Medication Adherence in Pediatric Sickle Cell Disease and Hematopoietic Stem Cell Transplantation: An Integrative Review of Literature

Abstract

Background

With the emergence of haploidentical transplantation, children with sickle cell disease (SCD) are increasingly pursuing hematopoietic stem cell transplantation (HSCT) as a curative treatment approach. However, suboptimal medication adherence remains a persistent challenge in both SCD and HSCT populations. Adherence to complex medication regimens is crucial to reducing the risk of severe complications and early mortality, yet no synthesis has evaluated patterns of adherence among patients with SCD post-HSCT.

Method

We conducted an integrative review, searching PubMed, CINAHL, and PsycINFO from April 2025 to May 2025 for studies measuring medication adherence in children (≤21 years) with SCD and/or HSCT. Studies were included if they reported adherence rates and excluded if they involved adherence interventions or drug development trials.

Results

Eighteen studies met inclusion criteria: 12 addressed SCD and 6 focused on HSCT. No studies specifically examined adherence in patients with SCD post-HSCT. Adherence rates to disease-modifying medications in SCD ranged from 10% to 89%, while post-HSCT adherence ranged from 40% to 73%. Nonadherence was associated with increased complications across both populations.

Discussion

These findings highlight a critical research gap and provide a foundation for targeted adherence interventions. Addressing this gap is essential to advance nursing practice, improve adherence, and optimize clinical outcomes in pediatric hematology and HSCT care.

Keywords

sickle cell disease sickle cell anemia medication adherence hematopoietic stem cell transplantation integrative review

Introduction

Sickle cell disease (SCD) is the most common inherited blood disease in the United States, affecting approximately 100,000 individuals, with a homozygous frequency of 1 in every 300 births (Kavanagh et al., 2022). SCD is characterized by polymerization of hemoglobin S, resulting in stiff, sickle-shaped erythrocytes that obstruct microvascular flow, which causes acute and chronic pain and leads to progressive organ damage (Kavanagh et al., 2022; Piel et al., 2017). Affected individuals may experience significant complications, such as severe infection, acute chest pain, severe anemia, avascular necrosis, acute chest syndrome, stroke, and other organ damage (Boafor et al., 2016; Kavanagh et al., 2022; Piel et al., 2017). SCD is associated with decreased life expectancy, increased comorbidities, and decreased health-related quality of life (Lubeck et al., 2019; Osunkwo et al., 2021).

Disease-modifying therapies, such as penicillin prophylaxis and hydroxyurea, are essential to reduce disease burden and prevent complications in SCD. However, poor medication adherence is a significant challenge (Loiselle et al., 2016; Walsh et al., 2014). Among pediatric patients with chronic illnesses, it is estimated that 50% of medications are not taken as directed, with nonadherence rates as high as 75% in adolescents and young adults (Brown et al., 2016; McGrady & Hommel, 2013; Rapoff, 2010).

The World Health Organization (2003) defines adherence as “the extent to which a person's behavior—taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health care provider”. Nonadherence includes behaviors such as intermittently missing doses, overdosing, incorrect timing or frequency of administration, failure to initiate or refill a prescription, or premature discontinuation of therapy (Brown et al., 2016; Morrison et al., 2017). In pediatric and adolescent populations, the most critical determinant of nonadherence is the complexity and duration of treatment regimens (Belaiche et al., 2017; Coleman et al., 2012; Dew et al., 2018). Medication adherence is measured using a variety of methods, including self-report questionnaires, medication possession ratio (MPR), electronic medication adherence monitors, and drug assay levels. Each method has varying degrees of accuracy, which may influence adherence rates. Adherence thresholds may vary by study, but an adherence rate of 80% or higher is typically the benchmark for satisfactory adherence, particularly in chronic disease management (Anders et al., 2016; Kang & Barner, 2020; Subira et al., 2025).

Medication nonadherence is a major public health concern, contributing to an estimated 125,000 deaths and 25% of hospital admissions annually in the United States (Kini & Ho, 2018). The associated cost ranges from $100 to $500 billion annually, representing up to 16% of total U.S. health care expenditures (Iuga & McGuire, 2014; Kini & Ho, 2018; Neiman et al., 2018; Watanabe et al., 2018). Nonadherence is also associated with increased frequency of hospital admissions, increased length of hospitalization, higher readmission rates, and compromised quality of life (McGrady & Pai, 2019; Morrison et al., 2017).

The emergence of haploidentical donor transplantation has increased curative treatment options for SCD, resulting in more children pursuing hematopoietic stem cell transplantation (HSCT). However, individuals undergoing HSCT are also at increased risk of nonadherence due to the complex nature of therapy. Medication nonadherence posttransplant may lead to significant life-threatening complications such as graft-versus-host disease (GVHD), graft rejection, and systemic infections (Morrison et al., 2017; Pai et al., 2018). Individuals may also experience physical and emotional challenges due to transplant-related toxicities and debilitating GVHD that negatively impact quality of life (Nakamura et al., 2019). Many factors may contribute to nonadherence in the posttransplant setting, including the extensive nature of care, ongoing patient symptoms, and medication side effects (McGrady et al., 2014).

While medication adherence has been studied in pediatric SCD and HSCT recipients separately, no studies have examined adherence specifically in SCD patients post-HSCT. Therefore, the purpose of this integrative review was to synthesize current evidence on medication adherence rates among children and adolescents with SCD and/or those who have undergone HSCT. A secondary aim was to understand the effect of medication adherence on clinical outcomes and health care utilization to guide future research and inform clinical practice.

Method

Search Strategy

To conduct a comprehensive and effective integrative literature search, we systematically explored multiple electronic databases (Whittemore & Knafl, 2005). We selected PubMed for its extensive coverage of biomedical literature and CINAHL to uncover valuable nursing research related to medication adherence. We also used PsycINFO due to its comprehensive coverage of psychological research, which offers a significant role in understanding adherence literature. The literature search was conducted from April 2025 to May 2025. Search terms included “adherence,” “compliance,” “bone marrow transplant,” “hematopoietic stem cell transplant,” “stem cell transplant,” “sickle cell disease,” “sickle cell anemia,” “sickle cell disorders,” “hemoglobin SS disease,” “medication compliance,” “medication adherence,” “medication nonadherence,” “medication noncompliance,” “pediatric,” “child,” “adolescent,” “juvenile,” and “youth.” Limitations were the English language and human (not animal) subject research.

Inclusion criteria were (a) original research, (b) measurement of medication adherence, (c) participants undergoing treatment for SCD and/or HSCT, (d) participants ≤21 years old, and (e) publications in English. Exclusion criteria were (a) adherence not reported, (b) studies involving adherence interventions or drug development trials, (c) adherence measurement not related to medication use, (d) non-peer-reviewed reports or abstracts, and (e) systematic reviews or meta-analyses. Given that SCD is a prevalent global health concern, studies conducted outside the United States were included to provide a better understanding of adherence.

Clinical trials involving drug development require strict adherence protocols to accurately determine the efficacy and safety of new medications, and adherence-promoting interventions are often included within the study design. Therefore, drug development studies and other adherence intervention research were excluded, as they may overestimate adherence rates that do not accurately represent real-world behaviors.

Pediatric medication adherence research, specifically in SCD and HSCT, is limited. Therefore, to ensure a comprehensive understanding of adherence rates within this specialized area, all relevant reports published through May 2025 were included in the review. To be consistent with most pediatric medication adherence research, children and adolescents up to 21 years of age were included.

The PRISMA flow diagram (Fig. 1) illustrates the record selection process (Page et al., 2021). After removing duplicates, 183 records remained, and of those, 48 were screened in full-text review for eligibility. Among those, 20 articles evaluated adherence interventions and were excluded. An additional 11 reports were removed: 2 included participants older than 21 years, and 9 did not provide medication adherence rates. A hand search of the reference list revealed one seminal study from 1990. In total, 18 studies met inclusion criteria and were included in the final review.

Figure 1

PRISMA Flow Diagram

Results

Twelve out of the 18 studies focused on medication adherence of hydroxyurea and/or penicillin in children and adolescents with SCD (Table 1), while 6 examined adherence following HSCT (Table 2). No studies specifically examined medication adherence in patients with SCD undergoing HSCT.

Table 1

Adherence in Pediatric Sickle Cell Disease by Medication Type

Author (year)	Design type	Sample/setting	Patient age	Adherence measurement	Adherence or nonadherence incidence	Health/health care-related outcome
Hydroxyurea
Thornburg et al. (2010a)	Cross-sectional study	N = 75 Southeast United States	Mdn = 11.2 years, range = 3.5–17.8 years	Multimodal: clinic visits, self-report (Visual Analog Scale, Modified Morisky Scale), medical provider report, pharmacy refill data	49%–84% adherence rates	N/A
Anders et al. (2016)	Retrospective cohort study	N = 273 Northeast United States	Mdn = not reported, range = 5–8 years	Mean PDC and MPR of ≥80%	Approximately 30% adherence rate by PDC and MPR	N/A
Badawy et al. (2017a)	Cross-sectional study	N = 34 Midwest United States	Mdn = 13.5 years, range = 12–18 years	MCV, HbF biomarker, and MMAS-8 self-report	74% of patients reported low adherence on MMAS-8 that was supported by laboratory values	Poor adherence was associated with worse HRQOL, including worse fatigue, more severe pain, impaired mobility, social isolation, and depression
Badawy et al. (2018)	Cross-sectional study	N = 34 Midwest United States	Mdn = 13.5 years, range = 12–18 years	MCV, HbF biomarker, and MMAS-8 self-report	74% of patients reported low adherence on MMAS-8 that was supported by laboratory values	Poor adherence was associated with increased hospitalizations, ED visits, and longer LOS
Kang and Barner (2020)	Retrospective cohort study	N = 655 Southeast United States	Mdn = not reported, range = 2–18 years	MPR ≥80%	73% adherence rate for children (age 2–12 years ), 10% adherence rate for adolescents (13–18 years)	Children required fewer opioid prescriptions when compared to the adolescent cohort, 65% versus 84%. Adherent individuals across all child and adolescent age groups experienced decreased adverse outcomes compared to nonadherent individuals, including VOC (53% vs. 89%), AVN (5% vs. 15%), ACS (14% vs. 21%), and blood transfusion requirement (4% vs. 9%)
Reddy et al. (2022)	Retrospective chart review	N = 113 Midwest United States	Mdn = 14 years, range = 10–20 years	Laboratory values indicating adherence: median MCV ≥99.6, ANC ≤3.84 10³/ml, HbF ≥14.5%	Adolescents: median MCV 96.2, ANC 4.21 10³/ml, and HgF 12.4% Children: median MCV 95.4, ANC 4.93 10³/ml, and HgF 8.6%	Children and adolescents demonstrated overall low adherence, as indicated by laboratory data. Patients with higher HU adherence had decreased ED visits, hospitalizations, and shorter LOS when compared to those with lower adherence
Reeves et al. (2023)	Retrospective cohort study	N = 515 Southeast United States	Mdn = not reported, range = 1–17 years	MPR	53% median adherence rate	High levels of adherence (>75%) were required for a lower incidence of hospitalizations and ED visits. Even moderate adherence (>25%) was associated with decreased incidence of ACS
Subira et al. (2025)	Cross-sectional	N = 172 East Africa	Mdn = 8 years, range = 1–10 years	Caregiver responses from validated adherence questionnaire: good adherence: taking ≥80% of prescribed doses; moderate adherence: 50–79%; poor adherence: <50%	23.8% self-report good adherence; 76.2% report moderate-to-poor adherence	N/A
Oral antibiotic prophylaxis
Witherspoon and Drotar (2006)	Prospective cohort study	N = 64 Midwest United States	Mdn = not reported, range = 6 months–6 years	Average number of days between pharmacy refills, caregiver-reported, provider estimates	33% adherence rate per pharmacy refills, 57% per caregiver report, 50% per provider estimates	N/A
Patel et al. (2010)	Retrospective cohort study	N = 93 Midwest United States	Mdn = 7 years, range = 6 months–20 years	MPR	54.5% adherence rate	N/A
Bitaraes et al. (2008)	Prospective cohort study	N = 108 Southeast Brazil	Mdn = 2.1 years, range = 3 months–4.5 years	Medical record, urine assay, and standardized parent interview questionnaires	89% adherence rate per medical record, 6% per urine assay, 48% per parent report	N/A
Reeves et al. (2018)	Retrospective cohort study	N = 2821 Southeast United States	Mdn = 1.6 years, range = 3 months–5 years	≥300 days of antibiotic prescriptions per calendar year	18% of study patients adherent	N/A

Note. PDC = proportion of days covered; MPR = medication possession ratio; MCV = mean corpuscular volume; HbF = fetal hemoglobin; MMAS-8 = Modified Morisky Adherence Scale 8-items; HRQOL = health-realted quality of life; ED = emergency department; N/A = not applicable.

Table 2

Medication Adherence in Pediatric Stem Cell Transplantation

Author (year)	Design type	Sample and setting	Patient age	Transplant diagnosis	Adherence measurement	Adherence or nonadherence incidence	Health and health care-related outcome
Phipps and DeCuir-Whalley (1990)	Retrospective cohort study	N = 54 West Coast United States	Mdn = 9.1 years, range = 1 month–20 years	74% malignancy, 15% immune deficiency, 9% bone marrow failure, 2% other	Nursing diagnosis of nonadherence	52% nonadherence with oral antibiotics	N/A
McGrady et al. (2014)	Case study of a longitudinal prospective dataset	N = 6 Midwest United States	Mdn = 14 years, range = 12–16 years	Not specified	MEM with electronic pill cap monitors	Average adherence of 73% Notable decrease in adherence over time: 91% at 1 month, 80% at 3 months, <60% at 6 months posttransplant Children missed at least one dose of medication approximately 3 days per week	N/A
Belaiche et al. (2021)	Cross-sectional observational study	N = 39 France	Mdn = 9 years, range = 7.3–10.8 years	>50% malignancy	Self-reported questionnaire	25.6% reported good adherence, 71.8% reported moderate, and 2.5% reported poor Approximately 70% of patients take medications later than usual, and 13% report forgetting to take medications on some days	N/A
Skeens et al. (2020)	Retrospective descriptive study	N = 57 Midwest United States	Mdn = 8.5 years, range = 1 month–21 years	61% malignancy, 18% hemoglobinopathies, 9% metabolic disorder, 7% bone marrow failure, 5% immune deficiency	Tacrolimus levels, subjective reporting	Overall nontherapeutic drug-level rate was 60% Approximately 34% of patients had nontherapeutic levels 40% of the time	N/A
Pai et al. (2018)	Prospective, nonrandomized study	N = 50 Midwest United States	Mdn = 6.4 years, range = 0–16 years	32% immune deficiency, 30% malignancy, 32% bone marrow failure, 6% metabolic disease	MEM with electronic pill caps	Adherence rate of 63.2% at 1 month, 57.7% at 3 months, and 55.1% at 6 months following transplant discharge	Poor adherence to oral medication was associated with an increased risk of infection
Skeens et al. (2019)	Retrospective descriptive study	N = 64 Midwest United States	Mdn = 7 years, range = 1 month–21 years	64% malignancy, 16% hemoglobinopathies, 8% metabolic disorder, 6% bone marrow failure, 5% immune deficiency,	Tacrolimus MLVI	Median MLVI 2.68	Patients who developed GVHD had MLVI >3 (indicating nonadherence)

Note. MEM = mediation event monitoring; MLVI = tacrolimus medication level variability index; GVHD = graft-versus-host disease; N/A = not applicable.

Study Characteristics

Setting

Most studies (83%) were conducted in the United States. Two studies of medication adherence among children with SCD were conducted outside the United States. Subira et al. (2025) evaluated hydroxyurea adherence in East Africa, and Bitaraes et al. (2008) examined penicillin adherence in Brazil. One study on posttransplant adherence was conducted in France by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (Belaiche et al., 2021).

Sample

Sample size varied widely across studies. In the SCD studies, sample size ranged from 34 to 28,271 participants (Badawy et al., 2017a; Badawy et al., 2018; Reeves et al., 2018). Studies involving HSCT generally included smaller cohorts, ranging from six participants in McGrady et al. (2014) to 64 in Skeens et al. (2019). Both SCD and HSCT studies included participants across the pediatric and adolescent lifespan (1 month to 21 years old). Among the six HSCT studies, only two reported including patients with hemoglobinopathy as the transplant diagnosis; however, it is unclear whether these participants had a confirmed SCD diagnosis (Skeens et al., 2019; Skeens et al., 2020).

Design

In the SCD cohort, two studies employed prospective designs (Bitaraes et al., 2008; Witherspoon & Drotar, 2006). Similarly, within the HSCT cohort, Pai et al. (2018) conducted a prospective nonrandomized study, and McGrady et al. (2014) analyzed a longitudinal prospective dataset. The remaining studies across both cohorts used cross-sectional or retrospective designs.

Medication Adherence in SCD

Overall adherence rates to disease-modifying therapies varied significantly across studies, ranging from 10% to 89%. Variability was also observed across different methods of measuring adherence. Eight studies evaluated hydroxyurea adherence, with publication dates ranging from 2010 through 2025 (Anders et al., 2016; Badawy et al., 2017a; Kang & Barner, 2020; Reddy et al., 2022; Reeves et al., 2023; Subira et al., 2025; Thornburg et al., 2010a). Four studies examined adherence to antibiotic prophylaxis, the most recent of which was published in 2018 (Patel et al., 2010; Reeves et al., 2018; Witherspoon & Drotar, 2006). A range of adherence measurement approaches was reported across the studies and is summarized in Table 1 and described in more detail below.

Hydroxyurea Adherence Rates

Thornburg et al. (2010a) analyzed hydroxyurea adherence rates in 75 children ages 3.5 to 17.8 years using a multimodal assessment of adherence, including number of clinic visits (recommended versus actual), caregiver self-report (via the Modified Morisky Scale and a Visual Analog Scale [VAS]), provider report, and pharmacy refill data. Reported adherence rates ranged from 49% to 84% depending on measurement method. Only 49% of participants refilled a 30-day supply of medication five or more times in a 6-month period with 59% refilling four or more times. Despite this, relatively high levels of adherence were reported through VAS (82%), the Modified Morisky Score (84%), and medical provider estimate (85%). Adherence to scheduled hydroxyurea follow-up clinic visits was 77%.

Anders et al. (2016) evaluated Medicaid data in 273 children with SCD to measure adherence using MPRs and proportion of days covered (PDC) for the therapy period, spanning the first and last fill. The mean PDC in the first year was 56.3%, and only 30% met the ≥80% adherence threshold. More recently, Subira et al. (2025) evaluated 172 children, ages 1 to 10 years, with SCD in East Africa. Adherence was measured by caregiver questionnaire; approximately 24% reported good adherence (≥80% of doses), with 76% reporting moderate to poor adherence.

Hydroxyurea Adherence and Outcomes

Reeves et al. (2023) evaluated hydroxyurea adherence by MPR in children with SCD ages one to 17 years enrolled on Medicaid during 2005–2012. This multistate study included data from Florida, Illinois, Louisiana, Michigan, South Carolina, and Texas. Among the 2,474 children screened, 515 (18.7%) had initiated hydroxyurea therapy. High levels of adherence (>75%) were required for a lower incidence of hospitalizations and emergency department visits. Even moderate adherence (>25%) was associated with decreased incidence of acute chest syndrome (Reeves et al., 2023).

In an evaluation of Texas Medicaid claims from 2011 to 2016, Kang and Barner (2020) reported that children (age 2–12 years) were more adherent to hydroxyurea than adolescents (13–18 years), 73% and 10%, respectively. Children required fewer opioid prescriptions when compared to the adolescent cohort, 65% versus 84% (Kang & Barner, 2020). Adherent individuals across all child and adolescent age groups experienced decreased adverse outcomes than nonadherent individuals, including vaso-occlusive crisis (53% vs. 89%), avascular necrosis (5% vs. 15%), acute chest syndrome (14% vs. 21%), and blood transfusion requirement (4% vs. 9%; Kang & Barner, 2020).

Reddy et al. (2022) completed a 5-year retrospective chart review of 113 children and adolescents with SCD prescribed hydroxyurea therapy. Routine complete blood count and fetal hemoglobin laboratory results measured adherence. Adolescents and children demonstrated overall low levels of adherence. Individuals with higher fetal hemoglobin, higher mean corpuscular volume (MCV), and lower absolute neutrophil count (ANC) (indicating adherence) required fewer emergency department visits and hospitalizations, decreased length of stay, and decreased incidence of chronic pain (Reddy et al., 2022).

Among 34 adolescents with SCD (age 12–18), 75% reported low hydroxyurea adherence on Modified Morisky Adherence Scale 8-items (MMAS-8) self-report that was consistent with laboratory findings (Badawy et al., 2017a; Badawy et al., 2018). Poor adherence was associated with more frequent hospitalizations, emergency department visits, and longer length of stay (Badawy et al., 2018). Patients with increased health utilization also experienced worse fatigue, more severe pain, impaired mobility, and social isolation (Badawy et al., 2018). Poor adherence was also associated with worse health-related quality of life, including worse fatigue, more severe pain, impaired mobility, social isolation, and depression (Badawy et al., 2017a).

Antibiotic Prophylaxis Adherence Rates

In a large study by Reeves et al. (2018) including 2,821 young children (3 months–5 years) with SCD across multiple states, only 18% had >300 days of filled antibiotic pneumococcal prophylaxis. Witherspoon and Drotar (2006) conducted a prospective study involving 64 children with SCD aged 6 months to 6 years. The researchers examined adherence to penicillin using various measurement methods and found the following rates: 57% based on caregiver reports, 50% based on clinical evaluations, and only 33% according to prescription refill monitoring. In a prospective trial including 108 children under 5 years old, Bitaraes et al. (2008) also identified discrepancies in antibiotic adherence across different measurements, with reported adherence rates of 89% from medical record reviews, 56% from urine tests, and 48% per parent reports. Patel et al. (2010) evaluated adherence to a variety of maintenance medications in 93 children and adolescents (≤18 years) with SCD. Among the children who were prescribed penicillin prophylaxis, 55% (n = 62) were considered adherent by demonstrating a MPR ≥75% (Patel et al., 2010). None of the studies included in the review evaluated the effect of antibiotic prophylaxis on health or health care outcomes.

Medication Adherence in Pediatric HSCT

Medication adherence in children and adolescents following HSCT was poor, with reported rates of 40% to 73% (McGrady et al., 2014; Pai et al., 2018; Phipps & DeCuir-Whalley, 1990; Skeens et al., 2020). McGrady et al. (2014) reported on medication adherence among six children (ages 12–18 years) post-HSCT. Data was obtained from a larger, prospective study that examined adherence using medication event monitoring with electronic pill cap monitors. Data from pill bottles were downloaded at four time points (1, 3, 6, and 9 months) following transplant discharge. Researchers found adherence rates to be relatively stable at 91% in the first month following transplant hospital discharge; however, the trend decreased over time to less than 60% at 6 months postdischarge. Participants also missed at least one dose of medication on an average of 3 days per week (McGrady et al., 2014).

A cross-sectional, multicenter study that included 39 children (7.3–10.8 years), examined medication adherence 3–6 months post-HSCT (Bealaiche et al., 2021). Although the study included both adult and pediatric participants, pediatric data was analyzed and reported separately and was therefore included in this review. Caregivers and/or patients completed a self-reported questionnaire for adherence measurement. Medication adherence was estimated as good in 25.6%, moderate in 71.8%, and poor in 2.5% of patients. Approximately 70% of patients reported taking medication later than usual, and 13% reported not taking medications at all on some days.

In a seminal study by Phipps and DeCuir-Whalley (1990), nonadherence was determined by nursing documentation in a retrospective chart review. Among the 54 children (1 month–20 years) included in the study, 52% were reported as nonadherent with oral antibiotics. Investigators also found the highest incidence of nonadherence in children 2–12 years of age (Phipps & DeCuir-Whalley, 1990). However, additional research by Skeens et al. (2020) reported nontherapeutic immunosuppression levels, indicating nonadherence, most frequently occurring in children 1–5 years old. The retrospective study included 57 children aged 1 month to 21 years. The overall nontherapeutic drug level rate was 60%, and approximately 34% patients had nontherapeutic levels 40% of the time (Skeens et al., 2020).

Only two of the six HSCT studies examined the effect of medication adherence on health outcomes which included the incidence of infection and GVHD (Pai et al., 2018; Skeens et al., 2019). Skeens et al. (2019) used tacrolimus medication level variability index (MLVI) to assess the development of GVHD and hospital readmission. The retrospective study included 64 patients (1 month–21 years) post-HSCT. Patients with elevated MLVI, representing subtherapeutic immune suppression, had a greater incidence of GVHD than those with lower levels (p = .024).

In a prospective nonrandomized study by Pai et al. (2018), including 50 transplant recipients (0–16 years), adherence was measured by electronic cap monitoring. Investigators reported adherence rates of 63.2% at 1 month, 57.7% at 3 months, and 55.1% at 6 months following transplant discharge. Although researchers did not find a relation between adherence and GVHD post-allogeneic HSCT, there was an increased incidence of infection (p = .005) in patients who demonstrated nonadherence (Pai et al., 2018), with the most common documented infection across all time points being gram-positive cocci.

Discussion

This integrative review aimed to comprehensively identify and summarize existing research on medication adherence among pediatric patients with SCD and those undergoing HSCT. Across published literature, suboptimal medication adherence emerged as a persistent and significant challenge in both populations. The overall rates of adherence to medications ranged from 10% to 89% for SCD patients and 40% to 73% for HSCT recipients. Notably, there were no published studies that focused specifically on medication adherence in children with SCD post-HSCT.

Researchers employed various methods to measure adherence, including caregiver self-reports, provider reports, pill counts, electronic monitoring devices, pharmacy refill data, and monitoring of drug assay levels. Adherence rates tended to be higher when measured via self-report, but lower with objective measures such as pharmacy refill or drug assay data (Thornburg et al., 2010a; Witherspoon & Drotar, 2006). This finding is consistent with broader adherence literature, suggesting that both patient and provider reports often overestimate adherence rates (Walsh et al., 2014). This underscores the importance of using objective measures in conjunction with self-reports in adherence research and clinical practice (Shah et al., 2023). Furthermore, the lack of standardized measurement approaches for adherence creates challenges when comparing findings across studies and limits the generalizability of results.

Hydroxyurea has been shown to be effective in reducing the frequency of pain crises, acute chest syndrome, hospitalizations, and the need for red blood cell transfusions (Wang et al., 2011). Adherence rates for hydroxyurea during the landmark clinical trials assessing its efficacy ranged from 74% to 95% (Kinney et al., 1999; Thornburg et al., 2010b; Wang et al., 2011). However, this review found that after the U.S. Food and Drug Administration approved hydroxyurea for use in children, adherence rates dropped significantly, falling as low as 34% to 67% (Alvarez et al., 2009; Anders et al., 2016; Creary et al., 2019). The effectiveness of hydroxyurea in preventing complications associated with SCD may be diminished in real-world applications due to issues with nonadherence (Walsh et al., 2014).

Children with homozygous SCD are at increased risk of developing invasive pneumococcal disease caused by Streptococcus pneumoniae bacteria. This condition is serious and potentially life-threatening, as it can progress rapidly and may lead to death if not treated promptly (Yawn et al., 2014). Children who receive daily penicillin are 84% less likely to develop an infection than those without prophylaxis (Gaston et al., 1986). Experts recommend that children with SCD receive penicillin prophylaxis medication from infancy through the age of 5 (Yawn et al., 2014). Despite over three decades of education and support for antibiotic prophylaxis, our review found adherence rates as low as 18% (Reeves et al., 2018).

The primary concern for nonadherence in SCD and HSCT is the risk of adverse patient outcomes (Visintini et al., 2023). In this review, medication adherence had significant clinical implications across both populations. Increased adherence to hydroxyurea was associated with a reduction in hospitalization, emergency department visits, and length of stay (Badawy et al., 2018; Reddy et al., 2022; Reeves et al., 2023). Higher levels of adherence were also associated with decreased incidence of adverse health outcomes, including acute chest syndrome, vaso-occlusive crises and avascular necrosis (Kang & Barner, 2020; Reeves et al., 2023). Conversely, poor adherence was correlated with worse health-related quality of life (HRQOL), leading to more severe pain, fatigue, social isolation, and depression (Badawy et al., 2017a).

In the context of HSCT, children and adolescents who demonstrated nonadherence were shown to have a greater incidence of systemic infection and acute GVHD (Pai et al., 2018; Skeens et al., 2019). When individuals with SCD undergo HSCT, they are introduced to additional medications, potential risks, and treatment-related side effects (Kassim & Sharma, 2017). Strict adherence to complex oral medication regimens is necessary to prevent transplant-related complications and optimize outcomes (Morrison et al., 2017; Pai et al., 2018; Visintini et al., 2023). Increasing the complexity of care may cause an even greater risk of medication nonadherence and worse health-related outcomes.

Our review is subject to several important limitations that must be acknowledged. Firstly, we only included studies published in peer-reviewed journals, which may inadvertently exclude valuable research findings from gray literature, conference abstracts, or unpublished studies. Consequently, there may be additional investigations evaluating medication adherence in pediatric SCD and HSCT that we did not consider. Secondly, this review focused only on understanding medication adherence rates. We did not systematically explore the potential barriers and facilitators that impact medication adherence in SCD and HSCT. Several studies have attempted to address barriers to adherence in these patient populations (Chardon et al., 2022; Chardon et al., 2023; Hoegy et al., 2019; King et al., 2023; Badawy et al., 2017b; Curtis et al., 2019). By not addressing these critical factors, we miss the opportunity to provide an understanding of the unique challenges that influence adherence (Adams-Graves & Bronte-Jordan, 2016). Furthermore, we did not evaluate specific interventions designed to enhance medication adherence, which could offer insights into effective strategies and practices. Additionally, the small sample size of the included studies may limit the generalizability and robustness of our findings.

Overall, while our review contributes to the existing literature, further research exploring both the complexities of adherence and the effectiveness of targeted interventions is needed. SCD is distinct from other chronic illnesses due to its significant impact throughout an individual's life, the stigma associated with the disease, and the existing health care disparities (Hodges et al., 2020). Future research on medication adherence in children with SCD undergoing transplant is crucial to providing clinicians with the necessary resources to identify patients at risk for nonadherence and implement strategies to enhance adherence in real-world settings.

Summary

This integrative literature review indicates that children with SCD are at significant risk for medication nonadherence. Adherence to disease-modifying medications is crucial in improving health outcomes and reducing disease-related complications. Similarly, children who undergo HSCT also show nonadherence with immunosuppressive and antimicrobial medications in the acute posttransplant phase. Nonadherence can negatively impact health by increasing the risk of GVHD, infection incidence, and other transplant-related complications. As alternative donor transplantation becomes more accessible for patients with SCD, it is imperative to thoroughly examine medication adherence in this patient population.

Investigating medication adherence is important to provide clinicians with resources to identify patients at risk for nonadherence, recognize potential barriers and facilitators, and implement strategies to improve adherence in real-world applications. Understanding the reasons behind nonadherence, such as socioeconomic factors, psychological barriers, and medication regimen complexity, will enable health care providers to develop targeted interventions for sustained behavior change. By addressing these issues, we can improve adherence rates, enhance patient outcomes, and ultimately provide better quality of care for children with SCD undergoing transplantation.

Footnotes

ORCID iDs

Misty Evans

Micah Skeens

Lisa C. Lindley

Ethical Considerations

Ethical approval was not required for this integrative review.

Author Contributions

Misty Evans contributed to the conception of the review, performed a systematic review, prepared the first draft, and incorporated revisions. Samereh Abdoli, Micah Skeens, and Dominique Bulgin critically reviewed the manuscript. Lisa C. Lindley contributed to supervision and also critically reviewed the manuscript.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Misty Evans has a consulting relationship with Vertex Pharmaceuticals, Jazz Pharmaceuticals, and Alexion Pharmaceuticals. This relationship did not influence the research, preparation, or content of this manuscript.

References

Adams-Graves

Bronte-Jordan

(2016). Recent treatment guidelines for managing adult patients with sickle cell disease: Challenges in access to care, social issues, and adherence. Expert Review of Hematology, 9(6), 541–552. https://doi.org/10.1080/17474086.2016.1180242

Alvarez

Rodriguez-Cortes

Robinson

Lewis

Sang

C. D. P.

Lopez-Mitnik

Paley

(2009). Adherence to 151 deferasirox in children and adolescents with sickle cell disease during 1-year of therapy. Journal of Pediatric Hematology/Oncology, 31(10), 739–744. https://doi.org/10.1097/MPH.0b013e3181b53363

Anders

D. G.

Tang

Ledneva

Caggana

Green

N. S.

Wang

Sturman

L. S.

(2016). Hydroxyurea use in young children with sickle cell anemia in New York state. American Journal of Preventive Medicine, 51(1 Suppl 1), S31–S38. https://doi.org/10.1016/j.amepre.2016.01.001

Badawy

S. M.

Thompson

A. A.

Holl

J. L.

Penedo

F. J.

Liem

R. I.

(2018). Healthcare utilization and hydroxyurea adherence in youth with sickle cell disease. Pediatric Hematology and Oncology, 35(5–6), 297–308. https://doi.org/10.1080/08880018.2018.1505988

Badawy

S. M.

Thompson

A. A.

Lai

J. S.

Penedo

F. J.

Rychlik

Liem

R. I.

(2017a). Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease. Pediatric Blood & Cancer, 64(6), Article e26369. https://doi.org/10.1002/pbc.26369

Badawy

S. M.

Thompson

A. A.

Penedo

F. J.

Lai

J. S.

Rychlik

Liem

R. I.

(2017b). Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease. European Journal of Haematology, 98(6), 608–614. https://doi.org/10.1111/ejh.12878

Belaiche

Décaudin

Caron

Depas

Vignaux

Vigouroux

Coiteux

Magro

Sirvent

Hu Ynh

Turlure

Farge

Lioure

Bruno

De Berranger

Maillard

Bourhis

J. H.

Bay

J. O.

Bulabois

C. E.

… Yakoub-Agha

(2021). Medication non-adherence after allogeneic hematopoietic cell transplantation in adult and pediatric re cipients: A cross sectional study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy. Fundamental and Clinical Pharmacology, 35(2), 435–445. https://doi.org/10.1111/FCP.12593

Belaiche

Décaudin

Dharancy

Noel

Odou

Hazzan

(2017). Factors relevant to medication non-adherence in kidney transplant: A systematic review. International Journal of Clinical Pharmacy, 39(3), 582–593. https://doi.org/10.1007/s11096-017-0436-4

Bitaraes

E. L.

Oliveira

B. M.

Viana

M. B.

(2008). Compliance with antibiotic prophylaxis in children with sickle cell anemia: A prospective study. Journal de Pediatria, 84(4), 316–322. https://doi.org/10.2223/JPED.1819

10.

Boafor

T. K.

Olayemi

Galadanci

Hayfron-Benjamin

Dei-Adomakoh

Segbefia

Kassim

A. A.

Aliyu

M. H.

Galadanci

Tuuli

M. G.

Rodeghier

DeBaun

M. R.

Oppong

S. A.

(2016). Pregnancy outcomes in women with sickle-cell disease in low and high income countries: A systematic review and meta-analysis. BJOG: An International Journal of Obstetrics and Gynaecology, 123(5), 691–698. https://doi.10.1111/1471-0528.13786

11.

Brown

M. T.

Bussell

Dutta

Davis

Strong

Mathew

(2016). Medication adherence: Truth and consequences. The American Journal of the Medical Sciences, 351(4), 387–399. https://doi.org/10.1016/j.amjms.2016.01.010

12.

Chardon

M. L.

Klages

K. L.

Joffe

N. E.

Pai

A. L. H.

(2022). Caregivers’ experience of medication adherence barriers during pediatric hematopoietic stem cell transplant: A qualitative study. Journal of Pediatric Psychology, 47(6), 685–695. https://doi.org/10.1093/jpepsy/jsab138

13.

Chardon

M. L.

Klages

K. L.

Joffe

N. E.

Pai

A. L. H.

(2023). Recommendations for providing medication adherence support after pediatric hematopoietic stem cell transplant: Caregivers’ lived experience. Journal of Pediatric Hematology/Oncology Nursing, 40(1), 5–16. https://doi.org/10.1177/27527530221121723

14.

Coleman

C. I.

Limone

Sobieraj

D. M.

Lee

Roberts

M. S.

Kaur

Alam

(2012). Dosing frequency and medication adherence in chronic disease. Journal of Managed Care Pharmacy: JMCP, 18(7), 527–539. https://doi.org/10.18553/jmcp.2012.18.7.527

15.

Creary

Chisolm

Stanek

Hankins

O'Brien

S. H.

(2019). A multidimensional electronic hydroxyurea adherence intervention for children with sickle cell disease: Single-arm before-after study. JMIR mHealth and uHealth, 7(8), e13452. https://doi.org/10.2196/13452

16.

Curtis

Lebedev

Aguirre

Lobitz

(2019). A medication adherence app for children with sickle cell disease: Qualitative study. JMIR mHealth and uHealth, 7(6), e8130. https://doi.org/10.2196/mhealth.8130

17.

Dew

M. A.

Posluszny

D. M.

DiMartini

A. F.

Myaskovsky

Steel

J. L.

DeVito Dabbs

A. J.

(2018). Posttransplant medical adherence: What have we learned and can we do better? Current Transplantation Reports, 5(2), 174–188. https://doi.org/10.1007/s40472-018-0195-8

18.

Gaston

M. H.

Verter

J. I.

Woods

Pegelow

Kelleher

Presbury

Zarkowsky

Vichinsky

Iyer

Lobel

J. S.

(1986). Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. The New England Journal of Medicine, 314(25), 1593–1599. https://doi.org/10.1056/NEJM198606193142501

19.

Hodges

J. R.

Phillips

S. M.

Norell

Nwosu

Khan

Luo

Badawy

S. M.

King

Tanabe

Treadwell

Rojas Smith

Calhoun

Hankins

J. S.

Porter

(2020). Intentional and unintentional nonadherence to hydroxyurea among people with sickle cell disease: A qualitative study. Blood Advances, 4(18), 4463–4473. https://doi.org/10.1182/bloodadvances.2020001701

20.

Hoegy

Bleyzac

Rochet

De Freminville

Renard

Kebaili

Bertrand

Dussart

Janoly-Dumenil

(2019). Medication adherence after pediatric allogeneic stem cell transplantation: Barriers and facilitators. European Journal of Oncology Nursing, 38, 1–7. https://doi.org/10.1016/j.ejon.2018.11.006

21.

Iuga

A. O.

McGuire

M. J.

(2014). Adherence and health care costs. Risk Management and Healthcare Policy, 7, 35–44. https://doi.org/10.2147/RMHP.S19801

22.

Kang

H. A.

Barner

J. C.

(2020). The association between hydroxyurea adherence and opioid utilization among Texas medicaid enrollees with sickle cell disease. Journal of Managed Care & Specialty Pharmacy, 26(11), 1412–1422. https://doi.org/10.18553/jmcp.2020.26.11.1412

23.

Kassim

A. A.

Sharma

(2017). Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape. Hematology/Oncology and Stem Cell Therapy, 10(4), 259–266. https://doi.org/10.1016/j.hemonc.2017.05.008

24.

Kavanagh

P. L.

Fasipe

T. A.

Wun

(2022). Sickle cell disease: A review. JAMA, 328(1), 57–68. https://doi.org/10.1001/jama.2022.10233

25.

King

Cai

Barrera

Reddy

Heneghan

M. B.

Badawy

S. M.

(2023). Barriers to medication adherence in sickle cell disease: A comprehensive theory-based evaluation using the COM-B model. Pediatric Blood & Cancer, 70(9), Article e30440. https://https://doi.org/10.1002/pbc.30440

26.

Kini

P. M.

(2018). Interventions to improve medication adherence: A review. JAMA, 320(23), 2461–2473. https://doi.org/10.1001/jama.2018.19271

27.

Kinney

T. R.

Helms

R. W.

O'Branski

E. E.

Ohene-Frempong

Wang

Daeschner

Vichinsky

Redding-Lallinger

Gee

Platt

O. S.

Ware

R. E.

(1999). Safety of hydroxyurea in children with sickle cell anemia: Results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood, 94(5), 1550–1554. https://doi.org/10.1182/blood.V94.5.1550

28.

Loiselle

Lee

J. L.

Szulczewski

Drake

Crosby

L. E.

Pai

A. L.

(2016). Systematic and meta-analytic review: Medication adherence among pediatric patients with sickle cell disease. Journal of Pediatric Psychology, 41(4), 406–418. https://doi.org/10.1093/jpepsy/jsv084

29.

Lubeck

Agodoa

Bhakta

Danese

Pappu

Howard

Gleeson

Halperin

Lanzkron

(2019). Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Network Open, 2(11), e1915374. https://doi.org/10.1001/jamanetworkopen.2019.15374

30.

McGrady

M. E.

Hommel

K. A.

(2013). Medication adherence and health care utilization in pediatric chronic illness: A systematic review. Pediatrics, 132(4), 730–740. https://doi.org/10.1542/peds.2013-1451

31.

McGrady

M. E.

Pai

(2019). A systematic review of rates, outcomes, and predictors of medication non-adherence among adolescents and young adults with cancer. Journal of Adolescent and Young Adult Oncology, 8(5), 485–494. https://doi.org/10.1089/jayao.2018.0160

32.

McGrady

M. E.

Williams

S. N.

Davies

S. M.

Pai

A. L.

(2014). Adherence to outpatient oral medication regimens in adolescent hematopoietic stem cell transplant recipients. European Journal of Oncology Nursing, 18(2), 140–144. https://doi.org/10.1016/j.ejon.2013.11.007

33.

Morrison

C. F.

Martsolf

D. M.

Wehrkamp

Tehan

Pai

(2017). Medication adherence in hematopoietic stem cell transplantation: A review of the literature. Biology of Blood and Marrow Transplantation, 23(4), 562–568. https://doi.org/10.1016/j.bbmt.2017.01.008

34.

Nakamura

Z. M.

Nash

R. P.

Quillen

L. J.

Richardson

D. R.

McCall

R. C.

Park

E. M.

(2019). Psychiatric care in hematopoietic stem cell transplantation. Psychosomatics, 60(3), 227–237. https://doi.org/10.1016/j.psym.2019.01.005

35.

Neiman

A. B.

Ruppar

Garber

Weidle

P. J.

Hong

George

M. G.

Thorpe

P. G.

(2018). CDC Grand rounds: Improving medication adherence for chronic disease management—innovations and opportunities. American Journal of Transplantation, 18(2), 514–517. https://doi.org/10.1111/ajt.14649

36.

Osunkwo

Andemariam

Minniti

C. P.

Inusa

B. P. D.

El Rassi

Francis-Gibson

Nero

Trimnell

Abboud

M. R.

Arlet

J. B.

Colombatti

de Montalembert

Jain

Jastaniah

Nur

Pita

DeBonnett

Ramscar

Bailey

James

(2021). Impact of sickle cell disease on patients’ daily lives, symptoms reported, and disease management strategies: Results from the international sickle cell world assessment survey (SWAY). American Journal of Hematology, 96(4), 404–417. https://doi.org/10.1002/ajh.26063

37.

Page

M. J.

McKenzie

J. E.

Bossuyt

P. M.

Boutron

Hoffmann

T. C.

Mulrow

C. D.

Shamseer

Tetzlaff

J. M.

Akl

E. A.

Brennan

S. E.

Chou

Glanville

Grimshaw

J. M.

Hróbjartsson

Lalu

M. M.

Loder

E. W.

Mayo-Wilson

McDonald

Moher

(2021). The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ (Clinical Research ed.), 372, Article n71. https://doi-org.proxy.library.vanderbilt.edu/10.1136/bmj.n71

38.

Pai

A. L. H.

Rausch

Drake

Morrison

C. F.

Lee

J. L.

Nelson

Tackett

Berger

Szulczewski

Mara

Davies

(2018). Poor adherence is associated with more infections after pediatric hematopoietic stem cell transplant. Biology of Blood and Marrow Transplantation, 24(2), 381–385. https://doi.org/10.1016/j.bbmt.2017.10.033

39.

Patel

N. G.

Lindsey

Strunk

R. C.

DeBaun

M. R.

(2010). Prevalence of daily medication adherence among children with sickle cell disease: A 1-year retrospective cohort analysis. Pediatric Blood & Cancer, 55(3), 554–556. https://doi.org/10.1002/pbc.22605

40.

Phipps

DeCuir-Whalley

(1990). Adherence issues in pediatric bone marrow transplantation. Journal of Pediatric Psychology, 15(4), 459–475. https://doi.org/10.1093/jpepsy/15.4.459

41.

Piel

F. B.

Steinberg

M. H.

Rees

D. C.

(2017). Sickle cell disease. The New England Journal of Medicine, 376(16), 1561–1573. https://doi.org/10.1056/NEJMra1510865

42.

Rapoff

M. A.

(2010). Adherence to pediatric medical regimens (2nd ed.). Springer.

43.

Reddy

P. S.

Cai

S. W.

Barrera

King

Badawy

S. M.

(2022). Higher hydroxyurea adherence among young adults with sickle cell disease compared to children and adolescents. Annals of Medicine, 54(1), 683–693. https://doi.org/10.1080/07853890.2022.2044509

44.

Reeves

S. L.

Dombkowski

K. J.

Peng

H. K.

Phan

Kolenic

Creary

S. E.

Madden

Lisabeth

L. D.

(2023). Adherence to hydroxyurea and clinical outcomes among children with sickle cell anemia. Pediatric Blood & Cancer, 70(7), Article e30332. https://doi.org/10.1002/pbc.30332

45.

Reeves

S. L.

Tribble

A. C.

Madden

Freed

G. L.

Dombkowski

K. J.

(2018). Antibiotic prophylaxis for children with sickle cell anemia. Pediatrics, 141(3), Article e20172182. https://doi.org/10.1542/peds.2017-2182

46.

Shah

K. K.

Touchette

D. R.

Marrs

J. C.

(2023). Research and scholarly methods: Measuring medication adherence. Journal of the American College of Clinical Pharmacy, 6(4), 416–426. https://doi.org/10.1002/jac5.1771

47.

Skeens

M. A.

Dietrich

M. S.

Ryan-Wenger

Gilmer

M. J.

Mulvaney

S. A.

Akard

T. F.

(2019). The medication level variability Index (MLVI) as a potential predictive biomarker of graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Pediatric Transplant, 23(5), Article e13451. https://doi.org/10.1111/petr.13451

48.

Skeens

M. A.

Dietrich

M. S.

Ryan-Wenger

Gilmer

M. J.

Mulvaney

S. A.

Foster Akard

(2020). Transplantation and adherence: Evaluating tacrolimus usage in pediatric patients with cancer. Clinical Journal of Oncology Nursing, 24(5), E57–E64. https://doi.org/10.1188/20.CJON.E57-E64

49.

Subira

M. I.

Sr Ambrose

E. E.

Konje

(2025). Adherence to hydroxyurea therapy for pediatric sickle cell anemia in Tanzania: Evidence from Bugando Medical Centre. International Journal of Environmental Research and Public Health, 22(4), Article 616. https://doi.org/10.3390/ijerph22040616

50.

Thornburg

C. D.

Calatroni

Telen

Kemper

A. R.

(2010a). Adherence to hydroxyurea therapy in children with sickle cell anemia. The Journal of Pediatrics, 156(3), 415–419. https://doi.org/10.1016/j.jpeds.2009.09.044

51.

Thornburg

C. D.

Rogers

Z. R.

Jeng

M. R.

Rana

S. R.

Iyer

R. V.

Faughnan

Rees

R. C.

(2010b). Adherence to study medication and visits: Data from the BABY HUG trial. Pediatric Blood & Cancer, 54(2), 260–264. https://doi.org/10.1002/pbc.22324

52.

Visintini

Mansutti

Palese

(2023). Medication adherence among allogeneic haematopoietic stem cell transplant recipients: A systematic review. Cancers, 15(9), Article 2452. https://doi.org/10.3390/cancers15092452

53.

Walsh

K. E.

Cutrona

S. L.

Kavanagh

P. L.

Crosby

L. E.

Malone

Lobner

Bundy

D. G.

(2014). Medication adherence among pediatric patients with sickle cell disease: A systematic review. Pediatrics, 134(6), 1175–1183. https://doi.org/10.1542/peds.2014-0177

54.

Wang

W. C.

Ware

R. E.

Miller

S. T.

Iyer

R. V.

Casella

J. F.

Minniti

C. P.

Kalpatthi

R. V.

(2011). A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia. Lancet, 377(9778), Article 1663. https://doi.org/10.1016/S0140-6736(11)60355-3

55.

Watanabe

J. H.

McInnis

Hirsch

J. D.

(2018). Cost of prescription drug-related morbidity and mortality. The Annals of Pharmacotherapy, 52(9), 829–837. https://doi.org/10.1177/1060028018765159

56.

Whittemore

Knafl

(2005). The integrative review: Updated methodology. Journal of Advanced Nursing, 52(5), 546–553. https://doi.org/10.1111/j.1365-2648.2005.03621.x

57.

Witherspoon

Drotar

(2006). Correlates of adherence to prophylactic penicillin therapy in children with sickle cell disease. Children's Health Care, 35(4), 281–296. https://doi.org/10.1207/s15326888chc3504_1

58.

World Health Organization. (2003). Adherence to long-term therapies: Evidence for action. World Health Organization.

59.

Yawn

B. P.

Buchanan

G. R.

Afenyi-Annan

A. N.

Ballas

S. K.

Hassell

K. L.

James

A. H.

Jordan

Lanzkron

S. M.

Lottenberg

Savage

W. J.

Tanabe

P. J.

Ware

R. E.

Murad

M. H.

Goldsmith

J. C.

Ortiz

Fulwood

Horton

John-Sowah

(2014). Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA, 312(10), 1033–1048. https://doi.org/10.1001/jama