Abstracts

Introduction

Sickle cell disease is a type of structural hemoglobinopathy of genetic origin defined by the presence of S hemoglobin (HbS) ¹1. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med 2013; 64:451-66.. Individuals with homozygous genotype HbSS (referred as sickle cell anemia) tend to have greater morbimortality and manifest chronic anemia, frequently accompanied by recurrent vaso-occlusive crises, pain, and multiple organ failure ¹1. Kassim AA, DeBaun MR. Sickle cell disease, vasculopathy, and therapeutics. Annu Rev Med 2013; 64:451-66.^,22. Williams TN, Thein SL. Sickle cell anemia and its phenotypes. Annu Rev Genom Hum Genet 2018; 19:113-47.. Individuals with double heterozygotes (HbSC, HbSD, HbSE, and HbStal) tend to present mild or moderate clinical forms ³3. Piel FB, Weatherall DJ. Sickle-cell disease: a call to action. Trans R Soc Trop Med Hyg 2015; 109:355-6.^,44. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010., whereas those with sickle cell trait (HbAS) are more prone to be asymptomatic ⁵5. Lu X, Chaudhury A, Higgins JM, Wood DK. Oxygen-dependent flow of sickle trait blood as an in vitro therapeutic benchmark for sickle cell disease treatments. Am J Hematol 2018; 93:1227-35..

Global estimates suggest 5.7 million live births with HbS and 300,000 live births with HbSS per year, 75% of them in Sub-Saharan Africa ⁶6. Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med 2013; 10:e1001484.. An estimate shows approximately one case of sickle cell disease per 1,000 live births in Brazil ⁷7. Cançado RD, Jesus JA. A doença falciforme no Brasil. Rev Bras Hematol Hemoter 2007; 29:203-6., with the highest incidence in Bahia State (1:650), Rio de Janeiro (1:1,300), and Minas Gerais (1:1,383) ⁴4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010.^,88. Januario JN. Incidência da doença falciforme em um milhão de nascidos vivos em minas gerais (1998-2001). [Masters Thesis] Belo Horizonte: Universidade Federal de Minas Gerais; 2002.. From 1996 to 2016, 6,749 people died because of sickle cell disease, mostly in the Southeast (48.7%) and Northeast (31.6%) ⁹9. Dias MGR. Mortalidade por doença falciforme no Brasil: estudo retrospectivo (1996-2016). https://www.ciencianews.com.br/arquivos/ACET/IMAGENS/biblioteca-digital/hematologia/serie_vermelha/anemia_falciforme/54.pdf (accessed on 13/Sep/2021).
https://www.ciencianews.com.br/arquivos/... . Sickle cell disease inpatients treated with hydroxyurea presented higher survival rates in public hospitals of Mato Grosso do Sul State ¹⁰10. Araujo OMR, Ivo ML, Ferreira Júnior MA, Pontes ERJC, Bispo IMGP, Oliveira ECL. Survival and mortality among users and non-users of hydroxyurea with sickle cell disease. Rev Latinoam Enferm 2015; 23:67-73.. Mean survival reached the third decade of life, with the median age at death ranging from 26.5 years in Bahia State to 30 years in São Paulo and 31.5 years in Rio de Janeiro ¹¹11. Loureiro MM, Rozenfeld S. Epidemiology of sickle cell disease hospital admissions in Brazil. Rev Saúde Pública 2005; 39:943-9., below the survival rates in the United States and England ⁴4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010.^,1212. Gardner K, Douiri A, Allman M, Drasar E, Awogbade M, Thein SL. Survival in sickle cell disease: data from a well-resourced, national health system setting. Blood 2015; 126:71.^,1313. Gardner K, Douiri A, Drasar E, Allman M, Mwirigi A, Awogbade M, et al. Survival in adults with sickle cell disease in a high-income setting. Blood 2016; 128:71..

Some of those actions include universal access to neonatal screening ¹⁴14. Ministério da Saúde. Portaria nº 822, de 06 de junho de 2001. Diário Oficial da União 2001; 7 jun., including sickle cell disease and other hemoglobinopathies in the screening, as well as pneumococcal immunization ¹⁵15. Ministério da Saúde. Portaria nº 872, de 06 de novembro de 2002. Aprova o Protocolo clínico e diretrizes terapêuticas da doença Falciforme (Hidroxiuréia). Diário Oficial da União 2002; 8 nov., prophylactic penicillin ¹⁵15. Ministério da Saúde. Portaria nº 872, de 06 de novembro de 2002. Aprova o Protocolo clínico e diretrizes terapêuticas da doença Falciforme (Hidroxiuréia). Diário Oficial da União 2002; 8 nov.^,1616. Ministério da Saúde. Relatório nº 56. Penicilina oral para profilaxia em doença falciforme. http://conitec.gov.br/images/Incorporados/Penicilina-DoencaFalciforme-final.pdf (accessed on 17Jun/2020).
http://conitec.gov.br/images/Incorporado... , and hydroxyurea ¹⁵15. Ministério da Saúde. Portaria nº 872, de 06 de novembro de 2002. Aprova o Protocolo clínico e diretrizes terapêuticas da doença Falciforme (Hidroxiuréia). Diário Oficial da União 2002; 8 nov., recently indicated for children older than three years ¹⁷17. Ministério da Saúde. Portaria SAS/MS n. 55, de 29 de janeiro de 2010. Protocolo Clínico e Diretrizes Terapêuticas - Doença Falciforme. Diário Oficial da União 2010; 1 feb.. Studies suggested that these measures reduce mortality in children with sickle cell disease ¹⁸18. Lobo CLC, Ballas SK, Domingos ACB, Moura PG, Nascimento EM, Cardoso GP, et al. Newborn screening program for hemoglobinopathies in Rio de Janeiro, Brazil. Pediatr Blood Cancer 2014; 61:34-9.^,1919. Lobo CLDC, Nascimento EMD, Jesus LJCD, Freitas TGD, Lugon JR, Ballas SK. Mortality in children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil. Rev Bras Hematol Hemoter 2018; 40:37-42.^,2020. Prabhakar H, Haywood Jr. C, Molokie R. Sickle cell disease in the United States: looking back and forward at 100 years of progress in management and survival. Am J Hematol 2010; 85:346-53.^,2121. Goonasekera HW, Paththinige CS, Dissanayake VHW. Population screening for hemoglobinopathies. Annu Rev Genomics Hum Genet 2018; 19:355-80..

Contrary to international trends ²⁰20. Prabhakar H, Haywood Jr. C, Molokie R. Sickle cell disease in the United States: looking back and forward at 100 years of progress in management and survival. Am J Hematol 2010; 85:346-53.^,2222. Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr 2009; 154:541-5., sickle cell disease mortality rate increased in Brazil after the implementation of the neonatal screening program, probably due to a greater access to diagnosis ²³23. Arduini GAO, Rodrigues LP, Marqui ABT. Mortality by sickle cell disease in Brazil. Rev Bras Hematol Hemoter 2017; 39:52-6.^,2424. Lima ARG, Ribeiro VS, Nicolau DI. Trends in mortality and hospital admissions of sickle cell disease patients before and after the newborn screening program in Maranhão, Brazil. Rev Bras Hematol Hemoter 2015; 37:12-6.. Most of these studies were limited to one region of Brazil, the pediatric population, or hospital samples ²³23. Arduini GAO, Rodrigues LP, Marqui ABT. Mortality by sickle cell disease in Brazil. Rev Bras Hematol Hemoter 2017; 39:52-6.^,2525. Martins PRJ, Moraes-Souza H, Silveira TB. Morbimortalidade em doença falciforme. Rev Bras Hematol Hemoter 2010; 32:378-83.^,2626. Ballas SK. High mortality among children with sickle cell anemia and stroke who discontinue chronic blood transfusion after transition to an adult program. Blood 2010; 116:1629..

Thus, this study aims to assess the temporal trend in mortality from sickle cell disease in a longer period (1996 to 2019) to evaluate the effect of age and regional inequalities on the annual mortality rates and the median age at death.

Methods

Time-series study using data from the Brazilian Mortality Information System (SIM) of the Ministry of Health ²⁷27. Departamento de Informática do SUS. Informações de saúde. Sistema de Informações sobre Mortalidade. http://www2.datasus.gov.br/DATASUS/index.php (accessed on 01/Jan/2019).
http://www2.datasus.gov.br/DATASUS/index... . Inclusion criteria were deaths from Brazilian residents diagnosed with sickle cell disorders, coded as D57 - Sickle cell disorders (specifically, D57.0 - HbSS disease with crisis; D57.1 - HbSS disease without crisis; D57.2 - Sickle cell/Hb-C disease; D57.3 - Sickle cell trait; D57.8 - Other sickle cell disorders) according to the 10th revision of the International Classification of Diseases (ICD-10) ²⁸28. World Health Organization. ICD-10: international statistical classification of diseases and related health problems: tenth revision. https://apps.who.int/iris/handle/10665/42980 (accessed on 01/Jan/2019).
https://apps.who.int/iris/handle/10665/4... , in any field of the death certificate, from 1996 to 2019. Dead individuals aged 70 years or older (outliers) were excluded.

Outcomes were sickle cell disease mortality rates (per million inhabitants) and the median age at death. The population of mortality rates was retrieved from the census (2000 and 2010) and inter-census estimates (up to 2012) and projections (2013-2019), obtained at Brazilian Health Informatics Department (DATASUS) ²⁹29. Departamento de Informática do SUS. Projeção da população das Unidades da Federação por sexo e grupos de idade: 2000-2030. http://tabnet.datasus.gov.br/cgi/tabcgi.exe?ibge/cnv/projpopuf.def (accessed on 01/Apr/2021).
http://tabnet.datasus.gov.br/cgi/tabcgi.... . The exposure variables included age (years), sex, years of schooling (none, 1-7, 8-11, and 12 or more), marital status (single, married/stable union, widowhood/separated/divorced), skin color/race (white, black, brown, yellow, or indigenous), and geographic region of residence (North, Northeast, Southeast, South, or Central-West). Causes of death were classified according to genotype and ICD-10: HbSS (D57.0 - sickle cell anemia with crisis and D57.1 - Sickle cell anemia without crisis), and other genotypes, which include HbSC (D57.2 - Sickle cell/Hb-C disease), HbAS (D57.3 - sickle cell trait), HbS-beta (D57.4 - Sickle cell thalassemia), and D57.8 - Other sickle cell disorders ²⁸28. World Health Organization. ICD-10: international statistical classification of diseases and related health problems: tenth revision. https://apps.who.int/iris/handle/10665/42980 (accessed on 01/Jan/2019).
https://apps.who.int/iris/handle/10665/4... .

Statistical analysis

To describe the deaths, absolute and relative frequencies of sociodemographic variables and the median age at death (and interquartile range) according to genotype were estimated. Line graphs to assess the temporal trends of sickle cell disease mortality rates and the median age at death were built.

To identify changes in the magnitude or direction of the temporal trend of the mortality rates and median age at death, two different segmented regression models (called joinpoint) were performed - the first using Poisson distribution with the quasi-likelihood estimator (mortality rate) and the second using Gaussian distribution with maximum likelihood estimator (median age at death) ³⁰30. Muggeo VMR. Segmented: an R Package to fit regression models with broken-line relationships. R News 2008; 8:20-5.. The joinpoint regression model aims to identify one or more breakpoints in presence of change in the magnitude or direction of the time series and allows jointly estimating the beta coefficients for the different segments in time ³¹31. Kim HJ, Fay MP, Feuer EJ, Midthune DN. Permutation tests for joinpoint regression with applications to cancer rates. Stat Med 2000; 19:335-351.. Population was an offset for mortality rate, and the analysis was stratified by sex, region of residence, and age group. The median age at death was stratified by sex and region. The year was the linear predictor for both models. Then, the annual percent change (APC) defined by a constant percent variation per year during a time range in comparison to the previous year was estimated ³²32. Clegg LX, Hankey BF, Tiwari R, Feuer EJ, Edwards BK. Estimating average annual per cent change in trend analysis. Stat Med 2009; 28:3670-82.. Also, it was estimated the average annual percent change (AAPC), in order to summarize the trend over the study period 1996 to 2019, which allows comparisons among groups ³²32. Clegg LX, Hankey BF, Tiwari R, Feuer EJ, Edwards BK. Estimating average annual per cent change in trend analysis. Stat Med 2009; 28:3670-82.. APC and AAPC statistical significance were considered when the 95% confidence interval (95%CI) did not include zero ³²32. Clegg LX, Hankey BF, Tiwari R, Feuer EJ, Edwards BK. Estimating average annual per cent change in trend analysis. Stat Med 2009; 28:3670-82.. Comparisons among groups were valued when there was a difference of five or more percentage points in the AAPC estimates or an absence of overlap between their 95%CI.

The segmented packages of the R software, version 3.5.1 (http://www.r-project.org), were used for statistical analyses ³⁰30. Muggeo VMR. Segmented: an R Package to fit regression models with broken-line relationships. R News 2008; 8:20-5..

Results

Of 10,276 deaths caused by sickle cell disease in Brazil from 1996 to 2019, 468 were excluded due to other causes of death unrelated to sickle cell disease (ICD-10: D-05.7 ‒ other carcinoma in situ of breast) or individuals aged ≥ 70 years. Thus, the final sample totaled 9,808 deaths from sickle cell disease, 9,499 (96.8%) of which were HbSS, and 309 (3.2%) included other genotypes, such as HbSC (n = 52), HbAS (n = 39), HbS-beta (n = 1), and other sickle cell disorders (n = 217).

HbSS deaths were frequent in adults aged 20-39 years (43.3%), up to 7 years of schooling (59.2%), single (73.8%), brown skin color (53.4%), who lived in the Southeast (43.7%) and Northeast (31.9%) of Brazil. More than 40% of deaths from other genotypes occurred at the extremes of age: 21% in children and 23% in individuals 50 years or older (Table 1). The median age at death ranged from 20.5 in the North to 30.4 years in the South (Table 2).

From 2006 to 2019, the average mortality rate in Brazil was 2.2 deaths of sickle cell disease per one million inhabitants, highest values were found for individuals aged 20-29 years and those who lived in the South, the lowest in the North (Table 3). In the study period, there was an average annual increase of 4.6% in the mortality rate in Brazil due to sickle cell disease (AAPC = 4.58, 95%CI: 3.73; 5.43). The APC showed a 13% annual increase from 1996 to 2000 and subsequently reduced to 5% until 2010 (Table 3, Figure 1a). The trends were similar for both sexes (AAPC_Females = 4.68, 95%CI: 3.72; 5.65; AAPC_Males = 4.45, 95%CI: 3.25; 5.67) (Table 3, Figure 1b). All age groups and Brazilian regions showed an increase in the mortality rate (Figures 1c and 1d), with higher average annual percentage changes in individuals aged 30 years or more (AAPC₃₀ or + = 4.76, 95%CI: 3.47; 6.07) and those who lived in the North (AAPC_N = 5.76, 95%CI: 4.32; 7.22) and Northeast (AAPC_NE = 6.53, 95%CI: 5.45; 7.62) (Table 3). The latter presented a 12.3% annual increase in the mortality rate until 2006, the only region where it lasted until 2019, but with a lesser variation. In individuals aged 30 years or more, the mortality rate decreased after 2015 (Table 3, Figure 1d).

From 1998 to 2019, the median age at death increased annually by 24% in Brazil (AAPC = 23.73, 95%CI: 11.36; 37.47) (Table 3, Figure 2a). Although the AAPC was similar for both sexes (AAPC_Females = 34.34, 95%CI: 22.15; 47.75; AAPC_Males = 32.36, 95%CI: 19.23; 46.45), the period of the upward trend differed. Females had an annual increase of 93% from 2005 to 2010, and males had an annual increase of 43% from 2000 to 2019 (Table 3, Figure 2b). The South had the best survival improvement with an average annual increase of 59% (AAPC_S = 59.20, 95%CI: 12.81; 124.67) in the median age at death, markedly until 2009 (Table 3, Figure 2c).

Discussion

The study results showed an upward trend in the mortality rate from sickle cell disease in Brazil until 2010, accentuated in the Northern Brazil and those aged 30 or more years (1996 to 2019). Most deaths from sickle cell disease occurred in the second decade of life and the median age of death in Brazil increased by 24% from 1998 to 2019, more pronounced in the South and Southeast.

The upward trend in sickle cell disease mortality in Brazil in both sexes, all age groups, and regions may reflect the improvement in the quality of the mortality information system, particularly in the first decade of 2000 ³³33. Frias PG, Szwarcwald CL, Lira PIC. Avaliação dos sistemas de informações sobre nascidos vivos e óbitos no Brasil na década de 2000. Cad Saúde Pública 2014; 30:2068-80.. Previous Brazilian studies suggest that neonatal screening for sickle cell disease did not improve its access and quality of care and, consequently, has had no effect on mortality from this disease ¹⁹19. Lobo CLDC, Nascimento EMD, Jesus LJCD, Freitas TGD, Lugon JR, Ballas SK. Mortality in children, adolescents and adults with sickle cell anemia in Rio de Janeiro, Brazil. Rev Bras Hematol Hemoter 2018; 40:37-42.^,2424. Lima ARG, Ribeiro VS, Nicolau DI. Trends in mortality and hospital admissions of sickle cell disease patients before and after the newborn screening program in Maranhão, Brazil. Rev Bras Hematol Hemoter 2015; 37:12-6.^,3434. Sabarense AP, Lima GO, Silva LML, Viana MB. Characterization of mortality in children with sickle cell disease diagnosed through the Newborn Screening Program. J Pediatr 2015; 91:242-7.^,3535. Sabarense AP, Lima GO, Silva LML, Viana MB. Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil. Paediatr Int Child Health 2015; 35:329-32.^,3636. Wang WC. Newborn screening for sickle cell disease: necessary but not sufficient. J Pediatr (Rio J.) 2015; 91:210-2.. On the other hand, international studies suggest a downward trend in the mortality rate, particularly among children under five years of age ²⁴24. Lima ARG, Ribeiro VS, Nicolau DI. Trends in mortality and hospital admissions of sickle cell disease patients before and after the newborn screening program in Maranhão, Brazil. Rev Bras Hematol Hemoter 2015; 37:12-6.^,3737. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood 2010; 115:3447-52..

A study in the United States identified a reduction in the mortality rate of children and adolescents from 1983 to 2002, more pronounced among children under three years of age (68% reduction, 95%CI: 58; 75) and progressively lower in children aged 4-14 years ²²22. Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr 2009; 154:541-5.. Although the authors had attributed this reduction to the universal access to the newborn screening programs for hemoglobinopathies and the prophylactic penicillin, only one retrospective cohort study conducted in Jamaica provided robust evidence on the performance of newborn screening, followed by measures to prevent infection and orient parents about the disease ³⁸38. King L, Fraser R, Forbes M, Grindley M, Ali S, Reid M. Newborn sickle cell disease screening: the Jamaican experience (1995-2006). J Med Screen 2007; 14:117-22.^,3939. Runkel B, Klüppelholz B, Rummer A, Sieben W, Lampert U, Bollig C, et al. Screening for sickle cell disease in newborns: a systematic review. Syst Rev 2020; 9:250..

From 1990 to 2015, general mortality rate decreased in all regions and age groups in Brazil, and higher decreases occurred among children under 15 years of age ⁴⁰40. França E, Passos V, Malta D, Duncan B, Ribeiro A, Guimarães M, et al. Cause-specific mortality for 249 causes in Brazil and states during 1990-2015: a systematic analysis for the global burden of disease study 2015. Popul Health Metr 2017; 15:39.^,4141. Szwarcwald CL, Almeida WS, Teixeira RA, França EB, Miranda MJ, Malta DC. Inequalities in infant mortality in Brazil at subnational levels in Brazil, 1990 to 2015. Popul Health Metr 2020; 18(Suppl 1):4.. However, our results suggested that individuals with sickle cell disease did not benefit from poverty reduction, improvement in access to health services, and quality of life observed in Brazil ⁴²42. Cohen R, Alfonso Y, Adam T, Kuruvilla S, Schweitzer J, Bishai D. Country progress towards the Millennium Development Goals: adjusting for socioeconomic factors reveals greater progress and new challenges. Global Health 2014; 10:67..

The National Neonatal Screening Program in Brazil encompasses six diseases, including sickle cell disease and other hemoglobinopathies that were first screened in 2001 ⁴³43. Jesus JA. A implantação do Programa de Doença Falciforme no Brasil. BIS, Bol Inst Saúde (Impr) 2011:107-13.. In 2005, the coverage rate reached 80%, but only in 2013, a universal access to screening for sickle cell disease was implemented in all regions of the country ⁴⁴44. Silva-Pinto AC, Queiroz MCA, Zamaro PJA, Arruda M, Santos HP. The Neonatal Screening Program in Brazil, focus on sickle cell disease (SCD). Int J Neonatal Screen 2019; 5:11.. However, access to these tests in different regions of Brazil was unequal. São Paulo, Minas Gerais, and Rio de Janeiro were the first states to universalize access to the diagnosis of sickle cell disease, whereas the states in the North and Northeast regions were the last ⁴⁴44. Silva-Pinto AC, Queiroz MCA, Zamaro PJA, Arruda M, Santos HP. The Neonatal Screening Program in Brazil, focus on sickle cell disease (SCD). Int J Neonatal Screen 2019; 5:11.. This disparity might explain the higher increase in the mortality due to sickle cell disease in the North and Northeast compared to the Southeast.

After 2010, the mortality rate of sickle cell disease stabilized in Brazil, except in the Southeast, which presented a slight decrease. The latter might relate to the approval and access regulation of hydroxyurea in the public health system ¹⁵15. Ministério da Saúde. Portaria nº 872, de 06 de novembro de 2002. Aprova o Protocolo clínico e diretrizes terapêuticas da doença Falciforme (Hidroxiuréia). Diário Oficial da União 2002; 8 nov.^,4545. Freitas SLF, Ivo ML, Figueiredo MS, Gerk MAS, Nunes CB, Monteiro FF. Quality of life in adults with sickle cell disease: an integrative review of the literature. Rev Bras Enferm 2018; 71:195-205.^,4646. Wang CJ, Kavanagh PL, Little AA, Holliman JB, Sprinz PG. Quality-of-care indicators for children with sickle cell disease. Pediatrics 2011; 128:484-93.^,4747. Maximo C, Olalla Saad ST, Thome E, Queiroz AMM, Lobo C, Ballas SK. Amputations in sickle cell disease: case series and literature review. Hemoglobin 2016; 40:150-5.. Evidence suggests that hydroxyurea has improved hematological parameters and reduced hospitalizations and deaths ⁴⁸48. Meremikwu MM, Okomo U. Sickle cell disease. BMJ Clin Evid 2016; 2016:2402.^,4949. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033-48.. Despite efforts to expand access and improve the quality of care, the treatment of sickle cell disease is still restricted to blood centers in Brazilian capitals.

From 1998 to 2016, an increase of 9.6 years occurred in the median age at death from sickle cell disease in Brazil, reaching 31 years. A multicenter study carried out in the United States from 1978 to 1998 showed a median of 48 years for females and 42 years for males with the HBSS genotype and 68 and 60 years for females and males with the HbSC genotype ⁵⁰50. Maitra P, Caughey M, Robinson L, Desai PC, Jones S, Nouraie M, et al. Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe. Haematologica 2017; 102:626-36.^,5151. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330:1639-44.. Another study revealed that the median age at death increased from 28 to 46 years from 1979 to 2017 ⁵²52. Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, et al. Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann Emerg Med 2020; 76(3S):S28-S36., showing Brazil’s disadvantage compared to developed countries like the United States and the United Kingdom ⁴4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010.^,5252. Payne AB, Mehal JM, Chapman C, Haberling DL, Richardson LC, Bean CJ, et al. Trends in sickle cell disease-related mortality in the United States, 1979 to 2017. Ann Emerg Med 2020; 76(3S):S28-S36..

Brazil has more than 100,000 cases of sickle cell disease ⁷7. Cançado RD, Jesus JA. A doença falciforme no Brasil. Rev Bras Hematol Hemoter 2007; 29:203-6.^,5151. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330:1639-44., showing an incidence of approximately 1:1,000 live births ⁷7. Cançado RD, Jesus JA. A doença falciforme no Brasil. Rev Bras Hematol Hemoter 2007; 29:203-6., comparatively lower than in the United States (1:360) ⁴4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010.. The worse indicators in Brazil are probably related to lack of treatment access and restricted hematology services, as well as a delay in the use of new technologies in the Brazilian Unified National Health System (SUS), such as hydroxyurea, recommended for treatment since 2002, but freely available only in 2010.

One of the study strengths is the universal recording of the SIM, a tool for health surveillance in Brazil ⁵³53. Ministério da Saúde. Manual de procedimento do sistema de informações sobre mortalidade. Brasília: Ministério da Saúde; 2001. that may allow the generalizability of results. The trend analysis on mortality by the Joinpoint regression covered more than 20 years, including the period before and after implementing diagnosis and treatment for sickle cell disease in Brazil and explored demographic and regional heterogeneities. Moreover, the joinpoint regression model is a user-friendly statistical technique with simple interpretation ³⁰30. Muggeo VMR. Segmented: an R Package to fit regression models with broken-line relationships. R News 2008; 8:20-5..

Although previous studies have assessed mortality from sickle cell disease in Brazil, most have used hospital samples in referral centers ¹¹11. Loureiro MM, Rozenfeld S. Epidemiology of sickle cell disease hospital admissions in Brazil. Rev Saúde Pública 2005; 39:943-9.^,5454. Figueiredo JO. Morbidade e mortalidade por doença falciforme em Salvador, Bahia [Masters Thesis]. Salvador: Universidade Federal da Bahia; 2016.^,5555. Araujo OMR, Ivo ML, Ferreira Júnior MA, Pontes ERJC, Bispo IMGP, Oliveira ECL. Survival and mortality among users and non-users of hydroxyurea with sickle cell disease. Rev Latinoam Enferm 2015; 23:67-73.^,5656. Santo AH. Sickle cell disease related mortality in Brazil, 2000-2018. Hematol Transfus Cell Ther 2022; 44:177-85.. Compared to two recent studies ⁹9. Dias MGR. Mortalidade por doença falciforme no Brasil: estudo retrospectivo (1996-2016). https://www.ciencianews.com.br/arquivos/ACET/IMAGENS/biblioteca-digital/hematologia/serie_vermelha/anemia_falciforme/54.pdf (accessed on 13/Sep/2021).
https://www.ciencianews.com.br/arquivos/... ^,5656. Santo AH. Sickle cell disease related mortality in Brazil, 2000-2018. Hematol Transfus Cell Ther 2022; 44:177-85., our study covered a broader period, assessing the time before and after the adoption of policies targeting sickle cell disease, relevant to describe their effect and potential inequalities across sex, ages, and regions of Brazil.

Limitations include potential classification bias related to the cause of deaths, in the population used to estimate mortality rate as well as to the ecological design. The SIM is subject to classification errors in the cause of death, which was minimized by considering the recording of sickle cell disease in any field on the death certificate. Despite being used in previous studies ²⁴24. Lima ARG, Ribeiro VS, Nicolau DI. Trends in mortality and hospital admissions of sickle cell disease patients before and after the newborn screening program in Maranhão, Brazil. Rev Bras Hematol Hemoter 2015; 37:12-6.^,5757. Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, et al. Defining sickle cell disease mortality using a population-based surveillance system, 2004 through 2008. Public Health Rep 2016; 131:367-75., the general population incorrectly estimated individuals at risk of death from sickle cell disease. Studies in the United States and Europe use the Afro-descendant population, mostly affected by this genetic hemoglobinopathy ⁴4. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers 2018; 4:18010.. Alternatively, one study estimated the at-risk population using population-based records of sickle cell disease surveillance ⁵⁷57. Paulukonis ST, Eckman JR, Snyder AB, Hagar W, Feuchtbaum LB, Zhou M, et al. Defining sickle cell disease mortality using a population-based surveillance system, 2004 through 2008. Public Health Rep 2016; 131:367-75.. However, Brazil lacks more accurate estimates of the population affected by this hemoglobinopathy and is hampered by miscegenation, heterogeneity in the coverage of screening programs, and potential disparities in the incidence of this disease across country regions. Moreover, since this was an ecological study, it does not allow inferring the effects of the specific public health actions on mortality of sickle cell disease ⁵⁸58. Lima-Costa MF, Barreto SM. Tipos de estudos epidemiológicos: conceitos básicos e aplicações na área do envelhecimento. Epidemiol Serv Saúde 2003; 12:189-201..

Conclusions

In conclusion, our study showed an increase in the mortality rate and that the gain observed in survival with sickle cell disease in Brazil was lower than in developed countries, particularly for patients who live in the North or Northeast regions. Thus, government measures to expand the diagnosis and treatment of sickle cell disease in Brazil must be improved and put in force in a decentralized manner. These findings can contribute to the management of resources for these patients of the SUS. Future studies may assess hospitalizations for sickle cell disease to investigate factors related to the quality of hospital care for individuals with this hemoglobinopathy.

Acknowledgments

This study was partly financed by the Brazilian Graduate Studies Coordinating Board (CAPES; finance code 001), by the Institutional Internationalization Program (PrInt) and, supported by Estácio de Sá University (productivity scholarship). The funders had no role in study design, data collection, and analysis or preparation of the manuscript.

References

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