JOURNAL OF WOMEN’S HEALTH Volume 16, Number 5, 2007 © Mary Ann Liebert, Inc. DOI: 10.1089/jwh.2007.CDC4
Report from the CDC Sickle Cell Disease: Current Activities, Public Health Implications, and Future Directions MELISSA CREARY, M.P.H., DHELIA WILLIAMSON, Ph.D., and ROSHNI KULKARNI, M.D.
ABSTRACT Sickle cell disease (SCD) is a genetic blood disorder caused by abnormal hemoglobin that damages and deforms red blood cells (RBCs). The abnormal red cells break down, causing anemia, and obstruct blood vessels, leading to recurrent episodes of severe pain and multiorgan ischemic damage. SCD affects millions of people throughout the world and is particularly common among people whose ancestors come from sub-Saharan Africa. Sickle cell trait (SCT) is an inherited condition in which both normal hemoglobin and sickle hemoglobin are produced in the RBCs. SCT is not a type of sickle cell disease. People with SCT are generally healthy. In SCD, clinical severity varies, ranging from mild and sometimes asymptomatic states to severe symptoms requiring hospitalization. Symptomatic treatments exist, but there is no cure for SCD. Although there has been extensive clinical and basic science research in SCD, many public health issues, such as blood safety surveillance, compliance with immunizations, follow-up of newborns with positive screening tests, stroke prevention, pregnancy complications, pain prevention, quality of life, and thrombosis, in people with SCT remain unaddressed. Currently, efforts are under way to strengthen SCD-related activities within the Centers for Disease Control and Prevention (CDC). To date, several activities are being or have been conducted by centers within CDC, including quality assurance of newborn screening tests for SCD, morbidity and mortality studies, genetic studies, and studies focusing on the protective effects of SCT for malaria. This paper discusses the public health implications of SCD, summarizes SCD-related activities within CDC, and points to future directions that the agency can take to begin to address some of these issues. INTRODUCTION
S
ICKLE CELL DISEASE (SCD) is a genetic blood dis-
order of hemoglobin that damages and deforms red blood cells (RBCs). The sickle-shaped
red cells sometimes break down (hemolysis) and cause anemia. They also obstruct blood vessels, causing ischemic organ damage and episodes of unpredictable and recurrent pain that are sometimes severe. There are several common forms of
Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia. The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry.
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SCD: SS, the most common and severe form of the disease (inheritance of one sickle cell gene from each parent); SC, a milder form of the disease (inheritance of one sickle cell gene and one gene for another abnormal type of hemoglobin called “C”); and S-beta-thalassemia (inheritance of one sickle cell gene and one gene for beta-thalassemia, another inherited hemoglobinopathy). Not all sickle cell patients will have anemia. Anemia references the low blood count that some of these individuals may experience. We refer to SCD as the most severe form of SCD (SS disease) throughout this paper. Individuals who inherit the sickle cell gene from one parent but whose other copy of the gene is normal are healthy carriers of the disorder and are said to have sickle cell trait (SCT).1 Figure 1 shows how two parents who have SCT can pass on the gene to have a one in four chance of having a child with sickle cell disease.
Prevalence SCD affects millions of people throughout the world and is particularly common among people whose ancestors come from sub-Saharan Africa, Spanish-speaking regions in the Western Hemisphere (South America, Cuba, and Central America), Saudi Arabia, India, and Mediterranean countries such as Turkey, Greece, and Italy.2 Each year, about 300,000 infants are born with major hemoglobin disorders, including more than 200,000 infants with SCD, in Africa.3 In some areas of sub-Saharan Africa, up to 2% of all children are born with the condition.3 In the United
States, SCD affects about 72,000 people, and 2 million people are carriers.2
Clinical manifestations Clinical manifestations of SCD depend on the type of disease, but the most severe and frequent manifestations usually occur in individuals with SS disease. The most common manifestations of SCD are multisystemic and related either to anemia (e.g., fatigue, jaundice, and shortness of breath) or to obstruction of blood flow by sickleshaped RBCs (e.g., pain and ischemic organ damage). Signs and symptoms initially manifest by 5–6 months of age and continue throughout life. The course of the disease is quite variable, ranging from asymptomatic patients (especially in the newborn period) to those with intermittent episodic events, often referred to as “crises,” and requiring frequent hospitalization for treatment. A sudden acute decrease of hemoglobin is referred to as “aplastic crisis” and can be due to infections. Pain crises, experienced by the majority of affected individuals, are the hallmark of SCD and are a result of vasoocclusion. Vasooclusion is an unpredictable ischemic event that occurs when the sickled RBCs block blood vessels.2 Sickle cell crises can be precipitated by dehydration, exposure to cold, infection, and environments with low oxygen tension (i.e., work at high altitudes).4 It can be acute, chronic, or both and is unpredictable and recurrent in nature. Ischemic organ damage secondary to vasoocclusion produces a severe clinical picture that includes stroke, pulmonary infarction (acute chest syndrome), priapism (prolonged painful erection), splenic infarcts or altered splenic function (leading to increased susceptibility to infections), and damage to kidneys and liver. Organ damage often results in other long-term disease-related conditions, such as delayed growth and puberty, and decreased lung function.2
Treatment
FIG. 1.
Genetic inheritance of sickle cell trait.
The goal of treating SCD is the prevention of complications. Available nonspecific treatments include penicillin prophylaxis, pain medications, blood transfusions, and vaccines. Hydroxyurea is a new therapy applied to SCD that has been shown to be successful in reducing the number of painful events and the recurrence of acute chest syndrome.1 It is a chemotherapeutic agent that increases fetal hemoglobin and decreases the white
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cell count. Taken daily, it takes approximately 3–6 months to be effective. Besides increasing fetal hemoglobin (HbF) production, it raises slightly the total hemoglobin concentration in the body. In a person with SCD, HbF reduces the likelihood that RBCs will sickle. Regular use might also reduce hospital stays and the need for blood transfusion in adults with SCD.5 Peripheral blood or bone marrow stem cell transplantation from matched siblings that promotes the formation of blood cells offers a cure for SCD, but the risks and morbidity of the procedure, coupled with the variable clinical severity of patients, restrict its use to a group of highly select patients.1 For most people, however, there is no cure for SCD. The average life expectancy for women with the most severe form of SCD (SS disease) is 48 years (based on data from the 1980s), although some people live into their 60s and beyond.1 With advances in management, men and women with SCD are enjoying an improved quality of life well into adulthood, when they can elect to plan a family.
Gynecological and reproductive issues Women with SCD experience more gynecological complications than those who do not have SCD. These include delayed menarche, dysmenorrhea, ovarian cysts, and fibrocystic disease of the breast. There is a high prevalence of menstrual association with vasoocclusive pain.6,7 There are no large multicenter studies that have addressed the issue of gynecological issues in adolescents and adult females with SCD. Pregnancy has been associated with exacerbation of SCD and can place women at additional risk for obstetrical complications. Pregnant women with SCD can experience increased frequency of sickling and pain from ischemic necrosis of bone marrow or other organs. Infections and pulmonary complications are also more common. The most common obstetrical complications include gestational hypertension, preterm birth, and small-for-gestational-age infants. The precise reason for these complications is unclear. Maternal mortality is elevated, but rates have declined since 1972.1 More than one third of pregnancies in women with SCD terminate in abortion, stillbirth, or neonatal death, according to the National Institutes of Health (NIH) Cooperative Study of SCD.8 Despite their chronically high cardiac output due to anemia, women with SCD rarely die of
heart disease, but almost all eventually have some degree of ventricular dysfunction from hypertrophy and diastolic dysfunction. These underlying changes make affected women less tolerant of the additional increase in cardiac output needed in pregnancy.9 However, appropriate management by healthcare providers familiar with SCD and high-risk obstetrical care can bring about a successful pregnancy for most women with SCD.10 Women with SCD who are of childbearing age have many choices regarding family planning, and potential parents should be offered screening (if they are unaware of their sickle cell status) and preconception counseling. Counseling includes discussion of contraception, complications associated with pregnancy, and the importance of maintaining good health habits, with vitamin and iron supplementation as needed. Both parents, as they plan the pregnancy, should receive genetic counseling to determine their chances of having a child with SCD. This risk is best calculated after each partner has been tested for hemoglobinopathies.1 It is equally important that those who carry the SCT become knowledgeable of their carrier status and educated on how they can potentially pass the trait or disease on to their offspring.
CDC PUBLIC HEALTH ACTIVITIES RELATED TO SCD Following is a brief summary of various SCDrelated activities that are being or have been conducted within CDC.
Reproductive health studies Using contraception and becoming pregnant are major decisions for a woman with SCD because of the potential for related medical complications. There have not been any clear guidelines for contraceptive use among these women. As part of the World Health Organization (WHO) development of global guidance for family planning, Legardy and Curtis11,12 conducted a systematic review in which they assessed whether the use of progesterone-only contraceptives was associated with adverse health effects among women with sickle cell anemia. Eight studies satisfied the eligibility criteria for the review; none of them identified any adverse events or clinically or statistically significant adverse hematological
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or biochemical changes associated with using these contraceptive methods. Six studies suggested that users experienced a decrease in clinical symptoms and less severe and frequent painful crises than nonusers.11,12
Newborn screening For more than 26 years, CDC’s Environmental Health Laboratory has been providing quality assurance and proficiency testing for the testing of newborns for preventable diseases. Within 48 hours of a child’s birth, a sample of blood is obtained from a heel stick, and the blood is analyzed for treatable diseases, including phenylketonuria, SCD, and hypothyroidism. More than 98% of all children born in the United States are tested for these disorders. Such screening ensures that affected babies can be identified early and appropriate treatment and management can be initiated to prevent potentially irreversible negative health outcomes. The sample, called a blood spot, is tested at a state public health or other participating laboratory. CDC’s Environmental Health Laboratory evaluates the performance of all participating laboratories (73 domestic and 1 or more laboratories in each of 53 other nations), ensuring proper analysis of blood spots and providing technical assistance as needed to resolve diagnostic problems.13 CDC also supports both economic and epidemiological evaluations of newborn screening and genetic testing. A number of economic studies have questioned the cost-effectiveness of universal screening for SCD in areas of low prevalence. Grosse et al.14 reviewed the available information on the cost-effectiveness of screening for SCD in the United States and England and concluded that universal SCD screening at the national level met conventional criteria for costeffectiveness. Decisions in both countries to implement universal screening for SCD in all jurisdictions reflected concerns with the logistical and ethical challenges of screening newborns for different disorders on the basis of local demographic composition or maternal ethnicity, as well as the low absolute cost of universal screening.14
Morbidity and mortality studies CDC has been involved in several studies of SCD morbidity and mortality. Yoon et al.15 used population-based hospital discharge data from California and South Carolina to estimate the con-
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tribution of birth defects and genetic diseases to pediatric hospitalizations. Of the 17 groups of conditions examined, 3 (SCD, thalassemia, and cardiovascular defects) together accounted for 43% and 35% of all pediatric hospitalizations related to birth defects and genetic diseases in South Carolina and California, respectively. SCD alone accounted for half of all hospitalizations related to birth defects and genetic diseases among black or African American children. Although SCD and thalassemia represent a high proportion of hospitalizations, the average costs associated with these hospitalizations were relatively low.15 Ashley-Koch et al.16 conducted a study of the contribution of SCD to the occurrence of developmental disabilities. The researchers identified 22 children with SCD among all children 3–10 years of age who were identified with one of four developmental disabilities and who resided in a five-county area in metropolitan Atlanta, Georgia, during 1991–1993. Of those 22 children, all were black or African American, 14 (64%) were male, 16 (73%) had mental retardation, 14 (64%) had cerebral palsy, 1 (4.5%) had hearing loss, 1 (4.5%) had visual impairment, 13 (59%) had a history of stroke, and 9 (41%) exhibited more than one disability. The study concluded that children with SCD were at a higher risk for developmental disabilities, especially mental retardation and cerebral palsy associated with stroke, than children in the general population.16 CDC researchers and newborn screening program staff in California, Illinois, and New York linked newborn screening and death records of infants born with SCD during 1990–1994.17 A total of 2487 children with presumed or confirmed SCD were identified by the three state newborn screening programs, among whom 27 deaths due to SCD were reported.17,18 All-cause mortality for black or African American children with SCD in California and Illinois was no higher than among all black or African American children born in the two states during the same period.
Genetic studies There have been two reports on the genetics of SCD by CDC researchers. In the first of these studies, Ashley-Koch et al.19 conducted a Human Genome Epidemiology (HuGE) review of the literature related to the HbS allelic variant of the betaglobin gene that causes SCD. This review provided extensive information regarding the morbidity and
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mortality associated with this variant of SCD, interactions of HbS and malaria, and the laboratory tests commonly used to detect the variant.19 In a second study, Crawford et al.20 characterized beta-globin haplotypes using blood spots from a population-based cohort of newborns from three state newborn screening programs (California, Illinois, and New York). A haplotype is the set of alleles from closely linked places on the gene carried by an individual and is usually inherited as a unit. Early studies of genetic variation within the beta-globin gene cluster demonstrated that the HbS mutation was found on only a few haplotypes, suggesting multiple origins of the HbS mutation. These haplotype backgrounds are helpful in tracing ancestry and the country of origin where the HbS mutation presumably originated in human history, (for example, Benin (BEN), Cameroon (CAM), Central African Republic (CAR), Senegal (SEN), and Saudi Arabia (SAUDI). This study was conducted on blood spots from newborns homozygous for HbS. Results from this study showed that the BEN haplotype was the most frequent (63%), followed by the CAR and SEN haplotypes (14% and 9%, respectively). The CAM and SAUDI haplotypes were the least frequent (4% and 2%, respectively). This information might help phenotype/genotype correlation and could be valuable in predicting clinical severity and outcomes.20
Malaria In 1979, the Division of Parasitic Diseases at CDC, in collaboration with the Kenya Medical Research Institute, established a research station in western Kenya that conducts studies related to the major public health problems of the country, especially malaria.21–23 People with SCT appear to have some protective advantage against malaria. As a result, the frequencies of sickle cell carriers are high in malaria endemic areas. However, most of the early studies that examined the relationship between SCT and malaria were cross-sectional, and some important data that might be relevant to the protective effects of SCT were missing (e.g., conducting cohort studies to determine the overall protective advantage against mortality and to determine if there is a protective advantage early in life before the acquisition of clinical immunity to malaria).21 Several projects are ongoing to address the need for more data in this area.
One of the birth cohort projects (Asembo Bay Cohort Project) was conducted in Kenya. Infants were followed from birth to 5 years of age, and overall mortality and monthly malaria-associated morbidity data were collected.21 Using data from this study, CDC researchers, in collaboration with the Kenya Medical Research Institute, found that SCT provides 55% protection against all-cause mortality, and most of this protection occurs within 2–16 months of birth, a period before the onset of clinical immunity in areas with intense transmission of malaria.21 This was the first demonstration of the protective effect of SCT against all causes of mortality using a birth cohort study in an endemic area. Although children with SCT did not get any protection from Plasmodium falciparum infection, 27% of children with SCT were protected against high-density P. falciparum infection, and 60% were protected against malaria-associated severe anemia, which is the major severe outcome associated with malaria in this area.21
PUBLIC HEALTH IMPLICATIONS SCD is a disorder that can be effectively managed with the systematic application of prevention strategies and regular monitoring and that requires a multidisciplinary team approach for all ages to address the needs of the affected population.24 Healthcare provider education should be a priority so that current information about SCD treatment can be effectively applied and transmitted to patients. Such an approach would encourage and maintain specialty physician availability (adult and pediatric hematologists) and would ensure transition of care and nationwide participation in clinical trials. In the United States, two million blacks or African Americans have SCT.2 They are generally asymptomatic; however, under certain circumstances, their RBCs can sickle, leading to serious morbidity or mortality. Complications can include increased urinary tract infections (UTIs) in women, gross hematuria, splenic infarction with altitude hypoxia, and life-threatening consequences from exercise, including exertional heat illness (heat stroke or renal failure) or idiopathic sudden death.25 Because people with SCT can pass the defective gene to their children, genetic counseling, education and family planning assistance are extremely important.
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There are also a number of psychosocial issues that affect both carriers and those with SCD. Guilt and anxiety have been reported among parents of children diagnosed as carriers of sickle cell disorders, as well as difficulty in distinguishing between carrier and disease status. The attitude of a noncarrier parent toward a carrier child can have a negative impact on the child’s self-perception and self-esteem. Anxiety and reduced optimism about future health have been reported among both carriers of sickle cell disorders and those who have the disoders.26 SCD has been extensively studied from a clinical and pathophysiological perspective, but little has been done to examine the sociological effects of the disease on patients. In both rural and urban settings, studies are needed to assess the effects of SCD on education, caregiving, and job welfare. For example, in the workplace, frequent absence from work because of complications and hospitalizations can cause prejudice and a lack of tolerance among work colleagues and management.4 There are also many issues related to the treatment of chronic pain. Because adequate control of the severe pain of SCD often requires narcotics, there is the risk of addiction. Drug seeking for adequate pain management by patients with SCD is sometimes viewed by healthcare providers as addictive behavior and results in stigmatization. More education of healthcare providers in chronic pain management is needed. For school-aged children, there is an urgent need for education of teachers to increase their understanding of the unique needs of a child with SCD. Specialized care for people with rare disorders can be problematic in rural areas, where resources are often lacking.27 Even in urban locations, there are relatively few centers devoted to the care of patients with SCD, and many times, rural areas lack even access to information and care. There is a pressing need for translation and communication of research findings from the centers conducting SCD research to the general medical community so that patients throughout the country can benefit. RBC transfusions are often used to treat acute and chronic SCD complications. Transfusions are indicated either for episodic events triggered by an acute complication or for planned medical interventions. In addition, some clinical problems require long-term suppression of the production of bone marrow sickle cells, which can be ac-
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complished by regular transfusions. The anticipated benefits of blood transfusions are carefully weighed against the risks of infections, immunological complications, and iron overload (requiring chelation therapy). Alloimmunization, the process whereby antibodies are formed that are directed toward antigens from other people, is one of the most serious transfusion complications.28 There is a need for monitoring of this population for complications related to transfusions, including infections and allergic reactions. Such monitoring can contribute to efforts to monitor the safety of the nation’s blood supply.
FUTURE ACTIVITIES Although CDC has conducted several studies focused on SCD and provides quality assurance for screening newborns for SCD, there are many public health issues that remain unaddressed. Such issues as blood safety and surveillance, immunizations, further follow-up of newborns after screening, stroke prevention, pregnancy complications, pain prevention, quality of life, and thrombosis in people with SCT are but a few of the issues that need to be examined from a public health perspective. Thrombogenetics and pharmacogenomics offer new and exciting approaches to hereditary diseases that could also be explored in this population. Recently, representatives from the Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, CDC, presented information at a meeting sponsored by the Sickle Cell Disease Association of America (SCDAA) to explore options in collecting incidence and prevalence data for SCD. Registries, surveillance systems, and clinical management tools are all potential ways to collect important information on the SCD population in the United States and abroad. The Division of Blood Diseases and Resources of the National Heart, Lung and Blood Institute, NIH, supports grants for comprehensive sickle cell centers to conduct multidisciplinary programs of basic, applied, and clinical research and to include relevant service activities in diagnosis, counseling, and education concerning SCD and related disorders. The Division of Services for Children with Special Needs, Maternal and Child Health Bureau, HRSA, supports follow-up services for newborns identified through screening
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either as having SCD or as being SCD carriers, which include notification to families, extended family testing, counseling, and education. These HRSA projects link state newborn screening programs, comprehensive sickle cell treatment centers, and healthcare professionals with community-based organizations to provide services. HRSA also supports the new Sickle Cell Service Demonstration program, created to develop systemic mechanisms for the prevention and treatment of SCD, which include coordinating service delivery for individuals with SCD, training of health professionals, and identifying and establishing other efforts related to the expansion and coordination of education, treatment, and continuity-of-care programs for individuals with SCD. We believe that CDC can play an important role as part of a coalition of federal agencies and nongovernmental organizations committed to address public health issues related to SCD.
REFERENCES 1. Dauphin-McKenzie N, Giles JM, Jacques E, Harrington T. Sickle cell anemia in the female patient. Obstet Gynecol Surv 2006;61:5. 2. National Heart, Lung and Blood Institute, National Institute of Health. Sickle cell anemia: Who is at risk? Available at www.nhlbi.nih.gov/health/dci/Diseases/Sca/ SCA_WhoIsAtRisk.html Accessed November 3, 2006. 3. Sickle cell anemia. Report by the Secretariat. Provisional Agenda Item from the 59th World Health Assembly, World Health Organization. Available at www.who.int/gb/ebwha/pdf_files/EB117/B117_34-en.pdf Accessed November 3, 2006. 4. Yardley-Jones A. What are the implications of sickle cell anaemia? Occup Med 1999;49:1. 5. Bateman N, Dana D. Hydroxyurea for sickle cell disease. Available at www.bchealthguide.org/kbase/topic/ detail/drug/hw254044/detail.htm Accessed November 3, 2006. 6. Terry A, Jacob M, Hsu L. Effect of depo-provera on frequency of sickle cell pain. Available at www.cse. emory.edu/sciencenet/undergrad/SURE/Posters/2002_terry. html Accessed November 30, 2006. 7. Samuels-Reid J, Scott RB. Characteristics of menstruation in sickle cell disease. Fertil Steril 1985;43:1. 8. Smith J, Espeland M, Bellevue R, et al. Pregnancy in sickle cell disease: Experience of the Cooperative Study of Sickle Cell Disease. Obstet Gynecol 1996;87:199. 9. Veille J, Hanson R. Left ventricular systolic and diastolic function in pregnant patients with sickle cell disease. Am J Obstet Gynecol 1994;170:107. 10. Hassell K. Pregnancy and sickle cell disease. Hematol Oncol Clin North Am 2005;19:5.
581 11. Legardy JK, Curtis KM. Progestogen-only contraceptive use among women with sickle cell anemia: A systematic review. Contraception 2006;73:195. 12. World Health Organization. Medical eligibility criteria for contraceptive use, 3rd ed. Geneva: World Health Organization, 2004. 13. Centers for Disease Control and Prevention. Quality assurance and proficiency testing for newborn screening. Available at www.cdc.gov/nceh/dls/newborn_screening.htm Accessed November 9, 2006. 14. Grosse S, Olney R, Baily M. The cost effectiveness of universal versus selective newborn screening for sickle cell disease in the US and the UK: A critique. Appl Health Econ Health Policy 2005;4:239. 15. Yoon PW, Olney RS, Khoury MJ, Sappenfield WM, Chavez GF, Taylor D. Contribution of birth defects and genetic diseases to pediatric hospitalizations: A population-based study. Arch Pediatr Adolesc Med 1997;151:11. 16. Ashley-Koch A, Murphy CC, Khoury MJ, Boyle CA. Contribution of SCD to the occurrence of developmental disabilities: A population-based study. Genet Med 2001;3:3. 17. Centers for Disease Control and Prevention. Mortality among children with sickle cell disease identified by newborn screening during 1990–1994—California, Illinois, and New York. MMWR 1998;47:169. 18. Olney R. Newborn screening for sickle cell disease. In: Khoury M, Burke W, Thomson E, eds. Genetics and public health in the 21st century. New York: Oxford University Press, 2000:431. 19. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (HbS) allele and SCD: A HuGE review. Am J Epidemiol 2000;151:9. 20. Crawford DC, Caggana M, Harris KB, et al. Characterization of -globin haplotypes using blood spots from a population-based cohort of newborns with homozygous HbS. Genet Med 2002;4:328. 21. Aidoo M, Terlouw DJ, Kolczak MS, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 2002;359:9314. 22. Terlouw DJ, Aidoo MA, Udhayakumar V, et al. Increased efficacy of sulfadoxine-pyrimethamine in the treatment of uncomplicated falciparum malaria among children with sickle cell trait in western Kenya. J Infect Dis 2002;186:11. 23. Terlouw DJ, Desai MR, Wannemuehler KA, et al. Relation between the response to iron supplementation and sickle cell hemoglobin phenotype in preschool children in western Kenya. Am J Clin Nutr 2004;79:3. 24. Okpala I, Thomas V, Westerdale N, et al. The comprehensive care of sickle cell disease. Eur J Haematol 2002;68:157. 25. Kark J. Sickle cell trait. Available at sickle.bwh.harvard.edu/sickle_trait.html Accessed November 4, 2006. 26. Laird L, Dezateux C, Anionwu E. Education and debate, Fortnightly review: Neonatal screening for sickle cell disorders: What about the carrier infants? BMJ 1996;313:407.
582 27. Telfair J, Haque A, Etienne M, Tang S, Strasser S. Rural/urban differences in access to and utilization of services among people in Alabama with sickle cell disease. Public Health Rep. 2003:118:27. 28. Swerdlow PS. Red cell exchange in sickle cell disease. In: Berliner N, Lee S, Linenberger M, Vogelsang, M, Bajus J, eds. Hematology: American Society of Hematology Education Program Book. Washington, DC: American Society of Hematology, 2006:48.
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