This chapter should be cited as follows:
Under review - Update due 2017

Toxoplasmosis in Pregnancy

Katherine A. Van kessell
Acting Instructor, Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
David A. Eschenbach, MD
Professor and Chair, Department of Obstetrics and Gynecology; DIrector, Division of Gynecology, University of Washington, Seattle, Washington

INTRODUCTION

Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii. When acquired during pregnancy, toxoplasmosis often goes unrecognized in the mother, but it can produce a severe congenital infection with ocular and neurologic damage to the infant. Up to 38% of women in the United States have immunity against T. gondii1 from a prior infection. This leaves about 62% of women at risk to acquire toxoplasmosis during pregnancy. Education about the primary prevention of toxoplasmosis has decreased the rate of primary infection, but it is still an important pathogen. Approximately 1 to 2 cases of congenital toxoplasma occur per 10,000 children born.2

Placebo-controlled prospective trials have not been conducted to evaluate the effectiveness of the treatment of toxoplasmosis in utero. However, multiple retrospective and prospective, noncontrolled studies have indicated that treatment may prevent or at least decrease the sequelae associated with this infection. Many European countries now have implemented universal antenatal screening, but the infection is less common in the United States and American pregnant women are not routinely screened for susceptibility. Many other prenatal screening tests routinely done in the United States are to detect even less common diseases. Further, tests to detect toxoplasma infection during pregnancy have improved and become more reliable. With an increasing number of studies showing the benefits of treatment in utero, the United States may need to adopt a universal screening regimen for T. gondii.

THE ORGANISM AND TRANSMISSION

T. gondii is a protozoan parasite with three different forms. The life cycle of T. gondii has been clearly delineated. The definitive host is the cat. 3 The oocyst produces the sporozoites in the enteroepithelial cells of the intestines. Oocysts are passed in the feces of cats for periods varying from 7 to 20 days after an initial infection. The oocysts are not infectious when shed but become infectious within 21 days of being shed unless extreme temperatures exist. Oocysts do not sporulate below 4°C or above 37°C. 4 The second form, referred to as tachyzoites, survive and multiply only in an intracellular location. Tachyzoites are easily destroyed by freezing and thawing or by contact with digestive stomach fluid. The organism multiplies every 4 to 6 hours, once host cell invasion has occurred. Last, the tissue cyst form of toxoplasma may contain few to many organisms. Tissue cysts form in the tissue of infected animals within a week of infection.5 The cyst can occur in any organ of the body but seems to have a particular predilection for brain and skeletal muscle.6

Excystation in the gut begins with ingestion of infectious oocysts by humans or other carnivores. Sporozoites are liberated and widely disseminate through the blood stream during the infective stage. Trophozoites then develop and multiply within cells, leading eventually to rupture and death of the cell and further dissemination of T. gondii. With the activation of the host immune antibody response, the third stage begins. Fetal infection occurs only during the acute phase of infection, when T. gondii in maternal blood are transported to the placenta and fetus. Antibody formation elicited in response to the parasite converts the parasite from the trophozoite to the tissue cyst form, and the parasite no longer circulates in blood to cause congenital infection. Thus, fetal infection has not been reported in women with chronic toxoplasmosis that occurred before pregnancy. The tissue cyst form can persist in tissue of adults, such as brain and muscle, throughout the life of the host, producing a chronic, latent infection.6,7

Several studies have delineated the major routes of transmission of T. gondii. Earlier studies established that ingestion of tissue cysts in infected meat and oocysts in soil, food, or water contaminated with cat feces were the two major routes of transmission.8,9 However, recent studies have established that contact with cats is not a significant risk factor for transmission during pregnancy. Rather, the most strongly predictive risk factors for acquiring toxoplasmosis during pregnancy are consumption of undercooked lamb, beef, or game, contact with soil, and travel outside the United States, Canada, and Europe.10

EPIDEMIOLOGY

In the United States, the incidence of acute maternal toxoplasmosis infection during pregnancy is estimated at 0.2% to 1.0%.7 Congenital fetal toxoplasmosis in the United States ranges from 1 to 2 per 10,000 live births.2 Within the United States, a large variation occurs in the seroprevalence of T. gondii antibody among pregnant women, ranging from a seropositivity prevalence of 3.3% among women in Denver to 30% among women in Los Angeles and Birmingham.3

There is debate about the need for universal serologic screening of T. gondii during pregnancy in the United States, as in France. In France, the rate of primary infection during pregnancy is much higher (1.2 to 16/1000) than in the United States, which of course relates to a higher rate of congenital toxoplasmosis (1.9 to 3.2/1000) in France than in the United States.3 Universal serologic screening for antibody to T. gondii begins at the first prenatal visit in France, and seronegative women are retested monthly until delivery. If seroconversion occurs during pregnancy, women are promptly treated with antiparasitic medications.

By contrast, serologic testing for toxoplasma has been haphazard in the United States. No universal screening regimen has been adopted in the United States, and some studies found universal screening to increase morbidity (from increased amniocentesis procedures) and overall costs.11,12 However, proponents of universal screening argue that screening occurs for even less common diseases, such as neonatal phenylketonuria (1/6000 to 1/15,000), HIV (1 to 9/10,000), and syphilis (1.5/10,000).2 In addition, with recent improvements in the polymerase chain reaction (PCR) assay for T. gondii, the need for fetal blood testing and cordocentesis has greatly diminished, and the morbidity associated with these fetal tests during pregnancy should be low.

MATERNAL INFECTION

Clinical Picture

Most women who acquire an acute infection with T. gondii are asymptomatic. Only about 10% of women have signs or symptoms during an acute infection.3 Lymphadenopathy is the most commonly recognized clinical manifestation of recent infection. Enlarged nodes are usually discrete, of variable firmness, nontender, and nonsuppurative. The lymphadenopathy may be associated with a flu-like illness, with fever, fatigue and headache.7 The groups of lymph nodes most commonly involved are the cervical, suboccipital, supraclavicular, axillary, and inguinal. More serious or specific symptoms such as polymyositis, dermatomyositis, and chorioretinitis occur rarely in adults with normal immunity.3

Diagnosis

Acute maternal infection is diagnosed by serologic testing, but serology in toxoplasmosis can often be confusing, and it is not as straightforward as one might expect. In countries such as France and Austria with routine screening and a high prevalence of toxoplasma, women are screened as frequently as every month to every 3 months during pregnancy. Thus, seroconversion is likely to be detected during pregnancy; in such cases, a seroconversion is easily differentiated from chronic infection. However, in countries such as the United States where routine screening is not practiced, a single positive serologic titer can not differentiate seroconversion from chronic infection.

Screening for the absence or presence of IgG or IgM specific antibodies is vital to make the diagnosis of acute toxoplasma infection in pregnancy. The Sabin-Feldman dye test, which primarily measures IgG antibodies, is the gold standard to detect T. gondii specific antibodies.7 Titers usually are not detectable until 1 to 2 weeks after the acquisition of T. gondii and then may persist at low levels for life. IgG antibodies are also detected with the IgG immunofluorescent antibody (IFA) test. The results of this test are comparable to the dye test, although some of the commercial kits give a moderately high percentage of false-positive results.7

Rising antibody titers to T. gondii must be documented to diagnose a woman suspected of acquiring a toxoplasma infection in pregnancy. The use of a single antibody titer has led to an increased rate of termination of pregnancy for suspected toxoplasmosis when, in fact, the woman may have acquired the infection before pregnancy. A stable IgG antibody titer indicates chronic infection, which poses no risk to the fetus.11 Serum samples obtained 3 weeks apart need to be tested for IgG titers to toxoplasmosis in the same laboratory on the same day. A fourfold or greater rise in IgG titer documents an acute toxoplasmosis infection. Variability of the test from day to day makes it imperative that paired sera used to document a rise in antibody be run in the same laboratory on the same day. The test variability is large enough that false-positive results are frequent when paired sera are tested at different laboratories or at different times on the same day.

The presence of IgM antibodies to toxoplasmosis are detected using an IFA test, immunosorbent agglutination assay (ISAGA), or enzyme-linked immunosorbent assay (ELISA). IgM can be detected within the first 2 weeks of infection using the ISAGA or ELISA methods. However, IgM titers can remain elevated for a year or more; thus, the presence of IgM antibody is not diagnostic of an acute toxoplasmosis infection. A fourfold rise in the IgG titer in two samples run in the same laboratory on the same day is evidence of an acute infection.

Because IgM can remain elevated for years, serum samples drawn at 3-week intervals need to be tested in the same laboratory on the same day. A rise in IgM titers is sufficient evidence of acute infection. By contrast, a single positive IgM titer can mean that the infection was acquired either during pregnancy or before conception. If the infection is acquired before conception, the fetus is very unlikely to be at risk for congenital toxoplasmosis. However, if infection was acquired during pregnancy, then congenital infection is possible. A negative IgM antibody test virtually rules out recently acquired infection unless the sera are tested too early after exposure. Women who are positive for IgG and negative for IgM are defined as immune and no further follow-up is necessary, because their fetuses are not at risk of congenital toxoplasmosis.2

In France, women are tested serologically for toxoplasmosis at their first prenatal visit. Seronegative (susceptible) women at their first prenatal visit are tested serologically every month or every trimester. Universal screening appears to lower the number of cases of congenital toxoplasmosis, but at a substantial cost.12 However, routine screening has not occurred in the United States because of the substantial cost of screening12 and because a debate exists on how effective in utero treatment is to prevent the manifestation of congenital toxoplasmosis.13

MATERNAL-TO-FETAL TRANSMISSION

Transmission of the parasite is quite dependent on the time in pregnancy that maternal infection is acquired (Table 1).14 The mean transmission rate in pregnancy is 29% to 35%.15,16 The later in pregnancy the maternal infection is acquired, the more frequently parasites are transmitted to the fetus, and the higher the incidence of congenital infection.17,18 However, the earlier in pregnancy the fetus is infected, the more severe is the clinical disease in the infant (Table 2). An exception to this rule occurs for the fetus exposed to maternal T. gondii infection before 15 weeks' gestational age; these fetuses appear to have a transmission rate of only 3.5% and thus an extremely low risk of acquiring congenital toxoplasmosis (see Table 1).19 In addition, toxoplasma infection acquired at or during conception has even a lower transmission rate of 0.6%.18 The transmission rate then rises steadily from 20% to 25% in the late second trimester to over 60% in the third trimester.19 Lastly, women who seroconvert at 24 to 30 weeks' gestation carry the highest risk (10%) of a severely congenitally infected infant, even though they were not at the gestational age of highest transmission.15 Although the frequency of infection is higher later in pregnancy, third-trimester congenital infections appear to be mild and only rarely result in a severely affected infant (see Table 2).

Table 1. Incidence of Congenital Toxoplasmosis According to Gestational Age at the Time of Maternal Infection


Weeks of

Infected

 

 

Gestation

Fetuses

All Fetuses

Incidence (%)

0–2

0

100

0

3–6

6

384

1.6

7–10

9

503

1.8

11–14

37

511

7.2

15–18

49

392

13

19–22

44

237

19

23–26

30

116

26

27–30

7

32

22

31–34

4

6

67

Unknown

8

351

 

Total

194

2632

7.4


Adapted from Hohlfeld P, Daffos F, Costa J-M et al: Prenatal diagnosis of congenital toxoplasmosis with polymerase-chain-reaction test on amniotic fluid. N Engl J Med 331:695–699, 1994

Table 2. Outcomes of Prenatally Diagnosed Untreated Congenital Toxoplasma Infection in Liveborn Infants


 

Percent of Infants With Indicated Severity of Infection

Trimester in Which Maternal Infection Acquired

Subclinical

Mild

Severe*

Stillbirth or Perinatal Death

First

2

1

6

5

Second

20

5

2

2

Third

53

6

0

0


*Severe disease was considered if chorioretinitis, intracranial calcifications, mental retardation, or neurologic disorders were present.
Adapted from Desmonts G, Couvreur J. Congenital toxoplasmosis: A prospective study of the offspring of 542 women who acquired toxoplasmosis during pregnancy. Pathophysiology of congenital disease. In Thalhammer O, Baumgarten K, Pollack A (eds): Perinatal Medicine, Sixth European Congress, pp 51–60. Stuttgart, Georg Thieme Verlag, 1979

FETAL INFECTION

Clinical Picture

If acute toxoplasmosis is acquired during pregnancy, the infant is at the risk of developing congenital toxoplasmosis. The classic triad of signs associated with congenital toxoplasma infection is chorioretinitis, cerebral calcifications, and hydrocephalus.3 However, only 10% to 15% of congenitally infected infants manifest signs of a congenital infection. The remaining 90% of infants with congenital toxoplasmosis are asymptomatic at birth (see Table 2). Unfortunately, this large group of infants with no observable sequelae at birth remain at high risk of developing symptoms months or even years after birth.2 Most infants with congenital toxoplasmosis at birth show nonspecific signs such as prematurity and growth retardation. The most common later sequelae are ocular (chorioretinitis). Late neurologic sequelae are also common in infants; these may begin with an elevated cerebrospinal fluid protein at birth, later developing into hydrocephalus, convulsions, and nystagmus. Congenital neurologic toxoplasmosis can lead to mental retardation and blindness later in life. Recent evidence also indicates that high maternal titers of antibody to T. gondii doubles the frequency of deafness among their children.1

DIAGNOSIS

Potential exposure of the fetus to T. gondii is established by serologic evidence of acute infection in the mother when a fourfold or greater increase occurs in IgG or IgM antibodies to toxoplasmosis. The next step is to determine whether the fetus has actually acquired T. gondii and has manifestations of congenital toxoplasmosis.

Earlier methods to diagnose in utero fetal infection included sampling of the placenta and fetal blood through the technique of periumbilical blood sampling (PUBS) and cordocentesis. These tests are difficult to perform and increase the risk of fetal bleeding and spontaneous miscarriage. Recently, PCR has been used to identify T. gondii in amniotic fluid. Amniotic fluid can be obtained easily in pregnancy compared with fetal blood. Early successes with the technique provided the impetus for several confirmatory studies and the drive to perfect PCR testing. As a result of the efforts, PCR testing of amniotic fluid has obviated the need for PUBS sampling. PCR has now become the optimal method to detect the exposure of the fetus to T. gondii infection. Thus, PCR testing of amniotic fluid is the standard of care to diagnose the fetal acquisition of toxoplasmosis in utero.

During the past several years, multiple studies have confirmed the efficacy of PCR since the initial report by Hohlfeld and associates19 and have found it to be both sensitive and specific.20,21,22,23 The specificity of PCR testing of amniotic fluid ranges from about 96% to 100%, and the sensitivity of PCR is about 81% (Table 3). Findings from these studies have reinforced the conclusion that a negative PCR result of amniotic fluid does not rule out congenital infection. However, with such a high specificity, this will prevent needless pregnancy terminations or administration of potentially toxic treatments. In addition, the sensitivity to detect congenital toxoplasmosis increased to 91% when a combination of PCR and mouse inoculation of amniotic fluid was performed (see Table 3). Most recently, by using the most conserved gene sequences among different strains of T. gondii, the sensitivity of PCR to detect fetal infection has improved further. In a recent report, as little as 0.05 T. gondii tachyzoites, in a 50-μL reaction volume, were detected in an in vitro assay.23

Table 3. Results of Prenatal Diagnosis in Congenitally Infected and Uninfected Fetuses


 

Tests of Amniotic Fluid

Tests of Fetal Blood

 

 

 

 

PCR With

 

 

 

 

 

Mouse

Cell

PCR

Mouse

PCR With

Mouse

IgM

IgA

Result

Inoculation

Culture

Assay

Inoculation

Cell Culture

Inoculation

Antibodies

Antibodies

No. of positive results* per no. of tests performed in infected fetuses

14/24

2/13

13/16

20/22

13/14

5/16

7/15

5/13

No. of positive results* per no. of tests performed in uninfected fetuses

1/66

0/35

2/49

3/24

2/9

0/41

2/43

1/39

Sensitivity (%)

58

15

81

91

93

31

47

38

Specificity (%)

98

100

96

88

78

100

95

97

Positive predictive value (%)

93

100

87

97

97

100

78

83

Negative predictive value (%)

87

76

94

91

88

79

84

83


PCR, polymerase chain reaction.
*At least 1 parameter.
Adapted with permission from Foulon W, Pinon J-M, Stray-Pederson B et al: Prenatal diagnosis of congenital toxoplasmosis:A multicenter evaluation of different diagnostic parameters. Am J Obstet Gynecol 181:843–847, 1999

Some children are diagnosed with toxoplasmosis after delivery by serologic evidence or by direct culture of the placenta. The fetus and newborn produce specific antibodies in response to toxoplasma infection. IgA was more frequently detected (60%) than IgM (50%) in infants with congenital toxoplasmosis. 16,27 IgM antibodies are the first to be produced in utero, followed by IgG and IgA antibodies. Thus, IgA antibodies are more commonly found in the newborn period than are IgM antibodies, because in some infants the IgM antibodies appear early and disappear before birth, whereas the later-produced IgA antibodies are still detected in serum after birth.16

Ultrasound is used to monitor fetal development and to identify manifestations of congenital infection such as hydrocephalus, ventriculomegaly, and intracranial calcifications.2 A combination of prenatal screening with ultrasound and amniotic fluid PCR and neonatal screening with antibody titers has led to a correct diagnosis of congenital toxoplasmosis in 98% of cases.16 About 75% of congenital toxoplasmosis cases were identified through prenatal screening,28,29,30,31 and the remainder were found only after neonatal screening. Thus, infants with signs of congenital infection at birth should undergo neonatal screening even if prenatal screening results were negative.

PREVENTION AND TREATMENT

Primary Prevention

Several recent studies examined the impact of primary prevention of toxoplasmosis in pregnancy. In a case-control study of French women, the following factors were highly associated with acute toxoplasma infection: poor hand hygiene (odds ratio [OR] = 9.9), frequent consumption of raw vegetables (OR = 3.1), having a pet cat (OR = 4.5), and consumption of undercooked beef (OR = 5.5) or lamb (OR = 3.1).24 In another study performed in six European centers, eating undercooked, raw, or cured meat contributed to 30% to 63% of cases of acute infection, and soil contact contributed to up to 17% of acute infections.8 Also, improved information about the risks associated with undercooked or cured meat likely reduces infection rates appreciably. In addition, improvements can be made in the labeling of meat according to farming and processing methods, and in measures to reduce infection in domestic animals.

Treatment of Congenitally Infected Fetuses and Infants

Depending on the laws of the state, two options exist to treat congenital toxoplasmosis. Termination of pregnancy is an option if the diagnosis is made prior to the gestational age at which termination is legal. The second option is treatment of in utero infection with antiparasitic drugs. In France, women diagnosed during pregnancy with acute toxoplasma infection are started on spiramycin, a macrolide antimicrobial that is concentrated in the placenta. Spiramycin is safe to use in pregnancy. Spiramycin can be obtained on request through the U.S. Food and Drug Administration only after serologic confirmation of infection at a reference laboratory. This antibiotic is traditionally given for the first 21 weeks of gestation or until term in fetuses who do not manifest signs of congenital infection (Table 4). The recommended dosage of spiramycin is 3 g/day or 1.5 g twice a day.18

Table 4. Treatment Regimens for Toxoplasmosis Based on Time of Diagnosis


Time of Diagnosis

Treatment Regimen

Duration

Maternal infection confirmed by serologies

Spiramycin 1.5 g PO BID

From diagnosis until delivery.

Diagnosis of fetal toxoplasmosis*

Pyrimethamine 50 mg PO QD and

Alternate 3 weeks of triple therapy

 

 sulfadiazine 1 g PO TID and

 with 3 weeks of monotherapy

 

 folinic acid 6 mg PO TID

 with spiramycin. Avoid triple

 

 

 therapy near term.†

Congenital toxoplasmosis in neonate

Pyrimethamine and sulfadiazine and folinic acid

6–24 months of therapy


BID = twice a day; PO = orally; QD = every day; TID = three times a day.
*By ultrasonographic finding consistent with toxoplasmosis and/or postitive amniotic fluid PCR and/or positive serologies from cordocentesis.
†May cause kernicterus.
Adapted from Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med 31:271, 1988

Although spiramycin appears to reduce the risk of transmission by almost 60%,30 it is not effective to treat an infected fetus or infant. Thus, if fetal infection is confirmed after 18 weeks of gestation, or if congenital toxoplasma infection is documented after birth, more potent antibiotic regimens are indicated than spiramycin. Pyrimethamine and sulfadiazine therapy has been associated with resolution of signs of active congenital toxoplasmosis, usually within the first week after initiation of therapy.25 Pyrimethamine and sulfadiazine act synergistically against T. gondii with a combined activity eight times greater than expected if their effects were only additive.26 Consequently, the simultaneous use of both drugs is indicated in all cases of suspected congenital fetal or infant infection (see Table 4). The dosage of this regimen includes pyrimethamine 50 mg per day, and sulfadiazine, 1 g orally three times a day. Leucovorin (folinic acid) is given at a dosage of 10 to 20 mg per day to provide folic acid. Pyrimethamine, a folic acid antagonist, is traditionally not used in the first trimester because of its teratogenic effects. Very high doses (12 mg/kg) of pyrimethamine in rats have produced stunting of growth, general hydrops, cranial bone defects, incomplete cranial and brain development, rachischisis, internal hydrocephalus, ventral hernias, situs inversus, and combinations of all of these defects.3

To date, conflicting evidence exists on the efficacy of treatment with antiparasitic drugs in utero. Thus far, there have been no placebo-controlled prospective studies evaluating drug treatment in utero compared with no treatment.13 Numerous studies {support} the concept that treatment in utero may decrease sequelae.14,16,18,22,29 However, these studies lack a comparison control group.

Treatment of infants with congenital toxoplasmosis has clearer results. A regimen of pyrimethamine and sulfadiazine, alternating monthly with spiramycin, is used in France. A regimen of pyrimethamine and sulfadiazine with leucovorin rescue is used in the United States.1 In both regimens, the antiparasitic therapies are continued for 1 year. Treatments can eradicate intracranial calcifications and improve neurologic function.32

CONCLUSION

As a result of improved diagnostic techniques, T. gondii infection can be reliably diagnosed. Several nations currently screen all women. Because of the severity of the sequelae of congenital toxoplasmosis and the possibility of effective treatment, screening should be considered in the United States.

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