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High-Dose Docosahexaenoic Acid in Newborns Born at Less Than 29 Weeks' Gestation and Behavior at Age 5 Years: Follow-Up of a Randomized Clinical Trial.
Gould, JF, Roberts, RM, Anderson, PJ, Makrides, M, Sullivan, TR, Gibson, RA, McPhee, AJ, Doyle, LW, Bednarz, JM, Best, KP, et al
JAMA pediatrics. 2024;(1):45-54
Abstract
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 Parents of surviving children who had not withdrawn from the original trial were invited to complete questionnaires when the child turned 5 years' corrected age.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.
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Effect of Docosahexaenoic Acid (DHA) Supplementation of Preterm Infants on Growth, Body Composition, and Blood Pressure at 7-Years Corrected Age: Follow-Up of a Randomized Controlled Trial.
Best, KP, Sullivan, TR, Gunaratne, AW, Gould, JF, Gibson, RA, Collins, CT, Makrides, M, Green, TJ
Nutrients. 2023;(2)
Abstract
Aim: To determine if supplementation of infants born <33 weeks’ gestation with higher dose docosahexaenoic acid (DHA) affects growth, body composition, and blood pressure at 7 y corrected age (CA) and if treatment effects differed by infant sex at birth and birth weight strata (<1250 and ≥1250 g). Methods: Seven-year follow-up of an Australian multicenter randomized controlled trial in which 657 infants were fed high-DHA (≈1% total fatty acids) enteral feeds or standard-DHA (≈0.3% total fatty acids) from age 2−4 d until term CA. Seven-year CA outcomes were growth (weight, height), body composition (lean body mass, fat mass, waist, and hip circumference), and blood pressure. Results: There was no effect of high-DHA enteral feeds compared with standard-DHA on growth, body composition, and blood pressure at 7-year CA either overall or in subgroup analysis by sex. There was a significant interaction between high-DHA and birthweight strata on height at 7-y CA (p = 0.03). However, the post-hoc analyses by birthweight strata did not reach significance (p > 0.1). High-DHA group infants were more likely to be classified as obese (relative risk 1.6 (95% CI 1.0, 2.6); p = 0.05). Conclusions: DHA supplementation of premature infants did not affect growth, body composition, or blood pressure at 7-year CA overall by sex and birthweight strata. The finding of a higher risk of obesity in children who receive high-DHA needs to be interpreted with caution due to the small number of children classified as obese.
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Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis.
Marc, I, Boutin, A, Pronovost, E, Perez Herrera, NM, Guillot, M, Bergeron, F, Moore, L, Sullivan, TR, Lavoie, PM, Makrides, M
JAMA network open. 2023;(3):e233934
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Abstract
IMPORTANCE High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking. OBJECTIVE To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation. DATA SOURCES PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions. STUDY SELECTION Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death. DATA EXTRACTION AND SYNTHESIS Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses. MAIN OUTCOMES AND MEASURES Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death. RESULTS Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%). CONCLUSIONS AND RELEVANCE Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.
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Enteral supplementation with high-dose docosahexaenoic acid on the risk of bronchopulmonary dysplasia in very preterm infants: a collaborative study protocol for an individual participant data meta-analysis.
Marc, I, Lavoie, PM, McPhee, AJ, Collins, CT, Simonyan, D, Pronovost, E, Guillot, M, Gould, JF, Mohamed, I, Beltempo, M, et al
BMJ open. 2023;(7):e076223
Abstract
INTRODUCTION Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks' postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation. METHODS AND ANALYSIS As part of an Australian-Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks' PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery. ETHICS AND DISSEMINATION The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals. PROSPERO REGISTRATION NUMBER CRD42023431063. TRIAL REGISTRATION NUMBER NCT05915806.
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Subgroup analyses of a randomized trial of DHA supplementation for infants born preterm with assessments of cognitive development up to 7-years of age: What happens in infants born <29 weeks' gestation?
Gould, JF, Bednarz, JM, Sullivan, TR, McPhee, AJ, Gibson, RA, Makrides, M
Prostaglandins, leukotrienes, and essential fatty acids. 2023;:102593
Abstract
A recent trial showed that high-dose docosahexaenoic acid (high-DHA) supplementation of infants born <29 weeks' gestation improves intelligence quotient (IQ) at five years' corrected age. However, this finding has not been detected by other trials of DHA, which either did not measure IQ or included more mature infants. We analyzed the subgroup of 204 infants born <29 weeks' from our earlier randomized trial of high-DHA (∼1 % total fatty acids) or standard-DHA (∼ 0.3 % total fatty acids). Participants were assessed for cognition at 18 months, and IQ and behavior at seven years' corrected age. No group differences were detected for mean cognitive, IQ or behavior scores. At 18 months, 18.8 % of children in the high-DHA group had a cognitive score <85, compared with 31.1 % of children in the standard-DHA group, but at seven years there was no difference. Although an underpowered post-hoc subgroup analysis, this study provides limited support to recommendations that infants born <29 weeks' gestation require supplemental DHA.
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Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.
Best, KP, Gould, JF, Makrides, M, Sullivan, T, Cheong, J, Zhou, SJ, Kane, S, Safa, H, Sparks, A, Doyle, LW, et al
BMJ open. 2023;(5):e071359
Abstract
INTRODUCTION Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT04586348.
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Growth of late preterm infants fed nutrient-enriched formula to 120 days corrected age-A randomized controlled trial.
Best, KP, Yelland, LN, Collins, CT, McPhee, AJ, Rogers, GB, Choo, J, Gibson, RA, Murguia-Peniche, T, Varghese, J, Cooper, TR, et al
Frontiers in pediatrics. 2023;:1146089
Abstract
OBJECTIVES We aimed to compare the effects of nutrient-enriched formula with standard term formula on rate of body weight gain of late preterm infants appropriately grown for gestational age. STUDY DESIGN A multi-center, randomized, controlled trial. Late preterm infants (34-37 weeks' gestation), with weight appropriate for gestational age (AGA), were randomized to nutrient enriched formula (NEF) with increased calories (22 kcal/30 ml) from protein, added bovine milk fat globule membrane, vitamin D and butyrate or standard term formula 20 kcal/30 ml (STF). Breastfed term infants were enrolled as an observational reference group (BFR). Primary outcome was rate of body weight gain from enrollment to 120 days corrected age (d/CA). Planned sample size was 100 infants per group. Secondary outcomes included body composition, weight, head circumference and length gain, and medically confirmed adverse events to 365 d/CA. RESULTS The trial was terminated early due to recruitment challenges and sample size was substantially reduced. 40 infants were randomized to NEF (n = 22) and STF (n = 18). 39 infants were enrolled in the BFR group. At 120 d/CA there was no evidence of a difference in weight gain between randomized groups (mean difference 1.77 g/day, 95% CI, -1.63 to 5.18, P = 0.31). Secondary outcomes showed a significant reduction in risk of infectious illness in the NEF group at 120 d/CA [relative risk 0.37 (95% CI, 0.16-0.85), P = 0.02]. CONCLUSION We saw no difference in rate of body weight gain between AGA late preterm infants fed NEF compared to STF. Results should be interpreted with caution due to small sample size. CLINICAL TRIAL REGISTRATION The Australia New Zealand Clinical Trials Registry (ACTRN 12618000092291). "mailto:maria.makrides@sahmri.com" maria.makrides@sahmri.com.
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Does SMS text messaging promote the early introduction of food allergens? A randomized controlled trial.
Netting, MJ, Gold, MS, Quinn, P, Palmer, S, Makrides, M, Green, TJ
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2022;(2):e13720
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PrEggNut Study: protocol for a randomised controlled trial investigating the effect of a maternal diet rich in eggs and peanuts from <23 weeks' gestation during pregnancy to 4 months' lactation on infant IgE-mediated egg and peanut allergy outcomes.
Palmer, DJ, Sullivan, TR, Campbell, DE, Nanan, R, Gold, MS, Hsu, PS, Netting, MJ, McWilliam, V, Koplin, JJ, Perrett, KP, et al
BMJ open. 2022;(6):e056925
Abstract
INTRODUCTION Clinical studies supported by immunological data indicate early life intervention strategies to be promising in reducing the growing global burden of food allergies. The events that predispose to food allergy, including the induction of allergen-specific immune responses, appear to be initiated early in development. Early exposure to food allergens in utero and via breast milk is likely to be important in initiating oral tolerance. We aim to determine the effectiveness of higher maternal food allergen consumption during pregnancy and lactation on infant food allergy outcomes. METHODS AND ANALYSIS This is a multisite, parallel, two-arm (1:1 allocation), single-blinded (outcome assessors, statistical analyst and investigators), randomised controlled trial. Pregnant women (<23 weeks' gestation) whose (unborn) infants have at least two biological family members (mother, father or siblings) with medically diagnosed allergic disease are eligible to participate. After obtaining written informed consent, pregnant women are randomised to either a high egg and peanut diet (at least 6 eggs and 60 peanuts per week) or standard (low) egg and peanut diet (no more than 3 eggs and 30 peanuts per week). The women are asked to follow their allocated diet from <23 weeks' gestation to 4 months' lactation. The primary outcome is food challenge proven IgE-mediated egg and/or peanut allergy in the infants at 12 months of age. Key secondary outcomes include infant sensitisation to egg and/or peanut and infant eczema. Our target sample size is 2136 women. Analyses will be performed on an intention-to-treat basis according to a pre-specified statistical analysis plan. ETHICS AND DISSEMINATION Ethical approval has been granted from the Women's and Children's Health Network Human Research Ethics Committee (approval number HREC/18/WCHN/42). Trial results will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER Australian New Zealand Clinical Trials Registry ACTRN12618000937213.
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High doses of enteral docosahexaenoic acid omega-3 supplementation for prevention of bronchopulmonary dysplasia in very preterm infants: a protocol for a systematic review and meta-analysis.
Marc, I, Boutin, A, Pronovost, E, Guillot, M, Bergeron, F, Moore, L, Makrides, M
BMJ open. 2022;(10):e064515
Abstract
INTRODUCTION Docosahexaenoic acid (DHA) supplementation in the neonatal period has been proposed to prevent bronchopulmonary dysplasia (BPD) in very preterm infants. We aim to determine the effects of an enteral supplementation with high doses of DHA on the risk for BPD at 36 weeks' postmenstrual age (PMA) in very preterm infants born less than 29 weeks' gestation compared with a control. METHODS AND ANALYSIS We will conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) searching PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, MedRxiv, ClinicalTrials.gov (up to 1 November 2021) as well as reference lists and citations of included articles and previous reviews. RCTs targeting infants born less than 29 weeks' gestation and evaluating the effect of high doses of DHA enteral supplementation in the neonatal period compared with a control will be eligible. Primary outcome will be BPD defined as the need for oxygen and/or ventilation at 36 weeks' PMA. Two authors will independently screen for inclusion, extract data and assess data quality using the Cochrane instrument (risk-of-bias tool 2.0). We will perform meta-analysis using random effects models. Prespecified subgroup analyses are planned for the infant gestational age and sex, the marine source of DHA, mode of administration and duration of exposure. Sensitivity analysis will be performed according to the accuracy of the BPD definition (ie, physiological definition) and according to the risk of bias of the RCTs. ETHICS AND DISSEMINATION This protocol for a systematic review and meta-analysis does not require ethics approval, as no primary data are collected. This study will assess the effectiveness of high doses of enteral DHA supplementation on BPD and provide evidence to clinicians and families for decision-making. Findings will be disseminated through conferences, media interviews and publications to peer review journals. PROSPERO REGISTRATION NUMBER CRD42021286705.