Clinical features at diagnosis of sickle cell disease prior to universal newborn screening in Alberta

Abstract

Objectives

Sickle cell disease (SCD) is an inherited multisystem disorder with complications starting in the first year of life. Newborn screening (NBS) can identify infants with SCD and is associated with decreased morbidity and mortality. Variation in availability of NBS in Canada, and lack of standardized screening for immigrant children, may lead to delayed diagnosis.

Methods

This was a retrospective cohort study of 126 children aged 0–18 years with SCD registered with the SCD clinic at the Alberta Children’s Hospital between January 2003 and January 2018, prior to province-wide universal NBS for SCD. Patient demographic information, circumstances of diagnosis, and other contextual information were collected from patient health records. Descriptive statistics were used to summarize data, with Mood’s median test used to compare medians between groups.

Results

Forty-three (35%) patients were born in Alberta. Patients were mostly (95.3%) of African descent. Of patients born in Alberta, 63% (26/43) were diagnosed at >12 months of age, with a median age at diagnosis of 18 months (IQR = 4–39). This was significantly older (P < 0.001) than children born in the USA or in Canadian provinces with SCD NBS programs, where the median age at diagnosis was zero months (N = 36). Of the 42% of patients born outside North America, 64% were diagnosed following an acute complication.

Conclusions

This study highlights the importance of NBS for early detection and management of SCD, and the importance of screening at-risk immigrants who may not have received NBS for SCD.

Sickle cell disease (SCD) is a multisystem-inherited disorder associated with life-threatening complications. It is caused by a structurally abnormal hemoglobin variant (HbS) and is characterized by recurrent vaso-occlusive episodes (e.g., painful crisis, acute chest syndrome, and stroke) and chronic end-organ damage (1,2). SCD is a significant health problem worldwide, occurring in over 273,900 infants each year (3). One in 500 African-Americans born in the USA will have SCD, and an estimated 100,000 SCD patients currently live in the USA (4). In Canada, it is estimated that 5000 people live with SCD, and demographic changes will likely lead to an increase in this number (5). In Ontario, approximately 1:2800 babies are born with sickle cell diseases annually (6), whereas in Alberta, the SCD birth incidence is about 1:2350 (7).

Ideally, diagnosis through universal newborn screening (NBS) allows for early recognition and referral to a comprehensive SCD program. Early diagnosis and follow-up permits timely implementation of educational and medical management shown to reduce SCD morbidity and mortality, such as vaccination, parent education, penicillin prophylaxis, hydroxyurea treatment, and trans-cranial doppler (TCD) for primary stroke prevention (8–10). NBS programs have significant public health benefit by decreasing pediatric morbidity and mortality for many conditions, including SCD (11–13). Canada’s lack of a national NBS program contributes to a staggered, patchwork implementation of NBS programs at the provincial and territorial level (14–16). The number of Canadian provinces with NBS for SCD is growing, and as of January 2022, universal SCD screening is carried out in seven of ten provinces (British Columbia, Alberta, Ontario, Quebec, New Brunswick, Nova Scotia, and Prince Edward Island) (17), and it will be phased into the Saskatchewan NBS panel during 2022.

The Government of Canada seeks to welcome an increasing number of immigrants annually (18). With a growing number of children in Canada arriving from regions with a high allele frequency of SCD genes and thus considered high risk to screen positive for SCD—it becomes increasingly important that systems exist to ensure that diagnosis is made at an early age (19,20). The absence of NBS for SCD in some regions may result in the occurrence of early disease-associated complications and an increased burden on the healthcare system (21). However, the presence of NBS in Canada alone cannot ensure that all cases of SCD are identified as many children with SCD living in Canada are born in parts of the world where NBS is not standard.

The hematology clinic of the Alberta Children’s Hospital (ACH) is the tertiary referral centre for all children with SCD in southern Alberta and portions of neighbouring provinces, a catchment population of over 2 million people. This specialty clinic provides comprehensive, multidisciplinary care and follow-up for children with SCD from birth until they reach 18 years of age. Universal NBS for SCD was initiated in Alberta in April 2019. We suspected that the average age of diagnosis for patients born in Alberta prior to April 2019 would be older than the age of patients with SCD born in Canadian provinces with a NBS or in the USA, where NBS occurs in all states. The objective of this study was to determine the age and features of initial clinical presentation for patients with SCD followed by the Alberta Children’s Hospital (ACH) SCD Program prior to the implementation of NBS.

METHODS

A retrospective health record review of patients with sickle cell disease who attended the ACH hematology clinic was conducted to determine the age of diagnosis and initial clinical presentation. This study was approved by the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary with a waiver of informed consents/assents.

Our team reviewed all 126 charts for patients with hemoglobin (Hb) disorders who had attended ACH SCD clinic during the period from January 2003 to January 2018. The chart review was conducted between January 2014 and January 2018. All children aged from birth to 18 years with a diagnosis of SCD (HbSS, Hb SB⁰, Hb SB⁺, Hb SC, and other Hb S variants) who were patients of the sickle cell clinic between January 2003 to January 2018, were included in the study (N = 126). Data collected included demographic variables, SCD diagnosis-related information such as the age of diagnosis, the reason for testing, and characteristics of first healthcare- related SCD presentation.

A late diagnosis was defined as a diagnosis at 12 months of age or later. We categorized potential reasons for testing in the absence of NBS as the following: positive family history, high-risk ethnicity, incidental finding when testing for another indication such as preoperative testing, or symptoms of a disease-related condition. The clinical course of SCD, including complications, the age when penicillin prophylaxis was initiated, and the age of TCD testing were collected as secondary measures.

Statistical analysis

Mean, median, standard deviation (SD), and interquartile range (IQR) were calculated for continuous variables, and frequency distributions were used to review the categorical data set. Age of diagnosis of Alberta-born patients and age of patients born in the USA and elsewhere in Canada where SCD NBS exists were compared using the non-parametric independent samples median test (Mood’s median test), and a P-value of < 0.05 was considered significant. The analysis was performed using SPSS for Macintosh Version 24 statistical software.

RESULTS

One hundred twenty-six patients with SCD (42.5% male, 57.5% female) met study inclusion criteria. Thirty-four percent (N = 43) of patients were born in Alberta, 15% (N = 19) in other Canadian provinces, 15% (n = 19) in the USA or UK, 30% in Africa (N = 37), and 5% (N = 16) in other parts of the world (Table 1). The majority (95.3%) self-identified as being of African descent, and 4.7% self-identified as being of other ethnic backgrounds including Arab, Latin American and South Asian. Most patients (83.5%) had HbSS, 9.4% HbSC, 5% HbS/beta thalassemia, and only 2.4% HbS with hereditary persistent hemoglobin F. Between 2003 and 2018 there was a six-fold increase in the number of patients with SCD that attended the hematology clinic at ACH (Figure 1).

Table 1.

Population demographics

	N = 126	Percent of total
Region of birth
Alberta	43	34%
Rest of Canada	19	15%
USA	11	8.5%
Africa	37	29.5%
Asia, Middle East	2	1.5%
UK	8	6%
Other	6	4.5%
Race/ethnicity
African	117	93%
Arab or South Asian	5	4%
Other/unknown	4	3%
Sex
Male	53	42%
Female	73	58%

Figure 1.

The growth of sickle cell disease clinic population in Southern Alberta.

The median age of diagnosis for patients born in Alberta was 18 months (IQR = 4-39; mean = 26, SD = 28). More than half of the patients who were born in Alberta (63%, n = 27) were diagnosed at 12 months of age or after (Table 2). Of those who were born in Alberta, 56.5% were identified due to a disease-related complication, 37% due to family history, and 6.5% due to incidental finding of low Hb/abnormal blood smear. Of patients born in Alberta, 17% were never started on penicillin prophylaxis due to being above the age of recommended penicillin prophylaxis at diagnosis; for the others, the median age of penicillin initiation was 15.5 months (IQR = 4–26; mean = 18.5, SD = 27). Around 80% of Alberta-born patients had TCD screening, with the median age of the first TCD being 36 months (IQR = 30–54; mean = 46, SD = 24). The remaining 20% did not receive TCD screening either due to parental refusal, being less than 2 years old at time of data collection, or TCD scheduled but not captured at the time of data collection. Our clinic offers TCD screening to all patients with SCD regardless of their genotype. Seventy percent of the patients had a positive family history of sickle cell anemia. Table 3 illustrates patient first presentations related to SCD. Of patients born outside North America, 64% were first identified as having SCD following an acute complication of their disease.

Table 2.

Age at diagnosis and reason for SCD testing in Alberta-born children

Age at diagnosis—Alberta-born children	N = 43	Percent of total
Younger than 12 months	17	40%
Older than 12 months	26	60%

Reason for SCD testing—Alberta-born children	N = 43	Percent of total
Family history	15	35%
Disease-related complication	23	53%
Neonatal screen	0	0%
Routine bloodwork	3	7%
Other or unknown	2	5%

Table 3.

First presentation^* of SCD in patients born in Alberta

First presentation of SCD	%(N = 43)
Vaso-occlusive crisis	41.3(19)
Aplastic crisis	2.2(1)
Poor growth	2.2(1)
Jaundice	6.5(3)
Vasculopathy/abnormal TCD	2.2(1)
Fever	19.6(9)
Splenic sequestration	8.7(4)
Dactylitis	4.3(2)
Low hemoglobin	2.2(1)
No complication	10.9(5)

Some patients may have more than 1 first presentation

For children born in the USA or in Canadian provinces with NBS currently available, the median age of diagnosis was 0 months (IQR = 0–9.6; mean 8.3, SD = 19) (n = 36), though some may have been born before the availability of NBS in their place of birth. The difference in median age of diagnosis between children born in Alberta and children born in the USA or Canadian provinces with current NBS was significant (P < 0.001).

None of the patients in our study population died before 18 years old during the chart review period.

DISCUSSION

This study revealed that more than half of the Alberta-born patients, and 34% of the sickle cell clinic patient population, received a delayed diagnosis. Most of these children were diagnosed only after presenting with a disease-related complication. It is also important to note that the majority of children with a diagnosis of SCD in our catchment area were born outside the province of Alberta. Most children born outside North America were only identified as having SCD by the healthcare system after presenting with an acute complication of SCD, suggesting a gap in care for children with SCD who move across provincial and international borders.

During the study timeline, the number of pediatric patients followed in the SCD clinic steadily increased, and this increase in SCD pediatric patients has been observed across the province (22). Immigration patterns make it likely that this trend will continue across much of Canada (23), making the ability to identify SCD highly relevant for pediatric care providers.

Our data also show that for most Southern Alberta-born patients with SCD, the initiation of penicillin prophylaxis and TCD screening was delayed relative to recommendations. For this subset of patients, the median age of initiation of penicillin prophylaxis was 15.5 months, and the median age of TCD screening was 36 months. One of the largest trials to assess mortality in children with SCD before the introduction of NBS and penicillin prophylaxis showed a spike in mortality between one and three years of age, primarily due to pneumococcal sepsis (24). The early use of prophylactic antibiotics has been shown to reduce the risk of pneumococcal infection by approximately 84% (25). Early TCD screening and resultant treatments based on TCD results reduce the risk of stroke in children with SCD (26). SCD guidelines now recommend that all children with SCD receive prophylactic penicillin starting at 2 months of age and continuing until at least 5 years of age (5), and TCD screening should commence at 2 years of age (10,27). Other studies have similarly shown a reduction in morbidity and mortality resulting from NBS for SCD, when coupled with comprehensive SCD management programs (11,12). Thus, late diagnosis prevents children with SCD from benefitting from early primary prevention such as penicillin prophylaxis and TCD screening.

Universal NBS for SCD became standard in Ontario and in every state of the USA by 2006 and was introduced in the maritime provinces in 2014 and Quebec in 2016 (17). Alberta began offering NBS for SCD in April 2019. Newborn screening in Alberta is universally offered but can be declined by parents. Recent analyses show that over 99% of registered infants born in Alberta are screened, and approximately 98% receive results within 10 days of age (28). Our study provides an understanding of diagnostic circumstances and characteristics of patients with SCD in a multicultural, high-income country before the implementation of the NBS. These data can serve to compare the timing of diagnosis, SCD-related complications, and early intervention pre-and post-NBS era and contributes to the growing literature (15,19) that supports the importance of a nationwide NBS mandate for SCD.

This study also highlights the importance of standardized screening of immigrant children at risk for hemoglobinopathy, and for considering the diagnosis of SCD in children who may not have been screened at birth. It is concerning that the majority of children who were born outside North America were only diagnosed when they developed a disease-related complication. Some families who know or suspect that their child has SCD may not bring this information to the attention of a healthcare provider before a complication arises. Most of the patients followed by the SCD program were born outside the province; therefore, even if they had been screened at birth, the result would not be available to a provider in Alberta unless revealed by the parent. Previous studies show that a complex array of factors, including social challenges relevant to people newly arrived in Canada, language barriers, and difficulty accessing the healthcare system may lead to gaps in healthcare for new residents (29). Disease-based stigma (30) may also lead to family not being quickly forthcoming with discussing or accepting the diagnosis of SCD. It is therefore crucial that primary care providers and specialists who care for children consider the need to screen children at risk for sickle cell disease when their status is unknown.

The limitations of our study include the retrospective nature of the health record review, which may have resulted in missing information. It was also difficult to accurately determine if a child born outside Alberta had been screened at birth if not noted in the health record, due to wide variation in NBS across Canada and internationally. Thus, the mean of age of diagnosis of children born in the USA or in a Canadian province where NBS currently occurs was 8.3 months, while the median was zero, likely because of the inclusion of children who did not receive a newborn screen and were diagnosed later. However, regardless of the screening status of a child born outside Alberta, the approach to their evaluation and management remained the same if their SCD status was unknown or not provided at the time of first contact with the Alberta healthcare system.

In conclusion, the findings of this study demonstrate that SCD diagnosis is delayed in regions where NBS is not offered, and diagnosis most often occurs following an acute complication. This adds to the growing body of published literature emphasizing the importance of universal NBS for SCD in racially diverse countries such as Canada. We emphasize the importance of maintaining vigilance to screen patients who may have not been screened at birth and to test patients with signs or symptoms of SCD complications. Finally, this study suggests that regional health authorities in ethnically diverse countries such as Canada regularly evaluate NBS panels to ensure new tests are added as population demographics change and new high-risk groups may emerge. Future efforts may focus on determining best practices in standardized screening for SCD in patients who did not receive NBS and reliable detection of children who develop complications of SCD.

FUNDING

There are no funders to report.

POTENTIAL CONFLICTS OF INTEREST

D.A.M. disclosed support from ASH and EBMT for attending meetings and/or travel. J.T.F. disclosed funding from the University of Calgary and Alberta Children’s Hospital Research Institute for unrelated projects, and that she acted as Alberta Childen’s Hospital Medical Director of Quality and Safety from 2018 to 2021. M.L. disclosed positions with the Canadian Hemoglobinopathy Society, as treasurer (2014–2019) and vice chair (2019–2021). M.S. reports a relationship with Takeda Pharmaceutical as Medical Editor for a 3rd party publication regarding PEGylation technology for Coagulation Factor replacement therapy, as well as a relationship with BAYER—FISHAWACK, as one of multiple authors on publications related to JIVI a coagulation factor. There are no other disclosures. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.