to the half-life of IgG, ∼30 days, until complete disappearance)
 • Auditory brainstem responses
  If CT has been confirmed:
   • shortly after birth and yearly audiologic evaluation afterward for the first 3 years of life
  If CT has not been confirmed but also has not been ruled out:
   • shortly after birth
Imaging evaluation
 • Computed tomography of the head should be considered when there is suspicion of CT to evaluate for the presence of intracranial calcifications, ventriculomegaly, hydrocephalus, etc. Head ultrasonography has been used mainly in cohorts in Europe,97,129,184 where the rate of symptomatic CT cases is very low compared with the United States. (Limited comparative data have shown that ultrasonography of the head had lower sensitivity than computed tomography of the head for intracranial calcifications96; published empirical data on the comparative performance of MRI, ultrasonography, or computed tomography of the head are lacking, but brain MRI could also be considered for the initial evaluation because it obviates the risk of radation associated with head CT.)
 • Abdominal ultrasonography at birth for intrahepatic calcifications and/or hepatosplenomegaly
  • For assistance with the diagnosis and management of infants or children with CT, contact Palo Alto Medical Foundation Toxoplasma Serology Laboratory, Palo Alto, CA; www.pamf.org/serology; http://www.pamf.org/serology/testinfo.html; telephone: (650) 853-4828; fax: (650) 614-3292; e-mail: toxolab@pamf.org; and/or Professor Rima McLeod from the Toxoplasmosis Center at the University of Chicago (Center of the National Collaborative Chicago-based Congenital Toxoplasmosis Study); telephone: (773) 834-4130. Additional information for the laboratory interpretation of serologic test results can be found in Press et al,185 Montoya et al,186 and Montoya et al.152 IVIG, intravenous immunoglobulin.

  • a Neonatal CSF serology: On the basis of available data routinely collected at the National Reference Laboratory for Toxoplasmosis, there is no evidence suggesting CSF serologic testing (CSF Toxoplasma IgM and/or CSF Toxoplasma IgG) could offer any incremental diagnostic information compared with the information gained from the following: (1) CSF cell count/protein/glucose and (2) CSF T gondii PCR and (3) CNS imaging alone for the diagnosis of CT and particularly for the diagnosis of CNS involvement during CT. (In the PAMF-TSL database [1992–2013], among 125 infants who had both Toxoplasma CSF PCR and CSF serologies [Toxoplasma IgG and IgM] performed, only 3 infants [2 neonates and a 15-month-old child] had positive CSF Toxoplasma IgM without a positive CSF Toxoplasma PCR. However, all 3 infants already had an established diagnosis of CT on the basis of serologic test results from blood samples that were diagnostic of CT [unpublished data].)

  • b Age at diagnosis of chorioretinitis: Only 7% of children with CT (20 of 281 CT cases) had chorioretinitis diagnosed at their first examination and only 40% (20 of 50) of children who had an eventual diagnosis of eye disease had lesions detected at their first examination.129,135 Wallon et al137 found, in cohorts of prenatally treated infants in France, that the initial eye lesions in children with CT were detected after 7 months of age in 75% of children and after 3 years of age in 50% of children with CT.