Socio-emotional and adaptive behaviour after severe anaemia in pre-schoolers at Lira Regional Referral Hospital, Uganda: a cross sectional study.

Background: Severe anaemia is a global public health challenge commonly associated with morbidity and mortality among children <5 years of age in Sub-Saharan Africa. However, less is known about the behavioural performance of preschool children surviving severe anaemia in low resource settings. We investigated social-emotional and adaptive behaviour in preschool children diagnosed with severe anaemia in Northern Uganda. Methods: We conducted a hospital based cross-sectional study among children 6 - 42 months who were treated for severe anaemia (n=171) at Lira Regional Referral Hospital, Uganda. Social emotional and adaptive behaviour were assessed 14 days post discharge using the Bayley Scales of Infant and Toddler Development, 3 rd edition. Age-adjusted z-scores for each domain were calculated using scores from healthy community children (n=88) from the same environment for each age category. Multiple linear regression was used to compare z-scores in the social-emotional and adaptive-behaviour scales between the two groups after adjusting for weight-for-age z-score, social economic status, mother’s education, father’s education and father’s employment on all the scales. Results: Compared with healthy community pre-schoolers, children with severe anaemia had poorer [adjusted mean scores (standard error)], social emotional [-0.29, (0.05) vs. 0.01, (0.08), P=0.002]; but not overall/ composite adaptive behaviour [-0.10, (0.05) vs. -0.01, (0.07), P=0.343]. Within the adaptive behaviour subscales, children with SA displayed signicantly poorer scores on the community use [adjusted mean score (standard error)], [-0.63, (0.10) vs. -0.01, (0.13), P<0.001]; and leisure [-0.35, (0.07) vs. -0.02, (0.07), P=0.036] skills. Conclusion: This study demonstrates that severe anaemia in the preschool period is associated with poor social-emotional scores in the short-term post clinical recovery in Northern Uganda. We recommend long-term follow-up to determine the course of these problems and appropriate interventions to reduce the behavioural


Background
Severe anaemia (SA), is a common public health problem among children under 5 years of age in resource-constrained areas with the highest mean severity in all low and middle income regions (1). The prevalence of SA among African children is notably high with a burden close to 63% (2). In malaria endemic areas, severe anaemia is a prevalent complication of malaria among African children especially those below 5 years in endemic countries (3,4).
Evidence that the brain is vulnerable during acute and chronic anaemia is provided by human and animal studies where acute anaemia has been linked to cognitive dysfunction and evidence of cerebral cellular hypoxia (11)(12)(13). Severe anaemia may lead to brain dysfunction and cerebral injury with the brain white matter identi ed as the predominant site of injury (13)(14)(15). Severe anaemia-induced injury may affect child growth and development including di culties in learning complex task, short term memory de cits and decreased motor control (13,15). The behavioural effects are of greatest concern because they can persist beyond treatment and resolution of anaemia (7,16). They may affect the mental, physical and social growth and development in children affecting their academic and career prospects later in life (7,9,17).
Behavioural outcomes after severe anaemia receive little or no attention in many public health spheres; despite causing so much disability partly due to the fact that emphasis is usually focussed on SA resolution and the reduction of risk factors of SA (3,4,(18)(19)(20)(21)(22). Therefore, the effect of SA on a child's behavioural outcomes is unknown. A recent study among Ugandan children with severe malaria and community children showed that severe malarial anaemia (SMA) was associated with internalizing and externalizing behavioural problems in children < 5 years old at 12 and 24 months (23). In this study, a behavioural assessment was conducted for children who had severe malarial anaemia.
To address the gaps in knowledge regarding behavioural outcomes in children with SA, we conducted a prospective cross-sectional study using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III) (24,25) to characterize the effect of SA on socio-emotional and adaptive behaviour among Ugandan pre-schoolers in the immediate period post recovery. The preschool years have been reported as a time of great cognitive, psychological and behavioural growth and brain development involving dynamic and elaborative developmental changes (26). We hypothesized that children with SA would have poorer social emotional and adaptive behavioural scores compared to community children.

Methods
This was a cross-sectional study with a sample of 259 pre-schoolers (171 with severe anaemia and 88 community children) aged 6-42 months conducted between August 2016 and June 2017 at Lira Regional Referral Hospital (LRRH) in Northern Uganda. Participants with SA were in-patients of an implementation research study on management and outcomes of severe anaemia in Ugandan children where SA was de ned as Haemoglobin (Hb) ≤ 5 g/dL (20,21). The healthy community children (CC) were siblings or neighbours of the enrolled children with SA who had been volunteered by the parents after invitation to participate in the study. They were examined at the time of enrolment to ensure that they did not have clinical pallor on clinical examination or a history of hospitalization for severe anaemia 6 months prior to enrolment.

Clinical And Demographic Assessment
Social economic status (SES) and demographic characteristics were obtained using a questionnaire of material possessions assessing housing quality, cooking resources, water accessibility and the presence of key amenities (radio, shoes for subject, mobile phone, poultry) in which lower SES scores have been associated with worse cognitive functioning in healthy Ugandan paediatric population under 5 years of age (27). Nutritional status was obtained by comparing physical indicators (height and weight) with the US CDC published norms and standardized z-scores (Epi Info 6, CDC 2000 Growth reference, Centers for Disease Control and Prevention, Atlanta, GA), to calculate height-for-age (HAZ), weight-for-age (WAZ) and weight-for-height z-scores (WHZ) (28). We followed internationally recognised cut-offs to consider children whose HAZ, WAZ, or WHZ fall more than two SDs below the international mean to be stunted, underweight or wasted, respectively (29).

Behavioural Assessment
Behavioural assessment was done using the Bayley III. It is one of the most commonly adapted comprehensive psychometric assessment tools used in research, in clinical practice, and to evaluate interventions as it assesses several developmental domains as a measure of early global development among very young children (24,25,30). The interviews with the caregivers were conducted in a quiet child-friendly room at the hospital. For uniformity and language concerns, trained assessors with Bachelor's degrees in Psychology and uent in Langi (a local dialect) administered the test to the child's primary caregiver.
Assessments were conducted 14 days post discharge for the caregivers of the children with SA and at enrolment for the CCs or when appropriate for the caregiver to return to the hospital for assessment. We interviewed the primary caregiver of each child using the social-emotional and adaptive behaviour scales of the Bayley-III (24,25). Majority of these were mothers, familiar with the child and could provide meaningful, accurate and complete response ratings of their child's personal, adaptive and social skills necessary for daily living. The social-emotional scale assesses emotional and social development as well as sensory processing that in uences a child's emotional responses based on the Greenspan Social-Emotional Growth Chart (31). The scale provides a general indication of a child's level of social-emotional development and presence or absence of sensory processing di culties (32). The scale assesses the child's functional, social and emotional milestones namely; self-regulation and interest in the world, relationship engagement, emotional engagement in an interactive and purposeful manner, communication with interactive emotional gestures, problem solving through interactive emotional gestures, communicating intentions and feelings using symbols and ideas, using symbols to express intentions, wishes or feelings more than basic needs, creating logical bridges between ideas and emotions (24,31,32).
Adaptive behaviour is a collection of skills (conceptual, social, and practical) for effective functioning that concern the way individuals meet their personal needs while meeting their demands in their environment (33,34). The adaptive behaviour scale is derived from items for children 0-5 years of the Parent/Primary Caregiver Form of the Adaptive Behaviour Assessment Scale -Second Edition -ABAS-II (35). The scale assesses ten areas categorized in three broader domains: (1) conceptual (communication, functional academics, and self-direction); (2) social (social and leisure); and (3) practical (self-care, home or school living, community use, health and safety) (33,36). A summation of the ten sub-scales composite scores was obtained to generate an overall adaptive behaviour score also known as the General Adaptive Composite (GAC) score.

Statistical Methods
Data were entered into Filemaker 11.0v3 (FileMaker Inc. US) database, and exported into IBM SPSS 23 for statistical analysis. For this study, raw scores for each scale were converted into an age and sex-speci c standardized z-score, based on the scores of healthy community children (CC, n = 88). The z-scores were computed as (actual score -mean score for a child's sex and age)/SD, where the mean score for a child's sex and age and SD were computed by tting a linear regression model to data for all CC children (37). Zscores have a mean of 0 and SD 1 in the CC reference population. Multiple linear regression was used to compare z-scores on all the scales between the two groups after adjusting for weight-for-age z-score, social economic status, mother's education, father's education and father's employment. We adjusted for multiple testing for the adaptive subscales using the Hommel's procedure (38) Table 1. Children with SA had lower social economic status, mother's education, father's education and father's employment statuses than CC children.   Associations with adaptive subscales have been adjusted for multiple testing using the Hommel's procedure (Hommel, 1988) and p < 0.05 is statistically signi cant.

Discussion
This study set out to examine the effect of SA on social-emotional and adaptive behaviour using the Bayley III among Ugandan pre-schoolers aged 6-42 months in the immediate period post recovery in Lira district, Northern Uganda. The study ndings showed that SA is associated with poor social-emotional behaviour among Ugandan preschool children.. We found no signi cant differences between the two groups on overall adaptive behaviour.
These results re ect the potential effect of severe anaemia that greatly affects African preschool children in resource-limited setting (2). One possible explanation for these results is that the altered socialemotional behaviour may be accounted for by the alterations in the frontal-striatal circuits and the mesolimbic/ meso-cortical dopamine levels as observed among children with iron de ciency anaemia (39). Though not assessed in the present study, iron de ciency is estimated to be the commonest contributor to the aetiology of severe anaemia and these iron status changes affects certain brain regions (40). These alterations in social-emotional behaviour are associated with poor overall developmental outcomes (39) and may affect school performance, personal relationships and consequently adaptive behaviour that draws together a person's cognitive and personality characteristics (33,41). Consequently, children with SA will be poor at negotiating complex social-emotional patterns and reaching functional emotional milestones that provide purpose to mental processes (24).
It is important to note that altered social-emotional behaviour as observed in the present study has been reported to affect how children react and experience their social and physical environment; thereby fuelling poor developmental outcomes that could signi cantly affect children's growth and development (42). Children's social-emotional development is reported to enhance children's adaptive behaviour, safety, home living, health, social relationships, self-awareness, emotional regulation, independence, academic outcomes and lifelong learning (43,44). This may be a possible explanation for the signi cantly poor performance on community use and leisure skills among children with SA. These skills have been reported to hamper skills needed to function in the community for example adequately exploring the environment, home living (helping with chores), health and safety (following safety rules and avoiding physical danger), and self-care (eating, dressing, toileting, brushing teeth) among infants and preschoolers (41). This could indicate that children with SA may not achieve their potential across multiple adaptive behaviour skills particularly in the social (leisure) and practical (community use) domains; which are necessary for young children to become increasingly more independent. De cits in these domains during the critical child development period, have the potential to affect the pre-schoolers' key functional developmental tasks (33,45). As a result, children with SA may be unable to encounter daily needs and manage the natural and social demands of the environment critical to child survival.
Furthermore, adaptive behaviours are intricately connected to other developmental domains such as cognition, motor and language skills; and as children grow older and begin to exhibit more sophisticated behaviour (33)(34)(35)46). Therefore, understanding the adaptive skills affected by SA in children may support the tailoring of interventions aimed at improving their functional outcomes. These interventions should focus on assessing and understanding the social emotional, sensory processing and adaptive skills present in early childhood (33). This is essential as these domains re ect the needs and feelings during the preschool years of life; critical to a child's future and survival (33,35).
While research on neurodevelopmental impairment among pre-schoolers surviving SA in LMICs is limited, this study indicates that pre-schoolers with SA have poorer social-emotional behaviour compared to their healthy counterparts. Understanding the social, emotional and behavioural development of pre-schoolers after illness is important as it re ects the critical aspects of the child's well-being, awareness of risks to brain function and the physiological adaptation to disease or environmental in uences on brain development during formative early years (30). Therefore, additional research on the neurodevelopmental needs of pre-schoolers with SA and the integration of early childhood development services into paediatric SA treatment programmes in LMICs is recommended. Assessing adaptive behaviour and functional abilities focuses on an essential dimension of human function essential in the diagnosis of impairment and intellectual disability (34).

Strength And Limitations
Our study provides important and novel data on the effect of SA on the socio-emotional behaviour among Ugandan pre-schoolers in a resource-constrained setting. Realizing the level and risk of disruption of brain development during formative early years due to SA and identifying the neurodevelopmental concerns early in life may direct early intervention services aimed at averting the impairment trajectories and improve functionality. The study also highlights the need for early and appropriate interventions across all skill areas to avert socio-emotional and behavioural challenges these children may develop and reduce the burden of future developmental risk and dysfunction that may be associated with severe anaemia among pre-schoolers in Uganda and other resource-constrained countries in Sub-Saharan Africa that could further burden the health system.
The current study has limitations worth noting. The aetiology and diagnosis the SA was largely symptomatic. We were not able to collect any further clinical data like malaria diagnosis. However, it is worth noting that anaemia among children in LMICs is a result of micronutrient de ciencies, acute and chronic in ammation, malnutrition and frequent infections (10) that may also affect socio-emotional behaviour. This study did not assess post transfusion Hb or if SA had cleared prior to assessment as both anaemia and transfusion are independently associated with organ injury and increased morbidity (5). Future research should assess post-discharge Hb prior to assessment. Socio-emotional and adaptive behaviour were assessed by caregiver reports of aspects of their child's development basing on their perceptions of their children and may be over-or under-represented. Parental reporting may be less valid in settings where the background level of awareness about early child development is low guided by cultural values and norms with a bias to portray their child in a positive light (43).
This was a cross-sectional study assessing the socio-emotional and adaptive behavioural skills performance in a resource-constrained setting at a single time point therefore causality could not be established and ndings may not be representative of the entire population. However we used healthy community children as a comparator group for normal test results in this age group in this area.

Conclusion
The investigations of this study demonstrate severe anaemia is associated with poorer social-emotional behaviour among pre-schoolers aged 6 to 42 months in Uganda. De cits reported in these areas could become signi cant risk factors for the later development of social and academic di culties. The