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Neurodevelopmental outcome of extremely preterm infants born to rural and urban residents' mothers in Australia ARTICLE in EARLY HUMAN DEVELOPMENT · MAY 2015 Impact Factor: 1.93 · DOI: 10.1016/j.earlhumdev.2015.04.014

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Early Human Development 91 (2015) 437–443

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Neurodevelopmental outcome of extremely preterm infants born to rural and urban residents' mothers in Australia Andrea N. Rodrigues a, Barbara Bajuk b, Julee Oei c,d, Kei Lui c,d, Mohamed E. Abdel-Latif a,e,⁎, for the NICUS Network a

The Clinical School, Australian National University, ACT, Australia Neonatal Intensive Care Units' (NICUS) Data Collection, NSW Pregnancy and Newborn Services Network (PSN), Sydney Children's Hospitals Network, NSW, Australia Department of Newborn Care, Royal Hospital for Women, NSW, Australia d School of Women's and Children's Heath, University of New South Wales, NSW, Australia e Department of Neonatology, Centenary Hospital for Women and Children, ACT, Australia b c

a r t i c l e

i n f o

Article history: Received 11 May 2014 Received in revised form 5 April 2015 Accepted 26 April 2015 Available online xxxx Keywords: Premature Preterm Low birth weight Rural Neurodevelopment Outcome

a b s t r a c t Background: Rural and remote residents in Australia have long experienced unfavourable health outcomes compared to their urban counterparts. Aims: To study neurodevelopmental outcome at 2–3 years of age, corrected for prematurity of extremely preterm infants admitted to a regional neonatal Australian network from rural and urban regions (based on usual location of maternal residence). Methods: A multicenter population-based cohort study in which surviving urban and rural infants b29 weeks of gestation born between 1998 and 2004 underwent neurodevelopmental assessment at 2–3 years of age, corrected for prematurity by a developmental assessment team. Moderate/severe functional disability was defined as developmental delay (GQ or MDI N 2 SD below the mean), cerebral palsy (aided for walking), sensorineural or conductive deafness (requiring amplification), and bilateral blindness (visual acuity b6/60 in the better eye). Results: Of the 1970 infants alive at 2–3 years of age, 268 (63.8%) rural and 1205 (77.7%) urban infants were evaluated. Infants lost to follow-up were of slightly higher gestational age and birth weight. Both rural and urban assessed groups were comparable in gestation and birth weight percentile. In comparison to their urban counterparts, the rural group had more outborn infants (19.8% vs. 4.6%, p b 0.001). They, however, did not have an increased risk of moderate/severe functional disability (OR 0.77, 95% CI 0.52–1.23, p = 0.176). This finding was not significantly altered by limiting the analysis to different gestational ages. Conclusion: Extremely premature surviving young children from rural areas of residence do not seem to have an increased risk for moderate/severe functional disability. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Rural and remote residents in Australia have long experienced unfavourable health outcomes compared to their urban counterparts [1]. Those living in rural and remote areas have a higher prevalence of acute and chronic disease, obesity, low birth weight, hospital admission, adverse health outcomes and decreased life expectancy at birth [2]. Rural areas in Australia encompass vast landscapes with relatively sparse

Abbreviations: CLD, chronic lung disease; FD, functional disability; IVH, intraventricular haemorrhage; NEC, necrotising enterocolitis; NICU, Neonatal Intensive Care Unit; PDA, patent ductus arteriosus; ROP, retinopathy of prematurity; RR, rural residing; UR, urban residing. ⁎ Corresponding author at: Department of Neonatology, The Australian National University Medical School, PO Box 11, Woden, ACT 2606, Australia. Tel.: +61 2 6174 7565. E-mail address: [email protected] (M.E. Abdel-Latif).

http://dx.doi.org/10.1016/j.earlhumdev.2015.04.014 0378-3782/© 2015 Elsevier Ireland Ltd. All rights reserved.

population density. New South Wales (NSW) and the Australian Capital Territory (ACT) cover an area of 815,810 km2 (10.5% of Australia's total area) and have a total population of 7,588,600 (33% of the total Australian population), with 35% of the population residing in rural and regional areas [3]. Factors that contribute to a rural health disadvantage include geographic isolation and difficulties accessing healthcare, shortage of health services and healthcare providers, including general practitioners and obstetric specialists [4], and a larger Indigenous population who experience substantially poorer health outcomes than nonIndigenous Australians [5]. Due to the lack of specialist obstetric facilities, and the complications associated with preterm birth outside of a tertiary centre [6], it is recommended that mothers at high risk of preterm birth in NSW and ACT be transferred to one of the 10 neonatal intensive care units (NICUs), concentrated in Sydney, Canberra and Newcastle. There are established services for the antenatal transfer of rural mothers requiring tertiary

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care to urban centres [6], however, the geographical vastness of NSW means that high risk births inevitably occur outside of specialised tertiary centres. The neonatal and paediatric emergency transport service (NETS) in NSW and ACT provides for postnatal transfer of critically ill newborn infants from rural centres to a tertiary hospital that can provide appropriate support [6,7]. There is unequivocal evidence that tertiary centres are best equipped to manage the complications associated with extremely preterm birth [6,8], nevertheless this can be costly for the family and separation from the mother's support network can affect maternal and therefore infant outcomes [8]. We previously reported that the perinatal morbidity of preterm infants born in NSW and ACT did not differ significantly based on rural and urban residence, however mortality was higher in the rural group [9]. Aside from the immediate challenges, however, preterm birth has also been associated with increased risk of long-term neurodevelopmental disabilities compared with term pregnancies, especially if the risk factors and complications at birth are insufficiently managed [10]. Higher rates of cerebral palsy, intellectual disability and sensory impairment, as well as specific learning disability and neuromotor dysfunction have been reported in infants born prematurely [11]. This study aims to compare the neurodevelopmental outcomes at 2–3 years of age of extremely preterm infants born to rural residing (RR) mothers with those of urban residents (UR) in NSW and ACT, Australia. We hypothesise that neurodevelopmental outcomes will be comparable between rural and urban residents.

2.3. Definitions The mothers and infants were classified as being rural or urban residents based on the usual residence of the mother at the time of the infant's birth. NSW and the ACT were divided into 16 geographically based local health districts, 8 covering the Sydney metropolitan region, 7 rural and regional NSW and 1 ACT health district. A mother was classified as urban if her usual residence was located in the Sydney Metropolitan, Illawarra, Hunter or ACT health districts as per the reports on NSW health [2] and corresponding with the categories in the accessibility–remoteness index of Australia [15]. 2.4. Follow-up assessment All surviving children were offered a follow-up assessment at age 2– 3 years, corrected for prematurity. The majority of children (90.0) were assessed by developmental assessment team at tertiary hospital. If the parents were unable or unwilling to travel to a tertiary hospital, then a local paediatrician or family physician examined the child (10.0%), and the child was referred for detailed developmental assessment service or a tertiary hospital if indicated. Each assessment included examination of hearing, vision, neurological function and developmental assessment using the Griffiths Mental Developmental Scales [16] (GMDS) (85%) or Bayley Scales of Infant Development—II (BSID-II) [17]. The children's heights, weights and head circumferences percentiles were determined, using the NSW population-based birth weight charts at birth and the United States National Center for Health Statistics (NCHS) growth curves at 2–3 years of age, corrected for prematurity. A full description of follow-up assessment is documented elsewhere [12].

2. Materials and methods 2.5. Outcome measures 2.1. Study design and data sources This study was a retrospective analysis of data extracted from two prospectively collected databases: 1. The Neonatal Intensive Care Units' Data Collection, an ongoing prospective statewide audit of infants admitted to the 10 NICUs in NSW and the ACT during the neonatal period for one of the following reasons: gestational age b32 weeks, birth weight ≤1500 g, assisted ventilation (mechanical ventilation or continuous positive airways pressure), or major surgery (opening of a body cavity). 2. Neonatal Intensive Care Units' follow-up data collection, an ongoing statewide audit at 2–3 years of age, corrected for prematurity, of infants born less than 29 weeks' gestation. A full description of the NICUS and follow-up data and the NSW and ACT neonatal service organization and networking is available elsewhere [6,7].

2.2. Study population and profile of infants who were lost to follow-up All surviving preterm infants born b29 weeks of gestation and admitted to one of the 10 NICUs in NSW and ACT between 1998 and 2004 who had neurodevelopmental follow-up at 2–3 years of age were included in the study. Fig. 1 provides the profile of the study group from birth to follow-up among rural and urban residing infants. Of the total 2701 infants with gestational age b29 weeks who were admitted to NICU between 1998 and 2004, approximately 78% were UR and 22% were RR. Of the 2103 infants discharged home after birth, 33 infants died after hospital discharge and 497 infants were lost to follow-up. This left a total of 268 RR and 1205 UR infants on whom assessments were conducted on at 2–3 years of corrected age. Total of 497 infants were lost to follow-up. A full description of the characteristics of infants who were lost to follow up (n = 497) compared to those who had followed-up assessment (n = 1473) is available elsewhere [12–14]. There were a significant number of RR infants who were lost to follow up (36.2% vs. 22.3%; p b 0.001).

The primary outcome measure for this study is functional disability (FD) at 2–3 years of age, corrected for prematurity, defined as follows [18]: 1. None/minimal FD: no developmental delay (GMDS-GQ or BSIDII-MDI 1 SD below the mean to 3 SD above the mean); 2. Mild: developmental delay (GMDS-GQ or BSIDII-MDI between 1 and 2 SD below the mean), mild cerebral palsy (able to walk without aids); 3. Moderate: developmental delay (GMDS-GQ or BSIDII-MDI between 2 and 3 SD below the mean), moderate cerebral palsy (able to walk with the assistance of aids), sensorineural or conductive deafness (requiring amplification with bilateral hearing aids or unilateral/bilateral cochlear implant); and 4. Severe: developmental delay (GMDS-GQ or BSIDIIMDI 3 or more SD below the mean), bilateral blindness (visual acuity of b6/60 in the better eye), severe cerebral palsy (unable to walk with the assistance of aids). The diagnosis of cerebral palsy was made if the child had non progressive motor impairment characterised by abnormal muscle tone and a decreased range or decreased control of movements accompanied by neurological signs [19]. Secondary outcome measures included growth at 2–3 years of age corrected for prematurity and short term neonatal outcomes (intraventricular haemorrhage (IVH), chronic lung disease (CLD), retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and length of NICU stay. 2.6. Statistical analysis Statistical analysis was performed using IBM SPSS Statistics (version 20.0; SPSS: SPSS, Inc., an IBM Company, Somers, NY, USA, 2011). Data are presented as number and percentage (%) with odds ratio (OR) and 95% Confidence Interval (CI) or median and interquartile range (IQR). The clinical and demographic characteristics were compared using the Chi-square test with continuity correction and the t-test where appropriate. We also performed stepwise multiple logistic regression elimination analysis to establish independent influence of “urban/rural residence”

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Fig. 1. Profile of infants from birth to follow-up among rural and urban infants born 1998–2004.

on adverse neurodevelopmental outcomes, after controlling for significant confounding factors (e.g. antenatal corticosteroid use) in addition to other predictors (outborn, gender, gestational age and birth weight) identified in other studies [20]. All p-values are two-sided and the significance level (p b 0.05) remained the same when multiple comparisons were performed. 3. Results 3.1. Profile of rural and urban infants who were lost to follow-up Among those lost to follow up, rural infants had comparable gestational ages (27.0 vs. 27.0 weeks) and birth weights (1020 vs. 1030 g) to urban infants but were less likely to have a birth weight less than the 10th percentile (0.7% vs. 7.2%; p = 0.005) or be discharged on home oxygen (6.6% vs. 13.9%; p = 0.028) and also had shorter duration of ventilation (2.0 vs. 3.6 days; p = 0.003). Clinical risk index for babies II (CRIB II) score, as a measure of severity of illness between the two groups was comparable (Table 1). 3.2. Perinatal and neonatal characteristics of rural and urban infants RR mothers were more likely to be younger (29.0 vs. 31.0 years; p b 0.001) and of Aboriginal origin (3.1% vs. 1.1%; p = 0.038) than UR mothers (Table 2). Significantly more RR infants were born outside of

a tertiary hospital (19.8% vs. 4.6%; p b 0.001). RR infants were less likely to be conceived using assisted reproduction techniques (10.1% vs. 15.8%; p = 0.017) and had shorter length of NICU stay (64.0 vs. 74.0 days; p b 0.001). There was no difference in the rates of multiple pregnancy, antenatal steroid use, pregnancy induced hypertension and other antenatal and perinatal characteristics (Table 2). Urban and rural infants were also comparable in gestational age, birth weight, the requirement for and duration of mechanical ventilation. There was no significant difference between urban and rural infants in the rates of early neonatal morbidities and risk factors known to be associated with neurodevelopmental outcomes, namely CRIB II score, IVH, NEC, CLD, severe ROP, postnatal steroid exposure and proven systemic sepsis (Table 2).

3.3. Rural status and developmental outcomes Table 3 outlines the neurodevelopmental outcomes of RR and UR children at 2–3 years of age, corrected for prematurity. RR children had a lower rate of moderate to severe functional disability, but this did not reach statistical significance (14.2% vs. 16.8%; OR 0.82, 95% CI 0.56–1.19; p = 0.34). The rates of cerebral palsy, bilateral blindness and bilateral deafness although marginally higher in RR children were not statistically significantly different (Table 3). RR and UR children were similar in height, weight and head circumference.

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Table 1 Antenatal and perinatal characteristics and major neonatal morbidities among urban and rural infants lost to follow-up. Characteristic

Urban (n = 345)

Rural (n = 152)

OR (95% CI)

p-Value

Maternal age, year Aboriginal ethnicity Primipara Assisted conception Multiple pregnancy Pregnancy induced hypertension Ante-partum haemorrhage Gestational diabetes Any antenatal corticosteroid Chorioamnionitisa Vaginal breech Caesarean section in labour Born in non-tertiary centre Apgar score b7 at 5 min Male gender Gestational age, week Birth weight, gram Birth weight b10th percentile Head circumference, cm Head circumference b10th percentile Surfactant therapy CRIB II score Mechanical ventilation Duration of ventilation, days Patent ductus arteriosus requiring treatment Proven systemic infection Intraventricular haemorrhage grade 3 or 4b Necrotising enterocolitis Chronic lung disease Post-natal steroid for CLD Home oxygen Retinopathy of prematurity grade 3 or 4b Length of intensive care stay, days Length of hospital stay, days

28.0 (23.0–32.0) 22 (6.4) 100 (29.0) 30 (8.7) 79 (22.9) 39 (11.3) 109 (31.6) 5 (1.4) 294 (85.2) 49 (21.0) 26 (7.5) 91 (26.4) 45 (13.0) 51 (14.9) 179 (51.9) 27.0 (26.0–28.0) 1030.0 (860.0–1200.0) 25 (7.2) 25.5 (24.0–26.5) 19 (6.1) 214 (62.0) 9.0 (8.0–11.0) 333 (96.5) 3.6 (0.5–13.0) 133 (38.6) 103 (29.9) 17 (4.9) 26 (7.5) 99 (28.7) 60 (17.4) 48 (13.9) 25 (7.2) 64.0 (45.0–85.5) 74.0 (62.5–93.5)

27.0 (21.0–30.0) 39 (25.7) 29 (19.1) 4 (2.6) 35 (23.0) 11 (7.2) 61 (40.1) 0 (0.0) 135 (88.8) 24 (22.9) 15 (9.9) 37 (24.3) 37 (24.3) 35 (23.2) 82 (53.9) 27.0 (26.0–28.0) 1020.0 (880.0–1140.0) 1 (0.7) 25.5 (24.0–26.5) 6 (4.3) 85 (55.9) 9.0 (8.0–11.0) 146 (96.1) 2.0 (0.0–5.5) 57 (37.5) 38 (25.0) 5 (3.3) 7 (4.6) 34 (22.4) 18 (11.8) 10 (6.6) 11 (7.2) 49.5 (36.0–73.0) 75.0 (64.0–91.7)

– 5.06 (2.88–8.91) 0.58 (0.36–0.92) 0.28 (0.10–0.82) 1.01 (0.64–1.59) 0.61 (0.30–1.23) 1.45 (0.98–2.16) – 1.38 (0.77–2.47) 1.13 (0.67–1.93) 1.34 (0.69–2.62) 0.90 (0.58–1.40) 2.15 (1.32–3.48) 1.71 (1.07–2.79) 1.09 (0.74–1.59) – – 0.08 (0.01–0.63) – 0.70 (0.28–1.80) 0.78 (0.53–1.14) – 0.88 (0.32–2.38) – 0.96 (0.65–1.42) 0.78 (0.51–1.21) 0.66 (0.24–1.81) 0.59 (0.25–1.40) 0.72 (0.46–1.12) 0.64 (0.36–1.12) 0.44 (0.21–0.89) 1.00 (0.48–2.09) – –

0.015 b0.001 0.027 0.023 1.000 0.220 0.081 0.330 0.350 0.814 0.488 0.714 0.003 0.034 0.744 0.936 0.544 0.005 0.898 0.610 0.237 0.965 1.000 0.003 0.903 0.318 0.561 0.311 0.174 0.152 0.028 0.854 b0.001 0.839

Data are presented as n (%), OR (95% CI) or median (IQR). Lost to follow-up group was set as a referent for odds ratio (OR) and 95% CI calculation. CRIB II denotes clinical risk index for babies score II. a Chorioamnionitis including clinically suspected cases. Data collected from 2001 onwards. Denominator is number of total followed-up from 2001 onwards. b Denominator is number of infants examined.

Fig. 2 demonstrates the relationship between the rate of moderate to severe disability and gestational age in rural and urban infants. In general, the rate of disability decreased with increasing gestational age, with no significant difference between urban and rural infants at each gestational age. Using stepwise multivariate analysis to control for confounding factors (Table 4), the adjusted risk of moderate/severe disability in RR infants was 0.77 (95% CI 0.52–1.23, p = 0.176). Factors significantly associated with moderate to severe functional disability were decreasing gestational age, SGA status, male gender and age at assessment.

4. Discussion With improvement in survival rates of preterm infants, increasing emphasis is now placed on the morbidities and neurodevelopmental outcomes of these survivors. We have previously demonstrated that the early neonatal morbidity rates were similar between premature infants b32 weeks of gestation born to RR and UR mothers [9]. In this present study, we found that the primary outcome of moderate to severe functional disability at 2–3 years was also similar between the two groups. Our data showed that RR mothers were more likely to be younger and of Aboriginal origin than UR mothers. Furthermore, more RR infants were born outside of a tertiary hospital. RR infants had shorter NICU length of stay but comparable length of hospital stay (NICU and step down or special care). This may reflect the fact that RR infants were transferred from NICU to step down or non-tertiary unit earlier to be closer to home.

Perinatal factors identified to be associated with adverse neurodevelopmental outcomes and cerebral palsy, such as CRIB II score [21,22], CLD, postnatal steroid use [23], IVH [24], sepsis and NEC [25] did not differ between the rural and urban groups (Table 2), which could explain the similar neurodevelopmental outcomes observed at 2–3 years of age. That rural infants have comparable short term morbidity rates is a testament to the advances in neonatal preterm care and efficacy of antenatal and postnatal transport systems in NSW and ACT [6,9]. Our follow-up rate of 74.8% is comparable to other published studies of neurodevelopment [26,27]. Our study showed a moderate to severe functional disability rate of 14.2–16.8%, which corresponds with previous reports of disability among preterm and low birth weight infants [18,23]. Results from this cohort also support the well demonstrated association of gestational age, SGA status and male gender with unfavourable neurodevelopmental outcomes (Table 4) [28,29]. A potential bias in this study may result from the differences in characteristics between the infants lost to follow up and those who were followed-up at 2–3 years [12–14]. On average, the infants who were followed-up were sicker and required more support in intensive care than those lost to follow up. However, we are unable to comment on parental socioeconomic characteristics and education, as we do not have data on these aspects. Castro et al. [27] found that children who attended follow-up were more likely to have potential risk factors for neurodevelopmental impairment than those lost to follow up. This could have introduced ascertainment bias and led to overestimation of the rate of neurodevelopmental impairment among survivors [26].

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Table 2 Antenatal and perinatal characteristics and major neonatal morbidities among urban and rural infants assessed at 2–3 years of age, corrected for prematurity. Characteristic

Urban (n = 1205)

Rural (n = 268)

OR (95% CI)

p-Value

Maternal age, year Aboriginal ethnicity Primipara Assisted conception Multiple pregnancy Pregnancy induced hypertension Ante-partum haemorrhage Gestational diabetes Any antenatal corticosteroid Chorioamnionitisa Vaginal breech Caesarean section in labour Born in non-tertiary centre Apgar score b7 at 5 min Male gender Gestational age, week Birth weight, gram Birth weight b10th percentile Head circumference, cm Head circumference b10th percentile Surfactant therapy CRIB II score Mechanical ventilation Duration of ventilation, days Patent ductus arteriosus requiring treatment Proven systemic infection Intraventricular haemorrhage grade 3 or 4b Necrotising enterocolitis Chronic lung disease Post-natal steroid for CLD Home oxygen Retinopathy of prematurity grade 3 or 4b Length of intensive care stay, days Length of hospital stay, days

31.0 (26.0–35.0) 13 (1.1) 405 (33.6) 190 (15.8) 325 (27) 215 (17.8) 359 (29.8) 23 (1.9) 1087 (90.2) 137 (20.7) 125 (10.4) 274 (22.7) 56 (4.6) 225 (18.8) 643 (53.4) 27.0 (26.0–28.0) 944.0 (775.5–1108.0) 122 (10.1) 24.7 (23.2–26.0) 94 (8.7) 857 (71.1) 10.0 (9.0–12.0) 1194 (99.1) 6.0 (1.4–19.0) 525 (43.6) 487 (40.4) 70 (5.8) 90 (7.5) 477 (39.6) 325 (27.0) 257 (21.3) 161 (13.4) 74.0 (56.0–96.0) 82.0 (69.0–102.0)

29.0 (23.0–33.0) 8 (3.1) 84 (31.3) 27 (10.1) 67 (25) 46 (17.2) 80 (29.9) 10 (3.7) 236 (88.1) 27 (19.9) 24 (9.0) 65 (24.3) 53 (19.8) 57 (21.3) 144 (53.7) 27.0 (26.0–28.0) 958.0 (780.0–1113.0) 30 (11.2) 24.7 (23.5–26.0) 24 (9.5) 194 (72.4) 10.0 (9.0–12.0) 266 (99.3) 6.0 (2.0–16.3) 122 (45.5) 108 (40.3) 23 (8.6) 20 (7.5) 119 (44.4) 83 (31.0) 49 (18.3) 26 (9.7) 64.0 (46.0–83.75) 82.0 (69.0–103.0)

– 2.82 (1.16, 6.88) 0.90 (0.68, 1.20) 0.60 (0.39, 0.92) 0.90 (0.67, 1.22) 0.95 (0.67, 1.35) 1.00 (0.75, 1.34) 1.99 (0.94, 4.24) 0.80 (0.53, 1.21) 0.87 (0.56, 1.35) 0.85 (0.54, 1.34) 1.09 (0.80, 1.48) 5.06 (3.38, 7.57) 1.18 (0.85, 1.63) 1.02 (0.78, 1.32) – – 1.12 (0.73, 1.71) – 1.16 (0.73, 1.86) 1.06 (0.79, 1.43) – 1.23 (0.27, 5.65) – 1.08 (0.83, 1.41) 1.00 (0.76, 1.30) 1.52 (0.93, 2.49) 1.00 (0.60, 1.65) 1.22 (0.93, 1.59) 1.21 (0.91, 1.62) 0.83 (0.59, 1.16) 0.70 (0.45, 1.08) – –

b0.001 0.038 0.520 0.017 0.559 0.861 1.000 0.111 0.347 0.923 0.560 0.650 b0.001 0.391 0.966 0.261 0.463 0.680 0.660 0.610 0.733 0.588 1.000 0.798 0.607 1.000 0.120 1.000 0.146 0.212 0.304 0.130 b0.001 0.649

Data are presented as n (%), OR (95% CI) or median (IQR). Urban group was set as a referent for odds ratio (OR) and 95% CI calculation. CRIB II denotes clinical risk index for babies score II. a Chorioamnionitis including clinically suspected cases. Data collected from 2001 onwards. Denominator is number of total followed-up from 2001 onwards. b Denominator is number of infants examined.

Wood et al. [23] found that postnatal transfer was independently associated with increased risk of cerebral palsy and severe motor disability, however this was not observed in the present study, which included a greater number of rural infants who required postnatal

transfer to a tertiary centre. This may provide indirect evidence for the efficiency of the NETS, which has significantly reduced the mortality and perinatal morbidity of outborn infants in NSW and ACT [6]. Another explanation could be the significant number of rural residents who were

Table 3 Neurodevelopmental and anthropometric outcomes of urban and rural infants born 1998–2004 and assessed at 2–3 years of age, corrected for prematurity. Characteristic

Urban (n = 1205)

Rural (n = 268)

OR (95% CI)

p-Value

Postnatal age at assessment, m Functional disability None/minimal Mild Moderate Severe Moderate to severe Developmental delay (GQ/MDI) −1 SD to −2 SD b−2 SD Cerebral palsy requiring walking aids Bilateral blindness Bilateral hearing loss Weight, kg Weight b10th percentile Height, cm Height b10th percentile Head circumference, cm HC b10th percentile

35.2 (27.4–36.7) – 826 (68.6) 176 (14.6) 122 (10.1) 80 (6.6) 202 (16.8) – 73 (6.9) 57 (5.4) 105 (8.7) 5 (0.4) 42 (3.5) 13.5 (12.0–15.0) 245 (21.8) 93.0 (89.3–97.0) 129 (12.5) 49.0 (48.0–50.4) 243 (22.2)

36.0 (33.7–37.0) – 194 (72.4) 36 (13.4) 22 (8.2) 16 (6.0) 38 (14.2) – 11 (4.8) 11 (4.8) 26 (9.7) 2 (0.7) 10 (3.7) 13.6 (12.3–15.0) 57 (23.1) 93.8 (89.5–97.0) 37 (15.4) 49.4 (47.6–50.7) 66 (27.5)

– – 1.20 (0.90, 1.61) 0.91 (0.62, 1.33) 0.79 (0.49, 1.28) 0.89 (0.51, 1.55) 0.82 (0.56, 1.19) – 0.66 (0.35, 1.27) 0.86 (0.45, 1.67) 1.13 (0.72, 1.77) 1.80 (0.35, 9.35) 1.07 (0.53, 2.17) – 1.06 (0.77, 1.46) – 1.34 (0.90, 1.98) – 1.29 (0.95, 1.77)

b0.001 0648 0.250 0.690 0.400 0.790 0.340 0.473 0.270 0.780 0.607 0.618 0.989 0.162 0.790 0.581 0.180 0.275 0.120

Data are presented as n (%), OR (95% CI) or median (IQR). Urban group was set as a referent for odds ratio (OR) and 95% CI calculation. GQ, general quotient; MDI, mental development index.

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and material resources may further compound the disadvantage already experienced by many preterm infants [31,33]. In conclusion, this study showed that extremely preterm infants born to rural residing mothers have comparable neurodevelopmental outcomes at 2–3 years of age to infants born to urban mothers. However, subtle disparities in cognitive development may not be apparent at this young age. Further follow-up should be performed in these infants to study any differences in cognitive function that may only emerge when these children enter school. Especially for rural residents and the Indigenous community, a lack of access to appropriate community supports and resources may negatively affect outcomes of preterm infants and further widen the urban-rural divide in health outcomes. Conflict of interest Fig. 2. Rate of moderate/severe functional disability in urban and rural infants stratified by gestational age.

The authors have no conflicts of interest to disclose. Acknowledgements

lost to follow-up, which may have introduced a bias in the results that could not be adjusted for. Results may have also been affected by the significant number of Aboriginal infants who were lost to follow up (n = 61 vs. only 21 who were followed-up), as Indigenous Australians are known to have substantial social disadvantage compared with non-Indigenous Australians [5], which can influence neurodevelopmental outcomes. Neurodevelopment in children is strongly influenced by parents' socio-economic status and educational background as well as social climate, family functioning and access to resources [30]. This is a limitation of our study, as our database did not collect data on parental socioeconomic status and education. However, because our data was drawn from defined geographical population of NSW and ACT, our results are unlikely to be biased by centre-based information. Despite comparable rates of moderate to severe functional disability in the urban and rural groups, milder degrees of neurodevelopmental deficits may be present, which may not be detected at the early age of follow-up [31]. It has been reported that even without apparent functional disability, extremely preterm infants can still have persistent sequelae such as cognitive deficit, academic underachievement and behavioural difficulties [32]. School performance and cognitive abilities in full and preterm children have strong associations with the child's social environment. Lack of access to appropriate social, educational

The authors thank the directors, the NICUS members and the audit officers of all tertiary units in supporting this collaborative study: NICUS, Dr Jennifer Bowen (Chairperson), Barbara Bajuk (Coordinator), Sara Sedgley (Research Officer); Canberra Hospital, A/Prof Zsuzsoka Kecskés (Director), Dr Hazel Carlisle, Lyn Barnes; John Hunter Children's Hospital, Dr Paul Craven (Acting Director), Chris Wake, Dr Rebecca Glover, Lynne Cruden; Royal Prince Alfred Hospital, A/Prof Nick Evans (Director), A/Prof David Osborn, Dr Girvan Malcolm, Dr Ingrid Rieger, Shelley Reid; Liverpool Hospital, Dr Jacqueline Stack (Acting Director), Dr Ian Callander, Kathryn Medlin, Kaye Marcin; Nepean Hospital, Dr Vijay Shindge (Acting Director), Dr Basiliki Lampropoulos, Mee Fong Chin; The Children's Hospital at Westmead, Prof Nadia Badawi (Director), Dr Alison Loughran-Fowlds, Caroline Karskens; Royal North Shore Hospital, Dr Mary Paradisis (Director), A/Prof Martin Kluckow, Claire Jacobs; Sydney Children's Hospital, Dr Andrew Numa (Director), Dr Gary Williams, Janelle Young; Westmead Hospital, Dr Mark Tracy (Director), Dr Melissa Luig, Jane Baird; and Royal Hospital for Women, A/Prof Kei Lui, Dr Lee Sutton, Diane Cameron. We also thank the babies and their families, the nursing and midwifery, obstetric and medical records staff of the obstetric and children's hospitals in NSW and the ACT.

Table 4 Multiple logistic regression model to determine independent factors associated with moderate/severe disability. Factor

Crude OR (95% CI); p-value

Adjusted OR (95% CI); p-value

Rural vs. urban residence 23–26 week subgroup 27–28 week subgroup No antenatal steroid vs. complete or some antenatal steroid Assisted conception Maternal age b20 years vs. 20–34 years ≥35 years vs. 20–34 years Aboriginal vs. other ethnicities Gestational age 23–26 vs. 27–28 week subgroup Birth weight percentiles SGA vs. AGA LGA vs. AGA Male vs. female sex Outborn Age at follow-up, months

0.82 (0.56–1.19); 0.298 0.77 (0.46–1.27); 0.307 0.90 (0.51–1.59); 0.709 1.45 (0.96–2.21); 0.080 1.24 (0.85–1.79); 0.264 p = 0.327 1.13 (0.59–2.15); 0.718 0.78 (0.6–1.10); 0.162 1.08 (0.50–2.35); 0.839 p b 0.001 2.27 (1.71–3.01); b0.001 p = 0.005 1.91 (1.29–2.4); 0.001 0.95 (0.52–1.74); 0.866 1.78 (1.33–2.37); b0.001 0.87 (0.50–1.51); 0.633 1.03 (1.00–1.05); 0.024

0.77 (0.52–1.23); 0.176 0.66 (0.39–1.30); 0.133 0.83 (0.46–1.49); 0.529 1.43 (0.93–2.20); 0.103 1.28 (0.87–1.89); 0.211 p = 0.237 1.31 (0.66–2.57); 0.437 0.77 (0.54–1.10); 0.155 1.18 (0.52–2.67); 0.699 p b 0.001 2.37 (1.77–3.15); b0.001 p = 0.001 2.16 (1.44–3.25); b0.001 0.90 (0.48–1.67); 0.738 1.87 (1.39–2.50); b0.001 0.86 (0.46–1.61); 0.640 1.03 (1.00–1.05); 0.025

Values are odds ratio (95% confidence interval); p-value. Analysis of rural residence was performed for the whole 23–28 week cohort and then stratified for the two subgroups of 23–26 weeks and 27–28 weeks gestational age with corresponding urban resident infants as the referent group. AGA indicates appropriate for gestational age; LGA, large for gestational age (N90th percentile) and SGA, small for gestational age (b10th percentile).

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Neurodevelopmental outcome of extremely preterm infants born to rural and urban residents' mothers in Australia.

Rural and remote residents in Australia have long experienced unfavourable health outcomes compared to their urban counterparts...
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