Screening for Hemoglobinopathies
Recommendation
Neonatal screening for sickle hemoglobinopathies is
recommended to identify infants who may benefit from antibiotic prophylaxis to
prevent sepsis. Whether screening should be universal or targeted to high-risk
groups will depend on the proportion of high-risk individuals in the screening
area, the accuracy and efficiency with which infants at risk can be identified,
and other characteristics of the screening program. All screening efforts must
be accompanied by comprehensive counseling and treatment services. Offering
screening for hemoglobinopathies to pregnant women at
the first prenatal visit is recommended, especially for those at high risk.
There is insufficient evidence to recommend for or against routine screening
for hemoglobinopathies in high-risk adolescents and
young adults, but recommendations to offer such testing may be made on other
grounds (see Clinical Intervention).
Burden of Suffering
Hemoglobin S is formed as the result of a single-gene defect causing
substitution of valine for glutamic
acid in position 6 of the b chain of adult hemoglobin. Persons homozygous for hemoglobin S (HbSS) have sickle cell anemia. Under conditions of low
oxygen tension, hemoglobin S polymerizes, causing the red blood cells of
persons with sickle cell anemia to assume a "sickled"
shape. This deformity of red blood cells leads to the symptoms of sickle cell
disease. Persons heterozygous for both hemoglobin S and hemoglobin C (HbSC) and persons heterozygous for both hemoglobin S and b-thalassemia (HbS/b-thal) also may
experience sickle cell disease, although their symptoms tend to be less severe
than those of persons homozygous for hemoglobin S.1 Sickle
cell disease affects an estimated 50,000 Americans2-4 and affects persons of many racial and ethnic backgrounds. Among infants
born in the U.S., sickle cell disease occurs in 1 in every 375
African Americans, 1 in 3,000 Native Americans, 1 in 20,000 Hispanics, and 1 in 60,000 whites.4
Compared to blacks in the
general population, the average life expectancy of patients with sickle cell
anemia is decreased by 25-30 years.5
Symptom severity and life expectancy vary considerably, with some patients
surviving beyond middle age and others dying during infancy or childhood.
Mortality in children with sickle cell disease peaks between 1 and 3 years
of age, and is chiefly due to sepsis caused by Streptococcus pneumoniae.1 Pneumococcal septicemia occurs at a rate of approximately 8
episodes per 100 person-years of observation in children under the age of 3 years
with sickle cell disease.6,7 The
case-fatality rate can be as high as 35%.8 After
infancy, patients with sickle cell disease are usually anemic and may
experience painful crises and other complications, including acute chest
syndrome, priapism, strokes, splenic
and renal dysfunction, bone and joint disease, ischemic ulcers, cholecystitis, and hepatic dysfunction associated with
cholelithiasis.4,9 The causes of premature death in adults are varied, and include sudden
death during acute pain episodes, stroke, infection, and chronic organ failure.5
Treatment for sickle cell disease may be expensive. This chronic illness places
a large economic and psychosocial burden on patients and their caretakers.9
About 2
million Americans are heterozygous for hemoglobin S and hemoglobin A (normal adult hemoglobin). This carrier state has been
termed sickle cell trait and is present in 8% of
the African American population.3 Except for a slightly
increased risk of exercise-related death under extreme conditions,10 persons with sickle cell trait experience negligible morbidity.11,12
Parents who are both carriers have a 25% probability with each
pregnancy of having a child with sickle cell disease. One in every 150
African American couples in the U.S. is at risk of giving birth to a child with
sickle cell disease (about 3,000 pregnancies per year).13,14
Certain thalassemias
may also be detected by screening for hemoglobinopathies.
Thalassemias result from genetic defects that cause
reduced synthesis of the polypeptide globin chains
that combine to form hemoglobin. The clinical severity of these syndromes is
related to the degree of reduction of a- or b-globin
synthesis.
The b-thalassemias
occur primarily among individuals of Mediterranean, African, or Southeast Asian origin. b-Thalassemia minor occurs in persons heterozygous for
a gene causing reduction in b-globin synthesis. Life
expectancy is normal, and the clinical severity of this state is related to the
specific defect and its effect on b-chain synthesis. b-Thalassemia major occurs in persons homozygous for
genetic defects in b-globin synthesis.
b-Globin synthesis in these
individuals is markedly reduced or absent. They suffer from severe anemia and
are transfusion dependent. Modern transfusion protocols and iron chelation therapy have greatly improved prognosis and some
patients survive beyond the third decade of life.15
b-Thalassemia major affects fewer than 1,000 Americans.16
a-Thalassemias are
common in persons of Southeast Asian descent and also occur in persons of
African and Mediterranean origin. a-Thalassemias
result from deletions of one or more of the four genes responsible for a-globin synthesis. Patients with a four-gene deletion
develop hydrops fetalis
secondary to severe anemia and die before or shortly after birth. Mothers of
these infants are at risk for toxemia during pregnancy, operative delivery, and
postpartum hemorrhage.17 The three-gene deletion is referred to as hemoglobin H disease and
affects about 1% of Southeast Asians.18 Three- and four-gene deletions
are rare in African Americans. Persons with hemoglobin H disease experience
chronic hemolytic anemia that is exacerbated by exposure to oxidants and may
require transfusion. Persons with a two-gene deletion have microcytic
red blood cells and occasionally mild anemia. The one-gene deletion is a
"silent" carrier state. These latter two conditions are often called
a-thalassemia trait. The exact prevalence of a-thalassemia trait is uncertain, but it is estimated to be 5-30% among
African Americans and 15-30% among Southeast Asians.18-20
Hemoglobin E trait is the third
most common hemoglobin disorder in the world and the most common in Southeast
Asia, where its prevalence is estimated to be 30%.18
Although hemoglobin E trait is associated with no morbidity, the offspring of
individuals who carry this hemoglobin variant may exhibit thalassemia
major (hemoglobin E/b-thalassemia) if the other
parent has b-thalassemia trait and contributes that
gene. This combination is the most common cause of transfusion-dependent thalassemia in areas of Southeast Asia.18
Accuracy of Screening Tests
Two-tier hemoglobin electrophoresis (cellulose acetate electrophoresis with
confirmation by citrate agar electrophoresis) or thin-layer isoelectric
focusing are widely used screening tests for hemoglobin disorders.4,21
High-performance liquid chromatography (HPLC) is a newer technique that offers
high resolution and is in use in at least one screening program.22
Techniques employing monoclonal antibodies and recombinant DNA technology are
not used widely.23 Blood for screening is collected in heparinized
tubes or, in the case of newborn screening, on filter paper (Guthrie paper
blotter).24
Electrophoresis is highly
specific in the detection of certain hemoglobin disorders, such as sickle cell
disease. In one study, all 138 children with hemoglobin S
identified by screening 3,976 African American newborns were found to have a sickling
disorder when retested at age 3-5 years.25
Another study of 131 infants detected by screening found only nine instances in which the sickling disorder required reclassification and no instance
in which a child originally diagnosed as having sickle cell disease was found
to have sickle cell trait.26 Ten years' experience with
universal screening of Colorado newborns (528,711 infants) using filter paper specimens and two-tier hemoglobin
electrophoresis was reported in 1990.27 Fifty infants with sickle cell
diseases (HbSS, HbSC, HbS/b-thal) and 27 infants with other hemoglobin
disorders were identified. Initial screening failed to identify four infants
with sickle cell disease, but three of these were diagnosed on routine
follow-up testing of infants suspected of having sickle cell trait. There were 32
false-positive results, 27 of which were confirmed to
have a hemoglobinopathy trait on follow-up testing.
The remaining five had normal hemoglobin. The test characteristics of HPLC may
be superior to those of two-tier electrophoresis. Data are yet to be published.
The yield in screening pregnant
women for hemoglobin disorders depends on the risk profile of the population
being tested. In one study, electrophoresis in combination with a complete
blood count was performed on 298 African American and Southeast
Asian prenatal patients. Ninety-four women (31.5%) had
a hemoglobin disorder (including sickle cell disease, sickle cell trait,
hemoglobin E, a-thalassemia trait, b-thalassemia trait, hemoglobin H, and hemoglobin C).19 In a larger
study in a different community, similar tests were performed on 6,641 prenatal patients selected without regard to race or ethnic origin.28 One
hundred eighty-five women (3%) had sickle cell trait, 68 (1%) had
hemoglobin C, 30 (0.5%) had b-thalassemia trait, and 17 (0.3%) had
other disorders (hemoglobin E, a-thalassemia trait,
hemoglobin H, hemoglobin E/b-thalassemia disease).
These results were obtained by combining electrophoresis with red cell indices.
When low mean corpuscular volume (MCV) was used as the only screening test to
detect thalassemia, the yield was 0.3-0.5%.29
Prenatal diagnosis of sickle
cell disease and other hemoglobinopathies in the
fetus has been aided by advances in techniques of obtaining and analyzing
specimens. Early tests involved the analysis of fetal blood obtained by fetoscopy or placental aspiration.30
Genetic advances, however, have provided a safer14 and
more practical method in which amniocytes are
obtained by amniocentesis and gene mutations are identified directly through
recombinant DNA technology.13 These techniques are highly
accurate (error rate less than 1%) in detecting sickle cell
disease and certain forms of thalassemia.14,30-33 The
principal disadvantage of using amniocentesis to obtain specimens is that it cannot
be performed safely until about 16 weeks' gestation, thus
delaying diagnosis and potential intervention until late in the second
trimester. Chorionic villus
sampling (CVS) is a means of obtaining tissue for DNA analysis as early as 10-12 weeks
of gestation and is an established technique for prenatal diagnosis (see
Chapter 41).34,35 Effectiveness of Early Detection
Screening for hemoglobin
disorders is usually discussed with respect to two target populations: neonates
and adults of reproductive age. Newborns with sickle cell disease benefit from
early detection through the early institution of prophylactic penicillin
therapy to prevent pneumococcal sepsis. A multicenter, randomized, double-blind, placebo-controlled
trial demonstrated that the administration of prophylactic oral penicillin to
infants and young children with sickle cell disease reduced the incidence of pneumococcal septicemia by 84%.36 Other
benefits of identifying newborns with sickle cell disease include prompt
clinical intervention for infection or splenic
sequestration crises and education of caretakers about the signs and symptoms
of illness in these children. A 7-year longitudinal study
reported lower mortality in children with sickle cell disease identified in the
newborn period than in children diagnosed after 3 months
of age (2% vs. 8%), but the investigators did not account for confounding variables in the
control group.37 A briefer longitudinal study (8-20
months) reported no deaths in 131 newborns detected through
screening.26 In the Colorado experience described above, 47 of the
50 newborns with sickle cell disease identified through screening remained
in the state beyond 6 months of age. None of the 47 died during the period of
observation.27
Screening older children and
adolescents is designed to detect carriers with sickle cell trait, b-thalassemia trait, and other hemoglobin disorders that have
escaped detection during the first years of life. Identification of carriers
before childbearing allows them to make informed reproductive choices by
receiving genetic counseling about partner selection and the availability of
diagnostic tests in the event of pregnancy. There is some evidence that
individuals who receive certain forms of counseling retain this information and
may encourage other individuals, such as their partners, to be tested.28,38-40 A
prospective study of 142 persons screened for b-thalassemia trait found
that 62 (43%) encouraged other persons to be screened.38
Compared with controls, those who had received counseling demonstrated
significantly better understanding of thalassemia
when tested immediately after the session. There is no direct evidence,
however, that individual genetic counseling by itself significantly alters
reproductive behavior or the incidence of births of infants with hemoglobin
disorders.9,41
Detection of carrier status
during pregnancy provides prospective parents with the option of testing the
fetus for a hemoglobinopathy. If the test is
positive, they have the time to discuss continuation of the pregnancy and to
plan optimal care for their newborn. Parents appear to act on this genetic
information. About half of pregnant women with positive tests for thalassemia refer their partners for testing and, if the
father is positive, about 60% consent to amniocentesis.28 If
sickle cell disease is diagnosed in the fetus, about 50% of
parents elect therapeutic abortion.32,42 In a recent study, 18,907 samples from pregnant women were screened for abnormal hemoglobin
including thalassemias and hemoglobin S. In 810 (4.3%), an
abnormal hemoglobin was identified; 66% occurred in mothers unaware
that they carried an abnormal hemoglobin, and 80%
occurred in mothers unaware that they were at risk for giving birth to a child
with a serious hematologic disorder. Eighty-six
percent of mothers who received counseling said they wanted their partner
tested and 55% of partners were tested. Seventy-seven pregnancies were identified as
being at risk because the partner also was a carrier of an
abnormal hemoglobin. Of these 77 pregnancies, the gestation was
too advanced for prenatal diagnosis in 12 cases and the condition for
which the pregnancy was at risk was too mild for this service to be offered in 12
others. Prenatal diagnosis was offered in the remaining 53
pregnancies and accepted by 25 couples (47%). Of 18
amniocenteses actually performed, 5 fetuses were found to have
clinically significant hemoglobinopathies and one of
these pregnancies was terminated.43
There is evidence from some
European communities with a high prevalence of b-thalassemia
that the birth rate of affected infants has declined significantly following
the implementation of routine prenatal screening,30 and
there are data suggesting a similar trend in some North American communities
that have introduced community education and testing for thalassemia.16 Time
series studies do not, however, prove that such trends are due specifically to
the effects of prenatal screening.
Recommendations of Other Groups
Screening for sickle cell disease in all newborns, regardless of their race or
ethnic origin, has been recommended by a National Institutes of Health
consensus conference8 and by a guideline panel convened by the Agency for Health Care Policy
and Research.4 Screening infants from high-risk groups (e.g., those of African,
Caribbean, Latin American, Southeast Asian, Middle Eastern, or Mediterranean
ethnicity) has been recommended by the World Health Organization,44 the
British Society for Haematology,45 the American Academy of Family
Physicians (AAFP),46 and the Canadian Task Force on the Periodic Health Examination.47 The
recommendations of the AAFP are currently under review. The American Academy of
Pediatrics48 and Bright Futures49 recommend routine screening
for hemoglobinopathies as required by individual
states. At present 29 states, Puerto Rico, and the District of Columbia mandate screening all newborns for hemoglobinopathies,
and 12 states offer screening as an option.50
The American College of
Obstetricians and Gynecologists,51 the British Society for
Haematology,45 and the Canadian Task Force47 recommend selective prenatal
screening and counseling of pregnant women from high-risk ethnic groups. The
Canadian Task Force47 recommends that parents with established positive carrier status be
offered prenatal DNA analysis of amniocentesis or CVS tissue sampling. No major
organizations recommend routine screening of adolescents and young adults for
carrier status.
Discussion
Hemoglobinopathies occur among all ethnic and racial
groups. Efforts at targeting specific high-risk groups for newborn screening
inevitably miss affected individuals due to difficulties in properly assigning
race or ethnic origin in the newborn nursery. In one study of more than 500,000 newborns, parental race as requested on a screening form was found to be
inaccurate or incomplete in 30% of cases.27
Proponents of selective screening of high-risk populations emphasize that,
especially in geographic areas with a small population at risk,
cost-effectiveness is compromised and considerable expense incurred in
screening large numbers of low-risk newborns to identify the rare individuals
with sickle cell disease or other uncommon hemoglobin disorders.52
Studies supporting this argument have compared universal screening to no
screening, not targeted screening. Recent research that accounts for the
additional procedural and administrative costs of targeted screening suggests
that universal screening may be the more cost-effective alternative.4
Whether to screen all infants (universal screening) or only those infants from
ethnic groups known to be at relatively high risk of having sickle cell disease
(targeted screening) is therefore a policy question to be addressed by
individual screening programs, taking into consideration cost-effectiveness analyses,
disease prevalence, and available resources.
There has been considerable
debate over the value of screening for hemoglobinopathies
in persons of reproductive age. Critics cite evidence that sickle cell
screening programs in the past have failed to adequately educate patients and
the public about the significant differences between sickle cell trait and
sickle cell disease. This has resulted in unnecessary anxiety for carriers and
inappropriate labeling by insurers and employers.53 In
addition, there is no evidence that counseling, however comprehensive, will be
remembered throughout the individual's reproductive life, influence partner
selection, alter use of prenatal testing, or ultimately reduce the rate of
births of affected children.9,29 Proponents
argue that these outcomes should not be used as measures of effectiveness since
the goal of genetic counseling is to facilitate informed decision making by
prospective parents.9,20,29 In this regard, clinicians are responsible for making the individual
aware of the diagnosis, the risk to future offspring, and the recommended
methods to reduce that risk, regardless of the strength of the evidence that
such counseling reduces the number of affected offspring.
CLINICAL INTERVENTION
Screening newborn infants for hemoglobinopathies with
hemoglobin electrophoresis or other tests of comparable accuracy on umbilical
cord or heelstick blood specimens is recommended
("A" recommendation). In geographic areas with a very low incidence
of hemoglobin disorders, selective screening of newborns may be more efficient
than universal screening. Infants with sickle cell disease must receive prompt
follow-up, including oral penicillin prophylaxis, diagnostic testing,
immunizations, and regular evaluations of growth and nutritional status. Their
families should receive genetic counseling regarding testing of family members
and risks to future offspring, information about the disease, education about
early warning signs of serious complications, and referrals for peer support groups
and sources of medical and mental health services.
Offering screening for hemoglobinopathies with hemoglobin electrophoresis or other
tests of comparable accuracy to pregnant women at the first prenatal visit is
recommended ("B" recommendation), especially for those who are
members of racial and ethnic groups with a high incidence of hemoglobinopathies (e.g., individuals of African,
Caribbean, Latin American, Mediterranean, Middle Eastern, or Southeast Asian
descent). Carriers identified through testing should be urged to have the
father tested and should receive information on the availability of prenatal
diagnosis if the father is positive and the fetus is at risk of having a
clinically significant hemoglobinopathy.
There is insufficient evidence to
recommend for or against screening for hemoglobinopathies
in adolescents and young adults from ethnic and racial groups known to be at
increased risk for sickle cell disease, thalassemias,
and other hemoglobinopathies in order for them to be
able to make informed reproductive choices ("C" recommendation).
Recommendations to offer such testing may be made on other grounds, including
burden of suffering and patient preference. If provided, testing should be
accompanied by counseling, which should include a description of the
significance of the disease, how it is inherited, the availability of a
screening test, and the implications to individuals and their offspring of a
positive result.