Obstetrics and Gynaecology - Research Publications

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    Brain tissue microstructural and free-water composition 13 years after very preterm birth
    Kelly, C ; Dhollander, T ; Harding, IH ; Khan, W ; Beare, R ; Cheong, JLY ; Doyle, LW ; Seal, M ; Thompson, DK ; Inder, TE ; Anderson, PJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2022-07-01)
    There have been many studies demonstrating children born very preterm exhibit brain white matter microstructural alterations, which have been related to neurodevelopmental difficulties. These prior studies have often been based on diffusion MRI modelling and analysis techniques, which commonly focussed on white matter microstructural properties in children born very preterm. However, there have been relatively fewer studies investigating the free-water content of the white matter, and also the microstructure and free-water content of the cortical grey matter, in children born very preterm. These biophysical properties of the brain change rapidly during fetal and neonatal brain development, and therefore such properties are likely also adversely affected by very preterm birth. In this study, we investigated the relationship of very preterm birth (<30 weeks' gestation) to both white matter and cortical grey matter microstructure and free-water content in childhood using advanced diffusion MRI analyses. A total of 130 very preterm participants and 45 full-term control participants underwent diffusion MRI at age 13 years. Diffusion tissue signal fractions derived by Single-Shell 3-Tissue Constrained Spherical Deconvolution were used to investigate brain tissue microstructural and free-water composition. The tissue microstructural and free-water composition metrics were analysed using a voxel-based analysis and cortical region-of-interest analysis approach. Very preterm 13-year-olds exhibited reduced white matter microstructural density and increased free-water content across widespread regions of the white matter compared with controls. Additionally, very preterm 13-year-olds exhibited reduced microstructural density and increased free-water content in specific temporal, frontal, occipital and cingulate cortical regions. These brain tissue composition alterations were strongly associated with cerebral white matter abnormalities identified in the neonatal period, and concurrent adverse cognitive and motor outcomes in very preterm children. The findings demonstrate brain microstructural and free-water alterations up to thirteen years from neonatal brain abnormalities in very preterm children that relate to adverse neurodevelopmental outcomes.
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    Investigating brain structural maturation in children and adolescents born very preterm using the brain age framework
    Kelly, C ; Ball, G ; Matthews, LG ; Cheong, JL ; Doyle, LW ; Inder, TE ; Thompson, DK ; Anderson, PJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-12-18)
    Very preterm (VP) birth is associated with an increased risk for later neurodevelopmental and behavioural challenges. Although the neurobiological underpinnings of such challenges continue to be explored, previous studies have reported brain volume and morphology alterations in children and adolescents born VP compared with full-term (FT)-born controls. How these alterations relate to the trajectory of brain maturation, with potential implications for later brain ageing, remains unclear. In this longitudinal study, we investigate the relationship between VP birth and brain development during childhood and adolescence. We construct a normative 'brain age' model to predict age over childhood and adolescence based on measures of brain cortical and subcortical volumes and cortical morphology from structural MRI of a dataset of typically developing children aged 3-21 years (n = 768). Using this model, we examined deviations from normative brain development in a separate dataset of children and adolescents born VP (<30 weeks' gestation) at two timepoints (ages 7 and 13 years) compared with FT-born controls (120 VP and 29 FT children at age 7 years; 140 VP and 47 FT children at age 13 years). Brain age delta (brain-predicted age minus chronological age) was, on average, higher in the VP group at both timepoints compared with controls, however this difference had a small to medium effect size and was not statistically significant. Variance in brain age delta was higher in the VP group compared with controls; this difference was significant at the 13-year timepoint. Within the VP group, there was little evidence of associations between brain age delta and perinatal risk factors or cognitive and motor outcomes. Under the brain age framework, our results may suggest that children and adolescents born VP have similar brain structural developmental trajectories to term-born peers between 7 and 13 years of age.
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    Very Preterm Early Motor Repertoire and Neurodevelopmental Outcomes at 8 Years
    Salavati, S ; Bos, AF ; Doyle, LW ; Anderson, PJ ; Spittle, AJ (AMER ACAD PEDIATRICS, 2021-09-01)
    BACKGROUND AND OBJECTIVES: Children born very preterm (<32 weeks' gestation) have more neurodevelopmental problems compared with term-born peers. Aberrant fidgety movements (FMs) are associated with adverse motor outcomes in children born very preterm. However, associations of aberrant FMs combined with additional movements and postures to give a motor optimality score-revised (MOS-R) with school-aged cognitive and motor outcomes are unclear. Our aim with this study was to determine those associations. METHODS: Of 118 infants born <30 weeks' gestation recruited into a randomized controlled trial of early intervention, 97 had a general movements assessment at 3 months' corrected age and were eligible for this study. Early motor repertoire including FMs and MOS-R were scored from videos of infant's spontaneous movement at 3 months' corrected age. At 8 years' corrected age, cognitive and motor performances were evaluated. Associations of early FMs and MOS-R with outcomes at 8 years were determined using linear regression. RESULTS: Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8-30.5; P < .001) compared with absent FMs. CONCLUSIONS: Favorable early motor repertoire of infants born <30 weeks is strongly associated with improved cognitive and motor performance at 8 years.
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    Mathematical performance in childhood and early adult outcomes after very preterm birth: an individual participant data meta-analysis
    Jaekel, J ; Anderson, PJ ; Bartmann, P ; Cheong, JLY ; Doyle, LW ; Hack, M ; Johnson, S ; Marlow, N ; Saigal, S ; Schmidt, L ; Sullivan, MC ; Wolke, D (WILEY, 2021-12-15)
    AIM: To investigate the strength of the independent associations of mathematics performance in children born very preterm (<32wks' gestation or <1500g birthweight) with attending postsecondary education and their current employment status in young adulthood. METHOD: We harmonized data from six very preterm birth cohorts from five different countries and carried out one-stage individual participant data meta-analyses (n=954, 52% female) using mixed effects logistic regression models. Mathematics scores at 8 to 11 years of age were z-standardized using contemporary cohort-specific controls. Outcomes included any postsecondary education, and employment/education status in young adulthood. All models were adjusted for year of birth, gestational age, sex, maternal education, and IQ in childhood. RESULTS: Higher mathematics performance in childhood was independently associated with having attended any postsecondary education (odds ratio [OR] per SD increase in mathematics z-score: 1.36 [95% confidence interval {CI}: 1.03, 1.79]) but not with current employment/education status (OR 1.14 per SD increase [95% CI: 0.87, 1.48]). INTERPRETATION: Among populations born very preterm, childhood mathematics performance is important for adult educational attainment, but not for employment status.
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    ADHD symptoms and diagnosis in adult preterms: systematic review, IPD meta-analysis, and register-linkage study
    Robinson, R ; Girchenko, P ; Pulakka, A ; Heinonen, K ; Lahdepuro, A ; Lahti-Pulkkinen, M ; Hovi, P ; Tikanmaki, M ; Bartmann, P ; Lano, A ; Doyle, LW ; Anderson, PJ ; Cheong, JLY ; Darlow, BA ; Woodward, LJ ; Horwood, LJ ; Indredavik, MS ; Evensen, KA ; Marlow, N ; Johnson, S ; de Mendonca, MG ; Kajantie, E ; Wolke, D ; Raikkonen, K (SPRINGERNATURE, 2022-01-07)
    BACKGROUND: This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns. METHODS: (1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis (n = 1385 preterm, n = 1633 term; born 1978-1995) examined differences in self-reported ADHD symptoms[age 18-36 years]; and (3) a population-based register-linkage study of all live births in Finland (01/01/1987-31/12/1998; n = 37538 preterm, n = 691,616 term) examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016. RESULTS: Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean z-score difference 0.00;95% confidence interval [95% CI] -0.07, 0.07). Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls (RR = 1.26, 95% CI 1.12, 1.41, p < 0.001). Among preterms, as gestation length (RR = 0.93, 95% CI 0.89, 0.97, p < 0.001) and SD birth weight z-score (RR = 0.88, 95% CI 0.80, 0.97, p < 0.001) increased, ADHD risk decreased. CONCLUSIONS: While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher. IMPACT: Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns. Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study. Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood.
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    Morbidity and mortality in hospitalised neonates in central Vietnam
    Tran, HT ; Doyle, LW ; Lee, KJ ; Dang, NM ; Graham, SM (WILEY, 2015-05-01)
    AIM: This study explored neonatal morbidity and mortality in hospitalised patients in central Vietnam and risk factors associated with mortality. METHODS: We conducted a prospective cohort study of all newborn infants (<28 days) hospitalised in a neonatal unit over a 1-year period and followed until discharge. The main outcome measures were case fatality rate and the rate of different clinical diagnoses. RESULTS: There were 2555 admissions during the study period. The leading primary causes of admissions were infections (41%), haematological problems such as jaundice (23%) and prematurity and its complications (18%). The overall case fatality rate was 8.6%, and it was 59% among very low-birthweight (<1500 g) neonates. Mortality was inversely associated with birthweight and gestational age. Of the 220 deaths, 57% occurred within the first 7 days of life. Although the causes of death were often multifactorial, the leading primary causes were infections (32%), prematurity and its complications (25%), birth defects (24%) and birth asphyxia (6%). Risk factors associated with death were being outborn, early gestational age, small for gestational age, confirmed sepsis and birth defects. CONCLUSION: Mortality rates were high among hospitalised neonates in central Vietnam, and this paper suggests interventions that might improve outcomes.
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    A high burden of late-onset sepsis among newborns admitted to the largest neonatal unit in central Vietnam
    Tran, HT ; Doyle, LW ; Lee, KJ ; Dang, NM ; Graham, SM (NATURE PUBLISHING GROUP, 2015-10-01)
    OBJECTIVE: The objective of this study is to determine the prevalence, causes and outcome of sepsis in hospitalized neonates in the largest neonatal unit in central Vietnam. STUDY DESIGN: A 1-year prospective cohort study of newborns admitted to the neonatal unit in Da Nang. A sepsis work-up including blood culture was undertaken before commencing antibiotics for neonates with suspected sepsis. RESULT: Of 2555 neonatal admissions, 616 neonates had 729 episodes of suspected invasive sepsis. A pathogen was isolated from blood in 115 (16%) episodes in 106 neonates. The prevalence of early-onset sepsis (EOS) was 8 (95% confidence interval (CI): 4 to 11) per 1000 admissions, and of late-onset sepsis (LOS) was 34 (95% CI: 27 to 41) per 1000 admissions. Of 86 neonates with LOS, 69 (80%) also fulfilled the criteria for nosocomial sepsis. The commonest bacterial causes of EOS were coagulase-negative Staphylococcus (CoNS) and Staphylococcus aureus, and of LOS were Acinetobacter, CoNS and Klebsiella pneumoniae. Fungal sepsis occurred in 35 neonates of which most were nosocomial sepsis. In vitro resistance to multiple antibiotics was common among Gram-negative bacteria. Antibiotics were prescribed and given to 68% of all admissions, and 14% of all admissions received four or more different antibiotics. The case fatality rate for confirmed sepsis was 46%. CONCLUSION: Late-onset, nosocomial sepsis was common and associated with a high mortality in hospitalized newborns in the largest neonatal unit in central Vietnam. These findings highlighted the need for improved infection control measures and antibiotic stewardship, which have since been implemented.
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    Investigating the brain structural connectome following working memory training in children born extremely preterm or extremely low birth weight
    Kelly, CE ; Harding, R ; Lee, KJ ; Pascoe, L ; Josev, EK ; Spencer-Smith, MM ; Adamson, C ; Beare, R ; Nosarti, C ; Roberts, G ; Doyle, LW ; Seal, ML ; Thompson, DK ; Anderson, PJ (WILEY, 2021-02-23)
    Children born extremely preterm (EP, <28 weeks' gestation) or extremely low birth weight (ELBW, <1,000 g) are a vulnerable population at high risk of working memory impairments. We aimed to examine changes in the brain structural connectivity networks thought to underlie working memory performance, after completion of a working memory training program (Cogmed) compared with a placebo program in EP/ELBW children. This was a double-blind, placebo-controlled randomized trial (the Improving Memory in a Preterm Randomised Intervention Trial). Children born EP/ELBW received either the Cogmed or placebo program at 7 years of age (n = 91). A subset of children had magnetic resonance imaging of the brain immediately pre- and 2 weeks post-training (Cogmed n = 28; placebo n = 27). T1 -weighted and diffusion-weighted images were used to perform graph theoretical analysis of structural connectivity networks. Changes from pre-training to post-training in structural connectivity metrics were generally similar between randomized groups. There was little evidence that changes in structural connectivity metrics were related to changes in working memory performance from pre- to post-training. Overall, our results provide little evidence that the Cogmed working memory training program has training-specific effects on structural connectivity networks in EP/ELBW children.
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    Temporal changes in rates of active management and infant survival following live birth at 22-24 weeks' gestation in Victoria
    Boland, RA ; Cheong, JLY ; Stewart, MJ ; Doyle, LW (WILEY, 2021-02-16)
    BACKGROUND: Management of livebirths at 22-24 weeks' gestation in high-income countries varies widely and has changed over time. AIMS: Our aim was to determine how rates of active management and infant survival of livebirths at 22-24 weeks varied with perinatal variables known at birth, and over time in Victoria, Australia. MATERIALS AND METHODS: We conducted a population-based cohort study of all 22-24 weeks' gestation live births, free of lethal congenital anomalies in 2009-2017. Rates of active management and survival to one year of age were reported. 'Active management' was defined as receiving resuscitation at birth or nursery admission for intensive care. RESULTS: Over the nine-year period, there were 796 eligible live births. Overall, 438 (55%) were actively managed: 5% at 22 weeks, 45% at 23 weeks and 90% at 24 weeks' gestation, but rates of active management did not vary substantially over time. Of livebirths actively managed, 263 (60%) survived to one year: 0% at 22 weeks, 50% at 23 weeks and 66% at 24 weeks. Apart from gestational age, being born in a tertiary perinatal centre and increased size at birth were associated with survival in those actively managed, but sex and plurality were not. Survival rates of actively managed infants rose over time (adjusted odds ratio 1.09 per year; 95% CI 1.01-1.18; P = 0.03). CONCLUSIONS: Although active management rates did not change substantially over time in Victoria, an overall increase in infant survival was observed. With increasing gestational age, rates of active management and infant survival rapidly rose.
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    Translating antenatal magnesium sulphate neuroprotection for infants born < 28 weeks' gestation into practice: A geographical cohort study
    Doyle, LW ; Spittle, AJ ; Olsen, JE ; Kwong, A ; Boland, RA ; Lee, KJ ; Anderson, PJ ; Cheong, JLY (WILEY, 2021-02-02)
    BACKGROUND: Magnesium sulphate was introduced for fetal neuroprotection in Australia in 2010. The aim of this study was to determine how often antenatal magnesium sulphate is used currently and its association with cerebral palsy in children born <28 weeks' gestation. MATERIALS AND METHODS: Participants comprised all survivors born <28 weeks' gestational age in the state of Victoria in 2016-17, and earlier, in 1991-92, 1997, 2005. Rates of cerebral palsy, diagnosed at two years for the 2016-17 cohort, and at eight years in the earlier cohorts, were compared across eras. Within 2016-17, the proportions of children exposed to antenatal magnesium sulphate were determined, and rates of cerebral palsy were compared between those with and without exposure to magnesium sulphate. RESULTS: Overall, cerebral palsy was present in 6% (11/171) of survivors born in 2016-17, compared with 12% (62/499) of survivors born in the three earlier eras (odds ratio (OR) 0.48, 95% confidence interval (CI) 0.25-0.94; P = 0.032). Data were available for 213/215 (99%) survivors born in 2016-17, of whom 147 (69%) received magnesium sulphate. Data on cerebral palsy at two years were available for 171 (80%) survivors with magnesium data. Cerebral palsy was present in 5/125 (4%) children exposed to magnesium sulphate and in 6/46 (13%) of those not exposed (OR 0.28, 95% CI 0.08-0.96; P = 0.043). CONCLUSIONS: Antenatal magnesium sulphate is being translated into clinical practice for infants born <28 weeks' gestation, but there is room for improvement. It is associated with lower rates of cerebral palsy in survivors.