Neurodevelopmental Follow-Up of High-Risk Newborns

INTRODUCTION

Though progress in newborn medicine since the 1960s has led to the dramatic increase of survival in treated patients, it may be offset by an increase in neurodevelopmental impairments in these patients. Moreover, these developmental issues are not always evident in the neonatal period but appear throughout the first year of life as neuromotor deficits or later in childhood as cognitive, educational, and socioemotional deficits. The term “neurodevelopmental outcome” appeared for the first time around 1976 when neonatologists began to systematically follow up high-risk newborns from their neonatal intensive care units (NICUs) and to document their neurological development throughout the first years of life and into childhood. These studies were based on earlier findings on normal developing children by Gesell and Ilg in the Yale Clinic of Child Development and by the Zurich longitudinal child development studies. To date, Medline lists around 12,000 research publications using the term “neurodevelopmental outcome,” with the number increasing yearly such that the number of publications has tripled since the last edition of this chapter. When new treatments are introduced in newborn medicine, neurodevelopmental outcome is now considered a primary endpoint, alongside survival and neonatal morbidity. Neonatal care does not cease on discharge from the nursery, and as a field we have ongoing responsibility to monitor and support the development of NICU graduates.

There is irrefutable evidence that critically ill neonates, such as those born very preterm or neonates with conditions affecting the brain (e.g., hypoxic-ischemic encephalopathy, congenital heart disease, intrauterine growth restriction), are at risk for long-term neurodevelopmental impairments. Areas of concern include sensory deficits, cognitive and learning difficulties, motor problems, and emotional-behavioral issues, which collectively can limit educational, vocational, social, and participatory opportunities. Neurodevelopmental concerns can present early and persist throughout life, or they may improve or worsen with increasing age. Some areas of concern may not become obvious until later in development when those skills emerge and are observable, such as high-level language and cognitive skills. If deficits are subtle, functional problems may not surface until children are faced with complex scenarios that challenge those abilities, such as during the transition to adolescence and the later years of school. Furthermore, there is marked individual heterogeneity with regards to the severity and nature of long-term impairments, even among infants with similar clinical journeys. Though there are numerous clinical and social factors that are associated with long-term outcomes, it remains difficult to predict which children will present with future challenges and the nature of those challenges.

Critically ill neonates warrant close and regular surveillance throughout childhood, given their high rate of neurodevelopmental impairments and the resources implemented in the neonatal period for their survival. Indeed, it is now widely accepted that these infants require such monitoring as part of the ongoing responsibility for care and optimization of their outcomes beyond merely survival and discharge from the NICU. Though surveillance in the first 2 to 3 years of life is typical for these children, less common is neurodevelopmental monitoring in the preschool period and beyond. Limiting surveillance to the first few years is inadequate because many developmental problems do not surface until later in life, and problems identified in infancy can appear to resolve with maturity but, in reality, evolve and present differently. Thus a challenge when assessing high-risk infants is determining whether a problem detected in infancy reflects a developmental delay or a persisting impairment. Although risk factors may assist with this differentiation, ongoing monitoring is ultimately needed to track development for signs of catch-up. So though standardized assessments of developmental status such as the Bayley Scales are important for detecting current strengths and weakness, these assessments are only moderately predictive of later functioning.

PRIMARY PURPOSE OF NEURODEVELOPMENTAL FOLLOW-UP

The primary purpose of neurodevelopmental follow-up for high-risk infants is to detect developmental problems as early as possible . This enables interventions to be implemented to support the child during a sensitive period of development and to maximize the chances of preventing or minimizing long-term functional consequences. Otherwise, if left unmanaged, early developmental problems can worsen, become pervasive and very difficult to treat, and ultimately lead to significant and complex impairments, which also present huge burdens on families and society. Early intervention is a key strategy for optimizing long-term developmental outcomes with concomitant effects on societal wealth and preservation of human capital. However, targeted remediation is dependent on the early detection of areas of concern.

Neurodevelopmental follow-up is a high priority for families of high-risk infants. Families are likely to be informed that their child has a higher than average chance for developmental problems and, accordingly, many seek regular feedback on the health and development of their child and what to expect in the future. Such information is important for managing parental anxiety and expectations, educating parents to monitor for signs for potential emerging problems, and family decision-making. It enables families to proactively plan and advocate for their child’s needs. Such planning and advocacy can be especially relevant at key developmental transition points when additional challenges may be encountered by a child, such as starting child care or changing schools. During these times, families are also likely to benefit from extra advice and support.

Many neurodevelopmental follow-up programs collect core data that can be used for clinical audits or research . Given constant advances in obstetrical and neonatal management, it is essential that data be collected on the development of high-risk infants to assess the effectiveness of ongoing changes in care. Neonatal clinicians should have a good understanding of this information, because it is relevant for clinical decision-making and counseling families. Unfortunately, this understanding often is not the case, with research demonstrating that clinicians tend to overestimate major disability in infants born extremely preterm. In the context of randomized controlled trials, efficacy of neonatal interventions should be judged according to long-term developmental outcomes, in addition to survival rates and neonatal morbidity, because some interventions may have adverse neurological consequences that are not obvious until middle childhood, adolescence, or even early adulthood. Data from follow-up programs can also be used for benchmarking neonatal services, with developmental outcomes for high-risk infants compared at local, regional, and national levels.

In summary, neurodevelopmental follow-up of high-risk infants is important for providing ongoing clinical support for the child and the family, with the aim of optimizing long-term health and development and reducing dependency on health, educational, and social services .

NEURODEVELOPMENT

To accurately identify deviations and delays in a child’s development, it is essential to have an appreciation of the normative developmental timing of different skills and abilities, as well as the processes that shape child development, which consist of physiological adaptations and disruptions, cumulative over time and embedded in sensitive periods. Factors compromising child development are both biological and contextual. Important biological risk factors are linked to the prenatal environment, such as intrauterine factors that lead to intrauterine growth restrictions and preterm birth and complications associated with these conditions, such as perinatal brain injury, as well as a lack of adequate nutrition and infections. Equally important are contextual risk factors , such as environmental toxins, drugs in the prenatal period, parental psychological health (depression, stress, anxiety), suboptimal early care environment, and low educational level ( Fig. 14.1 ).

Life Course Development

Child development is, by definition, dynamic over time , with both quantitative and qualitative changes in brain structure and functioning observed from birth to adulthood ( Fig. 14.2 ). Neurodevelopment commences early in fetal development, driven by genetic programs that are influenced by, and often dependent on, environmental experiences. For example, early perinatal experiences have the potential to both positively or negatively alter an individual’s life course trajectory, and a child’s family, school, and community experiences will mold his or her neurodevelopment and functional abilities in distinct ways. Given that early life experiences can affect an individual’s development over his or her life course, the term life course development is often used . These life experiences are unique for each individual, which helps to explain the vast interindividual variability in long-term outcomes for high-risk infants. Another challenge when assessing young children is the wide variations in rate in which skills emerge and mature ( Fig. 14.3 ). These dynamic changes across development and the critical influence of environmental exposures throughout the life span ( Fig. 14.4 ) can make pediatric prediction of diagnosis and prognosis difficult and unreliable. For this reason, ongoing monitoring of development across the life span and the collection of information from multiple sources are advised for high-risk infants. Thus long-term follow-up enables the reliable assessment of skills that do not become apparent until school age or later, as well as the determination of whether an early developmental deviation reflects a delay or ongoing impairment.

WHICH INFANTS NEED FOLLOW-UP

Numerous factors increase an infant’s risk for later developmental impairments ( Table 14.1 ) . A workshop on the follow-up of high-risk infants sponsored by the National Institute of Child Health and Development and the National Institute of Neurological Diseases and Stroke identified a wide range of biological, interventional, and socioenvironmental factors for infants born preterm and term that are associated with long-term impairments and warrant ongoing monitoring. More recently, an Australasian consortium that proposed a framework for specialized follow-up of high-risk infants used broader criteria to determine an infant’s risk and need for surveillance, including preterm birth, congenital disorders, birth asphyxia, infection, and family disadvantages.

Infants exposed to multiple risk factors may be considered at even greater risk for developmental problems . For example, a growth curve analysis of the cognitive trajectories of very preterm between the ages of 4 and 12 years found that neonatal cerebral white matter abnormalities (WMAs) and family social risk (early motherhood, low maternal education, minority ethnicity, low socioeconomic status, and single-parent family) contributed additively to children’s later cognitive outcome. Children with no WMAs and no family social risk fared the best, with the highest average cognitive trajectory. The second highest functioning group, performing on average 4.7 points lower, were those children who had no observable WMAs on term magnetic resonance imaging (MRI) but were raised in high social risk environments (more than social risk factors), reflecting the developmental effect associated with raising a child in a socioeconomically disadvantaged family environment. Children with neonatal WMAs but who were raised in a family environment unaffected by social and economic adversity obtained an average IQ score that was 7.4 IQ points lower than the lowest risk preterm group, whereas those with both risk factors (i.e., moderate to severe WMAs and high social risk) performed an average of 12 IQ points lower. Thus both medical and contextual factors are important in determining a child’s level of risk . It is also relevant to note that children from disadvantaged sociodemographic backgrounds are less likely to attend developmental follow-up, despite being at greater risk.

MODELS OF NEURODEVELOPMENTAL FOLLOW-UP

Despite the benefits of surveillance for high-risk infants, most institutions do not have the resources to closely monitor the development of all high-risk infants beyond the first couple of months posthospital discharge. Consequently, individual centers/regions usually target specific subgroups of children to follow up, with the timing and structure of follow-up dependent on the resources available. Broadly, surveillance models can incorporate (1) formal surveillance by neonatal follow-up specialists, (2) screening followed by formal surveillance by neonatal follow-up specialists when indicated, or (3) screening followed by referral to specialists in the community when indicated ( Fig. 14.5 ).

Surveillance by neonatal follow-up specialists (model 1) is typically reserved for the highest risk infants, because this model involves assessments by a multidisciplinary team (e.g., pediatrics, psychology, speech pathology, physiotherapy, occupational therapy) and is resource intensive. The structure of these follow-up programs varies depending on the age of the child and training of the follow-up specialists but should provide a comprehensive analysis of the child’s current strengths and challenges. Depending on the nature and severity of the challenges, children may be referred for more intensive evaluation or intervention services. Even though specialized neonatal follow-up is recommended for all high-risk groups outlined in Table 14.1 , due to limited resources it is often the case that only specific subgroups of infants can access these services. Well-resourced families may be able to organize multidisciplinary assessments themselves within the public health system or privately, but the specialists are less likely to have the same level of expertise with NICU survivors.

Models 2 and 3 commence with screening, comprising a parent interview and/or standardized questionnaires (e.g., Ages and Stages Questionnaire) designed to detect children experiencing developmental issues or at high-risk for emerging difficulties. Children qualify for a referral to a specialized neonatal follow-up program if screened to be at high-risk (model 2) or, alternatively, referred to specialist services in the child’s community (model 3). Models of care that incorporate screening can monitor the developmental status for a much larger range of neonatal conditions and a larger number of high-risk infants. These models aim to reserve limited health resources for those children who warrant surveillance (i.e., those who are experiencing developmental concerns), rather than targeting a specific population, some of whom will be developing well and not in need for formal specialist follow-up. However, screening is not perfect. It is typically based on parental perceptions of their child’s development, and some children will screen incorrectly as developing age appropriately and not warranting formal follow-up services, whereas others will screen incorrectly as being of high-risk and referred to specialist services that they do not need. Furthermore, the process for categorizing a child as being at high risk at screening has important implications; if the bar is set too high, a significant proportion of needy children will not be referred to specialist services, whereas if the bar is set too low, a significant proportion will be referred who do not need it.

TIMING OF FOLLOW-UP ASSESSMENTS

Following discharge from neonatal intensive care, infants will typically be monitored by either a neonatal specialist or pediatrician in the subsequent 3 to 12 months and then referred to a developmental specialist according to needs or existence of a formal follow-up program. Table 14.2 provides a list of recommended ages for follow-up and the relevant child outcomes and family factors to assess, based on expert opinion during an Australasian workshop. In general, it was recommended that high-risk infants be assessed regularly in the first 2 years (intervals of not more than 6 months) and then annually to school entry if the child is progressing well. For school-aged children (5 to 18 years), the expert workshop recommended less frequent follow-up with a focus on higher order cognitive functioning, academic progress, emotional and behavioral status, and social functioning. Throughout this period, additional visits may be indicated with the presence or emergence of specific medical or neurodevelopmental issues. The transition to adolescence and then adulthood may be associated with the emergence of new medical, cognitive, and mental health challenges and, as such, follow-up during these periods can be warranted. Table 14.2 also demonstrates that the neurodevelopmental domains of interest vary across recommended follow-up time points, reflecting the child’s changing developmental status and milestones, the emergence of specific abilities, and periods in which abilities are functionally important.

The follow-up framework from the Australasian workshop is outlined in Table 14.2 and was proposed as a guide for surveillance programs when structuring the timing of their follow-up and the domains to target. The National Institute for Health and Care Excellence (NICE) guidelines for the developmental follow-up of children and young people born preterm provide a pragmatic model of care. Though the assessment tools recommended in the NICE guidelines are widely available and easy to adopt for follow-up programs, they are broad measures, and more specialized evaluations will often be required. The European Standards of Care for Newborn Health provide a well-balanced framework that provides flexibility in implementation.

It is common for specialist neonatal follow-up programs to be funded to provide surveillance for only the first 24 to 36 months, although in some regions and centers there is a gradual trend to extend programs into the early school years. As already noted, this duration is inadequate, and follow-up for high-risk infants should continue to adolescence at least, because early developmental assessments are only moderately predictive of later outcomes, many domains of concern do not emerge or are not assessable until school-age or beyond, the nature of impairments can evolve and manifest differently with increasing age, and subtle but important problems may not surface until appropriately challenging scenarios are confronted.

For children born very preterm, it is important that their age be adjusted for the degree of prematurity for at least the first 24 to 36 months. Research demonstrates that children will be undeservedly disadvantaged on cognitive test measures without age correction, and adjusted developmental levels better predict future neurodevelopmental performance. This bias is most marked during early childhood but does persist to a lesser degree into school age. However, it needs to be acknowledged that age correction for prematurity may have implications for a child being eligible for much-needed interventions and services; for example, a child may meet criteria for early intervention services based on assessment results using chronological age but is not eligible when applying age correction, which increases assessment scores. Thus the decision to apply age correction beyond age 2 years is largely dependent on the purpose of the assessment and the needs of the child.

NEURODEVELOPMENTAL FOLLOW-UP PROGRAMS

Follow-up teams are typically multidisciplinary, reflecting the range of domains that need to be assessed. The composition of the team may vary across the follow-up time points to cater for the specific domains of interest and the measures to be administered. Programs that monitor development from infancy to school age may include pediatricians, neonatologists, developmental and behavioral pediatricians, child neurologists, developmental and clinical psychologists, neuropsychologists, physiotherapists, specialists in psychomotor development, occupational therapists, and speech pathologists.

A formal evaluation of a child’s developmental status and functioning is typically undertaken using standardized assessments of the child, some of which are discipline specific and require accredited training, as well as standardized parent questionnaires. Direct observation also provides invaluable information. Though there are instruments that rate observations of the child, qualitative features of the child’s developmental capacities and behaviors are more commonly done informally by experienced health professionals during natural interactions in the waiting room and during the assessment.

In addition to deciding on the developmental domains to assess, follow-up teams should select which standardized assessments to be used . The NICE guidelines, as well as the Adults born Preterm International Collaboration, propose common core measures for assessing young children and adults born preterm, but teams are likely to make decisions based on personnel training and expertise, as well as regional preferences and requirements. For most domains a range of standardized measures are available, and selection should take into account psychometric properties, including construct validity and test-retest reliability, as well as inter- and intratester reliability. One of the most important considerations should be how the measures are standardized. The tests should have norms that are based on age brackets that are relevant to the age range of the children attending the follow-up program, and the norms should be generalizable to the local population. For example, follow-up programs in the United States should use tests that have U.S. norms, whereas programs in the UK should prioritize tests with UK norms. Furthermore, preference should be given to the most recent revisions of tests, because norms shift with time and can be out of date if they are 10 to 20 years old. Administration time is an important pragmatic issue when selecting tests, and it is not uncommon for teams to select abbreviated measures so that a broad range of domains can be assessed in the scheduled appointment time.

Measurement error is an issue that needs to be acknowledged when assessing development and, as such, interpreting performance should consider the 95% confidence interval of test scores, qualitative observations, and feedback from parents. Measurement bias can also occur. Tester bias occurs when preassessment information of the child influences how the evaluator administers measures and interprets test performance. For example, an examiner may decide not to administer certain items or tests to a child he or she was told had a specific impairment, despite the child being able to complete some of the tasks. In assessments conducted for research purposes, it is critical that evaluators be blinded to details of the child that are relevant to the study (e.g., group membership, intervention arm) to minimize tester bias or the perception of tester bias. Another measurement bias, which is particularly common for behavioral questionnaires, is informant bias . Questionnaires are generally completed by a single person, usually the child’s primary caregiver, and their responses reflect their perceptions, which may differ from those of another respondent (e.g., teacher). For all respondents, perceptions can be influenced by their personality, past experiences, and mental health status. As such, there are numerous reports of significant discrepancies between parent and teacher responses and parent and self-informant responses. Ideally, perspectives from multiple informants will be sought, but this is often not practical.

Well-functioning follow-up programs have significant administrative support , which is needed to contact families, confirm appointments, and maintain communication. Families move, change contact details, and may not be motivated to attend the program. As a result, all programs have some degree of family withdrawal, noncompliance, or nonattendance. A point of concern is that children and families with developmental challenges and/or from socioeconomically disadvantaged backgrounds are overrepresented in this group who do not receive surveillance or are more difficult to engage. Families can be prepared for follow-up appointments during the hospitalization period, and early follow-up appointments can be organized prior to discharge. Some family circumstances make it challenging for families to attend appointments, in which case alternative arrangements should be considered, such as home visits, if possible, or referral to other services that increase the ease for families to attend.

FUNCTIONAL NEURODEVELOPMENTAL DOMAINS

Functional neurodevelopmental domains that should form part of a comprehensive follow-up program include (1) physical health/growth , (2) neuromotor function , (3) language , (4) cognition and learning , (5) emotional and behavioral well-being or mental health , and (6) social functioning . Details relating to each of these domains are discussed next and summarized in Table 14.3 , with an emphasis on those most pertinent to the follow-up of high-risk infants. This section will highlight relevant variables that neonatal follow-up programs should consider evaluating and how these may change in importance with the increasing age of the child. The focus of the follow-up in terms of the domains assessed and method of assessment will vary at different follow-up time points and will differ across follow-up programs to account for the purpose, resources, and time available for each individual program.