Congenital toxoplasmosis: Treatment, outcome, and prevention

INTRODUCTION — Toxoplasma gondii is a ubiquitous protozoan parasite that infects animals and humans. Toxoplasma infection typically is asymptomatic in immunocompetent hosts. However, serious disease can occur, most frequently in the setting of immunosuppression or congenital infection. The fetus, newborn, and young infant with congenital Toxoplasma infection are at risk of infection-associated complications, particularly retinal disease that can continue into adulthood.

The treatment, outcome, and prevention of congenital toxoplasmosis will be reviewed here. The clinical features and diagnosis of congenital toxoplasmosis are discussed separately. (See "Congenital toxoplasmosis: Clinical features and diagnosis".)

Toxoplasmosis in other patient populations is discussed in separate topic reviews:

●Pregnancy (see "Toxoplasmosis and pregnancy")

●Immunocompetent hosts (see "Toxoplasmosis: Acute systemic disease")

●HIV-infected patients (see "Toxoplasmosis in patients with HIV")

TREATMENT

Antiparasitic therapy

Whom to treat — Decisions about treatment and follow-up testing should be made in consultation with an infectious disease specialist and reference laboratory. Antiparasitic therapy is generally appropriate for infants (<12 months old) in whom a diagnosis of congenital toxoplasmosis is confirmed or highly likely, including [1,2]:

●Prenatally diagnosed infants – Infants diagnosed with congenital toxoplasmosis prenatally are treated postnatally, regardless of whether the mother received treatment during pregnancy. (See "Toxoplasmosis and pregnancy", section on 'Prenatal diagnosis'.)

●Symptomatic infection – For infants with clinical findings compatible with congenital toxoplasmosis (eg, chorioretinitis, intracranial calcifications, hydrocephalus), treatment is indicated if any of the following criteria are met:

•The diagnosis is confirmed with serology or polymerase chain reaction (PCR) performed by a reference laboratory. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Evaluation'.)

•The mother has recent documented T. gondii infection – In these infants, T. gondii infection should be confirmed (with maternal and infant serology and infant cerebrospinal fluid [CSF] PCR) and, in the absence of confirmative tests, alternative etiologies should be excluded (eg, congenital cytomegalovirus, Zika virus if maternal exposure risk is identified). (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Diagnosis' and "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Differential diagnosis' and "Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate".)

•Initial newborn serology results are equivocal – It is reasonable to start treatment in symptomatic infants with equivocal serology pending definitive testing, which may take months. If definitive testing does not confirm T. gondii infection, alternative diagnoses should be excluded. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Repeat testing' and "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Differential diagnosis'.)

●Asymptomatic or preclinical infection – For infants with confirmed T. gondii infection (with serology or PCR performed by a reference laboratory) who lack supportive clinical findings, we suggest antiparasitic treatment. In addition, it is reasonable to treat asymptomatic infants who have equivocal newborn serology, pending definitive testing (which may take months) [3]. The rationale for treating this group is to reduce the risk of late sequelae. Observational data suggest that early and prolonged treatment of asymptomatic infants may reduce long-term sequelae [4]. Deferring treatment in these infants is a reasonable alternative; however, there is a risk of late sequelae in untreated congenital toxoplasmosis. (See 'Efficacy' below.)

Treatment regimen

Preferred regimen — The preferred antiparasitic regimen consists of pyrimethamine plus sulfadiazine (or sulfamerazine or sulfamethazine) and folinic acid (leucovorin) [2,5-7]. Treatment protocols are not standardized, and there is considerable variation in practice in different parts of the world.

Data on comparative efficacy of different postnatal treatment protocols are lacking, and the choice depends on drug availability and the experience of the treating clinician or center [6]. Sulfamerazine and sulfamethazine are not available in the United States. The optimal doses and duration for these drugs are not established definitively and should be determined in consultation with specialists in pediatric infectious diseases.

We suggest:

●Pyrimethamine 2 mg/kg (maximum 50 mg/dose) once daily for two days, then 1 mg/kg (maximum 25 mg/dose) once daily for six months, and then 1 mg/kg (maximum 25 mg/dose) three times per week (ie, Monday, Wednesday, and Friday) to complete one year of therapy, plus

●Sulfadiazine 50 mg/kg every 12 hours, plus

●Folinic acid (leucovorin) 10 mg three times per week during and for one week after pyrimethamine therapy

The infant should be weighed weekly and the doses adjusted for weight gain [1]. Pyrimethamine should be temporarily withheld if the absolute neutrophil count (ANC) falls below 500 cells/microL. The dose of folinic acid may be increased as needed if the ANC falls below 1000 cells/microL. (See 'Adverse effects' below and 'Therapeutic monitoring' below.)

One year of treatment is recommended by many experts, though some centers extend treatment up to two years [1-3,5-9].

Glucocorticoids (prednisolone 0.5 mg/kg twice daily) are added if CSF protein is >1 g/dL or when active chorioretinitis threatens vision (see 'Treatment of new-onset chorioretinitis' below). Glucocorticoids are continued until elevated CSF protein or active chorioretinitis lesions are resolved. The benefit of adjunctive glucocorticoids in this setting is supported by observational data and expert opinion [1,2,7]; controlled trials are lacking.

Special considerations — Special considerations are necessary for infants with any of the following [1,10]:

●Renal insufficiency – Sulfadiazine is excreted in the kidney, and the dose may require adjustment for infants with renal insufficiency.

●Glucose-6-phosphate dehydrogenase (G6PD) deficiency – Sulfadiazine may cause hemolysis in infants with G6PD deficiency; clindamycin (20 to 30 mg/kg per day divided in four doses) may be substituted for sulfadiazine in infants with G6PD deficiency. The combination of pyrimethamine and clindamycin has been used to successfully treat toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome (AIDS) [11-13], and the authors of this topic have used it successfully in a child with severe G6PD deficiency. However, high-dose pyrimethamine has been reported to cause hemolytic anemia in some patients with G6PD deficiency, and such patients should be monitored closely. Combination antiparasitic therapy is recommended for treating Toxoplasma infection, so in children not able to take either pyrimethamine or sulfadiazine, clindamycin plus an alternative agent should be selected in consultation with an infectious disease expert.

●Allergy to sulfadiazine – For infants who develop an allergy to sulfadiazine, clindamycin may be substituted [11]. Desensitization has also been described [14].

●Other medications – Sulfadiazine may prolong the half-life of phenytoin (via interference with hepatic microsomal enzymes) and decrease excretion rate of clonazepam. Dosing adjustments may be necessary for these agents. Concomitant administration of carbamazepine and zidovudine may exacerbate bone marrow suppression and neutropenia.

Efficacy — The evidence for the efficacy of postnatal antiparasitic therapy for congenital toxoplasmosis comes from observational studies in infants, indirect evidence from clinical trials in adults with HIV, and in vitro studies [10,11,15-18]. There are no placebo-controlled randomized trials of antiparasitic therapy in infants. Cohort studies have demonstrated improved outcomes among treated infants compared with historical controls [1,4,19,20].

In the National Collaborative Chicago-Based Congenital Toxoplasmosis Study, 120 infants with congenital toxoplasmosis received 12 months of combination therapy (daily sulfadiazine, thrice-weekly folinic acid, plus two or six months of daily pyrimethamine followed by thrice-weekly pyrimethamine for the remainder of the year) [1,19]. Compared with historical controls (untreated or treated for one month), 12-month combination therapy was associated with improved neurologic, cognitive, ocular, and auditory outcomes over an average follow-up of 10.5 years [19]. Signs of active infection resolved within weeks in all treated infants who were evaluated [10]. Among infants with mild disease at birth (n = 24), all had normal cognitive, neurologic, and auditory outcomes; two infants (9 percent) developed new eye lesions. Among infants with moderate to severe disease at birth (n = 96), 72 percent had normal neurologic and cognitive outcomes and no patients had hearing loss. Approximately 85 percent had impaired vision, which was most often due to retinal disease present at birth; 36 percent developed new eye lesions during follow-up. There were no deaths in the mildly affected cohort and 11 deaths (11 percent) in the severely affected cohort. The average age at time of death was 4.9 years.

In another study, the New England Regional Toxoplasma Working Group described the outcomes of 49 infants identified through a serologic screening program [4]. The infants in this cohort had mild or subclinical infection without apparent disease at birth, though evaluation performed after being identified revealed elevated CSF protein, intracranial calcifications, or retinal lesions in 40 percent. Most infants were treated for one year (with the exception of one infant who died at two months of age and four others whose parents/caregivers discontinued treatment after six to eight months). Treatment regimens varied somewhat, but 40 of the 49 infants received the same regimen (pyrimethamine daily for six months then every other day for six months, sulfadiazine twice daily for 12 months, and folinic acid adjusted for hematologic changes). After treatment, only one child had a neurologic deficit (hemiplegia that was attributed to a cerebral lesion present at birth). Among the 39 children who had ophthalmologic follow-up at one to six years of age, four had lesions that may have developed postnatally. These findings suggest that early and prolonged treatment of asymptomatic infants may reduce the risk of long-term sequelae.

Adverse effects — The main side effect of pyrimethamine is neutropenia, which often occurs in conjunction with a viral illness [1,4,21]. Neutropenia generally resolves when the folinic acid dose is increased. In some cases, modification of the pyrimethamine dose is required. Other adverse effects may include aplastic anemia, hepatotoxicity, and hypersensitivity.

Skin exanthems (hives, allergic dermatitis) are the most common allergic reactions to sulfadiazine. Severe sulfadiazine-associated neutropenia can occur rarely and should be considered if neutropenia persists despite increased doses of folinic acid and/or temporary discontinuation of pyrimethamine [22].

Administration of a second sulfonamide drug (eg, trimethoprim-sulfamethoxazole) during combination therapy with pyrimethamine-sulfadiazine should be avoided because it may result in sustained bone marrow suppression [1].

Therapeutic monitoring — Complete blood counts (CBCs) should be monitored during therapy to evaluate drug-induced neutropenia and hemolysis (for patients with G6PD deficiency). We suggest the following intervals for monitoring the CBC:

●Once per week after starting daily pyrimethamine; the CBC can be spaced to every two weeks if counts remain stable

●Once per month when taking pyrimethamine every other day

The more frequent intervals should be used if there is an intercurrent illness or neutropenia. The folinic acid (leucovorin) dose should be increased if the ANC falls below 1000 cells/microL. Pyrimethamine should be temporarily withheld if the ANC is below 500 cells/microL. Persistent neutropenia despite withholding pyrimethamine may be caused by sulfadiazine.

Liver and renal function tests (aspartate transaminase and alanine transaminase or gamma-glutamyl transferase, bilirubin, alkaline phosphatase, blood urea nitrogen, and creatinine) are monitored every three to six months and as needed for follow-up of abnormal results.

Disease monitoring — Serologic follow-up is recommended for children with congenital toxoplasmosis until 18 months of age. Clinical follow-up is recommended throughout early childhood because of the risk of late sequelae. Routine ophthalmologic evaluations are especially important for infants and young children because they are unable to report changes in vision.

We suggest the following schedule for follow-up (table 1):

●Serologies – Serum Toxoplasma-specific immunoglobulins G and M (IgG and IgM) determinations every three to six months until 18 months or completion of therapy, whichever is longer. This is especially important for unconfirmed but highly suspected cases. During treatment, Toxoplasma-specific IgM typically falls to undetectable levels, but it commonly increases once therapy is discontinued. Similarly, some children have Toxoplasma-specific IgG rebound several months after completion of therapy. The clinical significance of these rebound titers is uncertain, but obtaining serology at the end of treatment and at one, three, and six months off of treatment may be of diagnostic value for the unconfirmed, highly suspected cases [1,23,24]. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Serology'.)

●Physical examination – Periodic physical examination should include:

•Neurodevelopmental assessments (see "Developmental-behavioral surveillance and screening in primary care")

•Routine eye and vision assessments (see "Vision screening and assessment in infants and children")

•Hearing assessment (see "Hearing loss in children: Screening and evaluation")

These assessments focus on identifying late manifestations of congenital toxoplasmosis infection. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Late manifestations'.)

●Eye examination – Repeated eye examinations by an ophthalmologist experienced with identifying Toxoplasma chorioretinal lesions in infants and toddlers should be obtained every three months until the age of 18 months, then every 6 to 12 months. The frequency of examinations should be adjusted as needed if retinal disease is present. Ophthalmologic examination should be performed earlier than scheduled if any symptoms that may be related to ocular disease occur. Some specialists recommend ophthalmology follow-up every three to six months until the child is old enough to report vision changes reliably [9]. The risk of new or recurrent chorioretinal disease is known to persist into adulthood, so a schedule of every 6- to 12-month examinations may be useful through adolescence.

●Neurologic examination – Pediatric neurologic examination every three to six months until one to two years of age. The frequency and duration of pediatric neurology follow-up are determined by the presence of neurologic abnormalities. (See "Detailed neurologic assessment of infants and children".)

Treatment of new-onset chorioretinitis — New-onset active chorioretinitis occurring beyond the initial period of treatment should be treated with combination pyrimethamine (plus folinic acid) and sulfadiazine therapy. Many experts also treat vision-threatening lesions with glucocorticoids (ie, prednisolone or prednisone) until acute inflammation resolves. However, it is unclear if adding a glucocorticoid to the treatment regimen improves efficacy [25]; some ophthalmologists use glucocorticoids only if there is clouding of the vitreous (vitreitis).

The doses for these agents are as follows [3]:

●Pyrimethamine 2 mg/kg (maximum 50 mg/dose) once daily for two days, then 1 mg/kg (maximum 25 mg/dose) once daily

●Sulfadiazine 75 mg/kg, then 12 hours later, 50 mg/kg twice per day

●Folinic acid (leucovorin) 10 mg three times per week

●Prednisolone (or prednisone) 1 mg/kg per day divided in two doses; maximum 40 mg/day

Pyrimethamine and sulfadiazine are continued until approximately two weeks after acute inflammation has resolved [3]. Folinic acid is continued during pyrimethamine therapy and for one week after pyrimethamine is discontinued. Prednisolone is continued until inflammation subsides and then is rapidly tapered (typical duration two to four weeks).

Acute inflammation often has a white, fluffy appearance but is not always easy to discern, especially when adjacent to an old pigmented scar. With appropriate treatment, acute lesions generally stabilize or resolve within four to eight weeks [26].

PROGNOSIS

Natural history of untreated disease — The prognosis in untreated infants with overt congenital toxoplasmosis disease at birth is generally poor. This was demonstrated in a case series of 156 patients from the 1940s, of whom 152 had overt neurologic or generalized manifestations of disease [27]. Mortality was 12 percent. The majority of patients developed intellectual disability (93 percent), seizures (81 percent), spasticity/palsies (70 percent), and severely impaired vision (60 percent). Other sequelae included hydrocephalus or microcephaly (33 percent) and deafness (15 percent).

Children with subclinical infection also may develop cognitive, motor, auditory, and visual impairment, but it is unclear how commonly this occurs [3,28-31]. In some reports, new chorioretinitis lesions developed in up to 90 percent of children with untreated congenital Toxoplasma infection [28,29].

Prognosis with treatment — Early and prolonged treatment appears to reduce the risk of adverse neurologic and vision outcomes, as discussed above (see 'Efficacy' above). However, treated infants remain at risk for developing sequelae later in life [3,22,32-36]. Available antiparasitic drugs are active against the tachyzoite form of T. gondii but do not effectively eradicate the bradyzoite form from the eye and central nervous system (CNS). Thus, recurrence of eye and CNS disease may occur after cessation of treatment. Chorioretinitis can result in retinal damage and loss of vision, which should be monitored closely.(See 'Disease monitoring' above.)

Reported risk factors for poor neurologic outcome include [1,19]:

●Severe CNS disease apparent at birth

●Prolonged uncorrected hydrocephalus

●Cerebrospinal fluid (CSF) protein >1 g/dL

●Cerebral atrophy

●Severe vision impairment

●Late diagnosis (ie, delayed initiation of treatment)

●Inadequate treatment course (several months or less)

Neurologic complications appear to be uncommon when combination therapy is initiated early (ie, in utero or within one to two months after birth) and continued for at least one year. However, late neurologic manifestations can rarely occur. In a prospective cohort study of 477 patients who were treated for congenital toxoplasmosis (pre- and/or postnatally) and followed for a median of 10.5 years, 2 percent developed late neurologic abnormalities, including hydrocephalus, seizures, encephalopathy, cortical atrophy, and aphasia [36].

New-onset or recurrent chorioretinitis develops in approximately one-third of treated patients and can occur years after stopping treatment [19,36]. In the prospective cohort study described above, 30 percent of treated infants developed chorioretinitis at a median age of 3.1 years (range 0 to 20.7 years), with peaks at 7 years and 11 to 13 years [36]. In this study, the majority of patients with chorioretinitis had normal vision (81 percent of those with unilateral lesions and 73 percent of those with bilateral lesions) and very few patients (<2 percent) had deterioration in vision during follow-up.

PREVENTION — Strategies for prevention include:

●Avoidance of exposure – Avoiding exposure to sources of Toxoplasma is an important way to prevent infection. This is particularly important for seronegative women of childbearing age and immunocompromised patients. Specific avoidance measures are discussed separately. (See "Toxoplasmosis and pregnancy", section on 'Prevention'.)

●Maternal screening – The diagnosis of toxoplasmosis during pregnancy and screening pregnant women for toxoplasmosis are discussed separately. (See "Toxoplasmosis and pregnancy".)

●Prenatal treatment – Treatment of maternal toxoplasmosis during pregnancy to prevent fetal infection is discussed separately. (See "Toxoplasmosis and pregnancy", section on 'Dosing, administration, and side effects' and "Toxoplasmosis and pregnancy", section on 'Efficacy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Toxoplasmosis" and "Society guideline links: TORCH infections".)

SUMMARY AND RECOMMENDATIONS

●Whom to treat – Decisions about initiating antiparasitic treatment for suspected congenital toxoplasmosis and follow-up testing should be made in consultation with a pediatric infectious disease specialist. Our approach is generally as follows (see 'Whom to treat' above):

•Prenatal diagnosis – For infants diagnosed with congenital toxoplasmosis prenatally, we recommend antiparasitic treatment (whether or not the mother received treatment) (Grade 1B). (See "Toxoplasmosis and pregnancy", section on 'Prenatal diagnosis'.)

•Symptomatic infants – For infants with clinical findings compatible with congenital toxoplasmosis (eg, chorioretinitis, intracranial calcifications, and/or hydrocephalus) who have the diagnosis confirmed with serology or polymerase chain reaction (PCR), we recommend antiparasitic treatment (Grade 1B). In addition, for symptomatic infants who are born to mothers with recent Toxoplasma gondii infection and those whose initial serology results are equivocal, we suggest antiparasitic treatment pending definitive testing (which can take months) (Grade 2C). The approach to confirming the diagnosis is described in detail separately. In the absence of confirmative testing, alternative etiologies should be excluded. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Diagnosis' and "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Differential diagnosis'.)

•Asymptomatic infants – For infants with confirmed T gondii infection (with serology or PCR performed by a reference laboratory) who lack supportive clinical findings, we suggest antiparasitic treatment (Grade 2C). In addition, it is reasonable to treat asymptomatic infants who have equivocal newborn serology, pending definitive testing (which may take months). Deferring treatment in these infants is a reasonable alternative; however, there is a risk of late sequelae in untreated congenital toxoplasmosis. (See "Congenital toxoplasmosis: Clinical features and diagnosis", section on 'Late manifestations'.)

●Treatment regimen – The choice of regimen depends on drug availability and the experience of the treating clinician or center. For most patients, we suggest a regimen consisting of pyrimethamine plus sulfadiazine (or sulfamerazine or sulfamethazine) plus folinic acid (leucovorin) rather than other regimens (Grade 2C). Sulfamerazine and sulfamethazine are not available in the United States. We suggest a 12-month course of therapy rather than shorter or longer courses (Grade 2C). (See 'Treatment regimen' above.)

●Monitoring – During therapy, complete blood counts (CBCs) should be monitored to evaluate drug-induced neutropenia and hemolysis; liver and renal function tests are monitored every three to six months. During and after treatment, all children should have clinical follow-up throughout early childhood to monitor for late sequelae (table 1). Routine ophthalmologic evaluations are especially important for infants and young children because they are unable to report changes in vision.(See 'Therapeutic monitoring' above and 'Disease monitoring' above.)

●Prognosis – If untreated, most infants with symptomatic congenital toxoplasmosis develop serious long-term sequelae, including intellectual disability, seizures, motor deficits, impaired vision, hydrocephalus, and hearing loss. It is unclear how commonly these sequelae occur in infants with subclinical or asymptomatic infection. Early and prolonged treatment appears to reduce the risk of adverse neurologic and vision outcomes, but treated infants remain at risk for long-term sequelae, particularly new-onset or recurrent chorioretinitis. Long-term neurologic deficits generally correlate with the severity of disease at the time of diagnosis. (See 'Natural history of untreated disease' above and 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ruth Lynfield, MD, and Jennifer Lee, MD, MS, who contributed to an earlier version of this topic review.