Toxoplasmosis and pregnancy

                                                         داء التوكسوبلازموز والحمل

INTRODUCTION  —

 Toxoplasma gondii is a ubiquitous protozoan parasite that infects humans in various settings. The parasite is mainly acquired during childhood and adolescence . In industrially developed, temperate climate countries, the prevalence of infection has declined over the last 30 years ,. Much higher rates of infection (up to 80 percent) are found in the tropics in communities exposed to contaminated soil, undercooked meat, or unfiltered water .

Once a person is infected, the parasite lies dormant in neural and muscle tissue and will never be eliminated. 

Evidence has been accumulating over the last 15 years that these findings are not applicable to parts of Latin America, where clinical manifestations of infection are much more common and more severe, probably because of the predominance of more diverse and more virulent parasite genotypes.

When toxoplasmic infection is acquired for the first time during pregnancy, infection can be transmitted to the fetus, resulting in congenital toxoplasmosis and associated neurological and ocular manifestations. In this topic, we will focus on primary maternal infection and its effect on the fetus.

SOURCES OF INFECTION  —

 Toxoplasma gondii is an obligate intracellular parasite that exists in three forms: the oocyst, which is shed only in cat feces; the tachyzoite (a rapidly dividing form observed in the acute phase of infection); and the bradyzoite (a slow growing form observed within tissue cysts) . During a primary infection, a cat can shed millions of oocysts daily from its alimentary canal for a period of one to three weeks. These oocysts become infective one to five days later and may remain infectious for over a year, especially in warm, humid environments. Cats typically develop immunity after a primary infection; therefore, recurrent infection with passage of oocysts is unlikely.

In developed temperate climate countries, the main source of maternal infection is thought to be ingestion of bradyzoites contained in undercooked or cured meat or meat products. Ingestion of oocysts, from contact with soil or water, or eating soil-contaminated fruit or vegetables is also a major source of infection .  

PATHOGENESIS  —

 Maternal toxoplasmosis infection is acquired orally. Fetal infection results from transmission of parasites via the placenta following primary maternal infection. It is likely that transmission occurs in most cases during the parasitemic phase in the days after infection and before the development of a serologic response. To survive and multiply, the tachyzoite invades host cells, especially in the brain and muscle, where it forms tissue cysts which can remain dormant for years. In immune competent animal models, tissue cysts can be formed within a week of infection . It is not known how long this process takes in the relatively immunologically immature fetus. The transition from acute infective tachyzoite form, which is responsible for cell damage, to the dormant bradyzoite form contained in tissue cysts impenetrable to antibiotics, has important implications for the therapeutic "window of opportunity."

MATERNAL INFECTION

Incidence  —

 The incidence of maternal infection during pregnancy ranges from 1 to 8 per 1000 susceptible pregnancies, with the highest reported rates in France . The risk of transmitting infection to the fetus increases steeply with the gestational age at seroconversion .

Immunocompetent women infected prior to conception virtually never transmit toxoplasmosis to the fetus, although rare exceptions have been reported . Immunocompromised women (eg, women with AIDS or taking immunosuppressive medications) may have parasitemia during pregnancy despite preconceptional infection; their infants are at risk of congenital infection .

Congenital toxoplasmosis secondary to reinfection is a rare event; this phenomenon has been reported in approximately six women over the past three decades . One well-documented case demonstrated that prior immunity to toxoplasma did not protect against reinfection with an atypical strain . 

Clinical manifestations  —

 Acute infection in the mother is usually asymptomatic. When symptoms of infection occur, they are nonspecific, such as fatigue, fever, headache, malaise, and myalgia. Lymphadenopathy is a more specific sign of the disease. In a prospective European cohort study, lymphadenopathy was noted in 7 percent of 1144 infected pregnant women before diagnosis of infection . 

Diagnosis  — 

Pregnant women who experience a mononucleosis-like illness, but who have a negative heterophile test, should be tested for toxoplasmosis as part of their diagnostic evaluation. We do not recommend routinely screening for toxoplasmosis in pregnancy.

Maternal infection during pregnancy is most accurately diagnosed when based on a minimum of two blood samples at least two weeks apart showing seroconversion from negative to positive toxoplasma-specific IgM or IgG.

Such serial testing of susceptible women is usually feasible only as part of a prenatal screening program. Monthly or three monthly retesting schedules operate in parts of Europe : the more frequently a woman is retested, the greater the chance of detecting infection early on, and when treatment is more likely to be effective. However, the costs of frequent testing and the chances of false positive results increase as the frequency of retesting increases . Thus, women may undergo invasive prenatal investigations and be treated unnecessarily. These potential harms have to be weighed against potential benefits of treatment, which have been found only for rare, serious neurological sequelae of congenital toxoplasmosis . 

The usefulness of a rising IgG titer has never been adequately evaluated and is subject to error because of lack of reproducibility in many laboratories when specimens are analyzed on different days. However, the combination of a positive IgM and negative IgG result, with both tests becoming positive two weeks later, thereby ruling out a nonspecific IgM response, is evidence of infection occurring about two weeks before the first positive IgM result . 

FETAL INFECTION

Incidence  — 

The risk of fetal infection increases with advancing gestational age at the time of maternal seroconversion. A meta-analysis of all available cohorts estimated the risk of transmission to be 15 percent when the mother seroconverted at 13 weeks, 44 percent at 26 weeks, and 71 percent at 36 weeks . Although these figures are based on women who were mostly treated during pregnancy, they are likely to be generalizable to untreated women, as there is no clear evidence that prenatal treatment administered in screening programs reduces the risk of mother to child transmission of toxoplasmosis .

Fetal sequelae  —

 Fetal ultrasound can be useful to provide diagnostic information, although findings are nonspecific. The most common intracranial sonographic findings in fetal toxoplasmosis are intracranial hyperechogenic foci or calcifications and ventricular dilatation, which are poor prognostic signs . Cerebral ventricular dilatation is generally bilateral and symmetrical. In one series of 32 proven infected cases, evolution was always very rapid over a period of a few days . In a European prospective cohort study , abnormal sonographic findings of intracranial calcification or ventricular dilatation were found in 7 percent (14/218) of infected fetuses; however, as reported in other studies, such lesions appear only after 21 weeks of gestation . Abnormal findings involving areas other than the brain (eg, ascites) are less specific for toxoplasmosis. Intrahepatic densities, increased thickness and hyperdensity of the placenta, ascites, and rarely pericardial and pleural effusions have also been observed. Serial ultrasound is useful if late termination is being actively considered.

Intrauterine growth restriction and microcephaly are not characteristic of congenital toxoplasmosis . Stillbirth appears to be a rare complication; a prospective European cohort study of 1208 infected women found the risk of stillbirth among 448 women infected during the first trimester was no higher than that in the general obstetrical population matched for age . An observed association between early maternal infection and preterm delivery may be due to obstetric intervention, rather than the disease itself.

Diagnosis  — 

The main purpose of prenatal diagnosis of fetal infection is to help decide whether to change prenatal treatment from spiramycin to a pyrimethamine -sulfonamide combination . As prenatal diagnosis requires amniocentesis, which is an invasive test with a small but well-established risk of miscarriage, clinicians need to ensure that women are sufficiently informed to enable them to weigh the potential benefits and risks when deciding whether to undergo prenatal diagnosis.  Although there have been no randomized controlled trials comparing types of treatment, none of the comparative cohort studies have provided any evidence that a pyrimethamine-sulphonamide combination is more effective than spiramycin for any outcomes related to congenital toxoplasmosis in humans .

In some women, prenatal diagnosis is important to aid in their decision as to whether to terminate the pregnancy. Exclusion of fetal infection by prenatal diagnosis can also prevent unnecessary postnatal treatment in children without clinical signs of toxoplasmosis and at low risk of congenital infection .

Polymerase chain reaction (PCR) for T. gondii DNA in amniotic fluid is the best method for diagnosing fetal infection, but accuracy varies among laboratories and techniques and sensitivity is lower in early than in late pregnancy . Real time PCR appears to be more sensitive than conventional PCR. The sensitivity of real time PCR testing was illustrated by a prospective French study of real time PCR for T. gondii that reported sensitivity and specificity of 92.2 and 100 percent, respectively; sensitivity was not affected by gestational age at the time of maternal seroconversion .

Whether any treatment reduces the risk of mother to child transmission remains controversial, as no randomized controlled trials evaluating this issue have been performed. 

The authors found weak evidence that treatment started within three weeks of seroconversion reduced mother-to-child transmission compared with treatment started after eight or more weeks (OR 0.48, 95% CI 0.28-0.80; p = 0.05), but they could not distinguish whether this was a real benefit of treatment or a bias due to late detection and inclusion in the cohort of women at increased risk of fetal infection. Only one in five women were treated within three weeks of seroconversion, despite the fact that most (76 percent) were identified in France, where a regimen of monthly retesting is mandated by law. Thus, even if early treatment is effective, it will be difficult to identify and treat women so quickly after seroconversion.

TREATMENT REGIMENS  —

 Despite the lack of evidence of treatment efficacy, prenatal treatment is usually offered to pregnant women who are diagnosed with toxoplasmosis. The uncertainty about treatment effectiveness, risk of adverse effects, and the high probability that the child will not be impaired should be discussed with women when deciding whether or not to treat.

Spiramycin  — Pregnant women who become infected during pregnancy are generally treated immediately with spiramycin (1 g orally every eight hours without food), which is a macrolide antibiotic similar to erythromycin . It is concentrated in the placenta, where it is thought to treat placental infection and thus helps to prevent transmission to the fetus, at least theoretically . The drug is licensed in Europe and Canada, and is available in the United States for use in pregnancy from Rhone-Poulenc (Montreal, Quebec) if an Investigational New Drug (IND) number is obtained from the Food and Drug Administration (FDA).

Pyrimethamine and sulfadiazine  —  Pyrimethamine is a folic acid antagonist which can cause dose-related bone marrow suppression with resultant anemia, leukopenia, and thrombocytopenia. It is teratogenic in animals when given in large doses . Sulfadiazine , another folic acid antagonist, works synergistically with pyrimethamine against T. gondii tachyzoites, and can also cause bone marrow suppression and reversible acute renal failure. Due to the potential toxicity of these drugs, their use during pregnancy should only be considered if fetal infection has been documented, although there is no clinical evidence that these drugs are more effective than spiramycin . There are no direct maternal benefits from these drugs.

Various dosing regimens have been proposed, but even in France, where prenatal screening has operated for 30 years, treatment regimens vary :

• A three-week course of pyrimethamine (50 mg once per day orally or 25 mg twice per day) and sulfadiazine (3 g/day orally divided into two to three doses), alternating with a three-week course of spiramycin (1 g orally three times per day) until delivery.
• Pyrimethamine (25 mg once per day orally) and sulfadiazine (4 g/day orally divided into two to four doses) administered continuously until term.
• Leucovorin calcium (folinic acid, 10 to 25 mg/day orally) is added during pyrimethamine and sulfadiazine administration to prevent bone marrow suppression. Monitoring of complete blood counts and platelet counts should be performed weekly, and treatment discontinued, if a significantly abnormal result is reported.

Other  —  Azithromycin has been used successfully to treat T. gondii in both an animal model and in humans with AIDS . It is a Category B drug that has been used safely for treatment of Chlamydia trachomatis infections in pregnancy. Large clinical trials are necessary to determine whether this agent, or perhaps clarithromycin , is an effective alternative to spiramycin to prevent in utero infection with T. gondii. Pyrimethamine (100 mg loading dose orally followed by 25 to 50 mg/day) combined with azithromycin (500 mg per day) has been found to have equivalent effects to the combination with sulfonamide in a randomized controlled trial of adult patients with toxoplasmic retinochoroiditis . Women intolerant of pyrimethamine may consider trimethoprim-sulfamethoxazole  or clindamycin . However, the safety and efficacy of these drugs for treating in-utero toxoplasmosis infection are unknown.

TERMINATION OF PREGNANCY  — A small proportion of women have their pregnancies terminated because of toxoplasmosis. Within the prenatal screening program in France, termination is discouraged unless there is definite evidence of fetal infection based on PCR performed in a reference laboratory and evidence of intracranial abnormalities on fetal ultrasound. The rationale for this approach is that most infected babies have a good prognosis and, on average, do not differ in their development at three to four years from uninfected children . However, fetuses with ultrasound evidence of intracranial lesions are thought to be at high risk of serious neurological sequelae or postnatal death. It is not clear whether prenatal treatment reduces these risks once intracranial lesions are apparent . In France, approximately 1.4 percent (17/1208) of infected women undergo termination and just over half of these pregnancies have proven fetal infection .

NEONATAL MANAGEMENT AND OUTCOME  — Toxoplasma infection in the newborn is discussed in detail separately. 

PREVENTION  — 

Prevention of primary infection is based upon avoidance of sources of infection. While access to reliable information on sources of infection is undoubtedly important, a systematic review found a lack of clear evidence that such information changes women's behavior during pregnancy [ 78 ]. Evidence from case control studies of risk factors in Europe has identified the following principal sources of infection:

• Travel to less developed countries is a major risk factor, especially to South America, where more virulent parasite genotypes predominate .
• Women should avoid drinking unfiltered water in any setting .
• Avoid ingesting soil by observing strict hand hygiene after touching soil. Fruit and vegetables should be washed before eating .
• Raw or undercooked meat is an important source of infection. Cutting boards, knives, and the sink and counters should be washed after food preparation. Avoid mucous membrane contact when handling uncooked meat. Women should also avoid tasting meat while cooking .
• Meat should be cooked to 152ºF (66ºC) or higher, or frozen for 24 hours in a household freezer (at less than -12ºC), both of which are lethal to tachyzoites and bradyzoites . Meat . There is weak evidence that meat that has been smoked or cured in brine is not safe. The risk of infection is likely to be increased when cured products involve meat from more than one animal and limited drying and curing, as in some local production methods .
• There is some evidence that shellfish can be infected with toxoplasma cysts.
• Owning a cat is only weakly associated with acute infection. This is probably because cats only excrete oocysts for three weeks of their life, and people are just as likely to be exposed to oocysts excreted by someone else's cat. Nevertheless, it seems sensible for pregnant women with cats to ask someone else to change the litter box daily (fresh cat feces are not infectious).

Hand washing is the single most important measure to reduce transmission of microorganisms from one site to another on the same patient. Thus, handwashing is important after activities such as preparing food or gardening.