Meta-analysis of CORN data on prevalence of sickle cell disease among black populations
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The Agency for Health Care Policy and Research (AHCPR) was established in December 1989 under Public Law 101 239 (Omnibus Budget Reconciliation Act of 1989) to enhance the quality, appropriateness, and effectiveness of health care services and access to these services. AHCPR carries out its mission by conducting and supporting general health services research, including medical effectiveness research, facilitating development of clinical practice guidelines, and disseminating research findings and guidelines to health care providers, policymakers, and the public.
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Historically, sickle cell anemia the most common form of sickle cell disease has been associated with high mortality in early childhood due to overwhelming bacterial infections, splenic sequestration crisis, and the acute chest syndrome. Over the past 20 years, it has been recognized that comprehensive medical care could reduce morbidity and mortality in children with sickle cell anemia. In 1986, a double-blind, randomized, controlled clinical trial demonstrated that twice-daily doses of oral penicillin reduced mortality and morbidity from pneumococcal infections in children under 5 years of age with sickle cell anemia and sickle betao-thalassemia. A National Institutes of Health Consensus Conference on Newborn Screening concluded that screening could reduce morbidity and mortality, provided screening was linked to the provision of health care services.
Shortly after these findings were disseminated, neonatal sickle cell screening became widespread in the United States and now exists in more than 40 States. The development of these screening programs was stimulated by funds from the Bureau of Maternal and Child Health of the Public Health Service. The remarkable growth of these screening programs illustrates how Federal and State partnerships can dramatically improve the quality of health care.
There remain, however, many unresolved issues related to neonatal sickle cell screening. This guideline addresses these issues and provides specific recommendations for the implementation and conduct of a screening program based upon currently available scientific literature and, when such literature is lacking, the expert opinions of the panel members. .ti 20 Sickle Cell Disease Guideline Panel
This clinical practice guideline sets forth a comprehensive program for identifying, diagnosing, and treating newborns and infants with sickle cell disease and recommends education and counseling strategies for their parents. Sickle cell disease comprises a group of genetic disorders characterized by the production of hemoglobin S, anemia, and acute and chronic tissue damage secondary to the blockage of blood flow by abnormally shaped red cells. Sickle cell anemia is the most common form of the disease, and it affects approximately 1 in 375 African-American infants. Although in the United States sickle cell disease is most commonly found in persons of African ancestry, it also affects other populations. The panel recommends screening of all newborns for sickle cell disease, since targeting specific groups will miss some infected infants. Samples of dried blood on filter paper or liquid blood samples should be used for hemoglobinopathy screening. Hemoglobin electrophoresis, isoelectric focusing, and high performance liquid chromatography are acceptable, reliable, and accurate testing methods. Infants identified on initial screening must be retested to establish a definitive diagnosis. Affected infants must be given twice-daily oral penicillin beginning at 2 months of age to reduce pneumococcal infections. Parents must be taught to recognize early signs and symptoms of specific complications, including fever, splenic sequestration crisis, respiratory distress, and dehydration. Appropriate medical followup includes regular visits to assess the infant's medical status and administration of age-appropriate immunizations, including pneumococcal, conjugated Haemophilus influenzae, and hepatitis B vaccines. Infants with sickle cell disease require the same well-child care as infants without disease. Education and nondirective genetic counseling should be offered to all parents of infants with sickle cell disease. The guideline stresses the need for a comprehensive and fully integrated approach to reduce morbidity and mortality from sickle cell disease. The guideline was developed by a private-sector panel of health care experts and a consumer representative and is based on the best science available, including hundreds of scientific sources and the expertise and experience of panel members, consultants, and peer and pilot reviewers.
This document is in the public domain and may be used and reprinted without special permission. AHCPR appreciates citation as to source, and the suggested format is provided below:
Sickle Cell Disease Guideline Panel. Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in Newborns and Infants. Clinical Practice Guideline No. 6. AHCPR Pub. No. 93 0562. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. April 1993.
Jeanne A. Smith, MD, MPH (Co-chair)
Associate Professor of Clinical Medicine
Columbia University
Thomas R. Kinney, MD (Co-chair)
Professor of Pediatrics
Duke University
Beverly Ames
Consumer Representative
Kwame Anyane-Yeboa, MD
Associate Professor of Pediatrics
Columbia University
Samuel Charache, MD
Professor of Medicine and Laboratory Medicine
Johns Hopkins University
Melvin Gerald, MD
Family Physician
Washington, DC
Serena Gilbert, MSW
Director, Department of Social Work
Prince George's Hospital Center
David Phoenix, DrPH
Associate Professor of Community Health and Preventive Medicine
Morehouse School of Medicine
Ruby Laverne Wesley, PhD, RN
Assistant Professor of Nursing
Wayne State University
Doris L. Wethers, MD
Professor of Clinical Pediatrics
Columbia University
Charles Whitten, MD
Associate Dean, School of Medicine
Wayne State University
Iola Williams, RN, PNP
Coordinator, Sickle Cell Program Department of Hematology/Oncology
Children's National Medical Center
Elliot Vichinsky, MD
Associate Adjunct Professor of Pediatrics
University of California, San Francisco
Many organizations and individuals made significant contributions during the development of this guideline. They are too numerous to list here, but their assistance is appreciated. Peer reviewers, individuals at institutions that provided pilot review, and consultants are acknowledged individually in the contributors section.
All persons, organizations, and agencies with an interest in the sickle cell guideline were invited to participate at a public meeting held in Washington DC on September 24, 1991. The panel gratefully acknowledges the valuable input received.
The panel also wishes to acknowledge input from several Public Health Service agencies including the Food and Drug Administration, the Centers for Disease Control, and the Armed Forces Institute of Pathology.
Mary L. Grady, Center for Research Dissemination and Liaison, Agency for Health Care Policy and Research, edited the guideline and coordinated its production and publication.
Finally, the panel thanks Robert Sprinkle, MD, and Patience Ejiogu-Akinosho, MPA, MPH, for their untiring efforts as research coordinators. Dr. Sprinkle's contributions as a health policy analyst were particularly noteworthy.
This Clinical Practice Guideline on Sickle Cell Disease was developed by a private-sector panel of internists, pediatricians, nurses, a family physician, geneticists, a social worker, a person with sickle cell disease, and the parent of a child with sickle cell disease. The panel was convened and supported by the Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. The guideline makes specific recommendations about the newborn population to be screened for sickle cell disease, laboratory methods for screening and diagnosing the disease, medical management of affected individuals, and counseling of parents whose children have sickle cell disease or trait.
The guideline is based on the best science available. Using the panel's literature search outline, data base specialists at the National Library of Medicine conducted a comprehensive literature search that yielded the titles, and usually the abstracts, of more than 7,000 relevant publications. Of these, over 2,000 papers and monographs were selected for further consideration; hundreds of these were used by the panel in formulating its recommendations. In addition, both oral and written suggestions for elements to be included in the guideline were solicited during an open forum held in Washington, DC, on September 24, 1991. Drafts of the guideline document were submitted for peer review to individuals and organizations representative of the spectrum of components required for a screening program. Peer reviewers assessed its validity, efficacy, and applicability. Most recommendations from this peer review were incorporated into the final document.
Sickle cell disease is a term for a group of genetic disorders characterized by production of hemoglobin S , anemia, and acute and chronic tissue damage secondary to the blockage of blood flow produced by the abnormally shaped red cells. Sickle cell anemia (Hb SS) is the most common type of sickle cell disease and is estimated to affect more than 50,000 Americans. The estimated prevalence of Hb SS in African-American live births is approximately 1 in 375; other common variants of the disease include hemoglobin SC disease (Hb SC) with an estimated prevalence of 1 in 835 African-American live births and sickle beta-thalassemia (S -thalassemia) 1 in 1,667 African-American live births. In the United States, sickle cell disease is most commonly found in persons of African ancestry, but it also affects persons of Mediterranean, Caribbean, South and Central American, Arabian, and East Indian ancestry.
Sickle cell trait is characterized by the inheritance of a normal globin gene and a s globin gene. Persons with sickle cell trait produce both normal hemoglobin and sickle hemoglobin but have a predominance of Hb A. When both parents have sickle cell trait, there is a 25 percent chance with each pregnancy that the infant will have sickle cell anemia.
This guideline on sickle cell disease provides specific recommendations for newborns and infants in several areas, including:
Population to be screened.
Laboratory methods and responsibilities.
Medical followup for infants with disease.
Education and decision-making counseling.
The panel recommends screening all newborns regardless of racial or ethnic background for sickle cell disease. This recommendation is based on several factors. First, twice-daily oral prophylactic penicillin reduces both morbidity and mortality from pneumococcal infections in infants with sickle cell anemia and sickle betao-thalassemia. Second, although sickle cell disease is more prevalent in certain racial and ethnic groups, it is not possible to define accurately an individual's heritage by physical appearance or surname. Screening targeted to specific racial and ethnic groups, therefore, will miss some affected infants, subjecting them to an increased risk of early mortality. Third, screening should benefit all babies equally, as State-sponsored newborn screening programs in the United States are supported at least in part by public funds and often are mandated by State law.
Universal screening is the best and most reliable method for casting the broadest possible net to identify affected infants. In addition to ensuring that all infants benefit equally from the screening program funded by State or Federal money, universal screening also is the most cost-effective screening method.
When feasible, laboratory testing should be linked to other neonatal screening programs to facilitate specimen collection, identification, and handling. There is no single best laboratory method for screening. Several techniques including hemoglobin electrophoresis, isoelectric focusing, and high performance liquid chromatography are acceptable, reliable, and accurate. Recent reports have advocated globin DNA analysis as an additional testing method. At present, this method is both costly and limited in the number of genotypes that can be identified. Metabisulfite sickle cell preparations and Hb S solubility testing, however, are not acceptable screening methods. The screening methodology should be selected in light of the program's available resources and knowledge of the technique and its limitations. The screening laboratory should participate in quality assurance and proficiency testing programs, regardless of the technique employed.
The initial screening sample should not be used to establish a definitive diagnosis for infants with suspected disease. A second sample must be collected from the infant to establish a diagnosis. Definitive diagnosis should be made by the physician caring for the infant using consultation as needed. Techniques to establish the definitive diagnosis include reassessment of the infant's hemoglobin phenotype, measurement of hemoglobin concentration and red cell indices, inspection of the red cell morphology, and correlation with the clinical history. Assessment of the hemoglobin phenotypes of the parents, including the amounts of fetal hemoglobin and hemoglobin A2 and the distribution of fetal hemoglobin within the parents' red cells, is useful in assigning a definitive diagnosis when both parents are available for study. Definitive diagnosis also can be established in some cases by direct analysis of the infant's globin DNA.
The laboratory should be responsible for sending test results to the health provider of record, the screening program's administrative component, and when applicable, the infant's hospital of birth. When permitted by law, test results also should be sent to the infant's mother. Reporting of results should include the hemoglobin phenotype, mention the diagnostic possibilities associated with the phenotype, and identify sources where additional information can be obtained.
Pneumococcal infections in infants with sickle cell anemia and sickle o-thalassemia account for significant morbidity and mortality. It has been documented unequivocally that these infections are reduced significantly by the administration of twice-daily oral penicillin. For this inexpensive and effective therapy to be beneficial, infants identified by screening must be located promptly, definitively diagnosed, and given penicillin. Parents must be educated as to the necessity for complying with this treatment. Parents also must be taught to recognize early signs of specific complications of sickle cell disease and be provided with anticipatory guidance related to the management of these complications. Specific instructions should be given in the recognition of fever, splenic sequestration crisis, respiratory distress, and dehydration. Parents should be taught to take the infant's temperature and be provided with specific guidelines for oral fluid therapy, analgesics, and antipyretics. A trusting relationship between the infant's health care provider and parent is essential, and the parent must be able to contact the provider when the infant is ill.
Appropriate medical followup must include regular visits to assess the child's medical status, administration of age-appropriate immunizations including pneumococcal, conjugated Haemophilus influenzae, and hepatitis B vaccines and provision of other infant-specific health care services. The importance of nutrition and well-child care should be stressed. The provider should assess the family's need for supportive social services, including those related to transportation, financial aid, and mental health, and make appropriate referrals when indicated. The provider also should provide anticipatory guidance related to psychosocial issues relevant to sickle cell disease.
Education services should be offered to all parents of infants who are identified with a hemoglobin abnormality. These services should be nondirective and conducted in an environment conducive to the free exchange of information. Parents should be offered the opportunity to be tested if desired. The education curriculum should define clearly differences between disease and trait conditions and provide information to parents on the risks of having future children with disease. Educators should be sensitive to parental anxieties and be willing to schedule additional sessions as needed. The education component adds substantial cost to the screening program, particularly in those areas where large numbers of African-American individuals reside, as 8 percent of this ethnic group can be anticipated to have sickle cell trait. Single gene educators specifically trained, properly supervised, and monitored can be used to meet this need.
Decision-making counseling should be offered to all parents of infants who are affected with disease and to those parents at risk for having other children infected with disease. This counseling should be provided by persons specially trained for this task, including physicians, genetic counselors, nurses, and medical social workers.
Overriding these recommendations is the basic tenet that a newborn sickle cell screening program must include several components that are operative and fully integrated if the program is to succeed in reducing morbidity and mortality from sickle cell disease. These components include an administrative component, a laboratory component, a medical followup component, and an education/counseling component.
Several different models have been used successfully in the United States to establish and monitor newborn hemoglobinopathy screening programs. In most instances, the State department of health is the agency responsible for the overall conduct of all components of the screening program. Usually that State department of health collaborates with a coordinating or advisory group within the screening jurisdiction.
Laboratory testing may be performed by a State laboratory or contracted to a laboratory based in a medical center, hospital, or other facility. Several strategies have been used to provide education and genetic counseling services. These include the use of State-employed genetic counselors or contracting with counselors who are based either in hospitals or community agencies. Several different approaches have been taken to the medical followup component. Some States provide no support, others provide funding for total care, and still others fund only consultative visits or prophylactic penicillin therapy.
For the screening program to be successful in documenting its ability to meet stated goals, each component must report to the program's administrative group, and the administrative component must have the authority and resources to correct identified deficiencies.
Neonatal screening and comprehensive health care can significantly reduce morbidity and mortality in infants with sickle cell disease. In addition to saving lives and reducing morbidity, neonatal sickle cell disease screening has other benefits, including the identification of individuals with sickle cell trait and other hemoglobin disorders, as well as couples at risk for having a child with a hemoglobin disease.
This guideline makes specific recommendations about the population to be screened for sickle cell disease, the laboratory methods currently acceptable for screening and diagnosis, the care of infants with sickle cell disease, and the provision of educational and decision-making counseling services to parents of affected infants and those whose infants have sickle cell trait.
The term sickle cell disease refers to a group of genetic disorders characterized by the presence of sickle hemoglobin , anemia, and acute and chronic tissue injury secondary to blockage of blood flow by abnormally shaped red cells. Normal hemoglobin, hemoglobin A , is composed of two alpha (a) globin chains and two beta (B) globin chains. In Hb S, the a chain is the same as in Hb A, but the B globin chain differs from the normal by the substitution of valine for glutamic acid at the sixth position (Bs). The most common type of sickle cell disease is sickle cell anemia in which the affected individual is homozygous for the Bs gene. Other common forms of sickle cell disease include the inheritance of the Bs gene and a gene for B-thalassemia (Hb S B-thalassemia) or another abnormal B globin gene. Examples of these latter conditions include Hb SC disease (Hb S and Hb C), Hb S OArab (HbS and Hb OArab) and Hb SD (Hb S and Hb D), and Hb SE (Hb S and Hb E) disease.
The hallmark features of sickle cell disease are chronic hemolytic anemia and both acute and chronic tissue injury. The amino acid substitution in the B globin of Hb S results in polymerization of the Hb S molecules within the red cell upon deoxygenation. This polymerization of Hb S produces a change in the red cell shape from a biconcave disc to a crescent or sickle shape. Upon reoxygenation, the red cell initially resumes a normal configuration, but after repeated cycles of sickling and unsickling, the erythrocyte is damaged permanently and hemolyzes. This hemolysis is responsible for the anemia in sickle cell disease.
The tissue injury is secondary to the obstruction of blood flow produced by the abnormally shaped red cells. All tissues within the body are at risk for damage as a consequence of the vascular obstruction produced by the sickled red cells. The more common complications include painful episodes involving soft tissues and bones, acute chest syndrome, priapism, cerebral vascular accidents, and both splenic and renal dysfunction. In sickle cell anemia, the splenic dysfunction develops during infancy and predisposes the infant to painful episodes involving soft tissues and bones, acute chest syndrome, priapism, cerebral vascular accidents, and both splenic and renal dysfunction. In sickle cell anemia, the splenic dysfunction develops during infancy and predisposes the infant to overwhelming infection from encapsulated bacteria, particularly members of the Streptococcus pneumoniae and Haemophilus influenzae species.
Sickle cell disease is estimated to affect more than 50,000 Americans and has been identified in persons from several different racial backgrounds. The estimated prevalence of the common sickle cell disease variants in African-American live births is approximately 1 in 375 for sickle cell anemia, 1 in 835 for Hb SC disease, and 1 in 1,667 for the sickle B-thalassemia disorders. While sickle cell disease is most commonly found in persons of African ancestry, it also affects persons of Mediterranean, Caribbean, South and Central American, Arabian, and East Indian ancestry.
In sickle cell trait, the individual has inherited both a normal B globin gene and a Bs globin gene. Individuals with sickle cell trait produce both normal hemoglobin and Hb S and have a predominance of Hb A. Red cells from persons with sickle cell trait do not sickle except under adverse circumstances. Persons with sickle cell trait have normal hemoglobin concentrations and normal red cell morphology. Approximately 8 percent of the African-American population in the United States has sickle cell trait. The prevalence of sickle cell trait is lower in other racial and ethnic groups.
The passage of the National Sickle Cell Anemia Control Act in 1972 authorized funding for research, testing, and education related to sickle cell anemia. Funds appropriated within the budget of the National Heart, Lung, and Blood Institute, National Institutes of Health, established several federally funded sickle cell screening programs, as did monies from the Bureau of Maternal and Child Health, Health Resources and Services Administration. These early programs focused on detecting persons with sickle cell trait so that they could be educated about the trait and its genetic implications. Education and genetic counseling for persons with sickle cell trait were important components of these early programs.
Newborn screening for sickle cell disease began in the United States in the early 1970s. These initial screening programs grew out of the recognition that sickle cell anemia was associated with significant morbidity and mortality. In 1970, the estimated median expected survival was 20 years for affected persons living in the United States (Scott, 1970). With advances in the diagnosis, treatment, and prevention of complications, the life expectancy of persons with sickle cell disease has improved. Presently there is an 85 percent chance that infants with Hb SS will survive to age 20 and a 92 percent change that babies born with Hb SC will survive to a similar age, (Leikin, Gallagher, and Kinney, 1989).
The principal causes of death in infants with Hb SS disease are overwhelming infections with Streptococcus pneumoniae organisms, cerebral vascular accidents, and acute splenic sequestration crisis (Emond, Collis, Darvill, et al., 1985 ; Leikin, Gallagher, and Kinney, 1989). The predisposition to pneumococcal infection is secondary to the functional asplenia that develops within the first 2 years of life (Pearson, Gallagher, Chilcote, et al., 1985). Twice-daily oral penicillin reduces both the morbidity and mortality from pneumococcal infection (Gaston, Verter, Woods, et al., 1986). Teaching parents to recognize the early signs of splenic sequestration crisis should reduce deaths from this complication.
Although laboratory procedures to detect sickle hemoglobin in newborns have been available for nearly two decades, neonatal screening for sickle cell disease was not widely implemented by State screening programs until the late 1980s (Garrick, Dembure, and Guthrie, 1973 ; Gilman, McFarlane, and Huisman, 1976 ; Schneider, Gustafson, and Haggard, 1970). Arguments against neonatal screening included the contention that little could be done to reduce either morbidity or mortality once sickle cell disease was detected. This position prevailed despite evidence that early identification and entry into comprehensive care favorably affected overall morbidity and mortality (Powars, Overturf, Weiss, et al., 1981). The position was invalidated by a randomized controlled clinical trial which demonstrated that twice-daily oral penicillin reduced both mortality and morbidity from infectious complications of sickle cell anemia (Gaston, Verter, Woods, et al., 1986).
Following the report on the beneficial effects of prophylactic penicillin, the National Institutes of Health convened a Consensus Conference to review evidence about the benefits of newborn screening for sickle cell disease. The conference panel concluded that screening could reduce morbidity and mortality, provided the screening program was linked to the provision of comprehensive health care services to affected infants (Consensus Conference, 1987).
Shortly after these findings were disseminated, sickle cell screening in the United States became widespread. The proliferation of screening programs was stimulated by funds from the Bureau of Maternal and Child Health which were earmarked to support screening programs that could demonstrate the ability of neonatal hemoglobinopathy screening to reduce morbidity and mortality. Today, newborn hemoglobinopathy screening is performed in more than 40 States, the District of Columbia, Puerto Rico, and the Virgin Islands. The remarkable growth in screening programs within the past few years illustrates how Federal and State partnerships can dramatically improve the quality of health care programs.
Although the findings of the Consensus Conference were published 6 years ago, there remain many unresolved issues surrounding neonatal sickle cell disease screening related to:
Definition of the essential screening program components and their respective responsibilities.
Definition of the population to be screened.
Standards for sample identification, collection, and shipment.
Standards for laboratory methods, quality control, quality assurance, and result reporting.
Education and genetic counseling services for the parents of identified heterozygotes and infants with disease.
Medical care for infants with sickle cell disease.
Cost effectiveness of neonatal sickle cell screening.
This guideline was developed to address each of these problematic areas. The guideline emphasizes the required components for a program, defines the population to be screened, addresses important laboratory and genetic counseling issues, and describes essential health services for infants identified with sickle cell disease. The guideline also discusses the cost effectiveness of neonatal screening for sickle cell disorders.
The panel recognizes that financial constraints may prevent a particular screening program from meeting all recommendations within the guideline. This guideline, however, provides the framework for the implementation and conduct of a screening program that will achieve the ultimate objective of reducing infant morbidity and mortality from sickle cell disease.
One of the panel's primary objectives was to determine the prevalence of sickle cell disease in different racial and ethnic newborn populations. Other objectives included determining the prevalence of other hemoglobinopathies that might be detected during screening. These data can be used to estimate the total cost and benefit of screening programs. Issues for future research are discussed at the end of this chapter.
All newborns should be screened for sickle cell disease by accurate laboratory techniques. The purpose of such screening is to reduce morbidity and mortality from sickle cell disease. Screening also can identify infants with sickle cell trait, as well as homozygotes and heterozygotes for other hemoglobin variants. Screening of populations with a low prevalence of Hb S is cost-effective when the screening is integrated into a laboratory that is also testing samples from a population with a high prevalence of Hb S.
This recommendation is based on the following analysis of various racial and ethnic populations and the reduction of morbidity and mortality from sickle cell disease by early identification, when coupled with comprehensive medical care and utilization of penicillin prophylaxis.
To evaluate the effectiveness of a screening program, several factors must be assessed (Frame, 1986). These include the incidence (or in the case of genetic abnormalities, prevalence) of the condition to be identified by the screening test. Sickle cell disease is more prevalent in some racial groups than in others. If prevalence differs between identifiable subgroups within the population, then it must be determined if the most cost-effective approach is to screen the entire population or only specific subpopulations.
Although many studies on the prevalence of sickle cell disease have been published, it is difficult to define accurately the probability that a specific newborn will have this condition. The U.S. population is very heterogeneous and is constantly changing, making it difficult to define with certainty the race of a specific individual. Race cannot be assigned solely by phenotypical characteristics or surnames. Similarly, race cannot be accurately defined by self-report or by the race of the parents, as these may differ. The lack of uniform standards for recordkeeping of racial or ethnic statistics may contribute to significant errors in the published reports of the prevalence of sickle cell disease in specific racial or ethnic groups.
Because of these difficulties, the guideline makes several assumptions.
The same method of assessing race and ethnicity that was used in the studies cited below will be used in the future to implement the guideline if such identification is required.
Data in the cited studies represent the U.S. population as a whole, and the studies represent independent samples from that population.
There often is significant heterogeneity within an ethnic group. For example, Hispanics (or those with Hispanic surnames), include European Spaniards, as well as persons from the Caribbean Islands, Mexico, and Central and South America. This guideline utilizes the Census Bureau's methods for defining specific ethnic groups.
A panel subcommittee was formed to develop prevalence estimates. The data used for the prevalence estimates cited in this guideline were derived primarily from a literature search described elsewhere in this guideline. The search produced 1,111 references dealing with population characteristics. After multiple reviews of the title and abstract lists, citations were selected for retrieval and data extraction. Articles were reviewed several times, and data were extracted using a standardized format. The panel's methodologist and subcommittee chair reviewed each article and the extracted data for completeness and accuracy. Twenty-two citations were used in this analysis.
Articles with data on the prevalence of hemoglobinopathies in U.S. population groups were categorized as follows.
Group 1 -- Articles with data on the prevalence of hemoglobinopathies among specific ethnic groups.
Group 2 -- Articles with data by geographic area and information about the ethnic/racial population studied but without prevalence data on specific ethnic/racial groups.
Group 3 -- Articles with data by geographic area alone, with no ethnic or racial data.
Articles that had no data, only had data about non-U.S. populations, or were judged by the reviewers to have serious flaws in methodology were not included. Following categorization, Group I contained 11 articles (Broghamer Jr, Lockwood, and Keeling 1981 ; Carr, and Chapatwala, 1988 ; Diaz-Barrios, 1989 ; Gardner, and Keitt, 1988 ; Grover, Wethers, Shahidi, et al., 1978 ; Huisman, Harris, Stewart, et al., 1991 ; Mack, 1989 ; Meany, and Riggle, 1992 ; Pass, Gauvreau, Schedlbauer, et al., 1986 ; Powars, 1989 ; Ralston, Kmetz, Keeling, et al., 1981 ; Therrell, Simmank, and Wilborn, 1989) and data from the Council of Regional Networks for Genetic Services . Three articles were included in Group II (Anyane-Yeboa, 1989 ; Harris, and Eckman, 1989 ; Vichinsky, Hurst, Earles, et al., 1988). Seven articles (Barnes, Komarmy, and Novack, 1972 ; Castro, Winter, Lee, et al., 1981 ; Foster, Forbes, Hayes, et al., 1981 ; Lobel, Cameron, Johnson, et al., 1989 ; Pearson, 1989 ; Schedlbauer, and Pass, 1989 ; Wethers and Grover, 1986) and additional data from CORN (not broken down by ethnic group) were included in Group III. Only Group I data were used to estimate prevalences.
Data from the articles in each group were collected in separate data bases on IBM compatible microcomputers; dBase IV software was used to build, maintain, and query these three data bases. The software was also used to compute prevalence rates at birth in those cases where the published data only contained raw numbers.
Data were displayed in the form of printed tables for review by the subcommittee. Data in two classes were eliminated from further consideration: (1) data that were clearly incomplete (that is, indicated prevalence rates of trait that were near or below disease rates, or indicated disease rates that were at least an order of magnitude higher than otherwise indicated for the population studied) and (2) data that were superseded by newer, more complete data from the same or a related source.
In some cases, the subcommittee contacted authors to determine whether additional data were available to fill in missing data in the published literature. Additional unpublished data were received from Dr. Astrid Mack 1 to supplement the published data on Florida prevalences.
A key source of data was the CORN 1990 Newborn Screening Report (Meany and Riggle, 1992), which contained data from many State screening programs. The CORN data represent the most recently published data but do not include a separate category for Hispanics. These data were combined separately from the other literature as well as with the rest of the literature.
The data were analyzed with Bayesian meta-analysis, using the FAST*PRO program (Eddy, and Hasselblad, 1992) (with Jeffrey's noninformative priors). Meta-analysis was used to help estimate the prevalence of sickling diseases for each ethnic and/or racial group for which data were available.
| Race and/or ethnic group | Mean prevalence | 95% confidence interval |
|---|---|---|
| White | 1.72 | 1.06 - 2.66 |
| White | 1.90 | 1.09 - 3.10 |
| Black | 289.00 | 277 - 300 |
| Black | 274.00 | 250 - 300 |
| Hispanic, total | 5.28 | 2.60 - 9.61 |
| Hispanic, Eastern States | 89.80 | 27.0 - 190 |
| Hispanic, Western States | 3.14 | 1.19 - 6.86 |
| Asian | 7.61 | 1.85 - 57.2 |
| Asian | 8.75 | 2.11 - 1.99 |
| Native Americans | 36.20 | 0.0351 - 182 |
| Race and/or Ethnic Group Interval | Mean prevalence | 95% confidence |
|---|---|---|
| White | 242 | 234-251 |
| White | 258 | 247-267 |
| Black | 7000 | 6910-7090 |
| Black | 6550 | 6530-6770 |
| Hispanic, total | 579 | 545-615 |
| Hispanic, Eastern States | 3040 | 2590-3550 |
| Hispanic, Western States | 508 | 476-543 |
| Asian | 133 | 103-169 |
| Asian | 106 | 77.6-142 |
| Native Americans | 181 | 30.1-464 |
| Race and/or Ethnic Group Interval | Mean prevalence | 95% confidence |
|---|---|---|
| White | 5.550 | 4.62-7.10 |
| White | 0.853 | 0.355-1.75 |
| Black | 35.300 | 28.6-43.1 |
| Black | 33.200 | 25.4-42.7 |
| Hispanic, total | 12.2 | 7.75-18.2 |
| Asian | 235.000 | 194-282 |
| Race and/or Ethnic Group Interval | Mean prevalence | 95% confidence |
|---|---|---|
| White | 223 | 215-2320 |
| White | 241 | 230-252 |
| Black | 332 | 325-339 |
| Black | 368 | 359-377 |
| Hispanic, total | 189 | 169-210 |
| Asian | 323 | 307-339 |
The data presented in this section of the guideline are from sickle cell screening programs. Although the results were obtained by different screening methods, the results are remarkably consistent for most races and ethnic groups. The data, however, show a marked difference between Hispanics from the Eastern United States (primarily Caribbean or Latin American origin) and those who live in the Western States (primarily of Mexican origin). Data for the Western States are from Texas and California; data for the Eastern States are from Florida and New York. Our analysis of these data revealed that Hispanics from the Eastern States have sickle cell disease rates approaching rates in the black population, while Hispanics from the Western States have lower rates, approximating those in the white population. This difference is not apparent when Hispanics are viewed as a single group.
Although no cases of sickle cell disease were encountered in Native Americans, the data for Native Americans are too sparse to yield conclusions about the prevalence of sickle cell disease in this group. The data also do not permit assessment of the prevalence of sickle cell disease among different Asian groups.
The CORN data demonstrate different prevalences of sickle cell disease among the black populations in different States. Figure 1
shows the density function for
sickle cell for each State and the effect of using meta-analysis to combine these results.
Louisiana and California (curves for these States peak on the left side of the figure) show
lower prevalences of sickle cell than Texas, Virginia, and Michigan (curves peak on the right).
Wisconsin (the broader peak on the left) lies in the middle. The dotted line represents the
results of the meta-analytic combination of the other lines. The reason for these differences
is not known, but they may stem from a difference in the admixture between racial and ethnic
groups in these areas. It should be emphasized that the selection of racial and ethnic
categories for use in this analysis does not imply that any of these groups are pure or even
consistently identified. For example, our analysis shows a higher prevalence of sickle cell
disease among whites than the analysis by Tsevat and colleagues (1991) . This is likely due to the inexact determination (or even
definition) of white. However, to the extent that the methods used to determine race or
ethnicity in our analysis are the same as those used in a future study, the same results should
be obtained.
Although there are significant reasons to believe that the populations studied do differ by location, the use of the hierarchic approach biased the results into higher prevalences. This occurred because many of the samples were of small to moderate size and had zero occurrences. When a large study with a low prevalence is combined with a small study with zero prevalence, the hierarchic approach yields a prevalence estimate that is higher than the prevalence of the large study. As a result, it was felt that straight Bayesian meta-analysis would yield a more accurate estimate of the mean. However, the use of Bayesian meta-analysis resulted in unreasonably tight confidence intervals that are difficult to believe. There is greater (but not measured) uncertainty about the estimates than indicated by the confidence intervals.
The cost-effectiveness of universal neonatal hemoglobinopathy screening is a complicated issue. Tsevat and colleagues (1991) found that the cost per life saved by universal screening would vary greatly among those populations with mixed racial composition. They equated the cost-effectiveness of universal screening solely with the prevention of death from pneumococcal sepsis by the administration of prophylactic penicillin to infants whose sickle cell disease would otherwise have been unrecognized prior to age 3 years. Their adaptation of risk-reduction data from the Prophylactic Penicillin Study (PROPS), however, biased their results against a policy of early diagnosis (Gaston, Verter, Woods, et al., 1986). All patients in PROPS were known to have sickle cell disease prior to entry, and all were followed carefully; almost two-thirds of the patients were older than 12 months when enrolled. Further, the theoretical population on which Tsevat's most striking result was based does not correspond to any existing U.S. screening jurisdiction.
Lane and colleagues (1992), using a computerized decision model to analyze their experience in Colorado, found that easily overlooked procedural and administrative costs associated with targeted screening could be high enough to make universal screening less expensive. Hidden costs included loss of economy of scale in the screening laboratory and additional personnel costs for determining each infant's ethnic background.
Sprinkle, Hynes, and Konrad (in press) projected the costs of finding cases of sickle cell disease in 53 U.S. jurisdictions (the 50 States, the District of Columbia, Puerto Rico, and the Virgin Islands) through universal neonatal hemoglobinopathy screening. They compared these costs to the costs projected for finding cases of phenylketonuria (PKU) through the universal neonatal screening practices long established for PKU in the same jurisdictions. Their estimates suggested that 35 jurisdictions would be able to find a case of sickle cell disease for less, often far less, than one-half the cost of finding a case of PKU. The remaining 18 jurisdictions could substantially reduce the per-case costs, typically for finding both diseases, by combining efforts with other States. In fact, many States already have used this approach to reduce costs. States with relatively few African-Americans tended to be States with small populations in which the efficiency of screening for PKU and other metabolic diseases also could be enhanced by such combination, whether or not they decided to screen for hemoglobinopathies. States deciding to simplify the screening of neonates at high risk for sickle cell disease by testing all neonates, regardless of racial classification, would have little trouble finding demographically complementary screening partners with which to form low-cost screening composites.
Although more than 40 States now screen for sickle cell disease, the number of States reporting usable data to CORN remains low. Much of the reported data are inconsistent or incomplete and could not be used in this analysis. Since the data reported here are not correlated with the type of screening program (universal vs. targeted), there is still some room for error. Improved and, more importantly, uniform methods for identifying and classifying subsets of the population are needed. Population subsets other than the general categories of blacks and whites still lack sufficient size to yield meaningful results. The prevalence among Hispanics, when analyzed by geographic area, reflects differences that should be substantiated with further data. In addition, researchers should investigate possible differences among Asians. An additional analysis of the cost- effectiveness of sickle cell screening for low-risk populations should be undertaken. This analysis should use actual prevalence data and include the benefits of early detection of sickle cell disease beyond the life-saving effects of penicillin prophylaxis.
The laboratory must use a screening procedure that will detect sickle hemoglobin in the newborn. The laboratory has a responsibility to transmit the infant's results to the infant's health care provider and hospital of birth. Test results must be reported in understandable language that includes the identified phenotype, diagnostic possibilities, and sources where additional information may be obtained. The laboratory also should inform the infant's mother of the screening result, unless prohibited by law.
The laboratory is responsible for detecting conditions in which sickle hemoglobin is present. The primary goal is to screen for sickle cell disease, including its common forms: sickle cell anemia (Hb SS), sickle-hemoglobin C disease (Hb SC), S beta+-thalassemia (Hb S B+-thalassemia), and SB°-thalassemia (Hb S B°-thalassemia), as well as uncommon types such as Hb S-D Punjab, Hb S/OArab, Hb S/Lepore, and Hb SE. Screening also will identify persons with sickle cell trait, hemoglobin C trait and disease, hemoglobin E trait, and Hb E disease.
Other laboratory responsibilities include accurate recordkeeping, the results reporting process, and quality assurance.
The principal hemoglobin in the newborn is fetal hemoglobin . Hb F is composed of two alpha (a) and two gamma (g) globins. During the last trimester, there is a progressive increase in B globin synthesis and a decrease in g-chain synthesis. In the normal-term infant, about 80 percent of the non-a globin is g-globin and 20 percent is globin. This accounts for the normal term infant having approximately 80 percent Hb F and 20 percent Hb A. Because the infant with sickle cell trait has both a normal B gene and a Bs gene, the infant will have a predominance of Hb F and both Hb A and Hb S. There always will be more Hb A than Hb S in these infants because a chains preferentially pair with normal B chains.
In normal infants, g-chain synthesis declines rapidly with a corresponding increase in B globins. By 1 year of age, the normal infant will have only 1 to 2 percent Hb F and 95+ percent Hb A. The remainder of the hemoglobin is Hb A2, composed of two a and two delta (d) globin chains.
| Cellulose Acetate | Isoelectric Electrophoresis | High Performance Focusing | Liquid Chromatography |
|---|---|---|---|
| Equipment cost | $2,500 | $4,000 | $30,000 |
| Cost per test (consumables) | $0.15-0.25 | $0.35-0.50 | $0.10-1.75 |
| Samples run per hour | 200 | 72 | 5-20 |
| Advantages | Semi-quantitative Simple to operate | Sharper bands | Automated Quantitative |
| Disadvantages | Densitometer for quantitation | Densitometer for quantitation | Complex to use |
Note: Labor costs will vary with number of samples per run.
| Cord Blood | Heel Stick | Heel Stick Heparinized Capillary | Filter Paper |
|---|---|---|---|
| Person obtaining specimen | RN or MD | RN or technician | RN or technician |
| Volume of sample | 3-5mL | 40µL | 10µL |
| Stability of sample | 2 weeks, 4°C | 1-2 weeks, 4°C | 1-2 weeks, 20°C |
| Equipment | Collection tube | Lancet Capillary tube | Lancet Filter paper |
| Cost per Specimen | $0.20 | $0.08 | $0.06 |
| Advantages | Sharp bands on testing sample volume Other specimens may be collected at same time | Sharp bands on testing | Easy to ship Easy to label Other specimens may be collected at same time |
| Disadvantages | Shipping difficult Labeling difficult May break in transit | Shipping difficult Labeling difficult May break in transit | Blurred bands |
| Author and Year | Laboratory Methods | Number Screened | Number retested | Number true positives | Number false negatives | Sensitivity (percent) | Comments |
|---|---|---|---|---|---|---|---|
| Kramer, et al., 1979 | CA/AG | 3,976 | 138 | 26 [1] | 0 | 100 | Only sample of trait and AA retested |
| Galacteros, et al., 1980 | CA/AG | 835 | 835 | 3 [1] | 0 | 100 | |
| Pass, et al., 1986 | CA/AG | 3,942 | 2,433 | 59 [1] | 8 | 88 | AA not retested. |
| Gardner and Keitt, 1988 | CA/AG | 2,058 | 154 | 17 [2] | 0 | 100 | Estimates adjusted to account for only 47% of traits retested. |
| Griffiths, et al., 1988 | CA/AG | 40,445 | 156 | 21 [1] | 0 | 100 | AA not retested. Retrospective review of AS. |
| Githens, et al. 1990 | CA/AG | 526,711 | 1,694 | 74 [1] | 10 | 88 | AA not retested. 53% of traits retested. |
| Kinney, et al., 1989 | CA/AG | 10,783 | 115 | 20 [2] | 0 | 100 | Only a sample of AA and trait retested. |
| Lobel, et al., 1989 | CA/AG | 48,000 (approx) | ? | 79 | 4 | 95.2 | AA not retested. |
| Wethers (unpublished) | CA/AG | 10,000 | 8,500 | 16 [2] | 1 | 94.1 | Initial testing of cord blood followed by capillary specimen sent |
| Galacteros, et al., 1980 | IEF | 835 | 835 | 3 [1] | 0 | 100 | |
| McMahon (unpublished) | IEF | 1,754 | 1,754 | 11 | 0 | 100 | |
| Kleman and Lorey (unpublished) | HPLC/IEF | 1,182,202 | 4,663 | 553 [3] | 1 | 99.99 | Screening by HPLC and confirmation by IEF. AA not retested. Only 25% of trait retested. |
* Sensitivity of pooled data using cellulose acetate followed by citrate agar: 93.1%.
Note: CA = cellulose acetate hemoglobin electrophoresis, alkaline pH; AG = agar gel hemoglobin electrophoresis, acid pH; IEF = isoelectric focusing; HPLC = high performance liquid chromatography. Result from testing of original specimen is confirmed by testing second specimen.
| Author and Year | Laboratory Methods | Number Screened | Number retested | Number true positives | Number false negatives | Sensitivity (percent) | Comments |
|---|---|---|---|---|---|---|---|
| Kramer, et al., 1979 | CA/AG | 3,976 | 138 | 110 [1] | 0 | 100 | See Table 7 |
| Galacteros, et al., 1980 | CA/AG | 835 | 835 | 833 [1] | 2 | 99.8 | |
| Gardner and Keitt, 1988 | CA/AG | 2,058 | 154 | 220 [2] | 4 | 98.2 | Estimates adjusted to account for only 47% of traits retested. |
| Kinney, et al., 1989 | CA/AG | 10,783 | 115 | 951 | 0 | 100 | Only a sample of AA and trait retested. |
| Wethers (unpublished) | CA/AG | 8,500 | 8,500 | 8,484 [1] | 2 | 99.9 | See Table 7 |
| Galacteros, et al., 1980 | IEF | 835 | 835 | 835 [1] | 0 | 100 | |
| McMahon (unpublished) | IEF | 1,754 | 1,754 | 11 | 0 | 100 |
* Sensitivity of pooled data using cellulose acetate followed by citrate agar: 99.9%.
Note: CA = cellulose acetate hemoglobin electrophoresis, alkaline pH; AG = agar gel hemoglobin electrophoresis, acid pH; IEF = isoelectric focusing; HPLC = high performance liquid chromatography. Result from testing of original specimen is confirmed by testing second specimen.
| Author and Year | Cellulose Acetate Disease | Citrate Agar Disease | Cellulose Acetate Followed Citrate Agar Disease | Isoelectric Focusing Disease | Column Chromatography [1] Disease | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Yes | No | Yes | No | Yes | No | Yes | No | Yes | No | |
| Galacteros, et al., 1980 | 5 | 783[2] | 5 | 783[2] | 3 | 785 [2] | ||||
| Schedlbauer and Pass, 1989 | 3 | 3,270 | 3 | 3,270[3] | ||||||
| Hicks and Hughes, 1975 | 26 | 483 | 27 | 483 | ||||||
| Jacobs, et al., 1986 | 11 | 81[2] | 11 | 81 [2] | 11 | 81 | ||||
| Schmidt, et al., 1976 | 3 | 831[2] | 3 | 831 [2] | ||||||
| Schroeder, et al., 1975 | 1 | 185 | ||||||||
Hemoglobins with similar charges have similar migration patterns during electrophoresis. Many more hemoglobins have similar motility on cellulose acetate. For example, hemoglobins D and G have migration patterns similar to hemoglobin S; Hb E and Hb OArab migrate similar to Hb C.[2] Hb F migrates between Hb A and Hb S on cellulose acetate at alkaline pH. In the newborn who has a large amount of Hb F, care must be taken to detect small amounts of Hb A and Hb S reliably.
Citrate agar electrophoresis is particularly useful because it separates clearly Hb F, A, S, and C. Agar electrophoresis distinguishes Hb S from G or D, and Hb C from E or O. Agar electrophoresis is rarely used as the primary electrophoretic method for screening, but it is used by many laboratories to confirm the presence of abnormal hemoglobins found by another technique. This practice of employing two laboratory methods is called a two-tier screening technique.
There are two tests for detection of Hb S that should not be used for newborn screening. These tests are: (1) the sickle cell preparation using sodium metabisulfite and (2) a solubility test using a concentrated phosphate buffer, a hemolyzing agent, and sodium dithionate. Both depend on the concentration of Hb S in the red cell or hemolysate. The low level of S hemoglobin in cells of the neonate is believed to explain the unreliability of these tests during the newborn period (Huntsman, Metters, and Yawson, 1972). These two methods should not be used for newborn screening or to confirm the presence of Hb S in the newborn.
The newborn sickle cell screening system is responsible for ensuring that the report of an infant identified as possibly having sickle cell disease is sent to the provider responsible for medical followup. The report must clearly indicate the likelihood that the infant may have sickle cell disease and stress the urgency for immediate followup.
| Screening Phenotype [1] | Possible Genotype | Parents [2] | Clinical Significance |
|---|---|---|---|
| FS | SS | AS x AS | Usually serious |
| S Beta°-thalassemia | AS x ATH° | Usually serious | |
| S/HPFH | AS x A/HPFH | None | |
| FSA | S Beta± thalassemia | AS x ATH+ | Variable |
| FSC | SC | AS x AC | Variable |
Distinguishing between sickle trait and sickle B+-thalassemia relies on estimating the relative proportions of hemoglobins A and S, as there is always more Hb A than Hb S in persons with sickle cell trait. Since these proportions can be difficult to estimate, great caution must be used. If a question exists, it is advisable to report the sample as probable S B+-thalassemia.
At a minimum, reports from the laboratory should be sent to the hospital of birth, the health care provider responsible for the child (if one has been identified), and the administrative office of the survey program. Health care providers should be notified of patients with clinically significant disease by certified mail to stress the importance of immediate action (Broghamer Jr, Lockwood, and Keeling, 1981). Records must be kept and assessed regularly to assure that all infants identified with possible disease are located and provided with followup that includes confirmation of the screening result and assignment of a definitive diagnosis. Since followup may be difficult (Miller, Stilerman, Rao, et al., 1990), lines of responsibility must be clearly drawn.
Whether the infant's parents should be notified directly depends largely on local circumstances or law. Sending such a report assures that the parents are informed, but if prior education about screening was inadequate or absent, unnecessary anxiety may be created by the report. Reports to parents should be delivered by mail. In those instances where disease is suspected, a telephone call to parents may be used. There are advantages to making the call either before or after the estimated arrival of the letter. The person making the telephone call must be specially trained.
| Venous Blood | Capillary Blood | (Heparinized Tubes) |
|---|---|---|
| Volume of sample | 2-5mL | 120-160µL (3-4 tubes) |
| Stability of sample | 2 weeks, 4°C | 1 - 2 weeks, 4°C |
| Equipment | Needle, Syringe, Tube | Lancet Tubes |
| Cost per specimen | $0.20 | $0.09 - $0.12 |
| Advantages | Similar to screening tests | |
| Disadvantages | Similar to screening tests | |
| Citrate Agar | Immunologic Electrophoresis | DNA Analysis Testing | |
|---|---|---|---|
| Equipment cost | Can use same equipment as for cellulose acetate electrophoresis | None for commercial kit. | Polymerase chain reactor $10,000. |
| Cost per specimen | $1-$1.50 (for commercial plates; negligible for homemade plates). | $3.50-$3.75 | $5-$100 |
| Advantages | Objective endpoint. Distinguishes S and C from G, D, E, O. | Easy to perform diagnosis from first sample if enough probes are used. | Definitive. |
| Disadvantages | Mobility of bands depends on concentration. Some extra bands. Not all lots of agar are satisfactory. | Commercial kits only test for Hb A and S. | Separate probe needed for each mutation. |
Definitive diagnosis should be established by a two-tier testing routine, immunoassays, or DNA analysis. Additional tests must include examination of the infant's blood smear and measurement of the infant's hemoglobin concentration and red cell indices. When both parents are available for testing and agree to be tested, characterization of the parents' hemoglobin phenotype and their levels of Hb A2 and Hb F can facilitate a definitive diagnosis for the infant. When one or both parents are unavailable for study, analysis of the infant's B globin gene complex by DNA/RNA methods may yield a definitive diagnosis.
The parent should be given an identification card bearing the child's definitive diagnosis, the facility that made the diagnosis, and sufficient information to permit rechecking of the laboratory records at a later date. Results of all confirmatory tests should be reported to the administrative office of the screening program to ensure that program objectives are met. As a component of laboratory quality assurance, it is essential that confirmatory test results be reported to the screening laboratory.
The procedures for establishing a definitive diagnosis must be comprehensive enough to include not only infants with sickle cell disease, but also those who may have other hemoglobin disorders (Hb CC, Hb EE, or E B-thalassemia) and those with other less common hemoglobin variants.
The laboratory must participate in a proficiency testing program and, when feasible, should retest at least a sample of all newborns screened to determine the sensitivity and specificity of its screening methodology.
There are multiple sources of error in screening for sickle cell disease. These include:
Sampling errors, including incorrect labeling of sample, contamination of sample with maternal blood or transfusion, and improper collection.
Transportation errors, including delays and exposure to high temperature.
Testing errors, including poor technique, improper methods, or incorrect interpretation.
Reporting errors secondary to patient misidentification or clerical errors.
Errors in retesting, similar to the above.
All testing must be done by laboratories licensed by their respective States and must meet the requirements of the Clinical Laboratory Improvement Act of 1988 (CLIA 88). As part of the CLIA requirements, laboratories must meet standards for quality control and must participate in an extramural proficiency testing program (Therrell, Panny, Davidson, et al., 1990). Such a program (ISQAL) for neonatal hemoglobinopathy testing has been established recently by the Centers for Disease Control. Of 37 States that participated, only 21 performed a two-tier test (Adam, and Bell, 1992). Of the 36 laboratories that participated in the study, 35 (97%) recognized that a sample from a carrier of hemoglobin D did not contain hemoglobin S; but 2 of 36 laboratories misdiagnosed a sample from an infant with sickle cell anemia. Filter paper samples that had been in transit for 3 to 10 days showed the same percentages of hemoglobins F, A, D, C, and S as they had contained initially, confirming earlier reports of filter paper sample stability for this length of time.
Results of followup testing must be considered a part of the proficiency testing process and be included with the results of other proficiency tests. Based on the evidence presented, it is suggested that both false-positive and false-negative reports should each be less than 0.01 percent of total samples.
The sensitivity and specificity of laboratory methods that detect sickle cell trait, other trait conditions, and the normal hemoglobin phenotype have not been defined for newborns because no studies have been done where infants with these conditions were retested at a later date. As part of the laboratory's quality assurance program, consideration should be given to developing a plan where statistically valid random samples from infants with all phenotypes would be retested to establish rates of sensitivity and specificity for the testing methods. The infants could be located through well-baby clinics. Careful explanations to the parents would be a requirement for such a program. While the cost of this type of program may be prohibitive, it would be desirable to ensure the accuracy of the screening methodology.
The evidence presented in this section suggests that cellulose acetate followed by citrate agar hemoglobin electrophoresis, isoelectric focusing, or high performance liquid chromatography are acceptable laboratory methods for screening newborns. The selection of a specific method should be based upon the personnel and financial resources available to the laboratory. The laboratory must function as a component of a comprehensive newborn screening program.
The health care provider who is notified that a newborn has a positive screening test for sickle cell disease has the responsibility of promptly establishing a definitive diagnosis. Parents of affected infants should be educated about the disease, the importance of ongoing care, and the critical role they can play in early detection and management of infections and complications.
The 1987 Consensus Development Conference on Newborn Screening for Sickle Cell Disease (Consensus Conference, 1987) concluded that newborn screening for sickle cell disease is essential. This conclusion was based on studies showing that prophylactic penicillin and comprehensive care provided by knowledgeable clinicians dramatically reduced mortality in sickle cell disease.
The Guideline Panel found clear, compelling evidence to support this conclusion. It is therefore imperative that the physician caring for the child with sickle cell disease establish a definitive diagnosis and provide appropriate education and counseling to the child's parents. When the infant is affected with Hb SS or Hb S Bo-thalassemia, prophylactic penicillin must be started by no later than 2 months of age. Since acceptable screening tests have a high degree of sensitivity and specificity, the infant who tests positive for sickle cell disease should be treated as a severely affected infant until a definitive diagnosis is established.
The Panel reviewed published evidence that early entry into care is difficult to achieve, especially for inner city families, in rural areas, and in other instances where families live far from the source of care (Listernick, Frisone, and Silverman, 1992 ; Miller, Stilerman, Rao, et al., 1990). The task is simplified if the parent is already familiar with the newborn screening program in their locality. In many followup programs, public health or community health nurses make the initial contact with parents of infants who have positive screening tests. The first contact is crucial in facilitating the family's involvement in comprehensive health care management (Wright, Brown, and Davidson-Mundt, 1992). If the newborn screening program provides a well-structured followup component, almost all newborns identified as affected can be entered expeditiously into care.
Since the original test is a screening test, the health care provider must establish a definitive diagnosis. Establishing a definitive diagnosis requires several steps, depending upon the hemoglobin phenotype identified by initial testing. In those instances where the type of sickle cell disease involves two abnormal Bglobins (Hb SE, Hb SD, Hb SOArab), the definitive diagnosis is established if the hemoglobin phenotype on a second sample is identical to the initial phenotype.
In those instances where the screening result has an FS phenotype, definitive diagnosis is more difficult because there are several different genotypes which have the FS phenotype in the newborn. Examples of the different genotypes include: sickle cell anemia ( Bs/Bs), Hb S Bo-thalassemia ( Bs/B o), Hb S B+-thalassemia ( Bs/ B+), and Hb S in association with the hereditary persistence of fetal hemoglobin.
Definitive diagnosis of the FS phenotype requires correlation with the infant's hemoglobin concentration, red cell indices, and red cell morphology. Definitive diagnosis can be facilitated by assessment of hemoglobin phenotype and quantities of Hb A2 and Hb F in the parents. Before the father is tested, the mother should be told that testing of the father may uncover non-paternity (Whitten, 1989). Methods for establishing the hemoglobin phenotype are discussed in the laboratory section of this guideline.
The first visit to the health care provider is the occasion to explain in simple language the basic facts about sickle cell disease. These basics should include a discussion of the signs and symptoms of the disease, its pathophysiology, and its mode of inheritance. The provider must educate the family about the clinical course of the disease, including what to expect, what to do, when to call for help, and how to reach help quickly (Rowley, and Huntzinger, 1983 ; Warren, Carter, Humpert, et al., 1982). It is essential that the parents become knowledgeable about routine child care responsibilities, including the measurement of body temperature. Nursing personnel are usually able to provide instruction on home management (Day, Brunson, and Wang, 1992). Several articles by experienced clinicians stress the importance of educating the parent (Brown, Miller, and Agatisa, 1989 ; Vichinsky, and Lubin, 1987). The education provided by the physician, nurse, social worker, and when available, support groups will assist parents greatly in complying with care (Davies, and Brozovic, 1989 ; Pearson, 1986 ; Vichinsky, Hurst, Earles, et al., 1988). The focus of the educational effort must be to teach parents to avoid, anticipate, and recognize problems. The provider must be sensitive to the earliest signs of illness and the importance of preventive care. In addition, providers must display empathy and be accessible in order to establish a long-term relationship with the parent and child.
Children with sickle cell anemia and the S Bo-thalassemia genotype are anemic by the age of 2 to 3 months (Bainbridge, Higgs, Maude, et al., 1985 ; O'Brien, McIntosh, Aspnes, et al., 1976), although those with SC and S B+-thalassemia may maintain their hemoglobin and hematocrit levels in the normal or near normal range. The health care practitioner should establish the child's individual steady-state hematologic baseline by obtaining a complete blood count and reticulocyte count periodically during visits for health care maintenance. This type of information should be given to the parent in writing along with other essential information -- type of sickle cell disease and size of the spleen -- so that it is available to medical personnel in the event the child is treated on an emergency basis by other than the usual health care providers.
Even though a positive family history for sickle cell disease is often lacking, a detailed family history should be obtained and a pedigree developed. The health care provider must remember that the sickle cell trait is not linked to skin color and is found not only in persons from Africa, but also in persons whose heritage is from the Mediterranean basin, the Caribbean, Central and South America, the Arabian peninsula, and India.
The health care provider who first contacts the parents should explore with them where the child can best receive medical care once a definitive diagnosis of sickle cell disease is established. This care can be provided by a family physician, pediatrician, or pediatric hematologist knowledgeable about sickle cell disease. In addition, care should be provided at a site that parents can access easily.
The health care provider, regardless of specialty, should have ready access to a tertiary care facility with sophisticated clinical laboratory and blood-banking facilities and modern imaging equipment suitable for the pediatric patient. Ideally, the patient should receive routine pediatric care in the same facility that manages complications of the disease. A shared approach to comprehensive care by a primary care provider and a specialist is a very satisfactory way to provide quality health care.
Penicillin prophylaxis should begin by 2 months of age for infants with suspected sickle cell anemia, whether or not the definitive diagnosis has been established.
| Study group | Study | Setting | Sample | Incidence of sepsis | Deaths | Percent |
|---|---|---|---|---|---|---|
| No comprehensive care or early intervention | Powars, et al., 1981 | California | 182 | 23 | 8 | 34.8 |
| Vichinsky, et al., 1988 | California | 64 | 11 | 4 | 36.4 | |
| Comprehensive care and early intervention | Powars, et al., 1981 | California | 75 | 11 | 0 | 0.0 |
| Vichinsky, et al., 1988 | California | 55 | 10 | 1 | 10.0 |
The high level of Hb F at birth prevents the newborn's red cells from sickling. Over the ensuing months, however, the concentration of Hb F declines, usually reaching a level that is too low to offer protection by age 6 months. It should be emphasized, however, that like most pediatric milestones, there is no magic age; rather, it is a continuum, and the infant must be considered at risk for sickle cell-related complications by age 2 months.
The most serious infections and complications in sickle cell anemia are pneumococcal sepsis and sepsis/meningitis (Leikin, Gallagher, and Kinney, 1989 ; Overturf, Powars, and Baraff, 1977 ; Powars, 1975 ; Seeler, Metzger, and Mufson, 1972 ; Zarkowsky, Gallagher, Gill, et al., 1986). These complications occur at a frequency 400 to 500 times higher in children with sickle cell anemia than normal children and are usually heralded by significant fever (McIntosh, Rooks, Ritchey, et al., 1980 ; Powars, 1975).
The best immediate, intrinsic defenses to pneumococcal infection are the phagocytic cells and the endothelial macrophages that line the splenic cords. This defense is unavailable to the child with sickle cell anemia or sickle Bo-thalassemia, as splenic function is lost during the first 2 years of life due to the congestion of the spleen with sickled cells. This deficiency, as well as a lack of opsonins and defective complement activation via the alternate pathway, contributes to the infant's increased vulnerability to sepsis from encapsulated bacteria. Once infection with these organisms begins, events move with frightening swiftness. Death occurs in approximately 25 percent of cases. Two reviews on spleen function are particularly relevant to the child with sickle cell disease (Sills, 1987 ; Spirer, 1980).
The role of prophylactic penicillin as the cornerstone of management to reduce morbidity and mortality from S. pneumoniae was defined by Gaston, Verter, Woods, and colleagues . This landmark study involved a multi-institutional, randomized, double-blind, placebo-controlled group of children 3 months to 5 years of age who had sickle cell anemia. Children in the study under 3 years of age were given oral penicillin twice a day, 125 mg per dose; children over 3 years received 250 mg twice a day. There were approximately 100 children in each group. Penicillin was so effective in lowering both morbidity and mortality that the study was terminated prematurely.
| Study group | Study | Setting | Sample | Infections | Deaths | Person-years Followup | ||
|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | |||||
| Penicillin + Pn vaccine | John, et al., 1984 | Jamaica | 97 | 7 | 2.5 | 2 | 28.6 | 275 |
| Pn vaccine only | 62 | 4 | 2.3 | 0 | 0.0 | 174 | ||
| Penicillin + H. influenzae B | 46 | 0 | 0.0 | 0 | 0.0 | 106 | ||
| H. influenzae B only | 27 | 2 | 3.8 | 0 | 0.0 | 106 | ||
| Penicillin + Pn vaccine | Gaston et al., 1986 | U.S. multi-State | 105 | 2 | 1.9 | 0 | 0.0 | 131.25 |
| Pn vaccine only | 110 | 13 | 7.9 | 3 | 23.1 | 137.5 | ||
Note: Pn vaccine = Pneumococcal vaccine.
The U.S. study did not use benzathine penicillin because injections are painful, and it would have created major logistical problems to ensure that each child received the injection on time. Current evidence indicates that injections need to be given every 3 weeks to maintain effective blood levels of penicillin (Kaplan, Berrios, Speth, et al., 1989). It should be emphasized that benzathine penicillin injection is an appropriate option for individual patients when the family will keep appointments consistently.
Equally worthy of emphasis is that aggressive efforts must be made by the health care provider to ensure compliance with an oral penicillin program. The parent must be clear about the importance of the prophylactic penicillin, how to give it, and the potentially dire consequences if it is not administered. Until the child is eating solid foods, a liquid preparation can be prescribed. This must be stored in the refrigerator and discarded after 2 weeks. Once the child is eating solids, pills can be dispensed and the mother instructed how to crush and administer the medicine with applesauce, sherbet, or another appropriate food.
Long-term compliance with any therapeutic regimen is difficult and requires constant reminders and reinforcement (Flanagan, 1980). Even the landmark penicillin prophylaxis study (Gaston, Verter, Woods, et al., 1986) estimated only about 60 percent compliance. Other authors have noted similar levels of compliance and suggested means of improving it (Buchanan, Siegel, Smith, et al., 1982 ; Cummins, Heuschkel, and Davies, 1991 ; Pegelow, Armstrong, Light, et al., 1991). The nurse in the clinic and the public health nurse who visits the home are in a unique position to reinforce the importance of compliance with the prescribed regimen (Day, Brunson, and Wang, 1992).
Long-term penicillin administration has proven to be safe and relatively nontoxic, not only from observations of sickle cell children (Anglin, Siegel, and Pacini, 1984 ; Gaston, Verter, Woods, et al., 1986), but also through even longer experience with rheumatic fever prophylaxis (Graff-Lonnevig, Hedlin, and Lindfors, 1988 ; International Rheumatic Fever Study Group, 1991). For the rare child who is allergic to penicillin, erythromycin ethyl succinate, 20 mg per kilogram divided into two daily doses, can be substituted.
Health care providers must educate parents about the early signs and symptoms of illness in the infant with sickle cell disease that require immediate medical attention. Also, health care providers must be aware of the urgency of promptly detecting and treating infections and other complications, including acute splenic sequestration, aplastic crisis, stroke, hand-and-foot syndrome, and acute chest syndrome.
The infant with sickle cell disease also is at risk for other life-threatening complications in addition to those related to bacterial infection. The practitioner must educate the parent about the importance of seeking medical advice when the infant exhibits signs and symptoms of illness, particularly temperature elevation greater than 101 degrees F (38.5 degrees C), changes in behavior (unusual somnolence or irritability), feeding disturbances (anorexia, vomiting, or diarrhea), pallor of mucus membranes, and/or rapid respirations.
The practitioner must approach fever in infants with sickle cell disease as an emergency. The importance of obtaining prompt medical consultation must be stressed to the parent. The suddenness of the appearance of sepsis and its high mortality rate have been well documented (Bainbridge, Higgs, Maude, et al., 1985 ; Powars, 1975 ; Seeler, Metzger, and Mufson, 1972). Health care workers must be aware of the importance of evaluating febrile sickle cell children promptly and the necessity for administering antibiotics that provide coverage for S. pneumoniae and H. influenzae.
The antibiotic should be given as soon as a blood culture is obtained (Bakshi, Grover, Cabezon, et al., 1991 ; Rogers, Morrison, Vedro, et al., 1990). This mandate should be followed even if the child is receiving penicillin prophylaxis. Several authors (Buchanan, and Smith, 1986 ; Wethers, 1992) have shown that sepsis can still occur despite the prescription of penicillin prophylaxis and administration of pneumococcal vaccine. This reinforces the need for continuing emphasis on compliance as well as constant alertness on the part of the doctors who care for these patients.
Fast or difficult breathing may indicate an Acute Chest Syndrome (ACS) -- that is, pulmonary involvement secondary to lung infarct or infection, alone, or in combination (De Ceulaer, McMullen, Maude, et al., 1985). ACS is a significant cause of mortality in children of all ages with sickle cell disease (Leikin, Gallagher, and Kinney, 1989). ACS usually requires hospitalization and, when indicated by hypoxemia or worsening anemia, administration of oxygen and/or red cell transfusion.
Acute splenic sequestration crisis is a potentially life-threatening complication of sickle cell disease. The child with acute splenic sequestration crisis has a sudden entrapment of a large portion of the blood volume in the spleen, with consequent cardiovascular compromise similar to that accompanying acute blood loss (Seeler, and Shwiaki, 1972 ; Topley, Rogers, Stevens, et al., 1981). The diagnosis is established by the findings of pallor, splenomegaly, and worsening anemia and when severe, signs of cardiovascular collapse. The reticulocyte count is elevated, and thrombocytopenia frequently is observed during a splenic sequestration crisis.
| Study group | Study | Setting | Sample | Patients/Episodes | Percent | Notes |
|---|---|---|---|---|---|---|
| Incidence of ASSC in sickle cell children in a comprehensive care program | Topley, et al., 1981 | Jamaica | 216 | 52/71 | 24.1 | |
| Brown, et al., 1989 | New York | 159 | 5/7 | 3.1 | ||
| Study group | Study | Setting | ASS Episodes | Mortality | Percent | Notes |
| Incidence of fatal ASSC in sickle cell children in comprehensive care | Topley, et al., 1981 | Jamaica | 71 | 10 | 14.1 | Bacteremia Related |
| Brown, et al., 1989 | New York | 5 | 1 | 20.0 | Bacteremia Related | |
| Incidence of fatal ASSC in SS children not in a comprehensive care program | Seeler and Shwiaki, 1972 | Chicago | 14 | 4 | 28.6 |
An aplastic crisis, precipitated by a temporary arrest of red cell production in the bone marrow, is usually caused by parvovirus infection. Pallor, fatigue, or decreased activity are the principal signs and symptoms (Centers for Disease Control, 1989 ; Thurn, 1988). A blood count reveals a fall in the hemoglobin and hematocrit levels and reticulocytopenia. Although aplastic crises are transient, a red cell transfusion is indicated if the infant is symptomatic from the anemia.
Stroke is a relatively infrequent complication in the young infant that is caused by occlusion of cerebral vessels. The median age for the occurrence of stroke in children is 7 years. However, any loss of consciousness in a child with sickle cell disease of any age, and any dysfunction of an extremity whether or not it is painful, should be investigated immediately. A child who drags a foot or stops using a hand may have a neurologic deficit, rather than a guarding response to pain. The child with any degree of neurologic symptoms should be seen promptly (Pavlakis, Prohovnik, Piomelli, et al., 1989).
Diagnostic procedures such as magnetic resonance imaging (MRI) of the brain and transcranial ultrasonography are useful in the evaluation of neurologic problems (Adams, McKie, Nichols, et al., 1992). If a thrombotic stroke has occurred, periodic red cell transfusions are the best therapy for preventing recurrence (Ohene-Frempong, 1991).
The most frequent initial complication of sickle cell disease is called hand-and-foot syndrome, or dactylitis. Signal symptoms include painful swelling of the hands and/or feet, which may or may not be symmetric. Often, there is evidence by x-ray findings of periosteal elevation and bone infarct. This swelling may be accompanied by warmth, redness, and fever (Bainbridge, Higgs, Maude, et al., 1985 ; Powars, 1975). Treatment is symptomatic and includes analgesics and hydration. Applications of local warmth by compresses, massage, or warm baths may provide relief. The parents should be encouraged to call the health care provider and have the child examined with the first occurrence of hand-and-foot syndrome. Thereafter, the parents should be encouraged to recognize the signs and symptoms and manage treatment on their own, provided the child is afebrile. Fever, as well as marked local findings of inflammation with exquisite tenderness, may hail the onset of osteomyelitis, characteristically caused by salmonella (Givner, Luddy, and Schwartz, 1981 ; Webb, and Serjeant, 1989). This is an infectious complication that can be a secondary event and always requires prompt medical attention. If osteomyelitis is suspected, the child should be seen as soon as possible. Appropriate evaluation may include bone aspiration, x-rays, bone and bone marrow scans, and bacterial culture (Kim, Alavi, Russell, et al., 1989).
The health care provider must recognize that the infant with sickle cell disease also requires the well-child care which is standard pediatric practice.
For infants with sickle cell disease, the schedule of health maintenance visits need not differ substantially from that for well children. The important symptoms of illness-related events and their clinical signs should be stressed and pertinent additional information shared during all visits, with periodic repetition for emphasis. The importance of strict compliance with prophylactic penicillin should be repeated at each visit. The parent should plan visits every other month during the first year and, if all is well, quarterly visits during the second year of life. The schedule of immunizations recommended by the American Academy of Pediatrics, Centers for Disease Control, or the American Academy of Family Physicians should be followed, including the 1992 recommendation that every child receive hepatitis B vaccine, which is especially pertinent for sickle cell children, since they may require transfusion and therefore are at risk for hepatitis B (Ndumbe, and Nyouma, 1990). If measles is epidemic in the child's neighborhood, measles vaccine should be given at 6 months of age, since community-acquired infection is frequently followed by pneumonia.
Infants with sickle cell disease should be immunized against Haemophilus influenzae at the age of 2 months.
Although all the immunizations are important, immunizations for H. influenzae and Streptococcus pneumoniae are particularly crucial. H. influenzae is another cause of serious morbidity and mortality in the young child with sickle cell disease (Zarkowsky, Gallagher, Gill, et al., 1986). Both normal infants and those with sickle cell disease can be protected from H. influenzae infection by administration of the highly immunogenic protein conjugated H. influenzae vaccine (Gigliotti, Feldman, and Wang, 1991 ; Marcinak, Frank, Labotka, et al., 1991).
The child should also be given 23 valent pneumococcal vaccine as soon as possible after the second birthday with a booster 2 to 3 years later (Buchanan and Schiffman, 1980 ; Chudwin, Wara, and Mathay, 1983 ; Hales, and Barriere, 1979 ; Overturf, 1982). Since the efficacy of this vaccine is incomplete, penicillin prophylaxis must be continued. The need for prophylaxis beyond the age of 5 years is currently under study.
During routine visits, attention should be paid to all usual health maintenance issues. Children with sickle cell anemia have higher than average baseline metabolic rates (Enwonwu, 1988). Close attention must be given to the child's diet to make sure all necessary nutrients and adequate calories are supplied. Multivitamins for at least the first 2 years of life are appropriate.
Additional folic acid has not been shown to be necessary in all children (Pearson, and Cobb, 1964 ; Serjeant, 1985). Although the iron salvaged during hemolysis is not lost to the body, the child with sickle cell disease does require dietary iron for growth and can become iron-deficient. Iron studies can be performed and supplemental iron given, if indicated. In addition to the periodic assessment of complete blood count and reticulocyte counts mentioned above, occasional liver function tests and renal function tests will uncover early evidence of organ damage.
Throughout all clinical visits, home management skills must be stressed to the parents. Parents must be taught neither to overprotect nor neglect their affected child but to treat the child as normally as possible (Belgrave, and Molock, 1991). However, there are certain everyday precautions that can be taken by the caregiver to minimize vasoocclusive episodes. Any condition that tends to cause dehydration may precipitate sickling in the microvasculature. The child should always be given liberal access to fluids, and this is even more important when the weather is warm. The child should always be carefully shielded from cool temperatures, since cold may slow the circulation, causing stasis and the precipitation of vasoocclusive episodes. Immersion in cold water should be avoided as well as excessive exposure to cold ambient temperatures; the child must be dressed warmly in cold weather. The health care provider must be able to assist and refer for proper assistance with such crucial ancillary services as transportation for medical care; Women, Infant and Children (WIC) programs; and social and/or psychosocial services.
The principal goal of newborn sickle cell disease screening is to reduce morbidity and mortality from sickle cell disease. This is achieved only by the provision of comprehensive health care to infants identified with sickle cell disease. Comprehensive health care includes the provision of counseling services to parents of infants with disease. A by-product of neonatal screening is the identification of newborns with sickle cell trait and newborns who have other hemoglobin diseases or are heterozygous for other variant hemoglobins. The screening program therefore has the opportunity to educate and counsel large numbers of people about sickle cell trait. Trait identification also provides a genetic window into the family that can result in the detection of couples at risk for having children with the disease or the identification of other family members with the disease or trait.
Newborn sickle cell screening programs must develop curricula and policies for the education and counseling of parents whose infants have sickle cell disease. The program also should consider development of policies and curricula for the education and counseling of parents of infants with sickle cell trait, as well as other hemoglobin variants. The education and counseling programs for persons with trait will add considerable expense to the screening program and must be considered carefully in light of the program's principal goal of reducing morbidity and mortality from disease.
Literature was reviewed by the panel related to sickle cell education and counseling. The panel concluded that there was insufficient documentation to support a definitive guideline in this area but felt it was important to provide recommendations for education and counseling because of their direct relationship with the screening process and the accepted principle that carriers of genetic disorders should be informed of their condition and be offered counseling. These recommendations are detailed below.
Sickle cell counseling can be defined as consisting of two discrete components: education and decision-making assistance.
The goal of sickle cell education is to have the person understand the essential facts about sickle cell disease and sickle cell trait. Appropriate objectives are required when designing the content of the education session. Objectives also are essential for the development, implementation, and evaluation of the education program. The educational program for parents of newborns identified with sickle cell disease or trait should include information on the following topics:
The difference between sickle cell trait and disease.
The risk of having a child with sickle cell anemia based on the parents' hemoglobin genotype.
The health status of persons with sickle cell trait.
The life span of persons with sickle cell trait.
The health problems associated with sickle cell anemia.
The variability in health problems among persons with sickle cell anemia.
The family planning options available to individuals with sickle cell trait and disease.
The prevalence of sickle cell trait and disease in various racial and ethnic groups.
The curriculum should be interactive and have scientific facts and concepts simplified and expressed in lay language, graphics to illustrate facts and concepts, and pre- and post-tests.
The information to be transmitted is complex. That complexity, coupled with the wide range of educational backgrounds, interests, and needs of those receiving the material, mandates the use of instructional techniques to ensure that there is a reasonable understanding of the information presented. Scientific jargon must be avoided. The greater the number of new or difficult words or terms used, the greater the likelihood that the individual will not grasp all the salient points. Use of graphics provides a second instructional tool. Visual aids effectively augment the spoken word.
During the educational session, the person must be given literature to supplement the information presented orally. Ideally, at least two types of literature should be provided: (1) a full description of the material covered, including a copy of all graphics and (2) a summary of the highlights or key points in the form of a fact sheet.
Using pre- and post-tests during educational sessions is beneficial for several reasons. Pre-testing can reveal misconceptions and inform the educator about the person's knowledge of the material. Post-testing can aid in assessing the effectiveness of the session and provide the educator with an opportunity to reinforce or clarify specific material. The post-test also provides an objective mechanism to assess the effectiveness of the session. Monitoring results of pre- and post-test performance by those responsible for the program should enhance effectiveness by identifying deficiencies.
During the session, the educator will present many new concepts and facts in a short period of time. It is unrealistic to expect that all people will fully comprehend and remember all presented material. The written material should help clarify aspects of the oral presentation. Literature also should assist the individual in explaining or discussing the information with other members of the family after the session. Written material also is valuable as a resource for those individuals who may wish to refer to the material months or years after the session.
Counseling designed to assist in decision making provides objective information to individuals at risk of having a child with sickle cell disease. The information enables the individuals to make informed decisions. The educational components of counseling are similar to those discussed above. In addition, the session should include specific information on the natural history of the type of sickle cell disease that may affect offspring and the resources that will be required to care for an affected child. Counseling for decision-making assistance must always be nondirective and objective. Counselors must never introduce personal biases or offer specific recommendations.
Counseling and education of parents of a child with sickle cell disease must be done in a kind and sensitive manner, as the parents frequently have feelings of grief, guilt, anxiety, or anger.
The goals of sickle cell disease counseling are to (1) provide an understanding of the inheritance of sickle cell disease and (2) provide those counseled with the information needed to make family planning decisions.
The counselor must be sensitive to the wide range of feelings, attitudes, personal and cultural values, and religious beliefs that can surface when genetic counseling is offered; they can affect marital and family planning decisions. Some of these factors include: attitudes about control over one's life, a desire to have children, views on potential for a cure, attitudes about taking risks, ability to cope with adversity, religious beliefs, and positions taken by significant others. These beliefs and values may give rise to uncertainty or cause conflicts in the value systems of individuals faced with difficult personal decisions. These persons can benefit enormously from the assistance of well-trained and empathetic counselors.
Because the decisions individuals must make can affect them for the duration of their lives, it is critical that they base their decisions on self-determination and self-interest rather than on the personal views of the counselor or on what might be considered societal norms.
During counseling sessions, the counselor should employ strategies and techniques designed to help the person fully understand all the factors that are personally meaningful regarding sickle cell-related marital and family planning decisions. The educational aspects have been described earlier.
Individuals with sickle cell trait and disease who are of child-bearing age have specific family planning decisions to make related to their sickle cell status. Examples of these types of decisions include whether or not they should marry a person who has sickle cell trait. For couples where both members have a sickle cell gene, the couple must decide if they want to take the chance of having a child with sickle cell disease. The previously cited personal values and attitudes may influence the answers to these questions and may influence reproductive decisions.
One counseling session may not be adequate to provide those counseled with a complete understanding of the genetic material presented and its implications. Persons should be told that they can have additional sessions to help them understand the issues.
Genetic counseling must be provided to all parents of infants with sickle cell disease. The content and conduct of these counseling sessions are similar to those described in the section on decision-making counseling. In addition, these sessions must stress the importance of health care maintenance, compliance with prescribed prophylactic penicillin, and the prompt medical evaluation of the infant at times of acute illness (see Medical Management section of this guideline). Ideally, this counseling should be provided by the physician responsible for medical management of the infant. Individuals providing these counseling services must be sensitive to the parent's potential feelings of anger or guilt and be supportive as the parent learns to cope with the child's illness.
Populations currently being screened for hemoglobin S include: African-American newborns in more than 40 States (all newborns in some States); 6-month-old infants to 18-year-old persons whose families receive Medicaid (in all States); all persons requesting testing in many cities (by community sickle cell organizations, and some comprehensive sickle cell centers); African-American pregnant women (by obstetricians); and African-American patients receiving medical care through some health maintenance organizations and private physicians.
The previously described educational curriculum should be offered to all adults with sickle hemoglobin and to the parents of all infants with sickle hemoglobin identified by the newborn screening program. Far fewer individuals will require the decision-making component as illustrated by the following example: for every 1,000 African-American infants screened, there will be about 80 identified with sickle cell trait, as the prevalence of the sickle gene in this population is about 8 percent. Education will be needed by all parents of these infants. However, only 3 to 4 of the 80 couples will require decision-making counseling because both parents have sickle cell trait. The volume of counseling needed, therefore, poses two key questions:
Are there enough geneticists and genetic counselors certified by the American Board of Human Genetics to meet the need?
If not, how can this need be met?
First, there is unquestionably an inadequate supply of board-certified personnel. The 1992-1993 membership directory of the American Society of Human Genetics lists 631 genetic counselors in the United States. Zinberg and Greendale report 103 American Board of Medical Genetics certified or eligible counselors for New York State (16 percent of the total number of counselors in the United States) and estimates the need in New York State at 154.5 counselors.
If 16 percent of all counselors are in one State, New York (Zinberg, and Greendale, 1991), and that number is considered to be inadequate, then it can be concluded that there is an inadequate number of counselors to meet the need across the country.
How can the need be met? The answer may lie in developing a cadre of individuals who are trained to provide only the educational component and to refer only those persons needing the decision-making component to trained health care professionals.
| Author and Year | Study Population | Counseling Technique | Results | ||
|---|---|---|---|---|---|
| Loader, et al., 1991 | 234 persons with sickle cell trait, 64 persons with beta-thalassemia | 20-minute video tape, individual counseling by genetic associates take-home brochure | Percent correct answers in pre vs post-tests | ||
| Component | Pre | Post | |||
| Manifestations | 43 | 73 | |||
| Genetics | 32 | 64 | |||
| Prenatal diagnosis | 38 | 69 | |||
| Whitten, et al., 1981 | 193 adults with sickle cell trait or parents of a child with sickle cell trait | Individuals counseled b6389y trained lay persons with some college background using a structured format and graphics; counseling sessions took 45 minutes; sessions were taped and analyzed for counselor and counselee performance | Correct answers in post-counseling test | ||
| Component | Number | Percent | |||
| Genetics | 170 | 87.5 | |||
| Risk of SC anemia | 141 | 76.2 | |||
| Incidence of SC anemia | 138 | 74.6 | |||
| Health status - SC trait | 171 | 90.9 | |||
| Life span - SC trait | 179 | 98.9 | |||
| Symptoms - SC anemia | 171 | 92.9 | |||
| Variability of symptoms | 128 | 77.1 | |||
| Life span - SC anemia | 137 | 75.3 | |||
| Options - SC trait | 156 | 86.2 | |||
| Reason for decisions | 131 | 75.7 | |||
| Rowley, et al., 1984 | Adults with beta-thalassemia trait in an HMO in Rochester, NY | Three methods compared: video tape and counselor-answered questions, structured session with counselor, open-ended discussion with counselor; assessments made at 2 and 10 months after counseling | All three methods increased scores on knowledge of genetics from about 50 to 80%. All three methods increased scores on knowledge of thalassemia from about 40 to 80%. There were no significant differences in either measure by counseling method | ||
| St. Clair, et al., 1978 | 32 women and 18 men with sickle cell trait | Counseling after being confirmed with sickle cell trait | Correct answers in post-counseling test | ||
| Component | Number | Percent | |||
| Health status - SC trait | 45 | 90 | |||
| Nature of disorder | 45 | 90 | |||
| Genetics of SC | 32 | 76 | |||
| Probability of SC anemia | 41 | 82 | |||
| Author and Year | Study Population | Counseling Methods | Results | |||
|---|---|---|---|---|---|---|
| Rowley, et al., 1984 | Adults with beta-thalassemia trait in an HMO in Rochester, NY | Three methods were compared: video tape and counselor-answered questions, structured session with counselor, open-ended discussion with counselor; assessments made at 2 and 10 months after counseling | All three methods increased scores on knowledge of genetics from about 50 to 80%; all three methods increased scores on knowledge of thalassemia from about 40 to 80%; there were no significant differences in either measure by counseling method | |||
| Cantor, et al., 1979 | General population in area surrounding Columbia and Charleston, SC | Television, radio, and newspapers were used as part of a mass-media educational program on cancer, substance abuse, and sickle cell anemia | Percent reached by characteristic and type of media | |||
| Population Characteristic | TV | Radio | Newspaper | |||
| Location | ||||||
| Rural | 0.0 | 5.6 | 16.7 | |||
| Town | 4.8 | 11.1 | 12.5 | |||
| City | 7.7 | 10.0 | 8.6 | |||
| Sex | ||||||
| Male | 0.0 | 14.3 | 23.5 | |||
| Female | 6.4 | 8.9 | 8.5 | |||
| Race | ||||||
| White | 7.5 | 6.3 | 10.4 | |||
| Black | 0.0 | 16.7 | 11.1 | |||
| Total percent of population reached | 4.8 | 9.1 | 11.7 | |||
| Author | Study Population | Counseling | Results |
|---|---|---|---|
| Neal-Cooper and Scott, 1988 | 74 sickle cell trait couples in Virginia; after exclusions, 35 available for evaluation | Couples contacted by counselors and encouraged to take part in education and counseling | After counseling, 8 couples (23%) were unsure of impact of new information; 14 couples (40%) did not believe the information would change childbearing plans; 13 couples (37%) believed it would; of the 25 couples followed, 18 had at least one pregnancy, including 2 who indicated possible change in childbearing plans |
| Grossman, et al., 1985 | Parents of 91 newborns with sickle cell trait in Maryland | Counseling offered to 74 couples who were reached; 32 accepted counseling, 13 said they would seek counseling elsewhere | Parents who received counseling showed an increase in knowledge and retained it until a second interview; no evidence of a change in reproductive planning was found |
Sickle cell trait education can be provided by individuals who have received proper specialized training.
In assessing whether a candidate has the qualifications to be a sickle cell educator, three factors should be considered:
Education and/or work experience.
Experience in education related to health and human services.
Certified approval documenting satisfactory completion of a course at a sickle cell educator training center.
Educational qualifications should include a minimum of a high school diploma, though it is preferable if the individual is a college graduate with course experience in at least one of the following: biology or genetics. An alternative to a college degree could be significant work experience in a health care facility in associated fields.
Each educator should receive a certificate of approval, which would be awarded after successful completion of a sickle cell training course. The certification process should include an examination that assesses the individual's knowledge of the required material and his or her ability to teach the material in an objective and nondirective fashion.
Such training courses should be developed, or endorsed, and supported by each State's newborn screening and followup program. All sickle cell educators should provide documentation to the screening program each year that they have updated their skills and knowledge. This annual update can be provided by approved training programs or through selective lectures by qualified individuals approved by the State's screening program.
In addition to educational requirements, sickle cell educators should possess excellent communication and interpersonal skills, an engaging personality, a commitment to excellence, and a belief that their role is important. They also should possess sufficient self-discipline to enable them to conduct on a day-to-day basis sessions that conform to the established protocol and/or curriculum.
The educational sessions for parents are invariably one-time, relatively brief (45 to 60 minutes), one-on-one encounters between two or more strangers. Thus, the educator should have the necessary interpersonal skills that enhance rapport. Inaccurate information might lead to imprudent decisions. Thus, the job requires individuals whose personal integrity motivates them to conduct each session to the best of their ability.
Decision-making counseling should only be conducted by individuals with professional backgrounds and training in guidance and counseling. These include genetic associates, clinical geneticists, nurses, medical social workers, and physicians.
Adequate quality assurance is an essential aspect of genetic counseling.
Because education and decision-making counseling are conducted in private, there is no guarantee that all educators and counselors, regardless of their training, will consistently follow the prescribed curriculum. Some form of quality control must be implemented. This may take the form of (1) audio-taping of sessions with periodic critiques of randomly selected tapes, (2) post-session interviews with counseled people, and/or (3) periodic scheduling of sessions with a trained, knowledgeable, simulated counselee.
Ongoing outcome evaluations of the program must be conducted. A quantifiable objective should be established for each content item. For example, at the end of each session a specified percentage of the people undergoing education or counseling should be able to provide a satisfactory answer to the question What is the chance for the first child of a trait x trait couple to have sickle cell anemia? Another goal might be that a specified percentage of counselees will provide correct answers to a certain percentage of the post-test questions. Future research is needed to determine what these goals should be.
Monitoring the counseling (process evaluation) will help ensure that counselors consistently adhere to the counseling curriculum. There is also a need to ensure that the counseling curriculum is adequate. Outcomes assessments can provide a starting point for developing strategies to improve the program. It must be recognized that shortfalls in the achievement of objectives can be related to several factors, including the counselor`s performance, the counseling curriculum, and characteristics of the person counseled. [Table 18]
The Panel's recommendations are based on both experience reported in the literature and personal experience. There is a need for further research to support these recommendations and to investigate possible alternative methods for the provision of sickle cell education and genetic counseling.
ABMG: American Board of Medical Genetics
AG: Agar gel
AHCPR: Agency for Health Care Policy and Research
a: Alpha
ASSC: Acute splenic sequestration crisis
B: Beta
Bs: Beta S
CA: Cellulose acetate
CDC: Centers for Disease Control
Cit Ag: Citrate agar electrophoresis
CLIA: Clinical Laboratory Improvement Act
CORN: Council of Regional Networks for Genetic Services
DNA: Deoxyribonucleic acid
Hb: Hemoglobin
Hb AS: Hemoglobin A and S (sickle cell trait)
Hb F: Fetal hemoglobin
Hb S: Hemoglobin S (sickle hemoglobin)
Hb SC: Hemoglobin SC disease
Hb SS: Hemoglobin SS (sickle cell anemia)
HMO: Health maintenance organization
HPFH: Hereditary persistence of fetal hemoglobin
HPLC: High performance liquid chromatography
IEF: Isoelectric focusing
ISQAL: Centers for Disease Control Hemoglobinopathy Quality Control Program
NCCLS: National Committee for Clinical Laboratory Standards
NIH: National Institutes of Health
PKU: Phenylketonuria
RNA: Ribonucleic acid
WIC: Women, Infants, and Children Program
Acute splenic sequestration crisis: The trapping of red cells in the spleen, leading to acute worsening of anemia, splenomegaly, and the potential for shock, vascular collapse, and death.
Anemia: Any condition in which there is a reduction of hemoglobin concentration below the normal range; can have many causes other than hemoglobinopathies.
Beta-thalassemia trait: A condition in which an individual inherits a normal beta globin gene and a beta globin gene that results in reduced synthesis of normal beta globin.
Compound heterozygote: Individual who has inherited two different abnormal genes for a characteristic.
Cord blood: Blood from an infant's umbilical cord.
Genotype: The genetic composition of an individual.
Hand-and-Foot Syndrome: Painful swelling of the hands and feet in patients with sickle cell disease.
Hemoglobin: A protein found in red cells that is responsible for the transport of oxygen. The protein consists of two pairs of globin chains with a heme moiety attached to each chain.
Hemoglobin AA: The normal hemoglobin genotype.
Hemoglobin AS: The hemoglobin genotype of an individual who has inherited a normal beta globin gene from one parent and a betas globin gene from the other parent. This genotype is also known as sickle cell trait.
Hemoglobin AC: The hemoglobin genotype of an individual who has inherited a normal beta globin gene from one parent and a beta C globin gene from the other. This genotype also is called hemoglobin C trait.
Hemoglobin D, E, G, O: Other abnormal hemoglobins.
Hemoglobin F: The predominant hemoglobin found in the fetus. The amount of Hb F decreases after birth and is found in only small amounts in children and adults.
Hemoglobin SC: The hemoglobin genotype of an individual with sickle cell disease who has inherited a betas globin gene from one parent and a beta C globin gene from the other.
Hemoglobin SS: The hemoglobin genotype of an individual who has inherited a betas globin gene from each parent.
Hemoglobinopathy: A generic term for inherited disorders of hemoglobin structure.
Heterozygote: Individual who has inherited two different genes for a characteristic.
Homozygote: Individual who has inherited the same gene for a characteristic from both parents (these genes may be normal or abnormal).
Painful episode: An acute episode of pain affecting one or multiple body sites which occurs in individuals with sickle cell disease.
Phenotype: The observed appearance of a characteristic. (This may differ from the genotype.)
Sickle beta-thalassemia (S B-thalassemia): A disorder resulting from the inheritance of a sickle (S) gene from one parent and a beta-thalassemia gene from the other. Conditions in this group are also designated as "+" or "o," depending on the severity of the synthetic defect. In the "+" type some normal beta chain is produced. In the "o" type, no normal beta globin is produced.
Sickle cell anemia: The hemoglobinopathy resulting from the inheritance of two betas globin genes (SS).
Sickle cell disease: A group of diseases characterized by the production of Hb S resulting from the inheritance of two betas globin genes (Hb SS), a beta S and a beta C gene (Hb SC), a beta S and a beta-thalassemia gene (Hb S beta-thalassemia), or a beta S gene and a gene for other abnormal hemoglobin which polymerizes with Hb S.
Sickle cell preparation (Metabisulfite): A test that identifies the presence of a sickling hemoglobin.
Solubility test: A test using dithionate to identify the presence of sickling hemoglobin.
Two-tier-system: A testing strategy where the presence of an abnormal hemoglobin identified by one technique is confirmed by a second test.
Unstable hemoglobin: An abnormal hemoglobin that denatures under normal conditions.
Beverly Ames
Consumer Representative
Kwame Anyane-Yeboa, MD
Associate Professor of Pediatrics
Columbia University
Samuel Charache, MD
Professor, Departments of Medicine and Pathology
Johns Hopkins University
Melvin Gerald, MD, MPH
President and Chief Executive Officer
Gerald Family Care Associates, P.C.
Serena K. Gilbert, MSW
Director, Department of Social Work
Prince George's Hospital Center
Thomas R. Kinney, MD, Co-chair
Professor of Pediatrics
Duke University
David Phoenix, DrPH
Associate Professor of Community Health and Preventive Medicine
Morehouse School of Medicine
Jeanne A. Smith, MD, MPH, Co-chair
Associate Professor of Clinical Medicine
Columbia University
Elliott Vichinsky, MD
Associate Adjunct Professor of Pediatrics
University of California, San Francisco
Ruby LaVerne Wesley, PhD, RN
Assistant Professor of Nursing
Wayne State University
Doris L. Wethers, MD
Professor of Clinical Pediatrics
Columbia University
Charles F. Whitten, MD
Associate Dean, School of Medicine
Wayne State University
Iola Williams, RN, PNP
Coordinator, Sickle Cell Program
Children's National Medical Center
Hanan Bell, PhD
Clinical Policies Analyst
American Academy of Family Physicians
Victor Hasselblad, PhD
Duke University
Peter Rowley, MD
Professor of Medicine, Pediatrics, Genetics, Microbiology, and Oncology
University of Rochester
Robert H. Sprinkle, MD, PhD
Center for Health Policy Research and Education
Duke University
Martin Steinberg, MD
Professor of Medicine
Associate Chief of Staff for Research
VA Medical Center,
Jackson, MS
Hanan Bell, PhD
Methodologist
American Academy of Family Physicians
Patience Ejiogu-Akinosho, MPA, MPH
Research Coordinator
Columbia University
Alfred O. Berg, MD, MPH
Professor and Associate Chair
Department of Family Medicine
University of Washington School of Medicine
Seattle, WA
George Buchanan, MD
Professor of Pediatrics
University of Texas
Health Science Center
Dallas, TX
George Cunningham, MD, MPH
Chief, Genetic Disease Branch
Department of Health Services
State of California
Berkeley, CA
James R. Eckman, MD
Associate Professor of Medicine
Emory University School of Medicine
Atlanta, GA
Ronald W. Hinkson
Health Educator
Sickle Cell Council of New Mexico, Inc.
Albuquerque, NM
George C. Hoffman,
MB, B Chir, FRC Path
Laboratory Hematology
The Cleveland Clinic Foundation
Cleveland, OH
Dolores E. Jackson,
MPA, RN, CNAA
Associate Executive Director, Nursing Services
Woodhull Medical and Mental Health Center
Brooklyn, NY
J. Mehsen Joseph, PhD
Director, Laboratories Administration
Maryland Department of Health and Mental Hygiene
Baltimore, MD
Archie B. Lewis, MSW
Coordinator,
Ohio Sickle Cell Program
Ohio Department of Health
Columbus, OH
Patricia Lowery, MD
Children's Health Center
Franktown, VA
Astrid Mack, PhD
Comprehensive Sickle Cell Program
University of Miami
School of Medicine
Miami, FL
Virginia V. Michels, MD
Chairman,
Department of
Medical Genetics
The Mayo Clinic
Rochester, MN
Kwaku Ohene-Frempong, MD
Associate Professor of Pediatrics
University of Pennsylvania
Philadelphia, PA
Susan R. Panney, MD
Director,
Office of Hereditary Disorders, LFHA
Maryland Department of Health and Mental Hygiene
Baltimore, MD
Kenneth A. Pass, PhD
Director, Newborn Screening Program
New York State Department of Health
Albany, NY
Howard Pearson, MD
Professor of Pediatrics
Yale University School of Medicine
New Haven, CT
Darleen R. Powars, MD
Professor of Pediatrics, Hematology/Oncology
University of Southern California
Los Angeles, CA
Gladys Robinson
Executive Director
Triad Sickle Cell Anemia Foundation
Greensboro, NC
Robert M. Schmidt, MD, MPH, PhD
Professor of Hematology,
Clinical Science and Gerontology
San Francisco State University
San Francisco, CA
Margaretta Seashore, MD
Department of Genetics
Yale School of Medicine
New Haven, CT
John E. Sorrentino
Executive Director
New England Regional Newborn Screening Program
Jamaica Plain, MA
Brad L. Therrell, PhD
Director,
Clinical Services Division
Bureau of Laboratories
Texas Department of Health
Austin, TX
Howard Anderson
President,
Midwest Association for Sickle Cell Anemia
Chicago, IL
Woodrow Brown
Executive Director,
Louvenia D. Barksdale Sickle Cell Anemia Foundation
Spartanburg, SC
John Chenault
Executive Director,
Sickle Cell Awareness Group of Greater Cincinnati
Cincinnati, OH
Barbara Davis Clark
President,
Sickle Cell Association of Connecticut
Hartford, CT
Julia Davis
President,
Volunteers in Aid of Sickle Cell Anemia
Philadelphia, PA
Magda B. Finch, MSN
Genetic Screening Coordinator,
Virgin Islands Department of Health
Kings Hill, St. Croix, VI
Vince Ford
Executive Director,
James R. Clarke Memorial Sickle Cell Foundation
Columbia, SC
Judith R. Harris
Executive Director,
Sickle Cell Council of New Mexico
Albuquerque, NM
Ella Holmes
President,
Harrison County Sickle Cell Foundation
Gulfport, MS
Lenora E. Nash
Executive Director,
Sickle Cell Organization of the Inland Counties
Riverside, CA
Marble Rice
Executive Director,
Oklahoma Chapter NASCD
Tulsa, OK
Gladys Robinson
Executive Director,
Triad Sickle Cell Anemia Foundation
Greensboro, NC
Fontanette White
Executive Director,
Sickle Cell Anemia Association of Texas
Ft. Worth, TX
Pat Williams
District Coordinator,
Baton Rouge Sickle Cell Anemia Foundation
Baton Rouge, LA
Marcia Wright
Executive Director,
Eastern Area Sickle Cell Association
Jacksonville, NC
algorithm nodes 1-10
algorithm nodes 11-21
An algorithm was developed as a visual display of the organization, procedural flow, and decision points in identifying and caring for newborns and infants with sickle cell disease, sickle cell trait, and other hemoglobinopathies and educating and counseling their parents. Numbers in the algorithm refer to the annotations that follow; chapter references are to the Clinical Practice Guideline on Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in Newborns and Infants.
1. The panel concluded that universal newborn screening should be conducted to detect sickle cell disease. This conclusion is based both on considerations of practicality and cost- effectiveness. Screening for hemoglobinopathies should be conducted in parallel with other conditions routinely screened for in newborns.
2. The panel concluded that sickle cell screening should be performed only in laboratories that meet appropriate standards of performance and reporting. Quality assurance activities and appropriate reporting practices are discussed in Chapter 2. The panel concluded that any of three methods are acceptable for sickle cell screening: (1) hemoglobin electrophoresis, (2) isoelectric focusing, and (3) high performance liquid chromatography. All are considered reliable and accurate. Metabisulfite sickle cell preparations and solubility testing, however, are not acceptable screening methods for newborns and should not be used to confirm the presence of hemoglobin S in newborns and infants.
Blood samples for testing may be submitted as anticoagulated blood from the umbilical cord or as dried blood spots collected onto filter paper. Each method has advantages and disadvantages. Filter paper samples are more easily integrated into existing newborn screening programs.
3-4. The common types of sickle cell abnormalities are discussed in Chapters 1 and 2. Parents of sickle cell trait infants should be offered education and counseling. Couples at risk for having an infant with sickle cell disease should be offered decision-making counseling.
Parents of infants with other diseases or heterozygote conditions should be offered education and counseling. Couples at risk for having a child with disease should be offered decision- making counseling.
5. The presence of another abnormal hemoglobin may warrant referral for medical care. Parents of children with trait should be offered counseling. These issues are discussed in Chapters 1, 2, and 4.
6. Reporting of preliminary screening results is discussed in Chapters 2 and 3.
7. Children with sickle cell disease identified on screening examination should be referred to a comprehensive care program without delay. Because confirmatory testing may not be complete for several weeks or months, it is important not to delay the basic elements of care, as described in nodes 9-12. The panel concluded that prophylaxis against pneumococcal infection is warranted in all children with sickle cell anemia and sickle betao-thalassemia. Administration of twice-daily oral penicillin has been demonstrated to reduce morbidity and mortality in these children. Children with sickle cell anemia also are at high risk for pneumococcal and Haemophilus influenzae infections. Immunization is extremely important (Chapter 3) and should be initiated by 2 months of age.
8. All positive screening tests for sickle cell disease require a second blood sample to confirm the initial hemoglobin phenotype. A definitive diagnosis should be established by the infant's physician.
9. Parents of infants with sickle cell disease must be counseled concerning the implications of their child's condition. Specifically, parents should be informed about the need for close vigilance with respect to the development of signs and symptoms that could indicate a serious medical problem. Any of the following warrant immediate medical consultation: (1) fever, (2) symptoms of respiratory tract infection, (3) increasing pallor, (4) increasing spleen size or abdominal distension, (5) weakness or numbness of an extremity, and (6) painful swelling of hands and feet. Information also should be provided concerning diet and adequate hydration. Parents should be trained in home management skills and should receive genetic counseling (Chapters 3 and 4).
10. The schedule of health maintenance visits need not differ from that used for a well child. Strenuous efforts must be made by the health care provider to ensure compliance with penicillin prophylaxis (Chapter 3).
11. Parents should be encouraged to seek immediate medical attention whenever the warning signs described in node 12 are noted.
12. Fever over 101 degrees F (38.5 degrees C) requires immediate medical evaluation. The parent also should be told that changes in behavior (unusual somnolence or irritability) or alimentation (refusing feeding, vomiting, or diarrhea) are other possible early signs of significant illness.
13. It is critical that all health care providers who care for patients with sickle cell disease be knowledgeable about the significance of fever in these children. The importance of evaluating febrile sickle cell children promptly and administering broad-spectrum antibiotics are emphasized. Management of febrile children with sickle cell disease is discussed in Chapter 3.
14-15. Acute anemia emergencies are common in children with sickle cell disease, particularly acute splenic sequestration and aplastic crises. Diagnosis and management of these conditions are discussed in Chapter 3.
16-17. Although relatively infrequent, both parents and providers must be alert for the possibility of a stroke. Any loss of consciousness or weakness of an extremity should be evaluated promptly.
18-19. The most frequent early complication of sickle cell disease is the hand-and-foot syndrome, or dactylitis (Chapter 3).
| Jurisdiction | Population Screened | Types of Screening | Laboratory Method(s)* | Comments |
|---|---|---|---|---|
| Alabama | Universal | Mandatory | CAE | |
| Alaska | Sends metabolic tests to Oregon | |||
| Arizona | Universal | Mandatory | Sends hemoglobinopathy tests to Colorado | |
| Arkansas | Universal | Mandatory | IEF | |
| California | Universal | Mandatory | HPLC, IEF | Screens in three regions with some regional private contracting. |
| Colorado | Universal | Mandatory | IEF | Screens for Arizona and Wyoming and for the dependents of Federal personnel in the Pacific. |
| Connecticut | Universal | Voluntary | Sends hemoglobinopathy tests to New York. | |
| Delaware | Universal | Voluntary | Sends all tests to Oregon. | |
| District of Columbia | Universal | Voluntary | IEF | Test performed at Howard University (along with tests from the Virgin Islands). |
| Florida | Universal | Mandatory | IEF | |
| Georgia | Non-universal | Mandatory Voluntary | CAE | Hemoglobinopathy screening is mandatory for religiously non-objecting members of 13 ethnic groups; it is voluntary for others. |
| Hawaii | ||||
| Idaho | Sends metabolic tests to Oregon. | |||
| Illinois | Universal | Mandatory | IEF | |
| Indiana | Universal | Mandatory | IEF, ELP | |
| Iowa | Universal | Mandatory | IEF | |
| Kansas | Universal | Voluntary | IEF | |
| Kentucky | Non-universal | Voluntary | IEF | Screening is universal in selected hospitals. |
| Louisiana | Non-Universal | Mandatory | IEF | |
| Maine | Sends metabolic tests (and occasional hemoglobinopathy tests) to Massachusetts. | |||
| Maryland | Universal | Voluntary | IEF | Screens for dependents of the U.S. Armed Forces in Germany. |
| Massachusetts | Universal | Mandatory | IEF | Performs hemoglobinopathy testing occasionally for Maine and more regularly for New Hampshire, Rhode Island, and Vermont. |
| Michigan | Universal | Mandatory | IEF | |
| Minnesota | Universal | Mandatory | IEF | |
| Mississippi | Universal | Mandatory | Sends all tests to Tennessee. | |
| Missouri | Universal | Mandatory | IEF | |
| Montana | ||||
| Nebraska | ||||
| Nevada | Universal | Mandatory | Sends all tests to Oregon. | |
| New Hampshire | Non-universal | Voluntary | Sends all tests to Massachusetts. | |
| New Jersey | Universal | Mandatory | IEF | |
| New Mexico | Voluntary | IEF | ||
| New York | Universal | Mandatory | CAE | Performs hemoglobinopathy testing for Connecticut. |
| North Carolina | Non-universal | Voluntary | IEF | |
| North Dakota | ||||
| Ohio | Universal | Mandatory | IEF | |
| Oklahoma | Universal | Voluntary | IEF | Switched from regional to universal screening in 1991. |
| Oregon | IEF | Screens for hemoglobinopathies for citizens of Delaware and Nevada but not yet for Oregonians. | ||
| Pennsylvania | Non-universal | Mandatory | IEF | Considering a change from regional (Philadelphia) universal screening to statewide universal screening. |
| Rhode Island | Mandatory | Sends all tests to Massachusetts. | ||
| Puerto Rico | Universal | Mandatory | CAE | For 1990, only 52 percent of live births were screened for hemoglobinopathies, 87 percent for PKU. |
| South Carolina | Universal | Mandatory | CAE | Performs metabolic testing for West Virginia. |
| South Dakota | ||||
| Tennessee | Universal | Mandatory | IEF | Performs all testing for Mississippi. |
| Texas | Universal | Mandatory | IEF | |
| Utah | Had a universal, mandatory program using IEF while federally supported. | |||
| Vermont | Non-universal | Voluntary | Sends all tests to Massachusetts. | |
| Virginia | Universal | Mandatory | IEF | |
| Virgin Islands | Universal | Voluntary | Sends all tests to Howard University's laboratory in Washington, DC | |
| Washington | Universal | IEF | Non-universal hemoglobinopathy screening abandoned for universal regional screening (May, 1991) and then statewide universal screening (November, 1991). | |
| West Virginia | Non-universal | Voluntary | Unspecified | Hemoglobinopathy screening (free) by parental request only. Sends metabolic tests to South Carolina. |
| Wisconsin | Universal | Mandatory | IEF | |
| Wyoming | Universal | Mandatory | Sends all tests to Colorado. |
* Laboratory-method acronyms: IEF (isoelectric focusing), CAE (cellulose acetate electrophoresis), ELP (electrophoresis, type unspecified), HPLC (high performance liquid chromatography).
A Brighter Heritage (Video, 17 min)
Chronic Illness in the Classroom (Video, 15 min)
Mississippi State Department of Health
Genetics Division
P.O. Box 1700
Jackson, MS 39215
Phone: 601-960-7619
The Infant and Young Child with Sickle Cell Anemia (a guide for parents, in English and Spanish)
Pneumococcal Infection and Penicillin
So Your Baby Has the Sickle Cell Trait (Spanish and English)
Also available: brochures on sickle cell trait, sickle beta-thalassemia, hemoglobin C disease, pain in children, and various complications
Texas Department of Health
Newborn Screening Program
1100 West 49th St
Austin, TX 78756-3199
Phone: 512-458-7000
Sickle Cell Anemia, (Medicine for the Public) (NIH Pub. No. 90-3058)
Clinical Center Communications
9000 Rockville Pike
Building 10, Room 1C255
Bethesda, MD 20892
Phone: 301-496-2563
Sickle Cell: A Selected Resource Bibliography (Cat. No. D002)
So I Have the Sickle Cell Trait (Cat. No. B050)
National Maternal and Child Health Clearinghouse
8201 Greensboro Drive
McLean VA 22102
Phone: 703-821-8955
Hemoglobin S (Spanish)
Hemoglobin C (Spanish and English)
All You Ever Wanted to Know About Sickle Cell Trait
Northern California Comprehensive Sickle Cell Center
Oakland, CA 94609
Phone: 510-428-3651
A Parent's Handbook for Sickle Cell Disease (Birth to age 6)
Education Programs Associates
1 West Campbell Ave, Building D
Campbell, CA 95008
Phone: 408-374-1210
The Family Connection Sickle--Cell Trait (English, French, Spanish)
The Family Connection--Hemoglobin C Trait (English, French, Spanish)
Newborn Screening for Your Baby's Health (English, Spanish)
Directory of Available Sickle Cell Services in New York State
Sickle Cell Anemia
New York State Department of Health
Newborn Screening Program
Wadsworth Center for Laboratories and Research
P.O. Box 509
Albany, NY 12201-0509
Phone: 518-473-7552
Sickle Cell Trait--Sickle Cell Anemia: There is Quite a Difference
California State Department of Health
Childrens Medical Services Branch
Sacramento, CA 95814
Phone: 916-654-0499
Sickle Cell Anemia--What is It?
Cincinnati Comprehensive Sickle Cell Center
Children's Hospital Medical Center
Cincinnati, OH 45229
Phone: 513-559-4200
Your Child and Sickle Cell Disease
Mid-South Sickle Cell Center
Le Bonheur Children's Medical Center
Memphis, TN 38103
Phone: 901-522-6792
Help (resource book listing sources of care for patients with sickle cell disease in the United States, Puerto Rico and the Virgin Islands)
Sickle Cell Disease--how to help your child to take it in stride
A Parent/Teacher Guide
Viewpoints
Also available: Brochures on recent advances, newsletter on chapter activities, fact sheets, and brochures on sickle cell trait, anemia, and other topics, home study kit, games, and a video on parenting.
National Association for Sickle Cell Disease
3345 Wilshire Blvd, Suite 1106
Los Angeles, CA 90010-1880
Phone: 800-421-8453
Thalassemia Information Sheet
Sickle Cell Anemia Public Health Information Sheet
March of Dimes
Birth Defects Foundation
1275 Mamaroneck Avenue
White Plains, NY 10605
Brochure for Parents of Children with Sickle Cell Disease
Howard University
Comprehensive Sickle Cell Center
2121 Georgia Ave
Washington DC 20059
Phone: 202-806-7930
Note: The above listings are not all inclusive. Additional material may be available from your own State or local health department, sickle cell agency, or community agency.
For each clinical practice guideline developed under the sponsorship of the Agency for Health Care Policy and Research (AHCPR), several versions are produced to meet different needs.
The Guideline Report contains the Clinical Practice Guideline with complete supporting materials, including background information, methodology, literature review, scientific evidence tables, and a comprehensive bibliography.
The Clinical Practice Guideline and the Quick Reference Guide for Clinicians are companion documents for use as desktop references for clinical decision making in the day-to-day care of patients. Recommendations, algorithms or flow charts, tables and figures, and pertinent references are included.
A Patient's Guide (for this guideline, a parent's guide), available in English and Spanish, is an informational booklet for the general public to increase consumer knowledge and involvement in health care decision making.
Guideline information also will be available for on-line retrieval through the National Library of Medicine, the National Technical Information Service, and some computer-based information systems of professional associations, nonprofit organizations, and commercial enterprises.
To order guideline products or to obtain further information on their availability, call the AHCPR Clearinghouse toll-free at 800-358-9295; from outside the United States only, call 301-495-3453; or write to: AHCPR Publications Clearinghouse, P.O. Box 8547, Silver Spring, MD 20907.
Mack, A., University of Miami, personal communication, 1991.
Common abnormal hemoglobins with similar electrophoretic mobility: Hb S, D, and G have similar electrophoretic mobility on cellulose acetate electrophoresis. Hemoglobin S is separable from hemoglobins D and G by agar electrophoreses; IEF and HPLC methods can distinguish dome D and G variants from Hb S. Hb C, E, and O have similar electrophoretic mobility on cellulose acetate electrophoresis. Hb C differs markedly from E and O on agar electrophoresis. Note: Letter designations refer only to electrophoretic mobility. In general, there is more than one abnormal hemoglobin with the same letter designation (for example, GSan Jose and GPhiladelphia; OArab and OIndonesia).
