Positive Impacts of the Universal Newborn Screening Program on the Outcome of Children with Sickle Cell Disease in the Province of Quebec: A Retrospective Cohort Study

Background

Sickle cell disease (SCD) is the most common monogenic disease worldwide. Benefits of preventive measures such as early penicillin prophylaxis and ease of neonatal diagnosis led to the inclusion of SCD in newborn screening programs (NSP) in the US and later in several Canadian provinces. Universal NSP was implemented in the province of Québec (QcNSP) in November 2013, close in time to the recommendation of early hydroxyurea (HU) therapy. Our study objective was to evaluate how the QcNSP impacted the clinical outcomes of SCD infants and children followed at CHU Ste-Justine between the age of 0-5 years of age. We hypothesized that the introduction of QcNSP has shortened the time to referral to SCD comprehensive centres and the time to HU initiation, while also reducing the number of acute SCD complications.

Methodology

This is a retrospective cohort study of patients referred to the pediatric comprehensive SCD centre at CHU Sainte-Justine (Montreal), a leading tertiary pediatric center in Canada from Jan 1-2000, to Dec 31-2019. To be included, patients had to be followed for at least two years. Two cohorts were defined: Cohort Pre-QcNSP included patients who had their first visit between January 1 ^st 2000 and October 31 ^st2013, whereas cohort post-QcNSP included patients who had their first visit between November 1st 2013 and December 31 ^st 2019.

SCD genotypes were stratified into two groups: HbSS/Sß ⁰ and SC/Sß ⁺. Reasons for referral were extracted. A Kaplan-Meier curve for hospitalization-free survival (HFS), a poisson regression for the number of VOC emergency (ED) visits and a logistic regression for clinical outcomes, adjusting for age at first visit, gender, place of birth, follow-up period and QcNSP were computed. The software R version 4.2.1 was used for all statistical analyses. The study was approved by the local IRB.

Results

Of 600 files examined, 410 met the inclusion criteria. 253 were referred pre-QcNSP, 157 post-QcNSP. There were equal gender representations in both groups, and no statistical differences between genotype representation between cohorts. Median age at 1st visit decreased from 1.2 [IQR: 0.2-6.0] pre-QcNSP to 0.2 years [IQR:0.1-4.8] post-QcNSP (p<0.001). The percentage of children born in the province of Qc diagnosed through NS increased from 48.1% (79) pre-QcNSP to 100% (102) post-QcNSP (p<0.004). The percentage of undiagnosed children born in Qc and referred after a first SCD-related complication (DRC) dropped from 42% to 0% (p<0.0001). The median age of HU-introduction for SS patients decreased from 4.5 [IQR:2.6-5.5] pre-QcNSP to 0.75 years [IQR:0.8-1.08] post-QcNSP (p<0.001). Similarly, the percentage of SS patients receiving HU by the age of 2 years old significantly increased from 28.6% preQcNSP to 59.3% post-DN patients (p=0.003). The overall percentage of SS patients eventually receiving HU was nevertheless statistically not different between cohorts (89.7% (61/68) post-QcNSP vs 82.5% (80/97) pre-QcNSP).

The number of hospitalizations in HbSS/Sß ⁰ decreased from 2 hospitalizations/pt-year pre-QcNSP [IQR 1.0-3.0] to 1.0 [IQR: 0.6-1.4] (p<0.001). Hospitalization-free survival (HFS) also improved (257 days post-QcNSP vs. 140 days pre-QcNSP, p<0.001) for HbSS/Sß ⁰ patients. Similarly, HFS for VOC was significantly longer post-QcNSP (1320 days vs. 573 days, p<0.002). Evaluating ED visits for VOC, HbSS/Sß ⁰ children referred pre-QcNSP had much greater risk of ED-VOC visits than post-QcNSP (1.44, CI 1.22-1.67); similarly, SS/Sb ⁰ children referred for DRC vs NS had a higher risk of ED-visit for VOC (0.25, CI 0.02-0.48). There was however no statistical difference in SC/Sß ⁺ patients.

Conclusion.

In Quebec, the universalization of the NSP has enabled early detection and referral of children with SCD to comprehensive care centre. Earlier access to this expertise ensures that children benefit from the essential preventive interventions that are vaccination, prophylactic penicillin, early HU-use as well as caregiver education. These combined interventions may explain in part the improvement in acute events. This cohort study highlights that universal NSP of SCD is an essential public health measure.