Increasing airway obstruction from 8 to 18†years in extremely preterm/low-birthweight survivors born in the surfactant era.

BACKGROUND: The evolution of airway obstruction into late adolescence of extremely preterm (gestational age <28 weeks) or extremely low-birthweight (birth weight <1000 g) survivors in the era after surfactant was introduced is unclear. OBJECTIVE: To compare changes in spirometry from 8 to 18 years of age of a geographical cohort of preterm survivors with normal birth weight controls, and to determine higher risk groups within the preterm cohort. METHODS: Of 297 extremely preterm/low-birthweight survivors born in 1991-1992 in the state of Victoria, Australia, 81% and 70% had spirometry at 8 and 18 years of age, respectively. Corresponding rates among 260 normal birth weight controls were 80% and 58%, respectively. Data were analysed using linear mixed models. RESULTS: The preterm group had substantial impairments in airflow at both ages compared with controls (eg, mean differences in z-score for FEV1; 8 years -1.02, 95% CI -1.21 to -0.82; 18 years -0.92, 95% CI -1.14 to -0.71). The preterm group had a greater increase in small airway obstruction between 8 and 18 years compared with controls. Within the preterm group, those who had bronchopulmonary dysplasia in the newborn period and those who were smokers at 18 years had airway obstruction that increased over time compared with those who did not. CONCLUSIONS: Preterm survivors born in the surfactant era had significant impairments in airflow through childhood into late adolescence that increased over time compared with controls. At-risk preterm participants include those who had bronchopulmonary dysplasia, and smokers at 18 years.

The cost of long-term follow-up of high-risk infants for research studies.

AIMS: Neonatal intensive care is expensive, and thus it is essential that its long-term outcomes are measured. The costs of follow-up studies for high-risk children who survive are unknown. This study aims to determine current costs for the assessment of health and development of children followed up in our research programme. METHODS: Costs were determined for children involved in the research follow-up programme at the Royal Women's Hospital, Melbourne, over the 6-month period between 1st January 2012 and 30th June 2012. The time required for health professionals involved in assessments in early and later childhood was estimated, and converted into dollar costs. Costs for equipment and data management were added. Estimated costs were compared with actual costs of running the research follow-up programme. RESULTS: A total of 134 children were assessed over the 6-month period. The estimated average cost per child assessed was $1184, much higher than was expected. The estimated cost to assess a toddler was $1149, whereas for an 11-year-old it was $1443, the difference attributable to the longer psychological and paediatric assessments. The actual average cost per child assessed was $1623. The shortfall of $439 between the actual and estimated average costs per child arose chiefly because of the need to pay staff even when participants were late or failed to attend. CONCLUSIONS: The average costs of assessing children at each age for research studies are much higher than expected. These data are useful for planning similar long-term follow-up assessments for high-risk children.

Developmental coordination disorder in geographic cohorts of 8-year-old children born extremely preterm or extremely low birthweight in the 1990s.

AIM: The aim of the study was to examine the prevalence of developmental coordination disorder (DCD) at the age of 8 years in a geographic cohort of extremely preterm or extremely-low-birthweight (EP/ELBW) children and a term-born comparison group, as well as associated academic outcomes, parents' perceptions of motor performance, and changes in prevalence during the 1990s. METHOD: Moderate DCD was defined as a score below the 5th centile on the Movement Assessment Battery for Children in children without cerebral palsy or intellectual impairment. DCD rates were compared in a group of 132 8-year-old children born in 1997 at 22 to 27 weeks' gestation or birthweight of less than 1000 g (49% male, 51% female) and a comparison group of 154 term-born children (55% male, 45% female). The Wechsler Intelligence Scale for Children - 4th edition and the Wide Range Achievement Test - 3rd edition were used to measure academic and cognitive outcomes. Parental perceptions of motor performance were measured using the physical function scale of the Child Health Questionnaire, parent-report form (CHQ PF50). The results for children with and without DCD were then compared. To assess changes in prevalence throughout the 1990s, DCD rates were compared with those found in children from the same region born in 1991 to 92. RESULTS: The mean number of completed weeks of gestation in the EP/ELBW children and in the comparison group of term-born children for whom data were available for analysis was 26.5 (SD 1.9) and 39.2 (SD 1.1) respectively, and the mean birthweight was 830 g (SD 163) and 3511 g (SD 462) respectively. The prevalence of DCD was 16% in the EP/ELBW group and 5% in the comparison group (odds ratio 3.45; 95% confidence interval [CI] 1.47-8.09%). Academic outcomes for reading, spelling, and arithmetic were poorer among children with DCD than among those without DCD (mean difference [95% CI] 10.2 [0.9-19.7; p=0.03], 8.9 [2.2-15.5; p=0.01], and 7.9 [1.4-14.5; p=0.02] respectively). Parental perceptions were poorly predictive of DCD. INTERPRETATION: EP/ELBW children have higher rates of DCD and experience more academic difficulties than term-born children. As parental perceptions are not a reliable screen, clinical assessments of motor skills in this vulnerable population are important.

Changes over time in quality of life of school-aged children born extremely preterm: 1991-2005.

OBJECTIVE: To compare health-related quality of life (HRQOL) at 8 years in children born extremely preterm (EP) with contemporaneous term-born controls over three epochs: 1991-92, 1997 and 2005. DESIGN: Prospective recruitment of geographic cohorts across three distinct eras. Utilities were calculated from the parent-completed Health Utilities Index (HUI), version 2 (1991-92 and 1997 cohorts) and version 3 (2005 cohort). Differences in utilities >0.05 are clinically important. SETTING: The state of Victoria, Australia. PATIENTS: 475 EP (<28 weeks' gestation) and 570 term controls. MAIN OUTCOME MEASURES: Utilities of children born EP compared with term controls within each era, and paired differences between an EP and matched controls compared across eras. RESULTS: Overall, 86% of survivors had utility data at 8 years of age; 475 EP and 570 controls. In all eras, parent-reported utilities were lower for children born EP compared with controls (difference in medians (95% CIs); 1991-92, -0.053 (-0.071 to -0.035); 1997, -0.053 (-0.072 to -0.034); 2005, -0.082 (-0.097 to -0.068)). Mean differences (MD) between EP children and matched controls within each era were lower in the 2005 cohort compared with both the 1991-92 cohort (MD -0.054, 95% CI -0.097 to -0.010) and the 1997 cohort (MD -0.053, 95% CI -0.097 to -0.009). CONCLUSION: Children born EP in the postsurfactant era have clinically important reductions in parent-reported HRQOL compared with controls, which may be worsening over time.

Temporal Trends in Neurodevelopmental Outcomes to 2 Years After Extremely Preterm Birth.

Importance: Survival of infants born extremely preterm (EP) (<28 weeks' gestation) has increased since the early 1990s. It is necessary to know whether increased survival is accompanied by increased neurodevelopmental disability. Objective: To examine changes in major (ie, moderate or severe) neurodevelopmental disability and survival free of major neurodevelopmental disability at 2 years in infants born EP. Design, Setting, and Participants: Four prospective longitudinal cohort studies comprising all EP live births at 22 to 27 weeks' gestation from April 1, 2016, to March 31, 2017, and earlier eras (1991-1992, 1997, and 2005), and contemporaneous term-born controls in the state of Victoria, Australia. Among 1208 live births during the periods studied, data were available for analysis of 2-year outcomes in 1152 children: 422 (1991-1992), 215 (1997), 263 (2005), and 252 (2016-2017). Data analysis was performed from September 17, 2020, to April 15, 2021. Exposures: Extreme preterm live birth. Main Outcomes and Measures: Survival, blindness, deafness, cerebral palsy, developmental delay, and neurodevelopmental disability at 2 years' corrected age. Developmental delay comprised a developmental quotient less than -1 SD relative to the control group means on the Bayley Scales for each era. Major neurodevelopmental disability comprised blindness, deafness, moderate to severe cerebral palsy, or a developmental quotient less than -2 SDs. Individual neurodevelopmental outcomes in each era were contrasted relative to the 2016-2017 cohort using logistic regression adjusted for gestational age, sex, birth weight z score, and sociodemographic variables. Changes in survival free of major neurodevelopmental disability over time were also assessed using logistic regression. Results: Survival to 2 years was highest in 2016-2017 (73% [215 of 293]) compared with earlier eras (1991-1992: 53% [225 of 428]; 1997: 70% [151 of 217]; 2005: 63% [170 of 270]). Blindness and deafness were uncommon (<3%). Cerebral palsy was less common in 2016-2017 (6%) than in earlier eras (1991-1992: 11%; 1997: 12%; 2005: 10%). There were no obvious changes in the rates of developmental quotient less than -2 SDs across eras (1991-1992: 18%; 1997: 22%; 2005: 7%; 2016-2017: 15%) or in rates of major neurodevelopmental disability (1991-1992: 20%; 1997: 26%; 2005: 15%; 2016-2017: 15%). Rates of survival free of major neurodevelopmental disability increased steadily over time: 42% (1991-1992), 51% (1997), 53% (2005), and 62% (2016-2017) (odds ratio, 1.30; 95% CI, 1.15-1.48 per decade; P < .001). Conclusions and Relevance: These findings suggest that survival free of major disability at age 2 years in children born EP has increased by an absolute 20% since the early 1990s. Increased survival has not been associated with increased neurodevelopmental disability.

Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation.

OBJECTIVE: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). METHODS: Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. RESULTS: Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. CONCLUSION: We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

Changing Neurodevelopment at 8 Years in Children Born Extremely Preterm Since the 1990s.

BACKGROUND AND OBJECTIVE: Survival of extremely preterm (EP; <28 weeks' gestation) infants has increased over the last 2 decades. Equivalent reductions in developmental morbidity in early childhood have not been consistently reported. The aim of this study was to determine trends in neurodevelopmental outcomes at 8 years of age of children born EP (22-27 completed weeks' gestation) over the past 2 decades. METHODS: Population-based cohorts of all EP survivors born in the state of Victoria, Australia in 1991-1992, 1997, and 2005 were recruited at birth. At 8 years of age, general intelligence (IQ), academic achievement, and neurosensory status were assessed. Major neurosensory disability was defined as any of moderate or severe cerebral palsy, IQ <-2 SD relative to term controls, blindness, or deafness. RESULTS: Rates of major neurosensory disability were similar in all eras (1991-1992, 18%; 1997, 15%; 2005, 18%), as were rates of IQ <-2 SD, cerebral palsy, blindness, and deafness. Mean z scores for IQ were similar across eras, but there was some evidence that scores for academic achievement were lower in 2005 than in 1997, and the odds of having academic problems were higher in 2005 than in both earlier eras. These outcomes were not explained by differences in known perinatal care or sociodemographic variables between eras. CONCLUSIONS: Contrary to expectations, rates of major neurosensory disability have not improved, and academic performance is poorer at early school age in 2005 than in earlier eras for EP children born in the state of Victoria, Australia.

Growth of extremely preterm survivors from birth to 18 years of age compared with term controls.

OBJECTIVES: To determine changes in height, weight, and BMI of extremely preterm (EPT; gestational age <28 completed weeks) survivors from birth to 18 years of age, compared with term controls. METHODS: Birth, discharge, and follow-up at ages 2, 5, 8, and 18 years of consecutive EPT survivors and contemporaneous term controls born in 1991-1992 in Victoria, Australia. Weight, height, and BMI were converted to z scores and compared between groups. Height z scores at age 2 and midparental height z scores were examined as predictors of height z score at age 18 years. RESULTS: Follow-up rates were >90% until 18 years, when 166 (74%) of 225 EPT subjects and 153 (60%) of 253 controls were assessed. EPT subjects had lower weight z scores than controls at birth, with a much greater difference at discharge, which reduced progressively until age 18 years. EPT children were shorter than controls at all ages, and this difference did not alter greatly over time. BMI z scores were lower in EPT children at younger ages, but by age 18 were similar between groups. Height at age 2 was a better predictor of height at age 18 in EPT participants, compared with midparental height. CONCLUSIONS: EPT survivors were substantially lighter than term controls from birth to late adolescence, although the gap in weight steadily decreased over time from a peak at the time of discharge. The height disadvantage in EPT children compared with controls remained constant over time and BMI scores were similar at age 18 years.

Bronchopulmonary dysplasia in very low birth weight subjects and lung function in late adolescence.

OBJECTIVES: The purpose of this work was to determine the relationship between lung function in late adolescence and bronchopulmonary dysplasia, to establish whether lung function changed more from earlier in childhood in those with bronchopulmonary dysplasia, and to assess the effect of different definitions of bronchopulmonary dysplasia on respiratory outcome. METHODS: Subjects were composed of 147 survivors of birth weight <1500 g from the Royal Women's Hospital (Melbourne, Australia) born during 1977-1982 and who had lung function tests at a mean age of 18.9 years. Of the 147 subjects, 33 (22%) had bronchopulmonary dysplasia in the newborn period. Lung function was measured according to American Thoracic Society guidelines. RESULTS: All of the lung function variables reflecting airflow were substantially diminished in the bronchopulmonary dysplasia group, but lung volumes were not significantly different. More subjects in the bronchopulmonary dysplasia group had reductions in airflow in the clinically significant range (eg, forced expired volume in 1 second/forced vital capacity ratio <75%; bronchopulmonary dysplasia: 42.4% [14 of 33]; and no bronchopulmonary dysplasia: 16.4% [18/114]). Results were not substantially affected after adjustment for confounding variables, including intrauterine growth restriction or birth weight. Compared with earlier in childhood, the forced expired volume in 1 second/forced vital capacity ratio deteriorated more in bronchopulmonary dysplasia subjects between 8 and 18 years. Lung function results varied little with different definitions of bronchopulmonary dysplasia. CONCLUSIONS: Subjects of very low birth weight with bronchopulmonary dysplasia in the newborn period have poorer lung function in late adolescence than those without bronchopulmonary dysplasia, and their lung function may be deteriorating at a more rapid rate.

Health and hospitalistions after discharge in extremely low birth weight infants.

Apart from higher rates of mortality and adverse neurosensory outcome, extremely low birth weight (ELBW, birth weight 500-999 g) children have more hospital readmissions and other health problems in the early years after discharge than do normal birth weight (NBW, birth weight >2499 g) children. Respiratory illnesses, including lower respiratory infections, are the dominant cause for hospital readmission. ELBW survivors with bronchopulmonary dysplasia (BPD) have even more ill-health and hospital readmissions than do ELBW survivors without BPD. ELBW survivors require closer surveillance after discharge, not only for adverse neurosensory outcome, but also for other general health problems in early childhood.