Prevention of haemoglobinopathies

Overview
Haemoglobinopathies (HBPs) are are amongst the commonest monogenic disorders worldwide and are the cause of tremendous suffering in patients who have no access to adequate disease management. Disease management, comprising blood transfusions, iron chelation and additional palliative medication, is risky and extremely costly. Bone marrow transplantation and emerging molecular therapies offer a cure, but are only available to a small minority of sufferers. Many communities with a high carrier rate for hHBPs have a large population of HBP patients, whose adequate disease management is not sustainable. For those communities, disease prevention is therefore the only sustainable choice, as it reduces suffering and cost long-term, with a moderate upfront investment in staff training and infrastructure. Population-wide prevention programmes to date are summarised in Table 1.

Table 1. ''Countries with longest experienced at the top. NBS= Newborn screening; * School and pregnancy screening interrupted in 1986 and 1995 respectively. # Mandatory before Church marriage only. & Mandatory before marriage. @ At secondary or high school level.''

Newborn screening
During the last decade, HBPs have been included in ongoing newborn screening (NBS) in a number of Northern European countries, in the USA and as pilot experiments in some South American and African states. NBS has been originally planned following the model used for metabolic diseases like Phenylketonuria (PKU), and thus for morbidity (secondary) prevention providing early treatment directly after birth, before irreversible organ damage occurs. Strictly speaking, sickle cell disease (SCD) and thalassaemia major (TM) do not need to be diagnosed at birth for urgent treatment directly after birth. The affected newborns are perfectly healthy at birth and stay symptomless for several months, until the fetal haemoglobin has disappeared. The pathological symptoms begins when postnatal HbA cannot be formed due to the total absence of normal beta globin chains (TM) or when red cells begin to sickle due to the increasing presence of HbS, for example in the common genotype combinations Hb S/S, HbS/C, S/D, S/E and S/beta thal, amongst others). Nevertheless, thanks to early diagnosis, NBS allows morbidity (secondary) prevention to be started in time about 6 months after birth. During the first 6 months one may confirm the disease at the genotype level, make a genotype/phenotype correlation and a prognosis and may tailor the best supportive treatment to be offered when the symptoms begin. In the same period parents can be counseled in a genetic center and become able to make a retrospective reproductive choice for the next child. Also parents at risk who had a carrier can be counseled for prospective primary prevention in the future. Obviously couples at risk who had a “non-carrier” (25%) are not identified by NBS until the first affected child is born. The benefit of NBS consists mainly of a lower risk of mortality during the first few years of life when patients may die of an acute condition while not yet diagnosed. This benefit comes with increased treatment costs which are already considerable for these patients and can be estimated around 2 million US $ per average patient treated in developed countries. While one could have expected that some primary retrospective or prospective primary prevention could have been reached after NBS, data have shown that this is not the case, at least not in The Netherlands, where after 7 years of NBS screening, no reduction of incidence has been monitored. The reasons can be searched in the partial report of carriers (HbS only), in the possibly directive counseling if focused on treatment rather than on explaining the severity of the progressive diseases, in the lack of motivation of part of the badly informed target population and last but not least in potential conflict of interests that, as suggested by Kabbak, could be felt in some systems, as conflicts of interest on the part of entrepreneurial scientists vs.clinicians, and institutions. Politics might be afraid of the public opinions of conservative voters if a screening campaign, which may imply medical abortion, is approved. Scientist might be tempted to propose treatment or prevention technologies more for their scientific reward than for the benefit of the patients and couples at risk. Prevention might reduce considerably the number of chronic patients in need of expensive treatment which might stimulate pediatricians to focus on treatment rather than on prevention. In addition, counseling given by pediatricians is bound to be optimistically directive not to distress the parents describing the severity of these progressive incurable diseases in the years to come. All these factors may prevent NBS from being a useful tool for at least partial retrospective and prospective primary prevention and therefore screening should be offered much earlier to couples at risk also in non-endemic immigration countries with large multiethnic populations. In fact, the epidemiology of HBP in most non-endemic immigration countries has already reached levels that, according to WHO recommendation, justify the implementation of carrier screening for prospective primary prevention.

Screening at School Level
Beside the Montreal experience mentioned above, two successful programs have been implemented in endemic Southern Europe (Table 1). A screening in Marseille has been shown successful, but the program has been stopped due to lack of funds and the very low incidence in the meanwhile well informed population. The Italian program in the Latium region is an exemplary one and is the longest ongoing (Table 1). The reason for screening is explained to parents and students, herewith reaching two generations and providing cascade screening for more family members as well and is therefore welcome by the local population. In Latium the incidence among natives has been zero for almost a decade, while it has increased among those recent immigrants that have not been reached by the screening protocol as yet. Although feasible, no school screening programs are available or have been planned in non-endemic immigration countries eventually coupled to a biology lesson. Ethnic discrimination could become a problem if the fact that everybody is carrier of recessive diseases regardless the ethnic origin is not well explained to the students.

Pre-Conception Screening
Screening young adults before pregnancy or marriage allows more prevention options, from adapting partner choice to remaining childless, using gamete donation, pre-implantation diagnostics (PGD) or, still the most common, prenatal diagnosis (PD). As mentioned above, screening before marriage or conception has been offered to couples at risk in endemic countries and in different ways. The mandatory way has been ongoing for a long time in Christian Greek Orthodox Cyprus where in order to marry in the Church, couples need among the usual documents also a lab result for HBP (Table 1). The same mandatory rule is applied in Islamic countries like Iran and the UAE’s before legal marriage. While in Cyprus there is no interference on partner choice, in Iran adapting partner choice has been advised as a first option and PD with legal medical abortion as a second. In the UAE’s adapting partner choice is the only advice provided while PD and (illegal) medical abortion are possibly done abroad. But for some Jewish minorities who are used to screen before marriage or pregnancy, screening is not customary among immigrants in most non-endemic countries where in fact there are not many structures available for a pre-conception / pre-marital screening that could operate at the national level. Conversely, screening early in pregnancy is socially accepted and is the most rational alternative already routinely offered at the national level for other inborn diseases.

Screening early in pregnancy
Screening early in pregnancy does not stigmatize the female partner (a risk in some cultures when screening before marriage) but on the contrary, it involves both parents in the process of choosing 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 fetal stage and knowing to bear a fetus that will become severely affected, is a difficult and 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 the situation while others may consider it as an act of mercy. While some parents may not feel restricted in exploring there medical options, others may feel religiously conflicted between their medical options and the decision to have an affected child who will likely have a shorter life with a severe progressive disease which can be treated but which is still incurable. Following the Mediterranean example, some immigration countries like the UK and the Netherlands are offering carrier screening early in pregnancy at different levels and/or in specific areas. Since in all non-endemic immigration countries all women are offered Rhesus and infectious diseases screening at the first pregnancy control, structures are available for offering HPB screening in early pregnancy that could operate at the national level (Table1).

Cost/benefit analysis
Koren et al. have recently calculated that the expenses for running a thalassaemia prevention program in Northern Israel during one year (2011) was about 400,000 US $, while the cost of basic treatment of a single patient for an average life expectancy was about 2,000,000 US $. Other authors have commented that primary prevention of HBP is not only financially justifiable but it is also an act of mercy sparing suffering to potential patients and families.