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Prevention of congenital Chagas disease by Benznidazole treatment in reproductive-age women. An observational study
Acta Tropica 174 (2017) 149–152
Contents lists available at ScienceDirect
Acta Tropica journal homepage: www.elsevier.com/locate/actatropica
Short communication
Prevention of congenital Chagas disease by Benznidazole treatment in reproductive-age women. An observational study María G. Álvarez, Carlos Vigliano, Bruno Lococo, Graciela Bertocchi, Rodolfo Viotti
MARK
⁎
Cardiology Department, Chagas Disease Section, Eva Perón Hospital, Buenos Aires, Argentina
A R T I C L E I N F O
A B S T R A C T
Keywords: Chagas disease Treatment Benznidazole Congenital transmission
Since the decline in new cases of infection by insect/vector, congenital Chagas disease has become more relevant in the transmission of Chagas disease. Treatment with benznidazole significantly reduces the parasitemia, which constitutes an important factor linked to vertical transmission. The objective of this study was to evaluate whether treatment with benznidazole previously administered to women of childbearing age can prevent or reduce the incidence of new cases of congenital Chagas disease. An historical cohort study that included all women in reproductive age (15–45 years) assisted in our center was designed. We included 67 mothers with chronic Chagas disease; 35 women had not been treated prior to pregnancy, 15 had been treated prior to pregnancy and 17 gave birth prior and after treatment with benznidazole. Eight mothers gave birth to 16 children with congenital Chagas disease (8/67, 12%). The prevalence of congenital Chagas was 16/114 (14%) children born to untreated mothers and 0/42 (0%) children born to benznidazole- treated mothers, p = 0.01. No significant differences were observed in clinical, serologic, epidemiological or socioeconomic baseline variables between mothers with and without children born with congenital Chagas. A 32% conversion rate to negative serology was observed in benznidazole-treated women after long-term follow up. Antiparasitic treatment administered to women in reproductive age can prevent the occurrence of congenital Chagas disease.
1. Introduction Since the decline in new cases of infection by insect/vector, congenital Chagas disease has become more relevant in the transmission of Chagas disease (Carlier and Torrico, 2003; Gurtler et al., 2003; Torrico et al., 2004). This way of infection is the main mode of spread of the disease in non-endemic countries, linked to migration flows, which has led to consider the globalization of Chagas disease (Muñoz et al., 2009; Buekens et al., 2008). Several medical guidelines recommend antiparasitic treatment until 14 years of age (Bern et al., 2007; Gascón et al., 2007; Ministerio de Salud de la Nación, 2012), and as a result many T. cruzi-infected women of reproductive age do not receive specific treatment. Treatment with benznidazole significantly reduces the parasitemia which is, the main factor related to congenital Chagas disease transmission (Hermann et al., 2004; Moretti et al., 2005; Carlier et al., 2015). Controlled studies using PCR assays showed a high rate of negative parasitemia, one year following treatment with (Molina et al., 2014; Torrico, 2013; Murcia et al., 2010). Treatment may also reduce parasite burden in tissues, and this impacts the number and frequency of parasitemia, even if no parasitic cure is achieved.
⁎
The objective of this research was to evaluate whether treatment with benznidazole administered to women of reproductive age can prevent or reduce the incidence of new cases of congenital Chagas disease. 2. Methods 2.1. Design and population A historical cohort study including all women of childbearing age (15–45 years) assisted in the Eva Peron Hospital, located in the outskirts of Buenos Aires, Argentina was designed. For the initial information, the general database was used to record address, phone number, date of benznidazole treatment and clinical data from women of childbearing age for potential inclusion in the study.From this hospitalary sample, the mother/child pairs with and without treatment with benznidazole prior to pregnancy were included. To achieve this goal, direct contact in the office, phone calls (3 calls at different times or days on average per patient), or a letter requesting attendance to the hospital were used. Children born in areas endemic for T. cruzi infection
Corresponding author at: José Hernández 3440, Villa Ballester, Provincia de Buenos Aires, Argentina. E-mail address: [email protected] (R. Viotti).
http://dx.doi.org/10.1016/j.actatropica.2017.07.004 Received 24 September 2016; Received in revised form 3 July 2017; Accepted 5 July 2017 Available online 15 July 2017 0001-706X/ © 2017 Elsevier B.V. All rights reserved.
Acta Tropica 174 (2017) 149–152
M.G. Álvarez et al.
were excluded from the study. 2.2. Variables in study A survey was designed with epidemiological, clinical and serological data of mother/child pairs including the following variables: present age; age of last pregnancy; residence time in an endemic area; years of education; overcrowding index (number of cohabiting/number of bedrooms); health insurance; abnormal ECG; age of benznidazole treatment; clinical and serologic time of follow-up; serologic evolution (negative seroconversion of 2 or 3 tests performed) and new ECG changes (i.e. disease progression). All patients of the cohort had been diagnosed at admission at the hospital with three serological tests carried out at the Instituto Nacional de Parasitología Dr. Mario Fatala Chaben, the reference center for diagnosis of Chagas disease in Argentina. In those children without diagnosis at the time of inclusion in the present study, a blood sample was obtained to assess conventional serologic tests at the reference center. After inclusion, women of reproductive age who had not been treated received 5 mg/kg/day of benznidazole for 30 days. Serologic testing was thereafter conducted every three years in average. 2.3. Statistical analysis The variables with normal distribution were expressed as mean ± 1 standard deviation, using the median and 25–75% interquartile range for those with non-Gaussian distribution. For comparative statistics Student t-tests, Wilcoxon Rank or the chi-square test or its variant, Fischer's exact test, was used as appropriate. The study protocol was approved by the Research Ethics Committee of the Hospital Eva Peron, accredited by the Central Ethics Committee of the Ministry of Health of Buenos Aires Province, Argentina. All patients provided an informed consent or parental consent in writing, as appropriate.
Fig. 1. Flow diagram of congenital Chagas disease in a cohort study comparing women of reproductive age with and without benznidazle treatment prior to pregnancy. A Seventeen women also gave birth in the untreated status of the disease.
3. Results
Table 1 Baseline mother characteristics, by congenital transmission group.
Eighty-six patients from the cohort of women of childbearing age with chronic Chagas disease were contacted (36 at office, 32 by telephone and 18 by postal mail). Nine mothers with no children and 10 mothers with children born in areas endemic for T. cruzi infection were excluded from the study. The study group comprised included 67 mothers and 156 mother-child pairs; 114 from untreated and 42 from women who had been treated at our health center. Eight mothers who had not received treatment prior to pregnancy out of the 67 included gave birth to children with congenital Chagas disease (12%). The prevalence of congenital Chagas disease was higher among untreated women compared with benznidazole- treated women (Fig. 1). Congenital Chagas disease was confirmed in 16 out of 114 (14%) children, all of them born to untreated mothers, vs. 0/42 children (0%) born to treated mothers, p = 0.01. The current age of the included children not differed significantly between those born with congenital Chagas disease (16.1 ± 9.6) and without the disease (16.1 ± 9.8), p = 1.0. In 4 out of 16 (25%) of the congenital cases, T. cruzi infection was confirmed by direct parasitological examination by the Strout technique, whereas the remaining 12 children (75%) were diagnosed by conventional serologic tests after one year of life. Baseline epidemiologic and socioeconomic parameters were not statistically significant between mothers who had children with congenital Chagas disease and those who gave birth to uninfected children including (Table 1). After admission in the study, treatment was offered to those women who had not been treated and, thus 64 out the 67 had received benznidazole by the end of the study. The serologic and clinical evolution of treated women vs untreated are shown in Table 2. Of note, a 32% rate of negative seroconversion (i.e. 2 or 3 negative tests out of 2 or three
Parameter
Mothers with congenital transmission (n = 8)
Mothers without congenital transmission (n = 59)
P
Age at admission (ys) Age of last pregnancy (ys) No. of mothers with ECG abnormalities (%) Years of schooling Overcrowding index No. of mothers with health insurance (%) Years of residence in endemic areas
44.4 ± 11.4 33.1 ± 5
42 ± 8.9 31.3. ± 5.2
0.56 0.37
12%(1/8)
14%(8/59)
0.94
7.6 ± 3.6 1.45 ± 0.8 50% (4/8)
8.3 ± 3.5 1.76 ± 0.8 46%(27/59)
0.58 0.33 0.92
4 (0–21)
13 (0–30),
0.30
previously positive tests) in patients with a follow-up period of 7 years. 4. Discussion Vertical transmission of T-cruzi infection was not observed in fertile women who had received benznidazole treatment prior to pregnancy. While 14% is higher than the prevalence expected for congenital Chagas disease in untreated mothers according to epidemiologic data in Argentina (Blanco et al., 2000), this findings can be explained by the bias related to the referral of patients to a specialized center. In contrast, no cases of congenital Chagas disease was observed in the same cohort and the same period of clinical and serologic monitoring of mothers who had been treated with benznidazole prior to pregnancy. Based on two randomized studies performed in children (de 150
Acta Tropica 174 (2017) 149–152
M.G. Álvarez et al.
Table 2 Clinical and serological outcome of mothers with chronic Chagas disease. ClinicalgroupA
No. of women with baseline abnormal EKG
Age of benznidazole treatment (years)B
Clinical follow-up (years)B
No. of women with negative seroconversionC
No. of women with change in clinical group
Untreated (n = 31)
3 (9.6%) Not associated to Chagas disease 6 (9.8%) related to Chagas disease
NA
2 (1–33)
0 (0%)
0 (0%)
30 (8–47)
5 (1–35)
20 (32%)
1 (1.6%)D
Treated (n = 61)
A Three out of 67 women included in the study without clinical follow up; 3 out 67 women with follow-up only in the untreated status and 28 women with follow-up in treated and untreated status. B Data are shown as median and range. C Conversion to negative findings on two or three serological tests. D Change from G1 to G2 clinical group, according to the modified Kuschnir clinical classification of chronic Chagas disease,after one year of treatment (Kuschnir et al., 1985; Viotti et al., 2011). NA, no applicable.
Acknowledgment
Andrade et al., 1996; Sosa Estani et al., 1998) the medical guidelines recommend specific treatment for chronic Chagas disease until 14 years of age. However, beyond the age of 14 in the everyday medical practice, treatment is not generally offered (Viotti et al., 2014). Therefore, infants congenital Chagas receive treatment while women of childbearing age who may potentially transmit the infection to their babies are not treated. The evidence-based medicine is the rational guidance of medical behavior based on scientific data, but should not be a dogma according to its creators (Acosta Artiles, 2015). In the case of Chagas disease it has generated an age limit for the indication of treatment that is fictional and scientifically unfounded (Viotti and Vigliano, 2007). Two recent case-control studies compared the incidence of congenital Chagas between treated and untreated mothers with similar findings to those presented herein (Fabre et al., 2014; Murcia et al., 2017). In the study of Fabbro et al., one of the centers was located in an endemic area. In the present study, children born in endemic areas for T. cruzi infection were excluded from the study to rule out the possibility of vector transmission. However, in both studies, no cases of congenital Chagas were observed in mothers who had received treatment with benznidazole prior to pregnancy. Likewise, the serological evolution was also similar confirming the efficacy of specific treatment in individuals older than 14 years of age (Viotti et al., 2006). No differences in clinical, epidemiological and socioeconomic baseline characteristics between women with and without children who were born with Chagas disease were found in our study. In other studies, the level of parasitemia has been pointed as a predisposing factor for the vertical transmission (Carlier et al., 2015; Bua et al., 2012), reinforcing the notion that decreasing parasite load might be beneficial in to avoid congenital infection. Since most women were treated after inclusion, in our study the time of follow up was short and very variable. However, from our data there was not a relationship between the clinical status and the rate of congenital transmission. Furthermore, five out of the six women in the G1 clinical group who were treated prior to pregnancy did not transmit congenital infection and did not show disease progression during follow-up. The remaining G1 woman who had not received treatment prior pregnancy gave birth to a T. cruzi-infected child, supporting that treatment itself more than the clinical status is the main determinant in congenital transmission. As conclusion, benznidazole treatment previously administered to women in reproductive age can prevent the occurrence of congenital Chagas disease.
We thank the medical students María V Leone, Agustina Lloberas and Daniela Montoya, who helped to send letters and phone calls. References Acosta Artiles, F.J., 2015. De Medicina basada en la evidencia a Medicina sustentada en hallazgos. Rev. Esp. Salud Pública 89, 339–342. Bern, C., Montgomery, S.P., Herwaldt, B.L., Rassi Jr., A., Marin-Neto, J.A., Dantas, R.O., et al., 2007. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 298, 2171–2181. Blanco, S.B., Segura, E.L., Cura, E.N., Chuit, R., Tulián, L., Flores, I., et al., 2000. Congenital transmission of Trypanosoma cruzi: an operational outline for detecting and treating infected infants in north-western Argentina. Trop. Med. Int. Health 5, 293–301. Bua, J., Volta, B.J., Velazquez, E.B., Ruiz, A.M., Rissio, A.M., Cardoni, R.L., 2012. Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification. Trans. R. Soc. Trop. Med. Hyg. 106, 623–628. Buekens, P., Almendares, O., Carlier, Y., Dumonteil, E., Eberhard, M., Gamboa-Leon, R., et al., 2008. Mother-to-child transmission of Chagas' disease in North America: why don't we do more? Matern. Child Health J. 12, 283–286. Carlier, Y., Torrico, F., 2003. Congenital infection with Trypanosoma cruzi: from mechanisms of transmission to strategies for diagnosis and control. Rev. Soc. Bras. Med. Trop. 36, 767–771. Carlier, Y., Sosa-Estani, S., Luquetti, A., Buekens, P., 2015. Congenital Chagas disease: an update. Mem. Inst. Oswaldo Cruz 110, 363–368. de Andrade, A.L., Zicker, F., de Oliveira, R.M., Almeida Silva, S., Luquetti, A., Travassos, L.R., et al., 1996. Randomized trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet 348, 1407–1413. Fabre, D.L., Danesa, E., Olivera, V., Codeó, M.O., Denar, S., Heredia, C., et al., 2014. Trypanocide treatment of women infected with Trypanosoma cruzi and its effect on preventing congenital Chagas. PLoS Negl. Trop. Dis. 8, e3312. Gascón, J., Albajar, P., Cañas, E., Flores, M., Gómez i Prat, J., Herrera, R.N., et al., 2007. Diagnóstico, manejo y tratamiento de la cardiopatña chagísica crónica en íreas donde la infección por Trypanosoma cruzi no es endámica. Rev. Esp. Cardiol. 60, 285–293. Gurtler, R.E., Segura, E.L., Cohen, J.E., 2003. Congenital transmission of Trypanosoma cruzi infection in Argentina. Emerg. Infect. Dis. 9, 29–32. Hermann, E., Truyens, C., Alonso-Vega, C., Rodriguez, P., Berthe, A., Torrico, F., et al., 2004. Congenital transmission of Trypanosoma cruzi is associated with maternal enhanced parasitemia and decreased production of interferon- gamma in response to parasite antigens. J. Infect. Dis. 189, 1274–1281. Kuschnir, E., Sgammini, H., Castro, R., Evequoz, C., Ledesma, R., Brunetto, J., 1985. Evaluation of cardiac function by radioisotopic angiography, in patients with chronic Chagas cardiopathy. Arq. Bras. Cardiol. 45, 249–256. Guías para la atención al paciente infectado con Trypanosoma cruzi (Enfermedad de Chagas). Ministerio de Salud de la Nación, Buenos Aires. Molina, I., Gómez i Prat, J., Salvador, F., Treviño, B., Sulleiro, E., Serre, N., Pou, D., Roure, S., et al., 2014. Randomized trial of posaconazole and benznidazole for chronic chagas' disease. N. Engl. J. Med. 370, 1899–1908. Moretti, E., Basso, B., Castro, I., Carrizo Paez, M., Chaul, M., Barbieri, G., et al., 2005. Chagas' disease: study of congenital transmission in cases of acute maternal infection. Rev. Soc. Bras. Med. Trop. 38, 53–55. Muñoz, J., Coll, O., Juncosa, T., Vergés, M., del Pino, M., Fumado, V., et al., 2009. Prevalence and vertical transmission of Trypanosoma cruzi infection among pregnant Latin American women attending 2 maternity clinics in Barcelona Spain. Clin. Infect. Dis. 48, 1736–1740. Murcia, L., Carrilero, B., Muñoz, M.J., Iborra, M.A., Segovia, M., 2010. Usefulness of PCR for monitoring benznidazole response in patients with chronic Chagasñ disease: a prospective study in a non-disease-endemic country. J. Antimicrob. Chemother. 65, 1759–1764. Murcia, L., Simón, M., Carrilero, B., Roig, M., Segovia, M., 2017. Treatment of infected women of childbearing age prevents congenital Trypanosoma cruzi infection by
Funding source This study was supported by “Beca Ramón Carrillo-Arturo Oñativia 2014”, Comisión Nacional Salud Investiga, National Ministry of Health, Argentina; Ministry of Health, Buenos Aires Province, Argentina.
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Viotti, R., Vigliano, C., 2007. Etiological treatment of chronic Chagas disease: neglected evidence by evidence-base medicine. Expert Rev. Anti Infect. Ther. 5, 717–726. Viotti, R., Vigliano, C., Lococo, B., Bertocchi, G., Petti, M., Alvarez, M.G., et al., 2006. Long-Term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment. A nonrandomized trial. Ann. Intern. Med. 144, 724–734. Viotti, R., Vigliano, C., Alvarez, M.G., Lococo, B., Petti, M., Bertocchi, G., et al., 2011. Impact of Aetiological treatment on conventional and multiplex serology in chronic Chagas Disease. PLoS Negl. Trop. Dis. 5, 1–7 e1314. Viotti, R., Alarcón de Noya, B., Araujo-Jorge, T., Grijalva, M.J., Guhl, F., López, M.C., et al., 2014. On behalf of the Latin American network for chagas disease (NHEPACHA). towards a paradigm shift in the treatment of chronic chagas disease. AAC 58, 635–639.
eliminating the parasitemia detected by PCR. J. Infect. Dis. 215, 1452–1458. Sosa Estani, S., Segura, E.L., Ruiz, A.M., Velazquez, E., Porcel, B.M., Yampotis, C., 1998. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas’ disease. Am. J. Trop. Med. Hyg. 59, 526–529. Torrico, F., Alonso-Vega, C., Suarez, E., Rodriguez, P., Torrico, M.C., Dramaix, M., et al., 2004. Maternal Trypanosoma cruzi infection, pregnancy outcome, morbidity, and mortality of congenitally infected and non-infected newborns in Bolivia. Am. J. Trop. Med. Hyg. 70, 201–209. Torrico, F., 2013. E1224—resultados de un ensayo clínico de prueba de concepto en pacientes con enfermedad de Chagas indeterminada crónica. In: Simposio ASTMH organizado por DNDi Enfermedad de Chagas: Avances recientes en Investigación y Desarrollo, Sesión n° 53. November 14. pp. 2013.
152
Contents lists available at ScienceDirect
Acta Tropica journal homepage: www.elsevier.com/locate/actatropica
Short communication
Prevention of congenital Chagas disease by Benznidazole treatment in reproductive-age women. An observational study María G. Álvarez, Carlos Vigliano, Bruno Lococo, Graciela Bertocchi, Rodolfo Viotti
MARK
⁎
Cardiology Department, Chagas Disease Section, Eva Perón Hospital, Buenos Aires, Argentina
A R T I C L E I N F O
A B S T R A C T
Keywords: Chagas disease Treatment Benznidazole Congenital transmission
Since the decline in new cases of infection by insect/vector, congenital Chagas disease has become more relevant in the transmission of Chagas disease. Treatment with benznidazole significantly reduces the parasitemia, which constitutes an important factor linked to vertical transmission. The objective of this study was to evaluate whether treatment with benznidazole previously administered to women of childbearing age can prevent or reduce the incidence of new cases of congenital Chagas disease. An historical cohort study that included all women in reproductive age (15–45 years) assisted in our center was designed. We included 67 mothers with chronic Chagas disease; 35 women had not been treated prior to pregnancy, 15 had been treated prior to pregnancy and 17 gave birth prior and after treatment with benznidazole. Eight mothers gave birth to 16 children with congenital Chagas disease (8/67, 12%). The prevalence of congenital Chagas was 16/114 (14%) children born to untreated mothers and 0/42 (0%) children born to benznidazole- treated mothers, p = 0.01. No significant differences were observed in clinical, serologic, epidemiological or socioeconomic baseline variables between mothers with and without children born with congenital Chagas. A 32% conversion rate to negative serology was observed in benznidazole-treated women after long-term follow up. Antiparasitic treatment administered to women in reproductive age can prevent the occurrence of congenital Chagas disease.
1. Introduction Since the decline in new cases of infection by insect/vector, congenital Chagas disease has become more relevant in the transmission of Chagas disease (Carlier and Torrico, 2003; Gurtler et al., 2003; Torrico et al., 2004). This way of infection is the main mode of spread of the disease in non-endemic countries, linked to migration flows, which has led to consider the globalization of Chagas disease (Muñoz et al., 2009; Buekens et al., 2008). Several medical guidelines recommend antiparasitic treatment until 14 years of age (Bern et al., 2007; Gascón et al., 2007; Ministerio de Salud de la Nación, 2012), and as a result many T. cruzi-infected women of reproductive age do not receive specific treatment. Treatment with benznidazole significantly reduces the parasitemia which is, the main factor related to congenital Chagas disease transmission (Hermann et al., 2004; Moretti et al., 2005; Carlier et al., 2015). Controlled studies using PCR assays showed a high rate of negative parasitemia, one year following treatment with (Molina et al., 2014; Torrico, 2013; Murcia et al., 2010). Treatment may also reduce parasite burden in tissues, and this impacts the number and frequency of parasitemia, even if no parasitic cure is achieved.
⁎
The objective of this research was to evaluate whether treatment with benznidazole administered to women of reproductive age can prevent or reduce the incidence of new cases of congenital Chagas disease. 2. Methods 2.1. Design and population A historical cohort study including all women of childbearing age (15–45 years) assisted in the Eva Peron Hospital, located in the outskirts of Buenos Aires, Argentina was designed. For the initial information, the general database was used to record address, phone number, date of benznidazole treatment and clinical data from women of childbearing age for potential inclusion in the study.From this hospitalary sample, the mother/child pairs with and without treatment with benznidazole prior to pregnancy were included. To achieve this goal, direct contact in the office, phone calls (3 calls at different times or days on average per patient), or a letter requesting attendance to the hospital were used. Children born in areas endemic for T. cruzi infection
Corresponding author at: José Hernández 3440, Villa Ballester, Provincia de Buenos Aires, Argentina. E-mail address: [email protected] (R. Viotti).
http://dx.doi.org/10.1016/j.actatropica.2017.07.004 Received 24 September 2016; Received in revised form 3 July 2017; Accepted 5 July 2017 Available online 15 July 2017 0001-706X/ © 2017 Elsevier B.V. All rights reserved.
Acta Tropica 174 (2017) 149–152
M.G. Álvarez et al.
were excluded from the study. 2.2. Variables in study A survey was designed with epidemiological, clinical and serological data of mother/child pairs including the following variables: present age; age of last pregnancy; residence time in an endemic area; years of education; overcrowding index (number of cohabiting/number of bedrooms); health insurance; abnormal ECG; age of benznidazole treatment; clinical and serologic time of follow-up; serologic evolution (negative seroconversion of 2 or 3 tests performed) and new ECG changes (i.e. disease progression). All patients of the cohort had been diagnosed at admission at the hospital with three serological tests carried out at the Instituto Nacional de Parasitología Dr. Mario Fatala Chaben, the reference center for diagnosis of Chagas disease in Argentina. In those children without diagnosis at the time of inclusion in the present study, a blood sample was obtained to assess conventional serologic tests at the reference center. After inclusion, women of reproductive age who had not been treated received 5 mg/kg/day of benznidazole for 30 days. Serologic testing was thereafter conducted every three years in average. 2.3. Statistical analysis The variables with normal distribution were expressed as mean ± 1 standard deviation, using the median and 25–75% interquartile range for those with non-Gaussian distribution. For comparative statistics Student t-tests, Wilcoxon Rank or the chi-square test or its variant, Fischer's exact test, was used as appropriate. The study protocol was approved by the Research Ethics Committee of the Hospital Eva Peron, accredited by the Central Ethics Committee of the Ministry of Health of Buenos Aires Province, Argentina. All patients provided an informed consent or parental consent in writing, as appropriate.
Fig. 1. Flow diagram of congenital Chagas disease in a cohort study comparing women of reproductive age with and without benznidazle treatment prior to pregnancy. A Seventeen women also gave birth in the untreated status of the disease.
3. Results
Table 1 Baseline mother characteristics, by congenital transmission group.
Eighty-six patients from the cohort of women of childbearing age with chronic Chagas disease were contacted (36 at office, 32 by telephone and 18 by postal mail). Nine mothers with no children and 10 mothers with children born in areas endemic for T. cruzi infection were excluded from the study. The study group comprised included 67 mothers and 156 mother-child pairs; 114 from untreated and 42 from women who had been treated at our health center. Eight mothers who had not received treatment prior to pregnancy out of the 67 included gave birth to children with congenital Chagas disease (12%). The prevalence of congenital Chagas disease was higher among untreated women compared with benznidazole- treated women (Fig. 1). Congenital Chagas disease was confirmed in 16 out of 114 (14%) children, all of them born to untreated mothers, vs. 0/42 children (0%) born to treated mothers, p = 0.01. The current age of the included children not differed significantly between those born with congenital Chagas disease (16.1 ± 9.6) and without the disease (16.1 ± 9.8), p = 1.0. In 4 out of 16 (25%) of the congenital cases, T. cruzi infection was confirmed by direct parasitological examination by the Strout technique, whereas the remaining 12 children (75%) were diagnosed by conventional serologic tests after one year of life. Baseline epidemiologic and socioeconomic parameters were not statistically significant between mothers who had children with congenital Chagas disease and those who gave birth to uninfected children including (Table 1). After admission in the study, treatment was offered to those women who had not been treated and, thus 64 out the 67 had received benznidazole by the end of the study. The serologic and clinical evolution of treated women vs untreated are shown in Table 2. Of note, a 32% rate of negative seroconversion (i.e. 2 or 3 negative tests out of 2 or three
Parameter
Mothers with congenital transmission (n = 8)
Mothers without congenital transmission (n = 59)
P
Age at admission (ys) Age of last pregnancy (ys) No. of mothers with ECG abnormalities (%) Years of schooling Overcrowding index No. of mothers with health insurance (%) Years of residence in endemic areas
44.4 ± 11.4 33.1 ± 5
42 ± 8.9 31.3. ± 5.2
0.56 0.37
12%(1/8)
14%(8/59)
0.94
7.6 ± 3.6 1.45 ± 0.8 50% (4/8)
8.3 ± 3.5 1.76 ± 0.8 46%(27/59)
0.58 0.33 0.92
4 (0–21)
13 (0–30),
0.30
previously positive tests) in patients with a follow-up period of 7 years. 4. Discussion Vertical transmission of T-cruzi infection was not observed in fertile women who had received benznidazole treatment prior to pregnancy. While 14% is higher than the prevalence expected for congenital Chagas disease in untreated mothers according to epidemiologic data in Argentina (Blanco et al., 2000), this findings can be explained by the bias related to the referral of patients to a specialized center. In contrast, no cases of congenital Chagas disease was observed in the same cohort and the same period of clinical and serologic monitoring of mothers who had been treated with benznidazole prior to pregnancy. Based on two randomized studies performed in children (de 150
Acta Tropica 174 (2017) 149–152
M.G. Álvarez et al.
Table 2 Clinical and serological outcome of mothers with chronic Chagas disease. ClinicalgroupA
No. of women with baseline abnormal EKG
Age of benznidazole treatment (years)B
Clinical follow-up (years)B
No. of women with negative seroconversionC
No. of women with change in clinical group
Untreated (n = 31)
3 (9.6%) Not associated to Chagas disease 6 (9.8%) related to Chagas disease
NA
2 (1–33)
0 (0%)
0 (0%)
30 (8–47)
5 (1–35)
20 (32%)
1 (1.6%)D
Treated (n = 61)
A Three out of 67 women included in the study without clinical follow up; 3 out 67 women with follow-up only in the untreated status and 28 women with follow-up in treated and untreated status. B Data are shown as median and range. C Conversion to negative findings on two or three serological tests. D Change from G1 to G2 clinical group, according to the modified Kuschnir clinical classification of chronic Chagas disease,after one year of treatment (Kuschnir et al., 1985; Viotti et al., 2011). NA, no applicable.
Acknowledgment
Andrade et al., 1996; Sosa Estani et al., 1998) the medical guidelines recommend specific treatment for chronic Chagas disease until 14 years of age. However, beyond the age of 14 in the everyday medical practice, treatment is not generally offered (Viotti et al., 2014). Therefore, infants congenital Chagas receive treatment while women of childbearing age who may potentially transmit the infection to their babies are not treated. The evidence-based medicine is the rational guidance of medical behavior based on scientific data, but should not be a dogma according to its creators (Acosta Artiles, 2015). In the case of Chagas disease it has generated an age limit for the indication of treatment that is fictional and scientifically unfounded (Viotti and Vigliano, 2007). Two recent case-control studies compared the incidence of congenital Chagas between treated and untreated mothers with similar findings to those presented herein (Fabre et al., 2014; Murcia et al., 2017). In the study of Fabbro et al., one of the centers was located in an endemic area. In the present study, children born in endemic areas for T. cruzi infection were excluded from the study to rule out the possibility of vector transmission. However, in both studies, no cases of congenital Chagas were observed in mothers who had received treatment with benznidazole prior to pregnancy. Likewise, the serological evolution was also similar confirming the efficacy of specific treatment in individuals older than 14 years of age (Viotti et al., 2006). No differences in clinical, epidemiological and socioeconomic baseline characteristics between women with and without children who were born with Chagas disease were found in our study. In other studies, the level of parasitemia has been pointed as a predisposing factor for the vertical transmission (Carlier et al., 2015; Bua et al., 2012), reinforcing the notion that decreasing parasite load might be beneficial in to avoid congenital infection. Since most women were treated after inclusion, in our study the time of follow up was short and very variable. However, from our data there was not a relationship between the clinical status and the rate of congenital transmission. Furthermore, five out of the six women in the G1 clinical group who were treated prior to pregnancy did not transmit congenital infection and did not show disease progression during follow-up. The remaining G1 woman who had not received treatment prior pregnancy gave birth to a T. cruzi-infected child, supporting that treatment itself more than the clinical status is the main determinant in congenital transmission. As conclusion, benznidazole treatment previously administered to women in reproductive age can prevent the occurrence of congenital Chagas disease.
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Funding source This study was supported by “Beca Ramón Carrillo-Arturo Oñativia 2014”, Comisión Nacional Salud Investiga, National Ministry of Health, Argentina; Ministry of Health, Buenos Aires Province, Argentina.
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