Pediatr Blood Cancer 2013;60:1482–1486

Sickle Cell Disease Related Mortality in the United States (1999–2009)

Dima Hamideh and Ofelia Alvarez*

INTRODUCTION

The number of individuals with sickle cell disease (SCD) in the

United States may approach 100,000 [1]. SCD affects 1 in 365

African-Americans and 1 in 1:16,305 Hispanic-Americans. Individ-

uals with SCD, especially sickle cell anemia (Hb SS), have a

shortened life expectancy [2]. Over the past four decades, there have

been substantial improvements in the medical care of individuals

with sickle cell anemia, leading to an increase in life expectancy from

14 years in 1973 to the mid to late 40s in the 1990s. In 1994, the

National Institutes of Health-sponsored multi-center Cooperative

Study of Sickle Cell Disease (CSSCD) estimated that the median

survival for individuals with Hb SS was 42 years for males and

48 years for female patients followed at the participating sickle cell

centers [2]. In 2004, the survival data from the Dallas cohort

indicated an 85.6%overall survival and an 88.5% stroke-free survival

at age 18 [3]. However, national trends of mortality for children and

adults are not known, especially given contemporary care. This paper

seeks to update national trends in mortality of individuals with SCD

across the United States from 1999 through 2009 in order to reflect

the benefits of modern therapy, and to document changes in the

causes and age at the time of death over this period.

METHODS

The Institutional Review Board of the University of Miami

deemed the study nonhuman research. We conducted the analysis

using the USmortality statistics for 1999–2009 available in the CDC

wonder website (http://wonder.cdc.gov/; compressed mortality files

and the multiple-cause mortality files) compiled by the Centers for

Disease Control and Prevention’s National Center for Health

Statistics for all 50 states and the District of Columbia. Those files

provide county-level national mortality and population database

derived from death certificates information and include data on the

state and county of residence, year of death, age category at death,

race, sex, and underlying cause-of-death along with up to twenty

additional multiple causes. The definition of SCD used in the dataset

is based on the International Classification of Diseases codes.

During 1979–1998, the ICD-9 code 282.6 for SCD, which include

all genotypes was used, but during 1999–2009 the more detailed

ICD-10 codes (D57.0, sickle-cell anemia with crisis; D57.1, sickle-

cell anemia without crisis; D57.2, double heterozygous sickling

disorders; and D57.8, other sickle-cell disorders) were reported

individually. As the sickle cell beta thalassemia (282.4; D56.8) code

was excluded from the analysis because ICD-9 and ICD-10 codes

did not distinguish sickle cell beta thalassemia from other

thalassemias, both datasets are comparable and allow us to identify

all individuals with SCD, exclusive of sickle cell beta thalassemia.

The rates of death in individuals with SCD were calculated per

black population, which constituted 97% of the population in this

dataset, in order to have more accurate population estimates. The

“black” racial classification could have included some individuals

of Hispanic ethnicity among the individuals who are African-

American or black, and certainly included other ethnicities such as

Haitians, Jamaicans, and other individuals of Caribbean descent.

The number of deaths, standardized crude rates, age-adjusted

rates, standard errors and 95% confidence intervals for death rates in

black individuals with SCD were obtained by age group, gender,

year of death, and cause of death according to ICD-10 codes.

Differences in crude mortality rates between 1979–1998 and 1999–

2009 were calculated for each age group according to previously

published method [4]. Level of significance is P< 0.05.

RESULTS

Overall Mortality

In the United States during the years 1999 through 2009, there

were 5,416 deaths in individuals with SCD being listed on the death

Background: Little is known about the national outcome ofchildren and adultswith sickle cell disease (SCD) given contemporarycare. Procedure:We investigated the number of deaths, standardizedcrude and age-adjusted mortality rates, and causes of death amongindividuals with SCD across the United States during 1999–2009according to death certificates by using a publicly available website(http://wonder.cdc.gov/). Data were compared to mortality during1979–1998. Results: When compared to 1979–1998, mortalitysignificantly decreased by 61% in infants <1 year of age, by 67% inchildren aged 1–4 years, and by 22–35% in children aged 5–19 years.After 19 years of age, mortality rates increased from 0.6 in the 15–19year group to 1.4/100,000 in the 20–24 year group, corresponding tothe transition period from pediatric to adult medical care, and this

increase was similar during 1979–1998. Although the age groupswith the highest mortality were 35–44 years for males and 45–54years for females, there was a tendency for longer survival becausethere were more deaths among those individuals 55–74 years of agecompared to previous years. For all individuals, the causes of deathswere cardiac disease (31.6%), respiratory (28.1%), renal (16.4%),infectious (14.4%), neurologic (11.9%), and gastrointestinal andhepatobiliary (9.2%) in nature. Cancer was the cause of death in<1%. Conclusion: Mortality during childhood has decreasedsignificantly. However, the transition period from pediatric to adultcare is critical. Risk-reduction, monitoring, and early treatmentintervention of cardiovascular disease in adults is warranted. PediatrBlood Cancer 2013;60:1482–1486. # 2013 Wiley Periodicals, Inc.

Key words: mortality; sickle cell disease; transition; survival

Division of Pediatric Hematology, University of Miami Miller School

of Medicine, MiamiFlorida

Conflict of interest: Nothing to declare.

�Correspondence to: Dr. Ofelia Alvarez, MD, Division of Pediatric

Hematology (D-820), PO Box 016960, Miami, Florida 33101 E-mail:

oalvarez2@med.miami.edu

Received 14 November 2012; Accepted 12 March 2013

�C 2013 Wiley Periodicals, Inc.DOI 10.1002/pbc.24557Published online 23 April 2013 in Wiley Online Library(wileyonlinelibrary.com).

certificate giving an all causemortality rate of 0.2 per 100,000 persons

irrespective of race. Only 2% (118 patients) were categorized as

Hispanic or Latino. From the total of 5,416, 5,223 deaths occurred in

black or African-American individuals with SCD giving an all cause

age-adjusted mortality rate of 1.3 (95% confidence interval 1.2–1.3)

per 100,000 black or African-American persons. Black males had an

all cause-age adjusted mortality of 1.3 whereas mortality for black

females was 1.2. During 1979–1998, the age-adjusted mortality rate

was 1.2 (95% confidence interval 1.2–1.3). Black males had an all

cause-age adjusted mortality rate of 1.4 whereas mortality rate for

black females was 1.1.

Sickle Cell Heterozygous Disorders

During 1999–2009, 51 deaths were reported in individuals with

double heterozygous sickling disorder. Only one death occurred in

other sickle-cell disorders. Eliminating those numbers did not affect

our results. Mortality causes and age at the time of death were not

specified for this subgroup in the dataset. As stated earlier, there

were no data for sickle-thalassemias.

Age-Specific Mortality

During the study period, the greatest decline in SCD-related

mortality rates occurred in children in the 1–4 year age group when

compared to years 1979–1998 (decrease of 67% from 1.3/100,000 in

1979–1998 to 0.4/100,000 in 1999–2009). Significant declines in sickle

cell-relatedmortality occurred in all pediatric groups up to age 19, with

decreases of 61% for children age 0–1 year, 35% for children age 5–9

years, 33% for children age 10–14 years, and 22% for those age 15–19

years. Young adults, 20–24 years of age, were especially vulnerable

with a high risk of mortality at the transition period between pediatric

and adult medical care (sharp increase from 0.6/100,000 for age 15–19

years to 1.4/100,000 for age 20–24 years) during 1999–2009.

When compared to 1979–1998, there were non-significant

declines in sickle cell-related mortality in early adulthood up to age

34; with decreases of 7% for individuals age 20–24 years and 2% for

those age 25–34 years. However, during both study periods, black

individuals 35–44 years of age had the highest mortality rate at 2.1

per 100,000 population. Age-specific death rates rose for those

between 45 and 74 years of age during the most recent time period,

with statistically significant increases of 24% for individuals aged

45–54 years, 67% for those aged 55–64 years and 30% for those

aged 65–74 years. There was a non-significant increase of 6% in the

age group 75–84 years of age at the time of death.

Figure 1 presents the age specific-mortality rates subdivided into

four time periods (1979–1988, 1989–1998, 1999–2003, and 2004–

2009). During 2004–2009, SCD mortality rates decreased during

childhood and early adulthood (1–34years of age) and increased during

late adulthood (55–84 years) when compared to 1999–2003. However,

the highest mortality occurred between 25 and 54 years of age.

Gender and Mortality

Figure 2 shows the crude mortality rate by gender according to

age groups. The highest crude mortality rate for males with SCD

was in the 35–44 years age group compared to 45–54 years age

group in females.

Causes of Death

Table I presents the causes of deaths during the period 1999–

2009. By descending order, deaths during 1999–2009 were

attributed to cardiovascular (31.6% of the causes of death),

followed by respiratory, genitourinary or renal, infectious,

neurologic, and gastrointestinal and hepatobiliary causes. Infec-

tious diseases were coded as a cause of death for 14.4% of all SCD-

related deaths. The number of deaths from infection has continued

to decline especially in the 1–4 years age group, with no reported

fatal pneumococcal infections in this age group since 2004. Nine

percent of individuals had cerebrovascular accident listed on their

death of certificate.

Location at the Time of Death

The data showed that most SCD deaths (69%) occur in an

inpatient facility. Fourteen percent were pronounced dead in the

emergency room, 2% upon arrival to the Emergency Department,

and 10% died at home. Disparities in trends by urbanization level

were also found. Age-adjusted mortality rates were somewhat

higher in the non-core/non-metro (1.4 per 100,000) when compared

to large central metro (1.3), large fringe metro (1), medium metro

(1.3), and small metro (1.2).

Fig. 1. Trends in age-specific death rates from SCD 1979–2009.

Fig. 2. Crude mortality rates by age and gender 1999–2009.

Pediatr Blood Cancer DOI 10.1002/pbc

Sickle Cell Disease-Related Mortality 1483

DISCUSSIONOur report provides contemporary national mortality data for

individuals with SCD.

The greatest decline in SCDmortality occurred in children 0–4-

year age groups when compared to years 1979–1998. A smaller, but

still significant, decline in SCD mortality occurred in all other

pediatric groups up to age 19.

Several advances in the diagnosis and medical care of

individuals with SCD may have contributed to the decrease in

mortality during childhood. The demonstration in 1986 that

prophylactic penicillin markedly reduces the incidence of

pneumococcal sepsis [5] provided a powerful incentive for the

widespread implementation of neonatal screening for SCD.

Subsequent experience demonstrated that neonatal screening,

when linked to timely diagnostic testing, parental education,

and comprehensive care, markedly reduces morbidity and mortality

from SCD in infancy and early childhood. Currently, universal

newborn screening and regular follow-up visits are the standard of

care across the United States, permitting the early implementation

of prophylactic penicillin and other preventive measures [6–10].

Another important measure to prevent pneumococcal disease is

vaccination. During the 1980s, the 23-valent pneumococcal

polysaccharide (PPV 23) vaccine and the Hemophilus influenza

B (Hib) vaccine were introduced in 1983 [11] and 1985 [12],

respectively, and most likely contributed to the decrease in SCD

mortality. In particular during 1989–1998, the introduction of those

vaccines contributed to the decline in mortality compared to the

period of 1979–1988. The continuous decline in SCD mortality in

children 1–4 years of age during 1999–2004 and 2005–2009 is most

likely due to the introduction of the Prevnar (PCV7) vaccine in

2000 [13]. Adamkiewicz et al. [14] reported a significant decline in

invasive pneumococcal infection after the PCV licensure. Since

2004, we found that no children 1–4 years of age died from

pneumococcal sepsis at the national level. Until a vaccine that

covers most of the serotypes is developed, the combination of

prophylactic penicillin, immunization with PPV-23, and the

addition of the PCV-7 [15–19], which has been replaced in recent

times by PCV-13 [20] should be the standard of care.

Other factors may have influenced SCD-related mortality in

children during this period. The Stroke Prevention Trial in Sickle

TABLE I. Causes of Deaths Among African-Americans/Blacks with Sickle Cell Disease During 1999–2009

Causes of death by system No. (%)

Most common causes within

each system (No., %)a

Blood and blood forming organs 5,223 (100) SCD without crisis (4,196, 79.3%)

SCD with crisis (1,027, 19.6%)

Cardiovascular 1,652 (31.6) Congestive heart failure (326, 6%)

Ischemic heart disease (252, 5%)

Hypertensive disease (214, 4%)

Arrhythmias (15, <1%)

Respiratory 1,470 (28.1) Pneumonia (331, 6%)

Pulmonary embolism (279, 5%)

Pulmonary hypertension (161, 3%)

ARDS (83, 2%)

Pulmonary edema (58, 1%)

Asthma (36, <1%)

Genitourinary 859 (16.4) Chronic renal failure (369, 7%)

Acute renal failure (144, 2%)

Infectious 755 (14.4) Other septicemia (592, 11%)

Viral hepatitis (72, 1%)

Streptococcal septicemia (36, <1%)

HIV (26, <1%)

Neurological 624 (11.9) Cerebrovascular accident (462, 9%)

Anoxic brain damage (71, 1%)

Meningitis/encephalitis (8, <1%)

Gastrointestinal 483 (9.2) Liver disease (342, 6.5%)

Disorders of gallbladder, biliary tree and pancreas (40, <1%)

Peptic ulcer disease (8, <1%)

Injury 315 (6) Aspiration, trauma, fracture (49, <1%)

Drug poisoningb (38, <1%)

Bone marrow transplant rejection (13, <1%)

Kidney transplant rejection (1, <1%)

Malignancy 33 (0.63) Breast(6), leukemia(4), kidney and bladder(3), prostate(3), MDS (2),

colon (1), other (14)c

Congenital/perinatal conditions 13 (0.25) Prematurity, congenital malformations, chromosomal abnormalities

Pregnancy, childbirth, and puerperium 3 (0.06) Pregnancy with abortive outcome, pre-eclampsia, eclampsia, infections,

venous complications

aSome patients may be listed more than once due to multiple causes of death; bDrug poisoning included opioid/narcotics overdose (17), cocaine (5),

non-opioid sedating drugs like benzodiazepines and antidepressants (7), and other drugs (9); cPercentages are not given due to low numbers.

Pediatr Blood Cancer DOI 10.1002/pbc

1484 Hamideh and Alvarez

Cell Anemia (STOP) has demonstrated the effectiveness of primary

stroke prevention by screening patients with Hb SS and S-beta0

thalassemia with transcranial Doppler ultrasound, followed by

rapid initiation of transfusion therapy for children who are at risk of

stroke [21]. There was a 75% decline in stroke rates in children in

the STOP cohort in the 3 years after the Stroke Prevention Trial

findings were published [22].

One of themain findings of this report is the increase inmortality

rate during young adulthood, when compared to patients 19 years

and younger. The vulnerability of the transition period between

pediatric and adult care has been confirmed by other studies [2,23].

Systemic issues during transition include limited access to adult

providers with the appropriate skills and knowledge, poor

communication between pediatric and adult providers, and lack

of insurance coverage and reimbursement for care coordination. A

successful transfer process and coordinated transition may reduce

mortality during early adulthood.

In 2009, African-Americans had an average life expectancy of

74.7 years [24]. The five leading causes of non-accidental deaths

among African-Americans in 2009 were heart disease, cancer,

stroke, diabetes, and kidney disease [25]. Although mortality

decreased during childhood, individuals with SCD live on the

average 30 years less than the general population. This has not

dramatically changed when compared to the results of the CSSCD

cohort reported almost two decades ago [2] because many patients

still die in their mid-thirties to mid-fifties. It is therefore imperative

that new treatment strategies are explored and rapidly translated

into patient care.

Most of the deaths were attributed to cardiovascular causes

including myocardial Infarction and hypertension, which is in

agreement with the most common causes of deaths among African-

Americans, except that they occurred earlier, with peak in the late

thirties to early fifties. Twenty-eight percent of the sickle cell-

related mortality causes were pulmonary in nature, followed by

kidney failure in 16%. Improvement in infectious causes of death

was observed. Infectious diseases were coded as a cause of death for

14% of all SCD-related deaths which was clearly lower than the

proportion of deaths from infection in the CSSCD infant cohort

(50%) [26], the Jamaican cohort (28%) [27], and the Dallas cohort

(20%) [3]; the latter reporting four deaths due to pneumococcal

sepsis.

It is important to underscore that although cancer is the second

most common of death among African-Americans, cancer was

reported as the cause of death in <1% of individuals with SCD.

Diabetes was not reported either as one of the main factors leading

to mortality. It is encouraging that data for the 2004–2009 period

showed that the mortality rates have been substantially reduced for

the majority of age groups, and that the burden of mortality is

increasingly shifting to later adulthood. In fact, there were

significant increases in mortality rates during the whole period

1999–2009 for the middle age groups, when compared to 1979–

1998, especially a 67% increase in the 55–64 years age group.

Mortality rates among individuals with SCD who died in rural

areas were higher than their urban counterparts. Americans who

live in rural areas may face a combination of factors (economic

factors, cultural and social differences, educational shortcomings)

that create disparities in health care not found in urban areas. Also,

the proximity to centralized care at a sickle cell center, university

hospital or tertiary care hospital, usually located in large cities, may

impact care.

Emphasis in the monitoring and early diagnosis of organ

dysfunction, in particular cardiovascular disease, is relevant to the

management of individuals with SCD. In our study, some of the

main causes of deaths were cerebrovascular accidents, congestive

heart failure, ischemic heart disease, pneumonia/acute chest

syndrome, and pulmonary embolism. Pulmonary hypertension

was reported as a cause in 3% of the deaths.

Cardiac and pulmonary causes were the main reasons for sickle

cell adult mortality during 2000–2005 at a sickle cell center [28].

Cardiac causes of death included pulseless electrical activity arrest,

myocardial infarction, and arrhythmias. The most common

premorbid conditions were acute chest syndrome or pneumonia

(58.1%), pulmonary hypertension (41.9%), systemic hypertension

(25.6%), congestive heart failure (25.6%), myocardial infarction

(20.9%), and arrhythmias (14.0%).

We showed that almost 20 percent of the patients died during a

pain episode during 1999–2009 (19.1% and 19.4% in 1999–2003

and 2004–2009, respectively). The patients who died during crisis

were mainly in the 20–54 years age group. During a pain episode,

the pulmonary artery pressure can increase [29]. In addition, acute

chest syndrome may occur, which is associated with mortality

especially in adults [30–32], and multi-organ failure [33] can

contribute to mortality. Because this dataset contains only the

diagnoses, which were documented in death certificates, it is not

possible to ascertain treatments received, including medications

received during a pain episode, or use of preventive measures for

pain such as hydroxyurea.

The Multi-Center Study of Hydroxyurea (MSH) proved clinical

efficacy for hydroxyurea, with statistically significant reductions in

pain episodes (44% lower), longer time to first pain episode, fewer

episodes of acute chest syndrome, and fewer patients who required

transfusions or hospitalization. In long-term follow-up, the

probability of 10-year survival was 86% in treated cases compared

with 65% in those not treated [34]. The use of hydroxyurea in

children has been investigated and was found effective to decrease

vaso-occlusive complications [35]. Researchers in Brazil demon-

strated that not only hydroxyurea is effective in reducing the

incidence of acute events, such as hospitalization and transfusions,

in children with SCD, but also impacts mortality. Untreated

children were found to be 4.6 times more likely to die than those

treated with hydroxyurea [36]. Therefore, hydroxyurea should be

prescribed more, with the intent to reduce morbidity and extend

survival. Nevertheless, the impact of hydroxyurea to prevent or treat

specific organ damage is less clear [35,37–39], and deserves further

investigation.

The current study has some limitations. Death certificates were

reported for administrative purposes and lack details about specific

SCD genotypes. There are no data for individuals with sickle cell

thalassemia, and those with sickle cell-hemoglobin C seemed

underrepresented in the dataset. In addition, the cause of death may

not have been consistently reported on death certificates, with

variable percentages listing no other cause. Despite these

limitations, the use of publicly available datasets is a valuable

resource, which allows for continuous surveillance of the

population and to observe mortality trends.

A national registry of patients with SCD, with prospective

systematic follow-up, might help define the epidemiology,

morbidity, and sickle cell-related mortality. The CDC-sponsored

Registry and Surveillance System for Hemoglobinopathies (RuSH)

Program is ongoing to pilot a registry in several states [40].

Pediatr Blood Cancer DOI 10.1002/pbc

Sickle Cell Disease-Related Mortality 1485

ACKNOWLEDGMENTS

We want to acknowledge the contributions of Lanetta Jordan,

MD MPH who sponsored the statistical analysis and Hua Li, MD

PhD who actually assisted with the statistical analysis.

REFERENCES

1. Hassel KL. Population estimates of sickle cell disease in the US. Am J Prev Med 2010;38:S512–S521.

2. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease: Life expectancy and risk factors

for early death. N Engl J Med 1994;330:1639–1644.

3. Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood

2004;103:4023–4027.

4. Kleinman JC. Mortality. In: Statistical notes for health planners, NCHS, 1977 (3): 1–16.

5. GastonMH, Verter JI,Woods G, et al. Prophylaxis with oral penicillin in children with sickle cell anemia:

A randomized trial. N Engl J Med 1986;314:1593–1599.

6. Vichinsky E, Hurst D, Earles A, et al. Newborn screening for sickle cell disease: Effect on mortality.

Pediatrics 1988;81:749–755.

7. Githens JH, Lane PA, McCurdy RS, et al. Newborn screening for hemoglobinopathies in Colorado: The

first 10 years. Am J Dis Child 1990;144:466–470.

8. Centers for Disease Control and Prevention Update. Newborn screening for sickle cell disease—

California, Illinois and New York 1998. MMWR Morb Mortal Wkly Rep 2000;49:729–731.

9. Frempong T, Pearson HA. Newborn screening coupled with comprehensive followup reduced early

mortality of sickle cell disease in Connecticut. Conn Med 2007;71:9–12.

10. Pass KA, Lane PA, Fernhoff PM, et al. US newborn screening system guidelines II: Follow-up of children,

diagnosis, management, and evaluation. Statement of the Council of Regional Networks for Genetic

Services (CORN). J Pediatr 2000;137:S1–S46.

11. No authors listed. An expanded pneumococcal vaccine. Med Lett Drugs Ther 1983;25:91–92.

12. Lepow ML, Samuelson JS, Gordon LK. Safety and immunogenicity of Haemophilus influenza type

b-polysaccharide diphteria toxoid conjugate vaccine in infants 9–15 months of age. J Pediatr 1985;

106:185–189.

13. Advisory Committee on Immunization Practices. Preventing pneumococcal disease among infants and

young children. Recommendations of the Advisory Committee on Immunization Practices (ACIP).

MMWR Recomm Rep 2000;49:1–35.

14. Adamkiewicz TV, Silk BJ, Howgate J, et al. Effectiveness of the 7-valent pneumococcal conjugate

vaccine in children with sickle cell disease in the first decade of life. Pediatrics 2008;121:562–569.

15. American Academy of Pediatrics, Committee on Infectious Diseases. Policy statement: Recommen-

dations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate

vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics 2000;

106:362–366.

16. Halasa NB, Shankar SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals

with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin

Infect Dis 2007;44:1428–1433.

17. Adamkiewicz TV, Sarnaik S, Buchanan GR, et al. Invasive pneumococcal infections in children with

sickle cell disease in the era of penicillin prophylaxis, antibiotic resistance, and 23-valent pneumococcal

polysaccharide vaccination. J Pediatr 2003;143:438–444.

18. American Academy of Pediatrics. Health supervision for children with sickle cell disease. Pediatrics

2002;109:526–535.

19. Talbot TR, Poehling KA, Hartert TV, et al. Elimination of racial differences in invasive pneumococcal

disease in young children after introduction of the conjugate pneumococcal vaccine. Pediatr Infect Dis J

2004;23:726–731.

20. American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for the

prevention of Streptococcus pneumoniae infections in infants and children: Use of 13-valent

pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23).

Pediatrics 2010;126:186–190.

21. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle

cell anemia and abnormal results on transcranial doppler ultrasonography. N Engl J Med 1998;339:

5–11.

22. Lee MT, Piomelli S, Granger S, et al. Stroke prevention trial in sickle cell anemia (STOP): Extended

follow-up and final results. Blood 2006;108:847–852.

23. Quinn CT, Rogers ZR, McCavit TL, et al. Improved survival of children and adolescents with sickle cell

disease. Blood 2010;115:3447–3452.

24. Murphy SL, Xu J, Kochanek KD. Deaths: Preliminary data for 2010. Natl Vital Stat Rep 60: 2012.

25. Centers for Disease Control and Prevention. (2012). Retrieved from http://wonder.cdc.gov/

26. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical events in the first decade in a cohort of infants with sickle

cell disease. Blood 1995;86:776–783.

27. Thomas AN, Pattison C, Serjeant GR. Causes of death in sickle-cell disease in Jamaica. BMJ.

1982;285:633–635.

28. Fitzhugh CD, Lauder N, Jonassaint JC, et al. Cardiopulmonary complications leading to premature deaths

in adult patients with sickle cell disease. Am J Hematol 2010;85:36–40.

29. Machado RF, Mack AK, Martyr S, et al. Severity of pulmonary hypertension during vaso-occlusive pain

crisis and exercise in patients with sickle cell disease. Br J Haematol 2007;136:319–325.

30. Mekontso Dessap A, Leon R, Habibi A, et al. Pulmonary hypertension and cor pulmonale during severe

acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 2008;177:646–653.

31. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle

cell disease. National Acute Chest Syndrome Study Group. N Engl J Med 2000;342:1855–1865.

32. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: A critical reappraisal. Blood 2012;120:

3647–3656.

33. Gardner K, Bell C, Bartram JL, et al. Outcome of adults with sickle cell disease admitted to critical care—

Experience of a single institution in the UK. Br J Haematol 2010;150:610–613.

34. Steinberg MH, McCarthy WF, Barton F, et al. The risks and benefits of long-term use of hydroxyurea in

sickle cell anemia: A 17.5 year follow-up. Am J Hematol 2010;85:403–408.

35. Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell

anaemia: A multicentre, randomised, controlled trial (BABY HUG). Lancet 2011;377:1663–1672.

36. Lobo C, Hankins JS, Moura P, et al. Hydroxyurea therapy reduces mortality among children with sickle

cell disease. Blood 2010;116: Abstract, 843.

37. Alvarez O, Miller ST, Wang WC, et al. Effect of hydroxyurea treatment on renal function parameters:

Results from the multi-center placebo-controlled baby hug clinical trial for infants with sickle cell

anemia. Pediatr Blood Cancer 2012;59:668–674.

38. Gordeuk VR, Campbell A, Rana S, et al. Relationship of erythropoietin, fetal hemoglobin, and

hydroxyurea treatment to tricuspid regurgitation velocity in children with sickle cell disease. Blood

2009;114:4639–4644.

39. deMontalembertM,Maunoury C, Acar P, et al.Myocardial ischaemia in childrenwith sickle cell disease.

Arch Dis Child 2004;89:359–362.

40. Hoots WK. The registry and surveillance in hemoglobinopathies: Improving the lives of individuals with

hemoglobinopathies. Am J Prev Med 2010;38:S510–S511.

Pediatr Blood Cancer DOI 10.1002/pbc

1486 Hamideh and Alvarez