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.
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.
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.
Options
Two 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.
Outcomes
Sensitivities and specificities of the diagnostic and screening tests.
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).
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.
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.
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.
Sponsors
The Canadian Task Force on Preventive Health
Care developed this guideline with funding from Health Canada.
Selected References
Source Document
Goldbloom R.B. Screening for hemoglobinopathies in Canada. In: Canadian
Task Force on the Periodic Health Examination. Canadian
Guide to Clinical Preventive Health Care. Ottawa: Health Canada,
1994; 206-18.
Other
Canadian Task Force on the Periodic Health Examination: The periodic
health examination. Can Med Assoc J. 1979;121:1193-254.