Exposure to poverty-related cumulative risk in early childhood can negatively affects cognitive developmental trajectories through limited cognitive stimulation and nutrition [1,2]. HIV-infected children are at a particular disadvantage if their care depends on impoverished HIV-infected caregivers, themselves at risk for impaired functioning.
There is increasing evidence that parent-directed interventions can improve child cognitive development [3–5], including in Uganda . Following earlier Ugandan feasibility and efficacy research [7,8], the present trial of caregiver training benefits for HIV-affected families was initiated in Tororo District, with 24% of the population living under the poverty line  and 5.8% HIV prevalence . This cluster randomized controlled trial (RCT) evaluated whether a year-long biweekly caregiver training intervention could improve caregiver mental health, quality of caregiving, and child neurodevelopmental outcomes in HIV-infected children.
Procedures and participants
After Institutional Review Board approval by Michigan State University and Makerere University School of Medicine, 18 subcounties (unit of randomization) in Tororo and Busia districts were randomly assigned to treatment arms. Staff conducting child assessments (blind to cluster allocation) and the study coordinator (not blind to cluster allocations) enrolled study participants.
Women and child dyads (N = 120) were identified over a 12-month period from AIDS support (TASO) clinics. A female caregiver provided written consent for her and her child. Child eligibility was based on confirmed perinatally acquired HIV infection, being between 2 and 5 years of age, and no history of neurological insult, with a female caregiver able to participate.
Participants in both study arms received a biweekly nutritional supplement. The interventions were provided in 1-hour sessions with each caregiver alternating biweekly between home and the project office at Tororo District Hospital. All intervention providers were Ugandan Makerere University Psychology or Social-Work graduates who received a 2-week training in their respective intervention and participated in weekly supervision and a week-long refresher training.
Caregiver training interventions
Mediational Intervention for Sensitizing Caregivers (MISC). MISC is a model for training caregivers to enhance their children's development  based on Feuerstein's [12,13] theory of cognitive modifiability.
Uganda Community Based Association for Child Welfare Program (UCOBAC). The comparison condition was a manualized nutrition and hygiene information program designed for impoverished households by UCOBAC (http://ucobac.org/).
Study data were collected at baseline, at 6 months (midway through training), at 1 year (completion of training), and at a 12-month follow-up (24 months after baseline). Measures of caregiver mental health and all child outcomes were previously used in Uganda [7,8].
Demographics: Child demographics included age, sex, and current use of HAART (yes/no). Caregiver demographics included marital status (married/unmarried), education (any/none), and relationship to study child (mother/other).
Mullen Scales of Early Learning (MSEL) assesses visual reception, gross motor skills, fine motor skills, receptive, and expressive language. A composite score provides a measure of for example, the general measure of fluid intelligence thought to underlie general cognitive ability.
Color Object Association Test (COAT) evaluates object placement memory with principal outcomes of immediate memory (assessed by number of recalled items) and overall total recall (assessed by number of correctly placed items).
Early Childhood Vigilance Test[16,17] assesses sustained attention, with the principal outcome of the proportion of time looking at an animation video as scored from a computer-mounted webcam video.
Behavior Rating Inventory of Executive Function-Preschool version (BRIEF)  evaluates behavior, attention and cognitive problems related to disruption of executive functions as reported in a series of questions to the principal caregiver; a combined Global Executive Composite (GEC) score is generated .
Caldwell Home Observation for the Measurement of the Environment (HOME)  assesses quality of child–caregiver interactions in the home using 45 yes/no items. More ‘yes’ answers indicate higher quality interactions.
Observing Mediational Interactions (OMIs). Intervention trainers collected 5-min videos every 6 months of caregivers bathing, feeding, and working with their child. Videos were scored by an independent observer using a standard rubric [11,20] to count specific occurrences of focusing, exciting, expanding, encouraging, and regulating interactions. Total number of interactions was used as a mediation indicator of caregiving quality.
Hopkins Symptoms Checklist-25[21,22] contains subscales for anxiety (10 symptoms) and depression (15 symptoms). Caregivers indicated frequency of each symptom in the last 2 weeks on a scale of 0 (not at all) to 3 (a lot). Subscale scores were calculated using mean item responses.
Caregiver functioning indicated how much difficulty caregivers had completing 12 tasks of daily living identified during a brief qualitative study, with responses from 0 (no difficulty at all) to 4 (cannot complete it). An impairment scale was calculated using mean item responses.
Sample size was calculated based on the magnitude of effects seen in a prior study ; with 54 (MISC) and 58 (UCOBAC) children, an unadjusted effect size of 0.53 was detectable with 0.80 power in two-sided tests at P = 0.05. Baseline intervention arm comparisons were calculated using t, chi-square, or Fisher's exact tests. Linear mixed effects (LME) models were employed. Correlations arising from repeated measures were accounted for by specifying an autoregressive covariance structure. Inclusion of a random effect for clusters (unit of randomization) was explored, but the resulting intraclass correlation coefficients were virtually zero across outcomes.
Each outcome was analyzed separately using LME with common covariates. Time was entered as a categorical variable with levels corresponding to 6, 12, and 24 months. Time-by-intervention interactions were included to capture potential changes in differences by intervention arm over time. The least squares (adjusted) means for each time point and trial arm were output from the LME models, and differences between them by trial arm were tested to assess immediate and sustained intervention effects.
Variation in caregiver quality assessed, via the HOME and OMI, was explored post hoc as a potential mediator of intervention effect on child outcomes. Caregiver mental health and functioning at baseline were explored as potential moderators of intervention effects on child outcomes. For analysis of MSEL subscale scores, Benjamini and Hochberg  procedure for the control of false discovery rate was applied. SAS 9.4 (SAS Institute, Cary, North Carolina, USA) was used for all analyses.
Of the 118 child–caregiver dyads who began the interventions, 112 children (95%) and 109 caregivers (92%) completed the mid-program assessment (6 months after baseline); 107 children and caregivers (91%) completed the postprogram assessment (12 months after baseline); and 106 children (90%) and 100 caregivers (85%) completed the follow-up assessment (24 months after baseline) (Supplement 1, http://links.lww.com/QAD/B116).
MISC and UCOBAC child–caregiver dyads are demographically similar and comparable in outcome scale scores at baseline (Table 1); only for the BRIEF scale of inhibitory self-control did MISC children score worse than UCOBAC children. At baseline, caregivers reported moderate mental health problems and low functional impairment.
Children in both interventions experienced positive neurological and cognitive development changes (Table 2). MSEL scores are presented age standardized, so a decrease is interpreted as study children on average not making development gains on a similar trajectory as children from high-income countries, on which standardized scores are based. Of the five MSEL subscales, MISC had a significant impact on receptive language score postintervention [adjusted mean difference = 3.13, 95% confidence interval (CI) 0.08, 6.18]; this effect did not remain significant after Benjamini–Hochberg adjustment and was attenuated at the maintenance follow-up (adjusted mean difference = 2.56, 95% CI −0.50, 5.63). At postprogram assessment, MISC children had significantly worse (higher) BRIEF metacognition and inhibitory self-control subscales and global executive function scores than UCOBAC. None of these differences were maintained at the maintenance follow-up. There were no other statistically significant effects of MISC on child outcomes.
Caregivers in both intervention arms experienced improvements in mental health and functionality over time (Table 2). MISC caregivers reported near significant fewer depression symptoms at the maintenance assessment (adjusted mean difference = −0.17, 95% CI −0.34, −0.02), as well as significantly less functional impairment postprogram (adjusted mean difference = −0.15, 95% CI −0.28, −0.01).
Mediation and moderation
For the exploratory mediation analysis, MISC participants showed greater increases over time in average HOME scores (mid-program: 22.45; postprogram: 23.60; 12-month follow-up: 24.00) than UCOBAC participants (mid-program: 20.36; postprogram: 20.38; 12-month follow-up: 19.89), with significant differences by arm at all time points (P < 0.001). HOME and MSEL receptive language scores were significantly associated across the full sample, irrespective of intervention arm. Controlling for HOME score in the LME with the MSEL receptive language outcome resulted in the trial arm variable losing significance, indicating probable mediation. Similar results were obtained with the OMI score as a potential mediator.
In the exploratory moderation analysis, no significant interactions were found between baseline caregiver mental health and trial arm for any of the MSEL outcomes. For caregiver functionality, better baseline caregiver functionality was associated with smaller gains in receptive language.
Participation in both intervention conditions resulted in improved outcomes for children and caregivers. MISC led to additional small improvements in child receptive language acquisition and caregiver mental health. The lack of effects for other developmental domains may be a result of UCOBAC being an active control condition, which enhanced the caregiver's attention to their child's nutrition and health.
MISC caregivers showing greater improvement over time in mental health compared with controls is in line with prior findings . With the MISC program encouraging caregivers to value their own ideas about childrearing, a possible mechanism by which MISC may impact caregiver mental health is through an increase in parenting-related self-efficacy and empowerment.
Baseline MSEL scores were indicative of an at-risk sample. Compared with similarly aged populations in the USA, our sample had significantly lower MSEL scores [24,25], but similar to other HIV-infected samples in Uganda . Although children in our study showed gains in cognitive development over time, their measured rate of improvement is less than that seen in the USA, which is why the standardized scores appear to decline over time.
In exploratory analyses, quality and quantity of caregiver–child interactions were identified as potential mediators of MISC's impact on receptive language; having confirmation of the hypothesized mediation model strengthens the study findings. We also found that MISC appears to be more effective in improving language outcomes of children whose caregivers reported better functionality in tasks of daily living at the beginning of program participation.
Several limitations should be noted. The MSEL and COAT have been previously used in Uganda [7,26]; however, standardized local norms were not available. We used scores standardized based on non-lower and middle income countries samples rather than raw scores to account for developmental growth. We were not able to formally test for spillover effects of the MISC intervention into the control condition, but through fidelity monitoring, we think this was minimal. There is a chance through multiple testing for identifying significant differences by chance.
With more than 200 million children not reaching their developmental potential due to poverty, illness, and lack of social and educational resources, improved early caregiving is important . Both interventions resulted in improvements for HIV-infected children, providing additional support for the importance of early childhood programming.
The research was supported by NIH grant RO1 HD070723 (PIs: M.B. and J.K.B.). S.M.M. was supported by NIMH Global Mental Health training grant (MH103210). The study sponsor had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. J.K.B. M.B., I.F., S.M.M., and A.L. have full access to all of the data and take responsibility for the integrity of the data and the accuracy of the data analysis.
The University of Michigan Medical School Global Reach program and the Michigan State University College of Human Medicine and College of Osteopathic Medicine provided summer stipends to support summer research internships for a number of students during the study period, and the support of these programs and participation of these medical students are greatly appreciated. Dr Elizabeth Schut helped provide field-based and clinic-based medical support to our study children and households on a volunteer basis during medical school clinical training, and her efforts are greatly appreciated.
This effort is dedicated to Professor Pnina Klein (1945–2014), who dedicated her professional life to the development and promotion of the Mediational Intervention for Sensitizing Caregivers (MISC), and without whose efforts, this study would never have been possible.
J.K.B., as study PI, shared oversight over all aspects and phases of study design and implementation and wrote the first draft of the article. R.O.O., as Ugandan co-I, was responsible for management and oversight of Tororo-based research staff and intervention providers, contributed to editing the article. I.F., as the on-site scientific director of study and contributed to writing the article. N.N., as Ugandan co-PI, was responsible for psychiatric care and referral, Ugandan IRB submissions, and contributing to the editing of the article. A.S. was responsible for all statistical analyses and data presentation and drafted the data analysis plan. J.A. led the on-site assessment team and outcomes scoring and contributed to the editing of the article. D.G. was responsible for adaptation of MISC to study context and training and certification of MISC research assistants, support of MISC training team, and contributed to the editing of the intervention description in the article. C.S. was responsible for adaptation of MISC to the study context, training and certification of MISC research assistants, support of MISC training team, and contributed to the editing of the intervention description in the article. S.M.M. was responsible for finalization of all study protocols, caregiver assessment validations, and participated in drafting and editing of the article. J.A. assisted in on-site study protocol implementation, caregiver assessments, and contributed to the editing of the article. T.M. assisted in the evaluation of caregivers and contributed to the development of the article. M.J.B., as study PI, shared oversight over all phases of study design and implementation and participated in drafting and editing the article. All authors approved the article as submitted.
Trial registration: clinicaltrials.gov identifier: NCT01640561
Conflicts of interest
There are no conflicts of interest.
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caregiver intervention; child development; HIV-infected children; lower and middle income countries; psychosocial
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