Neurodevelopmental outcomes at 7 years’ corrected age in preterm infants who were fed high-dose docosahexaenoic acid to term equivalent: a follow-up of a randomised controlled trial

BMJ Open

Mar 2015

DOI: 10.1136/bmjopen-2014-007314

Citations:95

Influential Citations:4

Interventional (Human) Studies

Enhanced Details

Methods

Multicentre randomized, blinded trial conducted at five Australian tertiary hospitals. Participants: infants born <33 weeks’ gestation; exclusions included major congenital or chromosomal abnormalities; 657 randomized; 626 eligible for 7-year follow-up; 604 consented; groups: high-DHA n=291 and standard-DHA n=313; follow-up assessments at 7 years corrected age conducted by blinded psychologists.

Intervention

High-DHA regimen from age 2-4 days until term corrected age: high-DHA group received enteral feeds with ~1% total fatty acids DHA and high-DHA preterm formula (~1.0% DHA, ~0.6% AA); mothers of breastfed infants took DHA-rich tuna oil capsules to raise breast milk DHA to ~1%. Standard-DHA regimen used standard preterm formula (~0.35% DHA); placebo capsules; ~20 mg/kg/day DHA. After discharge, continue DHA via breast milk or DHA-enriched formula; overall target intake ~50 mg/kg/day in high-DHA vs ~20 mg/kg/day in standard-DHA.

Results

No significant difference in Full Scale IQ at 7 years (high-DHA 98.3; standard-DHA 98.5; adjusted mean difference −0.3; 95% CI −2.9 to 2.2; p=0.79). No significant differences in secondary outcomes. In prespecified subgroup analyses, a sex by treatment interaction for parent-reported executive function and behaviour indicated poorer outcomes for girls on high-DHA, but scores remained in the normal range and may reflect chance due to multiple tests. Conclusion: supplementation delivering ~1% of total fatty acids as DHA in the neonatal period did not show long-term cognitive or developmental benefits by age 7.

Limitations

No teacher-based behavior assessments; some outcomes rely on parent reports; 20 children assessed with alternate IQ measures; 22 primary-outcome data missing and imputed; multiple subgroup analyses increase risk of spurious findings.

Abstract

Objective To determine if improvements in cognitive outcome detected at 18 months’ corrected age (CA) in infants born <33 weeks’ gestation receiving a high-docosahexaenoic acid (DHA) compared with standard-DHA diet were sustained in early childhood. Design Follow-up of a multicentre randomised controlled trial. Randomisation was stratified for sex, birth weight (<1250 vs ≥1250 g) and hospital. Setting Five Australian tertiary hospitals from 2008 to 2013. Participants 626 of the 657 participants randomised between 2001 and 2005 were eligible to participate. Interventions High-DHA (≈1% total fatty acids) enteral feeds compared with standard-DHA (≈0.3% total fatty acids) from age 2–4 days until term CA. Primary outcome Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence (WASI) at 7 years CA. Prespecified subgroup analyses based on the randomisation strata (sex, birth weight) were conducted. Results 604 (92% of the 657 originally randomised) consented to participate (291 high-DHA, 313 standard-DHA). To address missing data in the 604 consenting participants (22 for primary outcome), multiple imputation was performed. The Full Scale IQ was not significantly different between groups (high-DHA 98.3, SD 14.0, standard-DHA 98.5, SD 14.9; mean difference adjusted for sex, birthweight strata and hospital −0.3, 95% CI −2.9 to 2.2; p=0.79). There were no significant differences in any secondary outcomes. In prespecified subgroup analyses, there was a significant sex by treatment interaction on measures of parent-reported executive function and behaviour. Scores were within the normal range but girls receiving the high-DHA diet scored significantly higher (poorer outcome) compared with girls receiving the standard-DHA diet. Conclusions Supplementing the diets of preterm infants with a DHA dose of approximately 1% total fatty acids from days 2–4 until term CA showed no evidence of benefit at 7 years’ CA. Trial registration number Australian New Zealand Clinical Trials Registry: ACTRN12606000327583. show less