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SPATIAL DISTRIBUTION OF NEWBORNS WITH SICKLE CELL TRAIT IN SERGIPE, BRAZIL

ABSTRACT

Objective:

To use the spatial distribution of the sickle cell trait (SCT) to analyze the frequency of hemoglobin S (HbS) carriers in Sergipe.

Methods:

The sample consisted of all individuals born in Sergipe from October 2011 to October 2012 who underwent neonatal screening in the public health system. Tests were carried out in basic health units and forwarded to the University Hospital laboratory, where they were analyzed. We used spatial autocorrelation (Moran’s index) to assess the spatial distribution of heterozygous individuals with hemoglobinopathies.

Results:

Among 32,906 newborns, 1,202 showed other types of hemoglobin besides Hemoglobin A. We found a positive correlation between the percentage of black and multiracial people and the incidence of SCT. Most SCT cases occurred in the cities of Aracaju (n=273; 22.7%), Nossa Senhora do Socorro (n=102; 8.4%), São Cristóvão (n=58; 4.8%), Itabaiana (n=39; 4.2%), Lagarto (n=37; 4.01%), and Estância (n=46; 4.9%).

Conclusions:

The spatial distribution analysis identified regions in the state with a high frequency of HbS carriers. This information is important health care planning. This method can be applied to detect other places that need health units to guide and care for sickle cell disease patients and their families.

Keywords:
Sickle cell disease; Sickle cell trait; Neonatal screening; Residence characteristics

RESUMO

Objetivo:

Basear-se na distribuição espacial do traço falciforme (TF) para analisar a frequência dos portadores da hemoglobina S (HbS) em Sergipe.

Métodos:

A amostra foi constituída por todos os indivíduos nascidos em Sergipe, no período de outubro de 2011 a outubro de 2012, submetidos à triagem neonatal pelo Sistema Único de Saúde, ano de início da triagem universal no Estado. Os testes foram realizados em unidades básicas de saúde e encaminhados para o laboratório do Hospital Universitário, onde foram analisados. A análise da distribuição espacial dos indivíduos heterozigotos para hemoglobinopatias foi realizada por autocorrelação espacial (índice de Moran).

Resultados:

Dentre os 32.906 recém-nascidos estudados, 1.202 apresentaram outras hemoglobinas além da Hemoglobina A. Houve correlação positiva entre a porcentagem de negros e mestiços e a incidência de TF. A maioria dos casos foi encontrada nos municípios de Aracaju (n=273; 22,7%), Nossa Senhora do Socorro (n=102; 8,4%), São Cristóvão (n=58; 4,8%), Itabaiana (n=39; 4,2%), Lagarto (n=37; 4,01%) e Estância (n=46; 4,9%).

Conclusões:

Na análise de distribuição espacial por autocorrelação, identificaram-se regiões no Estado com maior frequência de HbS, o que é de extrema importância para o planejamento do sistema de saúde, podendo a mesma metodologia ser aplicada para identificação de outros locais com maior necessidade de centros para cuidados e orientações a portadores de doença falciforme e seus familiares.

Palavras-chave:
Doença falciforme; Traço falciforme; Triagem neonatal; Distribuição espacial

INTRODUCTION

Sickle cell anemia (SCA) is the most common monogenic disease in the world and is associated with mutant hemoglobin (HbS), which forms polymers in the red blood cells of patients, leading to chronic anemia. SCA is endemic in many regions where malaria is or was prevalent due to the protective nature of the carrier state11. Tewari S, Brousse V, Piel FB, Menzel S, Rees DC. Environmental determinants of severity in sickle cell disease. Haematologica. 2015;100:1108-16. https://doi.org/10.3324/haematol.2014.120030
https://doi.org/https://doi.org/10.3324/...
and where the proportion of African descendants is higher.22. Lervolino LG, Baldin PE, Picado SM, Calil KB, Viel AM, Campos LA. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev Bras Hematol Hemoter. 2011;33:49-54. http://dx.doi.org/10.5581/1516-8484.20110015
https://doi.org/http://dx.doi.org/10.558...
Throughout the American Continent, the distribution of HbS - more prevalent in populations along the eastern coast - closely matches the distribution of people of African descent.33. Piel FB, Patil AP, Howes RE, Nyangiri AO, Gething PW, Dewi M, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381:142-51. https://doi.org/10.1016/S0140-6736(12)61229-X
https://doi.org/https://doi.org/10.1016/...

In Brazil, SCA is more prevalent in the Northeast and three states of the Southeast region - São Paulo, Rio de Janeiro, and Minas Gerais. Overall, in the state of Bahia, in the Northeastern region, the incidence was 1:677 live births. The high prevalence of sickle cell disease (SCD) in those regions can be historically explained by the forced migration of individuals brought to Brazil as slaves from Africa during the colonial period, mainly for working in sugar cane plantations in the Northeast and gold mines in the Southeast.44. Arduini GA, Rodrigues LP, Marqui AB. Mortality by sickle cell disease in Brazil. Rev Bras Hematol Hemoter. 2017;39:52-6. http://dx.doi.org/10.1016/j.bjhh.2016.09.008
https://doi.org/http://dx.doi.org/10.101...

Sickle cell trait (SCT) is a carrier state of SCA with one copy of normal beta globulin gene and one copy of sickle variant gene-producing heterozygous (HbAS).55. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151:839-45. https://doi.org/10.1093/oxfordjournals.aje.a010288
https://doi.org/https://doi.org/10.1093/...
Although SCT is considered a harmless condition, complications including hypercoagulability, venous thromboembolic events, renal disease, exertional rhabdomyolysis, and exercise-related sudden death have been reported.66. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y. Complications associated with sickle cell trait: a brief narrative review. Am J Med. 2009;122:507-12. https://doi.org/10.1016/j.amjmed.2008.12.020
https://doi.org/https://doi.org/10.1016/...
Individuals with SCT are often not informed or fully educated about their SCT carrier status, which leads to confusion about health risks and mistrust of the underlying intentions for screening.77. Naik RP, Haywood C. Sickle cell trait diagnosis: clinical and social implications. Hematology Am Soc Hematol Educ Program. 2015;1:160-7. https://doi.org/10.1182/asheducation-2015.1.160
https://doi.org/https://doi.org/10.1182/...
Therefore, genetic counseling and guidance are important for families that have a child with HbAS.88. Guimarães CT, Coelho GO. The importance of genetic counseling at sickle cell anemia. Cien Saude Colet. 2010;15:1733-40. http://dx.doi.org/10.1590/S1413-81232010000700085
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The Southeastern region of Brazil has shown a high prevalence of SCT - one SCT carrier in every 27 births. Nevertheless, according to the Ministry of Health, SCT is present in approximately 5.3% of the population in Bahia - the state with the highest percentage.22. Lervolino LG, Baldin PE, Picado SM, Calil KB, Viel AM, Campos LA. Prevalence of sickle cell disease and sickle cell trait in national neonatal screening studies. Rev Bras Hematol Hemoter. 2011;33:49-54. http://dx.doi.org/10.5581/1516-8484.20110015
https://doi.org/http://dx.doi.org/10.558...

Patients with SCT are everywhere in Northeastern Brazil. In the state of Sergipe, the prevalence of HbAS among blood donors is 4.1%.99. Vivas WL, Rebouças DS, Fabbro AM, Cipolloti R. Heterozigosity to hemoglobinopathies in blood donors from the Hemotherapy Center in Sergipe, NE-Brazil. Rev Bras Hematol Hemoter. 2006;28:284-7. http://dx.doi.org/10.1590/S1516-84842006000400013
https://doi.org/http://dx.doi.org/10.159...
However, the prevalence among newborn infants in the general population, as well as their spatial distribution, is not known. The Newborn Screening Program (NSP) is a public health project that screens all babies for a range of conditions, including phenylketonuria, congenital hypothyroidism, SCD, and cystic fibrosis.1010. Carvalho TM, Santos HP, Santos IC, Vargas PR, Pedrosa J. Newborn screening: a national public health programme in Brazil. J Inherit Metab Dis. 2007;30:615. https://doi.org/10.1007/s10545-007-0650-7
https://doi.org/https://doi.org/10.1007/...
The use of geotechnologies and spatial analysis of HbAS SCT may enable effective health care planning to address the needs of this population.

This study aimed to describe the spatial distribution of individuals with HbAS SCT by using data from the NSP for hemoglobinopathies in the state of Sergipe, Northeastern Brazil.

METHOD

This study was conducted in the state of Sergipe, the smallest federal unit in terms of territory extension in Brazil (21,910 km2). Sergipe is in the Northeastern region and comprises 75 cities, grouped into three mesoregions: Eastern, Agreste, and Sertão Sergipano. Its Human Development Index (HDI) is 0.681, life expectancy at birth is 72.1 years, and the infant mortality rate is 18 per 1,000 live births.1111. Brazil - Ministério do Planejamento, Desenvolvimento e Gestão. Instituto Brasileiro de Geografia e Estatística - IBGE [homepage on the Internet]. Portal do IBGE - Censo Demográfico - Censo 2010 [cited 2017 Aug 9]. Rio de Janeiro: IBGE; 2010. Available from: Available from: https://www.ibge.gov.br/estatisticas/sociais/populacao/9662-censo-demografico-2010.html?edicao=9749&t=resultados
https://www.ibge.gov.br/estatisticas/soc...
Approximately 50% of the population lives below the Poverty Index.1212. Sergipe - Secretaria de Estado do Turismo. Avaliação Ambiental Estratégica do PRODETUR Nacional no estado de Sergipe [homepage on the internet] Sergipe: PRODETUR; 2014. [cited 2017 Aug 4]. Available from: Available from: http://www.turismo.gov.br/sites/default/turismo/DPROD/AVALIACAO_AMBIENTAL/SE/AAE_SE.pdf
http://www.turismo.gov.br/sites/default/...
The population has many ethnic and national origins, including especially Portuguese, Germans, Italians,1313. Ennes MA. A imigração estrangeira em Sergipe (1875-1930). História (São Paulo). 2011;30:312-34. and black Africans.1414. Mott LR. Sergipe del Rey: população, economia e sociedade. Aracaju: Fundação Estadual de Cultura; 1986.

The studied population included live births in the first year of implementation of NSP for hemoglobinopathies in Sergipe (October 2011 to October 2012), consisting of about 80% of the live births in the state during this period. The remaining 20% of newborn babies were screened at private outpatient clinics and data from this population is not available. The screening program collected heel prick samples up to 30 days after birth, and babies with positive screening were retested. Tests were carried out in basic health units and forwarded to the University Hospital laboratory, where they were analyzed. Isoelectric Focusing Electrophoresis was performed to identify HbAS SCT, as recommended by the Brazilian government directive MS 822/01. Data regarding gender, ethnicity, birth date, and zip code of birth were also collected. Information about population estimates and self-reported ethnicity were gathered from the Brazilian Institute of Geography and Statistics,1515. Brazil - Ministério do Planejamento, Desenvolvimento e Gestão. Instituto de Brasileiro de Geografia e Estatística - IBGE [homepage on the Internet]. Portal do IBGE - Geociência - Distribuição espacial da população segundo cor ou raça Censo 2010 [cited 2017 Aug 15]. Avaliable from: Avaliable from: http://www.ibge.gov.br/geociencias-novoportal/cartas-e-mapas/sociedade-e-economia/15963-distribuicao-espacial-da-populacao-segundo-cor-ou-raca-pretos-e-pardos.html?=&t=sobre
http://www.ibge.gov.br/geociencias-novop...
available on the website of the Technology Department of the public health system (Departamento de Informática do Sistema Único de Saúde - DATASUS).1616. Brazil - Ministério da Saúde - DATASUS [homepage on the Internet]. Informações de saúde- estatísticas vitais - mortalidade e nascidos vivos: nascidos vivos 2011-2012 [cited 2017 Aug 12]. Available from: Available from: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sinasc/cnv/nvSE.def
http://tabnet.datasus.gov.br/cgi/tabcgi....

We calculated the cumulative incidence of HbAS SCT with the proportion of new cases during the period of study divided by the total population at risk. The existence of spatial patterns of HbAS SCT in Sergipe was measured by the Moran’s Index (I). Analyses were made by area (cities).

We adopted the global spatial autocorrelation Moran’s I statistics to assess the degree of similarity between a certain location and its neighboring units. Positive values (between 0 and +1) were associated with spatial clustering patterns, whereas negative values (between 0 and -1) indicated a spatial dispersion pattern. Moran’s I value close to zero represented a random pattern of distribution. We elaborated a Moran scatter plot to visualize the results. Observations in the lower left (Low-low) and upper right (High-high) quadrants represented potential spatial clusters, while observations in the upper left (Low-high) and lower right (High-low) suggested potential spatial outliers. The slope of the scatter plot corresponded to the value for global Moran’s I.1717. Anselin L, Syabri I, Kho Y. GeoDa: an introduction to spatial data analysis. Geogr Anal. 2006;38:5-22. The location of clusters or hotspots of HbAS SCT were examined by the Local Indicators of Spatial Association (LISA) cluster map. We used the Benjamini-Hochberg False Discovery Rate (FDR) to adjust the p values. We also adopted the Kernel method, a statistical non-parametric interpolation technique, in which a distribution of points or events is transformed into a “continuous risk surface”. This procedure allowed us to filter the variability of the data set, without, however, changing its local characteristics in an essential way.1818. Bailey TC, Gatrell AC. Interactive spatial data analysis. New York: Longman Group Limited; 1995. The analyses were performed with the R-language (R 2.8.1) and TerraView (4.2.2).1919. Brazil - Instituto Nacional de Pesquisas Espaciais [homepage on the Internet]. Coordenação geral de observação da Terra (OBT) - Divisão de Processamento de Imagens [cited 2017 Aug 17]. Available from: Available from: http://www.dpi.inpe.br/terralib5/wiki/doku.php
http://www.dpi.inpe.br/terralib5/wiki/do...
We considered significant a p<0.05.

The local Research Ethics Committee approved this study under the Approval Protocol CAAE-06347012.0.0000.0058.

RESULTS

The study included 32,906 children born in the state of Sergipe from October 2011 to October 2012. A total of 921 children had HbAS SCT, 242 had hemoglobin A (HbA) with another non-S hemoglobin, and 21 were diagnosed with SCD (Table 1). Figure 1 shows the spatial distribution of 921 cases of HbAS Sickle Cell Trait in Sergipe State.

Table 1
Distribution of abnormal results identified by neonatal screening for hemoglobinopathies in Sergipe, 2011-2012.

Figure 1
Distribution of HbAS sickle cell trait cases in the cities of Sergipe, 2011-2012.

HbAS presented a positive spatial correlation with the percentage of self-identified non-white individuals, indicating that, in Sergipe, both conditions have clustering characteristics (Moran’s Index 0.2339; p<0.001). According to the Moran scatter plot, the first quadrant of the coordinate system represented the spatial connectivity of the high observed value area unit surrounded by the high observed value region (High-high). The High-high clustering areas are mainly located in Aracaju (capital and main city of the state of Sergipe) and surrounding cities (Figure 2).

Figure 2
Moran dispersion diagram for the incidence of HbS and population of black and multiracial people in Sergipe, 2011-2012.

By using LISA, we detected hotspots of HbAS in the Agreste and Eastern regions, especially in Aracaju and surrounding cities (Figure 3).

Figure 3
Spatial distribution by the LISA method testing the association between the incidence of HbS and the percentage of black and multiracial people in the cities of Sergipe, 2011-2012.

Most cases of HbAS SCT were found in the cities of Aracaju (n=273; 22.7%), Nossa Senhora do Socorro (n=102; 8.4%), São Cristóvão (n=58; 4.8%), Itabaiana (n=39; 4.2%), Lagarto (n=37; 4.01%), and Estância (n=46; 4.9%) (Figure 4).

Figure 4
Kernel thematic map showing the density of SCT cases in the cities of Sergipe, 2011-2012.

DISCUSSION

The incidence of HbS has been detected by neonatal screening in several Brazilian states,2020. Adorno EV, Couto FD, Neto JP, Menezes JF, Rêgo M, Reis MG, et al. Hemoglobinopathies in newborns from Salvador, Bahia, Northeast Brazil. Cad Saude Publica. 2005;21:292-8. http://dx.doi.org/10.1590/S0102-311X2005000100032
https://doi.org/http://dx.doi.org/10.159...
,2121. Araújo MC, Serafim ES, Castro WA, Medeiros TM. Prevalence of abnormal hemoglobins in newborns in Natal, Rio Grande do Norte, Brazil. Cad Saude Publica. 2004;20:123-8. http://dx.doi.org/10.1590/S0102-311X2004000100027
https://doi.org/http://dx.doi.org/10.159...
,2222. Soares LF, Rocha OA, Oliveira EH, Vieira JF. Neonatal screening in the state of Piauí: an urgent need - a study on the prevalence of sickle cell disease in newborns. Rev Bras Hematol Hemoter. 2012;34:392-3. http://dx.doi.org/10.5581/1516-8484.20120096
https://doi.org/http://dx.doi.org/10.558...
and this study was the first to report it for Sergipe. Universal neonatal screening could identify affected babies before any symptoms, as well as asymptomatic heterozygous individuals, who can still transmit the gene to their offspring. The geographical distribution of this “silent” population is of extreme interest.

Sergipe still has quilombola communities, which are rural, suburban, or urban communities where enslaved descendants live and share a strong link to their African origins.2323. Brazil - Instituto Nacional Colonização e Reforma Agrária [homepage on the Internet]. Quilombolas [cited 2017 Aug 20]. Available from: Available from: http://www.incra.gov.br/estrutura-fundiaria/quilombolas/comunidades-certificadas
http://www.incra.gov.br/estrutura-fundia...
Quilombola communities contributed to the maintenance of HbS areas because they used to be isolated and had many consanguineous marriages. They are still quite closed communities. The lack of miscegenation in these regions might have allowed the maintenance of the high incidence of HbS.

Geographical distribution has been used to study diseases in epidemiological analyses.2424. Freitas LR, Duarte EC, Garcia LP. Analysis of the epidemiological situation of leprosy in an endemic area in Brazil: spatial distribution in the periods 2001 - 2003 and 2010 - 2012. Rev Bras Epidemiol. 2017;20:702-13. https://doi.org/10.1590/1980-5497201700040012
https://doi.org/https://doi.org/10.1590/...
,2525. Matozinhos FP, Meléndez GV, Pessoa MC, Mendes L, Gomes CS, Costa MA. Spatial distribution of obesity in an urban Brazilian area. Cienc Saude Coletiva. 2015;20:2779-86. http://dx.doi.org/10.1590/1413-81232015209.00442015
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,2626. Hino P, Villa TC, Cunha TN, Santos CB. Spatial distribution of endemic diseases in Ribeirão Preto, São Paulo State. Cienc Saude Coletiva. 2011;16 (Suppl.):1289-94. http://dx.doi.org/10.1590/S1413-81232011000700062
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,2727. Muller EV, Aranha SR, Roza WS, Gimeno SG. Spatial evolution of cardiovascular mortality in Paraná State, Brazil: 1989-1991 and 2006-2008. Cad Saude Publica. 2012;28:1067-77. http://dx.doi.org/10.1590/S0102-311X2012000600006
https://doi.org/http://dx.doi.org/10.159...
This tool becomes important in the study of genetic diseases when there is a possibility of intervention with genetic guidance, as in the case of increased incidence of healthy carriers of the gene that causes the condition. Therefore, knowing the regions of Sergipe with higher incidence of heterozygous individuals is useful to guide the planning of health care actions for patients with SCA, as well as informing the situation to asymptomatic carriers and counseling the families, which may change the incidence profile of SCD in this population.

Screening for β-thalassemia trait in countries around the Mediterranean Sea region led to a drastic drop in the incidence of thalassemia cases because the affected families were informed about the carrier condition and had the opportunity to decide on their reproductive future.2828. Horn ME, Dick MC, Frost B, Davis LR, Bellingham AJ, Stroud CE, et al. Neonatal screening for sickle cell diseases in Camberwell: results and recommendations of a two-year pilot study. Br Med J (Clin Res Ed). 1986;292:737-40. http://dx.doi.org/10.1136/bmj.292.6522.737
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This experience raises the expectation that a similar approach with SCT individuals and their families could eventually affect the incidence of SCD. Regardless of the impact of screening in reducing the incidence of cases, individuals should be informed about their SCT condition to analyze their reproductive decisions better.

The distribution of new cases of HbS detected by the NSP is similar to that of cases of SCD in cities of Sergipe previously reported in another strategy.2929. Ilozue C, Cipolotti R, Melo CA, Gurgel RQ, Cuevas LE. Estimating the post-neonatal prevalence of sickle cell disease in a Brazilian Population. Trop Med Int Health. 2010;15:1125-31. https://doi.org/10.1111/j.1365-3156.2010.02597.x
https://doi.org/https://doi.org/10.1111/...
This result reinforces the need of support by health services in cities with a higher number of patients, focusing on treatment of acute events and medical follow-up, and informing asymptomatic heterozygotes and their families about the carrier condition.3030. Bombard Y, Miller FA. Reply to Ross’ commentary: reproductive benefit through newborn screening: preferences, policy and ethics. Eur J Hum Genet. 2012;20:486-7. https://doi.org/10.1038/ejhg.2012.25
https://doi.org/https://doi.org/10.1038/...

The incidence of SCT in Sergipe, according to NSP, was 2.7%, which is lower than the value estimated by Vivas99. Vivas WL, Rebouças DS, Fabbro AM, Cipolloti R. Heterozigosity to hemoglobinopathies in blood donors from the Hemotherapy Center in Sergipe, NE-Brazil. Rev Bras Hematol Hemoter. 2006;28:284-7. http://dx.doi.org/10.1590/S1516-84842006000400013
https://doi.org/http://dx.doi.org/10.159...
in Aracaju (4.1%). This probably happened because the previous study estimated the HbAS proportion among blood donors, who may have agreed to a blood donation request from relatives with SCD.

The result of the universal screening in Sergipe reveals spatial randomness (p-value of black and multiracial people <0.05). We found a positive spatial correlation, that is, high values ​​of a variable will have high values of the same variable in their adjacency. The association between SCD and black individuals was present since the beginning of the disease characterization.3131. Maio MC, Monteiro S. In times of racialization: the case of the ‘health of the black population’ in Brazil. Hist Cienc Saúde-Manguinhos. 2005;12:419-46. http://dx.doi.org/10.1590/S0104-59702005000200010
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In order to obtain the benefits of universal neonatal screening for hemoglobinopathies, besides the screening test, adequate medical follow-up should be available for patients with SCD, and their families should be informed about the condition.3232. Milne RI. Assessment of care of children with sickle cell disease: implications for neonatal screening programmes. BMJ. 1990;300:371-4. https://doi.org/10.1136/bmj.300.6721.371
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The implementation of these actions should be based on spatial distribution, prioritizing the regions with a higher incidence of HbS.

We emphasize that the data collection started in 2011, when the public health system implemented the universal neonatal screening in Sergipe. However, the population distribution changed since 2011 due to migrations, which can have modified the findings of this study. Also, we only assessed individuals treated in the public health system, so the frequency of hemoglobinopathies in the private system is not known.

Despite these limitations, we found a positive spatial correlation between the incidence of HbAS SCT and a large proportion of black and multiracial people, indicating a clustered characteristic of the condition in the state of Sergipe. We detected hotspots of HbAS SCT in the Agreste and Eastern regions, especially in Aracaju and surrounding cities.

REFERENCES

Funding

  • This study did not receive funding.

Data availability

Data citations

Brazil - Ministério da Saúde - DATASUS [homepage on the Internet]. Informações de saúde- estatísticas vitais - mortalidade e nascidos vivos: nascidos vivos 2011-2012 [cited 2017 Aug 12]. Available from: Available from: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sinasc/cnv/nvSE.def

Publication Dates

  • Publication in this collection
    09 Mar 2020
  • Date of issue
    2020

History

  • Received
    21 Sept 2018
  • Accepted
    18 Jan 2019
  • Published
    24 Feb 2020
Sociedade de Pediatria de São Paulo R. Maria Figueiredo, 595 - 10o andar, 04002-003 São Paulo - SP - Brasil, Tel./Fax: (11 55) 3284-0308; 3289-9809; 3284-0051 - São Paulo - SP - Brazil
E-mail: rpp@spsp.org.br