Mortality and Causes of Death in Children with Sickle Cell Disease in the Netherlands.
Authors: van der Plas Evelyn M. , van den Tweel Xandra W. , Heijboer Harriët , Geskus Ronald B. , Biemond B. J. , Peters Marjolein , Fijnvandraat Karin 
Published: October 2019

Abstract
Abstract 1519
Poster Board I-542

Introduction
Despite the increasing incidence of sickle cell disease (SCD) in the Netherlands, mortality among this patient group has never been investigated. Studies on mortality in patients with SCD from the USA demonstrated that survival at the age of 20 years has improved from 79% for those born before 1975 to 89% in patients born after 1975. A recent study in the USA (2004) reflects the benefits of modern comprehensive care for SCD patients as survival increased to 94% by 18 years of age.
The aim of this study was to collect information on the mortality rate and causes of death of children with SCD living in the Netherlands that were born before nationwide neonatal screening was implemented in 2007. This information is essential to provide a baseline for monitoring the effect of health care interventions, such as the introduction of nationwide neonatal screening. Causes of death may provide insight in areas where further improvement in the healthcare for SCD patients should be implemented.

Patients and Methods
All patients that were diagnosed with sickle cell disease (HbSS, HBSC, HbS-beta0, HbS-beta+) before the age of 18 years at the laboratory of the Academic Medical Center (AMC) in Amsterdam in 1985-2006 were included in the study. The AMC is one of the two large comprehensive care centers in the Netherlands, providing care to 30-40% of all Dutch SCD patients. Patients were followed from the time point of diagnosis onwards. Vital status at the end of study was determined by the last hospital visit or personal contact between January 2007 and March 2008. The causes of death were derived from hospital records. Survival estimates were obtained using the Kaplan-Meier estimator.

Results
In this time period we identified 298 pediatric patients with SCD. Homozygous sickle cell disease (HbSS) was present in 189 (63%) patients. The total time of follow-up was 2621 patient years. Twenty four patients (8%) were lost to follow up. The median age of the patients at the end of the observation period was 14.5 years (IQR 8.7-21.0 years). Twelve patients had died and all deaths were SCD related. Stroke (3 patients; 25%) and sepsis/meningitis (3 patients; 25%) were the most common causes of death. Four children (33%) died under 3 years of age. In two of them, death coincided or occurred shortly after the diagnosis of SCD. Three patients (25%) were between 3-18 years and 5 patients (42%) were older than 18 years at the time of death.
A similar proportion of patients with the HbSS and HbSC genotype died (respectively 4.2% (95% CI: 1.9-7.9%) and 4.2% (95% CI: 1.0-10.8%)). The overall mortality rate was 0.46 deaths (95% CI: 0.25-0.77) per 100 patient years. The estimated survival rate of children with SCD at the age of three years was 93% (95% CI: 87-100%). At the age of 18 the survival was 91% (95% CI: 84 -99%).

Discussion
The fact that a similar proportion of patients with the HbSS and HbSC genotype died is striking, as HbSC generally has a milder phenotype than HbSS. In the absence of a neonatal screening program, early death from severe infection may have contributed to a relatively high mortality in HbSC patients. Although the estimated survival at the age of 18 years is comparable to recent findings in a neonatally screened cohort from the USA, the mortality rate of 0.46 deaths per 100 patient years is high in comparison to the mortality rate of 0.13 per 100 patient years in an East London cohort of SCD patients. This may partly be explained by a younger age of this East London cohort (median 7.8 years). However, the benefits of a longer standing neonatal screening program within the UK is likely to contribute to the low mortality rate in the East London cohort as well.Conclusions: In children with SCD living in the Netherlands, born before nationwide neonatal screening was implemented in 2007, 91% survives until the age of 18. Infection and stroke are the most common causes of death. Further study of children with SCD born after 2007, when neonatal screening was implemented, will elucidate whether neonatal screening for SCD has improved survival in these patients.

Disclosures
No relevant conflicts of interest to declare.