In a large double-blind randomized controlled trial we found that 400 mg/day DHA from 18 to 22 weeks' gestation through parturition reduced the occurrence of colds in offspring at 1 month of age and influenced illness duration at 1, 3, and 6 months. At 1 month, infants in the DHA group experienced shorter duration of cough, phlegm, and wheezing, but longer duration of rash. At 3 months, infants in the DHA group spent 14% less time ill from any illness compared with the placebo group and experienced shorter duration of “other illnesses” such as ear infections and sore throats, but longer duration of nasal congestion. At 6 months, infants in the DHA group experienced shorter duration of nasal secretion, difficulty breathing, fever, rash, and “other illnesses,” but longer duration of vomiting. We noted a general trend that infants in the DHA group were less likely to experience upper respiratory symptoms at 1 and 3 months; however, not all differences were statistically significant.
Overall, infants in the DHA group were determined to be healthier on the basis of the observation that fewer of these infants experienced a cold at 1 month, and they experienced a significantly shorter duration of all illnesses at 3 months, but longer duration of a few symptoms at certain time points. The increased duration of vomiting in the DHA group at 6 months of age may have been caused by either viral or a bacterial illness, or by gastrointestinal upset (“spitting up”) attributable to sensitive stomach or acid reflux. Longer duration of rash, perhaps atopic dermatitis, or a simple diaper rash caused by sensitive skin, diet, or wearing a soiled diaper for too long, occurred more frequently in the DHA group than in the placebo group at 1 month of age.
We conducted 36 statistical tests of differences in the duration of various symptoms. The number of significant results (12) is greater than would be expected because of chance alone. We are therefore confident that the significant findings are not a result of multiple testing alone. Although we observed some heterogeneity in our results, 9 of the 12 significant estimates were in the direction of a beneficial effect of DHA. The slight heterogeneity in results may be explained by the differing etiology of symptoms (ie, viral infection, bacterial infection, atopic response) and DHA's mechanism of action on their etiologies, which is unknown. Our study was sufficiently powered to demonstrate clinically relevant differences between treatment groups.
Illness symptoms were reported by the mother and not confirmed by a health care professional; therefore, we were unable to distinguish between, for example, diaper rash and clinical atopic dermatitis. A high proportion of mothers sought care for their infant's illness symptoms, likely because of the free access to health care within the IMSS hospital system. Self-reporting of morbidity data using recall questionnaires can introduce bias attributable to memory loss.29,30
Because treatment groups shared similar baseline characteristics and double-blinding was maintained throughout the study, recall was unlikely to be biased by treatment group.31
In addition, the use of health calendars/diaries and the high rate of literacy in this study likely greatly aided in maternal recall of child illness during interviews.32
The high occurrence of certain illness symptoms may be related to the low rate of exclusive breastfeeding.33
Breastfeeding was common because intent to breastfeed was an inclusion criterion for participation, but the prevalence of exclusive breastfeeding was low; however, there were no differences between the groups.
To our knowledge, 1 randomized controlled trial has been conducted to examine the effect on infant immune function of n
-3 PUFA supplementation in pregnancy.34–36
We did not identify any studies that examined the influence of prenatal DHA on infant morbidity. Unlike our study, that study included only atopic pregnant women, the primary outcome of interest was allergic immune response, and the supplement was fish oil, rather than DHA. In that study, fish oil supplementation in pregnancy lowered cord blood concentration of the cytokine interleukin 13, modified neonatal neutrophil production, did not influence neonatal immunoglobulin E concentrations, and lowered the risk of a positive reaction to a specific skin prick test at 1 year. The investigators also found a positive correlation between maternal n
-3 PUFA concentration and immunoglobulin A concentration in breast milk, indicating that n
-3 PUFA in pregnancy might modulate infant immune function by means of breast milk immunoglobulin protection.37
Our findings extend those results to the clinical manifestations of infant immune function.
Several studies have evaluated the influence of LCPUFA supplementation during childhood on illness occurrence and severity and immune function.9,11,14–17,38
Children aged 18 to 36 months who were given formula containing DHA for 60 days had a lower occurrence of respiratory illness.16
Thai schoolchildren aged 9 to 12 years who consumed fish oil–enriched milk for 6 months experienced fewer episodes and shorter duration of illness compared with controls.15
Infants fed formula enriched with DHA and arachidonic acid during the first year of life experienced fewer upper respiratory infections than did the placebo group.17
Infants who consumed an LCPUFA-supplemented formula had a decreased incidence of bronchiolitis/bronchitis compared with controls.9
Term infants who were given formula supplemented with LCPUFA had enhanced presence and function of infant CD3+
cells compared with controls.38
Children aged 5 to 7 years who were given a dietary supplement containing arachidonic acid and DHA for 7 months had improved immune cell phenotypes, compared with children who were given a placebo.14
Danish infants who were provided fish oil from 9 to 12 months of age had higher Lactobacillus paracasei
–induced interferon γ amounts than controls, suggesting that fish oil may influence maturation of the infant immune system.39
Dietary EFA supplementation in children aged 36 to 49 months at risk of recurrent respiratory infections reduced the number of infective episodes and days with fever.11
A systematic review of randomized controlled trials of LCPUFA supplementation of infant formula in preterm infants demonstrated no effect on severe adverse outcomes such as sepsis or necrotizing enterocolitis.12
In summary, numerous studies have shown that n
-3 PUFA supplementation in childhood reduced the occurrence and duration of illness, particularly respiratory illness.
Results from our study could be generalized to other populations of pregnant women of middle-to-lower socioeconomic status who have similarly low dietary DHA intakes. DHA intakes in our study population were low (median: 80 mg/day) compared with the recommended intake of at least 200 mg/day.26,40
Intake of n
-3 PUFA in the United States is an estimated 1.6 g/day, and intake of DHA is ~100 to 200 mg/day.41
Our study population experienced lower infectious disease rates than are reported from many developing countries, in particular for diarrhea and fever.