Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years.

BACKGROUND: Docosahexaenoic acid (DHA) is a component of neural tissue. Because its accretion into the brain is greatest during the final trimester of pregnancy, infants born before 29 weeks' gestation do not receive the normal supply of DHA. The effect of this deficiency on subsequent cognitive development is not well understood. METHODS: We assessed general intelligence at 5 years in children who had been enrolled in a trial of neonatal DHA supplementation to prevent bronchopulmonary dysplasia. In the previous trial, infants born before 29 weeks' gestation had been randomly assigned in a 1:1 ratio to receive an enteral emulsion that provided 60 mg of DHA per kilogram of body weight per day or a control emulsion from the first 3 days of enteral feeds until 36 weeks of postmenstrual age or discharge home, whichever occurred first. Children from 5 of the 13 centers in the original trial were invited to undergo assessment with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) at 5 years of corrected age. The primary outcome was the full-scale intelligence quotient (FSIQ) score. Secondary outcomes included the components of WPPSI. RESULTS: A total of 1273 infants underwent randomization in the original trial; of the 656 surviving children who had undergone randomization at the centers included in this follow-up study, 480 (73%) had an FSIQ score available - 241 in the DHA group and 239 in the control group. After imputation of missing data, the mean (±SD) FSIQ scores were 95.4±17.3 in the DHA group and 91.9±19.1 in the control group (adjusted difference, 3.45; 95% confidence interval, 0.38 to 6.53; P = 0.03). The results for secondary outcomes generally did not support that obtained for the primary outcome. Adverse events were similar in the two groups. CONCLUSIONS: In infants born before 29 weeks' gestation who had been enrolled in a trial to assess the effect of DHA supplementation on bronchopulmonary dysplasia, the use of an enteral DHA emulsion until 36 weeks of postmenstrual age was associated with modestly higher FSIQ scores at 5 years of age than control feeding. (Funded by the Australian National Health and Medical Research Council and Nu-Mega Ingredients; N3RO Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820.).

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial.

BACKGROUND: Infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia, admission to a neonatal intensive care unit (NICU), and not being exclusively breastfed. Many clinicians encourage women with diabetes in pregnancy to express and store breastmilk in late pregnancy, yet no evidence exists for this practice. We aimed to determine the safety and efficacy of antenatal expressing in women with diabetes in pregnancy. METHODS: We did a multicentre, two-group, unblinded, randomised controlled trial in six hospitals in Victoria, Australia. We recruited women with pre-existing or gestational diabetes in a singleton pregnancy from 34 to 37 weeks' gestation and randomly assigned them (1:1) to either expressing breastmilk twice per day from 36 weeks' gestation (antenatal expressing) or standard care (usual midwifery and obstetric care, supplemented by support from a diabetes educator). Randomisation was done with a computerised random number generator in blocks of size two and four, and was stratified by site, parity, and diabetes type. Investigators were masked to block size but masking of caregivers was not possible. The primary outcome was the proportion of infants admitted to the NICU. We did the analyses by intention to treat; the data were obtained and analysed masked to group allocation. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000217909. FINDINGS: Between June 6, 2011, and Oct 29, 2015, we recruited and randomly assigned 635 women: 319 to antenatal expressing and 316 to standard care. Three were not included in the primary analysis (one withdrawal from the standard care group, and one post-randomisation exclusion and one withdrawal from the antenatal expressing group). The proportion of infants admitted to the NICU did not differ between groups (46 [15%] of 317 assigned to antenatal expressing vs 44 [14%] of 315 assigned to standard care; adjusted relative risk 1·06, 95% CI 0·66 to 1·46). In the antenatal expressing group, the most common serious adverse event for infants was admission to the NICU for respiratory support (for three [<1%] of 317. In the standard care group, the most common serious adverse event for infants was moderate to severe encephalopathy with or without seizures (for three [<1%] of 315). INTERPRETATION: There is no harm in advising women with diabetes in pregnancy at low risk of complications to express breastmilk from 36 weeks' gestation. FUNDING: Australian National Health and Medical Research Council.

Breastmilk banking and the Mercy Health experience.

Breastmilk banking provides an alternative to infant formula, not a substitute for mother's own milk.

Mediation Analysis to Untangle Opposing Associations of High-Dose Docosahexaenoic Acid With IQ and Bronchopulmonary Dysplasia in Children Born Preterm.

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.

Temporal Trends in Neurodevelopmental Outcomes to 2 Years After Extremely Preterm Birth.

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.

Changes in long-term prognosis with increasing postnatal survival and the occurrence of postnatal morbidities in extremely preterm infants offered intensive care: a prospective observational study.

BACKGROUND: Decisions regarding provision of intensive care and post-discharge follow-up for infants born extremely preterm (<28 weeks' gestation) are based on the risks of mortality and neurodevelopmental disability. We aimed to elucidate the changes in probability of three outcomes (death, survival with major disability, and survival without major disability) with postnatal age in extremely preterm infants offered intensive care, and the effect of postnatal events on the probability of survival without major disability. METHODS: In this prospective observational study, we used data from three geographical cohorts composed of all extremely preterm livebirths offered intensive care at birth during three distinct periods (1991-92, 1997, and 2005) in Victoria, Australia. Participants were assessed at 8 years' corrected age for major neurodevelopmental disability, defined as moderate or severe cerebral palsy, general intelligence more than 2 SDs below term-born control means, blindness, or deafness. Probabilities of outcomes conditional on survival to different postnatal ages were calculated by logistic regression. Multivariable logistic regression was used to assess factors predictive of survival with major disability. FINDINGS: 751 (82%) of 915 extremely preterm livebirths free of lethal anomalies were offered intensive care, of whom 546 (73%) survived to age 8 years. Of the 499 survivors assessed, 86 (17%) had a major disability. With increasing gestational age at birth or days of postnatal survival, the probability of death decreased and of survival without major disability increased. By contrast, the probability of survival with major disability varied little with gestational age or postnatal survival. In survivors, major disability was associated with the occurrence of four important postnatal events: grade 3 or 4 intraventricular haemorrhage (odds ratio 2·61 [95% CI 1·11-6·15]), cystic periventricular leukomalacia (9·17 [3·57-23·53]), postnatal corticosteroid use (1·99 [1·03-3·85]), and surgery (2·78 [1·51-5·13]). 241 survivors (48%) had no major postnatal events during the newborn period, and had the lowest prevalence of major disability (17 participants [7%]). The probability of survival without major disability decreased with increasing number of major events (0·93 [0·89-0·96] for no events vs 0·31 [0·11-0·59] for three or more events). INTERPRETATION: Long-term prognosis in terms of death and major neurodevelopmental disability changes rapidly after birth for extremely preterm infants. Counselling of families and post-discharge planning should be individualised to changing circumstances following birth. FUNDING: National Health and Medical Research Council of Australia.

Probiotics, prematurity and neurodevelopment: follow-up of a randomised trial.

OBJECTIVE: To determine the impact of one probiotics combination on the neurodevelopment of very preterm children at 2-5 years corrected gestational age (CA). DESIGN: Follow-up study of survivors of a double-blinded, placebo-controlled, randomised trial of probiotic effects on late-onset sepsis in very preterm infants that found reduced necrotising enterocolitis. SETTING: 10 tertiary perinatal centres in Australia and New Zealand. PATIENTS: 1099 very preterm infants born <32 weeks' gestation and weighing <1500 g. INTERVENTION: Probiotics (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis) or placebo administered from birth until discharge home or term CA, whichever came sooner. MAIN OUTCOME MEASURES: Major neurodevelopmental impairment comprised any of moderate/severe cerebral palsy (Gross Motor Function Classification System score 2-5), motor impairment (Bayley-III Motor Composite Scale <-2SD or Movement Assessment Battery for Children <15th centile if >42 months' CA), cognitive impairment (Bayley-III Composite Cognitive or Language Scales <-2SD or Wechsler Preschool and Primary Scale of Intelligence Full Scale Intelligence Quotient <-2SD if >42 months' CA), blindness or deafness. RESULTS: Outcome data were available for 735 (67%) participants, with 71 deaths and 664/1028 survivors assessed at a mean age of 30 months. Survival free of major neurodevelopmental impairment was comparable between groups (probiotics 281 (75.3%) vs placebo 271 (74.9%); relative risk 1.01 (95% CI 0.93 to 1.09)). Rates of deafness were lower in probiotic-treated children (0.6% vs 3.4%). CONCLUSION: Administration of the probiotics combination Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis to very preterm babies from soon after birth until discharge home or term CA did not adversely affect neurodevelopment or behaviour in early childhood. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN012607000144415.

Feasibility of comprehensive, unattended ambulatory polysomnography in school-aged children.

STUDY OBJECTIVES: Although unattended ambulatory polysomnography (PSG) is frequently performed in adults, few studies have been performed in children. The objective of this study was to evaluate the feasibility of comprehensive, ambulatory PSG, including electroencephalography, in school-aged children in the home environment. METHODS: A total of 201 children, born premature with birth weights of 500-1,250 grams, currently aged 5-12 years and living in Canada and Australia, underwent unattended ambulatory PSG. RESULTS: PSG was initially technically satisfactory in 183 (91%) cases. Fourteen studies were satisfactory when repeated, resulting in an overall satisfactory rate of 197 (98%). Artifact-free signals were obtained for ≥ 75% of recording time in more than 92% of subjects, with the exception of nasal pressure, which was satisfactory for ≥ 75% of recording time in only 67% of subjects. However, thermistry signals were satisfactory for ≥ 75% of recording time in 92% of subjects, and some measure of airflow was present for ≥ 75% of recording time in 96% of subjects. Children slept very well, with a long total sleep time (534 ± 73 [mean ± SD] minutes), high sleep efficiency (92% ± 5%), and low arousal index (9 ± 3/h). Parents and children reported a high rate of satisfaction with the study. CONCLUSIONS: This large, international study has shown that comprehensive, unattended, ambulatory PSG is feasible, technically adequate and well-tolerated in school-aged children when performed under research conditions. Further studies regarding the cost efficacy of this approach, and generalizability of the findings to a clinical population, are warranted.

Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial.

BACKGROUND AND OBJECTIVE: Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis (NEC) in preterm infants, with unclear effect on late-onset sepsis. This study aimed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. METHODS: A prospective multicenter, double-blinded, placebo-controlled, randomized trial compared daily administration of a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 10(9) total organisms) with placebo (maltodextrin) in infants born before 32 completed weeks' gestation weighing <1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. RESULTS: Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zealand were randomized. Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%; relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to treat 43, 95% confidence interval 23 to 333). CONCLUSIONS: The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe.