Diagnosis, Treatment, and Prevention of Congenital Toxoplasmosis in the United States

Congenital toxoplasmosis (CT) is a parasitic disease that can cause significant fetal and neonatal harm. Coordinated efforts by pregnant women, researchers, physicians, and health policy makers regarding potential primary and secondary preventive measures for CT and their implementation may lead to a lower incidence of CT as well as lower morbidity and mortality rates associated with CT. In the United States, the age-adjusted seroprevalence of Toxoplasma gondii among women of childbearing age (15–44 years) has declined over time (15%, 11%, and 9% in 1988–1994, 1999–2004, and 2009–2010, respectively; among US-born women only, the seroprevalence rates during these time periods were 13%, 8%, and 6%, respectively). Thus, approximately 91% of women of childbearing age in the United States are susceptible to Toxoplasma infection. Should these women become infected during pregnancy and remain undiagnosed and untreated, they could deliver an infant with CT. However, the incidence of acute primary infection is likely very low in the current era and is probably much lower than the 1.1 in 1000 pregnant women originally reported in 1960s.There are 3 ways CT can occur. First, CT can develop through transmission of T gondii to the fetus from a previously seronegative, immunocompetent mother who acquired acute primary infection during pregnancy or within 3 months before conception. Second, CT can occur through reactivation of toxoplasmosis in a previously T gondii–immune pregnant woman who was severely immunocompromised during pregnancy. Third, CT can result after reinfection of a previously immune pregnant mother with a new, more virulent strain (eg, after international travel or after eating undercooked meat from areas where more virulent atypical strains predominate).In cohorts of women who have been screened routinely during pregnancy and treated accordingly once primary infection was diagnosed, the mother-to-child transmission (MTCT) rate was <5% after an acute primary maternal infection very early in pregnancy, but MTCT rates were much higher with acute maternal infections acquired later in pregnancy (15%, 44%, and 71% after maternal seroconversions [acute primary infections] at 13, 26, and 37 weeks of gestation, respectively).1 The risk of MTCT in untreated women may be higher. Factors (any or a combination) associated with an increased risk of MTCT are as follows: (1) acute T gondii infection during pregnancy, (2) immunocompromising conditions, (3) lack of antepartum treatment, (4) high T gondii strain virulence, and (5) high parasite load.The incidence of CT, according to early cumulative published data from the New England Newborn Screening Program over a 12-year period (1988–1999), was 0.91 cases per 10 000 live births, which would have translated to the birth of approximately 365 infants with CT in the United States each year. The incidence of CT decreased after 1999 and, over the past 9 years (2006–2014), was approximately 0.23 cases per 10 000 live births. The true incidence of CT in the United States might be higher, because the sensitivity of the newborn screening test (blot-spot immunoglobulin [Ig] M test) is approximately 50% to 75%, and fetal losses attributable to severe CT were not counted.Recent data from the National Reference Laboratory for Toxoplasmosis in the United States showed that 85% of 164 infants with CT identified over a period of 15 years were severely affected: 92% had chorioretinitis, 80% had intracranial calcifications, 68% had hydrocephalus, and 62% had all of these manifestations. These data were based on cases referred to reference toxoplasmosis centers in the United States, and they were not population based. The generalizability of these findings at a population level may be limited. The rate of symptomatic CT among infants diagnosed via the New England Newborn Screening program (1986–1992) was 40% (25% with eye disease at birth or follow-up and 29% with central nervous system [CNS] disease). However, in neonatal screening programs, spontaneous abortion, fetal demise, and pregnancy terminations attributable to severe CT are not captured. The rates of symptomatic CT in European cohorts are much lower than in the United States. Possible reasons for those disparities include differences in T gondii strains and the absence of antepartum screening and treatment of CT in the United States. In addition, differences between population-based, prospectively identified CT cases versus more selected cases referred to reference centers may bias reporting estimates.Evidence in favor of antepartum treatment benefits to decrease the risk of MTCT of CT is variable and accumulated from several observational studies. One randomized therapeutic trial has been conducted in pregnancy.2 European data from the Systematic Review on Congenital Toxoplasmosis (SYROCOT) international consortium, which performed a meta-analysis of individual patient data published in 2007,1 suggested that the odds of MTCT were 52% lower (odds ratio [OR]: 0.48; 95% confidence interval [CI]: 0.28–0.80) when antepartum treatment was promptly initiated within 3 weeks after maternal seroconversion as compared with ≥8 weeks. The overall risk of transmission among women with primary infection in France decreased from 29% to 24% (P = .022) after 1992, when monthly antepartum screening became mandatory. These rates do not represent rates of MTCT without compared with prenatal treatment, because the majority of the women in France diagnosed with acute Toxoplasma infection, even in the earlier period when the frequency of prenatal screening was less intense, were prenatally treated. These rates may call into question the efficacy of treatment in preventing MTCT, because women in the postimplementation era were more likely to be identified by serologic testing alone rather than by ultrasonographic abnormalities in the setting of established infection. An alternative explanation for this paradoxical phenomenon is that early prenatal screening and treatment led to a decrease in fetal deaths, and thus the effect on the risk of MTCT was not very prominent. In other words, with prompt initiation of prenatal treatment, children who would have otherwise died of CT survive, making the decrease in MTCT less impressive. Evidence that supports this hypothesis includes data from the same prospective cohort study from Lyon, France, by Wallon et al,3 published in 2013, which showed a significant reduction in symptomatic disease among infected pregnant women when comparing cases reported before 1995 with those after 1995, when amniotic fluid (AF) testing by polymerase chain reaction (PCR) was initiated (from 11% before 1995 to 4% after 1995; P < .001). In Austria, where there is a nationwide antepartum screening program (the Austrian Toxoplasmosis Register), Prusa et al4 reported a sixfold lower risk of MTCT in women who received antepartum treatment compared with untreated women (9% [87 of 1007] vs 51% [32 of 63]), but this finding may have also been related to the timing of identification during gestation. In a recently published retrospective cohort study by Hotop et al5 from Germany, where spiramycin is given until the 16th week of pregnancy, followed by at least 4 weeks of combination therapy with pyrimethamine, sulfadiazine, and folinic acid (independently of the infection status of the fetus, with subsequent treatment determined according to the infection status of the fetus), very low rates of MTCT of CT (4.8% [33 CT cases infants/685 pregnant women]) were reported. An early Cochrane systematic review by Peyron et al6 published in 2000 evaluated the effect of treatment in pregnancy and concluded that, despite more than 3200 articles, only 9 studies had evaluated the effectiveness of prenatal treatment on the risk of MTCT, and these results were conflicting, resulting in insufficient evidence to evaluate the efficacy of treatment.Some observational studies have evaluated the association of antepartum treatment and symptomatic infant disease. Recent reanalysis of data from 14 European centers7 suggested that antepartum treatment was associated with lower odds of severe neurologic sequelae in infants with CT (OR: 0.24; 95% CI: 0.07–0.71) (the authors advised caution in interpretation because the study included only 23 such very severely affected cases of CT and, of these, there were 9 terminations). In the Wallon et al3 prospective cohort study mentioned previously, the risk of symptomatic CT among infected mothers in France decreased from 11% to 4% (P < .001) after 1995 when T gondii testing with AF PCR assay was initiated, but the increase in the mild maternal infections included in the latter group may have played a role as well. Recent data from Germany by Hotop et al5 also showed a lower risk of symptomatic disease with early versus late initiation of maternal treatment (19% with early therapy versus 70% with late antepartum therapy; P = .006).One cost-effectiveness model was recently developed by Stillwaggon et al7 to evaluate the implementation of universal antepartum screening after the French protocol of monthly serologic screening during pregnancy (including confirmatory testing at a reference laboratory of any positive results) with antepartum treatment, fetal ultrasonography/AF PCR assay, and infant follow-up/treatment.8 This decision analysis made a number of assumptions, including a cost of $12 per test, an estimated cost of fetal death of over $6 million, and an incidence of acute primary maternal infection during pregnancy of 1 in 1000 (including additional sensitivity analyses). It also assumed that treatment was highly efficacious and inexpensive. Although the study concluded that screening in the United States would be cost-effective, it remains unclear whether these conclusions would be reached if data were used assuming higher costs of screening, lower costs of loss, and less efficacy of treatment. A previous decision analysis did not arrive at the same conclusion.9 An early Cochrane systematic review on treatments for toxoplasmosis during pregnancy published in 2000 suggested that in countries where screening or treatment is not routine, these technologies should not be introduced outside the context of a carefully controlled trial.6Infants with suspected/proven CT may need to be managed in consultation with toxoplasmosis reference centers in the United States. The diagnostic criteria for CT include any of the following: (1) persistence of positive Toxoplasma IgG antibodies beyond 12 months of age (gold standard); (2) positive Toxoplasma IgG antibodies and positive Toxoplasma IgM antibodies and/or positive Toxoplasma IgA antibodies; (3) positive Toxoplasma PCR assay results from amniotic fluid, peripheral blood, cerebrospinal fluid (CSF), urine, or other body fluids; and (4) positive neonatal Toxoplasma IgG antibodies (but negative Toxoplasma IgM and IgA antibodies) and serologic evidence of acute maternal T gondii infection during pregnancy and evidence of clinical manifestations suggestive of CT.At the National Reference Laboratory for Toxoplasmosis (Palo Alto, CA) and the Toxoplasmosis Center (Chicago, IL), clinical evaluation of infants with suspected CT includes detailed physical examination, neurologic evaluation, ophthalmologic examination (preferably by a retinal specialist), and brainstem auditory evoked responses. Imaging evaluation includes the following: (1) computed tomography of the head (or head ultrasonography) and (2) abdominal ultrasonography. If CT has not been confirmed but also has not been ruled out, an infant’s workup includes complete clinical evaluation and serial IgG antibody titers every 4 to 6 weeks after birth until complete disappearance of Toxoplasma IgG antibodies.At the National Reference Laboratory for Toxoplasmosis and the Toxoplasmosis Center, treatment of infants with suspected CT is continued for 12 months and includes pyrimethamine plus sulfadiazine plus folinic acid. Pyrimethamine: 2 mg/kg per day, orally, divided twice per day for the first 2 days; then from day 3 to 2 months (or to 6 months [considered for symptomatic CT]), 1 mg/kg per day, orally, every day; and after that, 1 mg/kg per day, orally, 3 times per weekSulfadiazine: 100 mg/kg per day, orally, divided twice per dayFolinic acid (leucovorin): 10 mg, 3 times per week In cases of severe chorioretinitis or elevated CSF protein concentration ≥1 g/dL, corticosteroids may be considered (after 72 hours of anti-Toxoplasma therapy).CT is a parasitic disease that can cause significant fetal and neonatal harm. Coordinated efforts by pregnant women, researchers, physicians, and health policy makers regarding potential primary and secondary preventive measures for CT and their implementation may lead to a lower incidence of CT as well as lower morbidity and mortality rates associated with CT. The purpose of this technical report is to summarize available information regarding the diagnosis, treatment, and prevention of CT.The following clinical areas were targeted:First, a PubMed search for publications in English language with the use of the following search strategies was performed: (1) (congenital toxoplasmosis) AND (mother to child transmission OR mother to fetus transmission OR mother to infant transmission) (up to September 15, 2014), (2) (congenital toxoplasmosis [ti]) AND (outcome OR follow-up OR chorioretinitis OR eye disease OR ocular disease OR intracranial calcifications OR ventriculomegaly OR hydrocephalus) (up to August 31, 2014), and (3) (toxoplasmosis [TI] AND United States) (January 1, 2004, to September 15, 2014) (see Supplemental Table 14). Second, the reference lists of key publications were screened to identify additional pertinent articles. Third, the evidence from some early key publications from cohorts of infants with CT whose mothers had not received antepartum treatment was also reviewed, because such older cohorts are more similar to the cohorts of children with CT still seen in the United States, where the majority of infants with CT are born to mothers without antepartum treatment. Fourth, we perused the systematic reviews already performed by the European Toxoprevention Study (EUROTOXO) group, the European Initiative for the study of CT on the following topics: (1) burden of disease from CT,10 (2) evaluation of diagnostic performance of diagnostic tests for CT,11 (3) assessment of postnatal treatment effects,12 (4) strategies for the prevention of CT,13 and (5) evaluation of adverse effects from antepartum and postnatal treatment of CT.14A total of 457 articles were screened; 403 articles were identified with PubMed searches (288 with the first 2 searches and 130 with the third search strategy), 50 additional articles were identified by hand-screening the reference lists of key publications, and 225 articles were finally considered to be pertinent to this technical report and were included.The identified evidence consisted of observational studies. Currently, there are no randomized controlled trials (RCTs) performed for the evaluation of different therapeutic approaches for CT, according to an early systematic review from the Cochrane Pregnancy and Childbirth Group (up to date as of February 2006) by Peyron et al.6The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system15,16 was used to assess the quality of evidence. The GRADE system is a step toward recognition that evidence from observational studies might become the vehicle for generating evidence for policy makers, especially in situations in which RCTs are considered unethical and large treatment effects have been documented in observational studies. According to the GRADE system (Fig 1), the quality of evidence for the effectiveness of antepartum screening and treatment would be considered of high quality on the basis of the following 2 criteria: “exceptionally strong evidence from unbiased observational studies” and “further research is unlikely to change our confidence in our estimates.” The quality of evidence for the effectiveness of postnatal treatment would be considered of moderate quality on the basis of the criterion “exceptionally strong evidence from unbiased observational studies”; however, “further research, if performed, is likely to affect our confidence in the estimate of efficacy and may change our estimate.”T gondii is an obligate intracellular parasite with worldwide distribution that infects approximately one-third of the human population and a wide range of animals and birds. Infection with T gondii in humans can have devastating consequences for fetuses, children, immunocompromised patients, and immunocompetent individuals infected with virulent strains. Although members of the Felidae family are the definitive hosts, cat ownership per se is not correlated with the prevalence of human infection in most studies.17–22 The parasite has 3 infectious stages: (1) tachyzoites, which are responsible for rapid spread of the parasite between cells and tissues and for the clinical manifestations of toxoplasmosis; (2) bradyzoites, which are within tissue cysts and stay dormant for the life of the host unless the individual becomes severely immunocompromised; and (3) sporozoites, which are within oocysts, are shed by members of the felid family, and widely disseminate the agent in the environment.23 Approximately half of infected individuals do not exhibit the conventional risk factors for acute infection or report clinical symptoms suggestive of acute toxoplasmosis at the time of their primary infection.24,25 A survey of 76 women who gave birth to infants with CT indicated that 61% of these women had no exposure to cat litter or raw meat, 52% had no acute toxoplasmosis-like febrile illness during pregnancy, and 52% had neither of the 2.24,25 Serologic testing is the only method that can reliably establish whether an individual has ever been infected, is chronically infected, or is experiencing an acute infection.Genotyping studies have allowed the identification of 3 main clonal lineages of T gondii (types 1, 2, and 3) in Europe, North America, and South America.26,27 Atypical strains that do not fall within these 3 clonal lineages have been frequently reported in North America and South America. In Western Europe, the predominant T gondii strain implicated in human disease was type 2,28 in North America all 3 main clonal lineages strains were implicated in human disease (types 1, 2, and 3), and an additional new fourth clonal lineage (type 12) was recently identified.29 In South America, mainly types 1 and 3 and atypical strains were identified28,30,31; and in Africa, mainly type 3 and recombinant types 1/3, 1/2, and 1 were detected.32 In North and South America, atypical and more virulent strains have been implicated in more aggressive clinical manifestations in immunocompetent individuals.33–36It has been suggested that differences in T gondii strains may at least partially explain the observed differences in the clinical spectrum of CT in different parts of the world and particularly in Europe, North America, and South America. In the United States, more severe disease, and even preterm birth, has been associated with infections with non–type 2 strains37; and in South America, more severe ocular disease has been reported in children with CT as compared with that reported in Western European countries.38Atypical T gondii strains have been reported from several areas of the world,39–49 including, but not limited to, Central and South America, Australia, and Africa. This distribution of strains may need to be considered when clinical syndromes consistent with severe toxoplasmosis are encountered in individuals returning from these areas.Humans are incidental hosts and become infected primarily by the oral route, that is, by ingestion of oocysts present in contaminated food, water, or soil or by ingestion of tissue cysts contained in infected meat23 (Table 1). They also can become infected in utero by transplacental transmission of the parasite from an acutely infected mother to the fetus, from an infected organ donor in the setting of organ transplantation,50–53 and rarely, by blood transfusion or laboratory accidents.54 Recent studies suggested that oocysts were the predominant route of transmission of T gondii infections in the United States; 78% (59 of 76) of pregnant women with acute primary T gondii infections during pregnancy who gave birth to infants with CT had serologic evidence suggestive of being infected by oocysts.24,55Different types of locally produced meat from retail meat stores in the United States (eg, pork, lamb, goat, wild game meat) have been found to be contaminated with T gondii.40,47,57–60 Moreover, with the globalization of the food market, imported meats from other countries (that could be infected even with atypical, more virulent T gondii strains) also can be found in the United States and Europe. Freezing (below –20°C [–4°F] for at least 48 hours)61 and thorough cooking to at least 63°C (145°F) for whole cut meat (excluding poultry), 71°C (160°F) for ground meat (excluding poultry), and 74°C (165°F) for poultry (whole cut or ground)62,63 have been shown to inactivate T gondii tissue cysts. Neither microwave cooking nor chilling at 5°C for 5 days is sufficient to kill tissue cysts (microwave cooking may not generate a homogenous temperature of 67°C [153°F]).61,64The following risk factors for acute T gondii infection were reported in a US study20: eating raw ground beef, rare lamb, or locally produced cured, dried, or smoked meat; working with meat; eating raw oysters, clams, or mussels; drinking unpasteurized raw goat milk; or having ≥3 kittens in the household. Eating raw oysters, clams, or mussels is a novel risk factor that was recently identified; however, in selected populations in the United States or in other parts of the world,65,66 additional/different risk factors (eg, contact with cat feces or drinking untreated water) also have been implicated. Untreated water has been found to be a source of major community outbreaks of acute toxoplasmosis in Canada and Brazil.67,68In up to 50% of individuals in whom an acute T gondii infection was confirmed, it was not possible to identify a known risk factor for their infection.24 Thus, toxoplasmosis should be considered in the differential diagnosis of ill patients with symptoms suggestive of toxoplasmosis, even in the absence of known risk factors for T gondii infection.Community outbreaks of acute toxoplasmosis have been described in several parts of the world,34,49,69–74 including North America.67 Outbreaks of acute Toxoplasma infection within families (ie, with more than 1 family member being infected) have been documented in the United States,74 and the prevalence of within-family clusters of acute Toxoplasma infections in the United States has also been studied.75 Although a cost-benefit analysis of routine screening of additional family members of index cases with acute toxoplasmosis might be useful, until such a study is completed, it is important for physicians to be aware of this phenomenon and consider screening additional family members of index cases diagnosed with acute toxoplasmosis, especially if pregnant women, immunocompromised patients, or young children live in such households.74 Young children living in such households who acquire acute T gondii infection might not be able to appropriately communicate problems with their vision if acute toxoplasmic chorioretinitis occurs.A seasonal pattern for acute toxoplasmosis has been recently identified in Europe76 and the United States.77 In France, the first highest peak of acute Toxoplasma infections during pregnancy was observed between August and September, and the second highest peak was observed between October and December.76 In the United States, a similar peak during December was observed for cases of acute toxoplasmic lymphadenopathy referred to the Palo Alto Medical Foundation Toxoplasma Serology Laboratory (PAMF-TSL),77 the National Reference Laboratory for the Centers for Disease Control and Prevention and the US Food and Drug Administration (FDA).In the United States, the rates of T gondii IgG-seropositive individuals has decreased over the past 2 decades. Data from the most recent NHANES for 2009–201078,79 showed an overall age-adjusted seroprevalence in people older than 6 years of 12.4% (95% CI: 11.1–13.7%) (The respective unadjusted seroprevalence rate was 13.2% [95% CI: 11.8–14.5%].) The age-adjusted seroprevalence among women of childbearing age (15–44 years) in the whole US population was 9.1% (95% CI: 7.2–11.1%) in 2009–2010 compared with 11% in 1999–2004 and 15% in 1988–1994. For US-born women of childbearing age, the respective seroprevalence rates were 6%, 8%, and 13% in 2009–2010, 1999–2004, and 1988–1994, respectively. Most US women of childbearing age are susceptible to Toxoplasma infection. If women become infected during pregnancy, they could give birth to an infant with CT. People born outside the United States were significantly more likely to be seropositive than people born in the United States (25.1% vs 9.6%, respectively).78 Seroprevalence rates were also higher in persons with a Hispanic versus a non-Hispanic white racial background (15.8% vs 10.2%, respectively).78 In addition, seroprevalence rates in children living on farms in Wisconsin have been reported to be fivefold higher than rates in children not living in farms (18% [29 of 159] vs 4% [8 of 184], respectively).80In the United States, toxoplasmosis was found to be the second leading cause of death and the fourth leading cause of hospitalizations attributable to foodborne illnesses.81,82 Recent cumulative US data over an 11-year study period (2000–2010) identified 789 toxoplasmosis-associated deaths, with a cumulative productivity loss attributable to toxoplasmosis of $815 million.83 Black and Hispanic persons had the highest toxoplasmosis-associated mortality. HIV infection, lymphoma, leukemia, and connective tissue diseases were associated with increased risks of toxoplasmosis-associated deaths.83 Population-based data estimated that T gondii infects approximately 1.1 million people each year in the United States84; toxoplasmic chorioretinitis is estimated to occur in approximately 2% of T gondii–infected individuals (approximately 21 000 people in the United States per year), and symptomatic chorioretinitis in approximately 0.2% to 0.7% of T gondii–infected individuals (approximately 4800 people in the United States per year).84According to the 2010 report by the Council of State and Territorial Epidemiologists, reporting of toxoplasmosis is not mandatory in most of the United States.85 As of 2010, toxoplasmosis was a reportable disease only in 19 states; in an additional 9 states, toxoplasmosis was previously a reportable disease, but not as of 2010.T gondii seroprevalence rates vary in different parts of the world86 and can range from <10% in some northern European countries87 to as high as 60% to 80% (eg, in Mexico88 and Brazil89,90).The incidence of acute primary T gondii infections during pregnancy in the United States, according to the National Institutes of Health–sponsored Collaborative Perinatal Project in 22 845 women (1959–1966) who were screened every 2 months during pregnancy, at birth, and at 6 weeks postpartum, was estimated to be 1.1 cases per 1000 pregnant women.91 However, that is likely to be an overestimate of the true incidence of acute T gondii infections during pregnancy in the current era, with the overall decrease in T gondii seroprevalence. Extrapolating from recent data from the New England Newborn Screening Program of the incidence of CT of approximately 0.23 per 10 000 live births, and after taking into account that this value might underestimate the true incidence of CT by approximately 50%, the true incidence of CT could be as high as double that value (approximately 0.5 CT cases per 10 000 live births). The incidence of CT may also be higher in areas and in subpopulations in the United States with higher overall T gondii seroprevalence rates.66,78 Then, assuming an overall MTCT rate of 25% (consistent with more recent data), the estimated incidence of acute primary infection during pregnancy in the United States would have been approximately 0.2 per 1000 pregnant women. If these numbers (0.2–1.1 acute cases per 1000 pregnant women) are extrapolated to the approximately 4 million pregnancies per year in the United States,92 approximately 800 to 4400 women per year in the United States acquire acute T gondii infections during pregnancy.Of note, when France first began antepartum screening for toxoplasmosis in the early 1980s, the incidence rate of acute primary T gondii infections during pregnancy at that time was 4 to 5 per 1000 (the population seropositivity rate at that time was very high, and the percentage of nonimmune, susceptible pregnant women was low).93Recently reported rates of acute primary infections during pregnancy in other countries ranged from 0.5 in 1000 pregnancies in Sweden94 to 2.1 in 1000 pregnancies in France (95% CI: 1.3–3.1).95 However, chronologic and methodologic differences between such studies preclude accurate direct comparisons.Data regarding the risk of MTCT of T gondii infection come from studies in which almost all women were routinely screened during pregnancy and therefore received antepartum treatment once primary infection was diagnosed.1,3,96 The SYROCOT meta-analysis of individual patient data from an international consortium, provided important information from 26 countries participating in the consortium. However, data for the effect of antepartum treatment on the MTCT risk were based only on European cohorts that had antepartum screening/treatment programs; neonatal cohorts from the United States, Brazil, and Col