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Prenatal omega-3 LCPUFA and symptoms of allergic disease and sensitization throughout early childhood – a longitudinal analysis of long-term follow-up of a randomized controlled trial

Prenatal omega-3 LCPUFA and symptoms of allergic disease and sensitization throughout early... Background: Randomized controlled trials of prenatal omega (ω-3) long chain polyunsaturated fatty acid (LCPUFA) supplementation are suggestive of some protective effects on allergic sensitization and symptoms of allergic disease in childhood. Due to the nature of the atopic march, investigation of any effects of this prenatal intervention may be most informative when consistently assessed longitudinally during childhood. Methods: Follow-up of children (n = 706) with familial risk of allergy from the Docosahexaenoic Acid to Optimize Mother Infant Outcome (DOMInO) trial. The intervention group received fish oil capsules (900 mg of ω-3 LCPUFA) daily from <21 weeks’ gestation until birth; the control group received vegetable oil capsules without ω-3 LCPUFA. This new longitudinal analysis reports previously unpublished data collected at 1 and 3 years of age. The allergic disease symptom data at 1, 3 and 6 years of age were consistently reported by parents using the "International Study of Asthma and Allergies in Childhood" (ISAAC) questionnaire. Sensitization was determined by skin prick test to age specific, common allergen extracts. Results: Changes over time in symptoms of allergic disease with sensitization (IgE-mediated) and sensitization did not differ between the groups; interaction p =0.49, p = 0.10, respectively. Averaged across the 1, 3 and 6-year assessments, there were no significant effects of prenatal ω-3 LCPUFA supplementation on IgE-mediated allergic disease symptoms (adjusted relative risk 0.88 (95% CI 0.69, 1.12), p = 0.29) or sensitization (adjusted relative risk 0.97 (95% CI 0.82, 1.15), p = 0.76). Sensitization patterns to common allergens were consistent with the atopic march, with egg sensitization at 1 year strongly associated with house dust mite sensitization at 6 years, (p < 0.0001). Discussion: Although there is some evidence to suggest that maternal supplementationwith900mg ω-3 LCPUFA has a protective effect on early symptoms of allergic disease and sensitization in the offspring, we did not observe any differences in the progression of disease over time in this longitudinal analysis. Further investigation into the dose and timing of ω-3 LCPUFA supplementation, including long-term follow up of children using consistent outcome reporting, is essential to determine whether this intervention may be of benefit as a primary prevention strategy for allergic disease. Conclusion: Maternal supplementation with 900 mg of ω-3 LCPUFA did not change the progression of IgE-mediated allergic disease symptoms or sensitization throughout childhood from 1 to 6 years. (Continued on next page) * Correspondence: karen.best@sahmri.com Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia School of Medicine, University of Adelaide, Adelaide, South Australia, Australia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Best et al. World Allergy Organization Journal (2018) 11:10 Page 2 of 11 (Continued from previous page) Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN); DOMInO trial ACTRN12605000569606,early childhood allergy follow up ACTRN12610000735055 and 6-year allergy follow up ACTRN12615000498594. Keywords: Allergy, Omega-3, Paediatric, Perinatal, Prevention, Pregnancy, Asthma, Allergic disease, Atopy, Background (predominantly as EPA) on cumulative wheeze (independ- The relentless increase in the worldwide prevalence of aller- ent of sensitization) at 3–5 years of age [19]and atopic gic disease has heightened the need for primary prevention asthma at 16 and 24 years of age [20, 21]. [1]. Although the rise is unlikely to be due to a single factor, Longitudinal analyses have long been recognized as an there is consensus that the cause may be due to our chan- important tool for obtaining high quality evidence about the ging lifestyle, including diet and environment. Diet in indus- determinants of development across the lifespan [22]. How- trialized countries has changed dramatically over the last ever, RCT’sof ω-3 LCPUFA supplementation to date, have 50 years, particularly in the balance of fats consumed. Opti- only reported allergic disease outcomes from distinct mal health requires a relative balance of omega-3 (ω-3) and follow-up time points, often with inconsistent outcomes omega-6 (ω-6) fatty acids, however studies report that some which prevent any analysis to investigate change over time. ‘Western’ diets contain an overabundance of ω-6 fats at the Given the progressive and heterogenous nature of allergic expense of ω-3 fats [2]. Theimpactof thischangemay carry disease, we aim to investigate if prenatal ω-3 LCPUFA sup- heightened importance for the prenatal period, when the plementation will modify the course of allergen sensitization developing fetus is reliant solely on the maternal diet. or allergic disease symptoms over time (from 1 to 6 years of There is increasing evidence to support modulation of age). Previously published 1 and 3-year of age allergic dis- fetal immune development following prenatal ω-3 ease outcomes from our RCT were based on physician LCPUFA supplementation [3–5]. Diets high in ω-3 examination and diagnosis of allergic disease, [17, 23] LCPUFA (from fish and fish oils) increase cell membrane whereas the 6-year results were based on parent reported docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapenta- symptoms using the ‘International Study of Asthma and enoic acid (EPA; 20:5 ω-3), competing with the synthesis Allergies in Childhood’ (ISAAC) questionnaire [18]. In this of inflammatory arachidonic acid (AA, 20:4, ω − 6), which new analysis we have combined previously unpublished results in a reduction in prostaglandin E synthesis and in- ISAAC data collected at 1 and 3 years with 6-year data to hibition of cytokine and immunoglobulin E (IgE) produc- permit investigation of the effects of prenatal ω-3 LCPUFA tion associated with allergies [6]. supplementation on the progression of consistently parent Cohort studies have consistently reported that increased reported allergic disease symptoms. ω-3 LCPUFA consumption during pregnancy may reduce the risk of atopic eczema, asthma and sensitization to Methods house dust mite (HDM) [7], although it is difficult to infer Description of participants a causal link from these studies given the potential for re- This study is a longitudinal synthesis of data obtained at sidual confounding from environmental factors. Published the 1, 3 and 6 year follow up assessment of children at reviews assessing the effect of n–3 LCPUFAs in the pri- hereditary risk of allergic disease, born to mothers en- mary prevention of allergic disease have been conducted rolled in the multi-center, double-blind, DOMInO (DHA [7–13]. However, not all are systematic and most pool re- to Optimize Mother Infant Outcome) RCT [24]. The sults from varying supplementation periods including preg- methods of the DOMInO Trial have been published previ- nancy, pregnancy and lactation or the lactation period ously [24]. Briefly, women < 21 weeks’ gestation with a only, thus increasing the variability of results and poten- singleton pregnancy were randomly allocated to either tially diluting any causal effect of the intervention. Evidence treatment or control group through a computer driven from randomized controlled trials (RCTs) of prenatal sup- telephone randomization service stratified by center and plementation with ω-3 LCPUFA report consistent protect- parity (first birth versus subsequent births). Women were ive effects on the risk of IgE mediated eczema [14, 15]and asked to consume capsules containing either fish oil con- sensitization to egg [14–17] at 1 year of age. However, only centrate, providing ~ 800 mg/day DHA and 100 mg/day one of these trials extended follow-up to school age, EPA or control capsules containing a blend of three reporting a reduction in sensitization to HDM only and no non-genetically modified oils (rapeseed, sunflower, and effect on parent reported symptoms of IgE-mediated aller- palm) in equal proportions and designed to match the gic disease at 6 years of age [18]. Two trials from Denmark polyunsaturated, monounsaturated, and saturated fatty that have conducted follow up beyond infancy report a acid profile of the average Australian diet [25](Incromega protective effect of prenatal ω-3 LCPUFA supplementation 500 TG, Croda Chemicals, East Yorkshire, England). The Best et al. World Allergy Organization Journal (2018) 11:10 Page 3 of 11 supplementation period commenced at enrolment of the Women’sand Children’s Hospital and the Southern (< 21 weeks’ gestation) until delivery. All capsules were Adelaide Health Service, Adelaide, and trials were regis- similar in size, shape, and color, and neither the women tered on the Australian New Zealand Clinical Trials Regis- nor research staff were aware of the treatment allocated. try (ACTRN); DOMInO trial ACTRN12605000569606, Women reported their adherence to supplementation at early childhood allergy follow up ACTRN12610000735055 telephone calls at 28 and 36 weeks’ gestation and the con- and 6-year allergy follow up ACTRN12615000498594. centration of individual LCPUFA in plasma phospholipids from cord blood was assessed as an independent bio- Assessment of allergic disease marker of compliance. Pregnant women enrolled in the Early childhood follow-up appointments at 1 and 3 years DOMInO Trial from two South Australian Centers of age consisted of physician assessment of allergic disease (Flinders Medical Center and the Women’sand Children’s and interviewer administered parent reported symptom Hospital) were invited to participate in an early childhood questionnaires using the International study of Asthma allergy follow up if their unborn child had a familial his- and Allergy in Childhood (ISAAC) questionnaire [17, 23]. tory of allergic disease (mother, father, or sibling with a Additional funding was obtained to conduct a 6 year self-reported history of medically diagnosed eczema, follow up which did not include a physician assessment. asthma, or hay fever). Written informed consent was Children attended a clinic appointment and parents were sought (prior to birth) for the offspring to take part in an interviewed using ISAAC questionnaires to determine allergy assessment at 1 and 3 years of age (n = 706). Fam- allergic disease symptoms [18]. Allergic disease outcomes ilies of children who consented to the 1 and 3 years of age included in this longitudinal analysis are based on the par- allergy follow up were contacted again when the child ent reported symptoms ascertained via ISAAC question- turned 5 years and 9 months and invited to take part in naires at 1, 3 and 6 years of age. History of symptoms the 6-year of age follow up (n = 668), Fig. 1. Results of the related to the previous 12-month period and included ec- early childhood allergy follow up involving physician zema and wheeze at 1, 3 and 6 years, and rhinitis and examination to determine allergic disease outcomes at 1 rhino-conjunctivitis at 3 and 6 years. Eczema was defined and 3 years of age, and a subsequent school age follow up as the history of an itchy rash distributed to the facial, flex- study at 6 years of age using ISAAC questionnaire to de- ural or extensor surface of the skin. Wheeze was defined as termine allergic disease symptoms have been previously a history of wheezing or whistling in the chest. Rhinitis was published [17, 18, 23]. Approval for all allergy follow up defined as a history of sneezing or a runny or blocked nose was granted by the Human Research Ethics Committees when there have not been symptoms to suggest an upper Fig. 1 Flow of participants consented to the nested allergy follow-up of the DOMInO trial Best et al. World Allergy Organization Journal (2018) 11:10 Page 4 of 11 respiratory tract infection. Rhino-conjunctivitis was defined independence working correlation matrix was used in as a history of sneezing or a runny or blocked nose accom- each of these models to adjust for the dependence within panied by itchy-watery eyes when there have not been participants due to repeated measurements over time. In symptoms to suggest an upper respiratory tract infection the models the effects of treatment group, time (categor- [26]. All ISAAC questionnaires were administered consist- ical) and the interaction between treatment group and ently at each time point in accordance with guidelines de- time were assessed. Adjustment was also made for the tailed in the ISAAC user manual [27]. stratification variables parity (first birth vs. subsequent birth) and center, as well as the prognostic variables gen- Assessment of sensitization der and maternal history of allergic disease. Where the Sensitization was assessed at 1, 3 and 6 years by skin prick interaction term between group and time was not statisti- test (SPT) to common, age specific allergens. One of five ex- cally significant, a second model excluding the interaction perienced research nurses who were blinded to treatment term was fitted to estimate the effect of treatment over all group allocation and specifically trained in pediatric skin time points. The effect of treatment, whether at an indi- prick testing performed the SPTs. SPT’s were performed in vidual time point or across all time points, was described a standardized manner and nurses underwent quality assur- using relative risks and 95% confidence intervals. All ana- ance reviews every 6 months with one of the investigators. lyses were performed using SAS version 9.3 (SAS Institute Sensitization was defined as a positive reaction to at least Inc., Cary, NC, USA). one of the allergen extracts assessed. As per the Australasian Society of Clinical Immunology and Allergy (ASCIA) man- Results ual, a test was considered positive if the mean of the hori- Sample and participant flow zontal and perpendicular weal diameters was ≥3mmthan Enrolment to the nested early childhood allergy follow that of the negative control site at 15 min [28]. Food allergen up began in 2006. A total of 706 offspring were con- extracts were selected according to common foods per age sented between 2006 and 2008 to take part. Of these, group and aero-allergens were selected based on typical en- 666 (94.3%) infants completed allergy symptom ques- vironmental allergens in the geographical area of South tionnaires and skin prick testing at 1 year of age and 638 Australia, see Table 1. Glycerine and histamine (10 mg/mL) (90.3%) at 3 years of age. In 2012, following the exclu- were used as negative and positive controls at each time sion of deaths and withdrawals from the early childhood point. Allergen extracts that were assessed at 2 or more time sample, a total of 668 children remained eligible to par- points were included in the longitudinal analysis. ticipate in the 6-year allergy follow up. Six-year assess- ments were completed in August 2014 with a total 603/ Statistical analysis 668 (90.0%) allergy symptom questionnaires completed Longitudinal outcomes were compared between groups and 485/668 (73.0%) children undergoing SPT to deter- using log binomial generalized estimating equations. An mine sensitization, Fig. 1. Table 1 Allergen extracts assessed by SPT at 1, 3 and 6 years Baseline characteristics and compliance 1 year 3 years 6 years The baseline enrolment characteristics of the women Cow’s milk –– and their offspring who were consented to participate in allergy follow-up have been previously described [17]In Whole hen’s egg Whole hen’s egg Whole hen’s egg brief, mean maternal age at trial entry was 29.6 years Wheat Wheat – (SD 5.7 years) and 13.0% of the participating mothers Tuna Tuna – smoked during pregnancy. All unborn children had at Peanut Peanut Peanut least one first-degree relative with a history of medically – Cashew Cashew diagnosed allergic disease; 70% had a history of maternal – Sesame – allergic disease, 54.0% paternal disease and 29.0% allergic disease in both parents. A total of 39.8% were first born Perennial rye grass Perennial rye grass Perennial rye grass children and 47.7% were males. There were no import- Olive tree pollen Olive tree pollen Olive tree pollen ant differences in baseline characteristics at study enrol- Alternaria tenuis Alternaria tenuis Alternaria tenuis ment between the intervention and control groups. Cat Cat Cat Compliance with the intervention was high, with –– Dog 77.0% of mothers in the ω-3 LCPUFA group and 80.0% D. pteronyssinus D. pteronyssinus D. pteronyssinus of mothers in the control group reporting that they had missed zero to three capsules a week (from a total of 21 – D. farinae D. farinae capsules per week) at 28 weeks’ gestation. DHA concen- Abbreviations: D. pteronyssinus Dermatophagoides pteronyssinus, D. farinae Dermatophagoides farinae tration in the plasma phospholipids of cord blood from Best et al. World Allergy Organization Journal (2018) 11:10 Page 5 of 11 infants in the high-DHA group was greater than control from 5.3% at 1 year of age to 29.0% at 6 years of age. (DHA 3.54 to 13.68% vs control 3.51 to 11.21%; median, Longitudinal analysis found no evidence that the differ- 7.2% vs 6.1% total phospholipid fatty acids, P < 0.001). ence between the ω-3 LCPUFA and control groups in Fewer than 2.0% of mothers in each group chose not to the risk of ‘any’ IgE mediated allergic disease or ‘individ- take any capsules. ual IgE mediated allergic disease symptoms (eczema, rhinitis, rhino-conjunctivitis or wheeze)’ changed over Allergic disease symptoms time (group by time interaction p-values > 0.05). After The prevalence of ‘any’ allergic disease symptoms (irre- excluding the group by time interaction effect from the spective of sensitization) increased from 17.5% at 1 year models, there were no significant differences between of age to 49.3% at 6 years of age. Allergic disease symp- the prenatal ω-3 LCPUFA supplementation and control toms with evidence of sensitization were reported less groups in the risk of ‘any’ IgE-mediated allergic disease often but with a similar increase in prevalence over time or individual IgE-mediated allergic disease symptoms Table 2 Longitudinal analysis of allergic disease symptoms with sensitization at 1, 3 and 6 years of age a a b Outcome Year ω-3 LCPUFA Control RR P-value Interaction Adjusted RR Adjusted Interaction n (%) n (%) (95% CI) p-value (95% CI) p-value p-value Any allergic disease 1 15/363 22/330 0.62 0.14 0.51 0.63 0.16 0.49 symptoms with sensitization (4.13%) (6.67%) (0.33, 1.17) (0.33, 1.19) 3 58/313 61/291 0.88 0.45 0.89 0.48 (18.53%) (20.96%) (0.64, 1.22) (0.65, 1.23) 6 76/280 82/263 0.87 0.30 0.92 0.54 (27.14%) (31.18%) (0.67, 1.13) (0.71, 1.19) All years 0.85 0.18 0.88 0.29 (0.66, 1.08) (0.69, 1.12) Rhinitis symptoms 3 25/327 28/301 0.82 0.46 0.90 0.83 0.48 0.87 with sensitization (7.65%) (9.30%) (0.49, 1.38) (0.50, 1.39) 6 55/298 60/276 0.85 0.33 0.87 0.39 (18.46%) (21.74%) (0.61, 1.18) (0.63, 1.20) All years 0.84 0.27 0.86 0.32 (0.62, 1.14) (0.63, 1.16) Rhino-conjunctivitis 3 12/331 20/304 0.55 0.09 0.16 0.55 0.09 0.16 symptoms with sensitization (3.63%) (6.58%) (0.27, 1.11) (0.28, 1.11) 6 34/304 33/281 0.95 0.83 0.96 0.87 (11.18%) (11.74%) (0.61, 1.49) (0.61, 1.51) All years 0.81 0.30 0.81 0.31 (0.54, 1.21) (0.55, 1.21) Wheeze symptoms 1 16/357 29/329 0.51 0.03 0.13 0.52 0.03 0.13 with sensitization (4.48%) (8.81%) (0.28, 0.92) (0.29, 0.94) 3 36/317 35/295 0.96 0.84 0.96 0.87 (11.36%) (11.86%) (0.62, 1.48) (0.63, 1.49) 6 38/290 38/276 0.95 0.82 0.99 0.97 (13.10%) (13.77%) (0.63, 1.45) (0.65, 1.51) All years 0.83 0.26 0.85 0.33 (0.60, 1.15) (0.62, 1.17) Eczema symptoms 1 15/363 22/330 0.62 0.14 0.68 0.63 0.15 0.64 with sensitization (4.13%) (6.67%) (0.33, 1.17) (0.34, 1.18) 3 34/324 41/301 0.77 0.23 0.78 0.25 (10.49%) (13.62%) (0.50, 1.18) (0.51, 1.19) 6 24/303 26/277 0.84 0.53 0.88 0.65 (7.92%) (9.39%) (0.50, 1.43) (0.52, 1.50) All years 0.76 0.15 0.77 0.19 (0.52, 1.11) (0.53, 1.13) For ω-3 LCPUFA and control groups, data are number of subjects (percentage) Rhinitis & Rhino-conjunctivitis symptoms not assessed at 1 year Abbreviations: CI confidence interval, ω-3 LCPUFA long chain polyunsaturated fatty acid, RR relative risk ab Adjusted for enrolling centre, parity, child sex and maternal history of allergic disease Best et al. World Allergy Organization Journal (2018) 11:10 Page 6 of 11 (eczema, rhinitis, rhino-conjunctivitis, and wheeze) with exploratory analyses we investigated the relationship be- sensitization across all years (group p-values > 0.05), tween these two sensitization measures. Overall, the risk of Table 2. Although a difference between groups was HDM sensitization at 6 years of age was 40.3% in children observed at 1 year of age (aRR 0.51, 95% CI 0.28 to 0.92, with egg sensitization at 1 year of age compared to 13.2% in P = 0.03), the effect did not persist at 3 and 6 years, such children without egg sensitization (P < 0.0001), with the as- that overall the longitudinal analysis did not provide any sociation more pronounced in the ω-3 LCPUFA group (in- evidence of an effect of ω-3 LCPUFA supplementation. crease from 9.7 to 37.5%) than in the control group (17.3 to 42.1%). Given the strong association between sensitization Analysis of sensitization to individual allergen extracts outcomes, a mediation analysis was undertaken to test The prevalence of ‘any sensitization’ (≥1 positive SPT re- whether the effect of treatment on HDM sensitization at action to any allergen extract) increased with the age of 6 years of age was mediated through earlier effects on egg the child from 17.0% at 1 year of age to 50.0% at 6 years sensitization. Since adjustment for egg sensitization at 1 year of age. Sensitization outcomes were included in the lon- had little impact on the estimated effect of treatment on gitudinal analysis if the allergen extract was assessed at HDM sensitization at 6 years (relative risk changing from two or more time-points. Sensitization results for indi- 0.62 without adjustment, to 0.69 with adjustment), it seems vidual allergen extracts at 1, 3 and 6 years are presented that most of the effect of treatment on HDM sensitization in Figs. 2, 3, 4, 5, 6 and 7. Longitudinal analysis found was unrelated to earlier effects on egg sensitization. little evidence that the effect of treatment on ‘any sensitization’ or sensitization to individual allergen ex- Discussion tracts changed over time (group by time interaction This longitudinal analysis of our nested allergy cohort from P-values > 0.05). After excluding interaction effects, the DOMInO Trial [24] was designed to determine the ef- there were no significant differences between groups in fect of prenatal ω-3 LCPUFA supplementation on parent the risk of ‘any sensitization’ or ‘sensitization to individ- reported allergic disease symptoms and sensitization over ual allergen extracts’ across all years (group p-values > time. Our results show that a maternal dose of 900 mg of 0.05). However, the direction of effect was similar for ω-3 LCPUFA per day during pregnancy had no effect on many of the extracts across all years. The relative risk as- symptoms of allergic disease or sensitization over time. sociated with ω-3 LCPUFA supplementation ranged be- Long-term follow-up of perinatal interventions is critical tween 0.50 and 0.70 for hen’s egg, peanut, cashew and to evaluate effects which may manifest themselves only D. farinae, Table 3. after several years [29]. This is particularly important for prenatal interventions aimed at primary prevention of aller- Hen’s egg and HDM sensitization associations gic disease in which the timing of onset, the nature of clin- Although there was no evidence for a change in risk across ical symptoms and sensitization to specific allergens is all years, ω-3 LCPUFA supplementation was observed to de- known to be heterogeneous [30–33]. Longitudinal analysis crease the risk of hen’s egg sensitization at 1 year and HDM of multiple assessment throughout long-term follow-up is sensitization at 6 years, Table 3. Based on these results, in the optimal method to determine effects over time. To Fig. 2 Sensitization to one or more allergen extracts at 1, 3 and 6 years Best et al. World Allergy Organization Journal (2018) 11:10 Page 7 of 11 Fig. 3 Sensitization to hen’s egg at 1, 3 and 6 years (*denotes p = < 0.05) ensure consistency in outcome reporting we combined pre- analysis did not show any age dependent effects. Our results viously unpublished parent reported symptoms of allergic strongly support known associations between early disease (collected using ISAAC questionnaire) at 1 and sensitization to food protein and later sensitization to 3 years of age with 6-year ISAAC data. aero-allergens [34–36]. Prenatal ω-3 LCPUFA supplementa- Theprogressionintheprevalence of parentreportedal- tion was observed to significantly decrease the risk of hen’s lergic disease symptoms was consistent with the atopic egg sensitization at 1 year of age and HDM sensitization at march and increased from 17.5% at 1 year of age to 49.3% 6 years of age with the association more pronounced in the at 6 years of age. IgE mediated allergic disease symptoms ω-3 LCPUFA group. There is growing evidence that (symptoms and sensitization to ≥1 allergen extract) were re- early-life sensitization to hen’s egg and sensitization to ported less often with 5.3% at 1 year of age increasing to HDM predict asthma and rhino-conjunctivitis in childhood 29.0% at 6 years of age, longitudinal analysis found no sig- [37] adolescence [38]andadulthood[30]. We anticipated nificant differences between the ω-3 LCPUFA and control that the reduction in HDM sensitization would be a groups over time. Our previous work has reported a signifi- cascade effect of the effects of the intervention on cant reduction in sensitization to egg at 1 year of age [17] egg sensitization at 1-year of age, however, mediation and HDM at 6 years of age [18]following maternal ω-3 analysis to investigate sensitization associations, LCPUFA supplementation, however our longitudinal showed that most of the effect of treatment on Fig. 4 Sensitization to peanut 1, 3 and 6 years Best et al. World Allergy Organization Journal (2018) 11:10 Page 8 of 11 Fig. 5 Sensitization to cashew at 3 and 6 years HDM sensitization was unrelated to earlier effects outcomes and methodological issues. In regard to timing of on egg sensitization (relative risk changing from 0.62 supplementation, post-natal supplementation alone (either without adjustment, to 0.69 with adjustment). directly to theinfantor via breastmilk)hasnotproved The majority of RCTs designed to investigate the effect of beneficial in the reduction of allergic disease [13, 39]. Only prenatal ω-3 LCPUFA supplementation on childhood al- one trial has continued prenatal ω-3 LCPUFA supplementa- lergy have been driven by the plausible hypothesis that diets tion throughout the post-natal period [14]. Whilst sample high in ω-3 LCPUFAs may modulate the development of size of this trial was small and offspring follow up was immunoglobulin E (IgE) associated allergic disease [14–18, ceased at 2 years of age, results suggest that continued sup- 23]. Whilst there is a level of consistency with reports of plementation of breastfeeding mothers to compensate for protective effects of ω-3 LCPUFA on some sensitization the natural decline in maternal plasma ω-3 LCPUFAs, may outcomes, a lack of congruence regarding effects on allergic provide additional benefit to the development and matur- disease symptoms persist. Disparity in results between trials ation of the infant immune system. Compared with our may be attributed to several factors including, but not lim- study, other studies have used much higher doses of ω-3 ited to; timing and dose of the intervention, type of inter- LCPUFA that have ranged from 2700 mg/day [14, 19–21] vention (predominantly DHA vs. EPA), inconsistent to 3700 mg/day [16]. With benefit of the increasing evi- outcome reporting, the absence of long term follow-up of dence in this field now available, we recognize that our dose Fig. 6 Sensitization to D. farinae at 3 and 6 years (*denotes p = < 0.05) Best et al. World Allergy Organization Journal (2018) 11:10 Page 9 of 11 Fig. 7 Sensitization to cat at 1, 3 and 6 years Table 3 Longitudinal analysis of sensitization to allergen extracts at 1, 3 and 6 years of age a a b Outcome Year ω-3 LCPUFA Control RR (95% CI) P-value Interaction Adjusted RR Adjusted Interaction n (%) n (%) p-value (95% CI) p-value p-value Any Sensitization 1 50/349 (14.33%) 63/317 (19.87%) 0.72 (0.51, 1.01) 0.06 0.16 0.73 (0.52, 1.02) 0.07 0.10 3 77/303 (25.41%) 74/279 (26.52%) 0.96 (0.73, 1.26) 0.76 0.97 (0.74, 1.27) 0.83 6 124/248 (50.00%) 116/232 (50.00%) 1.00 (0.84, 1.20) > 0.99 1.05 (0.88, 1.25) 0.56 All years 0.94 (0.79, 1.12) 0.47 0.97 (0.82, 1.15) 0.76 Egg sensitization‡ 1 34/349 (9.74%) 51/317 (16.09%) 0.61 (0.40, 0.91) 0.02 0.55 0.62 (0.42, 0.93) 0.02 0.54 3 11/307 (3.58%) 15/280 (5.36%) 0.67 (0.31, 1.43) 0.30 0.68 (0.32, 1.44) 0.31 6 6/248 (2.42%) 5/232 (2.16%) 1.12 (0.35, 3.63) 0.85 1.16 (0.36, 3.73) 0.81 All years 0.65 (0.42, 1.01) 0.05 0.67 (0.43, 1.02) 0.06 Peanut sensitization 1 15/349 (4.30%) 22/317 (6.94%) 0.62 (0.33, 1.17) 0.14 0.98 0.65 (0.34, 1.22) 0.18 0.98 3 12/307 (3.91%) 18/280 (6.43%) 0.61 (0.30, 1.24) 0.17 0.63 (0.31, 1.27) 0.20 6 18/250 (7.20%) 29/232 (12.50%) 0.58 (0.33, 1.01) 0.05 0.61 (0.35, 1.06) 0.08 All years 0.60 (0.37, 0.98) 0.04 0.63 (0.39, 1.02) 0.06 Cat sensitization 1 7/349 (2.01%) 5/317 (1.58%) 1.27 (0.41, 3.97) 0.68 0.11 1.30 (0.42, 4.00) 0.65 0.12 3 24/303 (7.92%) 11/277 (3.97%) 1.99 (1.00, 4.00) 0.05 2.02 (1.02, 4.02) 0.04 6 30/247 (12.15%) 27/231 (11.69%) 1.04 (0.64, 1.69) 0.88 1.07 (0.66, 1.74) 0.79 All years 1.30 (0.80, 2.13) 0.29 1.34 (0.83, 2.18) 0.23 Cashew sensitization 3 5/307 (1.63%) 11/280 (3.93%) 0.41 (0.15, 1.18) 0.10 0.56 0.43 (0.15, 1.20) 0.11 0.50 6 9/249 (3.61%) 16/231 (6.93%) 0.52 (0.24, 1.16) 0.11 0.55 (0.25, 1.25) 0.15 All years 0.48 (0.21, 1.08) 0.08 0.50 (0.22, 1.14) 0.10 D. Farinae sensitization 3 16/303 (5.28%) 15/277 (5.42%) 0.98 (0.49, 1.94) 0.94 0.15 0.98 (0.50, 1.94) 0.96 0.18 6 31/246 (12.60%) 49/231 (21.21%) 0.59 (0.39, 0.90) 0.01 0.62 (0.41, 0.93) 0.02 All years 0.68 (0.46, 1.00) 0.05 0.70 (0.47, 1.03) 0.07 For ω-3 LCPUFA and control groups, data are number of subjects (percentage) Longitudinal analysis not performed for sensitization to ryegrass, olive, D. pteronyssinus and alternaria tenuis due to insufficient cases at 1/3 years Abbreviations: CI confidence interval, ω-3 LCPUFA long chain polyunsaturated fatty acid, RR relative risk ab Adjusted for enrolling centre, parity, child sex and maternal history of allergic disease Best et al. World Allergy Organization Journal (2018) 11:10 Page 10 of 11 of ω-3 LCPUFA may not have been adequate and it may be, whether prenatal ω-3 LCPUFA supplementation may be of that higher doses are needed to see a reduction in clinical benefit as a primary prevention strategy. outcomes of allergic disease. However, we are also cognizant Abbreviations of potential adverse effects of ω-3 LCPUFA supplementa- AA: Arachidonic acid; ACTRN: Australian New Zealand Clinical Trials Registry; tion as seen by the increased rate of obstetric interventions aRR: Adjusted relative risk; CI: Confidence interval; D. in the arm of the DOMInO Trial due to an increase in farinae: Dermatophagoides farinae; D. pteronyssinus: Dermatophagoides pteronyssinus; DHA: Docosahexaenoic acid; DOMInO: DHA to Optimize length of gestation in the intervention group [24]. Mother Infant Outcome; EPA: Eicosapentaenoic acid; HDM: House dust mite; To the best of our knowledge, this is the first longitu- IgE: Immunoglobulin E; ISAAC: International Study of Asthma and Allergies in dinal analysis of sensitization and parent reported allergic Childhood; LCPUFA: Long-chain polyunsaturated fatty acids; omega-3: ω − 3; omega-6: ω − 6; RCT: Randomized controlled trial; SPT: Skin prick test disease symptoms in the offspring following maternal ω-3 LCPUFA supplementation. The major strength of our Acknowledgements work is the use of data from the DOMInO Trial which We thank the children and their families who participated in this was primarily designed to investigate post-natal depres- long-term follow-up study and the research team members who supported the data collection at 1, 3 and 6 years. We also sion in women and neurodevelopment in children [24]. acknowledge the support of the Docosahexaenoic Acid to Optimise Long-term follow up of children from this well conducted Mother Infant Outcome (DOMInO) trial steering committee. RCT with excellent follow up rates and a low risk of bias has enabled a longitudinal analysis of allergic disease out- Funding The DOMInO Trial was supported by a grant from the Australian NHMRC comes that has not been possible in previous trials. Our grant (ID 349301). Treatment and placebo capsules were donated by consistently collected outcome measures have enabled Efamol, England. The combine 1 and 3-year follow-up study and the 6- combination of data from multiple time points into spe- year follow-up study were supported by an Australian NHMRC grant (ID 399389) and (ID 1027710). The funding body and the company donating cific analyses that investigate change over time. the capsules had no role in the study design or conduct; in the data A limitation of this analysis may be the use of the ISAAC collection, management, analysis, or interpretation; or in the preparation, questionnaire for the diagnosis of allergic disease symptoms, review, or approval of the manuscript. The contents of the published material are solely the responsibility of the authors and do not reflect particularly in infancy given that it has only been validated the views of the NHMRC. for 6–7 and 13–14 year old children [40]. There were some discrepancies between overall prevalence of allergic disease Data sharing diagnosis determined by parental reported symptoms from Data sharing requests can be made through the DOMInO Steering committee. Please contact maria.makrides@sahmri.com or karen.best@sahmri.com for ISAAC questionnaires at 1 and 3 years of age and physician further information. assessment. At 1 year of age, eczema with sensitization was reported less often using ISAAC questionnaires compared Authors’ contributions to physician diagnosis (3.5% vs. 9.2%) whilst at 3 years of KPB, MM & TRS conceived and designed the longitudinal analysis with DJP, MG, JM and DK providing substantial contribution to interpretation of the age, wheeze with sensitization was more frequently reported data. KPB, MM and TRS wrote the first draft of the manuscript. All authors by ISAAC questionnaires than physician diagnosed asthma revised the manuscript critically for important intellectual content and final (11.6% vs. 1.6%). This difference in outcome measures high- approval. KPB, MM, and TRS did the statistical analysis. lights the complexity of using wheeze a proxy for asthma Ethics approval and consent to participate diagnosis, particularly in children under pre-school age (< Written informed consent was sought (prior to birth) for the offspring to 6 years) when the many wheezing conditions of childhood take part in an allergy assessment at 1 and 3 years of age. Families of are prevalent. This disparity in outcome measures further children who consented to the 1 and 3 years of age allergy follow up were contacted again when the child turned 5 years and 9 months and highlight the difficulties surrounding consistent methods for consented to the 6-year allergy follow up. Approval for all allergy follow up allergic disease symptom definition and the importance of was granted by the Human Research Ethics Committees of the Women’s standardization of core outcome reporting. and Children’s Hospital and the Southern Adelaide Health Service, Adelaide. Competing interests Conclusion Dr. Best was supported by a MS McLeod Paediatric and Child Health Nursing Although there is some evidence to suggest that maternal PhD scholarship. Dr. Makrides was supported by an Australian NHMRC senior supplementation with 900 mg ω-3 LCPUFA has a protect- research fellowship (ID 1061704). Dr. Makrides has received non-financial support from Clover Corporation and Nestle Nutrition for research outside that ive effect on early symptoms of allergic disease and of the submitted work. Dr. Makrides serves on scientific advisory boards for sensitization, we did not observe any differences in the pro- Nestle, Fonterra, and Nutricia, and associated honoraria are paid to her gression of disease over time in this longitudinal analysis. institution to support conference travel and continuing education for postgraduate students and early career researchers. Dr. Palmer has consulted Further investigation into patterns of sensitization, classifi- for and received payment for lectures from Nestle Nutrition. The other authors have cation of atopy phenotypes and harmonization of clinical indicated they have no financial relationships relevant to this article to disclose. symptom recording are essential to progress this field. Long term follow-up of offspring (in adolescence and adulthood) Publisher’sNote following prenatal interventions are essential to determine Springer Nature remains neutral with regard to jurisdictional claims in true effects on the trajectory of disease and to confirm published maps and institutional affiliations. Best et al. World Allergy Organization Journal (2018) 11:10 Page 11 of 11 Author details 19. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil–derived fatty acids in Healthy Mothers, Babies and Children, South Australian Health and Medical pregnancy and wheeze and asthma in offspring. 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Prenatal omega-3 LCPUFA and symptoms of allergic disease and sensitization throughout early childhood – a longitudinal analysis of long-term follow-up of a randomized controlled trial

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Copyright © 2018 by The Author(s).
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Medicine & Public Health; Allergology; Immunology
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10.1186/s40413-018-0190-7
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Abstract

Background: Randomized controlled trials of prenatal omega (ω-3) long chain polyunsaturated fatty acid (LCPUFA) supplementation are suggestive of some protective effects on allergic sensitization and symptoms of allergic disease in childhood. Due to the nature of the atopic march, investigation of any effects of this prenatal intervention may be most informative when consistently assessed longitudinally during childhood. Methods: Follow-up of children (n = 706) with familial risk of allergy from the Docosahexaenoic Acid to Optimize Mother Infant Outcome (DOMInO) trial. The intervention group received fish oil capsules (900 mg of ω-3 LCPUFA) daily from <21 weeks’ gestation until birth; the control group received vegetable oil capsules without ω-3 LCPUFA. This new longitudinal analysis reports previously unpublished data collected at 1 and 3 years of age. The allergic disease symptom data at 1, 3 and 6 years of age were consistently reported by parents using the "International Study of Asthma and Allergies in Childhood" (ISAAC) questionnaire. Sensitization was determined by skin prick test to age specific, common allergen extracts. Results: Changes over time in symptoms of allergic disease with sensitization (IgE-mediated) and sensitization did not differ between the groups; interaction p =0.49, p = 0.10, respectively. Averaged across the 1, 3 and 6-year assessments, there were no significant effects of prenatal ω-3 LCPUFA supplementation on IgE-mediated allergic disease symptoms (adjusted relative risk 0.88 (95% CI 0.69, 1.12), p = 0.29) or sensitization (adjusted relative risk 0.97 (95% CI 0.82, 1.15), p = 0.76). Sensitization patterns to common allergens were consistent with the atopic march, with egg sensitization at 1 year strongly associated with house dust mite sensitization at 6 years, (p < 0.0001). Discussion: Although there is some evidence to suggest that maternal supplementationwith900mg ω-3 LCPUFA has a protective effect on early symptoms of allergic disease and sensitization in the offspring, we did not observe any differences in the progression of disease over time in this longitudinal analysis. Further investigation into the dose and timing of ω-3 LCPUFA supplementation, including long-term follow up of children using consistent outcome reporting, is essential to determine whether this intervention may be of benefit as a primary prevention strategy for allergic disease. Conclusion: Maternal supplementation with 900 mg of ω-3 LCPUFA did not change the progression of IgE-mediated allergic disease symptoms or sensitization throughout childhood from 1 to 6 years. (Continued on next page) * Correspondence: karen.best@sahmri.com Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia School of Medicine, University of Adelaide, Adelaide, South Australia, Australia Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Best et al. World Allergy Organization Journal (2018) 11:10 Page 2 of 11 (Continued from previous page) Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN); DOMInO trial ACTRN12605000569606,early childhood allergy follow up ACTRN12610000735055 and 6-year allergy follow up ACTRN12615000498594. Keywords: Allergy, Omega-3, Paediatric, Perinatal, Prevention, Pregnancy, Asthma, Allergic disease, Atopy, Background (predominantly as EPA) on cumulative wheeze (independ- The relentless increase in the worldwide prevalence of aller- ent of sensitization) at 3–5 years of age [19]and atopic gic disease has heightened the need for primary prevention asthma at 16 and 24 years of age [20, 21]. [1]. Although the rise is unlikely to be due to a single factor, Longitudinal analyses have long been recognized as an there is consensus that the cause may be due to our chan- important tool for obtaining high quality evidence about the ging lifestyle, including diet and environment. Diet in indus- determinants of development across the lifespan [22]. How- trialized countries has changed dramatically over the last ever, RCT’sof ω-3 LCPUFA supplementation to date, have 50 years, particularly in the balance of fats consumed. Opti- only reported allergic disease outcomes from distinct mal health requires a relative balance of omega-3 (ω-3) and follow-up time points, often with inconsistent outcomes omega-6 (ω-6) fatty acids, however studies report that some which prevent any analysis to investigate change over time. ‘Western’ diets contain an overabundance of ω-6 fats at the Given the progressive and heterogenous nature of allergic expense of ω-3 fats [2]. Theimpactof thischangemay carry disease, we aim to investigate if prenatal ω-3 LCPUFA sup- heightened importance for the prenatal period, when the plementation will modify the course of allergen sensitization developing fetus is reliant solely on the maternal diet. or allergic disease symptoms over time (from 1 to 6 years of There is increasing evidence to support modulation of age). Previously published 1 and 3-year of age allergic dis- fetal immune development following prenatal ω-3 ease outcomes from our RCT were based on physician LCPUFA supplementation [3–5]. Diets high in ω-3 examination and diagnosis of allergic disease, [17, 23] LCPUFA (from fish and fish oils) increase cell membrane whereas the 6-year results were based on parent reported docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapenta- symptoms using the ‘International Study of Asthma and enoic acid (EPA; 20:5 ω-3), competing with the synthesis Allergies in Childhood’ (ISAAC) questionnaire [18]. In this of inflammatory arachidonic acid (AA, 20:4, ω − 6), which new analysis we have combined previously unpublished results in a reduction in prostaglandin E synthesis and in- ISAAC data collected at 1 and 3 years with 6-year data to hibition of cytokine and immunoglobulin E (IgE) produc- permit investigation of the effects of prenatal ω-3 LCPUFA tion associated with allergies [6]. supplementation on the progression of consistently parent Cohort studies have consistently reported that increased reported allergic disease symptoms. ω-3 LCPUFA consumption during pregnancy may reduce the risk of atopic eczema, asthma and sensitization to Methods house dust mite (HDM) [7], although it is difficult to infer Description of participants a causal link from these studies given the potential for re- This study is a longitudinal synthesis of data obtained at sidual confounding from environmental factors. Published the 1, 3 and 6 year follow up assessment of children at reviews assessing the effect of n–3 LCPUFAs in the pri- hereditary risk of allergic disease, born to mothers en- mary prevention of allergic disease have been conducted rolled in the multi-center, double-blind, DOMInO (DHA [7–13]. However, not all are systematic and most pool re- to Optimize Mother Infant Outcome) RCT [24]. The sults from varying supplementation periods including preg- methods of the DOMInO Trial have been published previ- nancy, pregnancy and lactation or the lactation period ously [24]. Briefly, women < 21 weeks’ gestation with a only, thus increasing the variability of results and poten- singleton pregnancy were randomly allocated to either tially diluting any causal effect of the intervention. Evidence treatment or control group through a computer driven from randomized controlled trials (RCTs) of prenatal sup- telephone randomization service stratified by center and plementation with ω-3 LCPUFA report consistent protect- parity (first birth versus subsequent births). Women were ive effects on the risk of IgE mediated eczema [14, 15]and asked to consume capsules containing either fish oil con- sensitization to egg [14–17] at 1 year of age. However, only centrate, providing ~ 800 mg/day DHA and 100 mg/day one of these trials extended follow-up to school age, EPA or control capsules containing a blend of three reporting a reduction in sensitization to HDM only and no non-genetically modified oils (rapeseed, sunflower, and effect on parent reported symptoms of IgE-mediated aller- palm) in equal proportions and designed to match the gic disease at 6 years of age [18]. Two trials from Denmark polyunsaturated, monounsaturated, and saturated fatty that have conducted follow up beyond infancy report a acid profile of the average Australian diet [25](Incromega protective effect of prenatal ω-3 LCPUFA supplementation 500 TG, Croda Chemicals, East Yorkshire, England). The Best et al. World Allergy Organization Journal (2018) 11:10 Page 3 of 11 supplementation period commenced at enrolment of the Women’sand Children’s Hospital and the Southern (< 21 weeks’ gestation) until delivery. All capsules were Adelaide Health Service, Adelaide, and trials were regis- similar in size, shape, and color, and neither the women tered on the Australian New Zealand Clinical Trials Regis- nor research staff were aware of the treatment allocated. try (ACTRN); DOMInO trial ACTRN12605000569606, Women reported their adherence to supplementation at early childhood allergy follow up ACTRN12610000735055 telephone calls at 28 and 36 weeks’ gestation and the con- and 6-year allergy follow up ACTRN12615000498594. centration of individual LCPUFA in plasma phospholipids from cord blood was assessed as an independent bio- Assessment of allergic disease marker of compliance. Pregnant women enrolled in the Early childhood follow-up appointments at 1 and 3 years DOMInO Trial from two South Australian Centers of age consisted of physician assessment of allergic disease (Flinders Medical Center and the Women’sand Children’s and interviewer administered parent reported symptom Hospital) were invited to participate in an early childhood questionnaires using the International study of Asthma allergy follow up if their unborn child had a familial his- and Allergy in Childhood (ISAAC) questionnaire [17, 23]. tory of allergic disease (mother, father, or sibling with a Additional funding was obtained to conduct a 6 year self-reported history of medically diagnosed eczema, follow up which did not include a physician assessment. asthma, or hay fever). Written informed consent was Children attended a clinic appointment and parents were sought (prior to birth) for the offspring to take part in an interviewed using ISAAC questionnaires to determine allergy assessment at 1 and 3 years of age (n = 706). Fam- allergic disease symptoms [18]. Allergic disease outcomes ilies of children who consented to the 1 and 3 years of age included in this longitudinal analysis are based on the par- allergy follow up were contacted again when the child ent reported symptoms ascertained via ISAAC question- turned 5 years and 9 months and invited to take part in naires at 1, 3 and 6 years of age. History of symptoms the 6-year of age follow up (n = 668), Fig. 1. Results of the related to the previous 12-month period and included ec- early childhood allergy follow up involving physician zema and wheeze at 1, 3 and 6 years, and rhinitis and examination to determine allergic disease outcomes at 1 rhino-conjunctivitis at 3 and 6 years. Eczema was defined and 3 years of age, and a subsequent school age follow up as the history of an itchy rash distributed to the facial, flex- study at 6 years of age using ISAAC questionnaire to de- ural or extensor surface of the skin. Wheeze was defined as termine allergic disease symptoms have been previously a history of wheezing or whistling in the chest. Rhinitis was published [17, 18, 23]. Approval for all allergy follow up defined as a history of sneezing or a runny or blocked nose was granted by the Human Research Ethics Committees when there have not been symptoms to suggest an upper Fig. 1 Flow of participants consented to the nested allergy follow-up of the DOMInO trial Best et al. World Allergy Organization Journal (2018) 11:10 Page 4 of 11 respiratory tract infection. Rhino-conjunctivitis was defined independence working correlation matrix was used in as a history of sneezing or a runny or blocked nose accom- each of these models to adjust for the dependence within panied by itchy-watery eyes when there have not been participants due to repeated measurements over time. In symptoms to suggest an upper respiratory tract infection the models the effects of treatment group, time (categor- [26]. All ISAAC questionnaires were administered consist- ical) and the interaction between treatment group and ently at each time point in accordance with guidelines de- time were assessed. Adjustment was also made for the tailed in the ISAAC user manual [27]. stratification variables parity (first birth vs. subsequent birth) and center, as well as the prognostic variables gen- Assessment of sensitization der and maternal history of allergic disease. Where the Sensitization was assessed at 1, 3 and 6 years by skin prick interaction term between group and time was not statisti- test (SPT) to common, age specific allergens. One of five ex- cally significant, a second model excluding the interaction perienced research nurses who were blinded to treatment term was fitted to estimate the effect of treatment over all group allocation and specifically trained in pediatric skin time points. The effect of treatment, whether at an indi- prick testing performed the SPTs. SPT’s were performed in vidual time point or across all time points, was described a standardized manner and nurses underwent quality assur- using relative risks and 95% confidence intervals. All ana- ance reviews every 6 months with one of the investigators. lyses were performed using SAS version 9.3 (SAS Institute Sensitization was defined as a positive reaction to at least Inc., Cary, NC, USA). one of the allergen extracts assessed. As per the Australasian Society of Clinical Immunology and Allergy (ASCIA) man- Results ual, a test was considered positive if the mean of the hori- Sample and participant flow zontal and perpendicular weal diameters was ≥3mmthan Enrolment to the nested early childhood allergy follow that of the negative control site at 15 min [28]. Food allergen up began in 2006. A total of 706 offspring were con- extracts were selected according to common foods per age sented between 2006 and 2008 to take part. Of these, group and aero-allergens were selected based on typical en- 666 (94.3%) infants completed allergy symptom ques- vironmental allergens in the geographical area of South tionnaires and skin prick testing at 1 year of age and 638 Australia, see Table 1. Glycerine and histamine (10 mg/mL) (90.3%) at 3 years of age. In 2012, following the exclu- were used as negative and positive controls at each time sion of deaths and withdrawals from the early childhood point. Allergen extracts that were assessed at 2 or more time sample, a total of 668 children remained eligible to par- points were included in the longitudinal analysis. ticipate in the 6-year allergy follow up. Six-year assess- ments were completed in August 2014 with a total 603/ Statistical analysis 668 (90.0%) allergy symptom questionnaires completed Longitudinal outcomes were compared between groups and 485/668 (73.0%) children undergoing SPT to deter- using log binomial generalized estimating equations. An mine sensitization, Fig. 1. Table 1 Allergen extracts assessed by SPT at 1, 3 and 6 years Baseline characteristics and compliance 1 year 3 years 6 years The baseline enrolment characteristics of the women Cow’s milk –– and their offspring who were consented to participate in allergy follow-up have been previously described [17]In Whole hen’s egg Whole hen’s egg Whole hen’s egg brief, mean maternal age at trial entry was 29.6 years Wheat Wheat – (SD 5.7 years) and 13.0% of the participating mothers Tuna Tuna – smoked during pregnancy. All unborn children had at Peanut Peanut Peanut least one first-degree relative with a history of medically – Cashew Cashew diagnosed allergic disease; 70% had a history of maternal – Sesame – allergic disease, 54.0% paternal disease and 29.0% allergic disease in both parents. A total of 39.8% were first born Perennial rye grass Perennial rye grass Perennial rye grass children and 47.7% were males. There were no import- Olive tree pollen Olive tree pollen Olive tree pollen ant differences in baseline characteristics at study enrol- Alternaria tenuis Alternaria tenuis Alternaria tenuis ment between the intervention and control groups. Cat Cat Cat Compliance with the intervention was high, with –– Dog 77.0% of mothers in the ω-3 LCPUFA group and 80.0% D. pteronyssinus D. pteronyssinus D. pteronyssinus of mothers in the control group reporting that they had missed zero to three capsules a week (from a total of 21 – D. farinae D. farinae capsules per week) at 28 weeks’ gestation. DHA concen- Abbreviations: D. pteronyssinus Dermatophagoides pteronyssinus, D. farinae Dermatophagoides farinae tration in the plasma phospholipids of cord blood from Best et al. World Allergy Organization Journal (2018) 11:10 Page 5 of 11 infants in the high-DHA group was greater than control from 5.3% at 1 year of age to 29.0% at 6 years of age. (DHA 3.54 to 13.68% vs control 3.51 to 11.21%; median, Longitudinal analysis found no evidence that the differ- 7.2% vs 6.1% total phospholipid fatty acids, P < 0.001). ence between the ω-3 LCPUFA and control groups in Fewer than 2.0% of mothers in each group chose not to the risk of ‘any’ IgE mediated allergic disease or ‘individ- take any capsules. ual IgE mediated allergic disease symptoms (eczema, rhinitis, rhino-conjunctivitis or wheeze)’ changed over Allergic disease symptoms time (group by time interaction p-values > 0.05). After The prevalence of ‘any’ allergic disease symptoms (irre- excluding the group by time interaction effect from the spective of sensitization) increased from 17.5% at 1 year models, there were no significant differences between of age to 49.3% at 6 years of age. Allergic disease symp- the prenatal ω-3 LCPUFA supplementation and control toms with evidence of sensitization were reported less groups in the risk of ‘any’ IgE-mediated allergic disease often but with a similar increase in prevalence over time or individual IgE-mediated allergic disease symptoms Table 2 Longitudinal analysis of allergic disease symptoms with sensitization at 1, 3 and 6 years of age a a b Outcome Year ω-3 LCPUFA Control RR P-value Interaction Adjusted RR Adjusted Interaction n (%) n (%) (95% CI) p-value (95% CI) p-value p-value Any allergic disease 1 15/363 22/330 0.62 0.14 0.51 0.63 0.16 0.49 symptoms with sensitization (4.13%) (6.67%) (0.33, 1.17) (0.33, 1.19) 3 58/313 61/291 0.88 0.45 0.89 0.48 (18.53%) (20.96%) (0.64, 1.22) (0.65, 1.23) 6 76/280 82/263 0.87 0.30 0.92 0.54 (27.14%) (31.18%) (0.67, 1.13) (0.71, 1.19) All years 0.85 0.18 0.88 0.29 (0.66, 1.08) (0.69, 1.12) Rhinitis symptoms 3 25/327 28/301 0.82 0.46 0.90 0.83 0.48 0.87 with sensitization (7.65%) (9.30%) (0.49, 1.38) (0.50, 1.39) 6 55/298 60/276 0.85 0.33 0.87 0.39 (18.46%) (21.74%) (0.61, 1.18) (0.63, 1.20) All years 0.84 0.27 0.86 0.32 (0.62, 1.14) (0.63, 1.16) Rhino-conjunctivitis 3 12/331 20/304 0.55 0.09 0.16 0.55 0.09 0.16 symptoms with sensitization (3.63%) (6.58%) (0.27, 1.11) (0.28, 1.11) 6 34/304 33/281 0.95 0.83 0.96 0.87 (11.18%) (11.74%) (0.61, 1.49) (0.61, 1.51) All years 0.81 0.30 0.81 0.31 (0.54, 1.21) (0.55, 1.21) Wheeze symptoms 1 16/357 29/329 0.51 0.03 0.13 0.52 0.03 0.13 with sensitization (4.48%) (8.81%) (0.28, 0.92) (0.29, 0.94) 3 36/317 35/295 0.96 0.84 0.96 0.87 (11.36%) (11.86%) (0.62, 1.48) (0.63, 1.49) 6 38/290 38/276 0.95 0.82 0.99 0.97 (13.10%) (13.77%) (0.63, 1.45) (0.65, 1.51) All years 0.83 0.26 0.85 0.33 (0.60, 1.15) (0.62, 1.17) Eczema symptoms 1 15/363 22/330 0.62 0.14 0.68 0.63 0.15 0.64 with sensitization (4.13%) (6.67%) (0.33, 1.17) (0.34, 1.18) 3 34/324 41/301 0.77 0.23 0.78 0.25 (10.49%) (13.62%) (0.50, 1.18) (0.51, 1.19) 6 24/303 26/277 0.84 0.53 0.88 0.65 (7.92%) (9.39%) (0.50, 1.43) (0.52, 1.50) All years 0.76 0.15 0.77 0.19 (0.52, 1.11) (0.53, 1.13) For ω-3 LCPUFA and control groups, data are number of subjects (percentage) Rhinitis & Rhino-conjunctivitis symptoms not assessed at 1 year Abbreviations: CI confidence interval, ω-3 LCPUFA long chain polyunsaturated fatty acid, RR relative risk ab Adjusted for enrolling centre, parity, child sex and maternal history of allergic disease Best et al. World Allergy Organization Journal (2018) 11:10 Page 6 of 11 (eczema, rhinitis, rhino-conjunctivitis, and wheeze) with exploratory analyses we investigated the relationship be- sensitization across all years (group p-values > 0.05), tween these two sensitization measures. Overall, the risk of Table 2. Although a difference between groups was HDM sensitization at 6 years of age was 40.3% in children observed at 1 year of age (aRR 0.51, 95% CI 0.28 to 0.92, with egg sensitization at 1 year of age compared to 13.2% in P = 0.03), the effect did not persist at 3 and 6 years, such children without egg sensitization (P < 0.0001), with the as- that overall the longitudinal analysis did not provide any sociation more pronounced in the ω-3 LCPUFA group (in- evidence of an effect of ω-3 LCPUFA supplementation. crease from 9.7 to 37.5%) than in the control group (17.3 to 42.1%). Given the strong association between sensitization Analysis of sensitization to individual allergen extracts outcomes, a mediation analysis was undertaken to test The prevalence of ‘any sensitization’ (≥1 positive SPT re- whether the effect of treatment on HDM sensitization at action to any allergen extract) increased with the age of 6 years of age was mediated through earlier effects on egg the child from 17.0% at 1 year of age to 50.0% at 6 years sensitization. Since adjustment for egg sensitization at 1 year of age. Sensitization outcomes were included in the lon- had little impact on the estimated effect of treatment on gitudinal analysis if the allergen extract was assessed at HDM sensitization at 6 years (relative risk changing from two or more time-points. Sensitization results for indi- 0.62 without adjustment, to 0.69 with adjustment), it seems vidual allergen extracts at 1, 3 and 6 years are presented that most of the effect of treatment on HDM sensitization in Figs. 2, 3, 4, 5, 6 and 7. Longitudinal analysis found was unrelated to earlier effects on egg sensitization. little evidence that the effect of treatment on ‘any sensitization’ or sensitization to individual allergen ex- Discussion tracts changed over time (group by time interaction This longitudinal analysis of our nested allergy cohort from P-values > 0.05). After excluding interaction effects, the DOMInO Trial [24] was designed to determine the ef- there were no significant differences between groups in fect of prenatal ω-3 LCPUFA supplementation on parent the risk of ‘any sensitization’ or ‘sensitization to individ- reported allergic disease symptoms and sensitization over ual allergen extracts’ across all years (group p-values > time. Our results show that a maternal dose of 900 mg of 0.05). However, the direction of effect was similar for ω-3 LCPUFA per day during pregnancy had no effect on many of the extracts across all years. The relative risk as- symptoms of allergic disease or sensitization over time. sociated with ω-3 LCPUFA supplementation ranged be- Long-term follow-up of perinatal interventions is critical tween 0.50 and 0.70 for hen’s egg, peanut, cashew and to evaluate effects which may manifest themselves only D. farinae, Table 3. after several years [29]. This is particularly important for prenatal interventions aimed at primary prevention of aller- Hen’s egg and HDM sensitization associations gic disease in which the timing of onset, the nature of clin- Although there was no evidence for a change in risk across ical symptoms and sensitization to specific allergens is all years, ω-3 LCPUFA supplementation was observed to de- known to be heterogeneous [30–33]. Longitudinal analysis crease the risk of hen’s egg sensitization at 1 year and HDM of multiple assessment throughout long-term follow-up is sensitization at 6 years, Table 3. Based on these results, in the optimal method to determine effects over time. To Fig. 2 Sensitization to one or more allergen extracts at 1, 3 and 6 years Best et al. World Allergy Organization Journal (2018) 11:10 Page 7 of 11 Fig. 3 Sensitization to hen’s egg at 1, 3 and 6 years (*denotes p = < 0.05) ensure consistency in outcome reporting we combined pre- analysis did not show any age dependent effects. Our results viously unpublished parent reported symptoms of allergic strongly support known associations between early disease (collected using ISAAC questionnaire) at 1 and sensitization to food protein and later sensitization to 3 years of age with 6-year ISAAC data. aero-allergens [34–36]. Prenatal ω-3 LCPUFA supplementa- Theprogressionintheprevalence of parentreportedal- tion was observed to significantly decrease the risk of hen’s lergic disease symptoms was consistent with the atopic egg sensitization at 1 year of age and HDM sensitization at march and increased from 17.5% at 1 year of age to 49.3% 6 years of age with the association more pronounced in the at 6 years of age. IgE mediated allergic disease symptoms ω-3 LCPUFA group. There is growing evidence that (symptoms and sensitization to ≥1 allergen extract) were re- early-life sensitization to hen’s egg and sensitization to ported less often with 5.3% at 1 year of age increasing to HDM predict asthma and rhino-conjunctivitis in childhood 29.0% at 6 years of age, longitudinal analysis found no sig- [37] adolescence [38]andadulthood[30]. We anticipated nificant differences between the ω-3 LCPUFA and control that the reduction in HDM sensitization would be a groups over time. Our previous work has reported a signifi- cascade effect of the effects of the intervention on cant reduction in sensitization to egg at 1 year of age [17] egg sensitization at 1-year of age, however, mediation and HDM at 6 years of age [18]following maternal ω-3 analysis to investigate sensitization associations, LCPUFA supplementation, however our longitudinal showed that most of the effect of treatment on Fig. 4 Sensitization to peanut 1, 3 and 6 years Best et al. World Allergy Organization Journal (2018) 11:10 Page 8 of 11 Fig. 5 Sensitization to cashew at 3 and 6 years HDM sensitization was unrelated to earlier effects outcomes and methodological issues. In regard to timing of on egg sensitization (relative risk changing from 0.62 supplementation, post-natal supplementation alone (either without adjustment, to 0.69 with adjustment). directly to theinfantor via breastmilk)hasnotproved The majority of RCTs designed to investigate the effect of beneficial in the reduction of allergic disease [13, 39]. Only prenatal ω-3 LCPUFA supplementation on childhood al- one trial has continued prenatal ω-3 LCPUFA supplementa- lergy have been driven by the plausible hypothesis that diets tion throughout the post-natal period [14]. Whilst sample high in ω-3 LCPUFAs may modulate the development of size of this trial was small and offspring follow up was immunoglobulin E (IgE) associated allergic disease [14–18, ceased at 2 years of age, results suggest that continued sup- 23]. Whilst there is a level of consistency with reports of plementation of breastfeeding mothers to compensate for protective effects of ω-3 LCPUFA on some sensitization the natural decline in maternal plasma ω-3 LCPUFAs, may outcomes, a lack of congruence regarding effects on allergic provide additional benefit to the development and matur- disease symptoms persist. Disparity in results between trials ation of the infant immune system. Compared with our may be attributed to several factors including, but not lim- study, other studies have used much higher doses of ω-3 ited to; timing and dose of the intervention, type of inter- LCPUFA that have ranged from 2700 mg/day [14, 19–21] vention (predominantly DHA vs. EPA), inconsistent to 3700 mg/day [16]. With benefit of the increasing evi- outcome reporting, the absence of long term follow-up of dence in this field now available, we recognize that our dose Fig. 6 Sensitization to D. farinae at 3 and 6 years (*denotes p = < 0.05) Best et al. World Allergy Organization Journal (2018) 11:10 Page 9 of 11 Fig. 7 Sensitization to cat at 1, 3 and 6 years Table 3 Longitudinal analysis of sensitization to allergen extracts at 1, 3 and 6 years of age a a b Outcome Year ω-3 LCPUFA Control RR (95% CI) P-value Interaction Adjusted RR Adjusted Interaction n (%) n (%) p-value (95% CI) p-value p-value Any Sensitization 1 50/349 (14.33%) 63/317 (19.87%) 0.72 (0.51, 1.01) 0.06 0.16 0.73 (0.52, 1.02) 0.07 0.10 3 77/303 (25.41%) 74/279 (26.52%) 0.96 (0.73, 1.26) 0.76 0.97 (0.74, 1.27) 0.83 6 124/248 (50.00%) 116/232 (50.00%) 1.00 (0.84, 1.20) > 0.99 1.05 (0.88, 1.25) 0.56 All years 0.94 (0.79, 1.12) 0.47 0.97 (0.82, 1.15) 0.76 Egg sensitization‡ 1 34/349 (9.74%) 51/317 (16.09%) 0.61 (0.40, 0.91) 0.02 0.55 0.62 (0.42, 0.93) 0.02 0.54 3 11/307 (3.58%) 15/280 (5.36%) 0.67 (0.31, 1.43) 0.30 0.68 (0.32, 1.44) 0.31 6 6/248 (2.42%) 5/232 (2.16%) 1.12 (0.35, 3.63) 0.85 1.16 (0.36, 3.73) 0.81 All years 0.65 (0.42, 1.01) 0.05 0.67 (0.43, 1.02) 0.06 Peanut sensitization 1 15/349 (4.30%) 22/317 (6.94%) 0.62 (0.33, 1.17) 0.14 0.98 0.65 (0.34, 1.22) 0.18 0.98 3 12/307 (3.91%) 18/280 (6.43%) 0.61 (0.30, 1.24) 0.17 0.63 (0.31, 1.27) 0.20 6 18/250 (7.20%) 29/232 (12.50%) 0.58 (0.33, 1.01) 0.05 0.61 (0.35, 1.06) 0.08 All years 0.60 (0.37, 0.98) 0.04 0.63 (0.39, 1.02) 0.06 Cat sensitization 1 7/349 (2.01%) 5/317 (1.58%) 1.27 (0.41, 3.97) 0.68 0.11 1.30 (0.42, 4.00) 0.65 0.12 3 24/303 (7.92%) 11/277 (3.97%) 1.99 (1.00, 4.00) 0.05 2.02 (1.02, 4.02) 0.04 6 30/247 (12.15%) 27/231 (11.69%) 1.04 (0.64, 1.69) 0.88 1.07 (0.66, 1.74) 0.79 All years 1.30 (0.80, 2.13) 0.29 1.34 (0.83, 2.18) 0.23 Cashew sensitization 3 5/307 (1.63%) 11/280 (3.93%) 0.41 (0.15, 1.18) 0.10 0.56 0.43 (0.15, 1.20) 0.11 0.50 6 9/249 (3.61%) 16/231 (6.93%) 0.52 (0.24, 1.16) 0.11 0.55 (0.25, 1.25) 0.15 All years 0.48 (0.21, 1.08) 0.08 0.50 (0.22, 1.14) 0.10 D. Farinae sensitization 3 16/303 (5.28%) 15/277 (5.42%) 0.98 (0.49, 1.94) 0.94 0.15 0.98 (0.50, 1.94) 0.96 0.18 6 31/246 (12.60%) 49/231 (21.21%) 0.59 (0.39, 0.90) 0.01 0.62 (0.41, 0.93) 0.02 All years 0.68 (0.46, 1.00) 0.05 0.70 (0.47, 1.03) 0.07 For ω-3 LCPUFA and control groups, data are number of subjects (percentage) Longitudinal analysis not performed for sensitization to ryegrass, olive, D. pteronyssinus and alternaria tenuis due to insufficient cases at 1/3 years Abbreviations: CI confidence interval, ω-3 LCPUFA long chain polyunsaturated fatty acid, RR relative risk ab Adjusted for enrolling centre, parity, child sex and maternal history of allergic disease Best et al. World Allergy Organization Journal (2018) 11:10 Page 10 of 11 of ω-3 LCPUFA may not have been adequate and it may be, whether prenatal ω-3 LCPUFA supplementation may be of that higher doses are needed to see a reduction in clinical benefit as a primary prevention strategy. outcomes of allergic disease. However, we are also cognizant Abbreviations of potential adverse effects of ω-3 LCPUFA supplementa- AA: Arachidonic acid; ACTRN: Australian New Zealand Clinical Trials Registry; tion as seen by the increased rate of obstetric interventions aRR: Adjusted relative risk; CI: Confidence interval; D. in the arm of the DOMInO Trial due to an increase in farinae: Dermatophagoides farinae; D. pteronyssinus: Dermatophagoides pteronyssinus; DHA: Docosahexaenoic acid; DOMInO: DHA to Optimize length of gestation in the intervention group [24]. Mother Infant Outcome; EPA: Eicosapentaenoic acid; HDM: House dust mite; To the best of our knowledge, this is the first longitu- IgE: Immunoglobulin E; ISAAC: International Study of Asthma and Allergies in dinal analysis of sensitization and parent reported allergic Childhood; LCPUFA: Long-chain polyunsaturated fatty acids; omega-3: ω − 3; omega-6: ω − 6; RCT: Randomized controlled trial; SPT: Skin prick test disease symptoms in the offspring following maternal ω-3 LCPUFA supplementation. The major strength of our Acknowledgements work is the use of data from the DOMInO Trial which We thank the children and their families who participated in this was primarily designed to investigate post-natal depres- long-term follow-up study and the research team members who supported the data collection at 1, 3 and 6 years. We also sion in women and neurodevelopment in children [24]. acknowledge the support of the Docosahexaenoic Acid to Optimise Long-term follow up of children from this well conducted Mother Infant Outcome (DOMInO) trial steering committee. RCT with excellent follow up rates and a low risk of bias has enabled a longitudinal analysis of allergic disease out- Funding The DOMInO Trial was supported by a grant from the Australian NHMRC comes that has not been possible in previous trials. Our grant (ID 349301). Treatment and placebo capsules were donated by consistently collected outcome measures have enabled Efamol, England. The combine 1 and 3-year follow-up study and the 6- combination of data from multiple time points into spe- year follow-up study were supported by an Australian NHMRC grant (ID 399389) and (ID 1027710). The funding body and the company donating cific analyses that investigate change over time. the capsules had no role in the study design or conduct; in the data A limitation of this analysis may be the use of the ISAAC collection, management, analysis, or interpretation; or in the preparation, questionnaire for the diagnosis of allergic disease symptoms, review, or approval of the manuscript. The contents of the published material are solely the responsibility of the authors and do not reflect particularly in infancy given that it has only been validated the views of the NHMRC. for 6–7 and 13–14 year old children [40]. There were some discrepancies between overall prevalence of allergic disease Data sharing diagnosis determined by parental reported symptoms from Data sharing requests can be made through the DOMInO Steering committee. Please contact maria.makrides@sahmri.com or karen.best@sahmri.com for ISAAC questionnaires at 1 and 3 years of age and physician further information. assessment. At 1 year of age, eczema with sensitization was reported less often using ISAAC questionnaires compared Authors’ contributions to physician diagnosis (3.5% vs. 9.2%) whilst at 3 years of KPB, MM & TRS conceived and designed the longitudinal analysis with DJP, MG, JM and DK providing substantial contribution to interpretation of the age, wheeze with sensitization was more frequently reported data. KPB, MM and TRS wrote the first draft of the manuscript. All authors by ISAAC questionnaires than physician diagnosed asthma revised the manuscript critically for important intellectual content and final (11.6% vs. 1.6%). This difference in outcome measures high- approval. KPB, MM, and TRS did the statistical analysis. lights the complexity of using wheeze a proxy for asthma Ethics approval and consent to participate diagnosis, particularly in children under pre-school age (< Written informed consent was sought (prior to birth) for the offspring to 6 years) when the many wheezing conditions of childhood take part in an allergy assessment at 1 and 3 years of age. Families of are prevalent. This disparity in outcome measures further children who consented to the 1 and 3 years of age allergy follow up were contacted again when the child turned 5 years and 9 months and highlight the difficulties surrounding consistent methods for consented to the 6-year allergy follow up. Approval for all allergy follow up allergic disease symptom definition and the importance of was granted by the Human Research Ethics Committees of the Women’s standardization of core outcome reporting. and Children’s Hospital and the Southern Adelaide Health Service, Adelaide. Competing interests Conclusion Dr. Best was supported by a MS McLeod Paediatric and Child Health Nursing Although there is some evidence to suggest that maternal PhD scholarship. Dr. Makrides was supported by an Australian NHMRC senior supplementation with 900 mg ω-3 LCPUFA has a protect- research fellowship (ID 1061704). Dr. Makrides has received non-financial support from Clover Corporation and Nestle Nutrition for research outside that ive effect on early symptoms of allergic disease and of the submitted work. Dr. Makrides serves on scientific advisory boards for sensitization, we did not observe any differences in the pro- Nestle, Fonterra, and Nutricia, and associated honoraria are paid to her gression of disease over time in this longitudinal analysis. institution to support conference travel and continuing education for postgraduate students and early career researchers. Dr. Palmer has consulted Further investigation into patterns of sensitization, classifi- for and received payment for lectures from Nestle Nutrition. The other authors have cation of atopy phenotypes and harmonization of clinical indicated they have no financial relationships relevant to this article to disclose. symptom recording are essential to progress this field. Long term follow-up of offspring (in adolescence and adulthood) Publisher’sNote following prenatal interventions are essential to determine Springer Nature remains neutral with regard to jurisdictional claims in true effects on the trajectory of disease and to confirm published maps and institutional affiliations. Best et al. World Allergy Organization Journal (2018) 11:10 Page 11 of 11 Author details 19. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil–derived fatty acids in Healthy Mothers, Babies and Children, South Australian Health and Medical pregnancy and wheeze and asthma in offspring. 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World Allergy Organization JournalSpringer Journals

Published: Jun 15, 2018

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