Search

Context: Uncertainty exists about the benefit of dietary docosahexaenoic acid (DHA) on the neurodevelopment of preterm infants.Objective: To determine the effect of meeting the estimated DHA requirement of preterm infants on neurodevelopment at 18 months' corrected age.Design, Setting, and Participants: Randomized, double-blind controlled trial enrolling infants born at less than 33 weeks' gestation from April 2001 to October 2005 at 5 Australian tertiary hospitals, with follow-up to 18 months.Intervention: High-DHA (approximately 1% total fatty acids) enteral feeds compared with standard DHA (approximately 0.3% total fatty acids) from day 2 to 4 of life until term corrected age.Main Outcome Measures: Bayley Mental Development Index (MDI) at 18 months' corrected age. A priori subgroup analyses were conducted based on randomization strata (sex and birth weight < 1250 g vs > or = 1250 g).Results: Of the 657 infants enrolled, 93.5% completed the 18-month follow-up. Bayley MDI scores did not differ between the high- and standard-DHA groups (mean difference, 1.9; 95% confidence interval [CI], -1.0 to 4.7). The MDI among girls fed the high-DHA diet was higher than girls fed standard DHA in unadjusted and adjusted analyses (unadjusted mean difference, 4.7; 95% CI, 0.5-8.8; adjusted mean difference, 4.5; 95% CI, 0.5-8.5). The MDI among boys did not differ between groups. For infants born weighing less than 1250 g, the MDI in the high-DHA group was higher than with standard DHA in the unadjusted comparison (mean difference, 4.7; 95% CI, 0.2-9.2) but did not reach statistical significance following adjustment for gestational age, sex, maternal education, and birth order (mean difference, 3.8; 95% CI, -0.5 to 8.0). The MDI among infants born weighing at least 1250 g did not differ between groups.Conclusion: A DHA dose of approximately 1% total fatty acids in early life did not increase MDI scores of preterm infants overall born earlier than 33 weeks but did improve the MDI scores of girls.Trial Registration: anzctr.org.au Identifier: ACTRN12606000327583. [ABSTRACT FROM AUTHOR]

Importance: Children born at less than 29 weeks' gestation are at risk of behavioral difficulties. This may be due in part to the lack of transplacental supply of docosahexaenoic acid (DHA), a key fatty acid with structural and functional roles in the brain., Objective: To determine whether meeting the neonatal DHA requirement through supplementation is associated with improved behavioral functioning of children born at less than 29 weeks' gestation., Design, Setting and Participants: This was a follow-up of children from 10 Australian participating centers in a multi-center, blinded, parallel group randomized clinical trial of infants born at less than 29 weeks' gestation conducted from June 2012 and September 2015, excluding those with additional fatty acid supplementation or major congenital or chromosomal abnormalities. Follow-up took place from August 2018 to May 2021. Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age., Interventions: Infants were randomized to receive daily enteral emulsions providing 60 mg/kg/d of DHA or a soy-oil emulsion (with no DHA) from within the first 3 days of enteral feeding until 36 weeks' postmenstrual age or discharge home, whichever occurred first., Main Outcomes and Measures: The primary outcome of this follow-up was parent-rated behavior and emotional functioning as indicated by the Total Difficulties score of the Strengths and Difficulties Questionnaire. Parents also completed questionnaires about their child's behavioral manifestations of executive functioning, as well as a range of health outcomes to assess potential longer-term side effects of DHA intervention., Results: Primary outcome data were available for 731 children (76% of 958 surviving eligible children; 361 in the intervention group and 370 in the control group). Of these 731, 452 (47%) were female, and the mean (SD) corrected age at follow-up was 5.4 (0.5) years. Following imputation for missing data, the mean Total Difficulties score was the same in both groups (intervention group, n = 465; mean [SD], 11.8 [6.3]; control group, n = 493; mean [SD], 11.8 [6.0]; mean difference adjusted for sex, gestational age stratum, and hospital, 0.01; 95% CI, -0.87 to 0.89; P = .98). There was no evidence for differences between the groups in any secondary outcomes of behavior, executive functioning, or health., Conclusions and Relevance: In this follow-up of a randomized clinical trial, enteral DHA supplementation at the equivalent of the estimated in utero dose for infants born at less than 29 weeks' gestation did not improve behavioral functioning at age 5 years. There were no indications of adverse effects with DHA supplementation., Trial Registration: Australian New Zealand Clinical Trial Registry: ACTRN12612000503820.

Importance: High-dose omega-3 docosahexaenoic acid (DHA) supplementation of children born at less than 29 weeks' gestation has been shown to improve IQ despite increasing the risk of bronchopulmonary dysplasia (BPD). Given that BPD is associated with poorer cognitive outcomes, it is unclear whether the increased risk of BPD with DHA supplementation is associated with decreased benefit to IQ., Objective: To investigate whether the increased risk of BPD with DHA supplementation was associated with diminished IQ benefit., Design, Setting, and Participants: This cohort study used data collected from a multicenter, blinded, randomized controlled trial of DHA supplementation in children born at less than 29 weeks' gestation. Participants were recruited from 2012 to 2015 and followed up until 5 years' corrected age. Data were analyzed from November 2022 to February 2023., Interventions: Enteral DHA emulsion (60 mg/kg/d, to match the estimated in-utero requirement) or a control emulsion from the first 3 days of enteral feeds until 36 weeks' postmenstrual age or discharge home., Main Outcomes and Measures: Physiological BPD was assessed at 36 weeks' postmenstrual age. IQ was assessed at 5 years' corrected age using the Wechsler Preschool and Primary Scale of Intelligence, 4th Edition; children from the 5 highest-recruiting Australian hospitals were assessed. The total effect of DHA supplementation on IQ was divided into direct and indirect effects using mediation analysis, with BPD as the presumed mediating variable., Results: Among 656 surviving children from hospitals involved in IQ follow-up (mean [SD] gestational age at birth, 26.8 [1.4] weeks; 346 males [52.7%]), there were 323 children with DHA supplementation and 333 children in the control group. Mean IQ was 3.45 points (95% CI, 0.38 to 6.53 points) higher in the DHA group than the control group, despite an increase in the risk of BPD (160 children [49.7%] vs 143 children [42.8%] with BPD). The indirect effect of DHA on IQ via BPD was not statistically significant (-0.17 points; 95% CI, -0.62 to 0.13 points), with most of the effect of DHA on IQ occurring independently of BPD (direct effect = 3.62 points; 95% CI, 0.55 to 6.81 points)., Conclusions and Relevance: This study found that associations of DHA with BPD and IQ were largely independent. This finding suggests that if clinicians supplement children born preterm with high-dose DHA, any resulting increase in BPD risk would not be associated with meaningful reductions in the IQ benefit.

Importance: Survival of infants born extremely preterm (EP) (<28 weeks' gestation) has increased since the early 1990s. It is necessary to know whether increased survival is accompanied by increased neurodevelopmental disability., Objective: To examine changes in major (ie, moderate or severe) neurodevelopmental disability and survival free of major neurodevelopmental disability at 2 years in infants born EP., Design, Setting, and Participants: Four prospective longitudinal cohort studies comprising all EP live births at 22 to 27 weeks' gestation from April 1, 2016, to March 31, 2017, and earlier eras (1991-1992, 1997, and 2005), and contemporaneous term-born controls in the state of Victoria, Australia. Among 1208 live births during the periods studied, data were available for analysis of 2-year outcomes in 1152 children: 422 (1991-1992), 215 (1997), 263 (2005), and 252 (2016-2017). Data analysis was performed from September 17, 2020, to April 15, 2021., Exposures: Extreme preterm live birth., Main Outcomes and Measures: Survival, blindness, deafness, cerebral palsy, developmental delay, and neurodevelopmental disability at 2 years' corrected age. Developmental delay comprised a developmental quotient less than -1 SD relative to the control group means on the Bayley Scales for each era. Major neurodevelopmental disability comprised blindness, deafness, moderate to severe cerebral palsy, or a developmental quotient less than -2 SDs. Individual neurodevelopmental outcomes in each era were contrasted relative to the 2016-2017 cohort using logistic regression adjusted for gestational age, sex, birth weight z score, and sociodemographic variables. Changes in survival free of major neurodevelopmental disability over time were also assessed using logistic regression., Results: Survival to 2 years was highest in 2016-2017 (73% [215 of 293]) compared with earlier eras (1991-1992: 53% [225 of 428]; 1997: 70% [151 of 217]; 2005: 63% [170 of 270]). Blindness and deafness were uncommon (<3%). Cerebral palsy was less common in 2016-2017 (6%) than in earlier eras (1991-1992: 11%; 1997: 12%; 2005: 10%). There were no obvious changes in the rates of developmental quotient less than -2 SDs across eras (1991-1992: 18%; 1997: 22%; 2005: 7%; 2016-2017: 15%) or in rates of major neurodevelopmental disability (1991-1992: 20%; 1997: 26%; 2005: 15%; 2016-2017: 15%). Rates of survival free of major neurodevelopmental disability increased steadily over time: 42% (1991-1992), 51% (1997), 53% (2005), and 62% (2016-2017) (odds ratio, 1.30; 95% CI, 1.15-1.48 per decade; P < .001)., Conclusions and Relevance: These findings suggest that survival free of major disability at age 2 years in children born EP has increased by an absolute 20% since the early 1990s. Increased survival has not been associated with increased neurodevelopmental disability.

Importance: Birth before 32 weeks' gestation (very preterm [VPT]) and birth weight below 1500 g (very low birth weight [VLBW]) have been associated with lower cognitive performance in childhood. However, there are few investigations of the association of neonatal morbidities and maternal educational levels with the adult cognitive performance of individuals born VPT or VLBW (VPT/VLBW)., Objective: To assess differences in adult IQ between VPT/VLBW and term-born individuals and to examine the association of adult IQ with cohort factors, neonatal morbidities, and maternal educational level among VPT/VLBW participants., Data Sources: Systematic review of published data from PubMed and meta-analysis of individual participant data (IPD) of cohorts from 2 consortia (Research on European Children and Adults Born Preterm [RECAP] and Adults Born Preterm International Collaboration [APIC])., Study Selection: The meta-analysis included prospective longitudinal cohort studies that assessed the full-scale IQ of adults born VPT or VLBW and respective control groups comprising term-born adults., Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for analyses of individual participant data and identified 8 studies that provided data from 2135 adults (1068 VPT/VLBW and 1067 term-born participants) born between 1978 and 1995. Meta-analyses of IPD were performed using a 1-stage approach, treating VPT birth or VLBW and cohort as random effects., Main Outcomes and Measures: Full-scale IQ scores were converted to z scores within each cohort using the combined SD of VPT/VLBW participants and a control group of term-born participants, with scores centered on the mean of the control group., Results: A total of 426 records were identified and screened. After exclusions, 13 studies were included in the aggregate meta-analysis. The IPD meta-analysis included 8 of the 9 RECAP and APIC cohorts with adult IQ data. The mean (SD) age among the 8 IPD cohorts was 24.6 (4.3) years, and 1163 participants (54.5%) were women. In unadjusted analyses, VPT/VLBW participants had mean adult IQ scores that were 0.78 SD (95% CI, -0.90 to -0.66 SD) lower than term-born participants, equivalent to a difference of 12 IQ points. Among VPT/VLBW participants, lower gestational age (score difference per week of gestation, 0.11; 95% CI, 0.07-0.14), lower birth weight z scores (score difference per 1.0 SD, 0.21; 95% CI, 0.14-0.28), the presence of neonatal bronchopulmonary dysplasia (score difference, -0.16; 95% CI, -0.30 to -0.02) or any grade of intraventricular hemorrhage (score difference, -0.19; 95% CI, -0.33 to -0.05), and lower maternal educational level (score difference, 0.26; 95% CI, 0.17-0.35) were all significantly associated with lower IQ scores in adulthood., Conclusions and Relevance: In this IPD meta-analysis, lower gestational age, lower weight for gestational age, neonatal morbidities, and lower maternal educational levels were all important risk factors associated with lower IQ among young adults born VPT or VLBW.

Importance: Repeated doses of antenatal betamethasone are recommended for women at less than 32 weeks' gestation with ongoing risk of preterm birth. However, concern that this therapy may be associated with adverse neurocognitive effects in children with fetal growth restriction (FGR) remains., Objective: To determine the influence of FGR on the effects of repeated doses of antenatal betamethasone on neurocognitive function in midchildhood., Design, Setting, and Participants: This preplanned secondary analysis of data from the multicenter Australasian Collaborative Trial of Repeat Doses of Corticosteroids (ACTORDS) included women at less than 32 weeks' gestation with ongoing risk of preterm birth (<32 weeks) at least 7 days after an initial course of antenatal corticosteroids who were treated at 23 hospitals across Australia and New Zealand from April 1, 1998, through July 20, 2004. Participants were randomized to intramuscular betamethasone or saline placebo; treatment could be repeated weekly if the woman was judged to be at continued risk of preterm birth. All surviving children were invited to a midchildhood outcome study. Data for this study were collected from October 27, 2006, through March 18, 2011, and analyzed from June 1 through 30, 2018., Interventions: At 6 to 8 years of corrected age, children were assessed by a pediatrician and psychologist for neurosensory and cognitive function, and parents completed standardized questionnaires., Main Outcomes and Measures: The prespecified primary outcomes were survival free of any disability and death or survival with moderate to severe disability., Results: Of 1059 eligible children, 988 (55.0% male; mean [SD] age at follow-up, 7.5 [1.1] years) were assessed at midchildhood. The FGR rate was 139 of 493 children (28.2%) in the repeated betamethasone treatment group and 122 of 495 (24.6%) in the placebo group (P = .20). Primary outcome rates were similar between treatment groups for the FGR and non-FGR subgroups, with no evidence of an interaction effect for survival free of any disability (FGR group, 108 of 144 [75.0%] for repeated betamethasone treatment vs 91 of 126 [72.2%] for placebo groups [odds ratio [OR], 1.1; 95% CI, 0.6-1.9]; non-FGR group, 267 of 335 [79.7%] for repeated betamethasone vs 283 of 358 [79.0%] for placebo groups [OR, 1.0; 95% CI, 0.7-1.5]; P = .77) and death or moderate to severe disability (FGR group, 21 of 144 [14.6%] for repeated betamethasone treatment vs 20 of 126 [15.9%] for placebo groups [OR, 0.9; 95% CI, 0.4-1.9]; non-FGR group, 29 of 335 [8.6%] for repeated betamethasone vs 36 of 358 [10.0%] for placebo [OR, 0.8; 95% CI, 0.4-1.3]; P = .84)., Conclusions and Relevance: In this study, repeated antenatal betamethasone treatment compared with placebo was not associated with adverse effects on neurocognitive function at 6 to 8 years of age, even in the presence of FGR. Physicians should use repeated doses of antenatal corticosteroids when indicated before preterm birth, regardless of FGR, in view of the associated neonatal benefits and absence of later adverse effects., Trial Registration: anzctr.org.au Identifier: ACTRN12606000318583.

Importance: There are potential benefits and harms of hyperoxemia and hypoxemia for extremely preterm infants receiving more vs less supplemental oxygen., Objective: To compare the effects of different target ranges for oxygen saturation as measured by pulse oximetry (Spo2) on death or major morbidity., Design, Setting, and Participants: Prospectively planned meta-analysis of individual participant data from 5 randomized clinical trials (conducted from 2005-2014) enrolling infants born before 28 weeks' gestation., Exposures: Spo2 target range that was lower (85%-89%) vs higher (91%-95%)., Main Outcomes and Measures: The primary outcome was a composite of death or major disability (bilateral blindness, deafness, cerebral palsy diagnosed as ≥2 level on the Gross Motor Function Classification System, or Bayley-III cognitive or language score <85) at a corrected age of 18 to 24 months. There were 16 secondary outcomes including the components of the primary outcome and other major morbidities., Results: A total of 4965 infants were randomized (2480 to the lower Spo2 target range and 2485 to the higher Spo2 range) and had a median gestational age of 26 weeks (interquartile range, 25-27 weeks) and a mean birth weight of 832 g (SD, 190 g). The primary outcome occurred in 1191 of 2228 infants (53.5%) in the lower Spo2 target group and 1150 of 2229 infants (51.6%) in the higher Spo2 target group (risk difference, 1.7% [95% CI, -1.3% to 4.6%]; relative risk [RR], 1.04 [95% CI, 0.98 to 1.09], P = .21). Of the 16 secondary outcomes, 11 were null, 2 significantly favored the lower Spo2 target group, and 3 significantly favored the higher Spo2 target group. Death occurred in 484 of 2433 infants (19.9%) in the lower Spo2 target group and 418 of 2440 infants (17.1%) in the higher Spo2 target group (risk difference, 2.8% [95% CI, 0.6% to 5.0%]; RR, 1.17 [95% CI, 1.04 to 1.31], P = .01). Treatment for retinopathy of prematurity was administered to 220 of 2020 infants (10.9%) in the lower Spo2 target group and 308 of 2065 infants (14.9%) in the higher Spo2 target group (risk difference, -4.0% [95% CI, -6.1% to -2.0%]; RR, 0.74 [95% CI, 0.63 to 0.86], P < .001). Severe necrotizing enterocolitis occurred in 227 of 2464 infants (9.2%) in the lower Spo2 target group and 170 of 2465 infants (6.9%) in the higher Spo2 target group (risk difference, 2.3% [95% CI, 0.8% to 3.8%]; RR, 1.33 [95% CI, 1.10 to 1.61], P = .003)., Conclusions and Relevance: In this prospectively planned meta-analysis of individual participant data from extremely preterm infants, there was no significant difference between a lower Spo2 target range compared with a higher Spo2 target range on the primary composite outcome of death or major disability at a corrected age of 18 to 24 months. The lower Spo2 target range was associated with a higher risk of death and necrotizing enterocolitis, but a lower risk of retinopathy of prematurity treatment.

Importance: Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years., Objective: To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later., Design, Setting, and Participants: A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome., Interventions: Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed., Main Outcomes and Measures: Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist)., Results: Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009)., Conclusions and Relevance: Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age., Trial Registration: clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

Importance: Moderate and late preterm (MLPT) births comprise most preterm infants. Therefore, long-term developmental concerns in this population potentially have a large public health influence. While there are increasing reports of developmental problems in MLPT children, detail is lacking on the precise domains that are affected., Objective: To compare neurodevelopment and social-emotional development between MLPT infants and term-born control infants at age 2 years., Design, Setting, and Participants: This investigation was a prospective longitudinal cohort study at a single tertiary hospital. Participants were MLPT infants (32-36 weeks' completed gestation) and healthy full-term controls (≥37 weeks' gestation) recruited at birth. During a 3-year period between December 7, 2009, and November 7, 2012, MLPT infants were recruited at birth from the neonatal unit and postnatal wards of the Royal Women's Hospital, Melbourne, Australia. The term control recruitment extended to March 26, 2014. The dates of the data developmental assessments were February 23, 2012, to April 8, 2016., Exposure: Moderate and late preterm birth., Main Outcomes and Measures: Cerebral palsy, blindness, and deafness assessed by a pediatrician; cognitive, language, and motor development assessed using the Bayley Scales of Infant Development-Third Edition (developmental delay was defined as less than -1 SD relative to the mean in controls in any domain of the scales); and social-emotional and behavioral problems assessed by a parent questionnaire (Infant Toddler Social Emotional Assessment). Outcomes were compared between birth groups using linear and logistic regression, adjusted for social risk., Results: In total, 198 MLPT infants (98.5% of 201 recruited) and 183 term-born controls (91.0% of 201 recruited) were assessed at 2 years' corrected age. Compared with controls, MLPT children had worse cognitive, language, and motor development at age 2 years, with adjusted composite score mean differences of -5.3 (95% CI, -8.2 to -2.4) for cognitive development, -11.4 (95% CI, -15.3 to -7.5) for language development, and -7.3 (95% CI, -10.6 to -3.9) for motor development. The odds of developmental delay were higher in the MLPT group compared with controls, with adjusted odds ratios of 1.8 (95% CI, 1.1-3.0) for cognitive delay, 3.1 (95% CI, 1.8-5.2) for language delay, and 2.4 (95% CI, 1.3-4.5) for motor delay. Overall social-emotional competence was worse in MLPT children compared with controls (t statistic mean difference, -3.6 (95% CI, -5.8 to -1.4), but other behavioral domains were similar. The odds of being at risk for social-emotional competence were 3.9 (95% CI, 1.4-10.9) for MLPT children compared with controls., Conclusions and Relevance: Moderate and late preterm children exhibited developmental delay compared with their term-born peers, most marked in the language domain. This knowledge of developmental needs in MLPT infants will assist in targeting surveillance and intervention.

Importance: Mothers experience heightened depression and anxiety following very preterm (VPT) birth, but how these symptoms evolve during the first months after birth is unknown. Research on the psychological adjustment of fathers following VPT birth is limited., Objectives: To describe the trajectory and predictors of distress in parents of VPT infants during the first 12 weeks after birth, and to compare rates of depression and anxiety in parents of VPT infants with those in parents of healthy full-term (FT) infants shortly after birth and at 6 months' postnatal age., Design, Setting, and Participants: Longitudinal, prospective, follow-up cohort study of depression and anxiety symptoms in parents of VPT infants (<30 weeks' gestational age; admitted to the neonatal intensive care unit at the Royal Women's Hospital, Melbourne, Australia, between January 21, 2011, and December 23, 2013), documented every 2 weeks until age 12 weeks and at age 6 months, as well as in parents of healthy FT infants (≥37 weeks' gestational age; birth weight >2499 g; born at the Royal Women's Hospital between August 15, 2012, and March 26, 2014; not admitted to the neonatal nursery) shortly after birth and at age 6 months., Exposure: Birth of a VPT infant., Main Outcomes and Measures: Symptoms of depression (Center for Epidemiological Studies Depression Scale) and anxiety (Hospital Anxiety and Depression Scale)., Results: The study included 113 mothers (mean [SD] age at birth, 32.7 [5.3] years) and 101 fathers (mean [SD] age at birth, 34.7 [6.4] years) of 149 VPT infants (49% male; 84 singletons, 65 multiples; mean [SD] birth weight, 1021 [261] g) as well as 117 mothers (mean [SD] age at birth, 32.9 [4.8] years) and 110 fathers (mean [SD] age at birth, 35.9 [5.3] years) of 151 healthy FT infants (50% male; 149 singletons, 2 multiples; mean [SD] birth weight, 3503 [438] g). Mean scores and rates of depression and anxiety reduced over time for parents of VPT infants in the 12 weeks after birth: the mean (95% CI) change in depression score per week was -0.52 (-0.73 to -0.31; P < .001) for mothers and -0.39 (-0.56 to -0.21; P < .001) for fathers; the mean (95% CI) change in anxiety score per week was -0.16 (-0.26 to -0.05; P = .003) for mothers and -0.22 (-0.31 to -0.15; P < .001) for fathers. However, rates never dropped below 20%. Few perinatal or social risk factors predicted longitudinal changes in depression or anxiety. Compared with parents of FT infants, parents of VPT infants had higher rates of depression shortly after birth (mothers: 6% vs 40%; odds ratio [OR] = 9.9; 95% CI, 4.3 to 23.3; P < .001; fathers: 5% vs 36%; OR = 11.0; 95% CI, 4.1 to 29.6; P < .001) and at 6 months (mothers: 5% vs 14%; OR = 2.9; 95% CI, 1.0 to 8.2; P = .04; fathers: 6% vs 19%; OR = 3.4; 95% CI, 1.3 to 9.0; P = .01) as well as anxiety shortly after birth (mothers: 13% vs 48%; OR = 6.5; 95% CI, 3.3 to 12.6; P < .001; fathers: 10% vs 47%; OR = 7.8; 95% CI, 3.7 to 16.8; P < .001) and at 6 months (mothers: 14% vs 25%; OR = 2.1; 95% CI, 1.0 to 4.3; P = .05; fathers: 10% vs 20%; OR = 2.3; 95% CI, 1.0 to 5.3; P = .05)., Conclusions and Relevance: Mothers and fathers of VPT infants had elevated rates of depression and anxiety symptoms that declined over time, although remaining above expected levels throughout the newborn period and at 6 months.

Importance: Smaller cerebral volumes at hospital discharge in very preterm (VPT) infants are associated with poor neurobehavioral outcomes. Brain growth from the newborn period to middle childhood has not been explored because longitudinal data have been lacking., Objectives: To examine the pattern of growth of cerebral tissue volumes from hospital discharge to childhood in VPT infants and to determine perinatal risk factors for impaired brain growth and associations with neurobehavioral outcomes at 7 years., Design, Setting, and Participants: Prospective cohort study of VPT infants (<30 weeks' gestation or <1250 g) born between April 11, 2001, and April 26, 2004, and followed up at 7 years' corrected age. The setting was The Royal Women's Hospital and The Royal Children's Hospital, Melbourne, Australia. Of 224 VPT infants and 46 full-term (FT) infants, usable magnetic resonance imaging data at either infancy or 7 years were collected for 214 VPT children (95.5%) and 46 FT children (100%), while 126 VPT children (56.3%) and 31 FT children (67.4%) had usable magnetic resonance imaging data at both time points. Follow-up was conducted from April 28, 2008, to August 9, 2011. Our final analysis was on March 3, 2016., Exposure: Prematurity., Main Outcomes and Measures: Absolute tissue growth, defined as change in absolute tissue volume, between infancy and 7 years was calculated for cortical gray matter volume (GMV), white matter volume (WMV), and subcortical GMV. IQ, language, and motor function were measured at 7 years., Results: The study cohort comprised 260 participants. Their mean (SD) age was 7.5 (0.2) years, and 49.2% (128 of 260) were female. Early GMV deficits in VPT infants were magnified by 7 years, with less growth than FT controls. Growth differences were 31.4 (95% CI, 14.8-48.1) cm3 for cortical GMV and 1.7 (95% CI, 0.5-2.8) cm3 for subcortical GMV. Within the VPT group, greater growth was observed in boys for cortical GMV (31.9; 95% CI, 16.8-46.9 cm3), WMV (31.7; 95% CI, 19.7-43.7 cm3), and subcortical GMV (1.8; 95% CI, 0.8-2.8 cm3). After controlling for sex and maternal education, all tissue volumes in infancy correlated with IQ (r ≥ 0.35, P < .05) and language (r ≥ 0.29, P < .05). Seven-year volumes correlated with IQ (r = 0.28, P = .04 for cortical GMV), language (r = 0.29, P = .04 for cortical GMV), and motor functioning (r ≥ 0.29, P < .05 for all tissues). There was no evidence of any association between brain growth during childhood and outcomes in VPT infants., Conclusions and Relevance: Low brain volumes observed in VPT infants are exaggerated at 7 years. Low brain volume in infancy is associated with long-term functional outcomes, emphasizing the persisting influence of early brain development on subsequent growth and outcomes.

Importance: Antenatal magnesium sulfate given to pregnant women at imminent risk of very preterm delivery reduces the risk of cerebral palsy in early childhood, although its effects into school age have not been reported from randomized trials., Objective: To determine the association between exposure to antenatal magnesium sulfate and neurological, cognitive, academic, and behavioral outcomes at school age., Design, Setting, and Participants: The ACTOMgSO4 was a randomized clinical trial conducted in 16 centers in Australia and New Zealand, comparing magnesium sulfate with placebo given to pregnant women (n = 535 magnesium; n = 527 placebo) for whom imminent birth was planned or expected before 30 weeks' gestation. Children who survived from the 14 centers who participated in the school-age follow-up (n = 443 magnesium; n = 424 placebo) were invited for an assessment at 6 to 11 years of age between 2005 and 2011., Main Outcomes and Measures: Mortality, cerebral palsy, motor function, IQ, basic academic skills, attention and executive function, behavior, growth, and functional outcomes. Main analyses were imputed for missing data., Results: Of the 1255 fetuses known to be alive at randomization, the mortality rate to school age was 14% (88/629) in the magnesium sulfate group and 18% (110/626) in the placebo group (risk ratio [RR], 0.80; 95% CI, 0.62-1.03, P = .08). Of 867 survivors available for follow-up, outcomes at school age (corrected age 6-11 years) were determined for 669 (77%). Comparing the magnesium sulfate and placebo groups revealed no statistically significant difference in proportions with cerebral palsy (23/295 [8%] and 21/314 [7%], respectively; odds ratio [OR], 1.26; 95% CI, 0.84-1.91; P = .27) or abnormal motor function (80/297 [27%] and 80/300 [27%], respectively; OR, 1.16; 95% CI, 0.88-1.52; P = .28). There was also little difference between groups on any of the cognitive, behavioral, growth, or functional outcomes., Conclusions and Relevance: Magnesium sulfate given to pregnant women at imminent risk of birth before 30 weeks' gestation was not associated with neurological, cognitive, behavioral, growth, or functional outcomes in their children at school age, although a mortality advantage cannot be excluded. The lack of long-term benefit requires confirmation in additional studies., Trial Registration: anzctr.org.au Identifier: ACTRN12606000252516.

Context: Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age., Objective: To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age., Design, Setting, and Participants: Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years., Main Outcome Measures: Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness., Results: The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89)., Conclusion: Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.

Objective: To explore perinatal correlates of 3 simple measures of brain size, known as metrics, in very preterm infants at term-equivalent age and their relationship to 2-year neurodevelopmental outcomes., Design: Prospective cohort study of preterm infants born at a gestational age of less than 30 weeks or a weight of less than 1250 g between April 1, 2001, and December 31, 2003, and followed up at 2 years of corrected age., Setting: The Royal Women's Hospital and the magnetic resonance imaging unit at the Royal Children's Hospital., Patients: Two hundred thirty-six preterm infants., Interventions: Brain metrics--biparietal, bifrontal, and transverse cerebellar diameters--on magnetic resonance imaging for preterm infants at term-equivalent age and neurodevelopmental assessments at 2 years of corrected age., Main Outcome Measures: Mental Development Index and the Psychomotor Development Index of the Bayley Scales of Infant Development-Revised., Results: Higher birth weight z score, shorter duration of assisted ventilation, and postmenstrual age at magnetic resonance imaging were independently associated with increases in the 3 brain metrics, and male sex was associated with larger bifrontal and biparietal diameters. Only the biparietal diameter was predictive of cognitive and motor indices after adjustment for perinatal variables and social risk., Conclusion: This study provides further evidence of altered brain growth in preterm infants, relating to growth restriction and severity of illness, that in turn relate to neurodevelopmental outcome.

Objective: To assess the ability of the third edition of the Bayley Scales of Infant and Toddler Development (Bayley-III) to detect developmental delay in 2-year-old children who were extremely preterm and those carried to term., Design: Prospective cohort study., Setting: The state of Victoria, Australia., Participants: Subjects were consecutive surviving children who were born either at less than 28 weeks' gestational age (extremely preterm) or with less than 1000 g birth weight (extremely low-birth-weight; n = 221) in the state of Victoria, Australia, in 2005 and randomly selected controls who were both carried to term and of normal birth weight (n = 220)., Main Outcome Measure: Children were assessed by psychologists blinded to knowledge of group at 2 years of age, corrected for prematurity with the new Bayley-III scale., Results: Follow-up rates of both cohorts were high (>92%). Mean values for all composite and subtest scores for the extremely preterm/extremely low-birth-weight group were significantly below those of the control group (P < .001), with the magnitude of all group differences being in excess of two-thirds SD. Mean values for the extremely preterm/extremely low-birth-weight group approached the normative mean, but in contrast, the mean values for the control group were higher than expected, with composite scores being between 0.55 and 1.23 SD above the normative mean. Proportions of children with developmental delay were grossly underestimated using the reference values, but were within the expected range when computed relative to the mean (standard deviation) for the controls., Conclusion: The Bayley-III scale seriously underestimates developmental delay in 2-year-old Australian children.

Context: Prenatal magnesium sulfate may reduce the risk of cerebral palsy or death in very preterm infants., Objective: To determine the effectiveness of magnesium sulfate given for neuroprotection to women at risk of preterm birth before 30 weeks' gestation in preventing pediatric mortality and cerebral palsy., Design, Setting, and Patients: Randomized controlled trial at 16 tertiary hospitals in Australia and New Zealand with stratification by center and multiple pregnancy. A total of 1062 women with fetuses younger than 30 weeks' gestation for whom birth was planned or expected within 24 hours were enrolled from February 1996 to September 2000 with follow-up of surviving children at a corrected age of 2 years., Interventions: Women were randomly assigned to receive a loading infusion of 8 mL (4 g [16 mmol] of 0.5 g/mL of magnesium sulfate solution or isotonic sodium chloride solution [0.9%]) for 20 minutes followed by a maintenance infusion of 2 mL/h for up to 24 hours., Main Outcome Measures: Rates of total pediatric mortality, cerebral palsy, and the combined outcome of death or cerebral palsy at a corrected age of 2 years., Results: Data were analyzed for 1047 (99%) 2-year survivors. Total pediatric mortality (13.8% vs 17.1%; relative risk [RR], 0.83; 95% confidence interval [CI], 0.64-1.09), cerebral palsy in survivors (6.8% vs 8.2%; RR, 0.83; 95% CI, 0.54-1.27), and combined death or cerebral palsy (19.8% vs 24.0%; RR, 0.83; 95% CI, 0.66-1.03) were less frequent for infants exposed to magnesium sulfate, but none of the differences were statistically significant. Substantial gross motor dysfunction (3.4% vs 6.6%; RR, 0.51; 95% CI, 0.29-0.91) and combined death or substantial gross motor dysfunction (17.0% vs 22.7%; RR, 0.75; 95% CI, 0.59-0.96) were significantly reduced in the magnesium group., Conclusions: Magnesium sulfate given to women immediately before very preterm birth may improve important pediatric outcomes. No serious harmful effects were seen.

Context: The outcome into school age of regional cohorts of children born in the 1990s with birth weights less than 1000 g (extremely low birth weight, ELBW) or earlier than 28 weeks' gestation (very preterm) is not known., Objective: To determine the cognitive, educational, and behavioral outcome of ELBW or very preterm infants born in the 1990s compared with normal birth weight (NBW) controls., Design: Regional cohort study., Setting: Victoria, Australia., Participants: The ELBW or very preterm cohort was composed of 298 consecutive survivors born during 1991-1992. The NBW cohort was composed of 262 randomly selected children with birth weights of more than 2499 g., Main Outcome Measures: Cognitive ability, educational progress, and behavioral problems., Results: The follow-up rates from birth to 8 years of age for survivors were 92.3% (275/298) for the ELBW or very preterm cohort and 85.1% (223/262) for the NBW cohort. The ELBW or very preterm children scored significantly below NBW controls on full-scale IQ (mean difference, -9.4; 95% confidence interval [CI], -12.1 to -6.7; P<.001) and indices of verbal comprehension (mean difference, -6.8; 95% CI, -9.5 to -4.2; P<.001), perceptual organization (mean difference, -9.9; 95% CI, -12.7 to -7.2; P<.001), freedom from distractibility (mean difference, -8.1; 95% CI, -10.8 to -5.5; P<.001), and processing speed (mean difference, -6.7; 95% CI, -9.4 to -4.0; P<.001). The ELBW or very preterm children performed significantly worse than the NBW cohort on tests of reading (mean difference, -6.7; 95% CI, -9.5 to -3.9; P<.001), spelling (mean difference, -5.6; 95% CI, -8.0 to -3.3; P<.001), and arithmetic (mean difference, -8.8; 95% CI, -11.3 to -6.2; P<.001). Attentional difficulties, internalizing behavior problems, and immature adaptive skills were more prevalent in the ELBW or very preterm cohort., Conclusion: School-aged ELBW or very preterm children born in the 1990s continue to display cognitive, educational, and behavioral impairments.

Objective: To compare the growth and pubertal development of very low-birth-weight (VLBW) children (birth weight <1500 g) and normal-birth-weight (NBW) children (birth weight >2499 g) to adolescence to determine if, and at what age, VLBW children "catch up.", Design: Inception cohort study to age 14 years., Setting: Royal Women's Hospital, Melbourne, Australia., Patients: Eighty-six consecutive survivors with a birth weight less than 1000 g, 120 consecutive survivors with a birth weight of 1000 to 1499 g, and 60 randomly selected NBW controls. Children with cerebral palsy at age 14 years were excluded., Main Outcome Measures: Weight, height, and head circumference measurements at birth and ages 2, 5, 8, and 14 years converted to z (SD) scores., Results: At age 14 years, pubertal development was similar in NBW and VLBW children. At ages 2, 5, 8, and 14 years, VLBW children were significantly shorter and lighter and had smaller head circumferences than NBW children. The differences in height and weight between VLBW and NBW children were less apparent as SD scores improved in VLBW children over time. Within the VLBW group, compared with children with a birth weight of 1000 to 1499 g, those with a birth weight less than 1000 g had significantly lower weight z scores earlier in childhood but not at age 14 years, significantly lower height z scores only at age 2 years, and significantly lower head circumference z scores throughout childhood., Conclusion: This group of VLBW children experienced late catch-up growth to age 14 years but remain smaller than their NBW peers. Arch Pediatr Adolesc Med. 2000;154:778-784

We determined the heights and weights at ages 2, 5, and 8 years for the following three cohorts of children: group 1 with birth weights between 500 and 999 g; group 2 with birth weights between 1000 and 1499 g; and group 3 with birth weights more than 2500 g. By age 8 years, group 3 children were significantly heavier and taller than all children in groups 1 and 2 combined; group 1 children were significantly shorter than those in group 2, but their weights were similar. From ages 2 to 5 years, annual increments in weight and height were similar in all three groups; however, between ages 5 and 8 years, children in group 3 grew faster than those in groups 1 and 2 combined, and children in group 1 had smaller height increments than those in group 2. Of children with birth weights less than 1500 g, with a weight or height under the 10th percentile at age 2 years, only approximately one half were still below the 10th percentile for the corresponding measurement at age 8 years. Health variables determined before birth, such as maternal height or birth weight ratio, were more important than health after birth in predicting a height or weight below the 10th percentile at age 8 years in children with birth weights less than 1500 g.

The occipitofrontal circumference was measured in all available children in the following cohorts at ages 2, 5, and 8 years: group 1, consisting of 79 children with birth weight between 500 and 999 g; group 2, with 111 children with birth weight between 1000 and 1499 g; and group 3 with 56 children with birth weight greater than 2500 g; all were white with no signs of moderate or severe cerebral palsy. National Center for Health Statistics reference values indicated substantially more children with an occipitofrontal circumference lower than the 10th percentile, particularly at age 2 years, compared with Nellhaus reference data. Occipitofrontal circumference was the head measurement best correlated with the Full Scale IQ on the Wechsler Intelligence Scale for Children-Revised. Dolichocephaly, often seen in very-low-birth-weight children was unrelated to IQ, and correction of occipitofrontal circumference for dolichocephaly was rarely of clinical importance.

Rehospitalizations and ongoing health problems at 5 years of age were contrasted between 197 very-low-birth-weight (VLBW) children and 47 normal-birth-weight children. At 5 years of age, the VLBW children had a mean of 1.7 hospital admissions and 8.5 days in a hospital; these means were significantly more than the 0.5 admissions and 1.7 days, respectively, for the normal-birth-weight children. Overall, respiratory tract problems and ear, nose, and throat surgery were the most common reasons for readmissions. Malformations and intensive care sequelae infrequently caused readmissions. No combination of sociodemographic or perinatal variables identified the VLBW children who were destined for hospital readmissions. At 5 years of age, the VLBW children, compared with the normal-birth-weight children, had significantly more ongoing sensorineural problems (29.9% and 10.6%, respectively), ongoing respiratory problems (39.6% and 19.1%, respectively), and other morbidities (31.0% and 17.0%, respectively). The VLBW children, compared with the normal-birth-weight children, had more hospital admissions during the first 5 years of life and more ongoing problems at 5 years of age.

From Jan 1, 1977, to Jan 1, 1987, very-low-birth-weight (VLBW) infants consumed almost 90% of total patient-days of assisted ventilation of all infants born in one tertiary perinatal center. In the latter five years compared with the first five years, increasing resources allowed proportionately more VLBW infants to be offered assisted ventilation, and the patient-days of assisted ventilation consumed per live birth rose by almost 60%. All VLBW infants did not benefit equally from the increased assisted ventilation. Mortality in infants with birth weights below 1200 g decreased; unexpectedly, mortality in larger VLBW infants (birth weights, 1200 g to 1499 g) rose (relative odds, 3.11; 95% confidence intervals, 1.21 to 7.99). Despite the increased consumption of ventilator resources, there was no substantial impact on overall mortality in VLBW infants.