Neurodevelopmental disorders and somatic diagnoses in a national cohort of children born before 24 weeks of gestation

Abstract Aim This study investigated childhood diagnoses in children born extremely preterm before 24 weeks of gestation. Methods Diagnoses of neurodevelopmental disorders and selected somatic diagnoses were retrospectively retrieved from national Swedish registries for children born before 24 weeks from 2007 to 2018. Their individual medical files were also examined. Results We studied 383 children born at a median of 23.3 (range 21.9–23.9) weeks, with a median birthweight of 565 (range 340–874) grams. Three‐quarters (75%) had neurodevelopmental disorders, including speech disorders (52%), intellectual disabilities (40%), attention deficit hyperactivity disorder (30%), autism spectrum disorders (24%), visual impairment (22%), cerebral palsy (17%), epilepsy (10%) and hearing impairment (5%). More boys than girls born at 23 weeks had intellectual disabilities (45% vs. 27%, p < 0.01) and visual impairment (25% vs. 14%, p < 0.01). Just over half of the cohort (55%) received habilitation care. The majority (88%) had somatic diagnoses, including asthma (63%) and failure to thrive/short stature (39%). Conclusion Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long‐term support needs at an early stage.


| INTRODUC TI ON
During the last two decades, the survival of extremely preterm (EPT) infants, born before 28 completed weeks of gestation, has increased. This has partly been due to the more proactive care of infants born before they have completed 24 weeks. 1 Initiating intensive care for the most immature infants is a matter of debate, due to their high mortality, the heavy burden of neonatal morbidities and later sequelae. In Sweden, the one-year survival rates for infants born alive 2014-2016 with gestational age 22 and 23 weeks were 30% and 61%, respectively. 1 Neurodevelopmental disorders following EPT birth have been investigated by a number of studies with large cohorts. These disorders have included intellectual disabilities, cerebral palsy and visual and hearing impairment. 2 In addition, speech disorders, 3 attention deficit hyperactivity disorders (ADHD), 4-6 autism spectrum disorders (ASD), 7,8 psychological problems, 9 epilepsy 10 and sleep disturbances 11 have been reported after preterm birth but have not been included in the large cohort studies on neurodevelopmental outcome after EPT birth. The long-term sequelae of EPT birth also include dysfunction of other organ systems that manifest as respiratory dysfunction, 12 poor growth 13 and kidney dysfunction. 14 Outcome data for children born before 24 weeks are scarce. This is mainly due to the limited number of survivors and the fact that studies have not covered the broad range of follow-up diagnoses that these infants receive.
The wide range of neurodevelopmental disorders that have been reported in EPT infants indicates the need for long-term support.
Sweden has habilitation centres, where multi-professional teams of neurologists, physiotherapists and psychologists look after patients that have neurodevelopmental disorders with functional impairments. The number of children born EPT that are referred to habilitation centres may reflect the need for special support in this group.
Habilitation centres offer treatment, training and medical aids for the children and support for the parents. Low vision clinics offer corresponding services to habilitate visually impaired children.
The primary aim of this large, retrospective, national study was to report clinical diagnoses registered after children born before 24 weeks were discharged from neonatal care. We selected and documented the diagnoses that were likely to have a significant impact on the children's lives. In addition, we wanted to investigate the need that this patient group would have for medical care and habilitation services during childhood.

| Birth characteristics
Birth characteristics were recorded, including gestational age, which was determined by routine ultrasound assessments at 17-18 weeks, Conclusion: Most children born before 24 weeks had neurodevelopmental disorders and/or additional somatic diagnoses in childhood and were referred to habilitation services. Clinicians should be aware of the multiple health and developmental problems affecting these children. Resources are needed to identify their long-term support needs at an early stage.

K E Y W O R D S
extremely preterm birth, habilitation care, long-term support, neurodevelopmental disorders, somatic disorders

Key Notes
• This large registry-based study showed that 75% of Swedish children born before 24 weeks of gestation had neurodevelopmental disorders, including intellectual disabilities (40%), autism (24%) and 55% required habilitation services.
• Somatic disorders were diagnosed in 88% of the cohort: 63% had asthma and 39% failed to thrive and/or had a short stature.
• Boys were more likely to have intellectual disabilities and visual impairment than girls if they were born at 23 weeks.
birth weight and sex. The birth weight standard deviation (SD) was calculated. 16

| Childhood diagnoses
Diagnoses related to prematurity were divided into neurodevelopmental disorders and other somatic diagnoses.

| Statistical analysis
The statistical analysis was performed using IBM SPSS Statistics for Windows, Version 25.0. (IBM Corp).
Numbers and percentages are provided for categorical variables, with medians and ranges for continuous variables. We used Pearson's chi-square test and Fisher's exact test for dichotomous variables. Logistic regression was used to evaluate the relationships between age and diagnosis. The level of significance was set as a p value of <0.05.

| RE SULTS
We found that 16 of the 399 infants identified through the SWEDROP died before they could be followed up, and this meant that 383 infants were included in the study. The children's ages at the time of the last visit ranged from 2 to 13 years.
There were no significant differences between boys and girls (data not shown).

| Summary
The majority (96%) of the children had one or more of the diagnoses selected for this study. There were 15 children without any diagnoses, 10 girls and 5 boys, and they included one boy and one girl born at 22 weeks. The medical records clearly stated that 5 of the 15 children were healthy. The data were sporadic for 2 of the children, as they did not attend the planned follow-up visits after the neonatal period. There were medical file indications of disorders in the remaining 8 children, such as lung problems, allergies and neurobehavioral problems, but no ICD diagnoses had been recorded.

| DISCUSS ION
This was a retrospective national file review registry-based study of children born before 24 weeks of gestation, who were followed up until 2 to 13 years of age. We found that 75% had neurodevelopmental disorders at 2-13 years of age and more than half of the children (55%) required assistance from habilitation services.
Boys were more likely to be affected by intellectual and visual im-  Note: Data expressed as n and (%). Severe respiratory impairment is defined as requiring a home-ventilator and/or tracheostomy and/or having a need for oxygen supplementation up to at least two years of age or more. Any other somatic diagnosis is defined as one or more of the above-defined diagnoses and disorders.
Abbreviation: GA, gestational age. It has been suggested that more active treatment and increased survival may lead to fewer children affected by morbidities and/ or less severe diseases 29 but this has been questioned by others. 30 Changes in survival rates over the years, and differences between hospitals and countries, can be explained by a number of factors.
These include rates of initiating active life-supporting care and the quality of neonatal care for very immature infants. [31][32][33] The trend analyses carried out by our study found that the rates for cerebral palsy did not alter over time (data not shown), which means that initiating active care at younger gestational ages did not result in a lower incidence of cerebral palsy in this Swedish cohort. Trend analyses for other diagnoses were complicated, because they were age-dependent. Analyses between sites were not performed in our study, as the wide age ranges at follow-up, and variations in local The risk for the neuropsychiatric disorders ASD and ADHD is dramatically increased after extremely preterm birth and has been reported to be inversely related to GA at birth. 4,7 In one study, 15% of children born at 23-24 weeks were diagnosed with ASD, 4 compared to 24% of the children in our study. Since autism can be underrecognised at an early age, it cannot be ruled out that additional children might be affected. The proportion of children affected by ASD in our study was significantly higher than in previous reports, and this warrants further investigation in a controlled setting. In addition, almost a third (30%) of the children over 6 years of age in our study were diagnosed with ADHD. Because this was a retrospective study, we did not have access to the children's ADHD phenotype.
However, other studies have reported that EPT born children with ADHD are most likely to be affected by the inattentive subtype and associated intellectual disabilities. 5,6,37 More than half of all children (52%) in our study had been diagnosed with speech disorders, including impaired articulation and language development, and 13% had vocal cord paresis, which may impact both their voice and their respiration. 38 It is challenging to achieve optimal growth in those born EPT during the neonatal period and childhood. One study reported that children who were born EPT demonstrated catch-up growth in weight and length during childhood, but not head circumference. 13 Poor growth and gastrointestinal problems were common in our study, and 29% had severe constipation.
We found that 7% of the cohort were diagnosed with nephrocalcinosis or nephritis. Nephrocalcinosis is common after EPT birth, but usually resolves during childhood. 39 However, children born EPT are three times as likely to have chronic kidney disease as those born at term. 40 The majority (63%) of the children in our study had been diagnosed with asthma and/or childhood bronchopulmonary dysplasia, but these diagnoses are often difficult to distinguish from each other and are not consistently applied in different regions. In comparison, another study reported asthma-like disease in 40% of children born EPT and in 15% of controls born at term. 41 Functional difficulties, such as asthma and cerebral palsy, have been linked to anxiety and depression, which are commonly found in children born EPT. 9 Genetic factors, including sex, influence the development of EPT. 42 It is well known that boys are more vulnerable to oxidative stress-related complications of prematurity than girls. 43 We found no differences in the diagnosis rates between boys and girls, with one exception. Boys born at 23 weeks were more frequently diagnosed with an intellectual disability than girls born at the same age, and they also had higher risks of visual impairment and habilitation referrals.
Perinatal management is challenging when infants are born EPT. 44 There are debates about whether it is right to initiate intensive care for the most immature infants and whether clinicians should withdraw or withhold life-saving actions in certain cases, especially if infants have a severe brain injury. 45

| Strengths and weaknesses
One strength of this study is that we were able to use SWEDROP, which has 98% national coverage, to identify infants born before 24 weeks. 15 In addition, this study comprised validated data from 2007-2020 including 2-13 years of follow-up for a large number of infants in a rare patient group. The diagnoses were initially retrieved from national registries, but we also examined the individual medical charts of all the children to validate and complete diagnoses.
Furthermore, the Swedish personal identification numbers issued to all citizens enabled us to track the infants and children who were transferred to other hospitals or moved to other addresses.
This retrospective file review of national Sweden data did have some limitations. A major drawback was the large age range at the latest follow-up visit, which ranged from 2 to 13 years, as some diagnoses only become apparent later in childhood. 23 A further weakness was the variations in regional policies regarding follow-up assessments, as this might have affected referrals and the age at diagnosis.

| CON CLUS ION
Our study showed that 75% of infants born EPT, before 24 weeks of gestation, were affected by neurodevelopmental disorders during childhood and 88% had somatic disorders. The most common issues included asthma and childhood bronchopulmonary dysplasia, speech disorders, intellectual disabilities, failure to thrive, ADHD and ASD. Boys were more likely to have intellectual disabilities than girls. Further studies are needed to understand functional domains and social skills as these children grow up, so that relevant support can be provided. In addition, neonatal clinical practice needs to adopt a long-term perspective and clinicians treating children and adults should be aware of the complicated health problems of children born before 24 weeks.

ACK N OWLED G EM ENT
We thank research nurse Carola Pfeiffer-Mosesson for helping to collect the medical files from the Swedish hospitals and habilitation centres and the hospital staff who supplied them.

CO N FLI C T S O F I NTE R E S T
The authors have no conflicts of interest to declare.