Neuroimaging results, short-term assessment of psychomotor development and the risk of autism spectrum disorder in extremely premature infants (≤28 GA) - A prospective cohort study (preliminary report)

Extremely premature infants (born ≤28 weeks of gestation [GA], body weight <1000 g) are a high risk group for abnormal physical and psychomotor development. Among the major problems requiring detailed assessment are: growth, respiratory and vision disorders, motor and cognitive development. This is due to the fact that severe neurodevelopmental complications (cerebral palsy and cognitive developmental delays) that appear between 2 and 3 years of age, affect 12-18% of this population. Neurodevelopmental and psychological disorders, such as behavioral, cognitive and emotional disturbances, appear until school age, and even beyond. Autism spectrum disorder is observed in these children over 10 times more oThen than in the population of term neonates (8% vs. 0. 6%). Vision problems (including myopia, strabismus), especially in children with retinopathy of prematurity, affect between 20 and 50% of this population. This is indicated both by world research and the few studies conducted in Poland [1, 2, 3, 4, 5, 6, 7].

In addition to clinical examination, a significant role is assigned to neuroimaging studies in evaluating abnormalities and predicting prognosis in this population of children. There is no doubt that cranial ultrasound is and will remain the primary diagnostic tool as a non-invasive, easily accessible and inexpensive technique. However, it has significant limitations, so nowadays magnetic resonance imaging (MRI) is the best way to visualize the brain and the necessary technique for evaluating changes within it. MRI allows the visualization of the posterior fossa structures (cerebellum, brainstem), of the cortex and deep structures of cerebral hemispheres, including the thalami and basal ganglia, as well as for the assessment of myelination. Meta-analysis of the first world studies seeking correlations between ultrasound examinations performed during hospitalization, brain MRI in the 40th week of postconceptional age and neurological examination evaluating the long-term development of extremely prematurely-born babies indicates the important role of MRI in determining prognosis [9, 10, 11, 12].

With regard to cognitive development and functioning, extreme prematurity is a risk factor for learning dificulties, even in children with a normal level of intellectual development [13]. Possible and coinciding causes of these dificulties are deficits in executive functions [14], phonological processing [15], but also attention deficit hyperactivity disorder (ADHD), predominantly the inattentive type. Internalizing disorders, especially anxiety disorders, also play an important role [15]. In addition, an eightfold increase in the risk of autism spectrum disorders (ASD) [16] has been observed in extremely prematurely born infants compared to the term infant population. According to the Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-5), ASD is a complex neurodevelopmental disorder covering a broad range of deficits and symptoms in two major domains: 1) persistent deficits in social interaction and communication across multiple contexts, 2) restricted, repetitive patterns of behavior and activities, as well as unusual interests.

Among potential causes or factors correlating with ASD in this population (apart from genetic predispositions and primary and secondary infections), cerebellar and thalamic abnormalities are generally noted, which are visible on MR imaging only [17]. In addition, synaptogenesis dysfunction is also considered in the etiopathogenesis of various disturbances (such as emotional or cognitive disorders) in extremely preterm infants and is impossible to detect on ultrasound.

Due to the increased risk of mental disorders, including autism spectrum disorders, it seems important to include these infants in early psychological developmental assessment and psychiatric screening, which will allow early diagnosis and implementation of treatment [18, 19]. There are two types of screening tools for the detection of ASD: level 1 and level 2 screening measures. Level 1 screeners are designed to distinguish children with ASD from typically developing peers. In contrast, level 2 screeners serve to differentiate between the risk of ASD and other developmental disorders. A good screening tool for autism spectrum disorders is still sought for, as the most commonly used the M-CHAT test (a level 1 screener) gives many false-positive results in preterm infants [20, 21]. STAT (Screening Tool for Autism in Toddlers and Young Children, Stone et al., 2000; 2004 ), as a level 2 screening tool, has been recommended by the American Academy of Neurology (Filipek et.al., 2000). STAT is an interactive measure, conducted in a playful and joyful manner, and it only takes 20 to 30 minutes to administer. An important feature of this screener is that it can be used by a wide range of community specialists (psychologists, paediatricians, etc.). Among the few longitudinal, follow-up studies of premature infants’ development that have been carried out in Poland, none, to our knowledge, attempts to investigate the possible interconnections between neuroimaging results and neurodevelopmental outcomes, including the assessment of risk for autism spectrum disorder.

The aim of the study was to analyse the relationship between brain imaging results (US and MRI) and neurological, psychological and psychiatric development evaluations of two-year-olds born extremely prematurely.

The study population were infants born ≤28 GA and hospitalised at NICU between June 1, 2013 and December 31, 2015. We present the results of the first 12 children who were admitted to the study at the age of 2 years (corrected age) and had undergone both neuroimaging, and neurological, psychological and psychiatric assessments.

Data from the pregnancy period and characteristics of patients are presented in Table I. Gestational age ranged from 23 to 27 weeks of gestation, and birth weight from 580 g to 1100g. The high prevalence of prenatal corticosteroid treatment (83%) and delivery by caesarean section (83%) was noted. Corticosteroid treatment was required in 50% of cases during hospitalization, due to the long duration of mechanical ventilation (mean 22 days). 25% of the children were diagnosed with moderate or severe bronchopulmonary dysplasia (BPD). As many as 75% of the children have suffered from retinopathy of prematurity (ROP), requiring treatment (intraocular Lucentis or laser photocoagulation). Periventricular infarction was diagnosed in 3 children (25%), accompanied by a third degree of bleeding in 2 of them (in 1 case with posthaemorrhagic ventricular dilatation).

Table II summarizes brain imaging, neurological evaluation, assessment of psychomotor development, and screening for autism spectrum disorders in all individuals. Normal ultrasound scans and brain MR images, normal neurological examination and psychomotor development were found in 4 children (33.3%).

Psychomotor development evaluation and autism spectrum disorder screening were performed around 2 years of corrected age (between 1 and 10/12 and 2 and 1/12).

At least average psychomotor development results were found in 7 of 12 children (58%). In four of them, US and MRI showed no abnormalities, while a post-haemorrhagic ventricular dilatation was observed in 3 children (including 1 case in both neuroimaging methods) and haemorrhagic infarct (2 cases, on MRI only). No abnormalities were found in the cerebellum. It should be stressed that in the group of children with at least an average level of psychomotor development, abnormal results of neurological examination (ataxia, observation for CP) were detected in one patient only, while reduced results in at least two of the Children Development Scale sub-tests were present in 3 children (Motor − in all cases, Speech, Vocabulary, Social Behaviour and Scribbling and Drawing − in two, and Comparison – in one case).

Psychomotor development was assessed as lower than average (low or very low / global developmental delay) in 5 children (42%). Cerebellar or pericerebellar bleeding on MRI was reported in all these cases. Neurological examination was normal in 2 children.

Screening for autism spectrum disorder (STAT) was performed in 10 children (83%). It is important to mention that in all the children who presented the risk of autism spectrum disorder (4/10, i.e. 40%) abnormalities on MRI were detected: cerebellar haemorrhage in 3, frontal lobe post-haemorrhagic infarct in 1 child. Positive screening results were associated with abnormal psychomotor development in 3 children, but with abnormal neurological examination in 1 child only.

The study group is small and cannot provide a basis for statistical analysis, but there is a clear tendency to associate abnormal psychomotor development at the age of two years with abnormal brain MRI findings at term. Abnormalities were related to cerebellar pathology in all the cases. The same applies to screening for autism spectrum disorder. The increased risk of ASD has been reported in most cases with cerebellar haemorrhage. However, this result should be treated with great caution and needs to be verified in further diagnostic tests that will show how many of the children in the risk group actually meet the ASD criteria in further development. Such studies are planned as part of the continuation of this project.

US was normal in 4 cases with abnormalities in at least one field: neurological assessment, psychomotor development and STAT, including a case of cerebral palsy, while MRI was not normal in any of them.

In view of the increasing number of papers devoted to the association of cerebellar bleeding with neurodevelopmental problems of prematurely born children, its increased detection rate on MRI is clinically very meaningful. The superiority of MRI over US in this aspect (and not only this one) is not a new finding and has already been described (e.g. 23). In the recent paper by Parodi et al. it has been stated that microhaemorrhages proved to be undetectable by ultrasound even using mastoid fontanelle [24]. MRI is nowadays regarded as the gold-standard technique for the assessment of brain lesions associated with prematurity with emphasis on cerebellar (micro)haemorrhages. There is already quite a large number of studies (e.g. by Limperopoulos et al.) that link cerebellar damage in the premature brain with secondary underdevelopment of cortical projection regions in the contralateral cerebral hemisphere. Decreased prefrontal grey matter volume has been proven to be significantly associated with social and behavioural impairment [25]. In another recent paper Brossard-Racine and colleagues have proved on Diffusion Tensor Imaging (DTI) that preterm infants, even in the absence of overt cerebellar parenchymal injury detected on conventional MRI, have abnormal cerebellar microstructure reflected by fractional anisotropy (FA) and mean diffusivity (MD) alterations as compared with term-born controls [26]. So our focusing on cerebellar damage detected by MRI is clinically and scientifically justified, as the use of MRI increases our ability of prognostication and may be crucial for early therapy.

The preliminary results of our analysis are consistent with other authors suggesting a relatively high prevalence with an increased risk of autism spectrum disorders in children born prematurely [15, 27]. It should be stressed that the risk of ASD is not the same as definitive ASD clinical diagnosis. Furthermore, many authors point to the particularly high prevalence of prematurely-born babies whose positive screening results for ASD are not confirmed in clinical diagnosis [19]. This is especially true for children with various types of health complications, sensory abnormalities and psychomotor development difficulties [28, 29]. Screening tests may produce false-positive results in such circumstances [27]. An in-depth, psychological and psychiatric assessment of a child’s developmental profile, including the specificities of developmental dificulties and competencies, is therefore essential.

On the other hand, children with ASD symptoms may show results below their actual abilities in developmental scales not because of actual cognitive delay, but because of their dificulty in communicating with the diagnostician, refusal to follow instructions, over-absorbance in other activities, etc. These children, due to their adaptive, social and communication dificulties, o&en refuse to engage in a task, and in developmental assessment based on standardized measures they can achieve results that are lower than their actual development potential.

Significantly, early diagnosis of developmental dificulties, especially in extremely premature babies, cannot be regarded as stable in time. Hence, it is important to monitor development and adapt all forms of prevention, early intervention and treatment to the individual developmental needs of the child. This requires cooperation within a team of paediatrician-neurologist-psychologist-psychiatrist. It may cause problems due to significant difierences in the assessment of child development by difierent professionals. One of the reasons is the above-mentioned variable (time-varying) degree of child interaction with a particular examiner. There is no standardized questionnaire / interview tool for parental assessment of child development in Poland. Parents do not always provide the same information on subsequent visits to different professionals. In addition, specialists in different fields use different, not always compatible research tools. For example, a norm for premature infants (especially for extremely preterm ones) in psychomotor development assessment using the Denver scale (which is a screening tool) is the so-called boundary zone, which is very wide. This norm is accepted, because the destructive role of damage is more distinct in disorganizing orderly sequences of physiological processes than in the destruction of individual brain centres. As a consequence, the functional age of children whose brain was prenatally and perinatally significantly exposed to adverse factors remains far behind the chronological age, regardless of possible neurological deficits (30). In the CDS, which is a standardized tool for the general population, the same results will qualify a child below the norm (low or global delay) (Table II).

It should be emphasized that while the results presented here are preliminary, they have already encouraged a deeper reflection on the developmental trajectory complexity of children with extreme prematurity. The observed variety of possible configurations of neurological, psychological and psychiatric findings illustrates the scale of diagnostic and prognostic challenges in this group of children well, and encourages special caution. The results of the analysis indicate the need to take into account the information about development obtained from difierent sources and using difierent methods. They also encourage a prospective, long-term, multidisciplinary and multi-faceted follow-up of the development of children with extreme prematurity, including neurological, psychological and psychiatric assessments. Moreover, it should be stressed that the effectiveness of therapeutic interventions in the group of post-infancy children, related to the improvement of developmental outcomes, especially the level of the development of social and communication competences, has been confirmed by numerous studies [31, 32].

Without neglecting the primary role of transfontanelle ultrasound, we emphasize that magnetic resonance imaging is much more eficient in the evaluation of central nervous system lesions in preterm neonates and better correlates with their further development. The visualization of lesions e.g. in the posterior cranial fossa, remains the domain of MRI, although ultrasound is also performed through the mastoid fontanel. The potential association of these changes with abnormal psychomotor development at the age of two years and with autism spectrum disorder which is raised in the literature and indicated by the results of this preliminary report requires further studies and implies the use of MRI at a term-equivalent age.

The preliminary results of the present study indicate the complex relationships between neuroimaging results, neurological findings, and trajectories of psychological development in extreme preterms, requiring confirmation in further research. The functioning diversity of the children examined indicates the need to place extremely premature babies under well-planned, multi-specialty and long-term care which includes their mental development and functioning evaluation.