Sickle cell disease (SCD) is the most prevalent and severe autosomal recessively inherited hemoglobinopathy. It is associated with chronic hemolytic anemia, recurrent vaso-occlusive events, organ, and tissue ischemia, resulting in a broad range of acute and chronic complications.¹ In the Netherlands, approximately 2000 patients live with this disease, half of which are children. To diagnose patients early, universal newborn screening for SCD by high-performance liquid chromatography was introduced on January 1st, 2007. Between 2007 and 2022, 23 to 42 babies with SCD were born annually, amounting to 0.02% of all neonatally screened children.² This study aims to examine the morbidity and mortality of children diagnosed with SCD through newborn screening, 16 years after its introduction.

A nationwide prospective cohort study was conducted in children diagnosed with SCD through newborn screening between January 1st, 2007, and March 31st, 2023. Patients were followed until the end of the study, loss to follow-up, death, or successful stem cell transplantation, whichever occurred first. Children were considered lost to follow-up if not present at regular clinic visits for more than 2 years. Data on the total number of children diagnosed with SCD through newborn screening were provided by the Dutch Organization for Applied Scientific Research (TNO: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek). All eight SCD comprehensive care centers in the Netherlands participated in this study. Written informed consent was obtained from caretakers or legal guardians during the enrollment window between April 1st, 2021, and April 1st, 2023. Our national comprehensive care program is described in detail in Supplemental Appendix S1. For this study, the national working group of pediatric hematologists developed a standardized data extraction form. Data were collected from medical records by a medical doctor trained by pediatric hematologists. Ethical approval was provided by the Institutional Review Board of the Academic Medical Center Amsterdam and all participating centers. Definitions of the SCD-related complications are listed in Table S2. Regarding the statistical analyses, the number of events was presented as lifetime events. The incidence rate of death and SCD-related complications was calculated per 100 person-years for the total duration of follow-up and for the following age categories: 0–4, 5–11 and 12–16 years. All statistical analyses were performed using Statistical Package for the Social Sciences Statistics (SPSS, version 28) and R Studio (version 1.3.1093) software.

During this screening period, 540 children with SCD were diagnosed in the Netherlands. This study includes 391 of the complete cohort (72%), who were followed up for 3046.5 person-years (Figure S1). In total, 35 patients (6.5%) declined participation for reasons such as complex psychosocial problems or fear of data breaches. The remaining 114 eligible patients had not yet decided on participation for logistical reasons, for example, no-shows during the enrollment window. The included patients had a mean age of 7.8 years (±4.5) at the end of follow-up, and 188 were female (48%). SCD genotype HbSS/ HbSβ⁰ thalassemia was most prevalent (n = 240, 62%), followed by HbSC (n = 111, 28%), and HbSβ⁺ thalassemia and other genotypes (n = 40, 10%). Forty-one patients (11%) were lost to follow-up at a median age of 4.5 years (IQR 2.8–7.5), and most of them moved outside the Netherlands. Demographics are described in more detail in Table S3.

Out of 240 HbSS/ HbSβ⁰ thalassemia children, 177 were prescribed hydroxyurea (74%). Overall median age at the start of hydroxyurea therapy was 3.4 years (IQR 1.9–6.5). With regard to the updated prescription guidelines in 2007, 21/64 children with HbSS/ HbSβ⁰ thalassemia (33%) born after 2007, were prescribed hydroxyurea before the age of 1 year. Thirteen children, 12 with HbSS (12/240; 5%), had received chronic transfusion therapy, initiated at the median age of 6.9 years (IQR 4.7–8.8). Indications for chronic transfusion therapy included neurological complications such as cerebral vascular stenosis and ischemic infarcts, frequent VOCs, acute chest syndrome, and severe anemia. Eight patients had undergone stem cell transplantation at the median age of 6.8 years (IQR 2.7–10.6), of whom six patients with HbSS (6/226; 2.7%), 1 HbSβ⁰ thalassemia (1/14; 7.1%) and 1 HbSC (1/111; 0.9%) patient, for the following indications: frequent VOCs, acute splenic sequestration, recurrent acute chest syndrome and non-responsiveness to hydroxyurea.

The survival of children with SCD up to the age of 16 years was 98.7%. Five patients deceased during follow-up accounting for a mortality rate of 0.16 per 100 person-years (95% CI 0.14–0.19). Four of them (80%) passed away before the age of 2 years. The child mortality rate under the age of 5 years was 0.24 per 100 person-years (95% CI 0.22–0.26), with a survival probability of 99.0%. In HbSS (4/5), the mortality rate was 0.24 per 100 person-years (95% CI 0.23–0.26). In 3 out of 5 patients (60%), the cause of death was related to SCD, primarily attributed to infections (n = 2/3 cases) (Figure S2). Three out of five children passed away while abroad.

The life-time events of SCD-related morbidity are summarized in Table 1. The incidence rate for SCD-related complications was highest in the first four years of life, in particular for vaso-occlusive crises (VOC) with hospitalization, acute hemolytic crisis, severe infection, acute splenic sequestration, and overt arterial ischemic stroke. Acute chest syndrome was prevalent in all age categories, and its incidence increased with age. Cholelithiasis, avascular necrosis, and priapism were more prevalent in the age category 11–16 years.

VOCs requiring hospitalization including dactylitis, were the most common SCD-related complications in this cohort (n = 179/391, 82%). After the first episode of dactylitis or VOC, half of the children developed a recurrent VOC. The majority of these children had SCD genotype HbSS or HbSβ⁰ thalassemia (n = 134, 75%). The median age at first admission for VOC differed significantly between children with HbSS/ HbSβ⁰ and HbSC, (4.7 years, 95%CI 3.5–6.0) versus 10.1 years (95% CI 8.6–11.6), respectively, p < .001 (Figure S3). At the end of follow-up, 73% of the 130 patients with a history of VOC (73%) had been prescribed hydroxyurea.

There were 15 patients who developed a severe infection: meningitis (n = 6), osteomyelitis (n = 7), and sepsis (n = 2). All children who developed a severe infection were <10 years of age. All these patients were vaccinated according to the Dutch National Immunization Programme, 10 out of 15 used prophylactic antibiotics, of which 7 had a good compliance defined as <2 missed doses a week. Two children experienced a fatal outcome due to the severe infection as described earlier. Six children acquired meningitis at the median age of 2.4 years (IQR 1.7–2.9), mostly caused by Streptococcus pneumoniae (4/6, 67%). Seven children developed osteomyelitis at the median age of 4.6 years (IQR 2.7–6.6) caused by Salmonella enterica serotype Javiana (n = 1), Pseudomonas oryzihabitans (n = 1) and Staphylococcus Aureus (n = 1). Two children developed sepsis at the age of 7 days and 14 months. The youngest child born prematurely at 26 weeks gestation had a sepsis caused by coagulase-negative staphylococci from unknown origin at the neonatal intensive care unit. The other child developed sepsis abroad with a fatal outcome. Neurological complications also caused substantial morbidity, and are described in more detail in Supplemental Appendix S2.

In the Netherlands, childhood mortality due to SCD was shown to have decreased substantially from 0.27 per 100 person-years between 1985 and 2007³ to 0.16 per 100 person-years after the introduction of newborn screening in 2007.⁴ Our findings are comparable with the Dallas Newborn cohort (n = 940; survival of 98.4%),⁵ as well as with other nationwide cohorts in Europe: United Kingdom (0.17 per 100 person-years),⁶ Belgium (0.25 per 100 person-years),⁷ France (0.16 per 100 person-years)⁸ and Spain (0.6 per 100 person-years).⁹ Although newborn screening for SCD has proven to reduce mortality significantly in several studies, a national universal newborn screening program is not yet standard practice in several European countries.¹⁰ Following the introduction of newborn screening in the Netherlands, survival rates have shown improvement, but significant morbidity still persists. The highest incidence rates of SCD-related complications are observed within the first four years of life, underlining the importance of guidance by specialized comprehensive SCD care centers and vigilance for serious complications among caregivers, especially before traveling abroad.

However, this study also has limitations to take into account. A proportion of eligible children did not participate in the study, potentially introducing selection bias, particularly missing asymptomatic patients or those with minimal complaints who did not attend routine clinic visits. Factors such as language barriers and low socioeconomic status may have contributed to non-participation as well. Second, shared care with a regional hospital may have led to an underestimation of complications, as data were only collected from academic hospitals. Future studies should include a longer duration of follow-up with both children and adults with SCD covering the transition period to adult care. These data could help us to further identify risk factors for a severe phenotype at a young age, in order to provide patient-tailored care to prevent irreversible organ damage.

镰状细胞病（SCD）是最常见和最严重的常染色体隐性遗传性血红蛋白病。它与慢性溶血性贫血、复发性血管闭塞事件、器官和组织缺血有关，导致广泛的急性和慢性并发症。¹在荷兰，大约 2000 名患者患有这种疾病，其中一半是儿童。为了早期诊断患者，2007年1月1日开始采用高效液相色谱法对新生儿进行普遍的SCD筛查。2007年至2022年间，每年出生23至42名患有SCD的婴儿，占所有新生儿筛查儿童的0.02%。²本研究旨在调查新生儿筛查 16 年后通过新生儿筛查诊断为 SCD 的儿童的发病率和死亡率。

一项全国性前瞻性队列研究对2007年1月1日至2023年3月31日期间通过新生儿筛查诊断为SCD的儿童进行。对患者进行随访直至研究结束、失访、死亡或干细胞移植成功，以先发生者为准。如果儿童超过 2 年没有定期就诊，则被视为失访。通过新生儿筛查诊断出患有 SCD 的儿童总数的数据由荷兰应用科学研究组织 (TNO: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek) 提供。荷兰所有八个 SCD 综合护理中心都参与了这项研究。在 2021 年 4 月 1 日至 2023 年 4 月 1 日的注册窗口期间，从看护者或法定监护人处获得了书面知情同意书。我们的国家综合护理计划在补充附录 S1 中有详细描述。对于这项研究，国家儿科血液学家工作组开发了标准化的数据提取表格。数据由经过儿科血液学家培训的医生从病历中收集。阿姆斯特丹学术医学中心和所有参与中心的机构审查委员会提供了伦理批准。 SCD 相关并发症的定义列于表 S2。关于统计分析，事件的数量以终生事件的形式呈现。死亡率和 SCD 相关并发症的发生率按总随访期间和以下年龄组每 100 人年计算：0-4、5-11 和 12-16 岁。所有统计分析均使用社会科学统计统计包（SPSS，版本 28）和 R Studio（版本 1.3.1093）软件进行。

在此筛查期间，荷兰诊断出 540 名 SCD 儿童。这项研究包括整个队列中的 391 人 (72%)，并对他们进行了 3046.5 人年的随访（图 S1）。总共有 35 名患者 (6.5%) 因复杂的心理社会问题或担心数据泄露等原因拒绝参与。其余 114 名符合条件的患者因后勤原因尚未决定参与，例如在登记窗口期间未出现。随访结束时纳入的患者平均年龄为 7.8 岁 (±4.5)，其中 188 名女性 (48%)。 SCD 基因型 HbSS/ HbSβ ⁰地中海贫血最为常见 ( n  = 240, 62%)，其次是 HbSC ( n  = 111, 28%)，以及 HbSβ ⁺地中海贫血和其他基因型 ( n  = 40, 10%)。 41 名患者 (11%) 在中位年龄 4.5 岁 (IQR 2.8-7.5) 时失访，其中大多数人移居荷兰境外。表 S3 更详细地描述了人口统计数据。

在 240 名 HbSS/HbSβ ⁰地中海贫血儿童中，有 177 名接受了羟基脲治疗（74%）。开始羟基脲治疗时的总体中位年龄为 3.4 岁（IQR 1.9-6.5）。根据2007年更新的处方指南，21/64名2007年以后出生的HbSS/HbSβ ⁰地中海贫血儿童（33%）在1岁前服用羟基脲。 13 名儿童，其中 12 名患有 HbSS（12/240；5%），接受了长期输血治疗，中位年龄为 6.9 岁（IQR 4.7-8.8）。慢性输血治疗的适应症包括神经系统并发症，如脑血管狭窄和缺血性梗塞、频繁的VOC、急性胸部综合征和严重贫血。 8 名患者接受了干细胞移植，中位年龄为 6.8 岁（IQR 2.7-10.6），其中 6 名患者患有 HbSS（6/226；2.7%），1 名 HbSβ ^{0 名}地中海贫血患者（1/14；7.1%）和 1 名患者。 HbSC (1/111; 0.9%) 患者，适用于以下适应症：频繁挥发性有机化合物、急性脾隔离、复发性急性胸部综合征和对羟基脲无反应。

16 岁以下 SCD 儿童的生存率为 98.7%。随访期间有 5 名患者死亡，死亡率为每 100 人年 0.16 人（95% CI 0.14-0.19）。其中四人（80%）在两岁之前去世。 5岁以下儿童死亡率为每100人年0.24人（95% CI 0.22-0.26），生存概率为99.0%。在 HbSS (4/5) 中，死亡率为每 100 人年 0.24 例 (95% CI 0.23–0.26)。 5 名患者中有 3 名 (60%) 的死因与 SCD 有关，主要归因于感染（n  = 2/3 例）（图 S2）。五分之三的儿童在国外去世。

表 1 总结了 SCD 相关发病率的终生事件。 SCD 相关并发症的发生率在生命的前四年最高，特别是住院的血管闭塞危象 (VOC)、急性溶血危象、严重感染、急性脾隔离和明显动脉缺血性中风。急性胸部综合征在所有年龄段均普遍存在，且发病率随着年龄的增长而增加。胆石症、缺血性坏死和阴茎异常勃起在 11-16 岁年龄段更为常见。

需要住院治疗的 VOC（包括指炎）是该队列中最常见的 SCD 相关并发症（n  = 179/391，82%）。第一次出现指炎或 VOC 后，一半的儿童出现复发性 VOC。这些儿童中的大多数患有 SCD 基因型 HbSS 或 HbSβ ⁰地中海贫血（n  = 134，75%）。 HbSS/HbSβ ⁰和 HbSC儿童首次因 VOC 入院的中位年龄存在显着差异（4.7 岁，95% CI 3.5–6.0）与 10.1 岁（95% CI 8.6–11.6），p  < 0.001（图S3）。随访结束时，130 名有 VOC 病史的患者中，73% (73%) 服用了羟基脲。

有 15 名患者出现严重感染：脑膜炎（n  = 6）、骨髓炎（n  = 7）和败血症（n  = 2）。所有出现严重感染的儿童均小于 10 岁。所有这些患者都根据荷兰国家免疫计划接种了疫苗，15 名患者中有 10 名使用了预防性抗生素，其中 7 名患者依从性良好，定义为每周漏服剂量<2 次。如前所述，两名儿童因严重感染而死亡。 6 名儿童在中位年龄 2.4 岁时患上脑膜炎（IQR 1.7-2.9），主要由肺炎链球菌引起（4/6，67%）。 7 名儿童在中位年龄 4.6 岁（IQR 2.7-6.6）时患上骨髓炎，由肠沙门氏菌Javiana 血清型（n  = 1）、米假单胞菌（n  = 1）和金黄色葡萄球菌（n  = 1）引起。两名儿童在 7 天和 14 个月大时患上败血症。最小的婴儿在妊娠 26 周时早产，在新生儿重症监护室因不明来源的凝固酶阴性葡萄球菌引起败血症。另一个孩子在国外患上败血症并导致死亡。神经系统并发症也导致大量发病，补充附录 S2 中有更详细的描述。

在荷兰，SCD 导致的儿童死亡率已从 1985 年至 2007 年的每 100 人年 0.27 例大幅下降^3，2007年引入新生儿筛查后，死亡率为每 100 人年 0.16 例^。4我们的研究结果与达拉斯新生儿队列（n  = 940；存活率为 98.4%），⁵以及欧洲其他全国队列：英国（每 100 人年 0.17 人）、⁶比利时（每 100 人年 0.25 人）、⁷法国（每 100 人年 0.16）⁸和西班牙（每 100 人年 0.6）。⁹尽管多项研究已证明新生儿 SCD 筛查可显着降低死亡率，但在一些欧洲国家，国家全民新生儿筛查计划尚未成为标准做法。¹⁰荷兰引入新生儿筛查后，存活率有所提高，但发病率仍然很高。生命最初四年内，SCD 相关并发症的发生率最高，这凸显了专业综合性 SCD 护理中心的指导以及护理人员对严重并发症保持警惕的重要性，尤其是在出国旅行之前。

然而，这项研究也有其局限性需要考虑。一部分符合条件的儿童没有参加该研究，这可能会引入选择偏差，特别是漏掉无症状患者或那些没有参加常规诊所就诊的投诉很少的患者。语言障碍和社会经济地位低等因素也可能导致不参与。其次，与地区医院共享护理可能导致并发症的低估，因为数据仅从学术医院收集。未来的研究应包括对患有 SCD 的儿童和成人进行更长时间的随访，涵盖向成人护理的过渡期。这些数据可以帮助我们进一步确定年轻时严重表型的危险因素，以便为患者提供量身定制的护理，防止不可逆的器官损伤。