Caffeine for apnea of prematurity and brain development at 11 years of age

Objective Caffeine therapy for apnea of prematurity has been reported to improve brain white matter microstructure at term-equivalent age, but its long-term effects are unknown. This study aimed to investigate whether caffeine affects (1) brain structure at 11 years of age, and (2) brain development from term-equivalent age to 11 years of age, compared with placebo. Methods Preterm infants born ≤1250 g were randomly allocated to caffeine or placebo. Magnetic resonance imaging (MRI) was performed on 70 participants (33 caffeine, 37 placebo) at term-equivalent age and 117 participants (63 caffeine, 54 placebo) at 11 years of age. Global and regional brain volumes and white matter microstructure were measured at both time points. Results In general, there was little evidence for differences between treatment groups in brain volumes or white matter microstructure at age 11 years. There was, however, evidence that the caffeine group had a smaller corpus callosum than the placebo group. Volumetric brain development from term-equivalent to 11 years of age was generally similar between treatment groups. However, there was evidence that caffeine was associated with slower growth of the corpus callosum, and slower decreases in axial, radial, and mean diffusivities in the white matter, particularly at the level of the centrum semiovale, over time than placebo. Interpretation This study suggests any benefits of neonatal caffeine therapy on brain structure in preterm infants weaken over time and are not clearly detectable by MRI at age 11 years, although caffeine may have long-term effects on corpus callosum development.Claire E. Kelly, Wenn Lynn Ooi, Joseph Yuan-Mou Yang, Jian Chen, Chris Adamson, Katherine J. Lee ... et al

Changing consumption of resources for respiratory support and short-term outcomes in four consecutive geographical cohorts of infants born extremely preterm over 25 years since the early 1990s

OBJECTIVES:It is unclear how newer methods of respiratory support for infants born extremely preterm (EP; 22-27 weeks gestation) have affected in-hospital sequelae. We aimed to determine changes in respiratory support, survival and morbidity in EP infants since the early 1990s. DESIGN:Prospective longitudinal cohort study. SETTING:The State of Victoria, Australia. PARTICIPANTS:All EP births offered intensive care in four discrete eras (1991-1992 (24 months): n=332, 1997 (12 months): n=190, 2005 (12 months): n=229, and April 2016-March 2017 (12 months): n=250). OUTCOME MEASURES:Consumption of respiratory support, survival and morbidity to discharge home. Cost-effectiveness ratios describing the average additional days of respiratory support associated per additional survivor were calculated. RESULTS:Median duration of any respiratory support increased from 22 days (1991-1992) to 66 days (2016-2017). The increase occurred in non-invasive respiratory support (2 days (1991-1992) to 51 days (2016-2017)), with high-flow nasal cannulae, unavailable in earlier cohorts, comprising almost one-half of the duration in 2016-2017. Survival to discharge home increased (68% (1991-1992) to 87% (2016-2017)). Cystic periventricular leukomalacia decreased (6.3% (1991-1992) to 1.2% (2016-2017)), whereas retinopathy of prematurity requiring treatment increased (4.0% (1991-1992) to 10.0% (2016-2017)). The average additional costs associated with one additional infant surviving in 2016-2017 were 200 (95% CI 150 to 297) days, 326 (183 to 1127) days and 130 (70 to 267) days compared with 1991-1992, 1997 and 2005, respectively. CONCLUSIONS:Consumption of resources for respiratory support has escalated with improved survival over time. Cystic periventricular leukomalacia reduced in incidence but retinopathy of prematurity requiring treatment increased. How these changes translate into long-term respiratory or neurological function remains to be determined.Jeanie L Y Cheong, Joy E Olsen, Li Huang, Kim M Dalziel, Rosemarie A Boland, Alice C Burnett ... et al

Moderate and late preterm birth: effect on Brain size and maturation at term-equivalent age

PURPOSE: To compare the size of multiple brain structures, maturation in terms of both brain myelination and gyral development, and evidence of brain injury between moderate and late preterm (MLPT) and term-born infants at term-equivalent age. MATERIALS AND METHODS: The study was approved by the human research ethics committees of the participating hospitals, and informed parental consent was obtained for all infants. One hundred ninety-nine MLPT and 50 term-born infants underwent 3-T magnetic resonance (MR) imaging brain examinations at 38-44 weeks of corrected gestational age. T1- and T2-weighted MR images were compared between groups for size of multiple cerebral structures, degree of myelination in the posterior limb of the internal capsule, gyral maturation, signal intensity abnormalities, and presence of cysts by a single assessor who was blinded to the gestational group and perinatal course of the infants. Group differences were compared by using linear regression for continuous variables and logistic regression for categorical variables, and interrater and intrarater reliability was assessed by using intraclass correlation coefficients. RESULTS: Compared with those in the term-born control group, measurements of brain biparietal diameter, corpus callosum, basal ganglia and thalami, and cerebellum were smaller in infants in the MLPT group (all P ≤ .01), while extracerebral space was larger (P < .0001). Myelination of the posterior limb of the internal capsule was less developed, and gyral maturation was delayed in the MLPT group (both P < .001). Signal intensity abnormalities and cysts were uncommon in both groups, with 13 (6.5%) MLPT infants and one (2%) term infant having abnormalities. Inter- and intrarater reliability was good for most measures, with intraclass correlation coefficients generally greater than 0.68. CONCLUSION: MLPT birth is associated with smaller brain size, less-developed myelination of the posterior limb of the internal capsule, and more immature gyral folding than those associated with full-term birth. These brain changes may form the basis of some of the long-term neurodevelopmental deficits observed in MLPT children. Online supplemental material is available for this article.Jennifer M. Walsh, Lex W. Doyle, Peter J. Anderson, Katherine J. Lee, Jeanie L. Y. Cheon

Early developmental screening and intervention for high-risk neonates - from research to clinical benefits

With advances in neonatal care there has been an increase in survival rates for infants born very preterm and/or with complex needs, such as those who require major surgery, who may not have survived decades ago. Despite advances in survival, these infants remain at high-risk for a range of neurodevelopmental delays and/or impairments including motor, cognitive and emotional/behavioural challenges. Research has improved our ability to identify which infants are at high-risk of developmental delay and/or impairments, and there is mounting evidence that early interventions can improve outcomes of these infants. However, clinical practice varies throughout the world regarding recommendations for developmental screening. Moreover, intervention, when available, is often not commenced early enough in development. Given limited resources, those infants most at risk of developmental impairments and their families should be targeted, with further research needed on the cost-effectiveness of surveillance and early interventions.Alicia Jane Spittle, Peter John Anderson, Sarah Jane Tapawan, Lex William Doyle, Jeanie Ling Yoong Cheon

Executive function and academic outcomes in children who were extremely preterm

OBJECTIVES: Cognitive and behavioral impairments of children born extremely preterm (EP) (<28 weeks’ gestation) and extremely low birth weight (ELBW) (<1000 g) may change with age. We assessed the individual stability of behavioral executive function (EF) from 8 to 18 years of age in children born EP or ELBW and their academic outcomes. METHODS: Participants comprised 180 children born EP or ELBW from a large geographic cohort. We investigated the frequency of 4 developmental groups (persistent, remitting, late-onset, and typical development) on the basis of dichotomized scores (typical versus elevated) at ages 8 and 18 years in 2 indices (the Behavioral Regulation Index [BRI] and the Metacognition Index [MCI]) of the parental form of the Behavior Rating Inventory of Executive Function. Adolescent academic outcomes were measured by using the word reading, spelling, and math computation subtests of the Wide Range Achievement Test, Fourth Edition. RESULTS: Most participants had a typical EF (BRI 61%, MCI 53%), followed by persistent (BRI 15%, MCI 16%), late-onset (BRI 12%, MCI 19%), or remitting (BRI 12%, MCI 13%) executive difficulties. Groups with executive impairments at age 18 years (persistent and late onset) had poorer academic outcomes than the typical and remitting groups. Shifting impairment categories between 8 and 18 years old was relevant to later academic outcomes. CONCLUSIONS: Most children showed stable and age-appropriate EF, although persistent and transient difficulties were observed and related to uneven academic outcomes. Studying the origins and consequences of the developmental stability of EF may contribute to the development of interventions to decrease the adverse neurodevelopmental outcomes of preterm birth.Danielle S. Costa, Débora M. Miranda, Alice C. Burnett, Lex W. Doyle, Jeanie L.Y. Cheong, Peter J. Anderson, on behalf of the Victorian Infant Collaborative Study Grou

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.Stacey Peart, Jeanie Ling Yoong Cheong, Gehan Roberts, Noni Davis, Peter J Anderson, Lex W Doyle, for the Victorian Infant Collaborative Study Grou

Biological and social influences on outcomes of extreme-preterm/low-birth weight adolescents

BACKGROUND AND OBJECTIVES: The importance of biological versus social influences on long-term outcomes of extremely preterm children is debatable. The goal of this study was to determine the relative contributions of biological and social exposures to outcomes into adolescence in extremely preterm survivors, hypothesizing that biological exposures would be more important early, but social exposures would dominate later. METHODS: The study included 298 consecutive survivors born at 2499 g) control subjects who were used to standardize outcomes for the preterm group. Cognitive ability was assessed at 2, 5, 8, and 18 years of age. Academic achievement was assessed at 8 and 18 years of age. RESULTS: The differences between the preterm and control groups for cognitive and academic scores remained relatively constant over time. The biological variables most associated with worse outcomes within the extremely preterm group were intraventricular hemorrhage and postnatal corticosteroid therapy. Of the social variables, being reared in a multilingual household was disadvantageous early, with social class and maternal education becoming more important for later outcomes. The strength of the biological associations mostly equaled or exceeded those of social exposures, even in late adolescence. CONCLUSIONS: Contrary to expectations, several perinatal biological exposures had large and persistent adverse associations with cognitive and academic outcomes among extremely preterm survivors. As expected, some social variables assumed increasing importance in later years but mostly did not diminish or exceed the important biological associations.Lex W. Doyle, Jeanie L.Y. Cheong, Alice Burnett, Gehan Roberts, Katherine J. Lee, Peter J. Anderson and for the Victorian Infant Collaborative Study Grou

Early surgery and neurodevelopmental outcomes of children born extremely preterm

To (1) compare the neurodevelopmental outcomes at 8 years of age of children born extremely preterm (EP) who underwent surgical procedures during the course of their initial hospital admission with those who did not and (2) compare the outcomes across eras, from 1991 to 2005.Prospective observational cohort studies conducted over three different eras (1991-1992, 1997 and 2005). Surviving EP children, who required surgical intervention during the primary hospitalisation, were assessed for general intelligence (IQ) and neurosensory status at 8 years of age. Major neurosensory disability comprised any of moderate/severe cerebral palsy, IQ less than -2 SD relative to term controls, blindness or deafness.Overall, 29% (161/546) of survivors had surgery during the newborn period, with similar rates in each era. Follow-up rates at 8 years were high (91%; 499/546), and 17% (86/499) of survivors assessed had a major neurosensory disability. Rates of major neurosensory disability were substantially higher in the surgical group (33%; 52/158) compared with those who did not have surgery (10%; 34/341) (OR 4.28, 95% CI 2.61 to 7.03). Rates of disability in the surgical group did not improve over time. After adjustment for relevant confounders, no specific surgical procedure was associated with increased risk of disability.Major neurosensory disability at 8 years was higher in children born EP who underwent surgery during their initial hospital admission compared with those who did not. The rates of major neurosensory disability in the surgical cohort are not improving over time.Rodney W Hunt, Leah M Hickey, Alice C Burnett, Peter J Anderson, Jeanie Ling Yoong Cheong, Lex W Doyl

The relationship between ventricular size at 1 month and outcome at 2 years in infants less than 30 weeks' gestation

Background: Cranial ultrasound cerebral biometric measurements have been used in preterm neonates, particularly in cases of ventriculomegaly. While cerebral biometric measures using MRI have been found to correlate with long-term outcome, the relationship between cranial ultrasound biometric measures and neurodevelopmental outcome has not been established. Objective To assess the relationship between ventricular size at 1 month of age using cranial ultrasound and neurodevelopmental outcome at 2 years in very preterm infants. Method Digital cranial ultrasound images taken between 25 and 35 days of age of 44 infants born at less than 30 weeks’ gestation were analysed independently by two observers. Infants with significant ultrasound abnormalities were excluded. A range of ultrasound linear measures were correlated with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) motor, language and cognitive composite scores at 2 years using linear regression. Results Larger lateral ventricular sizes (anterior horn width, ventricular height, midbody ventricular height) and larger ventricular-brain biparietal ratios were related to poorer motor composite score at 2 years. A ventricular-brain ratio of less than 0.3 was reassuring with regard to motor outcome. Poorer language composite scores at 2 years were associated with larger midbody ventricular heights. There was little evidence of a relationship with the cognitive composite score. Conclusions Larger lateral ventricles in the parietal region at a month of age were related to poorer motor development at 2 years. Larger ventricular measurements were also related to slower early language development. The role of cranial ultrasound biometric measures as biomarkers of later outcome in very preterm infants warrants further investigation.ultrasound biometric measures and neurodevelopmental outcome has not been established. OBJECTIVE: To assess the relationship between ventricular size at 1 month of age using cranial ultrasound and neurodevelopmental outcome at 2 years in very preterm infants. METHOD: Digital cranial ultrasound images taken between 25 and 35 days of age of 44 infants born at less than 30 weeks' gestation were analysed independently by two observers. Infants with significant ultrasound abnormalities were excluded. A range of ultrasound linear measures were correlated with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) motor, language and cognitive composite scores at 2 years using linear regression. RESULTS: Larger lateral ventricular sizes (anterior horn width, ventricular height, midbody ventricular height) and larger ventricular-brain biparietal ratios were related to poorer motor composite score at 2 years. A ventricular-brain ratio of less than 0.3 was reassuring with regard to motor outcome. Poorer language composite scores at 2 years were associated with larger midbody ventricular heights. There was little evidence of a relationship with the cognitive composite score. CONCLUSIONS: Larger lateral ventricles in the parietal region at a month of age were related to poorer motor development at 2 years. Larger ventricular measurements were also related to slower early language development. The role of cranial ultrasound biometric measures as biomarkers of later outcome in very preterm infants warrants further investigation.Lisa M Fox, Pauline Choo, Sheryle R Rogerson, Alicia J Spittle, Peter J Anderson, Lex Doyle, Jeanie L Y Cheon

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.Jeanie L.Y. Cheong, Peter J. Anderson, Alice C. Burnett, Gehan Roberts, Noni Davis, Leah Hickey … et al. (the Victorian Infant Collaborative Study Group