PLoS ONE plos plosone PLOS ONE 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0291008 PONE-D-22-34542 Research Article Medicine and health sciencesHealth careCaregivers Medicine and health sciencesComplementary and alternative medicineHerbal medicine Medicine and health sciencesMedical conditionsGenetic diseasesAutosomal recessive diseasesSickle cell disease Medicine and health sciencesClinical geneticsGenetic diseasesAutosomal recessive diseasesSickle cell disease Medicine and health sciencesHematologyHemoglobinopathiesSickle cell disease Medicine and health sciencesPediatricsChild health Medicine and health sciencesPublic and occupational healthChild health Biology and life sciencesPsychologyPsychological attitudes Social sciencesPsychologyPsychological attitudes Biology and life sciencesNeuroscienceCognitive scienceCognitive psychologyDecision making Biology and life sciencesPsychologyCognitive psychologyDecision making Social sciencesPsychologyCognitive psychologyDecision making Biology and life sciencesNeuroscienceCognitive scienceCognitionDecision making People and placesPopulation groupingsAge groupsChildren People and placesPopulation groupingsFamiliesChildren Biology and life sciencesPsychologyBehaviorAnimal behavior Social sciencesPsychologyBehaviorAnimal behavior Biology and life sciencesZoologyAnimal behavior Caregivers’ use of herbal and conventional medicine to treat children with sickle cell disease at Jinja Regional Referral Hospital, Eastern Uganda: A cross-sectional study Caregivers’ use of herbal and conventional medicine to treat children with sickle cell disease https://orcid.org/0000-0001-8180-6134 Apolot Consiliate Conceptualization Data curation Formal analysis Investigation Methodology Project administration Resources Software Supervision Validation Visualization Writing – original draft Writing – review & editing 1 * Obakiro Samuel Baker Formal analysis Supervision Writing – review & editing 2 3 Mukunya David Formal analysis Supervision Writing – review & editing 1 Olupot-Olupot Peter Formal analysis Supervision Writing – review & editing 1 4 Matovu Joseph K. B. Conceptualization Formal analysis Supervision Validation Writing – review & editing 1 5 Department of Community and Public Health, Busitema University Faculty of Health Sciences, Mbale, Uganda Department of Pharmacology and Therapeutics, Busitema University Faculty of Health Sciences, Mbale, Uganda Natural Products Research and Innovation Centre, Busitema University Faculty of Health Sciences, Mbale, Uganda Mbale Clinical Research Institute, Mbale, Uganda Department of Disease Control and Environmental Health, Makerere University School of Public Health, Kampala, Uganda Mubuuke Aloysius Gonzaga Editor Makere University College of Health Sciences, UGANDA

The authors have declared that no competing interests exist.

 * E-mail: consiliate511@gmail.com 8 9 2023 2023 18 9 e0291008 17 12 2022 21 8 2023 2023 Apolot et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

Evidence suggests use of herbal and conventional medicines in the treatment of Sickle Cell Disease (SCD). We examined factors associated with caregivers’ use of combined herbal and conventional medicine to treat children with SCD.

 Methods

A cross-sectional study was conducted at Jinja Regional Referral Hospital between January and March 2022. Caregivers of children with SCD aged 1 to 18 years attending the Sickle Cell Clinic were interviewed using structured questionnaires. We collected data on caregivers’ socio-demographic characteristics, perceptions of and intentions to use either or both therapies, self-reported use of either or both therapies and community and health-related factors. A multivariable logistic regression model was computed to assess the factors independently associated with caregivers’ use of combined therapy, using Stata version 15.0.

 Results

372 caregivers were interviewed. On average, respondents were aged 34.3 years (Standard Deviation [SD]: ±9.8 years). 37% (n = 138) of the caregivers reported the use of both herbal and conventional medicine, 58.3% (n = 217) reported use of only conventional medicine, while 4.6% (n = 17) reported use of herbal medicine only. Higher odds of using combination therapy were found in caregivers aged 60+ years (adjusted odds ratio [AOR] = 11.8; 95% CI: 1.2, 115.2), those with lower secondary education (AOR = 6.2; 95% CI: 1.5, 26.0), those who believed in the safety of herbal medicine (AOR = 3.3; 95% CI: 1.5, 7.6) and those who thought that use of both therapies were safe (AOR = 7.7; 95% CI: 3.5, 17.0).

 Conclusion

More than one-third of the caregivers reported use of combined herbal and conventional medicine, most of whom were older (>60%) and had lower secondary education. There is need for targeted health promotion to educate caregivers about the dangers of using both herbal and conventional medicines in treating children with SCD.

 The authors received no specific funding for this work. Data Availability All the data are within the data and its supporting information files. Introduction

Globally, there is renewed interest in the use of complementary and alternative medicines (CAM) for disease management with a preponderance (80%) in Sub-Saharan Africa (SSA) [1, 2]. The use of herbal medicines varies from region to region ranging from 20% to 80% [1, 2]. Chronic health conditions such as sickle cell disease, diabetes, asthma, epilepsy, hypertension, HIV infection, and cancer [3–6] are among the common conditions in which complementary and alternative medicines are used. Worldwide, it is estimated that 300,000 babies are born annually with Sickle Cell Disease (SCD), most of whom (>90%) occur in SSA where about 10–40% of the population have the SCD trait [7]. The World Health Organization (WHO) approximates that SCD contributes to 6–16% of under-five mortality in many African countries, and this burden is projected to increase substantially in the next 40 years [8]. SCD also causes profound adverse health and socioeconomic effects among surviving children and their families, respectively [8]. In most parts of sub-Saharan Africa (SSA), SCD is a growing public health problem, but data on the burden of the disease is incomplete partly due to a lack of universal newborn screening, lack of SCD registries, and associated stigma. Within the current data limits, the vast part of Uganda has a sickle cell trait prevalence of between 9–21% with 1–2% of babies born with sickle cell disease (SCD) [7, 9]. These figures are high and rank this country the 5th with the highest burden of sickle cell disease in Africa [9].

In most SSA settings, care for SCD includes the prevention of bacterial and malaria infections through prophylactic medication. In addition, pneumococcal vaccinations, health education, and supplemental folic acid are given. Some SSA countries have introduced hydroxyurea, which is widely used in developed countries for the management of SCD. This novelty in these settings is gaining ground with new evidence of the benefits of its one among African populations [10, 11]. Given its chronic nature, treatment of SCD is often managed with other adjuvant therapies. Several studies have reported that there is growing use of herbal remedies in the management of symptoms in patients with SCD [12, 13]. This could be related to the perceived failure of conventional medicines in the community, amongst other notable factors which can be influenced by intrinsic or extrinsic factors.

This study was informed by Ajzen and Fishbein’s theory of planned behavior (TPB), a widely studied social psychology model which determines the effect of consciously intended behaviors. The Theory of Planned Behaviour shows that behavioral intention, which predicts whether an individual will perform a behavior, can be predicted by attitudes, the subjective norm, and perceived behavioral control, which are seen as predictor variables. In the context of this study, behavior refers to the use of herbal medicine, conventional medicine, or both, and behavioral intention refers to the caregiver’s determination to use either herbal medicine, conventional medicine, or both. Behavioral beliefs such as perceptions towards herbal and conventional medicine greatly influence the choice of treatment mode, as it directly impacts onto individual attitudes. Notably, literature has reported that some individuals have associated herbal medicine with perceived benefits, efficacy, and safety as compared to conventional medicines, where many dread drug side effects [13]

The historical use of herbal medicine pre-dates the industrial revolution, but formal descriptions of the concurrent use of herbal medicines and conventional medicines are a recent development. Among the medicinal plants commonly used for symptomatic management in SCD include aloe vera extracts, ginger, lemongrass, Aframomum meleguet (grains of paradise), garlic, carica papaya (unripe pawpaw), sorghum bicolor (leafstalk), seed of the cajanus cajan (pigeon peas) piper guineensis (dried fruit of ashanti pepper), pterocarpus osun, eugenia caryophyllala (cloves), and sorghum bicolor, fagara (f. zanthoxyloide) [12, 14]. The predictors favoring the utilization of herbal medicine, include affordability [13, 15], poor health service systems [6, 16], accessibility, and perceived efficacy. In addition, contributory factors comprise of shortage of conventional health professionals [17], inadequate health facilities, underfunding, mismanagement of the available health facilities [6], and cultural connotation [1, 2]. Remarkably, a study done in Sierra Leone reported that 14.8% of caregivers of adolescents with SCD faced catastrophic health expenditure during the course of treatment [18]. It is very likely that caregivers may end up oscillating between herbal and conventional medicine due to the financial strain that comes along with the chronicity of the disease. Furthermore, data establishes that the region of residency, being female, and living in homesteads with grandparents or elderly people contributed greatly to herbal medicine use [19].

Despite the growing use of CAM, concerns about the safety of using herbal medicine, along with conventional medicines, to treat children with SCD have been pointed out in the previous literature. For instance, some of these medicinal herbs may be intrinsically toxic especially since it was taken in non-standardized dosages [14]. Furthermore, concomitant use of herbal and conventional medicine may lead to counterproductive bidirectional drug-drug interactions. This is a great concern for sickle cell disease which is often associated with deteriorating multiorgan function including the kidneys, liver, and skeletal system, all of which participate in drug metabolic processes.

Previous studies have investigated the use of herbal medicine in sickle cell disease management [13]. However, to the best of our knowledge, no comprehensive studies have investigated the combined use of herbal and conventional medicine in sickle cell disease management using the theory of planned behavior. The study aimed to determine the prevalence and factors associated with caregivers’ use of herbal medicine and conventional medicine in the management of children with SCD.

 Materials and methods Study design and site

This was a cross-sectional study conducted at Jinja Regional Referral Hospital (JRRH), a 600-bed hospital in Jinja City, Eastern Uganda. It serves eleven surrounding districts of Bugiri, Iganga, Jinja, Kaliro, Kamuli, Kayunga, Mayuge, Luuka, Namayingo, Namutumba, and Buyende with an estimated catchment population of 3.5 million people. Annexed to Jinja Hospital is Nalufenya Children’s Hospital, from which the Sickle cell clinic operates [20]. The Sickle Cell Clinic (SCC) generally serves over 500 patients, and runs routinely, every Monday. During clinic days, i.e., on Mondays, the clinic serves about 30–50 patients. The choice for Jinja area was because it is ranked as one of the districts with a high burden for SCD in Uganda.

 Study population

This study was conducted among caregivers of children with sickle cell disease, enrolled in the Sickle Cell Clinic at Jinja Regional Referral Hospital. Caregivers were eligible for this study if they were caring for a child aged 1 to below 18 years. In this study’s context, a caregiver was referred to as any individual that is directly tending to the daily needs of the child living with sickle cell disease. For most caregivers of children with sickle cell disease, by the time the child is one year old, they have experienced the disease burden and are much aware of the chronicity and incurability of the disease and are therefore most likely to try other remedies outside conventional medicine. We excluded caregivers of children with sickle cell disease who were less than one year or had other chronic illnesses. This study considered a 62.9 prevalence of herbal use to manage sickle cell disease from a previous study by Busari et al. 2017 [13] with a precision of 5%, 95% confidence intervals, and a non-response of 10%. Based on these assumptions, we estimated a sample size of 394 participants.

 Sampling procedures

Official written consent to review registers of SCD clients was sought from the administration of JRRH. A retrospective review of patients’ data was conducted to determine the number of sickle cell patients and their locations over 3 years, from January 2019 to January 2021. Following the retrospective review, we identified 607 children with SCD registered in care over the three-year period. Of these, 412 children were in the age bracket (1 to below18 years), and therefore eligible to participate in the study. The Sickle Cell Disease register comprised the children’s date of last attendance at the SCC, child’s name, name of Next of Kin (NOK), address of the NOK at the time of registration, contact details of the NOK, and child’s age on the day of registration. A list of eligible children and their caregivers was generated. Caregivers were then identified through consecutive sampling. Phone calls were made to the eligible caregivers who were briefed about the study and scheduled for interviews. Caregivers whose phones were not reachable and those who reported that the children were already above 18 years were excluded. All participants eligible for the study provided written informed consent prior to the interview.

 Data collection procedures and methods

Data were collected by trained research assistants using a pretested structured interviewer-administered questionnaire developed based on the Theory of Planned Behaviour [21] and the literature review. The questionnaire was pretested on 5 caregivers, who were randomly chosen from the sickle cell clinic but who did not participate in the study. Pretesting was very helpful in ensuring that the questions were appropriate to the study population. The lead researcher (CA) worked with the research assistants to coordinate and mobilize the respondents. This was done to ensure that research standard operating procedures, quality, and data consistency were maintained throughout the study. The study’s aim and rationale were explained to caregivers and only those who volunteered to participate took part. Data were collected on caregivers’ socio-demographic characteristics, caregivers’ experiences in disease management; and individual, community, and health-related factors that predicted the use of HM, CM or both therapies. Data were also collected on the theoretical constructs of the Theory of Planned Behavior, that is; attitudes towards use of HM, CM or both therapies, subjective norms about use of HM, CM or both therapies, intention to use HM or CM and caregivers’ perceived behavioral control, defined as caregivers’ perception of the ease or difficulty of using either HM, CM or both therapies [21].

 Data management and analysis

Questionnaires were checked for completeness by the lead researcher at the end of the data collection process and stored in locked cabinets that were accessible only by authorized study staff. Data were analyzed using Stata version 15.0. We presented descriptive statistics as frequencies and means. We conducted regression analysis for the combined use of herbal and conventional medicine as the primary outcome. All caregivers who reported using both therapies were coded as one (1) while the rest (those who used either herbal or conventional medicine alone) were coded as zero (0). Logistic regression was used to compute the inferential statistics (i.e. determine the p-values and 95% confidence intervals) since the primary outcome was binary. All factors (that had a p<0.20 value at bivariate analysis were entered into the multivariate model. All factors that had a p-value of <0.05 in the final model were considered to be significantly associated with the primary outcome. Confounders and effect modifiers were controlled for statistically. All the possible confounders were included as control variables in the regression models. However, other confounding variables that might not have been accounted for at observation might still have remained.

 Ethical considerations

We obtained ethical approval from Mbale Regional Referral Hospital Research and Ethics Committee, approval number Mbale Regional Referral Hospital-2021-106. We further sought administrative clearance from the Hospital Director of Jinja Regional Referral Hospital and the Head of the Department of Paediatrics Section within the hospital. We obtained written informed consent from the participants before collecting data. Confidentiality and privacy of the study participants’ information were maintained throughout the study. Participation in the study was voluntary; participants had a right to withdraw from the study at any time without necessarily giving a reason.

 Results Respondents’ characteristics

Table 1 shows the characteristics of the caregivers interviewed as part of this study. A total of 372 (representing 94.4% of the sample) caregivers were interviewed during the study of whom 341 (91.7%) were females. The average age of respondents was 34.3 years (Standard Deviation [SD]: ±9.8 years). More than half (55.1%, n = 205) were aged 18 to 34 years, 88.4% (n = 329) were not married, 40.9% (n = 152) had primary education as their highest level of education, 29.6% (n = 110) were Protestants while 51.3% (n = 191) were Basoga by tribe.

10.1371/journal.pone.0291008.t001 Socio-demographic characteristics of the caregivers of children with sickle cell disease at Jinja Regional Referral Hospital.
Characteristics Frequency (n, %) Percentage(%)
Sex
    Female 341 91.7
    Male 31 8.3
Age-group
    18–34 205 55.1
    35–59 158 42.5
    60+ 9 2.4
Marital status
     Not married 329 88.4
    Married 43 11.6
Religion
     Catholic 85 22.8
    Muslim 108 29.0
    None 13 3.5
     Pentecostal/Born again 56 15.1
    Protestant /Anglican 110 29.6
Ethnicity
    Baganda 84 22.6
     Banyoli 28 7.5
    Basoga 191 51.3
     Other 69 18.5
Highest level of education
     No formal education 43 11.6
    Primary 152 40.9
    Lower Secondary 139 37.4
    Upper secondary 14 3.8
    Tertiary university 24 6.5
Occupation
    Casual workers for wages 94 25.3
    Formal employment/professional 25 6.7
    Subsistence farmer 186 50.0
    Unemployed 67 18.0
Use of herbal medicine, conventional medicine, and both herbal medicine and conventional medicine

Fig 1 shows the prevalence of use of herbal, conventional and combined therapies by caregivers of children with SCD. Overall, more than half of the caregivers (58.3%, n = 217) used only conventional medicine, slightly more than a third (37.1%, n = 138) used both conventional medicine and herbal medicine while 4.6% (n = 17) used herbal medicine alone.

10.1371/journal.pone.0291008.g001 Prevalence of use of herbal medicine, conventional medicine, and both herbal and conventional medicines by caregivers of children with SCD.

Table 2 shows the distribution of the use of herbal medicine, conventional medicine, and both herbal medicine and conventional medicine among children with sickle cell disease by caregiver characteristics. Use of herbal medicine alone was common among men (12.9%, n = 4), caregivers aged 35–59 years (7%, n = 11), Muslims (7.4%, n = 8), those with upper secondary education (14.3%, n = 2) and subsistence farmers (7.8%, n = 8). Use of conventional medicine alone was common among females (59.2%, n = 202); caregivers aged 18–34 years (69.3%, n = 142), and those with no formal education (81.4%, n = 35). Use of combined herbal and conventional medicine was common among caregivers aged 60+ years (77.8%, n = 7), Muslims (43.5%, n = 47), Pentecostal/Born-again Christians (42.9%, n = 24), caregivers with tertiary/University education (50%, n = 12) and those in formal employment or professional jobs (54.1%, n = 20).

10.1371/journal.pone.0291008.t002 Use of herbal medicine, conventional medicine, and combined therapy by caregivers of children with Sickle Cell Disease by caregiver characteristics.
Characteristic Total HM only (n, %) CM only (n, %) Both HM and CM (n, %)
Overall 372 17 (4.6) 217 (58.3) 138 (37.1)
Sex
Female 341 13 (3.8) 202 (59.2) 126 (37.0)
Male 31 4 (12.9) 15 (48.4) 12 (38.7)
Age-group
18–34 205 6 (2.9) 142 (69.3) 57 (27.8)
35–59 158 11 (7.0) 73 (46.2) 74 (46.8)
60+ 9 0 (0.0) 2 (22.2) 7 (77.8)
Marital status
Not married 329 15 (4.6) 192 (58.4) 122 (37.1)
Married 43 2 (4.7) 25 (58.1) 16 (37.2)
Religion
Atheist 13 0 (0.0) 9 (69.2) 4 (30.08)
Catholic 85 1 (1.2) 58 (68.2) 26 (30.6)
Muslim 108 8 (7.4) 53 (49.1) 47 (43.5)
Pentecostal/Born again 56 2 (3.6) 30 (53.6) 24 (42.9)
Protestant 110 6 (5.5) 67 (60.9) 37 (33.6)
Ethnicity
Baganda 84 2 (2.4) 60 (71.4) 22 (26.2)
Banyoli 28 1 (3.6) 18 (64.3) 9 (32.1)
Basoga 191 10 (5.2) 98 (51.3) 83 (43.5)
Other 69 4 (5.8) 41 (59.4) 24 (34.8)
Highest level of education
No formal education 43 1 (2.3) 35 (81.4) 7 (16.3)
Primary  152 9 (5.9) 90 (59.2) 53 (34.9)
Lower Secondary 139 5 (3.6) 72 (51.8) 62 (44.6)
Upper secondary 14 2 (14.3) 8 (57.1) 4 (28.6)
Tertiary/university 24 0 (0.0) 12 (50.0) 12 (50.0)
Occupation
Casual workers for wages 129 6 (4.7) 78 (60.5) 45 (34.9)
Formal employment/ professional 37 1 (2.7) 16 (43.2) 20 (54.1)
Subsistence farmer 103 8 (7.8) 63 (61.2) 32 (31.1)
Unemployed 103 2 (1.9) 60 (58.3) 41 (39.8)
Use of combined therapy by caregivers of children with sickle cell disease stratified by selected sickle cell disease management characteristics

Table 3 shows the use of combined therapy by caregivers of children with sickle cell disease stratified by selected sickle cell disease management characteristics. Use of combined therapy was higher among caregivers who reported than they used herbal medicine when they noticed that the child had sickle cell disease (43.3%, n = 13) than among those who started by administering conventional medicine at that time (36.5%, n = 125). About four in ten caregivers who had ever heard about hydroxyurea or were currently using hydroxyurea reported that they were using combined therapy. Use of combined therapy was higher among those who had used hydroxyurea for six or more months (50.0%, n = 13) than those who had used the drug for less than six months (30.8%, n = 8).

10.1371/journal.pone.0291008.t003 Use of combined therapy by caregivers of children with sickle cell disease by selected sickle cell disease management characteristics.
Variable Total Use of both herbal and conventional medicines P-value
No (n = 350, %) Yes (n = 225, %)
Kind of management given to the child on noticing the child had SCD 0.461
    Conventional medicine 342 217(63.4) 125(36.5)
    Herbal medicine 30 17(56.7) 13(43.3)
Heard about hydroxyurea capsules 147 86(58.5)+ 61(41.5) 0.156
Child currently taking Hydroxyurea capsules 60 36(60.0) 24(40.0) 0.823
How long the child has been on hydroxyurea 0.363
    Discontinued use 8 5(62.5) 3(37.5)
    Less than 6 months 26 18(69.2) 8(30.8)
    Over 6 months 26 13(50.0) 13(50.0)
Heard that herbal medicines are used for the management of SCD 329 200(60.8) 129(39.2) 0.0109
Source of information about herbal medicine 0.066
    Fellow caregivers of children with sickle cell 95 60(63.2) 35(36.8)
    Health professionals 8 4(50.0) 4(50.0)
Herbalists 40 22(55.0) 18(45.0)
    Media (TVs, radios, internet) 93 67(72.0) 26(28.0)
    Neighbors /friends 63 31(49.2) 32(50.8)
    Relatives 30 16(53.3) 14(46.7)
Ever discussed herbal medicine usage with the physician 34 17(50.0) 17(50.0) 0.103

Interestingly, only 39.2% (n = 129) of those who had ever heard that herbal medicines are used for the management of SCD reported use of combined therapy but source of information about herbal medicine seemed to influence use of combined therapy (P = 0.066). A higher percentage of caregivers who heard about herbal medicine from neighbours/friends (50.8%, n = 32); those who heard this information from health professionals (50%, n = 4) and nearly half of those who heard this information from herbalists (45%, n = 18) used combined therapy than those who heard about herbal medicine from other sources. Interestingly, half of the caregivers who reported that they discussed herbal medicine usage with a physician reported that they used combined therapy.

 Caregivers’ level of agreement with selected behavioral beliefs about the efficacy of herbal and conventional medicine and the use of combined herbal and conventional medicine

Table 4 shows the association between caregivers’ level of agreement with selected behavioral beliefs about the efficacy of herbal medicine and the use of combined therapy among caregivers of children with sickle cell disease. As shown, caregivers who agreed with the statement that herbal medicine is more effective than conventional medicine and those who agreed that herbal medicine possesses lesser side effects than conventional medicine were significantly more likely to report that they used both herbal and conventional medicine in managing the disease than those who disagreed with these beliefs (p< 0.05). Similarly, caregivers who agreed with the statement that herbal medicine is cheaper than conventional medicine or that herbal medicine is usually used as a supplementary rather than alternative to conventional medicine were also relatively more likely to use a combined therapy than those who disagreed with those beliefs.

10.1371/journal.pone.0291008.t004 Association between caregivers’ level of agreement with selected behavioral beliefs about the efficacy of herbal medicine and the use of combined therapy by caretakers of children with sickle cell disease.
Caregivers’ level of agreement with behavioral beliefs about the efficacy of herbal medicine Total N = 372 Both HM and CM use OR(95% CI) P-value
No (n, %) Yes (n, %)
Herbal medicine cures symptoms faster than conventional medicine 0.0001
    Disagree 248 186(75.0) 62(25.0) 1.0
    Agree 124 86(69.4) 38(30.6) 4.9(3.1, 7.7)
Herbal medicine has fewer side effects compared to conventional medicines 0.0001
    Disagree 216 176(81.5) 40(18.5) 1.0
    Agree 156 58(37.2) 98(62.8) 7.4(4.6, 11.9)
Herbal medicine is more effective in treating SCD than conventional medicine. 0.0001
    Disagree 269 199(74.0) 70(26.0) 1.0
    Agree 103 35(33.9) 68(66.1) 5.5(3.4, 8.9)
Herbal medicine is used as a supplementary therapy rather than an alternative to conventional medicine 0.0001
    Disagree 119 104(87.4) 15(12.6) 1.0
    Agree 253 130(51.4) 123(48.6) 5.0(3.0, 8.5)
People use herbal medicine for disease management because it is cheaper than conventional medicine 0.0001
    Disagree 177 133(75.1) 44(24.9) 1.0
    Agree 194 100(51.6) 94(48.4) 6.6(3.6, 11.9)
People use herbal medicine for disease management because it is very easy to access information concerning the use of herbal medicine in managing sickle cell disease in our community 0.0001
    Disagree 84 60(71.4) 24(28.6) 1.0
    Agree 288 174(60.4) 114(39.6) 2.8(1.8, 4.4)
People use herbal medicine because of cultural influence 0.230
    Disagree 103 58(56.3) 45(43.7) 1.0
    Agree 268 176(65.7) 65(24.3) 1.6(0.9, 2.8)
Herbal medicine is used because herbal medicine is readily available in my community 0.0001
    Disagree 52 36(69.2) 16(30.8) 1.0
    Agree 319 197(61.8) 122(38.2) 2.7(1.6, 4.2)
Attitudes of healthcare workers toward patients greatly influence the use of herbal medicine. 0.0001
    Disagree 177 123(69.5) 54(30.5) 1.0
    Agree 195 111(56.9) 84(43.1) 0.7(0.4, 1.1)
Long distances to and from the health facility are what make people resort to using herbal medicine in treating children with SCD. 0.436
    Disagree 69 45(65.2) 24(34.8) 1.0
    Agree 303 189(62.4) 114(37.6) 1.4(0.7, 2.6)
Good communication between vendors of herbal medicine and clients makes patients resort to using herbal medicines. 0.002
    Disagree 63 40(63.5) 23(36.5) 1.0
    Agree 309 194(62.8) 115(37.2) 2.0(1.3, 3.3)

Table 5 shows the association between the caregivers’ level of agreement with selected behavioral beliefs about the efficacy of conventional medicine and the use of combined therapy among caregivers of children with sickle cell disease. Caregivers who agreed with the statement that conventional medicine works better when used with herbal medicine, those who agreed that the high cost of conventional medicine made people resort to using herbal medicines, and those who agreed that there was a need to integrate the use of conventional medicine with herbal medicine in the management of sickle cell disease were significantly more likely to report that they used both herbal medicine and conventional medicine than those who disagreed with these beliefs (p< 0.0001).

10.1371/journal.pone.0291008.t005 Association between caregivers’ level of agreement with behavioral beliefs about the efficacy of conventional medicine and the use of combined therapy by caregivers of children with sickle cell disease.
Caregivers’ level of agreement with behavioral beliefs about the efficacy of conventional medicine Total Both HM and CM use COR(95% CI) P-value
N = 372 No (n, %) Yes (n, %)
Conventional medicine works better when used with herbal medicine
    Disagree 138 114(82.6) 24(17.4) 1.0
    Agree 236 120(50.8) 116(49.2) 5.0(3.0, 8.5) 0.0001
The high cost of conventional medicines makes people resort to using herbal medicines
    Disagree 155 117(75.5) 38(24.5) 1.0
    Agree 216 116(53.7) 100(46.3) 2.7(1.7, 4.2) 0.0001
There is a need for the integration of herbal and conventional medicine in the management of sickle cell disease
    Disagree 127 103(81.1) 24(18.9) 1.0
    Agree 245 131(53.5) 114(46.5) 3.7(2.2, 6.2) 0.001
Caregivers’ use of combined herbal and conventional medicine by selected Theory of Planned Behavior constructs

Table 6 shows caregivers’ use of combined herbal and conventional medicine by the selected Theory of Planned Behavior (TPB) constructs (i.e. intention, attitude, and subjective norms). Our findings show that intention to use both therapies and a good attitude towards the use of both, e.g. the belief that the use of both herbal and conventional medicine is both safe and beneficial, influenced the use of both herbal and conventional medicine. A higher proportion (60.3%, n = 79) of caregivers who believed that the opinions of their friends regarding their choice of treatment for sickle cell disease management were important to them reported higher use of combined therapy than those who believed in the opinions of their family members (49.0%, n = 108) or the health professionals (37.5%, n = 132). However, only 38.1% (n = 118) of those who believed that the decision to choose the mode of treatment was under their complete control reported that they used combined therapy, with a slightly higher percentage of use of combined therapy reported among those who believed that the decision to use a given mode of treatment is dictated by its availability and accessibility (46.4%, n = 129) or by the dictates of one’s surrounding (48.2%, n = 109).

10.1371/journal.pone.0291008.t006 Caregivers’ use of combined herbal and conventional medicine by selected Theory of Planned Behavior constructs.
Variable (Agree) Total n = 372 Both HM and CM use COR(95% CI) P-value
No (n, %) Yes (n, %)
Intention(Ref = Disagree)
Intend to use only conventional medicine for the treatment of disease 294 224 (76.2) 70 (23.8) 0.04(0.02, 0.1) 0.001
Intend to only use herbal medicines for the treatment of disease 85 58 (68.2) 27 (31.8) 0.7(0.4, 1.2) 0.001
Intend to use both herbal and conventional medicines for the treatment of disease 196 64 (32.7) 132 (67.3) 58.4(24.6, 139.1) 0.001
Attitude(Ref = Disagree)
Herbal medicines are safe 132 39 (29.5) 93 (70.5) 10.3(6.3, 16.9) 0.001
Herbal medicines are beneficial 158 45 (28.5) 113 (71.5) 19.9(11.4, 34.6) 0.001
Conventional medicines are safe 329 215 (65.3) 114 (34.7) 0.4(0.3, 0.8) 0.006
Conventional medicines are beneficial 357 226 (63.3) 131 (36.7) 0.7(0.2, 1.9) 0.436
Use of both conventional medicines and herbal medicines are safe 147 34 (23.1) 113 (76.9) 26.6(15.1, 46.8) 0.001
Use of both conventional medicines and herbal medicines are beneficial 161 37 (23.0) 124 (77.0) 47.2(24.5, 90.8) 0.001
Subjective norms(Ref = Disagree)
The opinion of your friends regarding your choice of treatment for sickle cell disease management is important to you 131 52 (39.7) 79 (60.3) 4.7(3.0, 7.4) 0.001
The opinion of your family regarding your treatment choice is very important to you. 220 112 (51.0) 108 (49.0) 3.9(2.4, 6.3) 0.001
The opinion of health professionals regarding your treatment choice is very important to you 352 220 (62.5) 132 (37.5) 1.4(0.5, 3.7) 0.501
Perceived behavioral control (Ref = Disagree)
You think that the decision to choose the mode of treatment is under your complete control 310 192 (61.9) 118 (38.1) 1.3(0.7, 2.3) 0.388
The availability and accessibility of a treatment mode makes it an easy choice for caregivers to use 278 149 (53.6) 129 (46.4) 8.2(4.0, 16.9) 0.001
Caregivers use either herbal or conventional medicines because their surrounding dictates it 226 117 (51.8) 109 (48.2) 3.7(2.3, 6.0) 0.001
Factors associated with the use of combined therapy by caregivers of children with sickle cell disease

Table 7 shows the factors associated with the use of combined therapy by caregivers of children with sickle cell disease. Caregivers aged 60+ years were nearly 12 times more likely to use both herbal medicine and conventional medicine compared to those aged 18–35 years (adjusted odds ratio [AOR] = 11.8; 95% Confidence Interval [95%CI]: 1.2, 115.2). The use of both conventional medicine and herbal medicine was strongly associated with caregivers who had attained lower secondary education (AOR = 6.2; 95% CI: 1.5, 26.0) compared to those with no formal education. The caregivers who agreed that they intended to only use conventional medicine for disease management were 90% less likely to use both conventional medicine and herbal medicine (AOR = 0.1; 95% CI: 0.1, 0.3). There was notably a strong association between the likelihood of caregivers who agreed that herbal medicines are beneficial (AOR = 3.3; 95% CI: 1.5, 7.6) and those who agreed that the use of both herbal medicine and conventional medicine is safe (AOR = 7.7; 95% CI: 3.5, 17.0) with the use of both herbal and conventional medicine.

10.1371/journal.pone.0291008.t007 Factors associated with the use of combined therapy by caregivers of children with sickle cell disease.
Variable Total (N = 372) Used combined therapy Yes (n, %) Crude Odds Ratio (95% CI) Adjusted Odds Ratio (95% CI)
Age
18–34 205 57(41.3) 1.0 1.0
35–59 158 74(53.6) 2.3 (1.5, 3.5) 1.3 (0.6, 2.7)
60+ 9 7(5.1) 9.1 (1.8, 45.1) 11.8 (1.2, 115.2)***
Ethnicity
Baganda 84 22(15.9) 1.0 1.0
Banyoli 28 9(6.5) 1.3 (0.5, 3.4) 0.9 (0.2, 3.9)
Basoga 191 83(60.1) 2.2 (1.2, 3.8) 1.4 (0.6, 3.6)
Other 69 24(17.4) 1.5 (0.8, 3.0) 1.1 (0.3, 3.3)
Highest level of education
No formal education 43 7(5.1) 1.0 1.0
Primary 152 53(38.4) 2.8 (1.1, 6.6) 2.5 (0.7, 9.4)
Lower secondary (S1 to S4) 139 62(44.9) 4.1 (1.7, 9.9) 6.2(1.5, 26.0)***
Upper secondary (S5 to S6) 14 4(2.9) 2.1 (0.5, 8.5) 4.0 (0.5, 32.0)
Tertiary university 24 12(8.7) 5.1 (1.6, 16.1) 2.6 (0.4, 19.1)
Occupation
Casual workers for wages 94 34(24.6) 1.0 1.0
Formal employment professional 25 17(12.3) 2.2 (1.0, 4.6) 1.3 (0.3, 5.2)
Subsistence farmer 186 61(44.2) 0.8 (0.5, 1.5) 1.7 (0.7, 4.2)
Unemployed 67 26(18.8) 1.2 (0.7, 2.1) 1.0 (0.4, 2.6)
Heard that Herbal medicines are used for the management of SCD 329 129(94.2) 2.7 (1.2, 6.1) 1.5 (0.5, 4.9)
Ever discussed herbal medicine usage with the physician 34 17(12.3) 1.8 (0.9, 3.6) 0.7 (0.2, 2.3)
Intention
Intend to use only conventional medicine for the treatment of disease(agree) 294 70(50.7) 0.04(0.02, 0.1) 0.1(0.1, 0.3)***
Attitude1
Herbal medicines are beneficial 158 113(83.1) 0.4 (0.2, 0.7) 3.3(1.5, 7.6)****
Conventional medicines are safe 329 114(82.6) 0.4 (0.2, 0.8) 0.7 (0.2, 2.0)
The use of both conventional medicines and herbal medicines is safe 147 113(81.9) 26.6(15, 46.8) 7.7(3.5, 17.0)***
Perceived Behavioural Control1
e availability and accessibility of a treatment mode make it an easy choice for caregivers to use 278 129(93.5) 8.2 (4.0, 16.9) 2.6 (0.9, 7.6)
Caregivers use either herbal or conventional medicines because their surrounding dictates it 226 109(79.0) 3.7 (2.3, 6.0) 0.9 (0.4, 2.1)

****P<0.01

***P<0.05

**P<0.1

*P<0.2 (Prob > chi2 = 0.001, R2 = 0.4985

1Indepedent items that were significant at the bivariate analysis, as shown in Table 5

 Discussion

Our findings showed that one-third (37.1%) of the caregivers used both herbal and conventional medicine for the treatment of their children with sickle cell disease. The relatively high prevalence of the use of both therapies may be attributed to the historical-cultural connotations Africans have attached to the use of herbal medicines [1, 2]. These trends, however, are not consistent throughout Africa, as findings from a study conducted in Ghana found a much lower prevalence of herbal use of 17.9% [22]. These two extremes suggest varying levels of development of the combined use of herbal and conventional medicine. Despite the variations in the prevalence of use of either herbal medication alone or in combination with conventional medicines, we note the global nature of the practice as all different regions have a degree of use. This immense variation in prevalence in the different settings is probably associated with discrepant comprehension of the use of herbal medicine and conventional medicine by various researchers because herbal medicine has always been a fundamental part of the African healthcare system.

Given that sickle cell disease is a chronic condition that is associated with various devastating symptoms, the probability that both conventional medicine and herbal medicine are used in the management of the disease is expected to be on the increase. Several studies have indicated this growing phenomenon, especially for chronic conditions [3–6, 23, 24]. Against this background, our findings fit into the global prevalence rates, but most importantly, there may be an increased risk of drug-herbal interactions that may be counterproductive. The results of the study provided partial support for the Theory of Planned Behaviour, given that the intentions to use both therapies predicted behavior (use of both CM and HM). Findings showed that over two-thirds of the caregivers who intended to use both herbal and conventional used both therapies. The Theory of Planned Behaviour proposes that intention is the most proximal determinant of behavioral outcomes, with attitudes, subjective norms, and perceived behavioral control proposed to predict intention [21]. The Theory of Planned Behaviour has been used successfully by many researchers to predict a variety of behaviors, including the practice of herbal medicine use [25–27].

In this study, findings showed that attitude and perceived behavioral control predicted behavior e.g. caregivers who believed that the use of both herbal and conventional medicine is safe and beneficial were more likely to use both herbal and conventional medicine. The findings could further be elaborated by the attitudes the caregivers have towards the use of conventional medicine only. Several studies have also revealed that belief in the efficacy and safety of herbal medicine, and intention to use herbal medicine or combined therapy seemed to be key determinants of future use of combined therapy compared to those who believed in the efficacy of conventional medicine alone [13, 14, 28].

In sickle cell disease, the low expectancy of a cure for these genetic conditions and a feeling of failure of conventional medicine are possible drivers for the increased concurrent use of herbal and conventional medicine. Relative to that, past experiences with herbal or conventional medicine and the emergence of herbal medicines that assimilate modern medicine substances could also have a contributory role towards the growing concurrent use of herbal and conventional medicines. According to a study done on con-current use of herbal and orthodox medicine in Ghana, it was noted that 25% of the respondents used herbal and conventional medicines owing to the perception that both medicine types work together for the management of the condition and 23.1% believed that the synergic effect of both medicines when combined in treating the prevailing disease condition, works better [28]. This finding corresponds with this study as results have shown a significant association between the use of herbal medicine and conventional medicine and the caregivers who believe that the use of both conventional medicine and herbal medicine is safe. Several studies also revealed that belief in the efficacy and safety of herbal medicine, and intention to use herbal medicine or combined therapy seemed to be key determinants of future use of combined therapy compared to those who believed in the efficacy of conventional medicine alone [13, 14, 28]. However, the combined use of herbal medicine and conventional medicine could hamper the standard management measures of sickle cell disease, by interfering with the potency of conventional medicines, and causing drug toxicity as most herbal medicines are not quantified before use. Nevertheless, a meta-analysis has concluded that attitude towards the behavior is the most important predictor of health behavior intention [27].

We found that perceived behavioral control was significantly associated with the use of combined therapy. More than a third of those who believed that the decision to choose the mode of treatment was under their complete control reported that they used combined therapy, with a slightly higher percentage of use of combined therapy reported among those who believed that the decision to use a given mode of treatment is dictated by its availability and accessibility. Affordability and accessibility are the reasons for using both medicines concurrently [24, 29–31]. This finding suggests that perceived behavioral control may have served as a proxy measure of actual control among the myriad of other influences that can impact the use of herbal and conventional medicine. Profoundly, caregivers are more likely to use both CM and HM on the basis of previous experiences owing to the chronic nature of the disease.

Subjective norms, however, did not emerge as a significant predictor of behavior. Notably, a higher proportion (60.3%) of caregivers who believed that the opinions of their friends regarding their choice of treatment for sickle cell disease management were important to them reported higher use of combined therapy. The absence of significant findings for the subjective norm in predicting behavioral intention is likely to be related to the limited variability of the construct. Most caregivers are likely to use both CM and HM owing to the pressure from other peer users. For example, in this study, we also noted that caregivers were significantly more likely to hear about the concurrent use of these medicines from friends or fellow caregivers hence, more likely to carry out the practice. In addition, the study showed that caregivers who had knowledge that herbal medicines were used for the treatment of sickle cell disease were significantly more inclined to use both herbal and conventional medicine concurrently for disease management. Therefore, some of the subjective norms and perceived behavioral control’s effect on the concurrent use of both therapies were explained by the attitude based on knowledge and past experiences.

Several studies in Nigeria and Norway found an association between the concurrent use of herbal and orthodox medicines and several socio-demographic characteristics including age, sex, level of education, and income level [28, 32, 33]. This study however found age and lower levels of education of respondents as the only factors associated with the concurrent use of herbal and orthodox medicines with individuals aged 60+ almost 12 times more likely to combine the two forms of drugs. This could be attributed to the long-lived experiences of the elderly which provides them with an adequate comparison of events between herbal medicine and conventional medicine use. The elderly caregivers are also less likely to be influenced by medical knowledge on disease management and are more likely to try other remedies or self-medicate with all forms of drugs before hospital visitation. These study findings are in congruence with a study done by [32] who also found that the usage of herbal and orthodox medicines increases with age. However, it is contrary to findings from a study done by Ameade et al, 2018 which showed that the concurrent use of herbal-conventional medicine was common among people below 30 years [28]. The variations could be attributed to the different sample sizes and populations used.

Caregivers with lower education are more inclined to use combination therapy as they could be less privileged income-wise, have less knowledge on the standard of care for sickle cell disease, and are also bound to be easily influenced by friends, relatives, and others into using both remedies or herbal medicine. This study’s findings are similar to a recent study done in Sierra Leone which also revealed that the use of herbal medicine is greatly linked to low educational levels [34]. However, this is in contrast with a study done in Nigeria [13] together with other studies done in the USA [35]; which revealed that higher levels of education were significantly associated with more usage of herbal medicine. Other studies, including Oreagba and colleagues, found that, despite the high prevalence (66.8%) of herbal medicine use by their study participants, there was no statistical significance between the level of education and herbal medicine use [23, 29]. Collectively, our findings and findings from previous studies suggest that age, education level, and beliefs associated with a certain remedy greatly contribute to the usage of both herbal and conventional medicines for the management of chronic health conditions [19, 28, 34].

Our study had some limitations as well as strengths. The period of withdrawal from the use of either herbal or conventional medicine or both was not captured is one of the study limitations. Capturing time could have been important in assessing how long a caregiver had withdrawn from a certain therapy. The other limitation is that this study was conducted in a health facility setting and caregivers could have feared to admit that they were using herbal medicines in the setting where they receive conventional medicine to treat children with sickle cell disease. If this happened, then, the prevalence of herbal medicine use alone or combined herbal and conventional medicine could have been underestimated. We tried to minimize this limitation by reassuring the caregivers of the confidentiality of the interviews as well as conducting interviews away from the hospital setting. It is important to note that we did not collect data about the caregivers’ relationship with the child; that is if they were parents, guardians, or other relatives. As such, we were not able to detect if there were any differentials in the administration of herbal or conventional medicine in the treatment of sickle cell disease based on the relationship between the child and the caregiver. This is an aspect that should be explored in future studies.

Besides, since sickle cell disease usually manifests from around six months [36, 37], it would also have been important to enrol caregivers with children starting from six months of age. However, we recruited caregivers with children who were older than six months. It is likely that we could have missed some views from caregivers within this age bracket. However, we intentionally excluded children below one (1) year because during this period, when the disease has just started to manifest, most caregivers may not have conclusive evidence of the disease, as they are still pondering between sickle cell disease or any other disease. Moreover, during this period, the majority of caregivers entirely trust health workers and fully rely on conventional medicine for disease management. However, by the time the child reaches one year of age, caregivers are more likely to look out for other remedies with the realization that the disease is not only a burden but also chronic and incurable. Nevertheless, we believe that our study is unique in that most previous studies have focused mainly on the use of herbal medicine alone or on the use of other complementary medicines in the treatment of sickle cell disease but not on the concurrent use of herbal and conventional medicine. In addition, the study, unlike other studies, was informed by the theory of planned behavior to determine caregivers’ behavioral intention to use either herbal or conventional medicine use. Based on the study’s findings, the percentage of caregivers using combined therapy to treat children with sickle cell disease is relatively high and this could compromise the health of these children as they are prone to drug toxicities and drug-drug interactions. Furthermore, disease complications could also arise as there are possibilities of herbal medicines interfering with the drug potency of conventional medicines.

 Conclusion

Slightly more than one-third of the caregivers reported the use of combined herbal and conventional medicines to treat children with sickle cell disease, the majority of whom were of older age (>60%) and had lower secondary education. Beliefs in the efficacy and safety of those who believed in the safety and/or efficacy of herbal medicine and beliefs in the safety of using both CM and HM were strongly associated with the use of combined HM and CM. These findings suggest a need for targeted health promotion to educate caregivers about the dangers of using both herbal and conventional medicines in treating children with sickle cell disease in this setting.

 Supporting information Dataset used in the analysis.

(XLSX)

We acknowledge the staff of Jinja Regional Referral Hospital for their cooperation and support during the study process. We are also grateful to the research assistants that participated in the data collection process. Our special regards also go to the study participants who took the time to take part in this study.

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Predictors of complementary and alternative medicine use in chronic pain patients. Pain Med. 2010;11(1):16–24. doi: 10.1111/j.1526-4637.2009.00767.x 20447293 Craik C. Sickle Cell Disease in Childhood: From. Bone. 2008;23(1):1–7. Meier ER, Miller JL. Sickle cell disease in children. Drugs. 2012;72(7):895–906. doi: 10.2165/11632890-000000000-00000 22519940 10.1371/journal.pone.0291008.r001 Decision Letter 0 Mubuuke Aloysius Gonzaga Academic Editor 2023 Aloysius Gonzaga Mubuuke This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

23 May 2023

PONE-D-22-34542Caregivers’ Use of Herbal and Conventional Medicine to Treat Children with Sickle Cell Disease at Jinja Regional Referral Hospital, Eastern Uganda: A cross-sectional StudyPLOS ONE

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The paper is relevant for the journal readership. The authors need to clarify on how sampling was done and also proof-read the paper to strengthen the grammar and language.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript describes a phenomenon that is common in Africa. Some findings were quite interesting. The use of herbal remedies among individuals with tertiary education, over 50% of the cohort used herbal remedies. The demographics was also quite interesting. Most of the respondents were unmarried. It would have been important to distinguish the caregivers that were actual parents in the study population.

Reviewer #2: The manuscript is well written, results are sound and support conclusions made. Methodology is largely logical except for a few things

1. The sampling criteria / procedure is not elucidated. Did you consecutively or randomly sample participants? Please clearly include it in the text.

2. Did you pretest the questionnaire you developed from the literature for suitability in your setting? Please provide more information on this.

3. Usually sickle cell disease manifests from around 6 months, by recruiting caretakers of patients from 1 year old, did you intentionally exclude those of infants receiving treatment? If so, clearly state it with reason.

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Reviewer #1: No

Reviewer #2: Yes: Andrew Marvin Kanyike

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 10.1371/journal.pone.0291008.r002 Author response to Decision Letter 0 Submission Version 1

11 Jun 2023

REVIEWER ONE

The manuscript describes a phenomenon that is common in Africa. Some findings were quite interesting. The use of herbal remedies among individuals with tertiary education, over 50% of the cohort used herbal remedies. The demographics were also quite interesting. Most of the respondents were unmarried. It would have been important to distinguish the caregivers that were actual parents in the study population.

RESPONSE: We thank the reviewer for these nice compliments and observations. The suggestion to distinguish caregivers who were actual parents from those who were not is very important as this would show whether there were differentials in terms of herbal/conventional drug administration by the actual parents and those who were not. However, in our study questionnaire, we did not include a question that would distinguish the actual caregiver who was a parent from one who was not and therefore, we are not able to carry out that categorization. We acknowledge this as a limitation and have clearly stated it in the discussion section on page 27.

REVIEWER TWO

The manuscript is well written, the results are sound, and support the conclusions made. The methodology is largely logical except for a few things.

1. The sampling criteria/procedure is not elucidated. Did you consecutively or randomly sample participants? Please clearly include it in the text.

RESPONSE: We thank the reviewer for the pleasant observations and comments. Study participants were recruited by consecutive sampling. The sampling criteria have been clearly indicated under the sampling strategy within the materials and methods section. For details, please see pages 6 and 7.

2. Did you pretest the questionnaire you developed from the literature for suitability in your setting? Please provide more information on this.

RESPONSE: Yes, Questionnaires were pretested on 5 caregivers of children with sickle cell disease who were randomly chosen from the sickle cell clinic. More information has been provided under the data collection tools within the methods section. For details, please see page 7.

3. Usually sickle cell disease manifests from around 6 months, by recruiting caretakers of patients from 1 year old, did you intentionally exclude those infants receiving treatment? If so, clearly state it with reason.

RESPONSE: We intentionally excluded children with sickle cell disease of 1 year and below because, at 6 months, when the disease has just started to manifest, most caregivers do not have conclusive findings of the diagnosis of the disease and are most likely to rely on conventional medicine for disease management. However, with time, caregivers are more likely to look out for other remedies with the realization that the disease is chronic, incurable, and burdensome. We have, however, acknowledged this as a limitation in the discussion section. For details, see page 27.

Submitted filename: Response to Reviewers.doc

 10.1371/journal.pone.0291008.r003 Decision Letter 1 Mubuuke Aloysius Gonzaga Academic Editor 2023 Aloysius Gonzaga Mubuuke This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

14 Jun 2023

PONE-D-22-34542R1Caregivers’ use of herbal and conventional medicine to treat children with sickle cell disease at Jinja Regional Referral Hospital, eastern Uganda: a cross-sectional studyPLOS ONE

Dear Dr. Apolot,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Aloysius Gonzaga Mubuuke

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

Thank you for making the revisions. Some aspects in the paper still need clarity:

1. You should define what you mean by `Care givers` in the context of your study.

2. Tables 4 and 5 should reflect the confidence intervals beyond presenting p-values

3. Regarding results in Table 6, what statistical tests were done with this particular data? There are no significant levels presented and no confidence intervals.

4. The theory of planned behaviour should be explained clearly in your introduction.

5. The discussion should show the strengths of the paper and implications of clinical management of children with sickle cell in relation to the study findings

6. Adult age in Uganda begins at 18 years. How then can you say you included children 1-18 years?

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Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

 10.1371/journal.pone.0291008.r004 Author response to Decision Letter 1 Submission Version 2

2 Aug 2023

EDITOR’S COMMENTS

1. You should define what you mean by `Care givers` in the context of your study.

RESPONSE: We thank the reviewer for the keen comments and observations.

The definition of caregivers in the context of this study has been defined in the Methods and materials section under study population on page 6.

2. Tables 4 and 5 should reflect the confidence intervals beyond presenting p-values

RESPONSE: For both tables 4 and 5, analysis was re-done and the confidence intervals have been reflected. This can be seen in the Results section on pages 16 for Table 4 and page 17 for Table 5.

3. Regarding the results in Table 6, what statistical tests were done with this particular data? There are no significant levels presented and no confidence intervals.

RESPONSE: We thank you for the inquiry.

A binary logistic regression was re-run to compute the p-values and the confidence intervals. This has been reflected in Table 6, in the Results section on page 19. The statistical tests done have also been re-emphasized on page 18.

4. The theory of planned behavior should be explained clearly in your introduction.

RESPONSE: We thank you for the observation.

The theory of planned behavior has been clearly explained in the Introduction section on page 4.

5. The discussion should show the strengths of the paper and implications of clinical management of children with sickle cell in relation to the study findings

RESPONSE: Thank you for the observations.

Some of the strengths of the study were already highlighted in the Discussion section, nevertheless; we have added another strength of the paper. This is clearly indicated in the Discussion section on page 27. The implications of clinical management of children with sickle cell in relation to the study’s findings have also been added to the Discussion section on page 27.

6. Adult age in Uganda begins at 18 years. How then can you say you included children 1-18 years?

RESPONSE: Thank you for the inquiry.

The study only included children from 1 year to those below 18 years. This has been re-emphasized in the method and materials sections under the sampling procedures and study population. This has been clarified on pages 6 and 7.

Other changes made in the manuscript

For Table 3, we opted to make some changes as the table does not show associations but rather a comparison of the proportions of caregivers who used a combined therapy against those who did not use based on the selected sickle cell disease management characteristics.

But for the rest of the tables, Tables 4, 5, and 6, the confidence intervals have been reflected beyond the p-values, as suggested by the editor.

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0291008.r005 Decision Letter 2 Mubuuke Aloysius Gonzaga Academic Editor 2023 Aloysius Gonzaga Mubuuke This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

21 Aug 2023

Caregivers’ use of herbal and conventional medicine to treat children with sickle cell disease at Jinja Regional Referral Hospital, eastern Uganda: a cross-sectional study

PONE-D-22-34542R2

Dear Dr. Apolot,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Aloysius Gonzaga Mubuuke

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

 10.1371/journal.pone.0291008.r006 Acceptance letter Mubuuke Aloysius Gonzaga Academic Editor 2023 Aloysius Gonzaga Mubuuke This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

30 Aug 2023

PONE-D-22-34542R2

Caregivers’ use of herbal and conventional medicine to treat children with sickle cell disease at Jinja Regional Referral Hospital, eastern Uganda: a cross-sectional study

Dear Dr. Apolot:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Dr. Aloysius Gonzaga Mubuuke

Academic Editor

PLOS ONE