Materials and methods
Participants comprised three cohorts of children born EP in the state of Victoria in 1991-1992, 1997 and 2005. All survivors were admitted to one of the four tertiary neonatal units in the state. Term-born controls were matched with the EP survivors for the expected date of delivery, child sex, mother’s health insurance status (private or public) and country of birth (primarily English speaking or not). Expected due date was based on obstetric ultrasound prior to 20 weeks’ gestation and was available for >90% of the cohort, otherwise menstrual history was used. Together the EP cohorts comprised 546 survivors over the three eras.14
Perinatal data, outlined in table 1, were collected during the newborn period. Cranial ultrasounds of EP infants were performed at least once during the first week of life, at 28 days and prior to discharge from the tertiary level nursery, as part of standard clinical care. IVH was graded according to Papile, with the worst grade of IVH (1 to 4) on either side recorded.3 Additionally, the presence of cystic periventricular leukomalacia (PVL) was recorded.
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Children were assessed at 8 years of age, corrected for prematurity to avoid a known bias in cognitive test scores.15 Social variables were collected, including lower social class (unskilled occupation of the main income earner in the family, or unemployed) and lower maternal education (<12 years of education for the 1991-1992 and 1997 cohorts and ≤ 12 years of education for the 2005 cohort). Intellectual, executive, academic and motor outcomes were assessed by psychologists and paediatricians blinded to perinatal details and group status. Cognitive ability was assessed using the Wechsler Intelligence Scale for Children (WISC)—Third Edition (1991-1992 cohort), WISC—Fourth Edition (1997 cohort) and the Differential Ability Scales—Second Edition (2005 cohort). Academic achievement was evaluated using the Wide Range Achievement Test: version 3 (1991-1992 and 1997 cohorts) or version 4 (2005 cohort). IQ and academic performance z-scores were generated by standardising scores against the mean values of the respective term-born control groups, adjusted for social variables.14 Impaired intellectual ability was defined as a z-score <-2. Impaired academic skills were defined as any z-score (reading, spelling and/or arithmetic) <-2. To assess EF in everyday life, the parent-completed Behaviour Rating Inventory of Executive Functioning was administered,16 with impaired EF defined as a standard score ≥65 on the Global Executive Composite, Behavioural Regulation Index or the Metacognition Index.
To assess motor skills, the Movement Assessment Battery for Children (MABC) first edition (1991-1992 and 1997 cohorts) or second edition (2005 cohort) was used. CP was diagnosed in children with loss of motor function along with abnormal tone and tendon reflexes, with severity determined by a functional classification (1991-1992 cohort) or the Gross Motor Function Classification System (1997 and 2005 cohorts).17 Motor dysfunction was defined as CP or MABC first edition <5th percentile or MABC second edition ≤5th percentile.
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Data on survival rates, intellectual ability, academic performance, motor function and executive function from these cohorts have been reported previously, but not in relation to grades of IVH.16 18 19
Data were analysed using IBM SPSS Statistics 22 and STATA/IC 15.1. The associations between different grades of IVH and dichotomous variables, such as rates of impairment at 8 years of age, were assessed using χ2 tests for trend, and between grades of IVH and continuous variables by analysis of variance. Data were then analysed by logistic regression, using generalised estimating equations to account for lack of independence in multiples within the same family. ORs for impairment were computed for IVH grades 1-2 and IVH grades 3-4, compared with the no IVH group as baseline. We added an interaction term between grade of IVH and era to the regression models to assess if any relationships between IVH and outcomes differed across eras. We did not consider imputation for missing data at 8 years was necessary because the follow-up rates were high for both cohorts: EP 91.4% and controls 85%.
Ethical approval for the different cohorts was obtained through the various Human Research Ethics Committees at the four neonatal units in the state of Victoria, Australia. Written informed consent was obtained from parents of all controls and for children born EP in 2005. In earlier cohorts, the follow-up of children born EP was considered routine clinical care.
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