Strengthening Newborn Screening: A Pilot Health Program Management for Sickle Cell Disease in Côte d’Ivoire

Newborn screening for sickle cell disease: whose reproductive benefit?

HemoTypeSC Demonstrates >99% Field Accuracy in a Sickle Cell Disease Screening Initiative in Children of Southeastern Uganda.

Is integrating sickle cell disease and HIV screening logical?

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.

Sickle cell disease (SCD) is a life-threatening disease requiring reliable early diagnosis. We assessed the acceptability and diagnostic performances of two rapid diagnostic tests (RDTs) to identify SCD (HbSS, HbSC, HbS/β-thalassaemia) or SCD carrier (HbS/HbC) in a pilot SCD newborn screening (NBS) strategy in Mali. All consenting delivering women were offered SCD NBS using cord blood sampling on two RDTs (SickleScan® and HemotypeSC®) compared to the high-performance liquid chromatography (HPLC) gold standard to detect SCD states. From April 2021 to August 2021, 4333 delivering women were eligible of whom 96.1% were offered NBS: 1.6% refused, 13.8% delivered before consenting and 84.6% consented; 3648 newborns were diagnosed by HPLC; 1.64% had SCD (0.63% HbSS, 0.85% HbSC, 0.16 HbS/β-plus-thalassaemia); 21.79% were SCD carrier. To detect accurately SCD, SickleScan® had a sensitivity of 81.67% (95% confidence interval [CI]: 71.88-91.46) and a negative predictive value (NPV) of 99.69% (95% CI: 99.51-99.87); HemotypeSC® had a sensitivity of 78.33% (95% CI: 67.91-88.76) and a NPV of 99.64% (95% CI: 99.44-99.83). To detect SCD carrier: SickleScan® sensitivity was 96.10% (95% CI: 94.75-97.45) and NPV, 98.90% (95% CI: 98.51-99.29); HemotypeSC® sensitivity was 95.22% (95% CI: 93.74-96.70) and NPV, 98.66% (95% CI: 98.24-99.03). Routine SCD NBS was acceptable. Compared with HPLC, both RDTs had reliable diagnostic performances to exclude SCD-free newborns and to identify SCD carriers to be further confirmed. This strategy could be implemented in large-scale NBS programmes.

The ASH consa consortium on newborn screening in Africa for sickle cell disease: Interim updates of progress in screening, follow-up and supporting initiatives

Health Equity in Sickle Cell Research and Access to Therapy

Children with sickle cell anemia and sickle cell trait are at an increased risk of invasive pneumococcal disease compared to children with normal hemoglobin. We assessed and compared pneumococcal vaccination status among these three groups. Children with sickle cell anemia and sickle cell trait were identified using Michigan newborn screening records (1997-2014); each child was matched to four children with normal hemoglobin based on age, Medicaid enrollment (at least 1 year from 2012-2014), race, and census tract. Vaccination records were obtained from the state's immunization system. Pneumococcal vaccine coverage (PCV7 or PCV13 depending on date of administration) was assessed at milestone ages of 3, 5, 7, and 16 months. The proportion of children with vaccine coverage at each milestone was calculated overall and compared among children with sickle cell anemia, sickle cell trait, and normal hemoglobin using chi-square tests. The study population consisted of 355 children with sickle cell anemia, 17,319 with sickle cell trait, and 70,757 with normal hemoglobin. The proportion of children with age-appropriate pneumococcal vaccination coverage was low at each milestone and generally decreased over time. Children with sickle cell anemia were more likely to be covered compared to children with sickle cell trait or normal hemoglobin. Despite higher pneumococcal vaccination coverage among children with sickle cell anemia, opportunities for improvement exist among all children. Targeted interventions will benefit from mechanisms to identify children with increased risks such as sickle cell anemia or trait to improve pneumococcal vaccination coverage among these groups.

The Portuguese Newborn Screening Program currently includes 28 pathologies: congenital hypothyroidism, cystic fibrosis, 24 inborn errors of metabolism, sickle cell disease and spinal muscular atrophy. This pilot study for sickle cell disease newborn screening, including 188,217 samples, was performed between May 2021 and December 2023, with phase I, including 24,130 newborns, in the Lisbon and Setubal districts and phase II, including 164,087 newborns, in the whole country. DBS samples were analyzed through capillary electrophoresis. In phase I, a high birth incidence of sickle cell disease was found (1:928 NBs), resulting from the identification of 24 HbSS and 2 HbSC patients. This birth incidence decreased but remained significant when the pilot study for sickle cell disease newborn screening was expanded to a national level, with the identification of 67 sickle cell disease patients (59 HbSS and 8 HbSC), revealing a birth incidence of 1:2449 NBs. These data suggest that this condition is becoming increasingly relevant in Portugal, thus reflecting a general European trend, where sickle cell disease is already recognized as a public health problem. Therefore, it highlights the importance of its integration into the Portuguese National Newborn Screening Program panel in January 2024, thus allowing the early identification and clinical follow-up of these patients.

Renal Functional Decline in Sickle Cell Disease and Trait.

A Prospective Pilot Newborn Screening and Treatment Program for Sickle Cell Anemia in the Republic of Angola

COVID-19 Outcomes in Individuals with Sickle Cell Disease and Sickle Cell Trait Compared to Blacks without Sickle Cell Disease or Trait

To evaluate feasibility of systematic neonatal screening for sickle cell disease in Chhattisgarh. A pilot study was done from February 2008 through January 2009 in Department of Pediatrics & Neonatology, Pt. J.N.M. Medical College & Dr.B.R.A.M. Hospital, Raipur (Chhattisgarh) on a total of 1,158 neonates. Blood samples from the neonates were taken after 48 h of birth on filter paper for detection of sickle cell anemia using Biorad hemoglobin variant Neonatal sickle cell short programme by high performance liquid chromatography (HPLC). On follow up, cases were analyzed by HPLC using Beta thalassemia short program to rule out false negative case and other hemoglobin variants. Of the 1,158 neonates screened, 628 were boys (54.2%) and 530 were girls (45.8%). Sickle cell disease was found in 3 cases (0.2%) (95%C.I 0.12-0.28), sickle cell trait was found in 68 cases (5.8%) (95%C.I 4.5-7.5). After 6-9 mo of age three cases of sickle cell diseases were reinvestigated, out of which one case turned out to be double heterozygous for sickle cell and beta thalassemia trait. Fourteen preterm neonates reported as normal in initial screening were called for follow up after 6 mo of age, 10 infants reported in OPD and 4 lost in follow up. These 10 infants were reinvestigated; 2 had sickle cell disease, 1 had sickle cell trait and 7 infants were normal. Sixty eight cases of sickle cell trait found with initial screening were also called for follow up after 6 mo of age; 61 cases reported in OPD between 6 mo to 1 y of age and 7 cases lost in follow up. Sixty one infants were reinvestigated; 60 had sickle cell trait and 1 had sickle cell disease which was reported earlier as Sickle cell trait (FAS). Thus on total follow up of cases, there were 5(0.4%) sickle cell disease, 61(5.26%) sickle cell trait, 1(0.08%) double heterozygous for sickle cell and beta thalassemia trait which needs mutation studies for thalassemia characterization (s/β(0) or s/β(+)). Early detection of sickle cell disease (SS) done by neonatal screening will help in early prevention and management of complications in postnatal period.

Sickle Cell Disease (SCD) is an increasing global health problem and presents significant challenges to European health care systems. Newborn screening (NBS) for SCD enables early initiation of preventive measures and has contributed to a reduction in childhood mortality from SCD. Policies and methodologies for NBS vary in different countries, and this might have consequences for the quality of care and clinical outcomes for SCD across Europe. A two-day Pan-European consensus conference was held in Berlin in April 2017 in order to appraise the current status of NBS for SCD and to develop consensus-based statements on indications and methodology for NBS for SCD in Europe. More than 50 SCD experts from 13 European countries participated in the conference. This paper aims to summarise the discussions and present consensus recommendations which can be used to support the development of NBS programmes in European countries where they do not yet exist, and to review existing programmes.

Sickle cell trait and sickle cell disease are thought to be independent risk factors for CKD, but the trajectory and predictors of kidney function decline in patients with these phenotypes are not well understood. Our multicenter, observational study used registry data (collected January 2005 through June 2018) and included adult black patients with sickle cell trait or disease (exposures) or normal hemoglobin phenotype (reference) status (ascertained by electrophoresis) and at least 1 year of follow-up and three eGFR values. We used linear mixed models to evaluate the difference in the mean change in eGFR per year. We identified 1251 patients with sickle cell trait, 230 with sickle cell disease, and 8729 reference patients, with a median follow-up of 8 years. After adjustment, eGFR declined significantly faster in patients with sickle cell trait or sickle cell disease compared with reference patients; it also declined significantly faster in patients with sickle cell disease than in patients with sickle cell trait. Male sex, diabetes mellitus, and baseline eGFR ≥90 ml/min per 1.73 m2 were associated with faster eGFR decline for both phenotypes. In sickle cell trait, low hemoglobin S and elevated hemoglobin A were associated with faster eGFR decline, but elevated hemoglobins F and A2 were renoprotective. Sickle cell trait and disease are associated with faster eGFR decline in black patients, with faster decline in sickle cell disease. Low hemoglobin S was associated with faster eGFR decline in sickle cell trait but may be confounded by concurrent hemoglobinopathies. Prospective and mechanistic studies are needed to develop best practices to attenuate eGFR decline in such patients.