Received: March 5, 2014
Accepted: March 6, 2014
Meditter J Hematol Infect Dis 2014, 6(1): e2014022, DOI 10.4084/MJHID.2014.022
This article is available on PDF format at:
Piero C. Giordano1 and Eliezer Rachmilewitz2
1
Emeritus Associated Professor, Clinical Biochemical Molecular
Geneticist. Hemoglobinopathies Laboratory; Dpt. of Human and Clinical
Genetics; Leiden University Medical Center.
2 Department of Hematology; The Edith Wolfson
Medical Center; Holon, Israel
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Article
Hemoglobinopathies
(HBP) are the most frequent genetic recessive diseases in human. These
conditions results from mutations in either the alpha or beta globin
genes, causing structural modifications (abnormal hemoglobins) or
expression defects (thalassemias) that will affect the formation of the
hemoglobin molecules.[1]
It is estimated that due to malaria selection, about 4% of the world
population, are carriers of significant HBP traits
particularly
in tropical and subtropical regions of the old world, in the
Mediterranean basin and south east Asia. Today however, due to massive
migrations, carriers of sickle cell disease (SCD) and thalassemia are
spread all over the world and need diagnostics and prevention.
Prevention of severe recessive diseases is because in every pregnancy
where the couple has clinically relevant mutation, there is a 25%
chance that the fetus will receive the mutated genes from both parents.
The clinical outcome in such cases is a severe disease such as
thalassemia major (TM) or SCD that, in spite of extensive and expensive
treatment will only aggravate until premature death.
When a full match hystocompatible donor is available, it is possible in
some cases to “cure” thalassemia by bone marrow transplantation (BMT).
However, even if successful, BMT may not repair the existing organ and
tissue damage and may result in major complications such as infections
and graft vs. host disease. Because of the complexity and the costs,
BMT is not available in many countries. Therefore the majority of the
patients will be treated with supportive therapies. For SCD it consists
of frequent hospitalizations and opioids during crises and management
of the many chronic and acute complications. For severe TM frequent
blood transfusions (one or two units every 2-3 weeks) are needed
lifelong![2]
Expensive chelation therapy must be
applied to get rid of the excess of iron (200mg in every
blood
unit). Without constant chelation the patients will develop iron
overload with severe damage to major organs and die mostly due to heart
failure.
If possible, the best treatment for all diseases is prevention.
Different kinds of secondary and primary prevention are applicable to
HBP. Morbidity (secondary) prevention is the kind of prevention offered
by newborn screening (NBS). Diagnosis at birth allows for both TM and
SCD early genotype/phenotype correlation, prognosis and
tailored/preventive treatment to be offered at the beginning of the
symptoms, which will be in most cases around 5-6 months of age.
Moreover, parents who had a sick child can be identified by NBS, and
can be counseled and consequently make a retrospective reproductive
choice for the next pregnancy. Similarly, parents at risk who had a
carrier of the disease (50%) will be recognized and may have a
prospective primary prevention in the future. However, couples at risk
who had a “non-carrier” (25%) child will remain unaware until the first
affected child is born.
It will be clear that NBS will not reduce the incidence of the disease
and that screening at an earlier stage is the best HBP prevention
strategy. In addition, it has been shown that mainly due to inadequate
counseling, primary prevention after NBS is not effective and that
screening should be offered early in pregnancy also in non-endemic
countries.[3]
Screening before pregnancy allows more
prevention options, from adapting partner choice to remaining
childless, having gamets donation, pre-implantation diagnostics (PGD)
or, the most common, prenatal diagnosis (PD). However, screening before
pregnancy is not customary in non-endemic countries while screening
early in pregnancy is socially the most rational alternative. Moreover,
screening early in pregnancy does not stigmatize the female partner
(common in some cultures when screening is carried out before marriage)
and it involves both parents in the process of choosing to accept or
not to have a severely affected child. The disadvantage is however that
screening early in pregnancy leaves as only prevention option PD and
medical abortion. Deciding to interrupt a pregnancy, even if in an
early stage and knowing to bear a severely affected fetus, is an
emotional process for most couples involving their moral feelings
and/or religious believes. Religious leaders have different views on
this matter, some may reject medical abortion regardless of the
situation and other may consider it as an act of mercy.
Practically, the standard PD procedure consists of extracting and
analyzing fetal DNA obtained from chorion villi collected by the 10th-12th week of
gestation or from the amniotic fluid 2 weeks later but non-invasive
technologies are upcoming.[4]
The risk of fetal loss is in good hands below 1%, without risk to the
mother, giving her the chance to give birth to another (healthy) child
in the future.
Primary prevention needs the support of public health authorities and
when it comes to investing money in prevention, medical and moral
arguments may have a relative impact and one has to show that primary
prevention is not only an act of mercy sparing huge suffering to
patients and families but that it is an intervention that reduces the
costs of public health as well.
Koren et al. approach this economical matter in a proper way, showing
that there are major differences in the expenses involved in prevention
compared to those involved in treatment of TM.[5]
The
expenses for running prevention program in Northern Israel during one
year (2011) was about 415.000 $, while the annual cost of basic
treatment of one patient including blood transfusions and iron
chelation was around 40.000 $ and for estimated life expectancy of 50
years, about 2.000.000 $. Moreover, these numbers do not account for
the treatment of the various complications, unlike the calculated
expenses for blood transfusions, iron chelation etc. that are more or
less the same in every patient. However, even if the
complications are not the same for every patient, according to the data
presented in table 5 of Koren’s paper, around 200.000 $ can be added to
the total cost for life expectancy of 2.000.000 $ over 50 years. By
enlarge, the costs of treating thalassemia patients is more or less in
the same ball park in Israel when compared to the Western countries
like U.K, U.S.A., Canada and Italy, while in Thailand they are less,
but still much higher than the cost of prevention. The authors could
also have taken into consideration that these patients, even when they
reach adult life, are often not self-supporting and are social security
dependent.
Although it seems so obvious that implementation of screening program
and prenatal diagnosis will save a lot of money in addition to sparing
huge suffering to patients and their families (up to 76000.000 $ in 10
years due to prevention of the birth of 45 affected newborns in
Northern Israel), there are still several problems that have to be
addressed. Some countries have implemented compulsory screening before
marriage (Cyprus, Iran, UAE). Although efficient, obligatory procedures
will encounter many objections in other countries. Therefore offering
the possibility of carrier screening early in pregnancy, eventually
coupled to rhesus screening which is offered in most countries at the
national level and well accepted, seems to be the most efficient
non-compulsory approach.[3,6,7]
In conclusion, since the expenses for treatment of HBP are considerably
higher when compared to prevention, even if they vary in different
countries, the paper of Koren et al. emphasizes to the medical
community and health authorities that the advantages of implementation
of a preventive policy which includes prenatal diagnosis, is not only
humane but is also economically justified.
References
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