Table 3.

Main features and results of studies investigating active supplementation of PUFA and early introduction of fish in diet.

References	Study design	Population	Conclusion
Active supplementation of PUFA
(52)	Multicenter, prospective, observational study	1,342 infants, supplemented in the first year of life	Infants fed formula supplemented with DHA/ARA (DHA + group) had a lower incidence of bronchiolitis/bronchitis compared with control group at 5 months (6.1 vs. 13.9%, p = 0.0001), 7 months (5.1 vs. 10.8%, p = 0.01), and 9 months (5.8 vs. 11.3%, p = 0.01). The incidence of upper airway infections was lower in DHA + group compared with control group at 1 month (6.6 vs. 12.1%, p = 0.05) and 12 months (16.2 vs. 24.2%, p = 0.01).
(53)	Multicenter, prospective, observational study	325 infants, supplemented in the first year of life	Infants fed formula supplemented with DHA/ARA, compared with controls, had lower incidence of bronchitis/bronchiolitis (OR 0.41; 95% CI: 0.24-0.70; p = 0.001) and croup (OR 0.23; 95% CI: 0.05-0.97; p = 0.045)
(54)	Randomized double-blind controlled trial	147 infants, supplemented from 5 days to 12 months of life	Infants fed formula supplemented with DHA/ARA had a significantly lower odds of having an increased number of episodes of upper respiratory infections (OR 0.32; 95% CI 0.14-0.75; p = 0.008), wheezing/asthma (OR 0.31; 95% CI 0.10-0.90; p = 0.03), wheezing/asthma/atopic dermatitis (OR 0.29; 95% CI 0.12-0.72; p = 0.008), or any allergy (OR 0.30; 95% CI 0.12-0.73; p = 0.008) during the first 3 years of life compared with the control group
(55)	Randomized controlled trial	91 infants, supplemented in the first year of life	Infants fed formula supplemented with DHA/ARA had a lower incidence of asthma and wheezing in the first 4 years of life compared the control group (OR 0.57; 95% CI 0.2-1.6)
(56)	Multicenter controlled intervention study	6,154 infants, supplemented in the first 2 years of life	Infants with higher intake of n – 3 PUFAs and oily fish had no significant difference in the incidence of allergic disease and wheeze compared with control cohorts (OR adjusted 0.91; 95% CI 0.79-1.06)
(57)	Randomized double-blind controlled trial	420 infants at high-risk of atopic diseases, supplemented from birth to 6 months	No differences in prevalence of allergic outcomes between infants in the fish oil and control groups at 12 months (37.8 vs. 39.5%)
(58)	Randomized controlled trial	616 infants with a family history of asthma, supplemented from 6 months or at onset of bottle-feeding and during the first 5 years of life	In children with a family history of asthma dietary fatty acid modification do not reduce the prevalence of asthma [absolute rik reduction (ARR) −4.8; 95% CI −12.5-2.9], or other atopic disorders at age 8 years.
Early introduction of fish in diet
(59)	Population based multiethnic prospective study	7,210 subjects Exposure in the first 14 months of life	Children who were given fish between 6 and 12 months had a lower risk of wheezing at 48 months (OR 0.64; 95% CI 0.43-0.94). When compared with introduction between 6 and 12 months, no introduction in the first year and introduction between 0 and 6 months were associated with an increased risk of wheezing at 48 months (OR 1.57; 95% CI 1.07–2.31 and OR 1.53; 95% CI 1.07-2.19, respectively).
(60)	Controlled, population-based, primary intervention trial	20,544 subjects Exposure in first 2 years of life	Eating fish at least once a week at one year of age was associated with a 40% and 34% reduction in the odds of asthma, and wheeze at 6 years of age
(61)	Prospective, longitudinal cohort study	4,171 subjects Exposure in the first year of life	The introduction of fish before the age of 9 months reduced the risk of recurrent wheeze (OR adjusted 0.6; 0.4-0.8).
(62)	Prospective cohort study	4,089 subjects Exposure in the first year of life	Children receiving fish between 3 and 8 months of age had a reduced risk for asthma at 4 years of age (OR adjusted 0.73, 95% CI 0.55-0.97).
(63)	Prospective cohort study	2,531 children Exposure in the first 12 months of life	Fish consumption in the first year of life is protective toward the development of asthma at the age of 4 years with adjusted OR 0.84 (95% CI = 0.57, 1.22).
(64)	Prospective cohort study	3,285 subjects Exposure in the first year of life	Children who consumed fish at 1 year of age had an overall reduced incidence of asthma up to the age of 12 (OR adjusted 0.80; 95% CI 0.65, 0.98; p = 0.034)
(65)	Double-blind controlled trial	738 subjects Exposure in the first 3 years of age	Inverse associations were seen between asthma and/or recurrent wheeze in 3-year-old children and dietary intakes of total PUFA (OR 0.65; 95% CI 0.38-1.09; p=0.10), omega-3 (OR 0.61; 95% CI 0.36-1.02; p=0.06), and omega-6 PUFA (OR 0.53; 95% CI 0.31-0.90; p=0.02), though this was statistically significant only for omega-6 PUFA intake.
(66)	Prospective cohort study	3,086 subjects Exposure in the first year of life	The association between children's consumption of fish at 1 year of age and asthma at 2 years was weak and insignificant. The binary logistic regression of the association between children's consumption of fish at 1 year of age and doctor-diagnosed asthma at 2 years showed any significant results (cod liver oil p = 0.43 and p = 0.54; any kind of fish p = 0.16; oily fish p = 0.86; lean fish p = 0.17; vegetables p = 0.42 and p = 0.86).