Neonatal screening and clinical care programmes for sickle cell disorders in sub-Saharan Africa: lessons from pilot studies

OBJECTIVES: Despite the widespread use of neonatal screening programmes for sickle cell disease in Western regions, few studies have focused on the special healthcare needs in sub-Saharan African countries. The purpose of this review is to evaluate the need for a neonatal screening programme for sickle cell disease, and if justified, to propose a realistic healthcare programme for sickle cell newborns in those countries based on personal experiences in Kinshasa (Democratic Republic of the Congo) and Ouagadougou (Burkina Faso) as well as from a review of the literature. REVIEW: There are well-established criteria for the development of neonatal screening programmes for sickle cell disease in sub-Saharan African countries. In particular, in regions where incidence of the disease is 0.5 per 1000 or higher, a sickle cell screening programme can be proposed that includes the systematic screening of all newborns, or the targeted screening of those newborns who have a mother with a sickle cell or haemoglobin C trait. Screening should be preferentially organized using cord blood, with a simple, effective and affordable screening method such as isoelectric focusing. If necessary, confirmation of results should be performed using another cost-effective technique such as citrate agar electrophoresis at an acidic pH. There is also a need for a sickle cell disease clinical care programme which should include: infection prophylaxis with penicillin and malarial prophylaxis; family training to identify early severe or persistent symptoms and the gravity of malarial crises; the evaluation of nutritional status and adequate fluid intake; and the importance of regular medical visits. Improved knowledge of the diagnosis was found to reduce the need for unnecessary and unsafe blood transfusions. CONCLUSIONS: This paper provides an overview of practices employed in neonatal screening and clinical care programmes for sickle cell disease in sub-Saharan African countries. The development of these programmes is pivotal to improving the health care of those affected by haemoglobin disorders. However, such programmes require major economic and organizational resources, which must taken into account and balanced against other local health priorities.     

Physician knowledge and adherence to prescribing antibiotic prophylaxis for sickle cell disease.

OBJECTIVE: The purpose of this research was to examine how physician characteristics were associated with: (i). physician knowledge of and adherence to sickle cell guidelines; and (ii). the types of educational programs about sickle cell disease desired by physicians. METHODS: A survey was developed to assess the research objective. After the survey was pre-tested and an institutional review board exemption was obtained, it was sent to a systematic random sample of 375 pediatricians and all 125 practicing hematologists in North Carolina. They were asked to answer a six-item knowledge test relating to the antibiotic prophylaxis guidelines. RESULTS: The response rate was 57%, of which 61% were pediatricians. Over half (56%) were in a practice with at least one pediatric sickle cell patient. Fifty-nine percent of physicians answered five or more questions correctly on the knowledge test. The question most physicians answered correctly (97%) pertained to the necessity of antibiotics for children with sickle cell disease. The question most frequently answered incorrectly (62%) pertained to prescribing antibiotics to a child with unconfirmed sickle cell disease. Logistic regression results indicated that the number of sickle cell patients seen in practice influenced the number of questions answered correctly. Sixty-six percent of physicians prescribed prophylactic antibiotics for 100% of their patients with sickle cell disease and therefore were 100% adherent. Eighty-one percent of pediatricians compared with 12% of hematologists were 100% adherent in prescribing antibiotics. Hematologists and those practicing at a medical school or university were less likely to be 100% adherent in prescribing antibiotic prophylaxis. CONCLUSION: The majority of physicians surveyed were relatively knowledgeable about sickle cell guidelines, however there may be a need for continuing education programs that focus on the issues of prescribing antibiotics to a child with unconfirmed sickle cell disease and penicillin dosage.     

Geographic differences in mortality of young children with sickle cell disease in the United States.

OBJECTIVES: Because geographic differences in health care have been found for many diseases, including those affecting children, there are probably geographic differences in the health care of young children with sickle cell disease. Consequently, survival of young children with sickle cell disease might differ among geographic areas. This study''s objective was to identify areas in the United States where young children with sickle cell disease are at especially high and low risk of dying. METHODS: Using U.S. death certificate data from 1968 through 1992, the authors calculated the mortality rates of 1- through 4-year-old black children with sickle cell disease for states, counties, and cities. Deaths from trauma, congenital anomalies, and perinatal conditions were excluded. RESULTS: From 1968 through 1980 and from 1981 through 1992, 1- through 4-year-old black children with sickle cell disease in Florida had a markedly higher risk of dying, and those in Pennsylvania had a markedly lower risk of dying, than the average 1- through 4-year-old black child with the disease in the United States. From 1981 through 1992, 1- through 4-year-old black children with sickle cell disease in Maryland had the lowest mortality rate in the nation. During the same time period, 1- through 4-year-old black children with sickle cell disease in five counties in Florida were at especially high risk, while in Baltimore no young black children with the disease died. These geographic differences in mortality of black children with sickle cell disease greatly exceeded geographic differences in mortality of black children without the disease. CONCLUSIONS: Marked differences exist across the United States in mortality of young black children with sickle cell disease. To improve survival for children with the disease in high mortality areas, evaluations should be made of the accessibility and quality of medical care, and of parents'' health care seeking behavior and compliance with antibiotic prophylaxis. In addition, efforts should be made to understand and duplicate the success of treatment programs in low mortality areas.     

Stress and Coping Among Mothers of Infants With a Sickle Cell Condition

Thirty-one mothers of infants with sickle cell anemia (n = 14) or sickle cell trait (n = 17) were interviewed to investigate the psychological stress they experienced and the coping strategies they used when first learning their child's diagnosis and when presently caring for their child. All children were diagnosed with sickle cell conditions through newborn screening. Mothers of children with sickle cell disease most often reported the expectation of pain for their child as a stressor, whereas mothers of children with sickle cell trait most often reported uncertainty of the diagnosis as a stressor. Although sickle cell trait is not a life-threatening condition, mothers of these infants reported a great deal of stress in regard to the health of their children and to their own ability to manage such stress. Mothers in both groups reported using Positive Reappraisal, Seeking Social Support, Self-Control, and Planful Problem Solving most frequently to cope with present stressors. The results also have implications for the use of newborn screening.     

Neonatal screening for hemoglobinopathies in Rio de Janeiro, Brazil]

OBJECTIVE: To describe the main results obtained in the first 15 months of neonatal screening for sickle cell disease in the state of Rio de Janeiro, Brazil, from August 2000 to November 2001. METHODS: Starting in August 2000, blood samples began to be collected for sickle cell disease screening from all newborns receiving care in primary health care clinics in the state of Rio de Janeiro. The samples were submitted to high-resolution liquid chromatography. If the resulting chromatogram was compatible with sickle cell disease, the child and the parents were referred for diagnostic confirmation and treatment. RESULTS: Between August 2000 and November 2001, 99 260 newborns were screened. There was one case of homozygous Hb C. On average, one of every 27 newborns who were screened presented sickle cell trait (Hb AS). Sickle cell disease was observed in 83 cases, or one new case in each 1 196 births. The 83 consisted of: 62 Hb S, 18 Hb SC, and 3 Hb SD. One child did not appear for diagnostic confirmation. The 82 children who were followed up by the program presented 15 intercurrent illnesses (upper respiratory infections, fever, splenic sequestration crises, hand-foot syndrome, and vascular occlusion), resulting in seven hospital admissions. Blood transfusions were necessary with 15 children, but none developed alloimmunization. All the other babies were doing well with the use of prophylactic penicillin. CONCLUSIONS: Our data show the importance of early diagnosis for sickle cell disease, so as to prevent the frequent infectious complications faced by these patients.     

Sickle hemoglobin (HbS) allele and sickle cell disease: a HuGE review

Sickle cell disease is caused by a variant of the beta-globin gene called sickle hemoglobin (Hb S). Inherited autosomal recessively, either two copies of Hb S or one copy of Hb S plus another beta-globin variant (such as Hb C) are required for disease expression. Hb S carriers are protected from malaria infection, and this protection probably led to the high frequency of Hb S in individuals of African and Mediterranean ancestry. Despite this advantage, individuals with sickle cell disease exhibit significant morbidity and mortality. Symptoms include chronic anemia, acute chest syndrome, stroke, splenic and renal dysfunction, pain crises, and susceptibility to bacterial infections. Pediatric mortality is primarily due to bacterial infection and stroke. In adults, specific causes of mortality are more varied, but individuals with more symptomatic disease may exhibit early mortality. Disease expression is variable and is modified by several factors, the most influential being genotype. Other factors include beta-globin cluster haplotypes, alpha-globin gene number, and fetal hemoglobin expression. In recent years, newborn screening, better medical care, parent education, and penicillin prophylaxis have successfully reduced morbidity and mortality due to Hb S.     

Sickle cell disease: current activities, public health implications, and future directions

Sickle cell disease (SCD) is a genetic blood disorder caused by abnormal hemoglobin that damages and deforms red blood cells (RBCs). The abnormal red cells break down, causing anemia, and obstruct blood vessels, leading to recurrent episodes of severe pain and multiorgan ischemic damage. SCD affects millions of people throughout the world and is particularly common among people whose ancestors come from sub-Saharan Africa. Sickle cell trait (SCT) is an inherited condition in which both normal hemoglobin and sickle hemoglobin are produced in the RBCs. SCT is not a type of sickle cell disease. People with SCT are generally healthy. In SCD, clinical severity varies, ranging from mild and sometimes asymptomatic states to severe symptoms requiring hospitalization. Symptomatic treatments exist, but there is no cure for SCD. Although there has been extensive clinical and basic science research in SCD, many public health issues, such as blood safety surveillance, compliance with immunizations, follow-up of newborns with positive screening tests, stroke prevention, pregnancy complications, pain prevention, quality of life, and thrombosis, in people with SCT remain unaddressed. Currently, efforts are under way to strengthen SCD-related activities within the Centers for Disease Control and Prevention (CDC). To date, several activities are being or have been conducted by centers within CDC, including quality assurance of newborn screening tests for SCD, morbidity and mortality studies, genetic studies, and studies focusing on the protective effects of SCT for malaria. This paper discusses the public health implications of SCD, summarizes SCD-related activities within CDC, and points to future directions that the agency can take to begin to address some of these issues.     

Recognition of children with sickle cell disease in The Netherlands

Timely recognition of clinical signs and symptoms of sickle cell disease remains of great importance because the neonatal PKU screening program in The Netherlands that was introduced in January 1st 2007 will not reach all children with this disease. Of children that have been diagnosed in the Emma Children's Hospital AMC, Amsterdam, 20% would not have been reached by this new program: immigrant's children born abroad and adopted children. It goes without saying that also in children that have been born in the Netherlands before January 1st 2007 the diagnosis sickle cell disease should be considered in cases of disease-specific clinical symptoms. The initial clinical manifestation of sickle cell disease in children born in the Netherlands is potentially life-threatening in 8% (7/88), e.g. a pneumococcal infection or an acute splenic sequestration. Painful crisis, paleness and jaundice are the most common presenting symptoms. The median age at diagnosis of the group of Amsterdam children was 25 months. In view of the potential health benefit it is advised to test children from populations at risk, that are under the medical attention of a hospital for any reason, for the presence of sickle cell disease. This applies especially to children with a pneumococcal infection.     

Current sickle cell screening program for newborns in New York City, 1979-1980.

The newborn screening program mandated by the New York State Public Health Law requires that every baby born in the state be tested for eight conditions including sickle cell anemia. Although sickle cell screening of newborns has been in operation since 1975, the follow-up program for case retrieval to obtain repeat blood samples for definitive diagnosis and referral of diagnosed patients for ongoing medical care was established only in 1979. Of the 106,565 blood samples tested in New York City Newborn Screening Laboratory, March 1, 1979 to February 29, 1980, 141 infants were identified on repeat blood testing as having various forms of sickle cell disease (SS, SC and S beta-Thalassemia) and were referred for ongoing medical care. Data received on 131 patients from follow-up clinics revealed that the disease diagnosis made by the Newborn Screening Laboratory was confirmed in all patients. There were no deaths reported among the study patients (131 infants) followed for the period of 8-20 months despite the life-threatening complications among eight patients. Binomial distribution of the data on Black infants according to the Hardy-Weinberg equation showed reasonable agreement between the observed and computed incidence of various forms of sickle cell disease.     

Newborn screening: complexities in universal genetic testing

Newborn screening (NBS)--in which each newborn infant is screened for up to 50 specific metabolic disorders for early detection and intervention--is the first program of populationwide genetic testing. As a public health intervention, NBS has greatly improved the lives of thousands of affected children. New technologies and new economic and social forces pose significant ethical and clinical challenges to NBS. Two primary challenges concern (1) accommodating clinical and ethical standards to rapid technological developments in NBS and (2) preparing public health systems to respond to the medical advances and social forces driving expansion of NBS programs. We describe and analyze these challenges through consideration of 3 disorders: phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, and cystic fibrosis.     

Is treatment adherence associated with better quality of life in children with sickle cell disease?

The association of treatment adherence with quality of life (QOL) and the role of sickle cell disease complications were explored in children with sickle cell disease. Primary caregivers of 43 children, ages 5 years and older, and 21 children, ages 8 years and older, completed a standardized measure of QOL during an admission for pain or fever to the hematology acute care unit. Adherence was measured through medical staff ratings, caregiver-report of sickle cell disease-related care activities, and matching of medical staff standard recommendations for treatment of pain and fever with sickle cell disease-related care activities. Sickle cell disease complications were assessed via medical file review. Pearson correlation coefficients indicated that better adherence was associated with poorer overall QOL. In follow-up analyses, although sickle cell disease complications were associated with adherence, it did not explain the negative correlation of adherence with QOL. Higher treatment adherence may interfere with activities that contribute to QOL for some children. Further research to investigate the role of sickle cell disease complications, as well as psychosocial factors, in determining both treatment adherence and QOL is suggested.     

Cost of hospitalizations associated with sickle cell disease in the United States.

OBJECTIVE: This study estimated the number and cost of hospitalizations associated with sickle cell disease in the United States. METHODS: To estimate the number of hospitalizations per year in the United States of people with sickle cell disease, the authors used data for the years 1989 through 1993 from national hospital discharge surveys conducted by the National Center for Health Statistics. The authors derived cost estimates using data from a 1992 national hospital discharge survey conducted by the Agency for Health Care Policy and Research and a 1992 survey of physicians conducted by the American Medical Association. RESULTS: During the years 1989 through 1993, there were on average an estimated 75,000 hospitalizations per year of children and adults with sickle cell disease. The average direct cost per hospitalization (in 1996 dollars) was estimated at $6300, for a total direct cost of $475 million per year. In 66% of hospital discharge records, government programs were listed as the expected principal source of payment. CONCLUSIONS: The cost of hospitalizations associated with sickle cell disease is substantial. Because government programs pay most of this cost, further government-funded research to develop interventions that prevent complications of the disease has great potential for cost savings as well as for reducing the suffering of those afflicted with this painful genetic disorder. These national cost estimates contribute to an understanding of the impact of sickle cell disease and should be useful in establishing research priorities.     

Impact of expanded newborn screening--United States, 2006

Universal newborn screening for selected metabolic, endocrine, hematologic, and functional disorders is a well-established practice of state public health programs. Recent developments in tandem mass spectrometry (MS/MS), which is now capable of multi-analyte analysis in a high throughput capacity, has enabled newborn screening to include many more disorders detectable from a newborn blood spot. In 2006, to address the substantial variation that existed from state to state in the number of disorders included in newborn screening panels, the American College of Medical Genetics (ACMG), under guidance from the Health Resources and Services Administration, recommended a uniform panel of 29 disorders, which was subsequently endorsed by the federal Advisory Committee on Heritable Disorders in Newborns and Children. After 2006, most states began to expand their panels to include all 29 disorders; currently, 21 states and the District of Columbia have fully implemented the ACMG panel. To estimate the burden to state newborn screening programs resulting from this expansion, CDC used 2001-2006 data from those states with well-established MS/MS screening programs to estimate the number of children in the United States who would have been identified with disorders in 2006 if all 50 states and the District of Columbia had been using the ACMG panel. This report describes the results of that analysis, which indicated that, although such an expansion would have increased the number of children identified by only 32% (from 4,370 to 6,439), these children would have had many rare disorders that require local or regional capacity to deliver expertise in screening, diagnosis, and management. The findings underscore the need for public health and health-care delivery systems to build or expand the programs required to manage the rare disorders detected through expanded newborn screening, while also continuing programs to address more common disorders.     

Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC.

Group B streptococcus (GBS) remains a leading cause of serious neonatal infection despite great progress in perinatal GBS disease prevention in the 1990s. In 1996, CDC, in collaboration with other agencies, published guidelines for the prevention of perinatal group B streptococcal disease (CDC. Prevention of perinatal group B streptococcal disease: a public health perspective. MMWR 1996;45[RR-7]:1-24). Data collected after the issuance of the 1996 guidelines prompted reevaluation of prevention strategies at a meeting of clinical and public health representatives in November 2001. This report replaces CDC's 1996 guidelines. The recommendations are based on available evidence and expert opinion where sufficient evidence was lacking. Although many of the recommendations in the 2002 guidelines are the same as those in 1996, they include some key changes: * Recommendation of universal prenatal screening for vaginal and rectal GBS colonization of all pregnant women at 35-37 weeks' gestation, based on recent documentation in a large retrospective cohort study of a strong protective effect of this culture-based screening strategy relative to the risk-based strategy * Updated prophylaxis regimens for women with penicillin allergy * Detailed instruction on prenatal specimen collection and expanded methods of GBS culture processing, including instructions on antimicrobial susceptibility testing * Recommendation against routine intrapartum antibiotic prophylaxis for GBS-colonized women undergoing planned cesarean deliveries who have not begun labor or had rupture of membranes * A suggested algorithm for management of patients with threatened preterm delivery * An updated algorithm for management of newborns exposed to intrapartum antibiotic prophylaxis Although universal screening for GBS colonization is anticipated to result in further reductions in the burden of GBS disease, the need to monitor for potential adverse consequences of intrapartum antibiotic use, such as emergence of bacterial antimicrobial resistance or increased incidence or severity of non-GBS neonatal pathogens, continues, and intrapartum antibiotics are still viewed as an interim strategy until GBS vaccines achieve licensure.     

Evaluating newborn screening program data systems--Georgia, 1998

All 50 states and the District of Columbia conduct newborn screening (NBS) programs that annually screen approximately 4 million infants for metabolic and other disorders to prevent mental retardation, disability, and death. In 1998, Georgia newborns were screened for eight disorders: phenylketonuria, galactosemia, tyrosinemia, homocystinuria, hypothyroidism, maple syrup urine disease, congenital adrenal hyperplasia, and sickle cell disease. Appropriate data that reflect progress toward achieving short- and long-term goals are necessary to assess the effectiveness of NBS and to inform public health policy decisions about which disorders to add or delete from screening. This report summarizes findings from an evaluation of data systems for metabolic and endocrine disorders in the Georgia NBS program and assesses the ability to measure progress toward short- and long-term goals. Although the data indicate that the program typically received specimens of sufficient quality for testing in a timely manner, additional data are needed to assess fully the effectiveness of the NBS program in identifying disorders.     

Confidentiality, genetic counseling, and public health: a case study on sickle cell trait

Sickle cell anemia is the most prevalent genetic disease in Brazil. Screening for sickle cell trait in blood donation centers has been recommended by the Brazilian government since 1976. This screening mechanism is one of most common forms of genetic screening for sickle cell disease in the country. This article is based on an ethnographic survey of individuals undergoing genetic counseling in a large blood donation center. The article contends that confidentiality should be a prerequisite for the broad dissemination of genetic information in public health. The ethical principle of confidentiality needs to be seen as a human right and public health issue.     

Sources of health insurance in the U.S.: analysis of state-level data and implications for public health programs.

Lack of health insurance coverage is associated with lack of accessibility to preventive health care services such as mammography screening, clinical breast examination, Papanicolaou smear test, digital rectal examination, proctoscopy examination, and cholesterol screening. State and federal public health agencies must have an understanding of insurance coverage of the population to plan intervention programs aimed at early detection of medical conditions. Using data from the March Supplement of the Current Population Survey for the years 1994, 1995, and 1996, this study examines the sources of health insurance coverage in the U.S. The implications of the findings for public health programs are discussed.     

Evaluation of coverage by a neonatal screening program for hemoglobinopathies in the Recôncavo region of Bahia, Brazil

In 2001, government ruling n. MS 822/01 by the Brazilian Ministry of Health made neonatal screening mandatory for hemoglobinopathies, with special focus on sickle cell disease, the most common hemoglobinopathy in Brazil. Bahia is the State of Brazil with the highest prevalence of this disease. The current paper reports on the prevalence of hemoglobin variants HbS and HbC, which cause sickle cell disease, in the cities of Cachoeira, Maragogipe, and S?o Félix, Bahia State. The overall proportion of carriers for the two forms of hemoglobin was 13%. From 2001 to 2003, the neonatal screening rate decreased from 82.6% to 46.4% in Cachoeira and increased from 37.0% to 56.2% in Maragogipe. Thus, only about one-half of children are being tested in these cities. The findings show that the public health care system in these cities is poorly prepared to screen for sickle cell disease in newborns and that there was a lack of health care personnel to follow up on newly diagnosed sickle cell patients or carriers of the sickle cell trait.     

The cost effectiveness of universal versus selective newborn screening for sickle cell disease in the US and the UK

We reviewed several cost-effectiveness analyses that modelled the costs and yield of newborn screening for sickle cell disease (SCD) in the US and the UK and discuss the ways in which newborn screening policies in each country evolved with regard to the results of the analyses. Each of the reviewed studies compared the projected cost of universal screening with that of selective screening of children from specific ethnic groups. Despite variability in assumptions, the studies concurred that universal screening in areas with low SCD prevalence would result in a higher cost per case detected, compared with selective screening of children in high-risk ethnic groups. Investigators expressed differing opinions about the economic justification of universal screening, which reflected differences in the understanding of cost effectiveness and in how study questions were framed. Ultimately, policy makers in both countries decided in favour of universal screening, which appears to reflect a growing consensus that ethnically targeted newborn screening is not an acceptable public health strategy. One way to interpret this outcome is that considerations of equity and logistics, including potential stigmatisation, missed cases, and the perceived difficulty and discomfort in ascertaining ethnicity or in separating specimens, trumped economic calculations regarding the relative efficiency of targeted screening. It is not the case that policy makers explicitly favoured equity over economic optimisation; rather, they appear to have given more credence and value to the expert opinion of screening specialists than to the results of economic analyses.     

Prevention of infectious diseases in the drepanocytic child

Children with sickle cell anemia are more exposed to infection than healthy children. Indeed, infections are the major cause of morbidity and mortality in children with sickle cell anemia, especially those aged 6 months to 5 years. Phagocytosis is reduced in these children. Polynuclear neutrophils reveal various poorly understood irregularities and are associated with a reduction of phagocytic power: zinc deficiency, reduced post-phagocytic oxidative metabolism, and a prevalence of neutrophils not forming red sheep-like globule carriers of immunoglobulin H. The power of the antibody which renders germs susceptible to phagocytosis in the serum is reduced in sickle cell patients. This may be tied to a disorder in the alternate complementary route with reduction of C3 and properdin. Sequestration of sickle cell-shaped red blood cells, splenic congestion, and short circuits of important functional territories contribute to spleen dysfunction, which occurs early. Common pathogens attacking sickle cell patients are pneumococci, salmonella species, and Haemophilus influenzae. They cause very grave infections (e.g., septicemia and purulent meningitis). Prevention of infections dwells on three perspectives: early screening for sickle cell anemia and for spleen dysfunction, preventive penicillin therapy, and vaccination. In Benin, vaccination is the only means to prevent infections. Essential vaccinations for children with sickle cell anemia include BCG, diphtheria-pertussis-tetanus, polio, and Rouvax. Strongly recommended vaccinations are Pneumovax 23, HEVAC B, TAB, vaccine against H. influenzae, and vaccine against mumps. A vaccine calendar for children with sickle cell anemia guides health workers when they must administer the vaccines and their boosters over a six year period. It is not yet universal in health facilities in Benin. A short- and long-term evaluation of the calendar's efficacy would allow one to appreciate its real impact on reducing morbidity and mortality in children with sickle cell anemia.