Data used to examine the association between treatment adherence and developmental outcomes are from one of the conditions of the Brain Research to Ameliorate Impaired Neurodevelopment - Home-based Intervention Trial (BRAIN-HIT), a randomized controlled trial (RCT) detailed elsewhere (clinicaltrials.gov ID# NCT00639184) [31, 32]. Implemented in rural communities of India, Pakistan, and Zambia, the overall aim of BRAIN-HIT was to evaluate the efficacy of an EDI program on the development of children in L/LMIC who are at-risk for neurodevelopmental disability due to birth asphyxia that required resuscitation. A group of children who did not require resuscitation at birth was evaluated using the same protocol to compare the efficacy of the EDI in those with and without birth asphyxia.
As detailed elsewhere [32, 33], mental development at 36 months of age was better in children with birth asphyxia who had received the EDI compared with those in the control condition (effect size = 4.6 points on the standardized scale from the Bayley Scales of Infant Development, see below), but there was no difference between trial conditions in the children without birth asphyxia. Psychomotor development was likewise higher in the EDI group, in this case for both the children with (effect size = 5.4) and without (effect size = 6.1) birth asphyxia, compared to those in the control condition. The issue of the effect of treatment dose on development is only relevant for the active EDI condition, and not the comparison condition, which intended to control for placebo, observation, and time effects and lacked a theoretically based developmental intervention. Therefore, only data from those randomized to receive EDI were analyzed in the present research, making this an observational study of that cohort. BRAIN-HIT was approved by the Institutional Review Board at each site and was conducted in accord with prevailing ethical principles.
Study population
Infants with birth asphyxia (resuscitated) and infants without birth asphyxia or other perinatal complications (non-resuscitated), born from January 2007 through June 2008 in rural communities in three sites in India, Pakistan and Zambia, were matched for country and chronological time and randomly selected from those enrolled in the First Breath Trial [34]. Infants were screened for enrollment into the BRAIN-HIT during the 7-day follow-up visit after birth [31], and were ineligible if: (1) birth weight was less than 1500 grams, (2) neurological examination at seven days of age (grade III by Ellis classification) [35], was severely abnormal (because they were not expected to benefit from EDI), (3) mother was less than 15 years old or unable/unwilling to participate, or (4) mother was not planning to stay in the study area for the next three years. Birth asphyxia was defined as the inability to initiate or sustain spontaneous breathing at birth using WHO definition (biochemical evidence of birth asphyxia could not be obtained in these settings) [36]. A list of potential enrollees was distributed to the investigators in each country to obtain written consent for the study, which was obtained during the second week after birth and before randomization to intervention conditions of the BRAIN-HIT.
Intervention procedures
Investigators at each research site selected EDI parent trainers who were trained in an initial 5-day workshop, which was led by the same experts at each research site. A second workshop was conducted before participating children began to reach 18 months of age to adapt the approach to children up to 36 months, again conducted by the same experts at each site. To maintain quality of implementation, the trainers were supervised with observations during actual home visits and constructive feedback was provided on a regular basis.
Each parent–child pair was assigned to the same trainer throughout the trial whenever possible, who was scheduled to make a home visit every two weeks over the 36-month trial period. As elaborated elsewhere [31, 32], the trainer presented one or two playful learning activities during each visit targeting developmentally appropriate milestones. These activities cover a spectrum of abilities across the cognitive, social and self-help, gross and fine motor, and language domains. The parent practiced the activity in the presence of the trainer who provided feedback. Cards depicting the activities were then left with the parent, who was encouraged to apply the activities in daily life with the child until the next home visit. The trainer introduced new activities in subsequent visits to enhance the child’s developmental competencies.
Treatment dose indicators
Two indicators of treatment dose were calculated. Home visit dose was measured based on each parent trainer keeping a record of visit dates. Following the first visit, visits were scheduled to occur every two weeks until the completion of the trial. A home visit was completed on schedule if it occurred within its assigned two week window following the preceding visit. We calculated the percentage of scheduled home visits completed for each participant for the full 36-month trial. The reason for each missed visit was coded as due to illness, weather, death in family, refusal, child or mother unavailable for another reason, parent trainer schedule conflict, and other reasons.
Program implementation dose was measured based on maternal report obtained by the trainer at each home visit of the proportion of days the assigned activities had been implemented since the previous visit. First, the number of days between subsequent completed visits was calculated (Yn). If the time between two home visits extended beyond 30 days, a maximum of 30 days was used. Program implementation credits were assigned for the time period between visits based on the mother’s report of implementation of activities, as follows: “not at all” (creditn = 1), “about one-quarter of days or less” (creditn = Yn*.25), “about one-half of days” (creditn = Yn*.50), “about three-quarters of days” (creditn = Yn*.75), and “almost every day or more” (creditn = Yn). The credits were then added together over the trial period, divided by the number of possible credits, and multiplied by 100. Thus, this score estimates the percent of days between each home visit that the mother reported implementing child stimulation activities. As an additional descriptive measure of treatment dose, the parent trainer was surveyed at the conclusion of the study to estimate how often the activities had been implemented between the home visits, using a five-point scale (from “never” to “always”).
Developmental outcome measures
The Bayley Scales of Infant Development – II (BSID) [37] was selected as the main outcome measure for this trial because it has been used extensively in various L/LMIC. The BSID underwent pilot-testing at each site to verify validity in the local context and a few items were slightly modified to make it more culturally appropriate (e.g., image of a sandal instead of a shoe). Evaluators across the sites were trained to standards in joint 4-day workshops conducted by experts before each yearly evaluation. The BSID was administered directly to each child by certified study evaluators, who were masked to the children’s birth history and randomization, in the appropriate language with standard material. Both the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) were used to measure developmental outcomes. Scores from the 36-month assessment, obtained just after the completion of the EDI, were used in this analysis as an indicator of treatment outcome.
Health and sociodemographic measures
Perinatal and neonatal health variables were obtained from records kept by the FIRST BREATH Trial [34]: child gender, birth weight (1500 g-2499 g, 2500 g-2999 g, 3000 + g), gestational age (28–36 weeks, 37+ weeks), number of prenatal visits (0, 1–3, 4+), and parity. Additional child health variables obtained as part of this trial at 12 months of age included weight for age/sex (<5th, 5th-14th, 15th + percentile) and complete immunization status.
Family demographic variables were obtained at enrollment in BRAIN-HIT using a structured parent interview: maternal age, education (none and illiterate, none but literate or primary, literate with some secondary), family assets and home living standard. The presence of 11 family assets (e.g., radio, refrigerator, bicycle) were tallied as a Family Resources Index and classified into three levels (0–1, 2–4, 5+). A Home Living Standard Index was calculated based on seven indicators (e.g., home building material, water source, type of toilet) and classified into three levels (0–4, 5–7, 8+). A socio-economic status (SES) measure was used to classify participants into three groups (quintile 1–3, 4, 5) [38].
Statistical analysis
Descriptive statistics were computed for child health and family demographic characteristics, treatment dose indicators (home visits dose and protocol implementation dose), and developmental outcomes (MDI and PDI at 36-months) for all individuals randomized to receive EDI. Child health and demographic characteristics were summarized separately for those randomized to receive EDI and included in the treatment dose analysis and those who were excluded from this analysis, and differences in mean values for continuous variables were tested using t-tests and categorical measures were tested using chi-square and Fisher exact tests. A Pearson correlation statistic was computed between the treatment dose characteristics.
Aim 1
In the absence of established criteria for adequate treatment dose for EDI and to determine where the effectiveness of the intervention may plateau, both treatment dose indicators were divided into quintiles. Those in quintile 1 had lowest dose and those in quintile 5 had the highest dose of the indicator in question. Descriptive statistics for the 36-month MDI and PDI were calculated for each quintile. General linear models were used to evaluate the associations of treatment dose quintile with 36-month MDI and PDI. In addition to the treatment dose indicator in question, covariates of interest included resuscitation status at birth, 12-month MDI or PDI, and site. If the omnibus 4-degree of freedom test for either MDI or PDI provided evidence of significant differences across quintiles of treatment dose, step-down tests were used to evaluate where those differences occurred.
Aim 2
To evaluate associations with treatment dose, initially all sociodemographic and child health variables and trial location were entered into linear regression models separately to predict both treatment dose variables. Selected for entry in multivariable models were variables that demonstrated P ≤ 0.20 in univariate association with the adherence variable in question when either adjusted by location alone or location and the variable by location interaction. We employed backward elimination with an alpha of 0.20 to choose the final models.