Fig. 20.1
Rates of maternal-fetal CMV transmission: risk of fetal infection and development of disabilities
While the majority of affected infants are asymptomatic at birth, 10–15 % exhibit signs of CMV-associated sequelae including thrombocytopenia, hepatitis, chorioretinitis, sensorineural hearing loss (SNHL), intrauterine growth restriction, and mental retardation. An additional 5–15 % of asymptomatic CMV-infected infants will develop late-onset sequelae, most commonly SNHL, within the first 2 years of life [6, 7]. The frequency of symptomatic newborns following non primary CMV infection is not defined. In fact, reported data are limited to case reports and small case series of symptomatic newborns of mothers with known preconceptional immunity, not proven reactivation or reinfection during pregnancy. Nonetheless, these data suggest that the risk for non-severe symptomatic infection at birth and sequelae, mainly hearing loss, are similar following non-primary maternal CMV infection as compared to primary infection.
20.1.1 Prevention of Infection During Pregnancy
There are two main sources of maternal CMV infection: sexual activity and contact with young children. However, the latter is considered the most important one as the high circulation rate of CMV in infants and children of preschool age puts seronegative pregnant women caring for young children at high risk for CMV infection [6]. Transmission occurs through direct contact with infectious bodily fluids such as saliva and urine; children who excrete CMV may spread infection to a parent and to other adults in the household [6]. CMV educational and hygienic measures have the potential to prevent primary maternal infection. A recent study provides evidence that a primary prevention strategy based on the identification and provision of adequate information to seronegative susceptible pregnant women at risk for primary infection is highly effective in reducing the rate of maternal primary CMV infection and, ultimately, congenital CMV infection. Specifically, women are invited to frequently wash their hands after exposure to young children’s bodily fluids as well as surfaces touched by children (toys, high chair, stroller, etc.), to avoid kissing children on the mouth/cheeks, and not to share utensils, food, drinks, washcloths, etc. The use of gloves and avoidance of sleeping in the same bed were not suggested.
Recent onset of sexual activity (last 2 years) in young women increases the risk for congenital CMV infection in their offspring; this finding suggests that recent sexual exposure to CMV may have occurred in the months or years before conception and also during pregnancy. The risk for congenital CMV infection remains elevated even when primary maternal infection occurs months before conception so it is preferable to wait at least 6 months after primary CMV infection before pregnancy. Another important aspect to underline is the relation between sexually transmitted infections during pregnancy (such as gonorrhea, chlamydia, genital warts, syphilis, and trichomoniasis) and primary CMV infection that could enhance the transmission of CMV from mother to fetus. In addition, because of the possibility of CMV transmission through sexual intercourse, pregnant women should be urged to adopt safe sexual practices if they are not engaged in a mutually faithful monogamous relationship.
Numerous reports have analyzed how to prevent primary maternal infection, and they have shown that CMV educational and hygienic measures have this prevention potential. In the first time, woman seronegative should be informed about CMV and prevention measures and hygiene recommendations to be adopted [8].
Future prospectives are based on development of an effective vaccine for prevention of CMV infection that could be of high epidemiological impact in this regard.
20.1.2 Prenatal Diagnosis
The first step in the prenatal diagnosis of congenital CMV infection is determination of maternal primary and secondary infection by serological testing (Fig. 20.2).
Fig. 20.2
Algorithm for the diagnosis and management of congenital CMV infection
In women with a proven or highly suspected, recent primary CMV infection, the second step is to propose the diagnosis of fetal infection by noninvasive (ultrasound examination) and invasive (amniocentesis) prenatal tests [9].
20.1.2.1 Diagnosis of Maternal Infection
The diagnosis of primary CMV infection in pregnant women is based on serological tests with detection of specific immunoglobulins type G (IgG) and type M (IgM). Seroconversion confirms primary infection but is usually difficult to identify in the absence of any available preconceptional serum specimen. Detection of specific IgM does not always indicate a recent primary infection because they may persist for months after primary infection, be detected during secondary infection, be the consequence of cross-reactivity with IgM elicited by a primary infection with another virus (e.g., Epstein-Barr), and be observed through polyclonal stimulation of the immune system [10].
However, such an approach is feasible only when a screening program is adopted and seronegative women are identified and prospectively monitored.
The IgG avidity assay can assist in determining the time of CMV infection, thus helping in distinguishing a recent, primary infection from one remote or recurrent. This assay is based on the observation that virus-specific IgG of low avidity is produced during the first months after onset of infection, whereas subsequently a maturation process occurs by which IgG antibody of increasingly higher avidity is generated. IgG antibody of high avidity is detected only in subjects with remote or recurrent CMV infection [11]. Avidity levels are reported as the avidity index, expressing the percentage of IgG bound to the antigen following treatment with denaturing agents.
An avidity index >60 % is highly suggestive of past or secondary infection, while an avidity index <30 % is highly suggestive of a recent primary infection (duration <3–4 months). Therefore, detection of a low avidity index indicates a primary infection within the 3–4 previous months, while a high avidity index excludes a primary infection within the 3–4 previous months. The avidity results should be interpreted accordingly with gestational age.
Hence serologic diagnosis of primary CMV infection during pregnancy is documented by either seroconversion (the appearance of CMV-specific IgG antibody in a previously seronegative woman) or detection of specific IgM antibody associated with low IgG avidity. A non-primary CMV infection is difficult to diagnose, and can be suggested by a significant rise of specific IgG antibody title and/or a detection of IgM in women who had detectable, high avidity specific IgG antibodies without IgM antibodies before pregnancy [12].
20.1.2.2 Diagnosis of Fetal Infection
Since intrauterine transmission of the virus occurs in only 30–40 % of pregnancies in women with primary infection and at a significantly lower rate in women with secondary infection, it is important in cases of proven maternal infection to find out if the fetus is infected (Fig. 20.2). When a pregnant woman has had a confirmed infection with CMV, a prenatal diagnosis of infection may be required to evaluate the fetal risks [13].
20.1.2.3 Amniocentesis
Isolation of the virus or the viral genome (DNA) in the amniotic fluid (AF) is the method of choice for the diagnosis of fetal infection.
To achieve the highest sensitivity, the amniocentesis should be performed at least 6–8 weeks after the onset of maternal infection and after 21 weeks of gestation, when fetal urination is well established. Some cases of false-positive results have also been reported when the neonate was not infected. These false-positive diagnoses may be explained by contamination of the AF with maternal blood during amniocentesis if the mother had a positive viral genome at the time of sampling. Even when the timing of amniocentesis is the best, some cases of false negative are shown: this situation could be an expression of a late transmission of CMV (>8 weeks after maternal seroconversion) [14].
Actually, it is possible to isolate CMV by conventional culture on fibroblasts or by the shell vial technique, which uses monoclonal antibodies to the major immediate early protein p72 and enables detection of the virus 16–24 h after amniotic fluid collection. However, PCR testing represents to date the main way to detect if the fetus is infected and has largely replaced the conventional culture.
A lot of studies have analyzed the relationship between viral load in amniotic fluid and symptomatic infection. Whereas a low viral load in amniotic fluid was consistently found to be associated with asymptomatic congenital infection, it was observed that high viral load in amniotic fluid was associated with either symptomatic or asymptomatic congenital infection. Only one study (Guerra et al.) reported that a DNA level >105 copies/ml amniotic fluid was a possible predictor of symptomatic congenital infection. The lack of a close association between CMV DNA quantification in amniotic fluid and fetal prognosis may be the result of different variables such as gestational age at maternal infection, timing of intrauterine transmission of infection, timing of amniocentesis, and particularly the unfeasibility of follow-up of infection during fetal life [15]. Hence, once primary CMV infection is diagnosed in a pregnant woman, amniocentesis should be offered to diagnose intrauterine CMV transmission, and in the case of a positive result, cordocentesis should be discussed for prognostic purposes, according to a recent report by Fabbri et al. This study has indicated that certain hematological, biochemical, and virological markers measured in fetal blood seem significantly related not only to infection but also to organ damage caused by HCMV infection and symptomatic postpartum sequelae. A panel of nonviral and viral assays were performed on fetal blood samples to integrate multiple markers of fetal organ damage caused by CMV infection. In particular, b2-microglobulin and a low platelet count were the best nonviral predictive markers from symptomatic infection, whereas immunoglobulin M (IgM) antibody and DNAemia represent the best virological markers. B2-Microglobulin alone or the combination of these four markers reached the optimal diagnostic efficacy [15].
20.1.2.4 The Role of Ultrasound (US)
When a fetal CMV infection is diagnosed during pregnancy, a close ultrasound (US) survey must be done because it will disclose structural and/or growth abnormalities related to CMV infection (Fig. 20.3). The ultrasound has another important role: if the woman is not serologically tested during the first trimester of pregnancy, sonographic examinations performed during pregnancy may be the only tool available to identify an affected fetus. Ultrasonographic findings are helpful but not diagnostic because CMV has features in common with other intrauterine infections and with other fetal diseases [16]. Moreover, ultrasound examination has a low sensitivity; in fact these abnormalities are observed in less than 25 % of infected fetuses [17].
Fig. 20.3
Clinical manifestations and laboratory findings associated with congenital CMV infection in the fetus and newborn
Authors have described different kinds of prenatal ultrasound findings in fetuses with CMV infection that are subdivided into extracerebral and cerebral anomalies.
The most frequent extracerebral ultrasound abnormalities are hyperechogenic bowel and hepatomegaly [18]. But other types are described such as intrauterine growth retardation (IUGR), oligohydramnios, ascites, liver calcifications, pericardial effusion, and hyperechogenic kidneys.
Given the particular neurotropism of CMV, congenital infection can cause a wide range of brain anomalies. Hydrocephaly and brain calcifications are the most common abnormalities. Other signs of fetal infection are intraventricular adhesions, periventricular pseudocysts, sulcation and gyral abnormal patterns, hypoplastic corpus callosum, cerebellar and cisterna magna abnormalities, and signs of striatal artery vasculopathy [19] (Figs. 20.4 and 20.5).
Fig. 20.4
(a–d) US cerebral features at 32 weeks of gestation after CMV primary infection at first trimester: (a, b) corpus callosum hypoplasia in sagittal and coronal view; (c) mild ventriculomegaly (atrium of 13 mms); (d) hyperechogenic spot of subcortical white matter
Fig. 20.5
Example of subependymal cyst at 22 weeks’ gestation after primary CMV infection
Magnetic resonance imaging (MRI) could be performed in cases of abnormal US findings or if a specific evaluation of the fetal brain is not technically possible by US. MRI has a greater sensibility than US, but it should not be performed when fetal US examination is strictly normal or when the brain lesions are so severe that it would not change the management of the pregnancy. MRI provides additional information and better results than US in detecting polar temporal lesions, microencephaly, and cortical anomalies [20].
Another aspect of the use of ultrasonography in the management of CMV infection is the study of placenta which seems to be related with the incidence of fetal infection. Numerous reports indicate that placentas from these births contain viral proteins, suggesting that placental infection and virus transmission to the infant are related causally. Placental histopathological abnormalities more frequently found in congenital CMV are calcifications, villitis, immature villi, thrombotic vasculopathy, neutrophil infiltration, placental infarct, and increased perivillous fibrin; CMV DNA and protein are also detectable by molecular testing as polymerase chain reaction and immunohistochemistry. Iwasengo examined CMV infection in stillbirths, showing that molecular testing during postmortem investigation has an important role to determine the contribution of CMV infection (CMV DNA was detected in 15 % of fetal or placental tissue). Moreover, fetal thrombotic vasculopathy was the only abnormality associated with CMV infection.
US placental evaluation includes size, localization, placental echostructure, and placental maximal vertical thickness [21]. Therefore, some authors have investigated ultrasound placental size (as measured by maximal placental vertical thickness) following maternal primary CMV infection to determine if it correlates with infection of the fetus.
The placental thickness of women with vertical transmission of infection seems to be larger than the placental thickness of mothers with fetuses or neonates without disease. Placental enlargement could result from placental vascular ramification, which compensate for hypoxia in utero. Sonographically thickened placentas (Fig. 20.6) have been previously associated with increased fetal and perinatal mortality, abnormally high birth weights, fetal hydrops, maternal diabetes, chromosomal abnormalities, maternal and fetal anemia, fetal heart failure, and congenital nephrotic syndrome. Although a thickened placenta is a nonspecific marker of fetal disease, it could be considered a valid prognostic index to suspect the fetal infection [22].
Fig. 20.6
(a, b) Placental characteristic in a case of CMV fetal infection at term of gestation: placental thickness above 45 mms and dishomogeneous echogenicity
20.1.3 Postnatal Diagnosis
Congenital CMV occurs transplacentally and may result in symptomatic or asymptomatic infection in the neonate.
Diagnosis in the neonate is made by viral detection in body fluids via PCR, culture, or antigen testing (pp65 antigen) within the first 3 weeks of life. The finding of CMV antibodies or viral DNA after this point makes congenital versus postnatally acquired infection (from cervical secretions, breastfeeding, or blood products) difficult to distinguish. Antibody titers cannot reliably make the diagnosis as maternal CMV IgG crosses the placenta, and neonates mount weak IgM responses. The preferred specimens are saliva and urine as newborns shed high levels of the virus from these fluids. Thus far, urine has been considered the gold standard [15].
However, difficulties in urine collection documented in some studies have led to a suggestion that saliva analysis may represent an easier, more practical, and less expensive approach, so some propose that saliva PCR should be considered the investigation of choice, although it is susceptible to contamination by maternal milk [10].
20.1.4 Prognosis of Infected Fetus
After the evidence of the infection of fetuses, the main issue is to predict which of them will be symptomatic at birth or later in life. A symptomatic infection was defined as the presence of an abnormal ultrasound and/or magnetic resonance imaging findings and/or histopathological findings of disseminated infection for fetuses terminated or dead in utero or as the presence of clinical symptoms up to 6 months of age for delivered newborns [23]. A lot of studies have shown that a single test or examination cannot predict the collective events that might lead to permanent damage. Although the role of ultrasound examination in predicting the presence of symptoms at birth has been emphasized by some authors, this has been questioned by other groups who find an ultrasound sensitivity of only 21 % in predicting symptomatic newborns.
New approaches have been proposed based on CMV DNA quantification in amniotic fluid or combined assessment of ultrasound findings and prognostic markers evaluated in the fetal blood.
Approximately 10 % of the infants born with congenital CMV infection have signs and symptoms at birth. Only half of these symptomatic infants have disseminated multiorgan involvement named cytomegalic inclusion disease (CID). Other infants have mild or subclinical manifestations of the disease [24]. In the typical form of CID, many organs are involved, mainly the reticuloendothelial system and the CNS. The main clinical abnormalities observed are hepatomegaly, splenomegaly, microcephaly, jaundice, petechiae, hypotonia/lethargy, or seizures. Elevated alanine aminotransferase, conjugated hyperbilirubinemia, and thrombocytopenia are the main laboratory abnormalities. Other manifestations occasionally present in symptomatic newborns include pneumonitis, dental defects, ocular defects (chorioretinitis, strabismus and optic atrophy, cataracts, microphthalmos, necrosis, calcifications, blindness, anterior chamber and optic disk malformations, and papillary membrane vestiges), and hearing loss, intrauterine growth retardation (IUGR), and prematurity (Fig. 20.3). Overall, in this symptomatic subgroup of congenitally infected infants, the mortality rate is around 15–30 %. Death is often due to multiorgan involvement with severe hepatic dysfunction, bleeding, disseminated intravascular coagulation, and secondary bacterial infection. In this condition, death mainly occurs in the first weeks of life. Around 90 % of the symptomatic infected newborns who survive will develop some degree of disability including psychomotor retardation usually associated with microcephaly and other neurological impairments, SNHL, visual impairment, and expressive language delays [25].
At the other extreme of the spectrum of CMV congenital infection are the asymptomatic forms of the disease. Without any systematic screening policy at birth, these infected newborns are most frequently left undiagnosed. Approximately 15 % of asymptomatic children will develop some degree of hearing loss following congenital CMV infection. Globally, CMV causes around 10 % of congenital SNHL, his deficit may be present at birth or develop later in childhood usually during the first year of life, with a great variability in the severity range. Development of new diagnostic tools such as dried blood spots (DNA detection in Guthrie cards) helps to retrospectively attribute SNHL to congenital CMV infection [26].
20.1.5 Therapy
The possibility to treat CMV infection is limited due to toxicity of drugs available. After ultrasound detection of fetus abnormalities and confirmation of the primary CMV infection in the mother and fetus (by amniocentesis), the only “therapeutic” option available to avoid the birth of a severely damaged infant is to terminate pregnancy [27, 28]. Many studies have been done to investigate how it is possible to prevent and treat fetal infection.
In particular, several studies have been developed to analyze the possibility to administrate human immunoglobulins with a double role: prophylactic and therapeutic. Before analyzing which are the actual approach with immunoglobulin, it’s important to explain the function of maternal immune system to protect the fetus. An important aspect to be analyzed is the role of maternal immune system to prevent virus transfer across the decidual-placental interface. Recent report suggests that CMV utilizes the fetal Fc receptor for its passage across the placenta. Physiologically, these receptors are used to transport maternal IgG from the intervillous space to the syncytiotrophoblast. In this way, IgG antibodies seem to have a protective role with regard to vertical transmission rates [4]. Due to their mechanism of action, CMV-specific immunoglobulins could be useful for the prevention of congenital CMV infection following primary CMV infection. In the absence of maternal CMV-specific antibodies, the administration of human cytomegalovirus immunoglobulins is thought to prevent the transmission of CMV from the mother with no specific immunity against CMV to the fetus. These immunoglobulins, known as hyperimmune globulins (HIG), are drawn only from selected donors with high-titer IgG antibodies after CMV infection. Therefore immunoglobulins could reduce the viral load and could thus decrease the probability of severe fetal disabilities. Besides infection of the fetus, active CMV infection of the pregnant women can also lead to impairment of placental function – which may be followed by spontaneous abortion (mainly at the beginning of pregnancy) or restriction of fetal growth [20]. In fact, it seems that the partial reduction in placental size after treatment with HIG provides further evidence that treatment with HIG could resolve fetal disease by neutralizing virus and reducing placental inflammation and insufficiency. The placenta is likely to be one site of action of HIG, and many of the manifestations of congenital CMV infection at birth, including intrauterine growth restriction or neurological damage, may be due to placental insufficiency. CMV modifies maternal immunity through an inflammatory process leading to abortion or immune-mediated disease, most commonly in the brain resulting from neurotoxicity of overexpressed cytokines [29]. Since an efficacious vaccine for CMV disease is still lacking, immunoglobulins are used to treat a large number of transplant patients. Currently, the only approved indication for cytomegalovirus hyperimmune globulins (CMV-HIG) in Europe is for patients who have undergone solid organ transplantation to prevent CMV reactivation and reinfection [30]. Although CMV-HIG are not approved for the prevention or therapy of congenital CMV infections, some authors have used this therapeutic option as so-called “off-label” mode, and results are very questionable, mainly because of the lack of serious large randomized controlled studies (Tables 20.1 and 20.2).
Table 20.1
Clinical studies that have investigated the effect of HIG treatment for the prophylaxis of vertical CMV transmission [4]
Author and design | Number of patients | Dosing regimen (PEIU/kg/dose) | Newborn follow-up (years) | Outcome parameter | Result HIG group | Control group | p |
|---|---|---|---|---|---|---|---|
Nigro et al. (2005) Props. nrd | 84 | 100 q4w 2–7 doses | 2 | Percentage of congenitally infected live births | 6/37 (16 %) | 19/47 (40 %) | p = 0.02 |
Buxmann et al. (2012) Retrosp. | 38 | 100–200 1–3 doses | 1-3 | Percentage of congenitally infected neonates/fetus | 9/38 (24 %) | — | — |
Revello et al. (2014) Prosp. rd | 123 | 100 q4w 3–6 doses | 0 | Percentage of congenitally infected neonates/fetus | 18/61 (30 %) | 27/62 (44 %) | p = 0.13 |
Table 20.2
Clinical studies that have investigated the therapeutic effect of HIG on CMV-related fetal anomalies and clinical outcome of evidently infected newborns [4]
Author and design | Number of patients | Dosing regimen (PEIU/kg/dose) | Newborn follow-up (years) | Outcome parameter | Result HIG group | Control group | p |
|---|---|---|---|---|---|---|---|
Nigro et al. (2005) Prosp. nrd | 45 | 200 (plus 400 i.a. or i.u. in 9 subjects) | 2 | Resolution or regress of fetal sonographic anomalies | 14/15 (93 %) | 0/7 | p < 0.001 |
1–3 doses | Percentage of symptomatic newborns | 1/31 (3 %) | 7/14 (50 %) | ||||
Buxmann (2012) Retrosp. | 3 | 180-200 (plus 500 i.a. or i.u.) 1–3 doses | 1–3 | Percentage of symptomatic newborns | 0/3 | — | — |
Nigro et al. (2012) Retrosp. | 64 | 200 | 1–5 | Resolution or regress of fetal sonographic anomalies | 9/14 (64 %) | 5/17 (29 %) | p < 0.001 |
1–4 doses | Percentage of symptomatic newborns | 4/31 (13 %) | 28/33 (85 %) | ||||
Nigro et al. (2012) Prosp. Ndr | 16 | 200 | 2–8 | Resolution of hyperechogenic bowel | 7/9 (78 %) | 3/8 (38 %) | p < 0.0004 |
1–3 doses | Percentage of infans with sequelae | 1/9 (11 %) | 8/8 (100 %) | ||||
Visentin et al. (2012) Prosp. Ndr. | 68 | 200 | 1 | Resolution or regress of fetalsonographic/MRI anomalies | 0/4 | 0/5 | p < 0.001 |
1 dose | Percentage of infans with sequelae | 4/31 (13 %) | 16/37 (43 %) | ||||
JCCIIFTSG (2012) Prosp. Unc. | 12 | 100–200 1–5 doses and/or 500–1800 2–6 doses | 2–6 | Resolution or regress of fetalsonographic/MRI anomalies | 9/12 (75 %) | — | — |
Percentage of infans with sequelae | 9/12 (75 %) | — |
Some studies on HIG administration suggest that there is a possible association between the treatment and both birth weight and duration of pregnancy; CMV may also cause low birth weight due to placental dysfunction with intrauterine hypoxia and malnutrition, even in asymptomatic infants [31]. Multiple doses of HIG seem to improve features of placenta and are correlated with both increasing birth weight and longer gestation, but only for infants born asymptomatic.
Finally, a recent randomized placebo-controlled trial of virus-specific hyperimmune globulin [32] has showed no significant reduction in the rate of transmission of CMV infection among women receiving hyperimmune globulin as compared with women receiving placebo. Moreover, from the cost-effectiveness point of view, results of that trial (related to reduction of vertical infection) are less than the threshold identified as the optimum for a screening program and treatment of primary maternal infection in pregnancy (CHIP study 2014).
Another therapeutic option recently proposed (always “off label”) is standard intravenous immunoglobulins (IVIG), obtained from unselected donor pools, including a varying proportion of donors previously exposed to CMV that seems to be a less expensive alternative to HIG [33].
Such experience has started since 2010 at the Infectious Disease Unit of Pescara General Hospital, Italy, and it is based on the monthly infusion of IVIG (0.5 g/kg of body weight). CMV IgG and IgM antibodies and IgG avidity indexes are assayed both before and after each IVIG infusion. Preliminary evaluation demonstrates that infusion of IVIG in woman with primary CMV infection significantly increases CMV IgG titers and avidity indexes on blood samples. Moreover, several study have suggested a possible efficacy of HIG administered either to the mother or the foetus in cases of proven foetal infection, in reducing the frequency and severity of foetal and newborn sequelae.
Finally, in a very recent study by Leruez-Ville et al. [34], experimental use of valacyclovir for pregnant women infected by CMV has been proposed. It is a multicenter open-label phase 2 study with one arm. The aim of this study was to evaluate the efficacy of oral valacyclovir, 8 g daily, for pregnant women carrying a symptomatic cytomegalovirus-infected fetus, defined by the presence of measurable extracerebral or mild cerebral ultrasound symptoms. Although results of this study indicate that high-dosage valacyclovir given in pregnancy is effective for improving the outcome of moderately symptomatic infected fetuses, it is not a randomized controlled trial. Other trials might be made in the future to improve the knowledge about new emerging and more potent anti-cytomegalovirus drugs that have not currently been tested in pregnancy.
20.2 Toxoplasma gondii Infection in Pregnant Women
Toxoplasmosis is a worldwide zoonosis caused by protozoan Toxoplasma gondii, whose acute stage is most frequently asymptomatic.
Infection occurs worldwide and the percentage of seropositive persons ranges from 5 % to 90 % [35]. These extreme variations are due to the different level of both exposure to the main sources of infection and hygienic standards between geographic areas. The sources of infection are ubiquitous.
Symptomatic infections usually cause a mononucleosis-like illness with low-grade fever, malaise, headache, and cervical lymphadenopathy. Other manifestations such as encephalitis, myocarditis, hepatitis, and pneumonia can rarely complicate acute disease. Primary infection in pregnant women, when is transmitted transplacentally, can cause congenital toxoplasmosis. Congenital toxoplasmosis can then lead to a wide array of manifestations, ranging from mild chorioretinitis, which can present many years after birth, to miscarriage, mental retardation, microcephaly, hydrocephalus, and seizures.
Prenatal care must include education about the prevention of toxoplasmosis infection in seronegative pregnant women, who – along with their primary care physicians and obstetricians – need to be informed about the risk factors for toxoplasmosis in order to lower the risk of congenital infection.
20.2.1 Toxoplasma gondii: Main Microbiologic Characteristics
Toxoplasma gondii is an obligate intracellular protozoan parasite which belongs to the subclass of Coccidia (order Eucoccidiorida, Family Sarcocystidae).
It has a complex life cycle with asexual reproduction taking place in diverse tissues of mammals and birds (secondary hosts) and sexual reproduction taking place in digestive epithelium of cats (primary host). Cats mainly become contaminated by ingesting animal flesh (mouse, bird) encysted with Toxoplasma gondii and rarely by ingesting oocysts directly from the feces of other cats. Infected cats are usually asymptomatic and begin to shed unsporulated oocysts in their feces 1–2 weeks after exposure. Within days to weeks, the oocysts sporulate and become infectious. Oocysts survive best in warm and humid conditions (garden, sand box, litter) and can remain infectious for many months. Oocysts withstand exposure to freezing for up to 18 months, especially if they are covered and out of direct sunlight. After ingestion by a secondary host (human, bird, rodent, domestic animal) oocysts release sporozoites, which change into tachyzoites. Tachyzoites are present during acute infection and are capable of invading cells and replicating. They are disseminated widely and circulate from 3 to 10 days in the immunocompetent host before changing into bradyzoites and forming cysts in various tissues, including the lymph nodes, muscle, brain, retina, myocardium, lungs, and liver. These cysts remain present during latent infection [36, 37]. Once infected, humans are believed to remain infected for life. Unless immunosuppression occurs and the organism reactivates, human hosts usually remain asymptomatic. If immunity wanes, such as with the use of immunosuppressive therapy or the acquired immunodeficiency syndrome, bradyzoites can resume rapid division and hematogenously disseminate as tachyzoites again [38, 39].
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