Maternal polyunsaturated fatty acids and allergic disease development in the offspring

To the Editor, The increasing global prevalence of allergic diseases makes it imperative to identify modifiable risk factors for allergic disease development. Maternal antenatal plasma fatty acid composition has been proposed as a risk factor of infant allergic disease.1,2 Polyunsaturated fatty acids (PUFAs) are key components of cell membranes and influence immune cell function by regulating membrane fluidity, intracellular signaling, and gene expression.3 They can be classified into n3 and n6 PUFAs, which are linked to production of antiinflammatory and proinflammatory molecules, respectively.3 The fetoplacental unit lacks the desaturase enzymes required to synthesize long chain PUFAs so that, during pregnancy, the fetus is dependent on transplacental supply of PUFAs from the mother.4 Only three studies conducted in European countries have examined the association of the ratio of PUFA precursors to products in the maternal bloodstream (e.g., in plasma phospholipids) with offspring allergic disease development and these have reported conflicting results.1,2,5 Dietary n3 PUFA alphalinolenic acid (ALA) undergoes desaturation to form longer chain n3 PUFAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).3 Similarly, dietary n6 PUFA linolenic acid (LA) competes for the same enzymes to form arachidonic acid (AA).3 These metabolites are further converted into immunomodulatory oxylipin mediators such as eicosanoids.3 Through their effects on the cell membrane, cell signaling, gene expression, and oxylipin production, PUFAs can influence production of cytokines involved in allergic disease. The ratios of ALA and LA to their respective unsaturated products indicate metabolism efficiency of the precursors.1 The balance of n3 to n6 PUFAs as well as PUFA precursors to their products may influence the risk of allergic disease development. In this study, we investigated longterm associations between maternal PUFAs in plasma phospholipids during pregnancy and the risk of offspring rhinitis, wheeze, eczema, and allergic sensitization up to age 8 years in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We hypothesized that higher n3 metabolites is protective against inflammation and allergy and that higher total n3:total n6 PUFAs, higher (DHA + EPA):AA and LA:AA ratios and lower ALA:(EPA + DHA) during pregnancy are associated with decreased proinflammatory cord blood cytokines at birth and consequently decreased risk of offspring allergic diseases in the first 8 years of life. Demographic data were gathered by intervieweradministered questionnaires. Offspring allergic outcomes were evaluated via modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires (Appendix S1). Offspring allergic sensitization was determined by skin prick testing at ages 18, 36 months, 5 and 8 years for common allergens in Singapore (Appendix S2). Maternal plasma phospholipids at gestational week 26 were measured using gas chromatography– mass spectrometry (Appendix S3) and infant cord blood cytokines were assayed using modified Luminex assay via DropArray multiplex assay (Appendix S4). Ethics approval was obtained from the Domain Specific Review Board of Singapore National Healthcare Group (D/2009/021) and the Centralized Institutional Review Board of SingHealth (2018/2767). Analyses were performed using the Statistical Package for the Social Sciences, Version 27 (IBM Cooperation, New York) (Appendix S5). After removing subjects with missing data on maternal plasma PUFAs concentrations and offspring allergic outcomes, 920 mother– offspring pairs were included in the study (Table 1). There were no differences between included and excluded participants except there was a higher proportion of nulliparous women among the excluded participants (Table S1). In multivariate Poisson analysis with adjustment for maternal age, history of allergy, parity, smoke exposure during pregnancy, educational attainment, mode of delivery, offspring's sex, breastfeeding practices, and offspring fish oil intake (DHA + EPA):AA (adjRR = 2.2, 95% CI = 1.1– 4.3) and total n3:total n6 PUFAs (adjRR = 2.3, 95% CI = 1.1– 4.9) increased the risk of wheeze by 18 months (Table 2). In stratified analyses by exposure to allergic sensitization by 18 months, these associations were only demonstrated in nonatopic children [(DHA + EPA):AA (adjRR = 2.9, 95% CI = 1.3– 6.7) and n3:n6 PUFA ratios (adjRR = 3.3, 95% CI = 1.3– 8.2)]. No associations were observed between maternal ALA:(DHA + EPA), LA:AA, ALA:LA, total

To the Editor, The increasing global prevalence of allergic diseases makes it imperative to identify modifiable risk factors for allergic disease development. Maternal antenatal plasma fatty acid composition has been proposed as a risk factor of infant allergic disease. 1,2 Polyunsaturated fatty acids (PUFAs) are key components of cell membranes and influence immune cell function by regulating membrane fluidity, intracellular signaling, and gene expression. 3 They can be classified into n-3 and n-6 PUFAs, which are linked to production of anti-inflammatory and pro-inflammatory molecules, respectively. 3 The fetoplacental unit lacks the desaturase enzymes required to synthesize long chain PUFAs so that, during pregnancy, the fetus is dependent on transplacental supply of PUFAs from the mother. 4 Only three studies conducted in European countries have examined the association of the ratio of PUFA precursors to products in the maternal bloodstream (e.g., in plasma phospholipids) with offspring allergic disease development and these have reported conflicting results. 1,2,5 Dietary n-3 PUFA alpha-linolenic acid (ALA) undergoes desaturation to form longer chain n-3 PUFAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 3 Similarly, dietary n-6 PUFA linolenic acid (LA) competes for the same enzymes to form arachidonic acid (AA). 3 These metabolites are further converted into immunomodulatory oxylipin mediators such as eicosanoids. 3 Through their effects on the cell membrane, cell signaling, gene expression, and oxylipin production, PUFAs can influence production of cytokines involved in allergic disease. The ratios of ALA and LA to their respective unsaturated products indicate metabolism efficiency of the precursors. 1 The balance of n-3 to n-6 PUFAs as well as PUFA precursors to their products may influence the risk of allergic disease development.
In this study, we investigated long-term associations between maternal PUFAs in plasma phospholipids during pregnancy and the risk of offspring rhinitis, wheeze, eczema, and allergic sensitization up to age 8 years in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We hypothesized that higher n-3 metabolites is protective against inflammation and allergy and that higher total n-3:total n-6 PUFAs, higher (DHA + EPA):AA and LA:AA ratios and lower ALA:(EPA + DHA) during pregnancy are associated with decreased pro-inflammatory cord blood cytokines at birth and consequently decreased risk of offspring allergic diseases in the first 8 years of life.
Demographic data were gathered by interviewer-administered questionnaires. Offspring allergic outcomes were evaluated via modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires (Appendix S1). Offspring allergic sensitization was determined by skin prick testing at ages 18, 36 months, 5 and 8 years for common allergens in Singapore (Appendix S2).
Maternal plasma phospholipids at gestational week 26 were measured using gas chromatography-mass spectrometry (Appendix S3) and infant cord blood cytokines were assayed using modified Luminex assay via DropArray multiplex assay (Appendix S4). Ethics After removing subjects with missing data on maternal plasma PUFAs concentrations and offspring allergic outcomes, 920 motheroffspring pairs were included in the study (Table 1). There were no differences between included and excluded participants except there was a higher proportion of nulliparous women among the excluded participants (Table S1).
In this study, we observed that maternal plasma ALA: We observed that higher maternal total n-3:total n-6 PUFAs and (DHA + EPA):AA ratios were associated with a higher risk of early life wheeze by 18 months, especially in non-atopic children.
This finding is supported by the Southampton Women's Survey which reported that AA was inversely associated with non-atopic persistent/late wheeze. 1 We postulate that lower maternal n-6 PUFA levels may increase susceptibility to infections, especially since wheeze in early life is largely caused by viruses or bacteria rather than allergy development. 7 In particular, AA has the strongest antibacterial and antiviral effect in the lungs, as compared to other PUFAs, possibly by disrupting the microbial cell membrane integrity. 8,9 Early exposure to n-6 PUFAs and AA in utero may promote robust immune system development, which protects against infections later in infancy. Further research is needed to elucidate the underlying mechanisms, with our study suggesting the association between n-3:n-6 PUFA and (DHA + EPA):AA ratios and offspring wheeze by 18 months is not mediated by cord blood cytokine concentrations.
Strengths of this study include the long-term follow-up of participants and the collection of data on allergic diseases, as well as skin .856 Note: Benjamini-Hochberg correction with false discovery rate at 0.40 and n = 32 was applied to each outcomes and significant p-value in bold.
a Adjusted for maternal age at delivery, history of allergy, parity, educational attainment, smoke exposure during pregnancy, mode of delivery, breastfeeding practices, and offspring's sex.
b Adjusted for maternal age at delivery, history of allergy, parity, educational attainment, smoke exposure during pregnancy, mode of delivery, breastfeeding practices, offspring's sex, and year 3 fish oil intake.
c Adjusted for maternal age at delivery, history of allergy, parity, educational attainment, smoke exposure during pregnancy, mode of delivery, breastfeeding practices, offspring's sex, and year 5 fish oil intake. We found no convincing evidence to suggest that maternal plasma n-3 PUFA is protective, nor that n-6 PUFA increases the risk of offspring allergy development. However, our results suggest that higher n-3 to n-6 PUFA ratios may be linked to increased risk of early life wheezing illness. Note: Benjamini-Hochberg correction with false discovery rate at 0.40 and n = 14 was applied to adjusted models of each outcomes and significant p-value in bold. a Adjusted for maternal age at delivery, history of allergy, parity, educational attainment, smoke exposure during pregnancy, mode of delivery, breastfeeding practices, and offspring's sex.