Search for a command to run...
Sickle cell disease (SCD) affects over 300 000 newborns annually, with the highest burden in sub-Saharan Africa and India.1 It imposes a significant financial burden on healthcare systems and affected families.2 Early diagnosis through newborn screening (NBS) and subsequent comprehensive care can reduce under-five mortality by nearly 90% in high-income countries (HICs).3 For NBS to be effective, a positive screening result must be followed by a seamless continuum of care encompassing confirmatory diagnosis, genetic counselling (GC), cascade screening of family members and timely initiation of prophylactic and therapeutic interventions. However, in most low- and middle-income countries (LMICs), post-screening care remains fragmented, with delayed diagnosis, missed confirmatory testing and inadequate follow-up.4 Furthermore, access to hydroxyurea (hydroxycarbamide), the cornerstone of SCD management, remains inconsistent, with only 20%–30% of eligible children receiving this critical therapy.5 Hence, we aimed to quantify progression through each stage of the SCD care continuum after newborn screening. We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines (Table S1) and registered the protocol with PROSPERO (CRD42024619540). MEDLINE, CINAHL, Embase and Cochrane Library were searched for original observational or interventional studies published between 2015 and 2024. Studies were eligible if (1) newborns were screened for SCD before 12 months of age and (2) at least one post-screening care component was reported for a defined cohort of screen-positive newborns. Eligible outcomes included: (a) confirmatory diagnosis, (b) parental receipt of GC, (c) cascade screening of family members or (d) initiation of prophylaxis (penicillin, folic acid [FA], pneumococcal vaccination [PV]) or hydroxyurea therapy (Table S2). Search results were imported into Covidence software for duplicate removal, two-stage screening (title/abstract and full-text) and data extraction. Two reviewers independently extracted data, which a third reviewer then cross-checked. Extracted variables included study characteristics and the number or proportion of participants receiving each component of post-NBS care. Data were downloaded in Microsoft Excel and analysed using STATA version 16 (StataCorp, College Station, TX, USA). Pooled estimates were generated using random-effects meta-analysis (with Freeman–Tukey transformation) and reported as proportions with 95% confidence intervals (CIs). For confirmatory testing, the denominator was the number of newborns testing positive on initial screening; for prophylactic or therapeutic interventions, it was the number diagnosed with SCD. Heterogeneity was assessed using chi-squared test and I2 statistic. Subgroup analyses were conducted across the World Health Organization (WHO) regions and parental screening status. Study quality and risk of bias were assessed using Joanna Briggs Institute (JBI) checklists, while publication bias was evaluated using ‘Doi’ plots and Luis Furuya-Kanamori (LFK) index. A total of 20 studies were included in the final review after screening (Figure S1). Of these, 14 were longitudinal, four were cross-sectional and two were retrospective cohort studies. The studies represented 14 countries from four WHO regions: Africa (n = 6), Europe (n = 6), Southeast Asia (n = 4) and the Americas (n = 4). Laboratory-based confirmatory methods were used in 15 studies, two studies utilised point-of-care (POC) devices, two employed a combination of both and one did not specify the screening method. Detailed information on included articles is given in Table S3. Table 1 presents the continuum of care of newborn SCD screening of all included studies. Six studies reported data on confirmatory testing, with the age at diagnosis ranging from 1 to 3 months. The pooled proportion of infants undergoing confirmatory testing was 76.0% (95% CI: 28%–100%; I2 = 100%, p < 0.01). Regional differences were observed: Africa (20%, 95% CI: 17%–24%), Europe (100%, 95% CI: 100%–100%) and the Americas (27%, 95% CI: 22%–32%). Only two studies documented GC, in which 87 and 93 families, respectively, received counselling. Cascade screening of family members was reported in a single study, where 18 of 87 screen-positive families underwent additional testing. Fifteen studies reported the initiation of penicillin prophylaxis, with the age at initiation ranging between 2 and 5 months. The pooled estimate was 89.0% (95% CI: 76%–98%; I2 = 98%, p < 0.01) with regional variation of 76% in Africa (95% CI: 44%–97%; I2 = 96%), 100% in Europe (95% CI: 89%–100%; I2 = 99%) and 69% in Asia (95% CI: 62%–75%; Figure 1A). Studies not reporting parental screening had a pooled proportion of 89% (95% CI: 76%–98%; I2 = 98%), compared to 74% (95% CI: 65%–82%) among those that did. Twelve studies documented the uptake of PV among SCD-diagnosed newborns, with a pooled proportion of 86.0% (95% CI: 72%–97%; I2 = 96%, p < 0.01) (Figure 1B). By region, the estimate was 61% in Africa (95% CI: 39%–80%) and 84% in Asia (95% CI: 68%–96%; I2 = 92%). Among studies not reporting parental screening, the pooled estimate was 84% (95% CI: 67%–96%), compared to 93% (95% CI: 64%–100%) in those that did. Eight studies reported on FA supplementation, with age of initiation ranging from 5 to 12 months. The pooled estimate was 87.0% (95% CI: 68%–98%; I2 = 94%, p < 0.01) (Figure 1C). Region-specific estimates were 76% in Africa (95% CI: 41%–98%) and 92% in Asia (95% CI: 62%–100%). Studies without parental screening reported a pooled proportion of 83% (95% CI: 64%–96%; I2 = 91%). Nine studies reported the initiation of hydroxyurea therapy, with age at initiation ranging from 0.7 to 3.4 years. The pooled estimate was 55.0% (95% CI: 23%–84%; I2 = 99%, p < 0.01; Figure 1D). Regionally, initiation was 61% in Europe (95% CI: 7%–100%) and 39% in Asia (95% CI: 33%–46%). Among studies without parental screening, the pooled estimate was 60% (95% CI: 7%–89%). Study quality was assessed using JBI critical appraisal checklists (Table S4). Seventeen studies were rated as having a low risk of bias, and three were rated as having a moderate risk of bias. In 19 studies, exposure measurement (NBS implementation) was found to be valid and reliable; however, one study lacked sufficient methodological details. Doi plots for all outcomes showed visual asymmetry. LFK indices indicated publication bias with values of 5.16 (confirmatory testing), −2.08 (penicillin), 5.37 (PV), 1.73 (FA) and 7.65 (hydroxyurea) (Figure S2). This meta-analysis synthesised evidence from 20 studies to evaluate NBS for SCD and the subsequent care continuum. Studies from LMICs reported similar ‘lost to follow-up’ patterns, with up to 60% of screen-positive infants missing confirmatory diagnosis or treatment due to systemic, financial and informational barriers.6 Such attrition substantially limits the benefits of early detection. Strengthening tracking systems, ensuring active follow-up through community-based counselling and integrating NBS with maternal and child health services are critical for achieving impact. Evidence from HICs demonstrates that structured care pathways markedly reduce attrition and improve survival outcomes.7 Hydroxyurea initiation emerged as a significant implementation gap. Although globally recognised as the standard of care for SCD, uptake occurred in only about half of eligible infants. Key barriers include the lack of paediatric formulations and challenges in their dose titration, limited provider familiarity and infrastructural constraints for laboratory monitoring.8, 9 The near absence of cascade screening and GC highlights a neglected but vital aspect of SCD prevention. This omission is particularly concerning, since the WHO and national guidelines recommend family-based interventions to identify carriers and offer reproductive counselling. Implementing culturally appropriate, community-based GC supported by trained health workers and embedded in maternal and child health services could enhance service utilisation and family engagement.10 A marked geographical disparity was also evident. Most studies originated from urban tertiary facilities, limiting applicability to rural or remote populations where healthcare access remains fragmented. While programmes in HICs achieved near-universal linkage from screening to care, those in LMICs reported substantially lower initiation rates.10-13 These gaps reflect systemic inequities in health financing, infrastructure and workforce capacity. Decentralising diagnostic and treatment services through mobile clinics, POC devices and task-shifting to trained non-specialist providers could help close this divide.14 High heterogeneity across studies may have influenced pooled estimates. Although subgroup analyses by region and parental screening status were undertaken, conducting a sensitivity analysis would have better explored the potential sources of variability. Data from national programmes and grey literature were not included due to limited availability and inconsistent reporting. Furthermore, some studies did not disaggregate data by genotype, reporting composite findings for HbSS, HbSβ, HbSC or HbSD-Punjab, which may affect interpretation. While NBS for SCD has gained momentum globally, our findings highlight a need to strengthen linkage-to-care mechanisms, particularly in LMICs. Establishing a uniform global policy framework could enhance the SCD care continuum and ensure equity. Aligning NBS with the WHO's Universal Health Coverage and the Global Strategy for Women's, Children's and Adolescent Health would facilitate timely confirmation, GC, family screening and universal access to prophylaxis, hydroxyurea, PV and nutritional support.15 Such integration would also strengthen parental education and improve implementation of welfare and monitoring programmes in LMICs. Among newborns with SCD, confirmatory testing was performed in 76% (95% CI: 28–100), penicillin prophylaxis in 89% (95% CI: 76–98), PV in 86% (95% CI: 72–97), FA supplementation in 87% (95% CI: 68–98) and hydroxyurea initiation in 55% (95% CI: 23–84). GC and cascade screening were infrequently reported. Strengthening family-centred services and expanding access to therapeutic interventions should be prioritised within national SCD programmes to ensure sustained care beyond newborn screening. Tanveer Rehman: Conceptualisation, data curation, formal analysis, methodology, supervision, visualisation, writing—review and editing. Srijeeta Mitra: Conceptualisation, data curation, formal analysis, methodology, resources, software, writing—original draft. Kalpita Ganpat Gawit: Data curation, formal analysis, methodology, resources, software, supervision, writing—original draft. Ravindra Kumar: Conceptualisation, methodology, supervision, visualisation, writing—review and editing. Sritama Dutta: Data curation, formal analysis, methodology, resources, software, writing—original draft. Ananya Anurakta Pattanaik: Data curation, formal analysis, methodology, resources, software, writing—original draft. Lakhan Majhee: Supervision, visualisation, writing—review and editing. Tanu Anand: Supervision, visualisation, writing—review and editing. Manisha Madkaikar: Supervision, visualisation, writing—review and editing. Sanghamitra Pati: Conceptualisation, methodology, supervision, visualisation; writing—review and editing. The authors are grateful to the Department of Health Research (DHR), Ministry of Health and Family Welfare, Government of India, for establishing the Model Rural Health Research Units, which provided the infrastructural and administrative support essential for this research. No funds, grants or other support were received by the authors for the submitted work. The authors have no competing interests to declare that are relevant to the content of this article. Not applicable as it involves secondary data already available in the public domain. The data that support the findings of this study are available in Medline at https://pubmed.ncbi.nlm.nih.gov/. These data were derived from the following resources available in the public domain: Medline, https://pubmed.ncbi.nlm.nih.gov/; Embase, https://www.elsevier.com/en-in/products/embase; CINAHL, https://about.ebsco.com/products/research-databases/cinahl-database. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.