Sickle cell screening in Europe: the time has come

Sickle haemoglobinopathies are among the most common genetic disorders in the world, affecting over 300 000 newborns annually, with estimates for further increases to over 400 000 annual births within the next generation (Piel et al, 2013). Both the World Health Organization (WHO) and United Nations have appropriately identified sickle cell disease (SCD) as a current global health burden. Ten years ago, the WHO estimated that haemoglobinopathies (mostly SCD, but also thalassaemia) were found in 71% of 229 countries, accounting for a substantial amount of mortality in children under 5 years of age (Modell & Darlison, 2008). The optimal care for children with sickle haemoglobinopathies begins with newborn screening (NBS), which can accurately establish the diagnosis before the onset of symptoms and allow early intervention with prophylactic penicillin, pneumococcal immunisations, caregiver education and preventive medical screening. In high-resource settings, access to hydroxycarbamide (hydroxyurea), a safe and effective disease-modifying therapy, provides an additional vital healthcare link between sickle cell diagnosis and treatment that helps reduce morbidity and mortality. In the United States, universal NBS for SCD has been in place for many years and represents a highly successful progamme (Therrell et al, 2015). England adopted a similar approach and recently reported a highly favourable initial evaluation (Streetly et al, 2018). In contrast, sickle cell screening and treatment programmes remain virtually non-existent in sub-Saharan Africa, which is disproportionately affected because of the high prevalence of sickle cell trait that confers protection against severe malaria. Europe and the UK now find themselves at crossroads with regard to NBS for SCD. Previously, few European countries had enough patients to warrant neonatal testing, and any limited testing typically used a targeted strategy based on ethnic ancestry. But migration patterns from the Middle East and Africa have changed dramatically over the past decade. Between 2010–2017, it is estimated that nearly 1 million sub-Saharan African migrants have sought asylum in Europe (Connor, 2018), and that trend is projected to continue well into the future. Nigeria, Ghana and Kenya are major sources of migrants to Europe, which is important when considering the very high prevalence of sickle cell trait and disease in these African countries. Migrant populations are often under-diagnosed and under-represented, particularly in European countries with low incidence rates, where migrant flow is rapidly changing (Martinez et al, 2014). Haemoglobinopathies are now found in all European countries with increasing prevalence (Inusa & Colombatti, 2017), an enlightening fact that prompted a pan-European consensus conference. In this issue of the Journal, Lobitz et al (2018) explain that the goals of this April 2017 conference were to summarise current European NBS efforts and epidemiological data, as well as identify key questions regarding the implementation and sustainability of comprehensive NBS programmes. Building on previous evidence-based guidelines, the manuscript includes a number of consensus statements and clear recommendations that form a backbone for future work by individual countries and the region as a whole. Many of the statements are well-accepted and therefore not controversial, such as highlighting the increasing burden of SCD in Europe; listing the sickle genotypes that can be accurately determined through NBS; describing laboratory methodologies that should be used for screening; stating the need for confirmatory testing, standardized data collection systems, and coordinated follow-up; and describing benefits of early diagnosis to improve clinical care. Somewhat surprisingly, there is no mention of offering disease-modifying therapy with hydroxycarbamide to children identified through the screening programme. An additional recommendation to evaluate screening programmes for cost-effectiveness is prudent, and likely to improve the scope and quality of the process. Taken together, these excellent recommendations represent best practices and should be adopted promptly by current and future European screening programmes. A few of the statements, however, may require further consideration before widespread adoption and implementation. Whom to screen, and specifically whether to recommend targeted screening of babies from certain ethnic ancestries versus universal screening of all babies, is really a question of resource allocation rather than scientific merit. The authors correctly recommend universal screening, because targeted screening will miss many affected babies due to a number of factors; accordingly, the suggestion about targeted screening as a “interim policy” solution is hard to justify for well-resourced European countries. Perhaps more debatable are the statements and recommendations about the best practice for babies who are identified as haemoglobinopathy carriers. Since these newborns do not have SCD, their trait status represents collateral information gained from the screening process and is not a true goal of the NBS programme. In the United States, efforts to track down babies with the most common forms of haemoglobinopathy trait (HbAS or HbAC), which is mathematically about 40 times the number of babies with SCD, have encountered logistical challenges and provided only modest evidence of success. While seemingly sensible and empowering for the affected families regarding future reproductive choices, there are legal, ethical and genetic issues related to trait notification. Should both parents also be tested, thus potentially leading to familial strife or even occasionally uncovering false paternity? Will one goal of counselling be to limit future offspring and prevent additional SCD births? Could a baby with asymptomatic HbAS or HbAC be subject to future medical or genetic discrimination? Such questions are difficult to answer, yet must be asked when considering the risks and benefits, as well as resources required, for notifying all families whose newborns are haemoglobinopathy carriers. This pan-European conference represents an important and pivotal first step towards wider NBS for the sickle haemoglobinopathies. These European and UK investigators deserve approbation for taking this opportunity to create consensus guidelines and recommendations for NBS practices. There is an urgent need to develop and initiate universal screening programmes across Europe, particularly in light of the rapid globalization of migration flows, which lead to greater diversity among populations and higher prevalence of SCD. Though it may take several years to implement and evaluate, the lessons of early and universal NBS across Europe can be predicted: reduced morbidity and mortality for children with SCD, which ultimately leads to better comprehensive care, higher quality of life for patients and reduced healthcare costs. Universal screening for SCD in Europe is an idea whose time has finally come.