++
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Abundant and convincing evidence demonstrates that medicines block transmission of Toxoplasma gondii from the pregnant woman to her fetus, kill tachyzoites, reduce or eliminate parasite burden, reduce or eliminate eye disease, reduce or eliminate brain disease, reduce severity of disease, eliminate meningitis, treat meningoencephalitis, and lower immune markers of infection.1, 2, 3, and 4 Earlier, there was some controversy in the literature (discussed in Reference 4), but currently, review of data from in vitro and experimental animal studies, attention to older publications of studies that were performed meticulously (reviewed in References 1, 2, 3, and 4), and several recent studies have clarified the efficacy and benefits of proper, early, and rapid diagnosis and medical treatment.5,6 The recent data demonstrate how important it is to establish such diagnosis and treatment as the standard for medical care to prevent the loss of productive lives to this disease. The time when the acute infection is diagnosed and treated is critical.1, 2, 3, 4, and 5 The earlier the infection is treated, the better the outcomes will be for fetus, infant, and congenitally infected person.5,6 For this reason, the focus of this chapter is to make clear how diagnosis and treatment of the fetus and infant can be optimized and how this is carried out practically.
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PREVENTION WITH EDUCATION DURING GESTATION
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The approach to diagnose, prevent, and treat infections of the fetus is summarized in Tables 116-1, 116-2, 116-3, 116-4, 116-5, 116-6, 116-7, and 116-8 and Figures 116-1, 116-2, 116-3, and 116-4. The pregnant woman with acute acquired T. gondii infection and the mother of a congenitally infected infant may have retinal disease caused by the parasite and should have a retinal examination. Simple instructions concerning avoiding means of acquisition of the parasite provide an opportunity to prevent some fetal infections in the pregnant woman. An educational pamphlet is provided in Chapter 57, Figure 57-3. This may be downloaded from the Internet without charge or copyright (http://www.toxoplasmosis.org/pamphlet.pdf) so it can be provided to pregnant patients or those considering becoming pregnant. However, environmental contamination by oocysts is common and often unrecognized. Risk cannot be eliminated entirely by education. Infection may occur in persons with no recognized risk factors.
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GESTATIONAL SCREENING: DIAGNOSIS, PREVENTION, AND TREATMENT OF THE ACUTELY INFECTED PREGNANT WOMAN AND FETUS
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Figure 116-1 and Figure 57-23 in Chapter 57 summarizes an approach used universally in France, where it successfully detects seroconversion during gestation to prevent transmission to the fetus and to identify infection in the fetus. This allows treatment without delay. In this approach,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 21 currently utilized in some of the best obstetrical practices in the United States, serologic screening for T. gondii specific antibody to immunoglobulin G (IgG) and immunoglobulin M (IgM) is performed once a month during gestation for all pregnant women who are seronegative and is initiated by the 11th week of gestation. Ideally, such screening would, and sometimes does, begin immediately before or early in gestation at the time pregnancy is noted, even when this is earlier than 11 weeks’ gestation. Screening is continued monthly through the time the infant is born and is performed at birth and when the infant is 1 month old to detect infections acquired late in gestation. This approach presents the opportunity to confirm when a pregnant woman seroconverts (ie, newly develops specific IgG antibody to T. gondii). This is done so that acute acquired infection can be proven by more specialized testing. In the United States, this specialized testing is performed in a reference laboratory (Table 116-7). This then enables the physician to prevent transmission from the newly infected pregnant woman to her fetus through treatment of the mother with spiramycin early in gestation (Table 116-1). Fetal ultrasounds are obtained every 2 weeks until term for mothers who seroconvert. It is then possible to diagnose infection in the fetus by ultrasound or amniocentesis. It enables treatment of the infected fetus when diagnosed by amniocentesis with polymerase chain reaction (PCR) testing of the amniotic fluid for T. gondii DNA or via ultrasound. The infected fetus can then be treated by treatment of the mother with pyrimethamine and sulfadiazine (with leucovorin, folinic acid). Clindamycin, clarithromycin, and azithromycin are second-line medicines used for pregnant women with significant hypersensitivity to sulfadiazine, but there are no data concerning their efficacy. Treatment of the infant continues after birth as described in Chapter 57 and here (Table 116-1; Figure 116-4).
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BIRTH: PLACENTA SAMPLES OBTAINED IN THE DELIVERY ROOM
++
Table 116-2 outlines how the placenta should be processed in the delivery room and afterward.2
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CLINICAL EVALUATION OF THE INFANT
++
Clinical evaluation of the infant is summarized in Table 116-5. Figures 116-2 and 57-8 and Tables 57-4, 116-5, 116-6, 116-7, and 57-8 include common manifestations of this infection,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, and 45 which should lead to prompt diagnostic evaluation. This highlights the importance of recognition by neonatologists and others caring for such an infant that these findings are manifestations of congenital toxoplasmosis. Details of diagnostic evaluation of the infant to exclude or establish manifestations of this disease are in Tables 116-2, 116-3, 116-4, 116-5, and 116-6 along with some comments about evaluation of the mother and other family members.2,40,42, 43, 44, 45, 46, and 47 The tables and figures in Chapter 57 also differently illustrate manifestations of this infection and diagnostic approaches.
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SAMPLE AMOUNTS NEEDED FOR SPECIALIZED TESTING AND USEFUL CONTACT INFORMATION
++
One of the areas of confusion sometimes is which samples and how much of them should be obtained for particular tests. Therefore, Tables 116-2, 116-3, and 116-4 and 116-6 provide this information. Table 116-7 provides contact information helpful for diagnosis and treatment and counseling pregnant women and their families and families for whom this diagnosis is suspected or proven.
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ANTIBODY LOAD IN SERUM AND CEREBROSPINAL FLUID
++
In certain circumstances (eg, birth of an infant who is completely normal with a low likelihood of transmission from an acutely infected mother, had negative amniotic fluid PCR for T. gondii infection in a reference laboratory, and had no manifestations at birth consistent with infection), a decision is made with the parents not to treat the infant but rather to follow serum antibody load. This is measured as shown in Tables 116-8 and 57-25 (Chapter 57). In this case, a physician monitors the measurement of IgG antibody specific for T. gondii each month. Serum is diluted 2-fold in parallel with the previous month’s sample and sensitivity of the dye test noted. Passively transferred maternal T. gondii-specific IgG will fall by 50% because the half-life of IgG is 30 days. At the same time, the physician monitors that and when the infant begins making his or her own IgG (quantitative immunoglobulin milligrams per deciliter measured in the local hospital’s laboratory; also see discussion in Chapter 57).
++
A similar equation can be used to calculate antibody load in cerebrospinal fluid (CSF) to demonstrate local production of antibody to T. gondii due to active brain infection. This is used only when the dye test titer is less than 1:1024 (~300 IU usually). A ratio of antibody produced in CSF of 4 or greater is considered indicative of local antibody production (Tables 116-4 and 57-25 [Chapter 57]).
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GUIDELINES FOR TREATMENT OF GESTATIONAL AND CONGENITAL TOXOPLASMOSIS
++
Table 116-1 provides guidelines for the treatment of the fetus, newborn infant, and child with congenital toxoplasmosis.2 A method for preparation of medicines and their administration2 is shown in Figure 116-4. In the unusual circumstance of an infant too sick to be able to utilize pyrimethamine and sulfadiazine by mouth or by feeding tube, intravenous administration of trimethoprim/sulfamethoxazole with clindamycin has been an alternate, but less-satisfactory, approach. Active choriodal neovascular membranes have been treated effectively with intraocular injection of ∝ vascular endothelial growth factor (∝-VEGF33; LUCENTIS®) in conjunction with anti-T. Gondii medicines (Figure 57-22). This has also been safely used to treat retinopathy of prematurity in infants.48
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TOXICITIES OF MEDICINES
++
The major toxicity encountered in treatment of the fetus is reversible neutropenia.24,26 Hypersensitivity to sulfadiazine appears to be much less often encountered as a serious complication in the pregnant woman and infant than in older children and adults.49 In the infant with congenital toxoplasmosis, the major toxicity of the medicines used to treat toxoplasmosis is reversible neutropenia. Most children maintain neutrophil counts of about 1000/mL3 (800–1200/mL3) during the year of treatment. Concomitant viral infections can result in diminution of the neutrophil count. This is managed by withholding pyrimethamine if absolute neutrophil count (ANC) falls to between 500 and 700. Both pyrimethamine and sulfadiazine are withheld if the ANC is less than 500. Leucovorin is increased to 15–20 mg/day these cases. Leucovorin is always continued for 1 week after discontinuing pyrimethamine because of the relatively long half-life of pyrimethamine (60–90 hours). Granulocyte colony-stimulating factor (G-CSF) has been used to maintain normal neutrophil counts when substantial neutropenia has been a recurrent or refractory problem. Teeth are gently cleaned with a soft pediatric toothbrush or washcloth to prevent development of dental carries due to the sugar suspension agent for the medicines. Three to four months after discontinuing treatment, commonly there is a rebound (elevation) in antibody titer of T. gondii-specific IgG, IgM, or IgA, usually without any recognized symptomology.24,26
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OUTCOMES AND PROGNOSIS
++
Medical and adjunctive treatment, such as prompt correction of hydrocephalus with ventriculoperitoneal shunt procedures, improves the prognosis.1, 2, 3, 4, 5, and 6,10,11,15,21,26, 27, 28,30,50,51 The earlier treatment is initiated, the better the prognosis will be.5,6 This infection, even when it causes hydrocephalus, is treated as expectant for excellent outcomes. Outcomes may be good, although this does not always occur.1, 2, 3, 4, 5, and 6,10,11,15,21,23,26, 27, and 28,30,50, 51, and 52 It is not possible to predict with certainty when outcomes will be favorable. There can be remarkable expansion and growth of cortical mantle with ventricular peritoneal shunting. Third ventriculostomies were found to fail often in this disease,16 presumably because of the associated inflammatory process, and thus are not used. When CSF protein is high, lavage of ventricles prior to placement of the shunt to prevent occlusion of the shunt has been used successfully. Figure 57-10 shows this improved prognosis as well as some of the problems that may occur. Brain calcifications often resolve or diminish in size with treatment in the first year of life.52
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COMPARISON OF CONGENITAL TOXOPLASMOSIS AT BIRTH IN FRANCE, AUSTRIA, GERMANY, AND THE UNITED STATES
++
Prenatal and postnatal treatment improve outcomes at birth and later in life.1, 2, 3, 4, 5, and 6,10,11,15,21,23,26, 27, and 28,30,50, 51, and 52 The more rapidly treatment is initiated to stop destruction of the fetus and infant’s eyes and to stop brain and systemic infection, the better the outcome will be. This empirical observation is supported by in vitro data and studies with experimental animals. The latter studies demonstrated that medicines used to treat the infection are effective in vitro and in vivo in killing the active tachyzoite that destroys tissue. A contrast of outcomes in France with those in the United States is informative.1,45 Table 116-9 and Figure 116-2 shows this contrast.45 In France, there is serologic screening monthly during gestation (Figure 116-1). This facilitates prompt diagnosis and treatment of the fetus without delay. In the United States, screening rarely occurs, and when it does, it may often be performed only once or twice in a more random manner, with consequent delays in treatment.1,45
++
+++
ANALYSIS OF COST-MINIMIZING STRATEGIES IN PERSPECTIVE
++
Because exposures often are unrecognized (Tables 57-1 and 57-2 and Figure 57-3),25,29,44 although education about risk factors can help to reduce acquisition of infection during gestation, serologic screening with prompt diagnosis and treatment or a vaccine are the only means that could almost entirely successfully prevent this disease and the suffering it causes.3 A vaccine is needed but has not yet been developed for human use. Serologic screening and treatment in gestation and in infancy are predicted to be cost minimizing.3 This is with the wide range of incidences of infection likely to occur in a variety of populations throughout the world (Figure 57-4).3,53Medicines that eliminate cysts and active infection would greatly facilitate treatment and improve outcomes, but are not available.
++
In 1990, Desmonts from France wrote the following:57
++
“There is a parasite, Toxoplasma, which is harmless for you but which can cause severe impairment in your child if you become infected during pregnancy. You will notice nothing but we could tell you now if you are immune; if you are not, we can monitor you during pregnancy. If you become infected we can detect the infection in your infant even if he looks normal; we can even detect it in utero and treat without delay. Yet we will do nothing, since all this is too expensive. But do not worry. Perhaps you are immune—and if you are not, you will probably escape infection when pregnant. If the worst does happen your fetus might still escape. And if your infant is severely impaired, there is no risk in having another baby because you will now be immune. Nevertheless, try not to get infected. Eat well-cooked meat and wash your hands. Good luck.”
++
Neonatologists can help improve care by recognizing manifestations promptly at birth and considering and testing for congenital toxoplasmosis in their patients to prevent some sequelae (Figure 116-2).
++
In 2011, we45 noted the following:
++
Congenital toxoplasmosis continues to be a tragedy for parents and children in the United States. Decades ago some countries responded to the challenge by implementing national programs for systematic serologic screening of all pregnant women. Others did so by performing routine serologic screening in all newborns. Yet, despite the fact that all studies performed in the United States continue to reveal that congenitally infected children are born severely affected each year, a national program or policy to address the threat of this disease is currently lacking.
++
We now have practical means to prevent and treat this infection that were outlined here. They can be easily implemented by obstetricians, perinatologists, neonatologists, and pediatricians. This will prevent suffering and loss of life, sight, cognition, motor function, and seizures from this disease. This can be accomplished by prompt diagnosis and treatment as presented in Chapter 57 and this chapter. This appears to be not only feasible but also likely cost minimizing.
++
This work was supported by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) R01 AI027530-21 and gifts from the Mann and Cornwell, Taub, Cussen-Kapnick, Rooney-Alden, Engel, Pritzker, Harris, Zucker, Samuel, and Mussilami families and NIH U01 5 U01 AI077887-05 and 2R01AI027530-18A2. We thank those families and physicians who have worked with us to help us learn more about how to diagnose, manage, and treat this disease and those who have taught us about it, especially George Desmonts, Jacques Couvreur, Philippe Thulliez, and Jack Remington.
++
This chapter is especially in honor of Dana, Chad, Dani Jo, Elena, Graham, Grant, Joshua, Lucky, Margaret, Miguel, Nicky, Robbie, Roxanne, and many others and their families who understand with special poignancy Edward Young’s statement “who would not give a trifle to prevent what they would give a thousand worlds to cure.”
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http://dx.doi.org/10.1016/0140-6736(90)92485-Z