Effects of Omega-3-6-9 fatty acid supplementation on behavior and sleep in preterm toddlers with autism symptomatology: Secondary analysis of a randomized clinical trial.

BACKGROUND: Children born extremely preterm disproportionately experience sequelae of preterm birth compared to those born at later gestational ages, including higher prevalence of autism spectrum disorder (ASD) and associated behaviors. AIM: Explore effects of combined dietary docosahexaenoic acid, eicosapentaenoic acid, gamma-linolenic acid, and oleic acid (omega 3-6-9) on caregiver-reported behavior and sleep in toddlers born at ≤29 weeks' gestation who were exhibiting symptoms commonly seen with ASD. STUDY DESIGN: 90-day randomized (1:1), double blinded, placebo-controlled trial. SUBJECTS: Thirty-one children aged 18-38 months received omega 3-6-9 (n = 15) or canola oil placebo (n = 16). OUTCOME MEASURES: Mixed effects regression analyses followed intent to treat and explored treatment effects on measures of caregiver-reported behavior (Child Behavior Checklist 1.5-5, Toddler Behavior Assessment Questionnaire - Short Form, Vineland Adaptive Behavior Scales, 2nd Edition) and sleep (Children's Sleep Habits Questionnaire, Brief Infant Sleep Questionnaire). RESULTS: Twenty-nine of 31 (94%; ntx = 13, nplacebo = 16) children randomized had data available for at least one outcome measure, 27 (87%; ntx = 12, nplacebo = 15) had complete outcome data. Children randomized to omega 3-6-9 experienced a medium magnitude benefit of supplementation on anxious and depressed behaviors (ΔDifference = -1.27, d = -0.58, p = 0.049) and internalizing behaviors (ΔDifference = -3.41, d = -0.68, p = 0.05); and a large magnitude benefit on interpersonal relationship adaptive behaviors (ΔDifference = 7.50, d = 0.83, p = 0.01), compared to placebo. No effects were observed on other aspects of behavior or sleep. CONCLUSIONS: Findings provide preliminary support for further exploration of omega 3-6-9 during toddlerhood to improve socioemotional outcomes among children born preterm, especially for those showing early symptoms commonly seen with ASD. Results need to be replicated in a larger sample. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT01683565.

Fatty Acid Supplementation and Socioemotional Outcomes: Secondary Analysis of a Randomized Trial.

BACKGROUND AND OBJECTIVES: Children born preterm experience socioemotional difficulties, including increased risk of autism spectrum disorder (ASD). In this secondary analysis, we tested the effect of combined docosahexaenoic acid (DHA) and arachidonic acid (AA) supplementation during toddlerhood on caregiver-reported socioemotional outcomes of children born preterm. We hypothesized that children randomly assigned to DHA + AA would display better socioemotional outcomes compared with those randomly assigned to a placebo. METHODS: Omega Tots was a single-site randomized, fully masked, parallel-group, placebo-controlled trial. Children (N = 377) were 10 to 16 months at enrollment, born at <35 weeks' gestation, and assigned to 180 days of daily 200-mg DHA + 200-mg AA supplementation or a placebo (400 mg corn oil). Caregivers completed the Brief Infant-Toddler Social and Emotional Assessment and the Pervasive Developmental Disorders Screening Test-II, Stage 2 at the end of the trial. Liner mixed models and log-binomial regression compared socioemotional outcomes between the DHA + AA and placebo groups. RESULTS: Outcome data were available for 83% of children (n treatment = 161; n placebo = 153). Differences between DHA + AA and placebo groups on Brief Infant-Toddler Social and Emotional Assessment scores were of small magnitude (Cohen's d ≤ 0.15) and not statistically significant. Children randomly assigned to DHA + AA had a decreased risk of scoring at-risk for ASD on the Pervasive Developmental Disorders Screening Test-II, Stage 2 (21% vs 32%; risk ratio = 0.66 [95% confidence interval: 0.45 to 0.97]; risk difference = -0.11 [95% confidence interval: -0.21 to -0.01]) compared with children randomly assigned to a placebo. CONCLUSIONS: No evidence of benefit of DHA + AA supplementation on caregiver-reported outcomes of broad socioemotional development was observed. Supplementation resulted in decreased risk of clinical concern for ASD. Further exploration in larger samples of preterm children and continued follow-up of children who received DHA + AA supplementation as they approach school age is warranted.

To attend, or not to attend: Examining caregiver intentions and study compliance in a pediatric, randomized controlled trial.

BACKGROUND/AIMS: The Intent to Attend is a brief questionnaire recommended by the National Research Council to address dropout concerns and improve prediction of missing data in clinical trials, although implementation has been very limited. As a formative study in pediatric research, the relationship between caregiver intentions and study compliance was investigated in a 180-day trial of dietary supplementation of preterm toddlers. Treatment effect estimation in the context of missing data was also explored. METHODS: Study compliance (i.e. study completion, supplement adherence, and diary completion) was tracked over three study visits. Baseline questionnaires asked caregivers about intentions concerning study completion via the Intent to Attend, screened for mental health symptoms (depression, trait anxiety), and captured family demographics. Simple and multiple logistic regression models were built to examine associations between caregiver intent and compliance outcomes. The Intent to Attend was also employed as an auxiliary variable to account for missing data within mixed models estimating the treatment effect on the primary outcomes. RESULTS: Of the 316 caregiver-child dyads included, 95% of caregivers with low intentions had a child complete the study, but only 87% of caregivers with high intentions had a child complete the study. Low intentions to complete the study were associated with a more than 60% lower odds of study non-completion, but the confidence interval included the null (odds ratio: 0.36; 95% confidence interval: 0.11, 1.20). No effect measure modification by caregiver mental health, child sex, or annual income was detected. Income was the only significant predictor of study non-completion; the lowest income group was almost four times more likely to be study non-completers compared with the highest income group, even after adjustment for child sex and caregiver mental health (adjusted odds ratio = 3.59, 95% confidence interval: 1.38, 9.31). When using Intent to Attend as an auxiliary variable, similar results were obtained when compared with the original treatment effect estimates on the primary outcomes. CONCLUSION: Contrary to prior adult studies, there is no clear relationship between caregiver intentions and study compliance. Findings elucidate the complexities of caregiver-child interactions during pediatric trial participation.

Docosahexaenoic Acid and Arachidonic Acid Supplementation and Sleep in Toddlers Born Preterm: Secondary Analysis of a Randomized Clinical Trial.

STUDY OBJECTIVES: This secondary analysis characterized sleep patterns for toddlers born preterm and tested effects of docosahexaenoic acid (DHA)+ arachidonic acid (AA) supplementation on children's caregiver-reported sleep. Exploratory analyses tested whether child sex, birth weight, and caregiver depressive symptomatology were moderators of the treatment effect. METHODS: Omega Tots was a single-site 180-day randomized (1:1), double-blinded, placebo-controlled trial. Children (n = 377) were age 10 to 16 months at enrollment, born at less than 35 weeks' gestation, assigned to 180 days of daily 200 mg DHA + 200 mg AA supplementation or placebo (400 mg corn oil), and followed after the trial ended to age 26 to 32 months. Caregivers completed a sociodemographic profile and questionnaires about their depressive symptomatology (Center for Epidemiologic Studies Depression Scale) and the child's sleep (Brief Infant Sleep Questionnaire). Analyses compared changes in sleep between the DHA+AA and placebo groups, controlling for baseline scores. Exploratory post hoc subgroup analyses were conducted. RESULTS: Eighty-one percent (ntx = 156; nplacebo = 150) of children had 180-day trial outcome data; 68% (ntx = 134; nplacebo = 122) had postintervention outcome data. Differences in change between the DHA+AA and placebo groups after 180 days of supplementation were not statistically significant for the entire cohort. Male children (difference in nocturnal sleep change = 0.44, effect size = 0.26, P = .04; sleep problems odds ratio = 0.36, 95% confidence interval = 0.15, 0.82) and children of depressed caregivers (difference in nocturnal sleep change = 1.07, effect size = 0.65, P = .006; difference in total sleep change = 1.10, effect size = 0.50, P = .04) assigned to the treatment group showed improvements in sleep, compared to placebo. CONCLUSIONS: Although there is no evidence of an overall effect of DHA+AA supplementation on child sleep, exploratory post hoc analyses identified important subgroups of children born preterm who may benefit. Future research including larger samples is warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT01576783. CITATION: Boone KM, Rausch J, Pelak G, Li R, Turner AN, Klebanoff MA, Keim SA. Docosahexaenoic acid and arachidonic acid supplementation and sleep in toddlers born preterm: secondary analysis of a randomized clinical trial. J Clin Sleep Med. 2019;15(9):1197-1208.

Docosahexaenoic and Arachidonic Acid Supplementation of Toddlers Born Preterm Does Not Affect Short-Term Growth or Adiposity.

BACKGROUND: Dietary DHA intake among US toddlers is low. Healthy physical growth is an important objective for the clinical care of children born preterm. OBJECTIVES: The aim of the trial was to examine the effects of supplementing toddlers born preterm with DHA and arachidonic acid (AA) for 180 d on growth and adiposity. METHODS: Omega Tots, a randomized placebo-controlled trial, was conducted between April 2012 and March 2017. Children born at <35 wk gestation who were 10-16 mo in corrected age were assigned to receive daily oral supplements of DHA and AA (200 mg each, "DHA + AA") or corn oil (placebo) for 180 d. Prespecified secondary outcomes included weight, length, head circumference, mid-upper arm circumference, triceps and subscapular skinfolds, BMI, and their respective z scores, and body fat percentage, which were measured at baseline and trial completion. Mixed-effects regression was used to compare the change in outcomes between the DHA + AA and placebo groups, controlling for baseline values. RESULTS: Among 377 children included in the analysis (median corrected age = 15.7 mo, 48.3% female), 348 (92.3%) had growth or adiposity data at baseline and trial end. No statistically significant differences between the DHA + AA and placebo groups in growth or adiposity outcomes were observed. For instance, the change in weight-for-age z scores was 0.1 for the DHA + AA group and 0.0 for the placebo group (effect size = 0.01, P = 0.99). However, post-hoc subgroup analyses revealed a statistically significant interaction between treatment group and sex, suggesting somewhat slower linear growth for females assigned to the DHA + AA group compared with the placebo group. CONCLUSIONS: Among toddlers born preterm, daily supplementation with DHA + AA for 180 d resulted in no short-term differences in growth or adiposity compared with placebo. If DHA supplementation is implemented after the first year of life, it can be expected to have no effect on short-term growth or adiposity. This trial is registered with clinicaltrials.gov as NCT02199808.

Effect of Docosahexaenoic Acid Supplementation vs Placebo on Developmental Outcomes of Toddlers Born Preterm: A Randomized Clinical Trial.

Importance: Intake of dietary docosahexaenoic acid (DHA) among toddlers is low. Supplementation may benefit developmental outcomes of toddlers who were born preterm. Objective: To determine whether 6 months of daily DHA supplementation improves developmental outcomes of toddlers who were born preterm. Design, Setting, and Participants: A randomized, fully masked, placebo-controlled trial was conducted from April 26, 2012, to March 24, 2017, at a large US pediatric academic center with 9 neonatal intensive care units. Children born at less than 35 weeks' gestation who were 10 to 16 months corrected age underwent 6 months of intervention. Of 2363 children assessed, 982 were eligible, 605 declined, and 377 enrolled and were randomized. Analyses were according to intent to treat. Interventions: One-to-one allocation to receive daily microencapsulated DHA, 200 mg, and arachidonic acid (AA), 200 mg (DHA+AA), or microencapsulated corn oil (placebo). Main Outcomes and Measures: The primary outcome specified a priori was Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), cognitive composite score at 16 to 22 months corrected age. Secondary outcomes were Bayley-III language and motor composite scores and Infant Behavior Questionnaire-Revised and Early Childhood Behavior Questionnaire effortful control and activity level scores. Subgroup analyses defined a priori were by income, sex, and birth weight. Results: Among 377 children randomized and included in the analysis (182 girls and 195 boys; median corrected age, 15.7 months), 338 children (89.7%) had complete data on the primary outcome. Bayley-III cognitive scores did not differ between the DHA+AA and placebo groups (difference in change, 0.5 [95% CI, -1.8 to 2.8]; effect size, 0.05; P = .66). Assignment to the DHA+AA group had a small to medium negative effect on Bayley-III language scores among children with lower birth weights (eg, a child with a birth weight of 1000 g assigned to receive DHA+AA experienced a 4.1-point relative decrease, while a child assigned to placebo did not; P = .03 for interaction). Supplementation had a similar negative effect on effortful control scores among children with annual household incomes greater than $35 000 (difference in change, -0.3 [95% CI, -0.4 to -0.1]; effect size, -0.37; P = .01). Bayley-III motor scores and activity level scores were unaffected. Conclusions and Relevance: Daily supplementation with 200 mg of DHA and 200 mg of AA for 6 months resulted in no improvement in cognitive development and early measures of executive function vs placebo, and may have resulted in negative effects on language development and effortful control in certain subgroups of children. These findings do not support DHA supplementation in the second year of life for children who are born preterm. Trial Registration: ClinicalTrials.gov Identifier: NCT01576783.

ω-3 and ω-6 Fatty Acid Supplementation May Reduce Autism Symptoms Based on Parent Report in Preterm Toddlers.

Background: Children born preterm are at increased risk of autism spectrum disorder (ASD). n-3 (ω-3) Combined with n-6 (ω-6) fatty acids including γ-linolenic acid (GLA) may benefit children born preterm showing early signs of ASD. Previous trials have reported that docosahexaenoic acid (DHA) promotes cognitive development in preterm neonates and n-3 fatty acids combined with GLA improve attention-deficit-hyperactivity disorder. Objectives: The objectives of the pilot Preemie Tots Trial were 1) to confirm the feasibility of a full-scale trial in toddlers born very preterm and exhibiting ASD symptoms and 2) to explore the effects of supplementation on parent-reported ASD symptoms and related behaviors. Methods: This was a 90-d randomized, fully blinded, placebo-controlled trial in 31 children 18-38 mo of age who were born at ≤29 wk of gestation. One group was assigned to daily Omega-3-6-9 Junior (Nordic Naturals, Inc.) treatment (including 338 mg eicosapentaenoic acid, 225 mg DHA, and 83 mg GLA), and the other group received canola oil (124 mg palmitic acid, 39 mg stearic acid, 513 mg linoleic acid, 225 mg α-linolenic acid, and 1346 mg oleic acid). Mixed-effects regression analyses followed intent-to-treat analysis and explored effects on parent-reported ASD symptoms and related behaviors. Results: Of 31 children randomly assigned, 28 had complete outcome data. After accounting for baseline scores, those assigned to treatment exhibited a greater reduction in ASD symptoms per the Brief Infant Toddler Social Emotional Assessment ASD scale than did those assigned to placebo (difference in change = - 2.1 points; 95% CI: - 4.1, - 0.2 points; standardized effect size = - 0.71). No other outcome measure reflected a similar magnitude or a significant effect. Conclusions: This pilot trial confirmed adequate numbers of children enrolled and participated fully in the trial. No safety concerns were noted. It also found clinically-significant improvements in ASD symptoms for children randomly assigned to receive Omega-3-6-9 Junior, but effects were confined to one subscale. A future full-scale trial is warranted given the lack of effective treatments for this population. This trial was registered at www.clinicaltrials.gov as NCT01683565.

Omega-3 and -6 fatty acid supplementation and sensory processing in toddlers with ASD symptomology born preterm: A randomized controlled trial.

BACKGROUND: Despite advances in the health and long-term survival of infants born preterm, they continue to face developmental challenges including higher risk for autism spectrum disorder (ASD) and atypical sensory processing patterns. AIMS: This secondary analysis aimed to describe sensory profiles and explore effects of combined dietary docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and gamma-linolenic acid (GLA) supplementation on parent-reported sensory processing in toddlers born preterm who were exhibiting ASD symptoms. STUDY DESIGN: 90-day randomized, double blinded, placebo-controlled trial. SUBJECTS: 31 children aged 18-38months who were born at ≤29weeks' gestation. OUTCOME MEASURE: Mixed effects regression analyses followed intent to treat and explored effects on parent-reported sensory processing measured by the Infant/Toddler Sensory Profile (ITSP). RESULTS: Baseline ITSP scores reflected atypical sensory processing, with the majority of atypical scores falling below the mean. Sensory processing sections: auditory (above=0%, below=65%), vestibular (above=13%, below=48%), tactile (above=3%, below=35%), oral sensory (above=10%; below=26%), visual (above=10%, below=16%); sensory processing quadrants: low registration (above=3%; below=71%), sensation avoiding (above=3%; below=39%), sensory sensitivity (above=3%; below=35%), and sensation seeking (above=10%; below=19%). Twenty-eight of 31 children randomized had complete outcome data. Although not statistically significant (p=0.13), the magnitude of the effect for reduction in behaviors associated with sensory sensitivity was medium to large (effect size=0.57). No other scales reflected a similar magnitude of effect size (range: 0.10 to 0.32). CONCLUSIONS: The findings provide support for larger randomized trials of omega fatty acid supplementation for children at risk of sensory processing difficulties, especially those born preterm.

Effect of Omega-3 and -6 Supplementation on Language in Preterm Toddlers Exhibiting Autism Spectrum Disorder Symptoms.

Delayed language development may be an early indicator of autism spectrum disorder (ASD). Early intervention is critical for children with ASD, and the present study presents pilot data on a clinical trial of omega-3 and -6 fatty acid supplementation and language development, a secondary trial outcome, in children at risk for ASD. We randomized 31 children to receive an omega-3 and -6 supplement or a placebo for 3 months, and measured their language abilities at baseline and after supplementation. Gesture use, but not word production, increased for children in the treatment group more than children in the placebo group. These results suggest possible effectiveness of omega-3 and -6 supplementation for language development in children at risk for ASD.