The history of newborn screening (NBS) for sickle cell disease (SCD) in Europe goes back almost 40 years. However, most European countries have not established it to date. The European screening map is surprisingly heterogenous. The first countries to introduce sickle cell screening on a national scale were France and England. The French West Indies started to screen their newborns for SCD as early as 1983/84. To this day, all countries of the United Kingdom of Great Britain and Northern Ireland have added SCD as a target disease to their NBS programs. The Netherlands, Spain and Malta also have national programs. Belgium screens regionally in the Brussels and Liège regions, Ireland has been running a pilot for many years that has become quasi-official. However, the Belgian and Irish programs are not publicly funded. Italy and Germany have completed several pilot studies but are still in the preparatory phase of national NBS programs for SCD, although both countries have well-established concepts for metabolic and endocrine disorders. This article will give a brief overview of the situation in Europe and put a focus on the programs of the two pioneers of the continent, England and France.

Objective: To determine (i) if electrospray mass spectrometry–mass spectrometry with the SpOtOn Diagnostics Ltd reagent kit for sickle cell screening could be integrated into the English newborn screening programme, under routine screening conditions, and provide mass spectrometry–mass spectrometry results which match existing methods, and (ii) if common action values could be set for all manufacturers in the study, for all assessed haemoglobins, to indicate which samples require further investigation. Methods: Anonymised residual blood spots were analysed using the SpOtOn reagent kit as per manufacturer’s instructions, in parallel with existing techniques at four laboratories. Mass spectrometry–mass spectrometry instrumentation at Laboratories A and B was AB Sciex (Warrington, UK) AP4000, and at Laboratories C and D, Waters Micromass (Manchester, UK), Xevo TQMS and Premier, respectively. Results: There were 23,898 results accepted from the four laboratories. Excellent specificity at 100% sensitivity was observed for haemoglobin S, haemoglobin C, haemoglobin E and haemoglobin O^Arab. A common action value was not possible for Hb C, but action values were set by manufacturer. The two haemoglobin D^Punjab cases at Laboratory D were not detected using the common action value. Conversely, false-positive results with haemoglobin D^Punjab were a problem at the remaining three laboratories. Conclusions: This multicentre study demonstrates that it is possible to implement mass spectrometry–mass spectrometry into an established screening programme while maintaining consistency with existing methods for haemoglobinopathy screening. However, one of the instruments investigated cannot be recommended for use with this application.

Objective: Beta thalassaemias are a group of hereditary red cell disorders resulting in a reduced or absent production of the main adult haemoglobin, adult haemoglobin. In England, the NHS Sickle Cell & Thalassaemia Screening Programme recommends reporting newborn beta thalassaemia disease as an incidental finding when detected whilst screening for sickle cell disease. The current action value to initiate further investigations is 1.5% adult haemoglobin, using high-performance liquid chromatography or capillary electrophoresis. We examined the reliability of this action value. Methods: A 44-month country-wide prospective study using data from 13 newborn screening laboratories in England. Results: There were 81 cases reported with an adult haemoglobin of 1.5% or less at first-line screen, of which nine were lost to follow-up. The six false-positive results were all of 32 weeks’ gestation or less. Of the 66 true-positives, 36 had confirmatory molecular results (11 of these cases also have results from tandem mass spectrometry), 19 had clinical confirmation and 11 had the results of both parents available which were consistent with the screening result. There was one false-negative, a confirmed beta thalassaemia major case with an adult haemoglobin of 1.7%, above the action value at first-line screen but known to be at risk from parental results and therefore referred into clinical care by the laboratory. Conclusions: This study demonstrates a positive predictive value of 91.7%, with a specificity of 99.9% and a sensitivity of 98.5%. These results confirm the reliability of the current action value.

Objective: England has universal screening for sickle cell disease in newborns, with a policy of reporting beta thalassaemia major where it is detected. We report a case with a high gamma/beta ratio (20.167), but all other tandem mass spectrometry results within expected normal limits. The second test did not support the presumed diagnosis of beta thalassaemia major. As the two results were discrepant, further investigations were carried out. Methods and results: Sanger sequencing identified a novel mutation HBB:c.40 G > A (Hb Tower Hamlets) with concomitant beta plus (severe) thalassaemia due to the HBB:c.92 + 5 G > C mutation. Conclusions: This case highlights considerations for policy makers and implementers of new methods in screening programmes. For the English screening programme, the importance of adherence to the two-part testing strategy for newborn haemoglobinopathy screening is demonstrated. When discrepancies occur in results between the two tests, a thorough investigation is indicated. Communication, training, incident review and oversight are vital aspects of any screening programme. Protocols, risk assessments and guidance require constant monitoring and review to ensure that they remain fit for purpose. When new methods are introduced, stringent application of these principles is recommended.