Abstracts
Introduction:
There are few studies that investigated whether Down syndrome (DS) interferes with references values for complete blood counts (CBC) test in children with the syndrome.
Objective:
This study aimed to analyze the results of CBC performed in children with DS.
Patients and methods:
Data from CBC of DS children were included; at the time of examination they were aged between 2 and 10 years and had no clinical signs and/or symptoms of infectious disease. The hematological parameters analyzed were: total number of erythrocytes (RBC), hemoglobin (Hb) concentration, hematological indices, platelet count, and total number of leucocytes. Additionally, we compared the collected parameters according to gender and age of the children studied.
Results:
A total of 203 CBC (100 girls and 103 boys) were evaluated. In general, no significant differences were observed in studied parameters between the values found in samples of DS children and the values described in the literature as a reference for children in this age group. No difference in the prevalence of anemia was observed in relation to gender (p = 0.33), 14/103 (13.6%) boys, and 11/100 (11%) girls had anemia. However, the Hb and hematological indices values found in boys was significantly lower than in girls (p < 0.001).
Conclusion:
This investigation is the first one in Brazil to present and analyze the CBC results of DS children, reporting that their hematological indices are within the expected range for children without DS. Additionally, it was found that 12.3% of them had anemia.
Down syndrome; hematological parameters; blood counts; anemia
Introdução:
São escassos os estudos que investigaram se a síndrome de Down (SD) interfere nos valores de referência para a avaliação do hemograma em crianças com a síndrome.
Objetivos:
Analisar os resultados dos hemogramas realizados em crianças com SD.
Casuística e métodos:
Foram incluídos os dados retirados dos hemogramas realizados em crianças com SD que, no momento do exame, tinham idade entre 2 e 10 anos e não apresentavam no exame clínico sinais e/ou sintomas de doença infecciosa. Os parâmetros hematológicos analisados foram número total de eritrócitos, concentração de hemoglobina (Hb), índices hematimétricos e número total de plaquetas e de leucócitos. Adicionalmente, foram comparados os parâmetros coletados em relação ao gênero e à idade das crianças estudadas.
Resultados:
No total, foram avaliados 203 hemogramas (100 meninas e 103 meninos). De maneira geral, comparando-se os valores encontrados nas amostras das crianças com SD e os valores já descritos na literatura como sendo de referência para crianças nessa faixa etária, não foram observadas diferenças significativas nos parâmetros estudados. Não se observou diferença na prevalência de anemia em relação aos gêneros (p = 0,33), sendo 14/103 (13,6%) meninos e 11/100 (11%) meninas com anemia. No entanto, na comparação entre os gêneros, observou-se que os meninos apresentaram Hb e índices hematimétricos significativamente menores que as meninas (p < 0,001).
Conclusão:
Esta investigação é pioneira no Brasil ao apresentar e analisar os resultados dos hemogramas das crianças com SD, relatando que seus índices hematológicos encontram-se dentro do esperado para crianças sem a SD. Adicionalmente, foi possível verificar que 12,3% delas apresentavam anemia.
Síndrme de Down; parâmetros hematológicos; hemograma; anemia
INTRODUCTION
Down's syndrome (DS), also known as trisomy 21, is the most common chromosomal change in
the world population, where about one in every 700 live births may have the
syndrome(11 Yang Q, Rasmussen AS, Friedman JM. Mortality associated with Down's
syndrome in the USA from 1983 to 1997: a population-based study. Lancet, Atlanta.
[Internet]. 2002; 359. Available at:
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08092-3/fulltext.
http://www.thelancet.com/journals/lancet...
).
At birth and during the first years of life, a Down child has already several health problems, among which the most important include congenital heart defect, hypotonia, hearing loss, thyroid disorders, and increased susceptibility to infections. Over the years, the clinical manifestations described in DS patients are similar to those of aging process, with higher prevalence of bacterial and viral infections, autoimmune diseases, and early progression to dementia, after 40 years of age. Due to these features, DS was long considered as a progeroid disease(22 Nisihara R, Massuda PH, Lupianes PM. Aspectos imunológicos da síndrome de Down. Rev Bras Clin Med. 2014;12(3):246-51.). Furthermore, respiratory tract infections are common, and may become recurrent, and still constitute a major cause of death for all ages(33 Bloemers BLP, Broers CJM Bont L, et al. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect. 2010;12:799-808.).
Currently, the most accepted hypothesis is that morphological changes of the thymus are
the main causes of immune abnormalities. The thymus is a primary lymphoid organ
responsible for the differentiation, selection and maturation of T lymphocytes. As a
result, it appears that thymic alterations observed in patients with DS affect the T
lymphocytes function, also causing an imbalance in the cytokine network(33 Bloemers BLP, Broers CJM Bont L, et al. Increased risk of respiratory
tract infections in children with Down syndrome: the consequence of an altered immune
system. Microbes Infect. 2010;12:799-808.,
44 Lima FA, Sampaio MC. O papel de timo no desenvolvimento do sistema
imune. Pediatria [Internet]. 2007;29(1):33-42. Available at:
http://pediatriasaopaulo.usp.br/upload/pdf/1200.pdf.
http://pediatriasaopaulo.usp.br/upload/p...
). DS fetuses shows changes of the
parameters used in the evaluation of thymic function: abnormal thymic anatomy and low
lymphocyte T receptor excision circles (TREC) count, which are used as thymic function
markers. This is likely to occur because some controlling genes of division and
proliferation of thymocytes are present on chromosome 21. It is not yet entirely clear,
but it is possible that in addition to abnormalities of the thymus, T and B lymphocytes
are also functionally defective(44 Lima FA, Sampaio MC. O papel de timo no desenvolvimento do sistema
imune. Pediatria [Internet]. 2007;29(1):33-42. Available at:
http://pediatriasaopaulo.usp.br/upload/pdf/1200.pdf.
http://pediatriasaopaulo.usp.br/upload/p...
,
55 Kusters MA, Verstegen MHJ, De Vries E. Down syndrome: is it really
characterized by precocious immunosenescence? Aging Dis. 2011;2(6).).
Anemia are considered common diseases in all countries, mainly affecting children and
pregnant women, especially in developing countries(66 Rodrigues VC, Mendes BD, Gozzi A, et al. Deficiência de ferro,
prevalência de anemia e fatores associados em crianças de creches públicas do oeste
do Paraná, Brasil. Rev Nutr, Campinas. [Internet]. 2011;24(3). Available at:
http://www.scielo.br/scielo.php?script=sci_arttextπ
d=S1415-52732011000300004.
http://www.scielo.br/scielo.php?script=s...
). Some authors have shown that DS children are more
predisposed to develop hematological disorders, such as anemia. This may be related to
the involvement of genes located on chromosome 21, participants of folate-methylation
cycle, an essential component for the hemoglobin formation and deoxyribonucleic acid
(DNA) synthesis(77 Trotta MBF, Azul JBS, Wajngarten M, et al. Inflammatory and
Immunological parameters in adults with Down syndrome. Immun Ageing. [Internet].
2011;8(4). Available at:
http://www.biomedcentral.com/content/pdf/1742-4933-8-4.pdf.
http://www.biomedcentral.com/content/pdf...
). Some of
these genes are responsible for coding protein and ribonucleic micro acid (RNAs), and
changes may promote not only impair to hematopoietic system, but also change the
differentiation of hematopoietic cells(88 Roberts I, O'connor D, Roy A, et al. The impact of trisomy 21 on foetal
haematopoiesis. Blood Cells Mol Dis. [Internet]. 2013;51(4):277-81. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23932236.
http://www.ncbi.nlm.nih.gov/pubmed/23932...
). Roberts et al.(88 Roberts I, O'connor D, Roy A, et al. The impact of trisomy 21 on foetal
haematopoiesis. Blood Cells Mol Dis. [Internet]. 2013;51(4):277-81. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23932236.
http://www.ncbi.nlm.nih.gov/pubmed/23932...
) suggest that trisomy impacts in a
complex way on the biology of hematopoietic progenitor cells, disrupting their growth
and differentiation during the embryonic stage. It is it possible that such disorders
would require changes in cells counts in a test such as complete blood counts (CBC).
Therefore, it is estimated that DS children are 10% to 20% more likely of developing
leukemia and myeloproliferative diseases than those without the
syndrome(99 Lange B. The management of neoplastic desorders of haematopoiesis in
children with Down's syndrome. British Journal of Hematology. [Internet]. 2000; 110:
512-24. Available at:
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2000.02027.x/pdf.
http://onlinelibrary.wiley.com/doi/10.10...
).
Only few studies have investigated whether DS interfere with reference ranges for the assessment of CBC in children with the syndrome. There are no studies in Brazil that show the prevalence of anemia in DS children.
OBJECTIVE
This study aimed to analyze the results of CBC performed in children with DS who did not show any symptoms of viral or bacterial infection at the time of the examination.
PATIENTS AND METHODS
This study was approved by the Ethics Committee on Human Research of Positivo University (Comitê de Ética em Pesquisa em Seres Humanos da Universidade Positivo [CEP/UP], mumber 667.592/2014). The study presents cross-sectional, observational and analytical design with historical data collection, carried out from May to July 2014. Clinical and demographic data were collected by review of medical records. All patients were seen at the pediatric clinic of a single pediatrician who is a reference for DS children care in Curitiba (PR), assisting patients by covenant and private health care.
The study included data taken from CBC, automated methodology with slides review, performed in children diagnosed with DS and confirmed by karyotype, which at the time of examination were aged between 2 and 10 years and had no signs and symptoms infectious disease at the time of clinical examination.
Children who were not in the stipulated age group and those that at the time of medical appointment presented symptoms of viral or bacterial infection or any complaints that could clearly affect the CBC results, were considered exclusion criteria for participation in the study.
The tests were performed on clinical laboratories in the city of Curitiba (PR), through automated blood cell counting method, using manual analysis as a routine tool to confirm erythrocyte indices changes on slides. Hematological parameters analyzed on the CBC reports were: total number, hemoglobin (Hb) concentration, packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, and total number of leukocytes. In addition, an analysis comparing the parameters evaluated in relation to gender and age of the studied children was performed.
Data were submitted in tabular form to statistical analysis, and Kolmogorov-Smirnov test, chi-squared test, Fisher's p test, and Mann-Whitney test were performed using Prisma 4.0 Program. We considered significant values less than p < 0.05.
RESULTS
A total of 203 CBC were evaluated, including 103 boys and 100 girls with DS, with mean age of 4.3 ± 2.08 years (between 2 and 10 years). The data found in this study were compared with those already established in the literature as a reference(1010 Greer MK, Foerster J, Rodgers GM, et al. Whintrobe, clinical hematology. Vol. l. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.) for children without DS at the same age group. In general, it was observed that the erythrocyte values found in samples from DS children are similar to those described for children without DS(1010 Greer MK, Foerster J, Rodgers GM, et al. Whintrobe, clinical hematology. Vol. l. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.). The mean of total erythrocyte count was 4.63 × 106 ± 0.45 cells/mm3. The mean total leukocyte count was 7300.5 ± 2893.92 cells/mm3. The mean hemoglobin was 13.7 ± 1.59 g/dl and the hematological indices, MCV, MCH and MCHC were close/similar to the values reported for children without DS of the same age(1010 Greer MK, Foerster J, Rodgers GM, et al. Whintrobe, clinical hematology. Vol. l. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.), the same occurs with the total number of platelet count (Table 1).
The values found for all parameters were similar for both genders (Table 2). There was no significant difference in prevalence of anemia in relation to gender (p = 0.33), and 14/103 (13.6%) boys and 11/100 (11%) girls had anemia. However, it was observed that boys presented Hb concentration levels and hematological indices significantly lower than girls (p < 0.001). The exception were the MCHC values, for which there was no significant difference (p = 0.76). Table 3 shows that 25/203 (12.3%) of the studied children had anemia, and average age of 3.3 ± 1.28 years (between 2 and 6 years) in this group. Among girls with anemia, 6/11 (54.5%) were younger than two years of age. Concerning the boys, prevalence of age regarding the presence of the condition was not observed. When evaluating the hematological indices of patients with anemia, it was found that 5/25 (20%) presented microcytic hypochromic anemia, while the other 80% presented normocytic normochromic anemia. As expected, increasing age resulted in increased hemoglobin values in children. However, the same does not apply to the number of leukocytes, since it does not significantly change with increasing age.
DISCUSSION
Although the number of children born per woman in recent years has significantly
decreased, the birth rate of DS children remains constant(1212 Mccabe LL, Mccabe ER. Down syndrome: issues to consider in a national
registry, research database and biobank. Mol Genet Metab. [Internet]. 2011; 104.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21501965.
http://www.ncbi.nlm.nih.gov/pubmed/21501...
). This is, in part, due to the
increase of average maternal age observed in the population(1212 Mccabe LL, Mccabe ER. Down syndrome: issues to consider in a national
registry, research database and biobank. Mol Genet Metab. [Internet]. 2011; 104.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21501965.
http://www.ncbi.nlm.nih.gov/pubmed/21501...
). Because of the increased knowledge
on all aspects involving the syndrome, in the last two decades the life expectancy of
individuals with DS exceeds double(1212 Mccabe LL, Mccabe ER. Down syndrome: issues to consider in a national
registry, research database and biobank. Mol Genet Metab. [Internet]. 2011; 104.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21501965.
http://www.ncbi.nlm.nih.gov/pubmed/21501...
).
DS is a challenge for the clinician due to the diverse and complex health problems that affect the SD child, so the appropriate care to this type of patient regards constant attention and awareness of possible complications. It is also known that in childhood, a major complication is related to the number of recurrent infections, especially pneumonia, which can result in serious damage to the patient. Many authors have investigated the SD patient's immune system, mainly focusing on the cellular functions and humoral response(55 Kusters MA, Verstegen MHJ, De Vries E. Down syndrome: is it really characterized by precocious immunosenescence? Aging Dis. 2011;2(6).). Few studies have addressed the presence of anemia in this population. Also there are few studies that provide parameters for laboratory tests interpretation for DS children.
The World Health Organization (WHO)(1313 World Health Organization. Preventing and controlling iron deficiency
anaemia through primary health care: a guide for health administrators and programme
managers. Geneva; 1989. Available at:
http://apps.who.int/iris/bitstream/10665/39849/1/9241542497_eng.
pdf?ua=1
http://apps.who.int/iris/bitstream/10665...
) defines anemia when the Hb content is below normal values for
the age, gender, physiological status, and altitude. The main signs that characterize it
are skin and mucosal changes, in addition to gastrointestinal and metabolic symptoms,
such as fatigue, palpitations, weakness, growth reduction, and reduction of cognitive
function; moreover, it can also affect immunity and thermoregulation(1414 Cook JD, Skikne BS, Baynes RD. Iron deficiency: the global perspective.
In: Hershko C, Koninjin AM, Aisen P, editors. Progress in iron research: advances in
experimental medicine and biology. New York: Plenum Press; 1994. p.
219-28.,
1515 Oski FA. Iron deficiency in infancy and childhood. N Engl J Med.
1993;329:190-4.). Anemic children may have delayed
neuromotor development that does not change, even after prolonged
treatment(1515 Oski FA. Iron deficiency in infancy and childhood. N Engl J Med.
1993;329:190-4.,
1616 Silva APR, Camargos CN. Fortificação de alimento: instrumentos eficazes
no combate a anemia ferropriva? Comun Ciênc Saúde. 2006;16(1):53-61.). It is worthful to mention that
some of these symptoms can be confused with those observed in the spectrum of DS
characteristics.
WHO estimates that in developing countries half of children under the age 4 years
present anemia. In the study of Rodrigues et al.(66 Rodrigues VC, Mendes BD, Gozzi A, et al. Deficiência de ferro,
prevalência de anemia e fatores associados em crianças de creches públicas do oeste
do Paraná, Brasil. Rev Nutr, Campinas. [Internet]. 2011;24(3). Available at:
http://www.scielo.br/scielo.php?script=sci_arttextπ
d=S1415-52732011000300004.
http://www.scielo.br/scielo.php?script=s...
), which investigates 256 children in 25
of early childhood education municipal centers (centros municipais de educação infantil
[CMEI]) in the city of Cascavel (PR), aged from 6 to 24 months, of both genders, the
prevalence of anemia was 29.7%. According to Monteiro et
al.(1717 Monteiro CA, Szarfarc SC. Estudo das condições de saúde das crianças no
Município de São Paulo, SP (Brasil), 1984-1985. Rev Saúde Pública.
1987;21(3):255-60.) there
is no data on the exact scale of the problem. These authors investigated 912 children
under the age of five years in São Paulo and showed that in the 1980s the prevalence of
anemia was 35.6%, increasing to 47.8% in the 90s. In 2001, Silva et
al.(1818 Silva LSM, Giugliane ERJ, Aerts DRGC. Prevalência e determinantes de
anemia em crianças de Porto Alegre-RS. Rev Saúde Pública.
2001;35(1):66-73.) studied
557 children between 0-36 months of age in municipal schools of Porto Alegre (RS) and
reported the presence of anemia in 47.8%. Santos et
al.(1919 Santos I, Cesar JÁ, Minten G, et al. Prevalência e fatores associados à
ocorrência de anemia entre menores de seis anos de idade em Pelotas, RS. Rev Bras
Epidemiol. 2004;7(4).)
investigated 306 children under the age of 6 years who were part of communities served
by the Ministry for Children (Pastoral da Criança), on the outskirts of Pelotas (RS),
and reported prevalence of anemia in 53% of them. In this study, we was observed that
12.3% (25/203) of the patients had anemia, with 14/103 boys and 11/100 girls. All
children with anemia were aged between 2 and 6 years, showing that this would be the age
group with higher risk. This fact is demonstrated in the study of Santos et
al.(1919 Santos I, Cesar JÁ, Minten G, et al. Prevalência e fatores associados à
ocorrência de anemia entre menores de seis anos de idade em Pelotas, RS. Rev Bras
Epidemiol. 2004;7(4).), with
the children from Pelotas (RS); the authors also showed that among children under the
age of 12 months, the prevalence was 81.1%, falling to 75.5% among children between
12-24 months of age, for 60.3% in the third year of life, 41.5% in the fourth year,
40.4% in the fifth, and 25.6% in the sixth year of age.
In southern Brazil, Neumann et al.(2020 Neuman NA, Tanaka OU, Szarfarc SC, et al. Prevalência e fatores de risco
para anemia no Sul do Brasil. Rev Saúde Pública. 2000;34(1):56-63.) observed a prevalence of 30.8% of anemia in 476
children studied. In Israel, Tenenbaun et al.(2121 Tenenbaum A, Malkiel S, Wexler ID, et al. Anemia in children with down
syndrome. Int J Pediatr. [Internet]. 2011. Available at:
http://www.hindawi.com/journals/ijpedi/2011/813541/.
http://www.hindawi.com/journals/ijpedi/2...
) have established that 8.1% of
children and adolescents with DS (n = 149) had anemia, such prevalence
did not differ much of the studied population. It is important to emphasize that the
sample analyzed in this study consisted of patients from pediatric office attended by
covenant and private health care.
Studies carried out in different locations and populations indicated high prevalence of iron deficiency anemia in Brazil. Unlike to malnutrition, the prevalence of iron deficiency anemia has increased in recent decades(2222 Cardoso JL, Santos MJD, Colossi MCJ. Anemia ferropriva e deficiência de ferro em crianças e fatores determinantes. Revista de Nutrologia. 2008;1(2):78-83.). According to the present study records, PCV and Hb levels of the boys was lower than that observed in girls. Prado et al.(2323 Prado MB, Mestrinheri L, Frangella GS, et al. Acompanhamento nutricional de pacientes com síndrome de Down atendidos em um consultório pediátrico. Mundo de Saúde. 2009;335-46.) reported in 2009, in the state of São Paulo, the anthropometric profile of 187 DS children, asserting that 80.2% of them had low weight and height in relation to age in both sexes, but more frequent among boys. In addition, the study determined that males have higher nutritional needs than females. Moreira et al.(2424 Moreira GC, Raimundo DF, Pereira Netto M. Avaliação do estado nutricional de crianças com síndrome de Down da APAE/Escola Estadual Walter Vasconcelos de crianças especiais do município de Muriaé-MG. Rev Científica da FAMINAS. 2007;3.), evaluated 17 DS children aged between 3-18 years in Minas Gerais, they showed that 12% of girls were overweight and 6% of boys were low-weight.
According to current knowledge, the total number of leukocytes of a child under 13 years
of age range from 4000-11000 cells/mm3(1111 Hoffbrand AV, Moss PAH. Fundamentos em hematologia. 6th ed. Porto
Alegre: Artmed; 2013.). There are few authors who have investigated the number of
leukocyte in the DS. Boy et al.(2525 Boy R, Neto JGB, Fontana C, et al. Síndrome de Down - análise clínica,
citogenética e epidemiológica de 165 casos. J Pediat. [Internet]. 1995;71(2):88-92.
Available at: http://www.jped.com.br/conteudo/95-71-02-88/port.pdf.
http://www.jped.com.br/conteudo/95-71-02...
) studied 165 DS children in 1995 and reported that
13.6% of them had leukopenia (< 5.000 cells/mm3). In this study, the
average number of leukocytes for children from 2-10 years of age was 7300 ± 2893
cells/mm3, which is within the parameters defined as normal white blood
cell (WBC) count for children without DS. In addition, we observed no change in
leukocyte values in relation to increasing age.
In the present study, due to the sample size, we decided not to evaluate the differential CBC count, since it suffers greater influence of age and other uncontrollable conditions, such as allergies, worm infestation, and viruses, which can cause difficulties in interpreting and analysis of data.
CONCLUSION
This research is the first in Brazil to present and analyze the CBC results of DS children, reporting that, despite all the changes caused by the syndrome, their hematological indexes are within the expected range for the same age children without DS. Additionally, we found that 12.3% of them had anemia.
-
1Yang Q, Rasmussen AS, Friedman JM. Mortality associated with Down's syndrome in the USA from 1983 to 1997: a population-based study. Lancet, Atlanta. [Internet]. 2002; 359. Available at: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08092-3/fulltext.
» http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(02)08092-3/fulltext -
2Nisihara R, Massuda PH, Lupianes PM. Aspectos imunológicos da síndrome de Down. Rev Bras Clin Med. 2014;12(3):246-51.
-
3Bloemers BLP, Broers CJM Bont L, et al. Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system. Microbes Infect. 2010;12:799-808.
-
4Lima FA, Sampaio MC. O papel de timo no desenvolvimento do sistema imune. Pediatria [Internet]. 2007;29(1):33-42. Available at: http://pediatriasaopaulo.usp.br/upload/pdf/1200.pdf.
» http://pediatriasaopaulo.usp.br/upload/pdf/1200.pdf -
5Kusters MA, Verstegen MHJ, De Vries E. Down syndrome: is it really characterized by precocious immunosenescence? Aging Dis. 2011;2(6).
-
6Rodrigues VC, Mendes BD, Gozzi A, et al. Deficiência de ferro, prevalência de anemia e fatores associados em crianças de creches públicas do oeste do Paraná, Brasil. Rev Nutr, Campinas. [Internet]. 2011;24(3). Available at: http://www.scielo.br/scielo.php?script=sci_arttextπ d=S1415-52732011000300004.
» http://www.scielo.br/scielo.php?script=sci_arttextπ d=S1415-52732011000300004 -
7Trotta MBF, Azul JBS, Wajngarten M, et al. Inflammatory and Immunological parameters in adults with Down syndrome. Immun Ageing. [Internet]. 2011;8(4). Available at: http://www.biomedcentral.com/content/pdf/1742-4933-8-4.pdf.
» http://www.biomedcentral.com/content/pdf/1742-4933-8-4.pdf -
8Roberts I, O'connor D, Roy A, et al. The impact of trisomy 21 on foetal haematopoiesis. Blood Cells Mol Dis. [Internet]. 2013;51(4):277-81. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23932236.
» http://www.ncbi.nlm.nih.gov/pubmed/23932236 -
9Lange B. The management of neoplastic desorders of haematopoiesis in children with Down's syndrome. British Journal of Hematology. [Internet]. 2000; 110: 512-24. Available at: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2000.02027.x/pdf.
» http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2141.2000.02027.x/pdf -
10Greer MK, Foerster J, Rodgers GM, et al. Whintrobe, clinical hematology. Vol. l. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.
-
11Hoffbrand AV, Moss PAH. Fundamentos em hematologia. 6th ed. Porto Alegre: Artmed; 2013.
-
12Mccabe LL, Mccabe ER. Down syndrome: issues to consider in a national registry, research database and biobank. Mol Genet Metab. [Internet]. 2011; 104. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21501965.
» http://www.ncbi.nlm.nih.gov/pubmed/21501965 -
13World Health Organization. Preventing and controlling iron deficiency anaemia through primary health care: a guide for health administrators and programme managers. Geneva; 1989. Available at: http://apps.who.int/iris/bitstream/10665/39849/1/9241542497_eng. pdf?ua=1
» http://apps.who.int/iris/bitstream/10665/39849/1/9241542497_eng. pdf?ua=1 -
14Cook JD, Skikne BS, Baynes RD. Iron deficiency: the global perspective. In: Hershko C, Koninjin AM, Aisen P, editors. Progress in iron research: advances in experimental medicine and biology. New York: Plenum Press; 1994. p. 219-28.
-
15Oski FA. Iron deficiency in infancy and childhood. N Engl J Med. 1993;329:190-4.
-
16Silva APR, Camargos CN. Fortificação de alimento: instrumentos eficazes no combate a anemia ferropriva? Comun Ciênc Saúde. 2006;16(1):53-61.
-
17Monteiro CA, Szarfarc SC. Estudo das condições de saúde das crianças no Município de São Paulo, SP (Brasil), 1984-1985. Rev Saúde Pública. 1987;21(3):255-60.
-
18Silva LSM, Giugliane ERJ, Aerts DRGC. Prevalência e determinantes de anemia em crianças de Porto Alegre-RS. Rev Saúde Pública. 2001;35(1):66-73.
-
19Santos I, Cesar JÁ, Minten G, et al. Prevalência e fatores associados à ocorrência de anemia entre menores de seis anos de idade em Pelotas, RS. Rev Bras Epidemiol. 2004;7(4).
-
20Neuman NA, Tanaka OU, Szarfarc SC, et al. Prevalência e fatores de risco para anemia no Sul do Brasil. Rev Saúde Pública. 2000;34(1):56-63.
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21Tenenbaum A, Malkiel S, Wexler ID, et al. Anemia in children with down syndrome. Int J Pediatr. [Internet]. 2011. Available at: http://www.hindawi.com/journals/ijpedi/2011/813541/.
» http://www.hindawi.com/journals/ijpedi/2011/813541/ -
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24Moreira GC, Raimundo DF, Pereira Netto M. Avaliação do estado nutricional de crianças com síndrome de Down da APAE/Escola Estadual Walter Vasconcelos de crianças especiais do município de Muriaé-MG. Rev Científica da FAMINAS. 2007;3.
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» http://www.jped.com.br/conteudo/95-71-02-88/port.pdf
Publication Dates
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Publication in this collection
Mar-Apr 2015
History
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Received
17 Oct 2014 -
Reviewed
09 Mar 2014 -
Accepted
10 Mar 2015