Summary
Children diagnosed with sickle cell disease (SCD) are at risk for the development of neurobehavioral problems early in life. Specific impairments in executive function skills, including working memory, have been documented in school-aged children with SCD. These executive skills are known to strongly contribute to early academic skills and preparedness for entering kindergarten. This study examined working memory and school readiness in preschool children with SCD compared to a healthy control group matched for race, sex, and parent education. Eighty-four patients diagnosed with SCD (61.9% HbSS/HbSβ0-thalassemia) and 168 controls completed testing. The average ages of patients and controls at testing were 4.53 (SD=0.38) and 4.44 (SD=0.65) years, respectively. The SCD group performed worse than controls on measures of executive function, working memory, and school readiness (p<0.01; Cohen’s D range: 0.32-0.39). Measures of working memory were associated with school readiness after accounting for early adaptive development. Multiple linear regression models among patients diagnosed with SCD revealed that college education of the primary caregiver was positively associated with school readiness (p<0.001) after controlling for sex, genotype, age, and early adaptive development. These results highlight the need to implement school readiness interventions in young children diagnosed with SCD emphasizing executive function skills.
Keywords: sickle cell, pediatrics, development, working memory, school readiness
Introduction
Children with sickle cell disease (SCD) are at risk for developing neurobehavioral problems from causes including strokes, silent cerebral infarcts, significant anemia, nutritional deficits, and growth delays.1,2 The impact of living with a chronic illness may further disrupt typical development of cognitive and academic skills.3 School-aged children with SCD demonstrate a decline in cognitive abilities that increases with age compared to normative expectations.4,5 School-aged children with SCD have more academic problems, including higher grade retention rates and lower standardized test scores.6–8 To identify these cognitive and academic difficulties early in life and facilitate treatment, it is important for haematologists to recognize neurobehavioral problems in SCD and facilitate care through a multidisciplinary approach.
Specific impairments in executive function (EF) skills are particularly prevalent in school-aged children with SCD.4,9,10 EF refers to a set of skills, including working memory, inhibitory control, and cognitive flexibility. EF skills begin developing during the first five years of life and are important for self-regulation, problem solving, and goal-directed activities.11 Working memory—a limited capacity system that temporarily stores and manipulates information while performing tasks12,13— is important for academic success from preschool through high school.14,15 The unique influence of working memory on academic performance persists even after controlling for broad cognitive development.16,17
Given a disproportionate number of children with SCD live in low socioeconomic status (SES) and poverty-stricken households,18 it is important to also consider the contribution of environmental factors. Extensive research documents the adverse effects of low SES and poverty on cognition and neurodevelopment in the general population.19–21 SES affects certain neurocognitive skills more than others – with younger, lower-income, children exhibiting poorer EF and language skills.22,23 Haematologists need to be aware of both medical and sociodemographic factors leading to neurobehavioral problems. Health inequities can drive and alter the disease course, even when medical care is optimal.
Of the few studies that have examined cognitive functioning in toddler- and preschool-aged children with SCD, most either examined data using a screener of overall cognitive ability24–27 or a broad measure of early development,28 thus lacking specific or granular information. Five studies examined performance across specific domains of neurocognitive functioning in preschool-aged children with SCD.29–33 Only two of these studies included a control group, and conclusions were limited by a small sample (22 cases with SCD).31,32 Performance on neurocognitive measures was related to SES but not SCD genotype or lab values.29,30 Prior studies have suggested a neuroprotective effect of hydroxyurea34,35, but these findings have not been documented in young children (<5 years of age) with SCD.30,36 Despite the prevalence of working memory impairments found in school-aged children with SCD and the documented association between working memory ability and academic success in the general population, limited research has specifically demonstrated working memory deficits in preschool children with SCD.
The study objective was to characterize working memory and school readiness skills in preschool children with SCD, and to compare these skills with those of demographically matched controls. Among patients with SCD, we examined associations between working memory and school readiness and investigated demographic and medical correlates of working memory and school readiness. We hypothesized that children with SCD would demonstrate lower scores than a control group on measures of working memory and school readiness and that performance measures of working memory would be positively associated with school readiness skills in both groups. Furthermore, we hypothesized that performance on measures of working memory and school readiness would be associated with SES, and to a lesser degree, medical factors (sickle genotype and lab values)..
Methods
Participants
All patients diagnosed with SCD between 48-68 months of age treated at St. Jude Children’s Research Hospital were eligible for the study. Matched control participants were included through The Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study.37 Briefly, CANDLE is a longitudinal prospective study of neurocognitive development that includes a cohort of mother-child dyads recruited during the second trimester of pregnancy in Shelby County, Tennessee (contains the city of Memphis and St. Jude Children’s Research Hospital). We prospectively matched two control participants for every one patient diagnosed with SCD. Control participants had no history of SCD or any major chronic medical condition (e.g., genetic disorder, diabetes mellitus, cancer, epilepsy). All SCD and control participants were primarily English speaking, resided in the same geographical area (same zip codes) and exposed to similar environmental factors (e.g., schools, healthcare services, neighborhoods). Patients and controls were excluded if they had sensory or motor impairment that would preclude valid testing (e.g., blindness, paresis), were treated with non-stimulant psychotropic medication, or were enrolled in kindergarten at the time of assessment. Control participants were frequency matched with respect to sex, race, and caregiver education level.
Demographic, medical, and treatment variables
Parents of patients with SCD completed a demographic history questionnaire that included questions about family demographic characteristics. Medical and treatment variables were abstracted from the medical record and included SCD genotype, abnormal or conditional transcranial doppler ultrasound (non-imaging) velocities (≥ 170 cm per second), stroke history (yes/no), and lab values (see Table 1). All lab values were the average of the last three clinic visits prior to the study visit. Treatment variables included history of hydroxyurea treatment (yes/no and duration) and history of chronic blood transfusions (yes/no). SCD patients with HbSS/HbSβ0-thalassemia received hydroxyurea according to NHLBI guidelines.33 For participants with HbSC/HbSβ+-thalassemia, hydroxyurea initiation was guided by the frequency of acute disease complications.38 All patients were treated with a maximum tolerated dose, as per our institution’s standard practice.
Table 1.
Demographic and medical characteristics of sample
| SCD | Controls | p | |
|---|---|---|---|
| n=84 | n=168 | ||
|
| |||
| Frequency (%) | Frequency (%) | ||
|
| |||
| Sex | NA | ||
| Female | 45 (53.57%) | 90 (53.57%) | |
| Male | 39 (46.43%) | 78 (46.43%) | |
|
| |||
| Race | NA | ||
| African American | 82 (98.80%) | 168 (98.80%) | |
| White | 1 (1.20%) | 2 (1.20%) | |
|
| |||
| Parent Education | NA | ||
| Less than HS | 7 (8.43%) | 12 (7.14%) | |
| HS Diploma | 18 (21.69%) | 34 (20.24%) | |
| Some college | 42 (50.60%) | 76 (45.24%) | |
| College degree or higher | 16 (19.28%) | 46 (27.38%) | |
|
| |||
| Sickle Cell Disease Genotype | --- | ||
| Hb SS/HbSβ0-thalassemia | 52 (61.90%) | -- | |
| Hb SC/HbSβ+-thalassemia/ Other | 32 (38.10%) | -- | |
|
| |||
| History of chronic blood transfusion | 4 (4.76%) | -- | -- |
|
| |||
| Hydroxyurea treatment history a | 43 (51.19%) | -- | -- |
|
| |||
| History of overt stroke b | 2 (2.38%) | -- | -- |
|
| |||
| History of conditional or abnormal TCD c | 12 (23.08%) | -- | -- |
|
| |||
| Mean (SD) | Mean (SD) | ||
|
| |||
| Age at evaluation (years) | 4.53 (0.38) | 4.44 (0.65) | 0.151 |
|
| |||
| SIB-R Early Development Index | 108.62 (18.30) | 108.68 (16.50) | 0.980 |
|
| |||
| Duration of hydroxyurea treatment (months) | 23.95 (14.18) | -- | -- |
|
| |||
| Hemoglobin (g/dL) | 9.92 (1.34) | -- | -- |
|
| |||
| WBC (x10e3/mm3) | 10.04 (3.22) | -- | -- |
|
| |||
| Fetal hemoglobin (%) | 23.79 (10.59) | -- | -- |
|
| |||
| Hemoglobin oxygen saturation, (%) | 99.23 (0.81) | -- | -- |
M, mean; SD, standard deviation; n, sample size; %, percent; SIB-R, Scales of Independent Behavior – Revised; TCD, transcranial doppler; WBC, white blood cell count;
P-values are based on two-sample t-tests. Patient characteristics (sex, race and parent education) used for matching are not subject to statistical testing comparing between SCD patients and controls. These values are presented in the table solely for demographic information. Hematologic indices were the average value of measurements collected within 3 months of or the one closest to neurocognitive assessment.
Ever treated with hydroxyurea therapy
Due to the limited number of cases, we did not assess group differences based on history of overt stroke
Only performed on patients with Hb SS/HbSβ0-thalassemia. TCD mean flow velocity values for each artery: normal (< 170 cm per second) and conditional/abnormal (≥ 170 cm per second).
For control participants, demographic data including sex, race, parent education, and age at assessment were obtained from the CANDLE database.
Neuropsychological Assessment
Patients diagnosed with SCD and matched controls completed a battery of neuropsychological measures supervised by a licensed psychologist. The Stanford-Binet Intelligence Scales–Fifth Edition (SB-5)39 was used to measure Working Memory. The Working Memory factor is composed of 2 subtests measuring both verbal and visual working memory.
School readiness was measured using the Bracken Basic Concepts Scale–Third Edition: Receptive (BBCS-3:R), School Readiness Composite (SRC),40 which assesses knowledge of fundamental pre-academic skills such as colors, letters, numbers and counting, sizes and comparisons, and shapes.
Parent ratings of EF, including working memory, were collected using the Behavior Rating Inventory of Executive Function–Preschool Version (BRIEF-P).41 The BRIEF-P is a parent questionnaire designed to assess behavioral manifestations of EF in preschool-aged children. We specifically examined the Working Memory and Global Executive Composite (GEC) scales.
Early adaptive development was measured using the Scales of Independent Behavior – Revised (SIB-R) Early Development Index (EDI).42 The SIB-R Early Development Form is a structured parent interview assessing functional independence and adaptive functioning across settings: school, home, workplace, and community.
On the SB-5, BBCS-3:R, and SIB-R higher scores are indicative of better performance or more advanced development. In contrast, higher scores on the BRIEF-P indicate more parent reported concerns or lower levels of EF. Scores presented for the SB-5, BBCS-3:R, and SIB-R are standard scores with a mean of 100 and SD of 15, whereas scores on the BRIEF-P are presented as T scores with a mean of 50 and SD of 10.
Statistical Analyses
The primary objective of the project was to compare working memory and school readiness in young children with SCD to demographically matched control children without SCD. The study required 84 evaluable patients with SCD and 168 demographically matched control children to achieve 80% power (one-tailed alpha=0.05) to detect an effect size of 0.33 (Cohen’s d).
The 2-sided two-sample t-test was used to compare continuous variables between the SCD patients and controls. The 2-sided two-sample t-tests were also used to compare the preschoolers with SCD and controls on neurocognitive performance. The Cohen’s D scores were also calculated as a measure of effect size on the neurocognitive performance. The Pearson’s correlations were calculated among the four neurocognitive measures to determine associations between neurocognitive and academic constructs. Separate linear regression models were built to examine associations between neurocognitive and academic constructs after controlling for the EDI. One multiple linear regression model was built for each of the four neurocognitive measures as the dependent variable, separately. For each model, the backward stepwise selection method was used to select predictors among sex, genotype, parent education, age, EDI and additional medical measures (hemoglobin, fetal hemoglobin level, absolute reticulocyte count, WBC count, and daytime Hb02). The inclusion criteria in the selection process was pvalue<= 0.10, with the first 5 predictors forced to be included in the final model regardless of if they met the criteria. For simplicity, we only presented the final models. History of hydroxyurea treatment was initially included in the multiple linear regression models but was removed because it was highly correlated with SCD genotype and caused undue collinearity.
All statistical analyses were conducted with the statistical software SAS 9.4 and SPSS Statistics 25.
Results
Demographic and medical characteristics
Table 1 displays demographic and medical characteristics of the sample. Patients diagnosed with SCD (n=84) were an average of 4.53 (SD=0.38) years of age at testing and healthy controls (n=168) were 4.44 (SD=0.65) years old. The majority of patients diagnosed with SCD (69.88%) and controls (72.62%) had parents that completed at least some college. Overall, there were no differences in sex, race, parent education, or age between patients and controls (all p>0.1).
The majority (61.90%) of patients with SCD were diagnosed with either the HbSS or HbSβ0-thalassemia genotype. At the time of neurocognitive testing, roughly half the sample of SCD patients (51.19%) had a history of hydroxyurea treatment, and those that received hydroxyurea were treated for an average of 23.95 (SD=14.18) months. Four patients (4.76%) had a history of chronic transfusion treatment and 2 SCD patients (2.38%) had a history of overt stroke. Among patients with HbSS or HbSβ0-thalassemia genotype, 12 out of 52 (23.08%) had a history of a conditional or abnormal transcranial Doppler velocity.
Comparison between participants with SCD and matched controls
Group comparisons on neurocognitive and academic measures are displayed in Table 2. Performance on the SB-5 Working Memory factor (t=−2.8, p<0.01, Cohen’s D=0.32) and BBCS-3:R School Readiness Composite (t=−2.9, p<0.01, Cohen’s D=0.39) revealed that SCD patients performed worse than demographically matched controls on both measures. Consistently, parent ratings on the Working Memory (t=2.73, p<0.01, Cohen’s D=0.37) and GEC (t=2.68, p<0.01, Cohen’s D=0.35) scales of the BRIEF-P indicated greater difficulties in these domains among SCD patients compared with control participants. All group differences remained after removing the 2 SCD cases with a history of stroke.
Table 2.
Comparison of neurocognitive performance between preschool children with sickle cell disease and healthy matched controls
| SCD Patients | Controls | ||||||
|---|---|---|---|---|---|---|---|
| Measure | Score | Mean (SD) | Mean (SD) | Absolute Mean Difference (95% CI) | Cohen’s D | t | p |
| SB-5a | Working Memory | 91.71 (13.65) | 96.74 (13.36) | 5.03 (1.49, 8.57) | 0.32 | −2.8 | 0.0056 |
| BBCS-3:R a | School Readiness | 89.0 (16.70) | 95.47 (16.42) | 6.47 (2.08, 10.87) | 0.39 | −2.9 | 0.0041 |
| BRIEF-P b | Working Memory | 55.95 (12.95) | 51.37 (12.03) | 4.58 (1.28, 7.89) | 0.37 | 2.73 | 0.0068 |
| BRIEF-P b | Global Executive function | 51.9 (13.66) | 47.43 (11.54) | 4.47 (1.18, 7.76) | 0.35 | 2.68 | 0.0079 |
SCD, sickle cell disease; SD, standard deviation; SB-5, Stanford-Binet Intelligence Scales – Fifth Edition; BBCS-3:R, Bracken Basic Concept Scale – 3rd Edition: Receptive; BRIEF-P, Behavior Rating Inventory of Executive Function – Preschool.
Performance measures included the Stanford-Binet Intelligence Scales – Fifth Edition and the Bracken Basic Concepts Scale – Third Edition: Receptive. Parent ratings of executive functioning collected using the Behavior Rating Inventory of Executive Function – Preschool Version.
Displayed values are Standard Scores with a mean of 100 and standard deviation of 15. Higher scores are indicative of better performance
Displayed values are T Scores with a mean of 50 and standard deviation of 10. Higher scores are indicative of greater symptoms (i.e., more problems)
Correlations between working memory and school readiness
The Pearson’s correlations between neurocognitive and academic measures among preschoolers with SCD are displayed in Table 3. The SB-5 Working Memory factor was strongly correlated with BBCS-3:R School Readiness Composite (r=0.54, p<0.001). Consistently, there were smaller, yet significant, correlations between the BRIEF-P Working Memory scale and the School Readiness Composite (r=−0.34, p<0.01), and between global EF (r=−0.24, p<0.05) and school readiness). The associations between the SB-5 Working Memory factor (p<0.001) and BRIEF-P Working Memory index (p<0.05) with the School Readiness Composite were maintained after including a measure of early adaptive development (SIB-R EDI) in regression models. However, the association between the GEC and School Readiness Composite no longer reached statistical significance after adding the EDI to the regression model (Table 4). Highly consistent correlations among measures were observed in the control group (see Supplemental Table 1). The SB-5 and BRIEF-P Working Memory scores displayed small correlations in both the SCD (r=−0.21, p=0.06) and control groups (r=−0.23, p<0.01), but only reached significance in the control group, likely due to a larger sample size.
Table 3.
Correlations between neurocognitive assessment measures among preschoolers with sickle cell disease
| BRIEF-P Working Memory | BRIEF-P Global Executive | BBCS-3:R School readiness | SB-5 Working Memory | |
|---|---|---|---|---|
| BRIEF-P Working Memory a | ---- | --- | --- | --- |
| BRIEF-P Global Executive a | 0.92*** | --- | --- | --- |
| BBCS-3:R School Readiness b | −0.34** | −0.24* | --- | --- |
| SB-5 Working Memory b | −0.21 | −0.13 | 0.54*** | --- |
BRIEF-P, Behavior Rating Inventory of Executive Function - Preschool; SB-5, Stanford-Binet Intelligence Scales – Fifth Edition; BBCS-3:R, Bracken Basic Concept Scale – 3rd Edition: Receptive;.
Values displayed are Pearson correlations. Performance measures included the Stanford-Binet Intelligence Scales – Fifth Edition and the Bracken Basic Concepts Scale – Third Edition: Receptive. Parent ratings of executive functioning collected using the Behavior Rating Inventory of Executive Function – Preschool Version.
p<0.05
p<0.01
p<0.001
Higher scores indicative of greater symptoms (i.e., more problems)
Higher scores indicative of better performance
Table 4.
Associations between school readiness and other neurocognitive measures assessed by linear regression controlling for adaptive development
| Estimate | SE | p | |
|---|---|---|---|
| Intercept | 17.72 | 12.93 | 0.175 |
| SB-5 Working Memory b | 0.63 | 0.12 | <0.001 |
| SIB-R EDI b | 0.12 | 0.09 | 0.171 |
|
| |||
| Intercept | 92.88 | 15.97 | <0.001 |
| BRIEF-P Working Memory a | −0.36 | 0.15 | 0.021 |
| SIB-R EDI b | 0.15 | 0.10 | 0.153 |
|
| |||
| Intercept | 79.75 | 15.48 | <0.001 |
| BRIEF-P Global Executive a | −0.20 | 0.15 | 0.183 |
| SIB-R EDI b | 0.18 | 0.11 | 0.089 |
BRIEF-P, Behavior Rating Inventory of Executive Function - Preschool; SB-5, Stanford-Binet Intelligence Scales – Fifth Edition.
Performance measures included the Stanford-Binet Intelligence Scales – Fifth Edition and the Bracken Basic Concepts Scale – Third Edition: Receptive. Parent ratings of executive functioning collected using the Behavior Rating Inventory of Executive Function – Preschool Version.
Higher scores indicative of greater symptoms (i.e., more problems)
Higher scores indicative of better performance
Predictors of neurocognitive outcomes
Multiple linear regression models for patients diagnosed with SCD are displayed in Table 5. Among patients diagnosed with SCD, parent education (whether the primary caregiver has at least a college degree), was positively associated with performance on the School Readiness Composite after controlling for sex, genotype, age, and the EDI. The estimated increase on the School Readiness Composite for having a primary caregiver with at least a college degree compared to otherwise is 17.37 (t=3.66, SE=4.74, p<0.001), controlling for other covariates. Consistently, there was a trend toward a positive association between parent education and SB-5 Working Memory performance after accounting for covariates. The estimated increase in SB-5 Working Memory for having a primary caregiver with at least a college degree compared to otherwise is 7.48 (t=1.86, SE=4.02, p=0.067), controlling for other covariates. Based on the models, we do not have evidence to support associations between any of the 4 outcomes (BRIEF-P Working Memory, BRIEF-P Global Executive, SB-5 Working Memory and BBCS-3:R School Readiness) and the other covariates (sex, genotype, and age; all p>0.05). No lab values (Hb, HbF, absolute reticulocyte count, WBC count, daytime oxygen saturation) were included in any of the final models as they did not meet the stay criteria of pvalue<=0.10 in the stepwise model selection procedure.
Table 5.
Multiple linear regression among preschool patients diagnosed with sickle cell disease
| BRIEF-P Working Memory a | BRIEF-P Global Executive a | BBCS-3:R School Readiness b | SB-5 Working Memory b | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Estimate | SE | p | Estimate | SE | p | Estimate | SE | p | Estimate | SE | p | |
| Intercept | 87.81 | 23.76 | <0.001 | 88.45 | 25.11 | <0.001 | 72.22 | 29.89 | 0.018 | 48.76 | 25.89 | 0.064 |
|
| ||||||||||||
| Sex | 2.40 | 2.90 | 0.411 | 3.54 | 3.06 | 0.251 | 1.13 | 3.64 | 0.757 | −2.14 | 3.17 | 0.503 |
|
| ||||||||||||
| Genotype | 2.89 | 2.90 | 0.323 | 1.91 | 3.07 | 0.535 | −5.35 | 3.71 | 0.154 | −0.17 | 3.18 | 0.956 |
|
| ||||||||||||
| Parent Education | −3.34 | 3.73 | 0.374 | −1.27 | 3.94 | 0.749 | 17.37 | 4.74 | <0.001 | 7.48 | 4.02 | 0.067 |
|
| ||||||||||||
| Age at assessment | −3.10 | 3.97 | 0.437 | −3.83 | 4.19 | 0.364 | 0.69 | 4.99 | 0.890 | 5.99 | 4.36 | 0.174 |
|
| ||||||||||||
| Early Development Index | −0.18 | 0.09 | 0.044 | −0.20 | 0.09 | 0.036 | 0.11 | 0.11 | 0.330 | 0.14 | 0.10 | 0.142 |
BRIEF-P, Behavior Rating Inventory of Executive Function - Preschool; SB-5, Stanford-Binet Intelligence Scales – Fifth Edition; BBCS-3:R, Bracken Basic Concept Scale – 3rd Edition: Receptive.
Performance measures included the Stanford-Binet Intelligence Scales – Fifth Edition and the Bracken Basic Concepts Scale – Third Edition: Receptive. Parent ratings of executive functioning collected using the Behavior Rating Inventory of Executive Function – Preschool Version.
Higher scores indicative of greater symptoms (i.e., more problems)
Higher scores indicative of better performance
Discussion
SCD is characterized by early and progressive neurocognitive dysfunction, with notable effects on EF and working memory.43 Due to these neurocognitive difficulties, preschool children with SCD are at risk for poor school readiness when they enter kindergarten.30 These school readiness skills, including literacy and numeracy, are highly predictive of later academic performance and grade retention.44 Consistent with our hypotheses, preschool children with SCD had worse performance on measures of school readiness and working memory relative to matched controls. Among SCD patients, performance on a measure of school readiness was associated with both performance (i.e., paper-pencil) and parent-rated measures of working memory after accounting for early adaptive development.
We observed deficits in working memory among preschool children with SCD compared to demographically matched controls. Working memory allows individuals to temporarily store and manipulate information while performing tasks.12,13 In children and adolescents with SCD, working memory is known to be an area of weakness,43,45 and has been the target of neurocognitive interventions.46,47 Working memory difficulties may arise from vasculopathies and subsequent tissue injuries to cortical and subcortical regions, particularly frontal watershed regions.48 The importance of working memory for quality of life outcomes such as school attainment and academic skills are well documented.14,15
Consistent with findings in the broader childhood population, working memory skills significantly contributed to performance on a measure of school readiness. In the general population, working memory and other executive skills are more strongly associated with school readiness than intellectual ability.49 Working memory allows a child to remain engaged in learning and follow classroom procedures.50,51 These findings suggest that school readiness interventions that emphasize EF and working memory skills that have been applied to the general population52,53 may be effective in preschool patients diagnosed with SCD. For example, the Red Light, Purple Light! school readiness intervention for children from low-income backgrounds specifically incorporates activities targeting early executive skills in addition to direct instruction in early numeracy and literacy.52 For successful implementation of these interventions with the SCD population, modifications to the content (e.g., language and idioms) and delivery (e.g., hospital setting) are likely needed.54
Consistent with prior research,8,29,30 SES was associated with neurocognitive and academic performance among preschoolers with SCD. Specifically, patients who grew up in a household with a caregiver that completed college scored significantly higher on a measure of school readiness than patients whose primary caregiver did not complete college. Although we observed the influence of SES on school readiness, we did not find evidence for associations between sickle genotype or any lab value with school readiness or working memory performance. The limited influence of medical factors on early cognitive development in SCD is consistent with several prior studies of young children with SCD29,30 but discrepant from findings among school-age and adolescent samples.2,35
Neurocognitive deficits were observed despite a large portion of the SCD sample receiving hydroxyurea treatment. Hydroxyurea treatment likely provides some neuroprotection,35 but neurocognitive difficulties still emerge. These findings are contrary to a recent study of school age SCD (HbSS/HbSβ0) patients who all initiated hydroxyurea treatment before 5 years of age.34 They found no differences in neurocognitive performance in treated patients compared to controls matched on age, race, and sex.34 The discrepant findings are potentially due to differences in sample size, age of the patients, outcome measures, proportion of the sample treated with hydroxyurea, or characteristics of the control group.
Due to the debilitating consequences of neurocognitive dysfunction in SCD, recent American Society of Hematology cerebrovascular guidelines endorsed the implementation of neurocognitive rehabilitation strategies in patients with SCD.55 However, to date, there have been limited attempts to address the neurocognitive and academic deficits observed in SCD through nonpharmacological approaches. An abundant literature has demonstrated that school readiness skills are highly malleable (i.e., can be taught and improved),56–58 and earlier rather than later intervention produces the greatest returns on investment.59,60 Due to the progressive nature of SCD, children’s brains may be more responsive to interventions in early childhood than at school age.35 Early treatment can thus prevent rather than remediate the neurocognitive effects of SCD. To facilitate these interventions, it is essential that haematologists and pediatricians can recognize and screen for these early difficulties and provide education to families about the neurocognitive risk associated with SCD. Furthermore, strategies that aim to reduce health disparities should be considered in the SCD population and should target the downstream effects of SES on health. For instance, health navigators (i.e., member of healthcare team who helps patients overcome barriers and increase access to quality care) can link patients to community resources (e.g., food banks, housing, transportation), therefore, helping remove the barriers to care that cause health inequities and associated health outcome disparities.
This study has several strengths, including a local demographically-matched control group as well as detailed medical, demographic, and treatment history for all participants. The study utilized several neurocognitive outcomes and included both performance measures and parent report. However, notable limitations do exist. Only patients with clinical indications received neuroimaging, therefore we lacked information on history of silent infarcts or vessel stenoses. Measurement of SES was limited to parent education. More detailed assessment of the home environment would provide further information about aspects of socioeconomic status associated with neurocognitive and academic outcomes. Yet, any additional measures of socioeconomic status are likely associated with parent education. Over half the patients diagnosed with SCD were treated with hydroxyurea, potentially limiting generalizability to all SCD patients who may not receive such early hydroxyurea treatment. Our sample was too small to conduct separate analyses based on SCD genotype.
To conclude, preschool children diagnosed with SCD display deficits in EF and working memory that contribute to poor school readiness. These early difficulties are associated with sociodemographic factors. School readiness is highly predictive of later academic performance and grade retention. There is a significant need to test and implement interventions incorporating early executive aspects of school readiness and parent education to prevent future academic deficits in young children diagnosed with SCD.
Supplementary Material
Acknowledgements
J.S.H. received funding from U01HL133996 during the conduct of this study. J.S.P. was supported by K01HL125495 at the time of this project. J.E.S. was supported by an NIH Loan Repayment Program at the time of this project. This research was supported by the American Lebanese Syrian Associated Charities (ALSAC).
Footnotes
Conflicts of interest
J.S.H. receives consultancy fees from Global Blood Therapeutics, CVS Health and UpToDate. A.M.H. receives consultancy fees from Global Blood Therapeutics. J.S.P. receives consultancy fees from Forma Therapeutics, Inc. There are no other conflicts of interest to report.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.