This study is funded by the National Heart, Lung, and Blood Institute under a K23 award designated Independent Clinical Trials Not Allowed (K23HL161328), reflecting the determination by the National Institutes of Health that the proposed research does not constitute an independent clinical trial. Aim 1 is an observational cohort study, and aim 2 is a feasibility pilot intended to inform a future randomized controlled trial. Accordingly, this study was not registered on ClinicalTrials.gov. This study includes 3 aims with different designs, and we selected a reporting guideline for each. We follow the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline for the aim 1 cohort [28], the TIDieR (Template for Intervention Description and Replication) for the aim 2 SCCCD intervention [29], and the COREQ (Consolidated Criteria for Reporting Qualitative Research) for the aim 3 interviews [30]. We report the protocol following the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2025 statement [31]. Completed TIDieR and SPIRIT 2025 checklists are provided as Checklists 1 and 2, respectively.

Participants are recruited through Washington University School of Medicine and the Sickle Cell Clinic at St. Louis Children’s Hospital (SLCH), a regional hub for pediatric SCD care that follows over 400 children and receives approximately 25 newborns with SCD annually. For aim 1, we will recruit 100 children, 50 with SCD and 50 demographically matched peers, who will complete developmental evaluations at 9, 18, and 30 months with concurrent caregiver surveys. For aim 2, an additional 25 children with SCD will be recruited to participate in a 12-month home-visiting intervention. Caregivers of children enrolled in aim 2 may also be invited to participate in a qualitative interview as part of aim 3.

Developmental evaluations will be conducted at 9, 18, and 30 months of age (±1 month) for children enrolled in both aim 1 and aim 2. Evaluations will take place in a dedicated child-friendly testing room on the Washington University School of Medicine campus, which has a padded floor, child-safe furniture, and space for caregivers to sit comfortably. Five accessible parking spots are reserved directly in front of the testing room, and the space is located within a 5-minute walk of public transportation. Visits will last approximately 60 to 90 minutes. Snacks will be provided to support child engagement during the evaluation, and caregivers will be compensated for their time and travel at each visit. Following institutional review board (IRB) amendment, evaluations may also be conducted in the family’s home for participants residing within the Greater St. Louis Metro area, in response to caregiver feedback regarding barriers to on-site attendance. Any changes are communicated to participants and shared with our community advisory board.

Demographic information and caregiver surveys will be collected using REDCap, a HIPAA-secure web-based data capture system, administered on a research tablet [36,37]. Survey data may also be completed by caregivers remotely via a secure web-link before or after the visit to reduce in-person visit burden. Assessors will be trained to maintain adherence to the evaluation protocol prior to data collection. Following each evaluation, the assessor will prepare a written summary report of the child’s developmental scores, review the results with the caregiver, and share the report with the child’s pediatrician and hematologist at the family’s request. If a developmental delay is identified (>1 SD below the mean), the research team will discuss the results with the caregiver and offer a referral to Early Intervention services, the federally funded, state-administered early intervention program available to eligible children under 3 years of age at no cost to families [38,39].

Retention strategies include SMS text message reminders prior to each scheduled visit; flexible scheduling, including early morning, evening, and weekend appointments; and reimbursement for parking or public transportation. Text message reminders have been effective in reducing visit cancelations in our prior work [20].

For aim 2, a pediatric occupational therapist with training in the PAT curriculum will conduct 12 monthly home visits with each enrolled family following the 9-month baseline evaluation. Visit scheduling will allow for up to 15 to 18 months of delivery to accommodate missed visits and ensure all families receive equivalent intervention dosage. Visits will be documented using daily notes that capture completed activities, caregiver engagement, visit duration, and any SCD-related topics reviewed.

For aim 3, semistructured interviews will be conducted with up to 35 caregivers of children enrolled in aim 2. Interviews will be conducted by the method of the participant’s choosing (eg, phone, HIPAA-secure video call, or in person) and are expected to last approximately 30 to 45 minutes. Interviews will be audio-recorded and transcribed verbatim. Two research team members will review all transcripts for accuracy prior to analysis. Caregivers will be compensated for their time.

All data will be stored with 2 levels of password protection. Paper consent documents will be maintained in a locked cabinet in a locked office. Data will be accessible only to the research team.

All outcome measures are summarized in Table 1. Demographic information will be collected from all participants at enrollment, including caregiver age, education, health literacy, marital status, household income, racial or ethnic identity, and number of children in the household. Clinical information collected for children with SCD will include SCD genotype, insurance status, hospitalizations and treatments, disease-modifying medication use, and neuroimaging results if available.

The Bayley Scales of Infant Development, Fourth Edition (Bayley-4) is the primary outcome measure and has been the gold standard for evaluating and identifying developmental delay in children for over 50 years [25]. The Bayley-4 is completed in 45 to 60 minutes and evaluates 5 developmental domains: cognition, fine motor, gross motor, receptive language, and expressive language. Raw scores are converted to scaled scores, where a score of 10 indicates performance at the 50th percentile. A score greater than 1 SD below the mean will be classified as a developmental delay.

The Ages and Stages Questionnaire, Third Edition (ASQ-3) is a caregiver report screener used widely in primary care and research settings that assesses development across the domains of communication, gross motor, fine motor, problem solving, and personal-social skills in approximately 10 minutes [10,40]. While the ASQ-3 is time- and cost-efficient, it is insufficiently detailed to identify early indicators of mild-to-moderate developmental delays when used alone [5,10,18,20,41,42].

The Survey of Well-Being of Young Children (SWYC) is a brief, validated caregiver report screener that captures developmental and behavioral milestones as well as family context factors including caregiver depression and social determinants of health [43,44]. The SWYC was added to the protocol following community partner and community advisory board input to capture additional environmental and contextual factors and to allow comparison with other commonly used screening measures.

The Infant Toddler Activity Card Sort (ITACS) is a picture-based caregiver report tool developed and validated by members of this team to identify concerns related to child participation in family activities and routines [33,34,45]. Caregivers are presented with photographs depicting common infant and toddler activities and asked to identify those that present a challenge for their child.

The Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) is a widely used caregiver report measure of executive functioning for children as young as 2 years of age, designed to identify how a child functions within the context of their individual environments [46]. The BRIEF-P will be administered at the 30-month time point only.

The Infant Toddler Home Observation for Measurement of the Environment Inventory [9] is a 42-item checklist completed by a research team member that evaluates the quality and quantity of stimulation and support available to the child in the home environment [47]. The HOME (Infant Toddler Home Observation for Measurement of the Environment) will be administered at all 3 time points for children enrolled in aim 2.

The Patient-Reported Outcomes Measurement Information System (PROMIS) Depression Short Form (8 items) will be completed by caregivers at each time point to assess caregiver mental health, given the established association between caregiver depression and child developmental outcomes [16,48,49]. Caregivers with concerning scores on the PROMIS Depression screener, based on prespecified cutoffs, will be referred to behavioral health services.

The SCCCD intervention is a multicomponent, home-based program delivered by a pediatric occupational therapist trained in both the PAT curriculum and SCD care. Following our previously successful protocol [20], the intervention integrates 3 components during monthly home visits: OT to monitor and address developmental delays, the PAT curriculum to support caregivers in promoting developmental milestones and positive parenting, and SCD-specific education covering clinical recommendations such as medication adherence and protective behaviors (eg, hydration). Delivery by a single provider across all 3 components is intentional, as this approach establishes a high level of rapport between the family and the interventionist over the course of the program.

The intervention is adapted from our pilot study to be feasible within this population while maintaining sufficient dosage to observe change [20]. Families of infants under 9 months of age will be enrolled, and 12 monthly home visits will be offered over the course of 1 year [50-52]. In practice, we anticipate that some families will miss visits due to health-related concerns associated with SCD; therefore, the program may extend up to 15 to 18 months to ensure all children receive equivalent intervention dosage. In our prior work, maintaining frequent contact with families through their preferred communication method (eg, SMS) increased visit completion to 80% [20]. The PAT curriculum provides a developmentally appropriate activity and caregiver handouts for each visit. OT during visits will target specific developmental delays identified through ongoing evaluation, and SCD education will be reviewed and updated at each contact.

OT is uniquely suited to deliver this intervention given the combined expertise in mental health, rehabilitation, and child development. The proposed SCCCD intervention package, which combined OT, PAT, and SCD education, reflects a theoretically grounded, practically feasible approach to improving developmental outcomes in a population with both biological and environmental risk factors. The intervention will be discontinued if the family requests to stop services.

Interventionists will be trained to maintain adherence to the SCCCD protocol prior to delivering visits. Using the Comprehensive Intervention Fidelity Guide, the intervention design, training, and delivery will be systematically evaluated [53]. Fidelity will be documented through daily visit notes that capture completed activities, caregiver engagement, visit duration, handouts provided, SCD topics reviewed, and any additional caregiver training or referrals made [54,55]. Visits scheduled and completed will be tracked throughout the intervention period.

To identify determinants that influence caregiver participation in developmental screening and the SCCCD intervention, we will use a mixed methods (QUAL → quan) approach guided by the Consolidated Framework for Implementation Research 2.0 (CFIR) [56-58]. The CFIR is one of the most widely used frameworks for understanding contextual determinants in implementation research and has been recently updated with greater emphasis on including recipients of the intervention as key informants [56], making it well suited for a caregiver-centered inquiry.

Semistructured interviews will be conducted with up to 35 caregivers of children enrolled in aim 2, organized around 3 CFIR construct domains: outer setting (eg, health care system and community context), intervention characteristics (eg, acceptability and perceived fit of the SCCCD), and inner setting (eg, family and social support). We are confident that thematic saturation will be reached [35,59]. Qualitative themes from interviews will be integrated with quantitative participation data from aim 2—including visit completion rates, home visit duration, and family engagement—to provide a comprehensive characterization of the contextual determinants that facilitate or impede caregiver participation.

Interviews will be audio-recorded and transcribed verbatim. Two research team members will use an iterative inductive and deductive thematic analysis approach to review all transcripts and generate themes for a preliminary codebook [60]. The preliminary codes will be applied to 4 interviews using NVivo software (version 14; Lumivero) [61]; any deviations will be discussed, and the revised codebook will be applied to all remaining interviews [62]. Codes will be analyzed for themes, and participation data from aim 2 will be summarized [63,64].

Participants who do not complete all evaluation time points will be analyzed using available data. Attrition will be documented across all aims, including the number of participants who withdraw, are lost to follow-up, or miss individual evaluation visits, and patterns of missingness will be reported.

This study has been approved by the Human Research Protection Office at Washington University School of Medicine (IRB 202104034 and 202407080), approved April 2021 and July 2024, respectively. This study poses minimal risks to children and families. Study personnel will complete mandated reporter training, and caregivers will be referred to supportive services if any psychological, environmental, or developmental concerns arise. All study procedures will be conducted in accordance with the ethical standards of the IRB.

Informed consent will be obtained from the parent or legal guardian for themselves and on behalf of the child before any study procedures. The consent process will take place in a private setting and will be conducted in person, by phone, or via HIPAA-secure video call. Caregivers will be given time to ask questions and will receive a copy of the signed consent document. Since all child participants are under 3 years of age, child assent will not be obtained. Caregivers may withdraw from the study at any time without consequence.

All data will be stored with 2 levels of password protection. Paper consent documents will be maintained in a locked cabinet in a locked office on the Washington University School of Medicine campus. Digital data will be collected via REDCap and will be accessible only to members of the research team. Any identifying information will be coded so that it can only be linked to individual participants by the research team.

The risks associated with this study are no greater than those encountered during a routine clinical or therapy visit. Caregivers may experience mild stress or anxiety when discussing their child’s development. To mitigate this, all research team members will be trained in strategies for communicating sensitively about developmental concerns with caregivers. All research staff interacting with participants will also complete mandatory reporter training for child abuse and neglect. Caregivers will have the option to complete surveys verbally if preferred. Caregivers with concerning scores on the PROMIS Depression screener will be referred to behavioral health services.

This study will provide the first prospective characterization of developmental trajectories in children with SCD across the first 3 years of life, using a psychometrically robust assessment battery and a demographically matched comparison cohort. Despite evidence that developmental delays affect at least 50% of young children with SCD [6,26], the trajectory of these delays from infancy has not been rigorously evaluated, and no disease-specific intervention has been formally tested in this age group. The SCCCD intervention combines OT, the PAT curriculum, and SCD-specific caregiver education and is adapted from a pilot protocol with demonstrated feasibility and preliminary effectiveness in this population [20,26]. The findings from this study will establish preliminary evidence for the SCCCD as a structured, home-based approach to improving developmental outcomes in children with SCD and will generate the implementation science evidence needed to support broader scale-up.

Two protocol adaptations were made following IRB approval and are documented here in the interest of transparency. First, in response to caregiver feedback regarding barriers to on-site attendance, evaluations may now be conducted in the family’s home for participants residing within the Greater St. Louis Metro area. This adaptation reflects the access barriers that have historically limited participation of Black and African American families in research and clinical programs and is consistent with the home-based delivery model of the SCCCD intervention. Second, the SWYC [43] was added to the assessment battery following input from community advisory board members, who recommended its inclusion to capture additional environmental and contextual factors and to allow comparison with other commonly used developmental screening measures used in community settings.

Several limitations should be acknowledged. Recruitment is concentrated at a single site, which may limit the generalizability of the findings to SCD programs in other regions. The English-language-only inclusion criterion, necessary given the validation constraints of the assessment measures, excludes non-English-speaking families and limits the diversity of the sample. Aim 2 does not include a randomized comparison condition; developmental outcomes for children who receive the SCCCD intervention will be compared to the aim 1 observational cohort, which introduces the potential for selection bias. Some outcome measures rely on caregiver report, which may be subject to response bias. Finally, participants who do not complete all evaluation time points will be analyzed using available data, and attrition will be documented and reported.

Early identification of developmental delays in children with SCD remains inconsistent, and the window for intervention in the first 3 years of life is frequently missed [12,15]. This study directly addresses that gap by characterizing developmental trajectories from infancy, testing a home-based intervention designed for this population, and identifying the contextual factors that will inform future implementation. The results will be shared through community partners, peer-reviewed publications, and scientific meetings. The study design reflects a deliberate commitment to reducing structural barriers to participation for families, including home-based delivery, flexible scheduling, transportation support, and ongoing community advisory board engagement. The results will provide the foundation for a future randomized controlled trial of the SCCCD intervention and inform clinical recommendations for developmental screening and early intervention in SCD.