Fish Oil–Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring
List of authors.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.)
Methods
Study Design
In this single-center, double-blind, placebo-controlled, parallel-group trial, pregnant women between 22 and 26 weeks of gestation were recruited into the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) pregnancy cohort.11 Women taking more than 600 IU of vitamin D per day and women with any endocrine, heart, or kidney disorder were excluded. The trial was approved by the local ethics committee and the Danish Data Protection Agency. Both parents of each child provided oral and written informed consent before enrollment.
At week 24 of pregnancy, women were randomly assigned in a 1:1 ratio to receive 2.4 g per day of n−3 LCPUFA (55% EPA and 37% DHA) in triacylglycerol form (Incromega TG33/22, Croda Health Care) or placebo (in the form of olive oil, containing 72% n–9 oleic acid and 12% n−6 linoleic acid [Pharma-Tech A/S]). (For complete information on the components of Incromega TG33/22, see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org. The trial protocol is also available at NEJM.org.) Both n−3 LCPUFA and placebo were administered in four identical 1-g capsules, with both investigators and participants unaware of group assignments. Neither the fish oil nor the placebo nor any medications, diagnostic equipment, or other materials used in the trial were donated. Similarly, no funding agency played any role in the design or conduct of the trial, the collection, management, or interpretation of the data, the preparation, review, or approval of the manuscript for publication, or the decision to submit the manuscript for publication. In addition, no pharmaceutical company and no company that produces n−3 LCPUFA was involved in the trial. The intervention was funded solely by COPSAC.
Supplementation continued until 1 week after delivery, and both investigators and participants remained unaware of group assignments until the youngest child in the trial reached 3 years of age. The trial was continued for an additional 2 years, during which the investigators determined whether children with persistent wheeze had asthma. Follow-up is still ongoing, with the investigators only (not the participants) remaining unaware of group assignments. A subgroup of 623 women also participated in a trial with a nested, factorial design in which they took 2400 IU of vitamin D3 per day during the third trimester of pregnancy,12 a subgroup of 51 women participated in a trial in which they were vaccinated against influenza A during pregnancy,11,13 and a subgroup of 72 children with persistent wheeze participated in a trial in which they took azithromycin or placebo during asthmatic episodes.14
The participating women completed a validated 360-item food frequency questionnaire so that their dietary intake in the 4 weeks before randomization could be assessed.15-17 Maternal whole-blood levels of EPA and DHA were assessed at the time of randomization and 1 week after birth.18,19 Samples of breast milk were obtained 1 month after birth and were analyzed for EPA and DHA levels. Maternal variation in the genes encoding fatty acid desaturase (FADS) was tagged by genotyping the single-nucleotide polymorphism (SNP) rs1535 in mothers of European descent (with genotyping performed by LGC Group). Adherence to the intervention was assessed by comparing the number of capsules returned with the number expected.
End Points
Pediatricians collected information during clinical visits scheduled at 1 week after birth, at 1, 3, 6, 12, 18, 24, 30, and 36 months after birth, and yearly thereafter. Additional visits for acute care were arranged whenever a child had symptoms related to the lungs, an allergy, or the skin. Asthma, allergy, and eczema were diagnosed and treated by COPSAC pediatricians in accordance with predefined algorithms.11
Diary cards were completed daily by parents from the birth of their child for the purpose of monitoring troublesome lung-related symptoms, including cough, wheeze, and dyspnea that severely affected the well-being of the child,11 skin-related symptoms, and symptoms related to infections of the lower respiratory tract. The diary cards were reviewed by COPSAC pediatricians, and the data were checked after being entered into the database.
Persistent wheeze or asthma (the primary end point) was diagnosed on the basis of a previously described quantitative diagnostic algorithm20,21 that included diary recordings of five episodes of troublesome lung symptoms within the preceding 6 months, each lasting for at least 3 consecutive days; symptoms typical of asthma; the rescue use of inhaled beta2-agonist; and response to a 3-month course of inhaled glucocorticoids followed by relapse after the end of treatment.20 Remission was defined as a period of 12 months without relapse. The diagnosis was termed “persistent wheeze” until a child reached 3 years of age and was termed “asthma” thereafter.
Infection of the lower respiratory tract was defined as a diagnosis of pneumonia or bronchiolitis on the basis of symptoms and clinical presentation (i.e., without confirmation by means of pathogen identification or radiologic or laboratory findings).22-24 Allergic sensitization was determined at 6 months and 18 months as a wheal larger than 2 mm in response to any skin-prick test (ALK-Abelló) or a specific IgE level of 0.35 kU per liter or higher against milk, egg, dog, or cat allergens (ImmunoCAP tests, Thermo Fisher Scientific).11 Allergic rhinoconjunctivitis was diagnosed longitudinally by COPSAC pediatricians on the basis of systematic interviews and was defined as allergic rhinitis, allergic conjunctivitis, or both. Lung function at 5 years of age was assessed by means of spirometry, specific airway resistance by means of whole-body plethysmography, and the lung-clearance index by means of multiple-breath washout.11 A diagnosis of eczema was based on the criteria defined by Hanifin and Rajka.25-27
Statistical Analysis
Power calculations were based on the 695 newborns included in the trial. With an assumed hazard ratio of 0.5 for the treatment group and an expected frequency of persistent wheeze or asthma of 12% for the control group, the design had a power of 73% for the detection of a difference, with a significance level of 0.05 (two-sided test). The effect on the development of persistent wheeze or asthma and eczema was assessed by means of Kaplan–Meier curves and quantified by means of Cox proportional hazards regression (P values correspond to Wald tests). Post hoc analyses were performed with the use of Bayesian statistical modeling to evaluate the importance of covariates and to quantify the degree of certainty for estimates of hazard ratios and risks, and multiple imputation was used to avoid issues related to missing data in these specific analyses. Additional methodologic details are outlined in the Supplementary Appendix and in the COPSAC2010 design paper.11
Results
Baseline Characteristics
A total of 736 pregnant women were randomly assigned to receive the intervention or placebo between November 2008 and November 2010, and the final study included 695 children, including five pairs of twins (Fig. S1 in the Supplementary Appendix). The baseline characteristics of the pregnant women and their children showed that randomization was not biased; similarly, there were no significant differences in pregnancy end points, including the rate of preterm birth (P>0.1 for all comparisons) (Table S2 in the Supplementary Appendix). Information on maternal dietary intake before the intervention was available for 594 mothers (Table S3 in the Supplementary Appendix). The intake and blood levels of EPA and DHA were associated (r=0.32, P<0.001).
FADS Genotypes
The maternal FADS genotype (rs1535) was identified in 660 mothers. Post hoc analyses showed that the minor allele (G) was associated with lower levels of EPA and DHA before the intervention and with higher levels of the upstream substrates of linoleic acid and alpha-linolenic acid before the intervention28 (Fig. S2 in the Supplementary Appendix).
Adherence
Table 1.
Table 1. Effects of n−3 LCPUFA on the Primary End Point.According to capsule count, 493 of 695 (70.9%) of the women had an intervention compliance of more than 80%, with no significant differences between the treatment and control groups. Supplementation resulted in increased blood levels of EPA and DHA (mean [±SD] relative percent of fatty acids measured in blood) from 4.9±1.3% to 6.1±2.0% as compared with a decrease from 4.9±1.2% to 3.7±1.1% in the control group (Fig. S3 in the Supplementary Appendix). The between-group difference in mean postintervention levels of EPA and DHA was 2.5 percentage points (95% CI, 2.2 to 2.7). Clinical follow-up for the initial 3-year double-blind period was completed for 664 children (95.5%), whereas clinical follow-up for the 5-year follow-up period was completed for 647 children (93.1%). The average age of the children for whom double-blind follow-up was completed was 4.0±0.6 years (Table 1, and Fig. S4 in the Supplementary Appendix), and the average age of the children at the time of statistical analysis in March 2016 was 6.0±0.6 years.
Primary End Point
During the prespecified, double-blind follow-up period, which covered children from birth to between 3 and 5 years of age, 136 of 695 children (19.6%) received a diagnosis of persistent wheeze or asthma, and this condition was associated with reduced lung function by 5 years of age, with parental asthma, and with a genetic risk of asthma (Table S4 in the Supplementary Appendix). The risk of persistent wheeze or asthma was 16.9% in the treatment group and 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), with a relative reduction in risk of 30.7% (Table 1). The effect estimate and significance level remained largely unchanged in adjusted analyses (i.e., with adjustment for twin status, sex, supplementation with a high dose of vitamin D3, and EPA and DHA level before randomization) (Table S5 in the Supplementary Appendix).
The preventive effect of supplementation appeared to be driven primarily by children of mothers who had low blood levels of EPA and DHA at randomization (the lowest third of the trial population), for whom the risk of persistent wheeze or asthma was 17.5% in the treatment group as compared with 34.1% in the control group (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011), corresponding to a relative reduction of 54.1% (Table 1).
There was no statistically significant interaction between supplementation with n−3 LCPUFA and high-dose vitamin D3 with regard to persistent wheeze (P=0.065). However, exploratory analyses stratified according to randomization to receive high-dose vitamin D3 suggested that the strongest effect of n−3 LCPUFA supplementation occurred in children of mothers who did not receive high-dose vitamin D3 supplementation (Table S6 in the Supplementary Appendix).
The number needed to treat to prevent a case of persistent wheeze or asthma was 14.6 among the entire cohort and 5.6 among women in the lowest third with regard to EPA and DHA levels before the intervention. The safety profiles for n−3 LCPUFA supplementation and olive oil appeared to be similar (Table S7 in the Supplementary Appendix).
Figure 1.
Figure 1. Risk of Persistent Wheeze or Asthma in Children According to n−3 LCPUFA Supplementation or Placebo during Pregnancy.LCPUFA denotes long-chain polyunsaturated fatty acids.
Figure 2.
Figure 2. Effect of n–3 LCPUFA Supplementation during Pregnancy on Persistent Wheeze or Asthma in Children According to Mother’s EPA and DHA Levels before Intervention.The effect of n−3 LCPUFA supplementation in pregnancy is shown in children born to women who were in thelowest third of the study population regarding blood levels of EPA and DHA (Panel A, <4.30%), the middle third (Panel B, 4.30 to 5.33%), and the highest third (Panel C, >5.33%). Blood levels of EPA and DHA were measured in women on the day of randomization, at week 24 of pregnancy.
During the continued follow-up period for children from birth to the age of 5 years, there was a reduced risk of persistent wheeze or asthma among the children in the treatment group as compared with the control group (Table 1 and Figure 1 and Figure 2). A similar difference in risk between groups was also found when statistical analyses were conducted in March 2016 that covered the period from birth to the ages of 5 to 7 years (mean age, 6.0 years) (Table 1).
In a post hoc analysis, the effect of supplementation seemed strongest in the children of mothers whose dietary intake of EPA and DHA was in the lowest third of that in the trial population (<321 mg per day) before the intervention and in the children of mothers who carried the FADS gene variant associated with low levels of EPA and DHA (the G allele at rs1535) (Table 1, and Fig. S5 in the Supplementary Appendix). The interaction between the intake of EPA and DHA and the FADS genotype on the effect of treatment is illustrated in Fig. S6 in the Supplementary Appendix.
Figure 3.
Figure 3. Prevalence of Persistent Wheeze or Asthma in Children Whose Mothers Received n−3 LCPUFA Supplementation or Placebo during Pregnancy.The yearly prevalence of persistent wheeze or asthma was lower among the children of mothers who received supplementation, and this effect did not appear to change between the ages of 2 and 5 years (Table 1 and Figure 3). A threshold analysis suggested that supplementation was effective up to a preintervention blood level of EPA and DHA of approximately 5.0 to 5.5% of total blood fatty acids (Fig. S7 in the Supplementary Appendix). In the children of mothers in the control group, there was a significant association between low maternal blood levels of EPA and DHA and the risk of persistent wheeze or asthma in their children (Table S8 in the Supplementary Appendix). There was no association between levels of EPA and DHA in breast milk collected when the child was 1 month old and later development of persistent wheeze or asthma (Table S9 in the Supplementary Appendix). Bayesian analyses confirmed the effect of the intervention with similar estimates for hazard ratios and for absolute and relative risks (see Supplementary Methods and Results and Tables S10 through 13 in the Supplementary Appendix).
Secondary and Post Hoc End Points
Table 2.
Table 2. Effects of n−3 LCPUFA on Secondary and Post Hoc End Points.Supplementation was associated with a reduced risk of lower respiratory tract infections in the first 3 years of life and up to 5 years of follow-up (Table 2, and Fig. S8 in the Supplementary Appendix) but not with other secondary end points, including the risk of asthma exacerbations, eczema, and allergic sensitization at 6 months and 18 months. There was also no statistically significant association between supplementation and the post hoc end points of allergic rhinoconjunctivitis and lung function at the age of 5 years.
Discussion
The risk of persistent wheeze or asthma was reduced by approximately 7 percentage points, or one third, in the first 5 years of life among children of women who received daily supplementation with n−3 LCPUFA during the third trimester of pregnancy. This effect was most prominent among children of women with low preintervention EPA and DHA blood levels. Supplementation was also associated with a reduced risk of infections of the lower respiratory tract but not with a reduced risk of eczema, allergic sensitization, or other secondary end points.
The trial results are strengthened by the use of centralized, longitudinal clinical follow-up, the daily recording of symptoms in a diary, and frequent visits to our clinical research unit for regular and acute care. COPSAC served as the de facto primary health care center for the birth cohort, thereby ensuring the use of a standardized approach to diagnosis and treatment. This approach greatly improves the reliability of the diagnoses. The additional Bayesian analyses confirmed the results of the predefined analyses, thereby supporting the robustness of the results.
We used a high dose of n−3 LCPUFA — corresponding to an increase estimated to be 10 times the normal daily intake in Denmark29 and 20 times that in most other countries, including Canada and the United States.30,31 It is possible that a lower dose would have sufficed.
The FADS region harbors several genetic variants. The SNP rs1535 was chosen because this SNP and its proxies in close linkage disequilibrium have been associated with n−3 LCPUFA levels in a genomewide association study32 and with blood levels of EPA and DHA during pregnancy.28
Several secondary and subgroup analyses were performed. These analyses should be considered as exploratory; the results need to be confirmed in subsequent studies. Furthermore, it is a limitation of our study that allergic rhinoconjunctivitis was not confirmed in tests of allergic sensitization by the age of 5 years.
We observed that supplementation had a greater effect on the children of mothers with low blood levels and low intake of EPA and DHA and on the children of mothers with a FADS genotype associated with low EPA and DHA blood levels. This pattern is biologically plausible and supports the supposition that the intervention had a causal effect. Furthermore, this pattern indicates that there is the potential for so-called “precision prevention” by targeting pregnant women with the FADS genotype associated with low levels of EPA and DHA and those with a low dietary intake of these fatty acids (Fig. S6 in the Supplementary Appendix).
The differences in the geographical and temporal incidences of asthma and wheezing indicate that lifestyle plays a major role, and our trial suggests that diets low in n−3 LCPUFA could contribute to these differences. The mechanisms may involve an imbalance between n−6 and n−3 lipid mediators, which may promote a proinflammatory state.33,34
There was no statistically significant interaction related to concurrent supplementation with vitamin D3 and n−3 LCPUFA, but there was a trend suggesting that n−3 LCPUFA supplementation was less effective in children receiving high-dose vitamin D3. Such an interaction would indicate that these supplements target the same disease pathway, and this possibility should be addressed in future studies.
Analysis of the prevalence of current persistent wheeze or symptoms of asthma showed that the effect of the intervention was largely unchanged between the ages of 2 years and 5 years (Figure 3). This finding suggests that the effect is not restricted to a “transient wheezing” phenotype.
The maternal baseline intake of n−3 LCPUFA was high in this Danish population relative to that of the global population (Table S14 in the Supplementary Appendix). It has been estimated that 80% of the global population consumes less than 250 mg of EPA and DHA per day,35 — a level that is well below 321 mg per day, the level below which we observed the highest treatment effect in our trial. Our data therefore suggest that a sizeable effect may be expected from supplementation in other populations worldwide; however, this suggestion is speculative, since other factors may be at play in such populations.
The implications of our findings on health and disease may be wide. The number needed to treat to prevent one case of persistent wheeze or asthma was 14.6 in the entire cohort and 5.6 among women with the lowest blood levels of EPA and DHA before intervention.
In conclusion, these findings show that n−3 LCPUFA supplementation during pregnancy was associated with a significantly diminished burden of wheezing and asthma in children in this Danish birth cohort. To address the question of whether similar effects could be seen in other populations, further studies are required.
Supplementary Material
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Citing Articles (181)
Letters
Figures/Media
- Table 1. Effects of n−3 LCPUFA on the Primary End Point.
Table 1. Effects of n−3 LCPUFA on the Primary End Point. - Figure 1. Risk of Persistent Wheeze or Asthma in Children According to n−3 LCPUFA Supplementation or Placebo during Pregnancy.
Figure 1. Risk of Persistent Wheeze or Asthma in Children According to n−3 LCPUFA Supplementation or Placebo during Pregnancy. LCPUFA denotes long-chain polyunsaturated fatty acids.
- Figure 2. Effect of n–3 LCPUFA Supplementation during Pregnancy on Persistent Wheeze or Asthma in Children According to Mother’s EPA and DHA Levels before Intervention.
Figure 2. Effect of n–3 LCPUFA Supplementation during Pregnancy on Persistent Wheeze or Asthma in Children According to Mother’s EPA and DHA Levels before Intervention. The effect of n−3 LCPUFA supplementation in pregnancy is shown in children born to women who were in thelowest third of the study population regarding blood levels of EPA and DHA (Panel A, <4.30%), the middle third (Panel B, 4.30 to 5.33%), and the highest third (Panel C, >5.33%). Blood levels of EPA and DHA were measured in women on the day of randomization, at week 24 of pregnancy.
- Figure 3. Prevalence of Persistent Wheeze or Asthma in Children Whose Mothers Received n−3 LCPUFA Supplementation or Placebo during Pregnancy.
Figure 3. Prevalence of Persistent Wheeze or Asthma in Children Whose Mothers Received n−3 LCPUFA Supplementation or Placebo during Pregnancy. - Table 2. Effects of n−3 LCPUFA on Secondary and Post Hoc End Points.
Table 2. Effects of n−3 LCPUFA on Secondary and Post Hoc End Points.
