The Knowledge Translation of Early Cerebral Palsy (KiTE CP) Study: Implementing Screening Among a High-Risk Prospective Cohort of Australian Infants.

OBJECTIVE: To describe the implementation of the international guidelines for the early diagnosis of cerebral palsy (CP) and engagement in the screening process in an Australian cohort of infants with neonatal risk factors for CP. STUDY DESIGN: Prospective cohort study of infants with neonatal risk factors recruited at <6 months corrected age from 11 sites in the states of Victoria, New South Wales, and Queensland, Australia. First, we implemented a multimodal knowledge translation strategy including barrier identification, technology integration, and special interest groups. Screening was implemented as follows: infants with clinical indications for neuroimaging underwent magnetic resonance imaging and/or cranial ultrasound. The Prechtl General Movements Assessment (GMA) was recorded clinically or using an app (Baby Moves). Infants with absent or abnormal fidgety movements on GMA videos were offered further assessment using the Hammersmith Infant Neurological Examination (HINE). Infants with atypical findings on 2/3 assessments met criteria for high risk of CP. RESULTS: Of the 597 infants (56% male) recruited, 95% (n = 565) received neuroimaging, 90% (n = 537) had scorable GMA videos (2% unscorable/8% no video), and 25% (n = 149) HINE. Overall, 19% of the cohort (n = 114/597) met criteria for high risk of CP, 57% (340/597) had at least 2 normal assessments (of neuroimaging, GMA or HINE), and 24% (n = 143/597) had insufficient assessments. CONCLUSIONS: Early CP screening was implemented across participating sites using a multimodal knowledge translation strategy. Although the COVID-19 pandemic affected recruitment rates, there was high engagement in the screening process. Reasons for engagement in early screening from parents and clinicians warrant further contextualization and investigation.

Long-term neurodevelopmental outcome in preterm infants with intraventricular haemorrhage.

BACKGROUND: Intraventricular haemorrhage (IVH) is one of the key risks for long-term neurodevelopmental issues. There remains controversy over the impact low-grade IVH has on the long-term outcome of premature infants. This study describes the long-term neurodevelopmental impact of Grade I and II IVH in former preterm infants in the early school years. METHODS: This is a retrospective cohort analysis from one tertiary neonatal intensive care unit (NICU) in Australia including all infants born at <30 weeks' gestation and admitted to the NICU between 2006 and 2013 with complete ultrasound reports and follow-up results. Results of standardised tests for neurodevelopmental outcomes at 5 and 8 years were compared between infants who suffered mild IVH and infants who had normal head ultrasounds. RESULTS: During the study period, 491 infants <30 weeks gestation were admitted; 275 patients had full follow-up data available. We found no significant difference in examined outcomes at 5- and 8-year follow-up. CONCLUSION: Mild IVH does not affect cognitive, motor and academic outcomes at school age.

Treatment of Primary Fetal Hydrothorax with OK-432 (Picibanil): Outcome in 14 Fetuses and a Review of the Literature.

BACKGROUND: Primary fetal hydrothorax (PFHT) is an uncommon condition with an estimated prevalence of 1 in 10,000/15,000 pregnancies. Therapeutic interventions include thoracocentesis, thoraco-amniotic shunting (TAS), and pleurodesis using OK-432. METHODS: A review of the literature was performed to identify all cases of PFHT treated with TAS and OK-432. All cases of PFHT referred to the Fetal Maternal Unit at Royal Prince Alfred Hospital between 2002 and 2012 were retrospectively reviewed. In the cohort of fetuses treated with OK-432, the main perinatal outcomes evaluated were termination of pregnancy, live birth, neonatal death, and fetal death in utero. Secondary outcomes included gestational age (GA) at diagnosis, GA at treatment, GA at resolution, birth weight, and GA at birth. The development of the children was screened using the Ages and Stages Questionnaires, Version 3 (ASQ-3, 2009). RESULTS: Primary hydrothorax was diagnosed in 31 fetuses, of which 14 had treatment with OK-432. One pregnancy terminated after treatment with OK-432. Survival was 85% (11/13): 100% in fetuses treated with OK-432 without hydrops, and 78% in those treated with hydrops. This compares well to the cases of TAS in the literature with an average survival of 63%: 85% in fetuses without hydrops and 55% with hydrops. The mean GA at birth was 36(+4) weeks and mean birth weight 3,007 g. Eight of the 9 children screened with ASQ-3 scored well within the normal range. CONCLUSION: OK-432 appears to be a valid treatment option in fetuses with PFHT, particularly in those diagnosed at early GAs.

Long term follow up of high risk children: who, why and how?

BACKGROUND: Most babies are born healthy and grow and develop normally through childhood. There are, however, clearly identifiable high-risk groups of survivors, such as those born preterm or with ill-health, who are destined to have higher than expected rates of health or developmental problems, and for whom more structured and specialised follow-up programs are warranted. DISCUSSION: This paper presents the results of a two-day workshop held in Melbourne, Australia, to discuss neonatal populations in need of more structured follow-up and why, in addition to how, such a follow-up programme might be structured. Issues discussed included the ages of follow-up, and the personnel and assessment tools that might be required. Challenges for translating results into both clinical practice and research were identified. Further issues covered included information sharing, best practice for families and research gaps. SUMMARY: A substantial minority of high-risk children has long-term medical, developmental and psychological adverse outcomes and will consume extensive health and education services as they grow older. Early intervention to prevent adverse outcomes and the effective integration of services once problems are identified may reduce the prevalence and severity of certain outcomes, and will contribute to an efficient and effective use of health resources. The shared long-term goal for families and professionals is to work toward ensuring that high risk children maximise their potential and become productive and valued members of society.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Influence of repetitive UVA stimulation on skin protection capacity and antioxidant efficacy.

BACKGROUND/AIMS: Topically applied antioxidants (AOs) are widely used in cosmetic products - especially in day and sun care - to help reduce oxidative stress caused by exogenous influences such as ultraviolet (UV) radiation. Despite several advances in recent years, little is known about the duration of protective effects by application of topical AOs, AO protection capacity (APC) or the activation of an endogenous protection capacity (EPC). METHODS: By measuring oxidative-stress-induced photon emission of human skin in vivo with the ICL-S method (induced chemiluminescence of human skin), the protective effect of daily AO treatment for 2 weeks was examined on 4 consecutive days after treatment. UVA-dose-independent effects were investigated by decay curve intersection point analysis. In addition, chemiluminescence signal integration was used to investigate the influence of different UVA doses for stimulation on the determined APC as well as the modulation of the EPC by repetitive UVA stimulation both forming the skin protection capacity (SPC). RESULTS: The SPC showed a strong dependency on the UVA dose used for stimulation. AO pretreatment was more effective against lower UVA doses. Over the course of 4 days, the AO-induced SPC did not change significantly for a given UVA dose. Analyzing the decay curve intersection point for 2 different UVA doses, however, revealed a decrease in SPC with time. In addition, we found that a repetitive UVA irradiation of 1 J/cm(2) caused a statistically significant protective effect against UVA irradiation by stimulation of endogenous mechanisms. CONCLUSION: Topically supplemented AOs provide a protective effect against oxidative stress for at least 3 days, supporting their widespread use in cosmetic products. Especially their interaction with cutaneous protective mechanisms should be investigated in more detail for maximal protection, as endogenous defense mechanisms are already triggered by 2 low-dose UVA irradiations within 24 h. In summary, the in vivo measurement of UVA-induced cutaneous chemiluminescence permits the UVA-dose-independent determination of the AO efficacy for better comparability of the results while also taking endogenous defense mechanisms into account.

Motor impairment and low achievement in very preterm children at eight years of age.

AIM: To examine the concurrence of motor impairment and academic underachievement in a group of very preterm children at 8 years of age. METHODS: All surviving children with a gestational age less than 30 weeks, admitted to the neonatal intensive care unit between 1987 and 1997, were prospectively enrolled in developmental follow-up. Children with a neurosensory disability or a low intelligence score (FSIQ < or = 75 points) were excluded. At 8 years of age the Bruininks Oseretsky Test of Motor Proficiency and standardised tests of academic achievement were administered to a sample of 323 very preterm children. RESULTS: One hundred and one (31.3%) of these very preterm children were identified as having Developmental Coordination Disorder (DCD). Of the children with DCD, 54.4% also had underachievement in literacy and/or numeracy. As the severity of motor impairment increased so too did the severity and complexity of underachievement. Significantly fewer children with motor impairments participated in after-school sporting activities. Children with DCD required more mechanical ventilation support during their hospital admission. CONCLUSIONS: This study demonstrated that a significant proportion of children born very preterm find both motor and academic skills difficult in early school years.

Phonology, rapid naming and academic achievement in very preterm children at eight years of age.

AIM: To examine the impact and additive effect of phonology and rapid naming deficits on reading, spelling and mathematics achievement in a group of very preterm children at 8 years of age. METHODS: All surviving children with a gestational age less than 30 weeks, admitted to the neonatal intensive care unit at Royal Prince Alfred Hospital, in 1994 and 1995, were prospectively enrolled in developmental follow-up. Children with a neurosensory disability or a low intelligence score (FSIQ

Educational and therapeutic resource dependency at early school-age in children who were born very preterm.

AIM: To examine the incidence of educational and therapeutic resource dependency in a group of very preterm children at 8 years of age. METHODS: All children with a gestational age less than 30 weeks, who survived to discharge from the neonatal intensive care unit at Royal Prince Alfred Hospital, between 1987 and 1994, were prospectively enrolled in developmental follow-up. At 8 years of age, information regarding resource dependency was obtained from parents and teachers using interviews and questionnaires. Standardized psychometric measures of cognition and academic achievement were administered. RESULTS: Information was obtained for 365 (73.3%) of surviving 8-year-old children; 65 (17.8%) had a neurosensory disability and 24 (36.9%) children in this group were in full-time special education. In those without neurosensory disability (n=300), seven (2.3%) children were already in full-time special education for an intellectual deficit. Among children in mainstream education, 154/293 (52.5%) had received or were still receiving additional assistance in some form (part-time special education, grade retention, therapeutic intervention or private tutoring). Difficulty in literacy was the most commonly reported problem. Resource dependency was not related to gestation nor predicted by intelligence in children without neurosensory disability, but was related to maternal education. Children who had had or were continuing to receive part-time assistance showed delays in academic skills at assessment. CONCLUSIONS: A high level of on-going resource dependency exists in this group in an attempt to maintain grade appropriate achievement. Resource dependency is not related to gestation in neurologically normal children. General cognitive measures of intelligence do not predict these problems in the majority of children.

Assessment of neurological status in preterm infants in neonatal intensive care and prediction of cerebral palsy.

The purpose of this study was to determine the diagnostic accuracy of a neurological assessment performed before discharge from the nursery to predict cerebral palsy at three years of age in preterm infants. Infants born < 31 weeks gestation between 1992 and 1996 were assessed using the Lacey Assessment of the Preterm Infant (LAPI) prior to discharge. Infants were classified as having no abnormality, possible abnormality, or definite abnormality. At three years of age, the infants had a neurological examination. Infants were stratified into those assessed at < or = 33 weeks postmenstrual age and those assessed at least once > 33 weeks postmenstrual age. Of the 203 infants, 36 were diagnosed with cerebral palsy at three years. Seven were assessed < or = 33 postmenstrual age and 29 were assessed > 33 weeks postmenstrual age. For infants assessed < or = 33 weeks and classified as having any abnormality (possible or definite), the LAPI had 86% sensitivity, 83% specificity, and 96% negative predictive value for subsequent cerebral palsy. The LAPI was less accurate when applied to infants < 33 weeks postmenstrual age. The LAPI is an accurate diagnostic tool in the preterm period for the prediction of normal motor development or cerebral palsy at three years of age. This information may be used to target intervention.

Predicting the outcome of specific language impairment at five years of age through early developmental assessment in preterm infants.

BACKGROUND: Very preterm infants (<30 weeks of gestation) are at increased risk of specific language impairment and systematic developmental follow-up is essential for the provision of targeted early intervention. AIMS: To define the predictive value of early language testing and stability of language development, and perinatal and demographic risk factors for the diagnosis of SLI at 5 years, in a cohort of preterm infants. STUDY DESIGN: We used a retrospective hospital based cohort study. SUBJECTS: Preterm infants <30 weeks of gestation, were cared for in NICU at RPAH, between 2004 and 2007, and prospectively enrolled in developmental follow-up. Standardised developmental assessment was done at 3 years utilising the Bayley Scales of Infant and Toddler Development-III and the Wechsler Preschool and Primary Scale of Intelligence-III was done at 5 years. OUTCOME MEASURES: Predictive value and stability of early language testing were assessed with respect to SLI at 5 years, using measures of diagnostic accuracy and kappa values. Multivariate logistic regression was performed during the distribution of perinatal and demographic risk factors for SLI. RESULTS: One-in-five met diagnostic criteria for SLI (19%, n=24). Limited diagnostic accuracy was found with early expressive language and the stability of language scores demonstrated only fair agreement (Cohen's κ .383). Multilingual status and extreme gestational age at 24-25 weeks were associated with a six-fold increased risk of SLI (OR 6.09, 95% CI 1.89-19.56; OR 6.09, 95% CI 1.28-29.0). CONCLUSION: We defined a high incidence of SLI among our cohort, but only a limited diagnostic accuracy of early language testing. Multilingual status and extreme prematurity were independent risk factors for SLI. It remains imperative to perform continued developmental assessments beyond pre-school age to identify language impairment with greater accuracy.

Low superior vena cava flow and effect of inotropes on neurodevelopment to 3 years in preterm infants.

OBJECTIVE: The goal was to report the 1- and 3-year outcomes of preterm infants with low systemic blood flow in the first day and the effect of dobutamine versus dopamine for treatment of low systemic blood flow. METHODS: A cohort of 128 infants born at <30 weeks of gestation underwent echocardiographic measurement of superior vena cava flow at 3, 10, and 24 hours of age. Forty-two infants with low superior vena cava flow (<41 mL/kg per minute) were assigned randomly to dobutamine or dopamine. Surviving infants underwent blinded neurodevelopmental assessments at corrected ages of 1 and 3 years. RESULTS: Seventy-six of 87 surviving infants were seen at 1 year and 67 at 3 years. Forty-four infants had low superior vena cava flow. At 3 years, with adjustment for perinatal risk factors, death was predicted by low superior vena cava flow, lower gestational age, and low 5-minute Apgar score. Substantial reductions in the Griffiths General Quotient were associated with low superior vena cava flow and birth weight of <10th percentile. Infants with low flow had significant reductions in personal-social, hearing and speech, and performance subscales. Death or disability at 3 years was predicted by low superior vena cava flow and lower gestational age. For infants treated with inotropes, no significant differences were found in clinical outcomes, except for reduced rates of late severe periventricular/intraventricular hemorrhage in the dobutamine group. At 3 years, infants in the dopamine group had significantly more disability and a lower Griffiths General Quotient. At the latest time measured, however, combined rates of death or disability were similar. CONCLUSIONS: Early low superior vena cava flow was associated with substantial rates of death, morbidity, and developmental impairments. No difference was found in combined rates of death and disability for infants assigned randomly to dopamine or dobutamine.

Low superior vena cava flow and neurodevelopment at 3 years in very preterm infants.

OBJECTIVES: Low superior vena cava (SVC) flow is common in the first hours after very preterm birth and has a strong association with subsequent periventricular/intraventricular hemorrhage. We report the neurodevelopmental outcome at 3 years of age of very preterm babies who had serial echocardiographic studies, including measures of SVC flow, during the first 48 hours after birth. STUDY DESIGN: A prospective observational study was performed on a cohort of 126 babies (<30 weeks), 103 of whom survived to discharge. Neurodevelopmental follow-up data, which included abnormal developmental quotient, abnormal motor score, and cerebral palsy, were available for 93% of this cohort at 3 years of age. Relations between 3-year outcome and early hemodynamic measures and clinical parameters were explored. RESULTS: After controlling for confounding variables, average SVC flow over the first 24 hours of life was significantly associated with the primary outcome of death or survival with any disability (P=.004) and with the secondary outcome of abnormal developmental quotient (P = .006). A greater number of low SVC flow readings during the first 24 hours was significantly related to death and adverse developmental outcome, but the individual lowest SVC flow was not, suggesting the importance of duration of low SVC flow. After adjustment, there was no significant association between average mean blood pressure over the first 24 hours and abnormal developmental outcome, whereas the proportion of mean blood pressure readings less than the gestational age showed a trend toward an association with death and any disability. CONCLUSIONS: Low early postnatal blood flow to the upper body and brain may be one factor in the causal pathway of impaired preterm neurodevelopmental outcome.