Canadian Task Force on Preventive Health Care

Structured Abstract

Please note: In 2003, the CTF updated its Grades of Recommendations to include an "I Recommendation" for situations where insufficient evidence exists to allow a recommendation to be made.  (Formerly, these situations were captured under a "C Recommendation".)  This change is not retroactive, and all "C Recommendations" made prior to 2003 have not been reevaluated in light of the new "I" recommendation grade.  For a discussion of these recommendation grades, please link to the 2003 article in the Canadian Medical Association Journal here.

Screening for Hemoglobinopathies in Canada

Adapted by Richard B. Goldbloom, OC, MD, FRCPC, Department of Pediatrics, Dalhousie University, from the report prepared for the US Preventive Services Task Force by John S. Andrews, MD and Modena E.H. Wilson, MD, MPH

These recommendations were finalized by the Task Force in March 1994

Up Contents

Up Objective

To make recommendations for screening Canadian adolescents, adults, and pregnant women for carrier status of hemoglobinopathies (thalassemia and sickle cell disease). Prenatal and neonatal screening is also included. This updates a 1979 Canadian Task Force report.

Up Burden of Suffering

The Thalassemias
The thalassemias are hereditary conditions due to mutations causing decreased or absent production of the alpha-globin or beta-globin chains of hemoglobin.  Beta-thalassemia major occurs in individuals homozygous for a genetic defect in beta-globin synthesis.  Infants with beta-thalassemia are usually born healthy and may remain so for as long as 2-3 years.  They then develop severe anemia, requiring regular transfusions and later, iron chelation therapy.  Affected individuals usually die in the third decade of life.  The cost of treatment is very high, estimated at $30,000 per year, over 30-35 years or almost $1 million per patient.

Alpha-thalassemias results from deletions in 1 or more of the 4 genes responsible for alpha-globin synthesis.  They are common in persons of Southeast Asian descent, but also occur in persons of African and Mediterranean origin.  Fetuses with a 4-gene deletion develop hydrops fetalis secondary to severe anemia and die before or soon after birth.  Mothers of these infants are at risk for toxemia during pregnancy, for operative delivery, and for post-partum hemorrhage.  The exact prevalence of alpha-thalassemia is uncertain, but is estimated to be 5-30% among African-Americans, and 15-30% among Southeast Asians.

Hemoglobin E trait is the third most common hemoglobin disorder in the world and the most frequent in Southeast Asia, where its prevalence is estimated to be 30%.

Sickle Cell Disease
The Sickle Cell Association of Ontario estimates the Black population of Canada at about 700,000, and growing.  The carrier frequency of the sickle gene is cited at 1 in 10 in the U.S.  The carrier rate may be higher in Canada, where the black population is composed largely of individuals of Caribbean (carrier rate 10-14%) and African origin (carrier rate 20-25% in West Africa).  Based on various assumptions, it has been estimated that as many as 67 black infants affected with sickle cell disease may be born annually in Canada.  Mortality in patients with sickle cell disease peaks between 1 and 3 years of age, chiefly due to sepsis caused by Streptococcus pneumoniae, estimated to occur in a frequency of 8 episodes per 100 person-years of observation in affected children under 3 years of age.  After infancy, patients with sickle cell disease are usually anemic and may experience painful crises and other complications, including acute chest syndrome, strokes, splenic and renal dysfunction, bone and joint symptoms, priapism, ischemic ulcers, cholecystitis and hepatic dysfunction associated with cholelithiasis.

Up Options

2 screening options for carrier status in pregnant women are currently used: 1) a complete blood cell test to identify hypochromia and microcytosis followed by hemoglobin electrophoresis when iron deficiency is ruled out, and 2) cellulose acetate or citrate agar electrophoresis using the thin layer isoelectric focusing process to identify hemoglobinopathies from blood samples with confirmation using high-performance liquid chromatography. Prenatal screening and counselling includes DNA testing of tissue samples from amniocentesis or chorionic villus testing.

Neonatal screening options include analysis of dried capillary blood samples collected on filter paper and cellulose acetate electrophoresis, or thin-layer isoelectric focusing and citrate agar electrophoresis liquid chromatography for confirmation. Screening for carrier status in nonpregnant adolescents and adults and counselling includes a complete blood cell test for hypochromia and microeycosis followed by hemoglobulin electrophoresis when iron deficiency is ruled out.

Treatment options include prevention of pneumococcal sepsis with penicillin prophylaxis and prompt clinical attention to infants who are affected.

Up Outcomes

Sensitivities and specificities of the diagnostic and screening tests.

Up Evidence

These recommendations were developed from materials prepared for the U.S. Preventive Services Task Force. MEDLINE was searched for 1998 - 1993 using the keywords anemia, hemoglobinopathies, sickle cell, and ethnic groups (epidemiology).

Recommendations were graded as:
A
 Good evidence to support the recommendation that the condition be specifically considered in a PHE. 
B
 Fair evidence to support the recommendation that the condition be specifically considered in a PHE. 
C
 Poor evidence regarding inclusion or exclusion of the condition in a PHE, but recommendations may be made on other grounds. 
D
 Fair evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE. 
E
 Good evidence to support the recommendation that the condition be specifically excluded from consideration in a PHE. 

Quality of evidence was rated according to 5 levels:
I
 Evidence from at least 1 properly randomized controlled trial (RCT). 
II-1
 Evidence from well-designed controlled trials without randomization. 
II-2
 Evidence from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group. 
II-3
 Evidence from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments could also be included here. 
III
 Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees. 

Up Values

The 13-member Task Force of experts in family medicine, geriatric medicine, pediatrics, psychiatry and epidemiology used an evidence-based method for evaluating the effectiveness of preventive health care interventions. Recommendations were not based on cost-effectiveness of options. Patient preferences were not discussed.

Background papers providing critical appraisal of the evidence and tentative recommendations prepared by the chapter author were pre-circulated to the members. Evidence for this topic was presented and deliberated upon in 1- to 2-day meetings, 2 to 3 times per year from January 1993 to June 1993. Consensus was reached on final recommendations.

Up Benefits, Harms, and Costs

Many categories of hemoglobinopathies, both thalassemias and sickle cell disease, exist and have varying degrees of morbidity and mortality. Tests are very accurate. One large study in Colorado that screened more than 525 000 infants with dried blood samples had only 4 false negative and 32 false positive results. Prenatal diagnosis is also very accurate using chorionic villus sampling or amniocentesis samples.

An RCT showed that prophylactic oral penicillin for infants and young children with sickle cell disease reduced mortality by 84%. A 7-year cohort study found lower mortality in children with sickle cell disease who were identified early (2% for identification at birth and 8% for identification at 3 months).

Although genetic counselling increases knowledge of carrier status, no evidence exists that shows changes in reproductive behaviours and incidence of births of infants with hemoglobin disorders.

Carrier status identification at birth increases testing of partners and fetuses and some parents choose abortion (1 abortion in 18 907 pregnancies with 77 pregnancies ascertained to be high risk). One European survey showed a decreased incidence of birth of infants with thalassemia after universal screening for carrier status.

Some cost data show that universal screening is more cost-effective than targeted screening. Targeted screening may also miss cases of hemoglobinopathies.

Inadequate education about hemoglobinopathies (e.g., the differences between sickle cell disease and sickle cell trait) have led to increased anxiety for carriers and inappropriate labelling by employers and insurers.

Up Recommendations

Recommendation grade [A, B, C, D, E]  and level of evidence [I, II-1, II-2, II-3, III] are indicated after each recommendation. Citations in support of individual recommendations are identified in the guideline text.

Up Validation

This report was externally peer reviewed.  The U.S. Preventive Services Task Force do not have current guidelines in place. The National Institutes of Health Consensus Development Conference on Newborn Screening for Sickle Cell Disease and other hemoglobinopathies recommends universal screening for sickle cell disease as does the Agency for Health Care Policy and Research. Both the World Health Organization and the British Society of Haematology recommend screening of high-risk infants.

Up Sponsors

The Canadian Task Force on Preventive Health Care developed this guideline with funding from Health Canada.

Up Selected References

Source Document

Other

Link to Full Text of this review

Link to Summary Table of Recommendations of this review

Link to Selected References list of this review

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