359
of disease at diagnosis was an important determinant of this increased risk. The relative risk was 1-0 for those with disease confined to the terminal ileum at diagnosis, 3-2 for terminal ileum and parts of the colon, and 56 for involvement of colon only. Patients aged under 30 at diagnosis carried a substantially higher risk than those diagnosed at older ages. Those with any colonic involvement at diagnosis before age 30 had the largest relative risk (20-9). Duration of follow-up did not seem to affect the risk estimates. Closer surveillance of patients with diagnosed Crohn’s disease may have led to a higher ascertainment of colorectal cancers in the study population than in the general population, and earlier detection would be expected to reduce mortality. However, the SMR in the two groups of subjects was not significantly different. This study may underestimate the relative risk of colorectal cancer because patients who had colectomies after moving away from the Uppsala health care region would not have been ascertained. Conversely, the person-years at risk, and therefore the expected number of cases of colorectal cancer within the cohort, would have been overestimated among those in whom the diagnosis was made before 1965 but who had unascertained colectomies. However, the impact on our risk estimates is probably small, because emigration from the region was negligible. Date of onset of symptoms might be more appropriate than date at diagnosis to calculate duration of follow-up, but reliable information of onset of the symptoms is impossible to retreive
retrospectively. The risk of colorectal
cancer
and Crohn’s disease varies
greatly (from 4-3 to 20-0) in different studies (table III) and may depend on extent of disease, age at diagnosis, and random variation. In the study from the Mayo Clinic2 no patient was older than 21 years at diagnosis, and 80% had colonic involvement. In the Birmingham study4 63% of the patients were under 30 years of age at diagnosis. Only one previous study analysed the risk of colorectal cancer in patients with Crohn’s disease by age before 30 at diagnosis.2 The relative risk of 20-0 among those younger than 30 years in that study is almost identical to our estimate of 20-9 in those with colonic involvement. In a recent study of the risk of colorectal cancer in ulcerative colitis (unpublished), we found relative risks for the age-group 15 to 29 years at diagnosis of 14-2 for left-sided colitis and 33-1 1 for pancolitis. The closeness of these latter risk estimates to those for Crohn’s disease with any colonic involvement suggests that there is little difference between young patients with ulcerative colitis and Crohn’s disease with respect to the risk of large-bowel cancer. Longer follow-up would increase the accuracy of these risk estimates. We thank Dr Richard Rothenberg for valuable help. This work was supported by a grant from the National Foundation for Ileitis and Colitis and a Nanna Svartz grant.
6. Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn’s disease—based on results from a regional patient group from the county of
Copenhagen. Gut 1985; 26: 146-50. Jacobsen O, Norgaard P, et al. Malignancy in Crohn’s disease. Scand J Gastroenterol 1986; 21: 82-86. 8. Gollop JH, Phillips SF, Melton LJ III, Zinsmeister AR. Epidemiologic aspects of Crohn’s disease: a population-based study in Olmsted County, Minnesota, 1943-1982. Gut 1988; 29: 49-56. 9. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn’s disease. A population study in central Israel. Scand J
7. Kvist N,
Gastroenterol 1989; 24: 346-50. 10. Glotzer DJ. The risk of cancer in Crohn’s disease. Gastroenterology 1985; 89: 438-41. 11. Garland CF, Lilienfeld AM, Mendeloff AI, Markowitz JA, Terrell KA, Garland FC. Incidence rates of ulcerative colitis and Crohn’s disease in fifteen areas of the United States. Gastroenterology 1981; 81: 1115-24.
REVIEW ARTICLE What is known about the prevention of congenital
toxoplasmosis?
The French programme for the prevention of congenital toxoplasmosis consists of the diagnosis and treatment with spiramycin of acute infections during pregnancy and monthly follow-up of all identified seronegative women. The major flaw is that the efficacy of spiramycin in preventing contamination of the fetus, or at least in reducing the extent of the infection, has never been evaluated in a randomised placebo-controlled clinical trial. Its evaluation would require the follow-up of children born to mothers contaminated during pregnancy for more than 6 months, a goal that is difficult to obtain in current practice. The cost of the programme depends largely on the proportion of non-immune women of childbearing age. Since the modes of contamination are known and are linked to living habits, it should be possible to reduce the risk of infection during pregnancy by adequate health education. This approach is still to be evaluated.
the prevention and treatment of congenital have aroused increased interest, and national toxoplasmosis prevention programmes have been envisaged by several countries, including the United States’ and the United In
recent years,
Kingdom.2 REFERENCES 1. Jones JH. Colonic cancer and Crohn’s disease. Gut 1969; 10: 651-54. 2. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF. Crohn’s disease and cancer. N Engl J Med 1973; 289: 1099-103. 3. Greenstein AJ, Sachar DB, Smith H, Janowitz HD, Aufses AH. A comparison of cancer risk in Crohn’s disease and ulcerative colitis. Cancer 1981; 48: 2742-45. 4. Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JAH, Allan RN. Malignancy in Crohn’s disease. Gut 1980; 21: 1024-29. 5. Hamilton SR. Colorectal carcinoma in patients with Crohn’s disease. Gastroenterology 1985; 89: 398-407.
ADDRESSES. Department of Medical Statistics, Gustave Roussy Institute, Villejuif, France (D Jeannel, PhD), Unit of Research in Biostatistics and Biomathematics, INSERM U263 Paris VII University, Paris (D Costagliola, PhD), Department of Tropical Diseases and Parasitology, Pitié-Salpétrière Hospital, Paris (G Niel, MD, M Danis, MD), Office of Communicable Diseases, National Department of Health, Paris (B Hubert, MD) Correspondence to Dr Dominique Jeannel, Department of Medical Statistics, Gustave Roussy Institute, rue Camille Desmoulins, 94805
Villejuif CEDEX,
France
360
France has had
national prevention programme for congenital toxoplasmosis since 1976. The programme aims at reducing the number of infected infants as well as the cerebral and ocular damage to contaminated infants. It includes mandatory systematic serological screening of all pregnant women, follow-up by monthly serological tests of all identified seronegative women, and thrice daily treatment with 1 g of spiramycin (ie, 9 x 109 IU daily) when acute infection is diagnosed in pregnancy. Besides mandatory serological surveillance, some clinicians give seronegative pregnant women information on ways of limiting the risk of contamination by toxoplasma. On the basis of French experience, one editorial concluded that there are "simple means whereby congenital infection can be prevented". However, in our view, things are not as a
testing an umbilical blood sample taken under ultrasonic guidance" (leaving open the possibility of abortion) or just after birth. The second group are the symptom-free infected newborn babies with serology results that do not allow a distinction to be made between active and passive immunisation. For these infants, the decline in IgG titres over 3 months or more, sometimes to very low levels (which reflects the elimination of maternal IgG) is followed by an increase caused by the active synthesis of antibodies against toxoplasma; this serological manifestation of congenital infection is sometimes associated with clinical features of congenital toxoplasmosis. Consequently, all children whose mothers are contaminated during pregnancy ought to be followed up for 8-14 months-ie, until complete serological negativity is observed in the uninfected infants.3,12
straightforward as they appear. Estimation of maternofetal transmission of
toxoplasma
Serological screening of pregnant women During pregnancy, the diagnosis of contamination is based on serology, and in France the first routine test is generally done when the woman is already at least 2 months’ pregnant. For about 93% of positive results, the differential diagnosis between chronic infection (which protects the fetus) and acute infection is clear, but in the remaining 7% it can only be made later, because of a high IgG level and/or the presence of IgM. In such cases, two more serological tests, separated by an interval of 3 weeks, are needed to determine whether the contamination occurred during or before pregnancy. The specificity of the IgM antibodies has to be checked by means of a search for rheumatoid factors and a study of their adsorption on human anti-IgG, or by the IgM immunosorbent agglutination assay.3v’
Spiramycin treatment of acute toxoplasma infections in pregnancy The French programme is based on the assumption that early treatment with spiramycin for acute infections occurring during pregnancy avoids contamination of the fetus, or at least reduces the extent of toxoplasma infection. Spiramycin is a true macrolide antibiotic, and it has essentially a cytostatic activity on toxoplasma.7 It is the only antibiotic that can be administered during pregnancy to treat acute toxoplasmosis without any side-effect. However, the evidence that spiramycin administration to a pregnant woman protects the fetus is indirect. Spiramycin concentrates in tissues, especially in the placentae and has a biological half-life of 8 hours, thus reducing the risk of
toxoplasmal placentitis.9 Spiramycin clearly crosses the placental barrier, since it has been found in cord blood samples taken in utero and at delivery.8 However, efficacy of clinical effect on the fetus when spiramycin is given to pregnant women (generally several weeks after contamination) has not been directly evaluated in a randomised placebo-controlled clinical trial. As stated by Henderson,2 "studies on the effectiveness of treating toxoplasma infections in pregnant women have produced mixed results".
Such a follow-up has proved difficult, and accurate data on maternofetal transmission of toxoplasma are consequently scarce. For example, a retrospective cohort study in six departments of obstetrics in the Paris area, which included 2216 pregnant women who were not immune at the beginning of pregnancy, identified 33 cases of acute infection during pregnancy." 31 of these were treated with spiramycin, and the other 2, who were infected during the last month of pregnancy, were not treated. Among their 33 newborn infants, 11 cases of congenital toxoplasmosis were diagnosed, and 6 infants were followed up for long enough to establish their seronegativity. The other 16 were lost to follow-up before a definite diagnosis could be made. From this study the minimum proportion of infected children born to contaminated mothers can be estimated at 33% (lower limit of 95% confidence interval, 17%). In a recent study of 746 cases of acute infection during pregnancy, all of which were treated with spiramycin, 42 cases of congenital toxoplasmosis were diagnosed, 39 antenatally and 3 after delivery.l4 The other infants were followed up for at least 3 months, but the study gave no information about the number lost to follow-up between ages 3 and 8 months, and the proportion of infected children may therefore have been greatly underestimated. In the above study, the small number of cases of congenital toxoplasmosis ("about 70% less than in a previous report") cannot be attributed to the initiation of spiramycin treatment at the time of diagnosis and its continuation until end of pregnancy, especially since the same therapeutic protocol was also used in previous studies.1z Thus, despite the size of the cohort, the study does not provide any arguments in favour of treating toxoplasma infections in pregnant women with spiramycin.
a
Diagnosis of congenital toxoplasmosis The expected outcome of the congenital toxoplasmosis programme is the diagnosis and treatment of all cases of congenital infection. The infected infants are divided into two groups, according to the time of diagnosis. For the first group, the diagnosis is made either during pregnancy, by
Cost of the French programme Another aspect
be considered when evaluating a prevention programme is its cost. This depends largely on the prevalence of chronic toxoplasma infection at childbearing age, since only the pregnancies of seronegative women are subject to monthly serological surveillance. The prevalence of chronic toxoplasmosis has been reported to be 90% in France,’ but this rate was based on data obtained in the 1960s, for the Paris area only; 15 at that time, the rates in other parts of the country were probably lower than the 80% estimate by Chevaliers in a cost-benefit evaluation of the French programme. A recent study in the Paris area has to
361
shown the prevalence to be 72% among pregnant women of French origin (SD 4%) and 51 % among migrant women (SD 4%)." Another study, conducted in fourteen of the twenty-nine regions of the country among women aged 15-45 years, showed that in some areas the prevalence was only 45%." These results indicate that many more seronegative women should be followed each year in France than has previously been suggested.
What about health education?
Congenital toxoplasmosis could also be prevented by avoiding contamination during pregnancy. Infection can be acquired by eating undercooked meat and unwashed raw fruits and vegetables and by contact with cats or cat litters. We carried out a prospective study of life-style characteristics by interviewing, at their first medical visit, 961 non-immune pregnant women from the Paris area. Comparison of the women contaminated during pregnancy with those who remained seronegative led to the
identification of three risk factors, two of them directly related to modes of infection-ie, eating undercooked meat and owning a cat; the third risk factor-eating regularly outside the home-was indirect." These results show that it should be possible to reduce the risk of infection by adequate health education. Foulon et all reported a non-significant reduction of the rate of seroconversion from 1-26% to 095% among non-immune pregnant women in a department of gynaecology in Brussels when patients were routinely given a written list of recommendations. In France, the provision of appropriate information is left to the initiative of the physician in charge of the pregnant woman. This has a major drawback: information about prevention is given only after a negative test-ie, usually when the woman is at least 2 months pregnant. Consequently, the acute infections occurring early in pregnancy, which are considered the most dangerous for the fetus, are not prevented. To be fully effective, information on the risks of contamination by toxoplasma during pregnancy should be given to all women of childbearing age before pregnancy. 19 In terms of cost, a national programme of health education is less expensive than the screening and treatment programme used in France, the difference in cost being greatest when the prevalence of chronic infection is lowest. For example, the analysis by Henderson’ for the United Kingdom showed that a screening and treatment programme would be at least four times more expensive than a health education campaign and, to be cost-effective, would have to prevent more than four times as many cases of
congenital toxoplasmosis. Conclusion
follow-up of the infants until they become seronegative (ie, for about 1 year) would be needed to establish how effective is spiramycin treatment of acute toxoplasma infections during pregnancy. In France, a controlled clinical trial of spiramycin treatment is now impossible for ethical reasons, because it has been used to treat infections during pregnancy for the past twenty years. It may, however, be possible in other countries. Some people claim that the role of health education in the prevention of congenital toxoplasmosis is "more of a moral than a scientific issue"20 and so need not be evaluated. We disagree with this, because we believe that, in order to determine what should be done in a given country, the potential of educational and screening strategies for the prevention of toxoplasmosis should be taken into consideration. We thank Dr Catherine Hill cntica) review of the script.
(Gustave Roussy Institute) for her helpful
REFERENCES Cabe R, Remington JS. Toxoplasmosis: the time has come. N Engl J Med 1988; 318: 313-15. 2. Henderson JB, Beattie CP, Hale EG, Wright J. The evaluation of new services: possibilities for preventing congenital toxoplasmosis. Int J Epidemiol 1984, 13: 65-72. 3. Jeannel D, Niel G, Danis M, Gentilini M. Le sérodiagnostic de la toxoplasmose chez la femme enceinte et le nouveau né. Rev Fr Gynecol Obstet 1988; 3: 133-44. 4. Desmonts G, Naot Y, Remington JS. An IgM immunosorbent agglutination assay for diagnosis of acute congenital and acquired toxoplasmosis. J Clin Microbiol 1981; 14: 486-91. 5. Chevalier M. Etude cout-avantage d’un système de prévention de la toxoplasmose congénitale. Bull Statist "Santé-Sécurité sociale" 1974; 3: 71-83. 6. Desmonts G, Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies. N Engl J Med 1974; 290: 1110-16. 7. Niel G, Videau D. Activité de la spiramycine in vitro sur Toxoplasma gondii. Réunion interdisciplinaire de chimiothérapie antiinfectieuse. 1. Mc
Paris, December, 1981, 121, p8. 8. Garin JP, Pellerat J, Maillard M. Bases théoriques de la prévention par la spiramycine de la toxoplasmose congénitale chez la femme enceinte. Presse Med 1968; 76: 2226 9. Gaillot J, Lemar M. Eléments de pharmacocinétique de la spiramycine chez l’homme. Réunion interdisciplinaire chimiothérapie antiinfectieuse. Paris, December, 1981, 43, p4 10. Forestier F, Daffos F, Rainaut M, Desnottes JF, Gaschard JC. Suivi thérapeutique foetomaternel de la spiramycine en cours de grossesse. Arch Fr Pediatr 1987; 44: 539-44. 11. Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynecol 1985; 153: 655-60. 12. Couvreur J, Desmonts G, Tournier G, et al. Etude d’une série homogène de 210 cas de toxoplasmose congénitale chez les nourrissons agés de 0 à 11 mois et dépistés de facon prospective. Ann Pédiatr 1984, 10: 815-19. 13. Jeannel D, Niel G, Costagliola D, et al. Epidemiology of toxoplasmosis among pregnant women in the Paris area. Int J Epidermiol 1988; 17: 595-601. 14. Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med
1988; 318: 271-75.
The
of health education do not depend on the prevalence of chronic toxoplasma infection at childbearing age but its results depend on how effectively the health message reaches the target population and leads to a change in behaviour. In this connection, it would be very useful to study the preventive effect of health education on toxoplasmosis, with serological monitoring of the prevalence of toxoplasmosis infection in non-immune pregnant women. The costs of a screening and treatment programme are high and vary with the prevalence of chronic toxoplasma infection at childbearing age. The efficacy of spiramycin treatment is uncertain, and a large randomised trial with costs
15. Desmonts G, Couvreur J, Ben Rachid MS. Le toxoplasme, la mère et l’enfant. Arch Fr Pédiatr 1965; 22: 1183-200. 16. Papoz L. Immunité pour la toxoplasmose, la rubéole et le cytomégalovirus chez les femmes en age de procréer en France. Bull Epidemiol Hebdom 1984; no 20: 2-3. 17. Jeannel D, Costagliola D, Niel G. The risk of contamination by toxoplasma during pregnancy in the Parisian area. Tenth international
meeting on clinical biostatistics, Maastricht, Netherlands, September, 1989. 18. Foulon W, Naessens A, Lauwers S, De Meuter F, Amy JJ. Impact of primary prevention on the incidence of toxoplasmosis during pregnancy. Obstet Gynecol 1988;; 72: 363-66. 19. Frenkel JK. Congenital toxoplasmosis: prevention or palliation? Am J Obstet Gynecol 1981; 141: 359-61. 20. Ho Yen O. Screening for congenital cytomegalovirus and toxoplasmosis. Lancet 1989; ii: 803.
of disease at diagnosis was an important determinant of this increased risk. The relative risk was 1-0 for those with disease confined to the terminal ileum at diagnosis, 3-2 for terminal ileum and parts of the colon, and 56 for involvement of colon only. Patients aged under 30 at diagnosis carried a substantially higher risk than those diagnosed at older ages. Those with any colonic involvement at diagnosis before age 30 had the largest relative risk (20-9). Duration of follow-up did not seem to affect the risk estimates. Closer surveillance of patients with diagnosed Crohn’s disease may have led to a higher ascertainment of colorectal cancers in the study population than in the general population, and earlier detection would be expected to reduce mortality. However, the SMR in the two groups of subjects was not significantly different. This study may underestimate the relative risk of colorectal cancer because patients who had colectomies after moving away from the Uppsala health care region would not have been ascertained. Conversely, the person-years at risk, and therefore the expected number of cases of colorectal cancer within the cohort, would have been overestimated among those in whom the diagnosis was made before 1965 but who had unascertained colectomies. However, the impact on our risk estimates is probably small, because emigration from the region was negligible. Date of onset of symptoms might be more appropriate than date at diagnosis to calculate duration of follow-up, but reliable information of onset of the symptoms is impossible to retreive
retrospectively. The risk of colorectal
cancer
and Crohn’s disease varies
greatly (from 4-3 to 20-0) in different studies (table III) and may depend on extent of disease, age at diagnosis, and random variation. In the study from the Mayo Clinic2 no patient was older than 21 years at diagnosis, and 80% had colonic involvement. In the Birmingham study4 63% of the patients were under 30 years of age at diagnosis. Only one previous study analysed the risk of colorectal cancer in patients with Crohn’s disease by age before 30 at diagnosis.2 The relative risk of 20-0 among those younger than 30 years in that study is almost identical to our estimate of 20-9 in those with colonic involvement. In a recent study of the risk of colorectal cancer in ulcerative colitis (unpublished), we found relative risks for the age-group 15 to 29 years at diagnosis of 14-2 for left-sided colitis and 33-1 1 for pancolitis. The closeness of these latter risk estimates to those for Crohn’s disease with any colonic involvement suggests that there is little difference between young patients with ulcerative colitis and Crohn’s disease with respect to the risk of large-bowel cancer. Longer follow-up would increase the accuracy of these risk estimates. We thank Dr Richard Rothenberg for valuable help. This work was supported by a grant from the National Foundation for Ileitis and Colitis and a Nanna Svartz grant.
6. Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn’s disease—based on results from a regional patient group from the county of
Copenhagen. Gut 1985; 26: 146-50. Jacobsen O, Norgaard P, et al. Malignancy in Crohn’s disease. Scand J Gastroenterol 1986; 21: 82-86. 8. Gollop JH, Phillips SF, Melton LJ III, Zinsmeister AR. Epidemiologic aspects of Crohn’s disease: a population-based study in Olmsted County, Minnesota, 1943-1982. Gut 1988; 29: 49-56. 9. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn’s disease. A population study in central Israel. Scand J
7. Kvist N,
Gastroenterol 1989; 24: 346-50. 10. Glotzer DJ. The risk of cancer in Crohn’s disease. Gastroenterology 1985; 89: 438-41. 11. Garland CF, Lilienfeld AM, Mendeloff AI, Markowitz JA, Terrell KA, Garland FC. Incidence rates of ulcerative colitis and Crohn’s disease in fifteen areas of the United States. Gastroenterology 1981; 81: 1115-24.
REVIEW ARTICLE What is known about the prevention of congenital
toxoplasmosis?
The French programme for the prevention of congenital toxoplasmosis consists of the diagnosis and treatment with spiramycin of acute infections during pregnancy and monthly follow-up of all identified seronegative women. The major flaw is that the efficacy of spiramycin in preventing contamination of the fetus, or at least in reducing the extent of the infection, has never been evaluated in a randomised placebo-controlled clinical trial. Its evaluation would require the follow-up of children born to mothers contaminated during pregnancy for more than 6 months, a goal that is difficult to obtain in current practice. The cost of the programme depends largely on the proportion of non-immune women of childbearing age. Since the modes of contamination are known and are linked to living habits, it should be possible to reduce the risk of infection during pregnancy by adequate health education. This approach is still to be evaluated.
the prevention and treatment of congenital have aroused increased interest, and national toxoplasmosis prevention programmes have been envisaged by several countries, including the United States’ and the United In
recent years,
Kingdom.2 REFERENCES 1. Jones JH. Colonic cancer and Crohn’s disease. Gut 1969; 10: 651-54. 2. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF. Crohn’s disease and cancer. N Engl J Med 1973; 289: 1099-103. 3. Greenstein AJ, Sachar DB, Smith H, Janowitz HD, Aufses AH. A comparison of cancer risk in Crohn’s disease and ulcerative colitis. Cancer 1981; 48: 2742-45. 4. Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JAH, Allan RN. Malignancy in Crohn’s disease. Gut 1980; 21: 1024-29. 5. Hamilton SR. Colorectal carcinoma in patients with Crohn’s disease. Gastroenterology 1985; 89: 398-407.
ADDRESSES. Department of Medical Statistics, Gustave Roussy Institute, Villejuif, France (D Jeannel, PhD), Unit of Research in Biostatistics and Biomathematics, INSERM U263 Paris VII University, Paris (D Costagliola, PhD), Department of Tropical Diseases and Parasitology, Pitié-Salpétrière Hospital, Paris (G Niel, MD, M Danis, MD), Office of Communicable Diseases, National Department of Health, Paris (B Hubert, MD) Correspondence to Dr Dominique Jeannel, Department of Medical Statistics, Gustave Roussy Institute, rue Camille Desmoulins, 94805
Villejuif CEDEX,
France
360
France has had
national prevention programme for congenital toxoplasmosis since 1976. The programme aims at reducing the number of infected infants as well as the cerebral and ocular damage to contaminated infants. It includes mandatory systematic serological screening of all pregnant women, follow-up by monthly serological tests of all identified seronegative women, and thrice daily treatment with 1 g of spiramycin (ie, 9 x 109 IU daily) when acute infection is diagnosed in pregnancy. Besides mandatory serological surveillance, some clinicians give seronegative pregnant women information on ways of limiting the risk of contamination by toxoplasma. On the basis of French experience, one editorial concluded that there are "simple means whereby congenital infection can be prevented". However, in our view, things are not as a
testing an umbilical blood sample taken under ultrasonic guidance" (leaving open the possibility of abortion) or just after birth. The second group are the symptom-free infected newborn babies with serology results that do not allow a distinction to be made between active and passive immunisation. For these infants, the decline in IgG titres over 3 months or more, sometimes to very low levels (which reflects the elimination of maternal IgG) is followed by an increase caused by the active synthesis of antibodies against toxoplasma; this serological manifestation of congenital infection is sometimes associated with clinical features of congenital toxoplasmosis. Consequently, all children whose mothers are contaminated during pregnancy ought to be followed up for 8-14 months-ie, until complete serological negativity is observed in the uninfected infants.3,12
straightforward as they appear. Estimation of maternofetal transmission of
toxoplasma
Serological screening of pregnant women During pregnancy, the diagnosis of contamination is based on serology, and in France the first routine test is generally done when the woman is already at least 2 months’ pregnant. For about 93% of positive results, the differential diagnosis between chronic infection (which protects the fetus) and acute infection is clear, but in the remaining 7% it can only be made later, because of a high IgG level and/or the presence of IgM. In such cases, two more serological tests, separated by an interval of 3 weeks, are needed to determine whether the contamination occurred during or before pregnancy. The specificity of the IgM antibodies has to be checked by means of a search for rheumatoid factors and a study of their adsorption on human anti-IgG, or by the IgM immunosorbent agglutination assay.3v’
Spiramycin treatment of acute toxoplasma infections in pregnancy The French programme is based on the assumption that early treatment with spiramycin for acute infections occurring during pregnancy avoids contamination of the fetus, or at least reduces the extent of toxoplasma infection. Spiramycin is a true macrolide antibiotic, and it has essentially a cytostatic activity on toxoplasma.7 It is the only antibiotic that can be administered during pregnancy to treat acute toxoplasmosis without any side-effect. However, the evidence that spiramycin administration to a pregnant woman protects the fetus is indirect. Spiramycin concentrates in tissues, especially in the placentae and has a biological half-life of 8 hours, thus reducing the risk of
toxoplasmal placentitis.9 Spiramycin clearly crosses the placental barrier, since it has been found in cord blood samples taken in utero and at delivery.8 However, efficacy of clinical effect on the fetus when spiramycin is given to pregnant women (generally several weeks after contamination) has not been directly evaluated in a randomised placebo-controlled clinical trial. As stated by Henderson,2 "studies on the effectiveness of treating toxoplasma infections in pregnant women have produced mixed results".
Such a follow-up has proved difficult, and accurate data on maternofetal transmission of toxoplasma are consequently scarce. For example, a retrospective cohort study in six departments of obstetrics in the Paris area, which included 2216 pregnant women who were not immune at the beginning of pregnancy, identified 33 cases of acute infection during pregnancy." 31 of these were treated with spiramycin, and the other 2, who were infected during the last month of pregnancy, were not treated. Among their 33 newborn infants, 11 cases of congenital toxoplasmosis were diagnosed, and 6 infants were followed up for long enough to establish their seronegativity. The other 16 were lost to follow-up before a definite diagnosis could be made. From this study the minimum proportion of infected children born to contaminated mothers can be estimated at 33% (lower limit of 95% confidence interval, 17%). In a recent study of 746 cases of acute infection during pregnancy, all of which were treated with spiramycin, 42 cases of congenital toxoplasmosis were diagnosed, 39 antenatally and 3 after delivery.l4 The other infants were followed up for at least 3 months, but the study gave no information about the number lost to follow-up between ages 3 and 8 months, and the proportion of infected children may therefore have been greatly underestimated. In the above study, the small number of cases of congenital toxoplasmosis ("about 70% less than in a previous report") cannot be attributed to the initiation of spiramycin treatment at the time of diagnosis and its continuation until end of pregnancy, especially since the same therapeutic protocol was also used in previous studies.1z Thus, despite the size of the cohort, the study does not provide any arguments in favour of treating toxoplasma infections in pregnant women with spiramycin.
a
Diagnosis of congenital toxoplasmosis The expected outcome of the congenital toxoplasmosis programme is the diagnosis and treatment of all cases of congenital infection. The infected infants are divided into two groups, according to the time of diagnosis. For the first group, the diagnosis is made either during pregnancy, by
Cost of the French programme Another aspect
be considered when evaluating a prevention programme is its cost. This depends largely on the prevalence of chronic toxoplasma infection at childbearing age, since only the pregnancies of seronegative women are subject to monthly serological surveillance. The prevalence of chronic toxoplasmosis has been reported to be 90% in France,’ but this rate was based on data obtained in the 1960s, for the Paris area only; 15 at that time, the rates in other parts of the country were probably lower than the 80% estimate by Chevaliers in a cost-benefit evaluation of the French programme. A recent study in the Paris area has to
361
shown the prevalence to be 72% among pregnant women of French origin (SD 4%) and 51 % among migrant women (SD 4%)." Another study, conducted in fourteen of the twenty-nine regions of the country among women aged 15-45 years, showed that in some areas the prevalence was only 45%." These results indicate that many more seronegative women should be followed each year in France than has previously been suggested.
What about health education?
Congenital toxoplasmosis could also be prevented by avoiding contamination during pregnancy. Infection can be acquired by eating undercooked meat and unwashed raw fruits and vegetables and by contact with cats or cat litters. We carried out a prospective study of life-style characteristics by interviewing, at their first medical visit, 961 non-immune pregnant women from the Paris area. Comparison of the women contaminated during pregnancy with those who remained seronegative led to the
identification of three risk factors, two of them directly related to modes of infection-ie, eating undercooked meat and owning a cat; the third risk factor-eating regularly outside the home-was indirect." These results show that it should be possible to reduce the risk of infection by adequate health education. Foulon et all reported a non-significant reduction of the rate of seroconversion from 1-26% to 095% among non-immune pregnant women in a department of gynaecology in Brussels when patients were routinely given a written list of recommendations. In France, the provision of appropriate information is left to the initiative of the physician in charge of the pregnant woman. This has a major drawback: information about prevention is given only after a negative test-ie, usually when the woman is at least 2 months pregnant. Consequently, the acute infections occurring early in pregnancy, which are considered the most dangerous for the fetus, are not prevented. To be fully effective, information on the risks of contamination by toxoplasma during pregnancy should be given to all women of childbearing age before pregnancy. 19 In terms of cost, a national programme of health education is less expensive than the screening and treatment programme used in France, the difference in cost being greatest when the prevalence of chronic infection is lowest. For example, the analysis by Henderson’ for the United Kingdom showed that a screening and treatment programme would be at least four times more expensive than a health education campaign and, to be cost-effective, would have to prevent more than four times as many cases of
congenital toxoplasmosis. Conclusion
follow-up of the infants until they become seronegative (ie, for about 1 year) would be needed to establish how effective is spiramycin treatment of acute toxoplasma infections during pregnancy. In France, a controlled clinical trial of spiramycin treatment is now impossible for ethical reasons, because it has been used to treat infections during pregnancy for the past twenty years. It may, however, be possible in other countries. Some people claim that the role of health education in the prevention of congenital toxoplasmosis is "more of a moral than a scientific issue"20 and so need not be evaluated. We disagree with this, because we believe that, in order to determine what should be done in a given country, the potential of educational and screening strategies for the prevention of toxoplasmosis should be taken into consideration. We thank Dr Catherine Hill cntica) review of the script.
(Gustave Roussy Institute) for her helpful
REFERENCES Cabe R, Remington JS. Toxoplasmosis: the time has come. N Engl J Med 1988; 318: 313-15. 2. Henderson JB, Beattie CP, Hale EG, Wright J. The evaluation of new services: possibilities for preventing congenital toxoplasmosis. Int J Epidemiol 1984, 13: 65-72. 3. Jeannel D, Niel G, Danis M, Gentilini M. Le sérodiagnostic de la toxoplasmose chez la femme enceinte et le nouveau né. Rev Fr Gynecol Obstet 1988; 3: 133-44. 4. Desmonts G, Naot Y, Remington JS. An IgM immunosorbent agglutination assay for diagnosis of acute congenital and acquired toxoplasmosis. J Clin Microbiol 1981; 14: 486-91. 5. Chevalier M. Etude cout-avantage d’un système de prévention de la toxoplasmose congénitale. Bull Statist "Santé-Sécurité sociale" 1974; 3: 71-83. 6. Desmonts G, Couvreur J. Congenital toxoplasmosis: a prospective study of 378 pregnancies. N Engl J Med 1974; 290: 1110-16. 7. Niel G, Videau D. Activité de la spiramycine in vitro sur Toxoplasma gondii. Réunion interdisciplinaire de chimiothérapie antiinfectieuse. 1. Mc
Paris, December, 1981, 121, p8. 8. Garin JP, Pellerat J, Maillard M. Bases théoriques de la prévention par la spiramycine de la toxoplasmose congénitale chez la femme enceinte. Presse Med 1968; 76: 2226 9. Gaillot J, Lemar M. Eléments de pharmacocinétique de la spiramycine chez l’homme. Réunion interdisciplinaire chimiothérapie antiinfectieuse. Paris, December, 1981, 43, p4 10. Forestier F, Daffos F, Rainaut M, Desnottes JF, Gaschard JC. Suivi thérapeutique foetomaternel de la spiramycine en cours de grossesse. Arch Fr Pediatr 1987; 44: 539-44. 11. Daffos F, Capella-Pavlovsky M, Forestier F. Fetal blood sampling during pregnancy with use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet Gynecol 1985; 153: 655-60. 12. Couvreur J, Desmonts G, Tournier G, et al. Etude d’une série homogène de 210 cas de toxoplasmose congénitale chez les nourrissons agés de 0 à 11 mois et dépistés de facon prospective. Ann Pédiatr 1984, 10: 815-19. 13. Jeannel D, Niel G, Costagliola D, et al. Epidemiology of toxoplasmosis among pregnant women in the Paris area. Int J Epidermiol 1988; 17: 595-601. 14. Daffos F, Forestier F, Capella-Pavlovsky M, et al. Prenatal management of 746 pregnancies at risk for congenital toxoplasmosis. N Engl J Med
1988; 318: 271-75.
The
of health education do not depend on the prevalence of chronic toxoplasma infection at childbearing age but its results depend on how effectively the health message reaches the target population and leads to a change in behaviour. In this connection, it would be very useful to study the preventive effect of health education on toxoplasmosis, with serological monitoring of the prevalence of toxoplasmosis infection in non-immune pregnant women. The costs of a screening and treatment programme are high and vary with the prevalence of chronic toxoplasma infection at childbearing age. The efficacy of spiramycin treatment is uncertain, and a large randomised trial with costs
15. Desmonts G, Couvreur J, Ben Rachid MS. Le toxoplasme, la mère et l’enfant. Arch Fr Pédiatr 1965; 22: 1183-200. 16. Papoz L. Immunité pour la toxoplasmose, la rubéole et le cytomégalovirus chez les femmes en age de procréer en France. Bull Epidemiol Hebdom 1984; no 20: 2-3. 17. Jeannel D, Costagliola D, Niel G. The risk of contamination by toxoplasma during pregnancy in the Parisian area. Tenth international
meeting on clinical biostatistics, Maastricht, Netherlands, September, 1989. 18. Foulon W, Naessens A, Lauwers S, De Meuter F, Amy JJ. Impact of primary prevention on the incidence of toxoplasmosis during pregnancy. Obstet Gynecol 1988;; 72: 363-66. 19. Frenkel JK. Congenital toxoplasmosis: prevention or palliation? Am J Obstet Gynecol 1981; 141: 359-61. 20. Ho Yen O. Screening for congenital cytomegalovirus and toxoplasmosis. Lancet 1989; ii: 803.
