Piero C. Giordano

Increasing multi-ethnicity in countries endemic or non-endemic for hemoglobinopathies has brought fundamental changes to the screening strategies for these traits. While in the past pre-screening on microcytosis was a reasonable method to economize upon follow up analysis, selecting low mean corpuscular volume means today missing all those normocytic carriers of common traits associated with severe conditions. Therefore, blood count should not be considered as a pre-selection tool but as additional information to be used for the interpretation of the provisional results, obtained by routine high throughput separation and measurement of the hemoglobin (Hb) fractions. Moreover, the moment of screening should be well planned depending on the social and cultural situation. Screening for genetic diseases in a modern multi-ethnic society should be offered to couples seeking progeny when both partners are more likely to be equally concerned with the good health of their children. In several societies screening before marriage and changing partner choice is culturally accepted. However, new generations are bound to disagree with these more or less imposed conditions and may decide not to renounce the choice of their partner asking for other preventive methods. In addition, a carrier state during pre-marital screening may in some cultures stigmatize the carrier, mostly the female with adverse social consequences. Therefore, screening for hemoglobinopathies early in pregnancy is the most sensible alternative in modern countries. Adding hemoglobinopathies to the routine rhesus screening using a simple separation of the Hb fractions on dedicated devices (high performance liquid chromatography or capillary electrophoresis) will virtually identify all female carriers of all common traits responsible for the severe conditions mainly sickle cell disease and thalassemia major in time for partner analysis, counseling and primary prevention.

The authors wish to add the following amendment and correction on their paper published in IJERPH [1]: Page 6139, Line 3 in Paragraph 3: “…Israel, [17,18],…” should read “…Israel and Palestine [17,18]…”.

The aims of this study are: i) to enquire whether informing healthy hemoglobinopathy carriers about their condition is a welcome initiative in The Netherlands; ii) to study whether using information letters and thorough explanation is associated with presence or absence of undesired feelings or emotions. We have approached 100 multi-ethnic carriers previously diagnosed in our lab. All subjects had previously received our information letter through their physician who was supposed to have provided an explanation of the letter if required. We have enquired whether the subjects had experienced negative or positive emotions after receiving our diagnosis and explanation and to which degree, if they were sufficiently informed and satisfied and if they would have considered prevention in case of risk. The rate negative versus positive feelings was calculated using a numerical distribution. We have registered negative feelings in a rate that was directly proportional to the lack of information. While the number of registered negative feelings in well-informed carriers was very low it was more present in badly informed. Nevertheless, all participants found carrier information a welcome initiative and over 80% of them declared to be in favor of prenatal diagnosis in case of risk.

Healthy carriers of severe Hemoglobinopathies are usually asymptomatic and only efficiently detected through screening campaigns. Based upon epidemiological data, screenings have been offered for decades to populations of endemic Southern Europe for primary prevention of Thalassemia Major, while for many populations of the highly endemic African and Asian countries prevention for Sickle Cell Disease and Thalassemia Major is mainly unavailable. The massive migrations of the last decades have brought many healthy carriers of these diseases to live and reproduce in non-endemic immigration areas changing the epidemiological pattern of the local recessive diseases and bringing an urgent need for treatment and primary prevention in welfare countries. Nonetheless, no screening for an informed reproductive choice is actively offered by the healthcare systems of most of these welfare countries. As a consequence more children affected with severe Hemoglobinopathies are born today in the immigration countries of Northern Europe than in the endemic Southern European area. Following the Mediterranean example, some countries like the UK and The Netherlands have been offering early pregnancy carrier screening at different levels and/or in specific areas but more accessible measures need to be taken at the national level in all immigration countries. Identification of carriers using simple and inexpensive methods should be included in the Rhesus and infectious diseases screening which is offered early in pregnancy in most developed countries. This would allow identification of couples at risk in time for an informed choice and for prenatal diagnosis if required before the first affected child is born.

COMMENT TO THE PAPER "PREVENTION OF BETA-THALASSEMIA IN NORTHERN ISRAEL - A COST-BENEFIT ANALYSIS” BY KOREN ET AL

Introduction After a first survey in 2001, the Dutch Association of Hematological Laboratory Research (VHL) advised its members to adopt a basic protocol for haemoglobinopathy carrier detection and to provide genetic information with all positive results to allow health-care professionals to inform carriers about potential genetic risks. This article reports on the compliance with these recommendations and their consequences. Methods Clinical chemists of all 106 Dutch laboratories were invited to answer a survey on patient population, diagnostic techniques used, (self-reported) knowledge, use and effect of the additional information. Results The average increase in diagnostic output was over 60% and the recommended basic protocol was applied by 65% of the laboratories. Over 84% of the laboratories reported to be aware of the additional recommendations and 77% to be using them. Most laboratories with limited diagnostic requests were still sending their cases to other laboratories and included the genetic information received from these laboratories in their diagnostic reports. The effect of information on subsequent ‘family analysis’ was estimated to be between 26 and 50%. Conclusions The present study shows an increase in diagnostic potential for haemoglobinopathy over the last decade, especially in the larger cities. Low ‘family testing’ rates were mostly found in areas with lower carrier prevalence or associated with local reluctance to pass the information to carriers. In spite of a dramatic improvement, too many carriers are still not informed because of lack of awareness among health-care providers and more education is needed.

Summary: The consistent multi‐ethnic migrations of the last decades have considerably changed the epidemiology of the hemoglobinopathies. Healthy carriers of these conditions are present today in many nonendemic parts of the world, and severely affected children are now born where these diseases were previously rare or unknown. Improving the competence in carrier diagnostics at the laboratory level is one of the first concerns when introducing management and primary prevention of the severe conditions in nonendemic areas. This review describes how and when carriers should be correctly diagnosed and informed. The essential technologies needed for basic carrier diagnostics in different situations are summarized in some detail, and interpretation of the results and a number of related problems are discussed. The role of the hematology laboratory is essential, particularly in nonendemic areas where the first line of health care is often insufficiently aware of hemoglobinopathy management. Carriers living in nonendemic areas can be appropriately diagnosed and informed regarding genetic risk and prevention by well‐organized laboratories. Both basic and specialized diagnostics are needed for the correct treatment for the anemic carriers, for primary prevention in couples at risk and for state‐of‐the art care of severely affected patients.

This chapter reports the essential elements needed to understand basic laboratory diagnostics consisting of separation and measurement of the hemoglobin fractions. Although well established, basic diagnostics require some background and some degree of experience for application and interpretation. Last generation methods, consisting of automatic systems like high performance liquid chromatography and capillary electrophoresis (CE), allow high through put analysis in adults and newborns. Newborn screening using CE is presented in some details, using as an example the Capillarysâ Neonat Hb system (Sebia, France), as an upcoming alternative, explaining the method, the interpretation of the results, the objectives, the follow up, the advantages, and the pitfalls.

Aims: To register the opinions and feelings of (presumed) unaware healthy hemoglobinopathy carriers, receiving information on their carrier status. Methods: We collected 259 interviews from the parents of secondary school students, after their children had been provisionally diagnosed as hemoglobinopathy carriers during the routine school screening campaign imbedded in the public health care program of the Latium region (Central Italy). After screening of the children, all parents received a standard reassuring letter informing them about the presumed healthy carrier status of their children and were invited for a confirmation of the trait and for an additional explanation if needed. Results: We have analyzed 219 interviews (84.5%) from indigenous subjects and 40 from allochthonous people (15.5%) being either recent immigrants or mixed couples. The average age of the parents was 45.5 years. Only 51 (19.7%) had previous knowledge of their carrier status, while the rest were unaware. When reading the letter with the provisional diagnostic result of their child, emotions that could be considered undesirable were present in about 60% of the cases. Nevertheless, the information was experienced as welcome, clear, and useful by 100% of the participants. When asked about the option of prenatal diagnosis (PD) in case of genetic risk, 85.7% and 87.5% of the autochthonous and allochthonous interviewed declared either to be in favor or to eventually consider PD, while only 14.3% and 12.5% would not consider it for various reasons. Discussion: During our study, we registered undesirable feelings as well as welcome reactions: the first being experienced during the very first reading of the letter and the second after reflection on and understanding of the content during the visit to the center later on. Significantly, satisfaction and understanding of the advantage of knowledge was registered in 100% of the cases during our enquiry.