Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring.

The New England journal of medicine

Dec 2016

DOI: 10.1056/NEJMoa1503734

Citations:370

Influential Citations:14

Interventional (Human) Studies

Enhanced Details

Methods

Design: single-center, double-blind, randomized, placebo-controlled, parallel-group trial in Copenhagen, Denmark (COPSAC2010). Participants: pregnant women at 22-26 weeks gestation; excluded if taking >600 IU/day vitamin D or with endocrine, heart, or kidney disorders. 736 women randomized; 695 children included in the analysis; offspring formed the COPSAC2010 birth cohort with follow-up including a 3-year double-blind period and a 2-year extension with investigators blinded.

Intervention

2.4 g/day of n-3 long-chain polyunsaturated fatty acids (fish oil) in triacylglycerol form (Incromega TG33/22; 55% EPA and 37% DHA), administered as four 1-g capsules daily from 24 weeks of gestation until 1 week after delivery.

Results

In the 3- to 5-year follow-up, the risk of persistent wheeze or asthma was 16.9% in the n-3 LCPUFA group vs 23.7% in the control group (hazard ratio 0.69; 95% CI 0.49-0.97; P=0.035), a relative reduction of 30.7%. The effect was strongest in children of mothers with the lowest pre-randomization EPA+DHA blood levels (17.5% vs 34.1%; HR 0.46; 95% CI 0.25-0.83; P=0.011). Supplementation also reduced lower respiratory tract infections (LRIs) (31.7% vs 39.1%; HR 0.75; 95% CI 0.58-0.98; P=0.033). No significant association with asthma exacerbations, eczema, or allergic sensitization. Number needed to treat to prevent one case of persistent wheeze or asthma was 14.6 overall and 5.6 among women in the lowest EPA+DHA tertile. Benefits persisted through ages 5–7 years. The findings support potential precision prevention by targeting women with low EPA+DHA or certain FADS genotypes; no strong interaction with high-dose vitamin D3 observed.

Limitations

Limitations: post hoc and exploratory subgroup analyses warrant replication; Danish population with relatively high baseline n-3 intake may limit generalizability to populations with lower intake; allergic rhinoconjunctivitis not confirmed by allergy testing by age 5; not all secondary endpoints were powered for; potential interaction with vitamin D3 remains uncertain; follow-up beyond 7 years ongoing.

Abstract

BACKGROUND Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lundbeck Foundation and others; ClinicalTrials.gov number, NCT00798226 .). show less