Toxoplasmosis is a systemic and cosmopolitan disease affecting about one third of the world population. The causative agent is Toxoplasma gondii, an obligate intracellular protozoan parasite, whose replication occurs in the intestine of cats and other felines, the only definitive hosts. Warm-blooded animals and humans are intermediate hosts.

Different strains have been identified, three main designated as type I, II, and III and other atypical, which differ in virulence and epidemiological pattern of occurrence. In Europe, 95% of human infecting T.gondii are type II, whereas in North America type II represents 43.9%, type III accounted for 18.2% and atypical strains accounted for the rest (1, 2). A recent study on genetic analyses of atypical strains revealed that a fourth clonal lineage (type 12 lineage) it is the dominant strain in wildlife of North America and accounts for the 46.7% of the isolated strains (3). The parasite genotype may play a role in determining the severity of disease: in South America the strains show greater genetic variability and are usually much more virulent (4, 5).

The infection is acquired mainly through the ingestion of raw or undercooked meat containing still viable cysts, through the ingestion of water, fruit, vegetables, shellfish, or by contact with earth contaminated by oocysts excreted in the feces of infected cats (Figure 1). T. gondii can also be transmitted via blood or leukocytes from immunocompetent and immunocompromised donors. The parasite persists lifelong as cysts in intermediate host (6).

With few exceptions, the acute phase in the immunocompetent adult is usually a subclinical or benign disease. In a minority there may be malaise, low-grade fever, and lymphadenopathy and chorioretinitis.

Primary infection induces the production of specific antibodies and lifelong immunity, but toxoplasmosis can reactivate in immunocompromised individuals (e.g., AIDS or treatment with corticosteroids).

In humans, the seroprevalence of T. gondii antibodies increases with age and varies considerably according to geographical location, health education, hygiene, food habits and climatic conditions, it decreased in the last decade due to a greater intake of frozen meat, better hygiene, progressive urbanization (7).

In Europe the IgG seroprevalence ranges from 30 to 50%, and in United States is about 9.1% of women of childbearing age. In South America, the prevalence varies from 30 to 80%, reaching 100% in the most advanced age groups of the poorest populations (8, 9). The overall global prevalence of acute infection in pregnant women is 1.1% but is higher in Eastern-Mediterranean region than in European region (7). The global IgM e IgG seroprevalence in pregnant women is 1.9 and 32.9%, respectively, with statistically significant differences between WHO regions (10).

Congenital toxoplasmosis occurs when maternal infection is acquired for the first time in pregnancy. During the phase of parasitemia, T. gondii may cross the placenta and enters the fetal circulation with a risk of fetal infection that increases with gestational age: this results in congenital infection affecting 25–30% of women treated during pregnancy (11). At 6, 18- and 30-weeks’ gestation of pregnancy, the risk of fetal infection is 2.2, 23, and 56%, respectively (12).

Incidence of acute infection among T. gondii seronegative pregnant women varies by geographic location; it is estimated in Austria, Sweden, France, and United States to be 0.8, 0.5, 2.1, and 0.2 per 1,000, respectively (8, 13, 14). The global incidence rate of congenital infection is estimated to be 1.5 cases/1,000 live births with higher burdens in South America, in some Middle Eastern countries and low-income countries and lower burdens in European countries (15). In particular incidence of congenital toxoplasmosis is 1.0/10,000 in Austria, 0.5/10,000 in United States and 2.9/10,000 live births in France (8, 13, 14).

The likelihood of fetal infection is low in the early pregnancy but increases in later stages. The chance of transmission increases by 12% per week of maternal gestation starting at 13 weeks of gestation (16, 17). The protective role of the placenta is more effective in the first trimester, allowing to the passage of parasites in less than 10% of cases. With the increasing of the vascularity, the placental barrier becomes more and more permeable, leading to parasite transmission in around 30% of cases in the second trimester, in 60–70% of cases in the third trimester, even more in the last weeks of gestation (18).

The mechanisms of T.gondii vertical transmission remain unclear, in particular the role of placenta-derived cytokines or chemokines. The syncytiotrophoblast has distinct resistance to T. gondii infection, at the level of attachment and post-entry replication, while cytotrophoblasts and extravillous trophoblasts seem not displaying the same kind of resistance, suggesting cell-type specific differences in mechanisms of resistance. In addition, trophoblasts respond to T. gondii infection through the specific induction of various cytokines and chemokines, including the robust induction of the regulatory T cell chemokine (19, 20).

The severity of fetal infection decreases with the increase of gestational age. During the first and second trimester, the infection may lead to miscarriage (around 3% of all cases) or still birth. Infected infants frequently show severe symptoms of congenital toxoplasmosis, with neurological disorders and ocular lesions, while in the latest phase of pregnancy the neonatal disease may be less severe or asymptomatic.

The higher risk of early and long term (within 3 years) clinical signs occurs in women who seroconverted between 24 and 30 weeks of gestation (about 10%); for infections occurring in the second and third trimester, the minimum risk is not less than 5% (12, 21). Therefore, dating maternal infection during pregnancy is of great relevance to establish the extent of fetal risks.

In this narrative literature review we provide an updated overview on diagnosis, therapy, and follow-up of toxoplasmosis in pregnancy and neonatal age.

We searched PubMed¹ for cohort, cross-sectional and case-control studies, reviews, expert consensus as well as case series or case reports published as articles or letters to the editor describing neonates with congenital toxoplasmosis. An extensive literature search has been performed up to 6 March 2022. The following keywords “Congenital Toxoplasmosis” AND “neonate” OR “infant” were searched as entry terms. We excluded all retrieved articles written in non-English language. Additional studies were identified by authors based on their knowledge on the field, if not already included by literature search.

In neonatal age, congenital toxoplasmosis is asymptomatic in 85% of cases. Infected newborn appears normal at the clinical examination, but he is at risk of developing ocular lesions later in life. In such a situation, it is hard to make a diagnosis without information on maternal serologic profile.

The classic triad described by Wolf in 1939 (hydrocephalus, intracranial calcifications, and chorioretinitis) is observed very rarely in present times. Neonatal manifestations, if present, may include hydrocephalus, microcephaly, intracranial calcifications, chorioretinitis, cataracts, convulsions, nystagmus, jaundice, petechiae, anemia, enlarged liver, and spleen, prematurity and severe intrauterine growth restriction with abnormally low birth weight (14, 21, 22) (Table 1). However, none of these symptoms is pathognomonic for toxoplasmosis and may suggest other congenital infections (CMV, Herpes simplex, rubella, syphilis) (6).

The prevalence and severity of principal signs of disease are significantly different in the United States, France, other Western European countries, Israel, and South America (23–30). The reported rate of severe congenital toxoplasmosis is higher in the United States and South America in comparison to European countries due to different and more virulent T. gondii strains implicated and in the absence of antepartum treatment in the United States (1, 14, 31–34). In Israel the proportion of severe disease is higher than in Europe probably because of the lack of systematic prenatal screening and treatment but is lower in comparison to United States (30).

A systematic review of cohort studies by SYROCOT (Systematic Review on Congenital Toxoplasmosis study group) shows that, during the first year of life, 19% of infected infants developed at least one of two clinical manifestations: 14% had ocular lesions and 9% had intracranial lesions or both (26).

Among ocular manifestations, the most frequent is chorioretinitis and the retinal lesions are usually in the posterior pole (22, 35). Most frequently occurs after a reactivation of the infection and in cases where the macula is involved there may be a loss of visual function (22, 36, 37). Worsening of central vision, because of macula involvement, may recover after resolution of the inflammation (22). Chorioretinitis is commonly recurrent and relapsing, but these episodes are rarely associated with systemic signs or symptoms (22). For any additional week of gestation, in case of maternal primary infection, the risk of chorioretinitis decreased by 3% but increases by 2.1 times when maternal primary infection occurred before 20 weeks of gestation and by 3.6 times in infants with additional clinical manifestations at birth (38).

Other ocular disorders, reported apart from recurrent focal chorioretinitis, that can contribute to visual impairment are strabismus, microphthalmia, cataract, retinal detachment, optic nerve atrophy, iridocyclitis, nystagmus, and glaucoma (22, 36). Some of these manifestations develop as a consequence of retinal lesions or can be related to neurological involvement like hydrocephalus (36). Indeed, is reported that infants with severe ocular manifestations also present with severe cerebral damage (35).

The ocular manifestations in congenital infected infants in Brazil are more severe than in the United States and Europe (24, 35, 39). Brazilian infants developed chorioretinitis more frequently and the lesions are multiple, larger, and more likely located in the posterior pole than the European infants (24). Several studies suggest that the marked difference in prevalence and severity of ocular involvement in Brazil is due to different prevention protocols and infection with atypical T. gondii strains more virulent which are predominate in Brazil but are rarely found in other countries (24, 40–42).

Involvement of the central nervous system is demonstrated by calcifications that follow the phenomena of vasculitis and necrosis and affect mainly the periaqueductal and periventricular regions. Sometimes the hydrocephalus may be the only manifestation of congenital toxoplasmosis; observational data show a frequency of 31% when the mother did not receive any therapy, compared to 0.8% in the newborns of treated women (16). In the SYROCORT study the risk of intracranial manifestations was higher in Brazilian and Colombian infants in comparison to other countries (26).

In pregnant women, when present, symptoms of toxoplasmosis are mild and non-specific (asthenia, low-grade fever, myalgia, and usually laterocervical lymphadenopathy), therefore, the diagnosis relies only on serological tests; in immunocompetent subjects, IgG, IgM, IgA, and IgE antibodies can be detected just after two weeks from the infection.

There is no consensus about serological screening for T. gondii IgG and IgM antibodies in pregnant women (5). It is rare in United States (8, 14), not currently recommended in Canada (43) but mandatory in France and Austria at the first trimester prenatal visit (13, 44, 45). The prenatal screening allows to identify anti-toxoplasma IgG seronegative women at risk of acquiring the infection in which the primary prevention is mandatory (5, 13, 44, 45).

Serum conversion is the most accurate marker of maternal infection (6). Positive IgG and negative IgM antibodies in the first and second trimester suggest that the infection has been acquired before the current pregnancy. When the first analysis is done during the third trimester, a negative IgM result cannot rule out an infection acquired in early pregnancy, since IgM could have become undetectable in a short time. Negative IgM rules out infection in the first two trimesters, but positive IgM is not always a certain marker of recent infection because IgM can persist beyond to years or can be non-specific IgM (6, 46, 47) (Table 2).

Reference laboratories use second level tests: IgG avidity test, and immunoblotting test essential tools to help to date the infection (6, 48, 49). A high IgG avidity index suggests that the infection was contracted at least 16 weeks before; a low or intermediate avidity index is considered markers of recent/acute infection (50, 51). Furthermore, avidity grows more slowly if pregnant woman is subjected to a specific therapy, since treatment could delay IgG appearance and reduce avidity maturation (48).

The immunoblotting test for IgG and IgM could be used to evaluate IgM specificity and allows an earlier identification of specific IgG (6).

The monthly screening during pregnancy, until delivery, allows a timely diagnosis of the maternal infection, so as to start an early specific treatment, in an attempt to prevent transmission, or to reduce the risk of serious injury.

All neonates at risk of congenital toxoplasmosis (proven maternal infection, with or without prenatal diagnosis) must perform a complete clinical and neurological check-up at birth, specific seroimmunological tests, direct and indirect dilated fundoscopy (to exclude chorioretinitis, or associated ophthalmological pathologies), and transfontanellar ultrasound examination (to rule out any ventricular dilatation, cerebral calcifications, porencephaly) (64).

Hepatic and cardiac ultrasound, brain computed tomography (CT) or magnetic resonance imaging (MRI) and electroencephalographic monitoring (EEG), are helpful when clinical and neurological symptoms are severe.

In congenital toxoplasmosis, chorioretinitis may be present even at birth, with chorioretinal scars or focal necrotizing retinitis. It may also appear unpredictably during childhood or adolescence, as a new manifestation or as a reactivation of a previous lesion (37). The symptoms are scotoma, pain, photophobia, blurred vision, and excessive watering of the eye (22).

A delay between maternal seroconversion and the beginning of treatment, and especially the presence of cerebral calcifications, are risk factors of retinochoroiditis during the first 2 years of life (77). In a prospective cohort study on 3 years old children with congenital toxoplasmosis, more than 90% of children with chorioretinitis had normal vision in the best eye, and only 9% had severe bilateral impairment (78).

In the active form, the specific therapy (Pyrimethamine + Sulfadiazine + folinic acid) must be applied for at least 1–2 weeks after resolution of clinical signs, the longest treatment being about 3 months. The efficacy of steroids in ocular toxoplasmosis has not been clearly demonstrated. Currently, they are used in association with the standard therapy only in severe inflammation, or when the lesions are close to the fovea or the optic disk. Corticosteroid therapy, without antiparasitic treatment, may result in large retinal lesions (60, 79).

A recent meta-analysis indicated that the combination of trimethoprim-sulfamethoxazole could be an alternative treatment (80). A long-term, intermittent regimen of this combination can be used in an effort to reduce the recurrence of chorioretinitis (81).

The follow-up of the newborn with congenital infection is mainly dedicated to the ophthalmological, neurological, auditory and serological aspects.

The knowledge about T. gondii life cycle is crucial to reduce exposure to major risk factors, such as raw or undercooked meats (especially lamb and pork), poor hand hygiene and improper cleaning of cooking utensils, consumption of unfiltered water, gardening and other soil contact, exposure to cat litter and travels to high-incidence countries (90). Furthermore, the vaccination of food animals, the decontamination of all meats and products destined for undercooked consumption, and the vaccination of cats are ongoing intervention strategies to reduce T. gondii disease burden, across the general population.

However, special considerations must apply to all pregnant women, where health education approaches are mainly aimed at the prevention of congenital toxoplasmosis. Dietary recommendations and behavioral factors, including pet care and environmental measures, can help to reduce the risk of acquiring toxoplasmosis in pregnant women or women of childbearing age (91). Randomized controlled trials have shown little evidence that prenatal education has a positive effect in reducing seroconversion for toxoplasmosis in pregnancy (92). A recent systematic review on hygiene measures as primary prevention of toxoplasmosis during pregnancy suggests the efficacy of health education on toxoplasma-related knowledge, behavior, and risk of seroconversion in pregnancy (93).

Health care professionals must be aware of the risk factors and of the recommendations to give to seronegative pregnant women at the beginning of pregnancy (Figure 4): the knowledge of these preventive measures will have a positive impact.

The correct hygienic-sanitary education of the seronegative pregnant woman (primary prevention), the systematic serological screening in pregnancy (secondary prevention) allowing early diagnosis and therapy of pregnant mother, the treatment of congenital infection and the follow-up of the newborn, have proved to be the cornerstones for addressing a public health problem such as congenital toxoplasmosis.

The development of new techniques for diagnosis of maternal infection, prenatal diagnosis and a therapeutic approach to limit vertical transmission and fetal injury of toxoplasmosis, can all concur for positive outcomes regarding health and quality of life.

Remarkable differences exist in public-health policies; research should be performed to assess the burden of congenital toxoplasmosis and the cost of care of the disease in each country (45). Furthermore, there is a need for implemented information programs and homogeneous guidelines, and more reference centers for the management of maternal or congenital infection, and for the post-natal follow-up of neonates with suspected congenital toxoplasmosis.

Despite great advances in basic clinical and scientific research, many questions remain to be addressed. We stress the necessity of less expensive serological tests, new drugs with less toxicity, more efficacy (allowing for a shorter treatment cycle), and able to eliminate resistant cysts (94, 95). Furthermore, improved pediatric formulations for established drugs would be useful (72).

Toxoplasmosis is still among the main infections that can be transmitted from mother to child and, when untreated, may have serious consequences; therefore, we must alert the health policy makers, not to make congenital toxoplasmosis a neglected disease.

LB and CT performed literature search and wrote the first draft of manuscript. CAu, CAc, FG, DD, and GS critically revised the manuscript. All authors approved the submitted and final versions of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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