Background
Early detection of developmental delays is crucial to provide optimal support. Identifying early markers that may signpost elevated risk for developmental delay is one way to improve these early detection and support efforts. Literature to date has shown that delays in early social and executive function markers may be predictive of later developmental delays and eventual neurodevelopmental diagnoses, such as autism [
1,
2]. Two at-risk infant groups that can show significant delays associated with social and executive function and have an elevated risk of meeting criteria for autism spectrum diagnoses include neonates admitted to the Neonatal Intensive Care Unit (NICU) and infants with, or at risk for, cerebral palsy (CP). Factors necessitating NICU admissions, such as premature birth, low birth weight and other medical complications like congenital heart disease, have been linked to developmental delays [
3], while up to 95% of individuals with CP present with at least one additional medical, neurological, or neurodevelopmental condition, extending beyond motor impairments core to the CP diagnosis [
4].
To illustrate, delays in both social development and executive function have been repeatedly observed across infants admitted to the NICU and infants with CP [
5‐
10]. For instance, cross-sectional studies of these high-risk infants have reported social impairments spanning from social-communicative difficulties in early childhood to social isolation and withdrawal in adolescence and adulthood [
6,
9‐
15]. These delays have been found to confer lifelong challenges including decreased quality of life, relationship issues and fewer educational and vocational opportunities [
16‐
18]. Additionally, there is growing evidence of attention and executive function delays in both NICU graduates and infants with CP, with attentional deficits detected from the first years of life and delays in executive function reported across the lifespan [
7,
19‐
23]. Similar to social impairments, these delays in executive function have been associated with poorer outcomes across academic achievement, employment and quality of life [
24,
25], further underscoring the importance of detecting delays early in development and providing appropiate supports.
While social and executive function impairments are common and considerably impact on daily function in and of themselves, these high-risk infants are also at heightened risk for developing autism. An elevated risk for autism has been linked with risk factors that lead to NICU admissions [
26,
27], with early medical complications like low birth weight, congenital heart disease and other birth defects being associated with an increased incidence of autism [
28‐
31]. Further, it is estimated that up to 30% of children with CP may go onto receive an additional diagnosis of autism [
32]. Early identification of social and executive function markers in these high-risk infants would thus help us to develop reliable markers of risk for autism and provide supports and interventions as early as possible.
Despite this, the identification of delay in social and executive functioning domains and a later diagnosis of autism is often not made until years after presentation to health services. Early detection and intervention are critical to safeguard the developmental trajectories of social and executive function and to optimize developmental outcomes [
33‐
35]. To date, however, there has been relatively little research exploring the early identification of these delays in high-risk infant cohorts, particularly in the first months of life. While past research has identified early signs of social and cognitive delays in the first year of life in NICU graduates [
36‐
39], there has been a lack of studies exploring early markers that can predict later social and executive function delays and autism diagnoses. Similarly, no research to date has evaluated early predictors of social and executive function delays in infants with CP, with much of the research efforts focused on motor impairments [
40]. This paucity of research highlights the need to explore early divergences in social and executive function in these high-risk cohorts during the first months of life, and to identify markers that can predict later developmental delays. Alongside this, despite the high prevalence of autism in both CP and NICU graduates, research examining the early emergence of autism in NICU graduates is scarce [
41,
42] and is non-existent for CP. Instead, much of the extant knowledge comes from studies of infants at familial risk for autism [
43,
44]. The search for early markers of autism in infants with CP and NICU graduates is therefore critical, both to expand our understanding of early markers of autism, and to ultimately advance our ability to detect and intervene across a broader range of at-risk infants.
While much of the evidence considering risk for autism comes from familial risk studies (e.g., infant siblings of autistic children), it has provided valuable insights into the early emergence of autism and its associated developmental delays. Thus far, reliable markers of autism have been established from the second year of life onwards. These markers include atypical social interaction and communication behaviours as well as distinct profiles of early temperament, motor development and attention [
1,
45‐
47]. However, there has been much less clarity on whether these markers exhibit predictive value in the first year of life, and particularly in the first 6 months [
48,
49]. Nevertheless, it is becoming increasingly apparent that the subtle and transient signs of atypical development in the first year
can be detected by adopting more sensitive measures [
50]. For example, studies adopting eye-tracking technology have identified atypical gaze patterns as one promising early marker of later autism [
51‐
55]. Likewise, atypicalities in brain structure and function have demonstrated predictive value from as early as the first few months of life, supporting the speculation that neural measures may provide a window for earlier detection, with neural alterations preceding behavioural changes in autism [
1,
50,
56‐
58]. Moreover, recent research has proposed a link between cortical and epidermal development, suggesting that skin barrier integrity and skin lipid profiles could also represent very early indicators for neurodevelopmental divergence [
59,
60]. Taken together, the existing evidence underscores the need to take a multi-modal approach that integrates both behavioural and neurobiological measures when examining developmental delays in early infancy. No previous studies have adopted such an approach to prospectively explore the early emergence of social and executive function impairments and risk for autism in infants with CP and NICU graduates. A prospective investigation of early social and executive function delays in these high-risk groups is therefore warranted, to better understand which infants are at increased risk for later social and executive function impairments and may go onto receive an autism diagnosis.
This article presents the protocol for a prospective longitudinal study, which tracks early social and executive function development as well as the risk for autism in two high-risk cohorts, specifically NICU graduates and infants with, or at risk for, CP. Infants are tracked from 3 to 7 months through to 2 years of age. The study will take a multi-modal approach to track early social and executive function development, using behavioural, neurobiological, and caregiver-reported everyday functioning markers. The data from this study has the potential to: (i) provide benchmarks for the early detection of delays in social and executive function and risk for autism in NICU graduates and infants with CP; and (ii) inform on interactions between social and executive function delays with related domains of broader development (e.g., motor, cognitive, language, caregiver well-being and caregiver perceived stigma). With these data, we will be able to establish prediction models for social and executive function delays as well as risk for autism in these high-risk infants, which will then help inform the development of more targeted early interventions. Finally, this study will provide a broader understanding of the early emergence of autism across a wider range of at-risk infants.
Study aims
The primary aim of this study is to identify markers of social and executive function delay in high-risk infants from as early as 3–7 months of age, and to explore how these markers may relate to an increased risk for autism at 2 years of age. High-risk infants will include NICU graduates and/or infants with, or at risk for, CP. Given that social and executive function impairments often occur alongside difficulties in motor, cognitive and language development, as well as poor parental wellbeing, the secondary aim is to examine the associations between the early markers of social and executive function and these broader developmental domains.
Discussion
This is the first study, we are aware of, to prospectively track the development of social and executive function as well as the risk for autism in CP and NICU graduates from early infancy through to 2 years of age. The study will take a multi-modal approach, integrating behavioural, neurobiological, and caregiver-rated everyday functioning markers, to identify the earliest signs of developmental delay. This will constitute a critical step towards the earliest detection and intervention opportunities in these high-risk cohorts. The findings of this study will also expand our knowledge on the early emergence of autism across the wider spectrum, beyond infants at familial risk for autism [
43,
44]. The increased autism prevalence estimates in CP (up to 30% [
32];) compared to the rate found in high-risk siblings (3–18% [
128];) highlights a key advantage of investigating early markers of autism in this population. Similarly, given that prematurity, low birth weight and other neonatal medical complications (e.g., congenital heart disease) that warrant admission to the NICU have been identified as key risk factors for autism [
26‐
31,
33,
129‐
132], this study holds the potential to deepen our understanding of early markers of autism in a more diverse, high-risk cohort. This broader understanding of autism will be pivotal to the development of more personalised intervention and supports.
One potential limitation of this study is the clinical heterogeneity of the study sample, which includes infants with, or at risk for, CP as well as NICU graduates, who are likely to present with various medical complications. This will be addressed by conducting exploratory subgroup analyses to examine how delayed developmental trajectories change across infants with different clinical presentations (e.g., CP, congenital heart disease, prematurity) and combined comorbidities. An inherent challenge to longitudinal studies is the potential for poor retention and follow-up. This study has been designed to minimize attrition rates by limiting the number of assessment visits, and by streamlining the questionnaires into a single online portal, with the option of completing the questionnaires at home. In addition to this, the sample size has been set to allow for 10% attrition. Another methodological challenge for this study is the limited availability of tools validated for infants with CP, who are likely to present with sensory and motor impairments. In consideration of this, some assessment tools have been modified to ensure that the motor problems do not interfere with the task performance (e.g., looking version of the A-not-B task [
79,
80];) and measures tested with children with CP have been selected when available (e.g., BISCUIT-Part 1 [
104];).
The results of this study will allow us to identify the potential behavioural, neurobiological, and everyday functioning markers of social and executive function delays in CP and NICU graduates at the earliest point in time. Furthermore, it will provide insights into early markers which may increase risk for autism in infants with CP and NICU graduates. To date, we have very little understanding of whether early social and executive functioning markers can be used to track developmental divergence over time in high-risk infants, and if they can predict risk for autism. Therefore, the results of this study will provide critical knowledge on early detection of delays in high-risk infants. This will ultimately inform the development of better, timely, and targeted detection and intervention approaches to optimize developmental outcomes in these high-risk cohorts.
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