Obstetrics and Gynaecology - Research Publications

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    Relationships between early postnatal cranial ultrasonography linear measures and neurodevelopment at 2 years in infants born at <30 weeks' gestational age without major brain injury
    Cuzzilla, R ; Cowan, FM ; Rogerson, S ; Anderson, PJ ; Doyle, LW ; Cheong, JLY ; Spittle, A (BMJ PUBLISHING GROUP, 2023-09)
    OBJECTIVE: To explore relationships of early postnatal cranial ultrasonography (cUS) linear measures of brain size and brain growth with neurodevelopment at 2 years in infants born <30 weeks' gestational age (GA) and free of major brain injury. DESIGN: Prospective observational cohort study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 139 infants born <30 weeks' GA, free of major brain injury on neonatal cUS and without congenital or chromosomal anomalies known to affect neurodevelopment. INTERVENTION: Linear measures of brain tissue and fluid spaces made from cUS at 1-week, 1-month and 2-months' postnatal age. MAIN OUTCOME MEASURES: Cognitive, language and motor scores on the Bayley Scales of Infant and Toddler Development, third edition at 2 years' corrected age. RESULTS: 313 scans were evaluated from the 131 children who were assessed at 2 years. Larger measures of the corpus callosum at 1 week, 1 month and 2 months, cerebellum and vermis at 2 months and faster positive growth of the cerebellum and vermis between 1 month and 2 months, were related to higher cognitive and language scores at 2 years. No relation between tissue measures and motor scores was found. Larger measures, and faster rate of increase, of fluid spaces within the first weeks after birth were related to better cognitive, language and motor outcomes at 2 years. CONCLUSIONS: Early postnatal cUS linear measures of brain tissue were related to cognitive and language development at 2 years in infants born <30 weeks' GA without major brain injury. Relationships between cUS linear measures of fluid spaces in the early postnatal period and later neurodevelopment warrant further exploration.
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    Growth of prefrontal and limbic brain regions and anxiety disorders in children born very preterm
    Gilchrist, CP ; Thompson, DK ; Alexander, B ; Kelly, CE ; Treyvaud, K ; Matthews, LG ; Pascoe, L ; Zannino, D ; Yates, R ; Adamson, C ; Tolcos, M ; Cheong, JLY ; Inder, TE ; Doyle, LW ; Cumberland, A ; Anderson, PJ (CAMBRIDGE UNIV PRESS, 2023-02-09)
    BACKGROUND: Children born very preterm (VP) display altered growth in corticolimbic structures compared with full-term peers. Given the association between the cortiocolimbic system and anxiety, this study aimed to compare developmental trajectories of corticolimbic regions in VP children with and without anxiety diagnosis at 13 years. METHODS: MRI data from 124 VP children were used to calculate whole brain and corticolimbic region volumes at term-equivalent age (TEA), 7 and 13 years. The presence of an anxiety disorder was assessed at 13 years using a structured clinical interview. RESULTS: VP children who met criteria for an anxiety disorder at 13 years (n = 16) displayed altered trajectories for intracranial volume (ICV, p < 0.0001), total brain volume (TBV, p = 0.029), the right amygdala (p = 0.0009) and left hippocampus (p = 0.029) compared with VP children without anxiety (n = 108), with trends in the right hippocampus (p = 0.062) and left medial orbitofrontal cortex (p = 0.079). Altered trajectories predominantly reflected slower growth in early childhood (0-7 years) for ICV (β = -0.461, p = 0.020), TBV (β = -0.503, p = 0.021), left (β = -0.518, p = 0.020) and right hippocampi (β = -0.469, p = 0.020) and left medial orbitofrontal cortex (β = -0.761, p = 0.020) and did not persist after adjusting for TBV and social risk. CONCLUSIONS: Region- and time-specific alterations in the development of the corticolimbic system in children born VP may help to explain an increase in anxiety disorders observed in this population.
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    Long-lasting effects of very preterm birth on brain structure in adulthood: A systematic review and meta-analysis
    Kelly, CE ; Shaul, M ; Thompson, DK ; Mainzer, RM ; Yang, JYM ; Dhollander, T ; Cheong, JLY ; Inder, TE ; Doyle, LW ; Anderson, PJ (PERGAMON-ELSEVIER SCIENCE LTD, 2023-04)
    Early life experiences, such as very preterm (VP) birth, can affect brain and cognitive development. Several prior studies investigated brain structure in adults born VP; synthesising these studies may help to provide a clearer understanding of long-term effects of VP birth on the brain. We systematically searched Medline and Embase for articles that investigated brain structure using MRI in adulthood in individuals born VP (<32 weeks' gestation) or with very low birth weight (VLBW; <1500 g), and controls born at term or with normal birth weight. In total, 77 studies met the review inclusion criteria, of which 28 studies were eligible for meta-analyses, including data from up to 797 VP/VLBW participants and 518 controls, aged 18-33 years. VP/VLBW adults exhibited volumetric, morphologic and microstructural alterations in subcortical and temporal cortical regions compared with controls, with pooled standardised mean differences up to - 1.0 (95% confidence interval: -1.2, -0.8). This study suggests there is a persisting neurological impact of VP birth, which may provide developmental neurobiological insights for adult cognition in high-risk populations.
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    Expiratory airflow at 7-8 years of age in children born extremely low birthweight from 14 years before to 14 years after the introduction of exogenous surfactant
    Doyle, LW ; Ranganathan, S ; Spittle, AJ ; Opie, G ; Mainzer, RM ; Cheong, JLY (ELSEVIER, 2023-08)
    BACKGROUND: It is unclear if expiratory airflow in survivors born extremely low birth weight (ELBW; 500-999 g) has improved after the introduction of exogenous surfactant into clinical practice in 1991. The primary aim of this study was to describe the changes in airflow at 7-8 years of age of survivors born ELBW in five discrete cohorts from 14 years before to 14 years after the introduction of exogenous surfactant into clinical practice. METHODS: The cohorts comprised consecutive survivors born ELBW in 1977-82 and 1985-87 at the Royal Women's Hospital, Melbourne, and in 1991-92, 1997 and 2005 in the state of Victoria, Australia. Survival rates to 2-years of age for infants born ELBW in the state of Victoria rose from approximately 1-in-4 to 3-in-4 over the time of this study. Expiratory airflow measurements at 7-8 years included the forced expired volume in 1 s (FEV1), converted to z-scores for age, height, sex, and race. FINDINGS: There were 596 ELBW participants with expiratory flow data, 280 (47%) of whom had bronchopulmonary dysplasia (BPD). Overall, there was little change in zFEV1 over the 28-year period (mean change per year; 0.003, 95% CI -0.010, 0.015, P = 0.67). There was, however, evidence of an interaction between BPD and year; zFEV1 in those who had BPD fell over time (mean change per year -0.019, 95% CI -0.037, -0.009, P = 0.035), whereas zFEV1 improved in those who did not have BPD (mean change per year 0.021, 95% CI 0.006, 0.037, P = 0.007). INTERPRETATION: Contrary to recent evidence, expiratory airflow of children born ELBW has not improved with the introduction of surfactant, and may be deteriorating in those who had BPD. FUNDING: National Health and Medical Research Council (Australia); Victorian Government's Operational Infrastructure Support Program.
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    Quantifying Bone Strength Deficits in Young Adults Born Extremely Preterm or Extremely Low Birth Weight
    Dao, T ; Robinson, DL ; Doyle, LW ; Lee, PVS ; Olsen, J ; Kale, A ; Cheong, JLY ; Wark, JD (WILEY, 2023-12)
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    Health-related quality of life in adults born extremely preterm or with extremely low birth weight in the postsurfactant era: a longitudinal cohort study
    Selman, C ; Mainzer, R ; Lee, K ; Anderson, P ; Burnett, A ; Garland, SM ; Patton, GC ; Pigdon, L ; Roberts, G ; Wark, J ; Doyle, LW ; Cheong, JLY (BMJ PUBLISHING GROUP, 2023-11)
    OBJECTIVES: To compare health-related quality of life (HRQoL) at 25 and 18 years in individuals born extremely preterm (EP, <28 weeks' gestation) or with extremely low birth weight (ELBW, birth weight <1000 g) with term-born (≥37 weeks) controls. Within the EP/ELBW cohort, to determine whether HRQoL differed between those with lower and higher IQs. METHODS: HRQoL was self-reported using the Health Utilities Index Mark 3 (HUI3) at 18 and 25 years by 297 EP/ELBW and 251 controls born in 1991-1992 in Victoria, Australia. Median differences (MDs) between groups were estimated using multiple imputation to handle missing data. RESULTS: Adults born EP/ELBW had lower HRQoL (median utility 0.89) at 25 years than controls (median utility 0.93, MD -0.040), but with substantial uncertainty in the estimate (95% CI -0.088 to 0.008) and a smaller reduction at 18 years (MD -0.016, 95% CI -0.061 to 0.029). On individual HUI3 items, there was suboptimal performance on speech (OR 9.28, 95% CI 3.09 to 27.93) and dexterity (OR 5.44, 95% CI 1.04 to 28.45) in the EP/ELBW cohort. Within the EP/ELBW cohort, individuals with lower IQ had lower HRQoL compared with those with higher IQ at 25 (MD -0.031, 95% CI -0.126 to 0.064) and 18 years (MD -0.034, 95% CI -0.107 to 0.040), but again with substantial uncertainty in the estimates. CONCLUSIONS: Compared with term-born controls, young adults born EP/ELBW reported poorer HRQoL, as did those with lower IQ compared with those with higher IQ in the EP/ELBW cohort. Given the uncertainties, our findings need corroboration.
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    Bronchopulmonary dysplasia and expiratory airflow at 8 years in children born extremely preterm in the post-surfactant era
    Doyle, LW ; Ranganathan, S ; Cheong, J (BMJ Publishing Group, 2023-05)
    Background: It is unclear if bronchopulmonary dysplasia (BPD) is independently associated with reduced expiratory airflow at school age. Objective: To determine the independent associations of moderate–severe BPD, mild BPD, gestational age and birth weight z-score with expiratory airflow in children born extremely preterm (EP; <28 weeks’ gestation). Methods: All EP survivors born in Victoria, Australia, in three eras (1991–1992, n=225; 1997, n=151; and 2005, n=170) were recruited at birth and 418/546 (77%) had valid spirometry data at 8 years. BPD was classified as moderate–severe (oxygen requirement at 36 weeks’ postmenstrual age), or mild (oxygen >28 days but not at 36 weeks’ postmenstrual age). Expiratory airflow variables, including the forced expired volume in 1 s (FEV1), were measured and values converted to z-scores. Results: Compared with no BPD (n=94), moderate–severe BPD (n=193) was associated with a substantial reduction in expiratory airflow (eg, zFEV1 mean difference −0.69, 95% CI −0.97 to –0.41; p<0.001), but mild BPD (n=131) was not (zFEV1 mean difference 0.01, 95% CI −0.28 to 0.31; p=0.93). On multivariable analysis, moderate–severe BPD remained strongly associated with reduced airflow (zFEV1 mean difference −0.63, 95% CI −0.92 to –0.33; p<0.001), but mild BPD (zFEV1 mean difference 0.04, 95% CI −0.26 to 0.34; p=0.27), gestational age (zFEV1 0.06 mean increase per week, 95% CI −0.05 to 0.17; p=0.29) and birth weight z-score (zFEV1 0.07 mean increase per SD, 95% CI −0.06 to 0.20; p=0.28) were not. Conclusions: In children born EP, moderate–severe BPD, but not mild BPD was independently associated with reduced expiratory airflow at 8 years.
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    Parent-recorded videos of infant spontaneous movement: Comparisons at 3-4 months and relationships with 2-year developmental outcomes in extremely preterm, extremely low birthweight and term-born infants
    Kwong, AKL ; Doyle, LW ; Olsen, JE ; Eeles, AL ; Zannino, D ; Mainzer, RM ; Cheong, JLY ; Spittle, AJ (WILEY, 2022-09)
    BACKGROUND: Infants born extremely preterm (EP, <28-week gestational age) or extremely low birthweight (ELBW, <1000 g) are at risk of developmental delay and cerebral palsy (CP). The General Movements Assessment (GMA) and its extension, the Motor Optimality Score, revised (MOS-R) (assesses movement patterns and posture), may help to identify early delays. OBJECTIVES: To compare differences in the MOS-R scored from parent-recorded videos between infants born EP/ELBW and term-born infants, to determine relationships between the MOS-R and 2-year cognitive, language and motor outcomes and if any relationships differ between birth groups and the association of the GMA (fidgety) with CP. METHODS: A geographical cohort (EP/ELBW and term-control infants) was assessed using the MOS-R inclusive of the GMA at 3- to 4-month corrected age (CA), and the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) at 2-year CA. Differences in mean total MOS-R between groups, relationships between MOS-R and 2-year outcomes and relationships between GMA (fidgety) and CP in infants born EP/ELBW were estimated using linear/logistic regression. RESULTS: Three hundred and twelve infants (147 EP/ELBW; 165 term) had complete MOS-R and Bayley-III assessments. Mean MOS-R was lower in infants born EP/ELBW than controls (mean difference -3.2, 95% confidence interval [CI] -4.2, -2.3). MOS-R was positively related to cognitive (β [regression coefficient] = 0.71, 95% CI 0.27, 1.15), language (β = 0.96, 95% CI 0.38, 1.54) and motor outcomes (β = .89, 95% CI 0.45, 1.34). There was little evidence for interaction effects between birth groups for any outcome. Absent/abnormal fidgety movements were related to CP in children born EP/ELBW (risk ratio 5.91, 95% CI 1.48, 23.7). CONCLUSIONS: Infants born EP/ELBW have lower MOS-R than infants born at term. A higher MOS-R is related to better outcomes for 2-year development, with similar relationships in both birth groups. Absent/abnormal fidgety movements are related to CP in EP/ELBW survivors.
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    Trends in survival, perinatal morbidities and two-year neurodevelopmental outcomes in extremely low-birthweight infants over four decades
    Zayegh, AM ; Doyle, LW ; Boland, RA ; Mainzer, R ; Spittle, AJ ; Roberts, G ; Hickey, LM ; Anderson, PJ ; Cheong, JLY (WILEY, 2022-09)
    BACKGROUND: Although outcomes for infants born extremely low birthweight (ELBW; <1000 g birthweight) have improved over time, it is important to document survival and morbidity changes following the advent of modern neonatal intensive care in the 1990s. OBJECTIVE: To describe trends in survival, perinatal outcomes and neurodevelopment to 2 years' corrected age over time across six discrete geographic cohorts born ELBW between 1979 and 2017. METHODS: Analysis of data from discrete population-based prospective cohort studies of all live births free of lethal anomalies with birthweight 500-999 g in the state of Victoria, Australia, over 6 eras: 1979-80, 1985-87, 1991-92, 1997, 2005 and 2016-17. Perinatal data collected included survival, duration and type of respiratory support, neonatal morbidities and two-year neurodevelopmental outcomes. RESULTS: More ELBW live births were inborn (born in a maternity hospital with a neonatal intensive care unit) over time (1979-80, 70%; 2016-17, 84%), and more were offered active care (1979-80, 58%; 2016-17, 90%). Survival to 2 years rose substantially, from 25% in 1979-80 to 80% in 2016-17. In survivors, rates of any assisted ventilation rose from 75% in 1979-80 to 99% in 2016-17. Cystic periventricular leukomalacia, severe retinopathy of prematurity and blindness improved across eras. Two-year data were available for 95% (1054/1109) of survivors. Rates of cerebral palsy, deafness and major neurodevelopmental disability changed little over time. The annual numbers with major neurodevelopmental disability increased from 12.5 in 1979-80 to 30 in 2016-17, but annual numbers free of major disability increased much more, from 31 in 1979-80 to 147 in 2016-17. CONCLUSIONS: Active care and survival rates in ELBW children have increased dramatically since 1979 without large changes in neonatal morbidities. The numbers of survivors free of major neurodevelopmental disability have increased more over time than those with major disability.
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    Early motor repertoire and neurodevelopment at 2 years in infants born extremely preterm or extremely-low-birthweight
    Kwong, AKL ; Doyle, LW ; Olsen, JE ; Eeles, AL ; Lee, KJ ; Cheong, JLY ; Spittle, AJ (WILEY, 2022-07)
    AIM: To determine the relationship between early motor repertoire and 2-year neurodevelopment in infants born extremely preterm (<28 weeks' gestation) or extremely-low-birthweight (ELBW) (<1000g). METHOD: This was a geographical prospective cohort of 139 infants born extremely preterm/ELBW (mean gestational age 26.7 weeks, standard deviation [SD] 2.0, 68/139 [49%] male), with parent-recorded videos suitable for scoring the General Movements Assessment (GMA). Motor repertoire was assessed using the Motor Optimality Score-Revised (MOS-R), with and without the fidgety movement subsection, and the GMA alone at 12 to 13+6  weeks corrected age and 14 to 15+6  weeks corrected age. At 2 years corrected age, impaired development was defined as Bayley Scales of Infant and Toddler Development, Third Edition motor and cognitive development scores 1SD or less relative to controls born at term; paediatricians diagnosed cerebral palsy (CP). RESULTS: Greater MOS-R scores at 14 to 15+6  weeks corrected age were associated with lower odds of CP (odds ratio [OR] per 1-point increase=0.83, 95% confidence interval [CI]=0.71-0.99), and motor (OR=0.93, 95% CI=0.87-0.99), or cognitive impairment (OR=0.94, 95% CI=0.88-0.99). Absent/abnormal GMA at 14 to 15+6 weeks was associated with CP and motor delay. There was little evidence that MOS-R scores at 12 to 13+6 weeks were associated with neurodevelopmental outcomes at 2 years. INTERPRETATION: Poorer MOS-R scores and absent/abnormal GMA, scored from parent-recorded videos at 14 to 15+6  weeks gestational age, are associated with CP and developmental impairment in 2-year-old infants born extremely preterm/ELBW.