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Maternal characteristics influence response to DHA during pregnancy
Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
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Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
Maternal characteristics influence response to DHA during pregnancy J.F. Gould a,b, A.J. Anderson a,b, L.N. Yelland a,b,c, R.A. Gibson b,d, M. Makrides a,b,e,n a
Women's and Children's Health Research Institute, 72 King William Road, North Adelaide, Australia South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia School of Public Health, University of Adelaide, Adelaide, Australia d FOODplus Research Centre, School of Agriculture, Food & Wine, University of Adelaide, Waite Campus, Adelaide, Australia e Discipline of Paediatrics, University of Adelaide, Adelaide, Australia b c
art ic l e i nf o
a b s t r a c t
Article history: Received 6 October 2015 Received in revised form 15 March 2016 Accepted 15 March 2016
We explored the degree to which maternal and offspring outcomes resulting from consuming prenatal docosahexaenoic acid (DHA, 800 mg/day) in a clinical trial were influenced by maternal characteristics. Among non-smokers, women who received DHA had heavier babies (adjusted mean difference (MD) ¼ 99 g 95% CI 45–153, po 0.01; interaction p¼0.01) and fewer low birth weight babies than control women (adjusted relative risk ¼ 0.43 95% CI 0.25–0.74, po 0.01; interaction p¼ 0.01). From women who had not completed further education, children in the DHA group had higher cognitive scores at 18 months compared with control children (adjusted MD ¼3.15 95% CI 0.93–5.37, p ¼0.01; interaction po 0.01). Conversely, the children of women who completed further education in the DHA group had lower language scores than control children (adjusted MD 2.82 95% CI 4.90 to 0.73, p ¼0.01; interaction p¼ 0.04). Our results support the notion that responsiveness to prenatal DHA may depend on the characteristics of specific population subgroups. & 2016 Elsevier Ltd. All rights reserved.
Keywords: DHA Omega-3 fatty acids Pregnancy Supplementation
1. Introduction The omega-3 long chain polyunsaturated fatty acid docosahexaenoic acid (DHA) has many postulated roles during pregnancy including extending the gestational period, increasing birth weight, enhancing child neurodevelopment and reducing the risk of child allergic disease early in postnatal life [1]. However, the extent of benefit for prenatal DHA supplementation for general populations has been difficult to elucidate. This may be partly explained by the fact that many trials were specifically designed to address the effect of DHA on a single outcome. For example, almost all of the trials that focussed on allergy outcomes only included women carrying fetus’ at high risk of allergies, while other trials that addressed the effect of prenatal DHA on developmental outcomes excluded preterm births, making generalizations across outcomes difficult. The largest randomized controlled trial (RCT) to date of maternal DHA supplementation in pregnancy (n ¼ 2399), the DHA to Optimize Maternal Infant Outcome (DOMInO) trial is relatively unique because it had broad inclusion criteria and assessed a range of birth and longer-term outcomes [2]. DHA supplementation did n Correspondence to: Women's and Children's Health Research Institute, Level 7, Clarence Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. E-mail address: [email protected] (M. Makrides).
http://dx.doi.org/10.1016/j.plefa.2016.03.011 0952-3278/& 2016 Elsevier Ltd. All rights reserved.
not affect the risk of development of postpartum depression at six weeks and six months after birth or have an effect on child cognitive development at 18 months or 4 years of age [2,3]. However, DHA supplementation in this RCT reduced the incidence of early preterm birth, increased the incidence of post-term inductions or post-term pre-labour caesarean sections, increased the mean birth weight by 68 g, and reduced the risk of atopic eczema at one but not three years of age [2,4,5]. Although broad inclusion criteria improve the generalizability of trial results, heterogeneity of the sample may mask the benefits of the intervention in certain subgroups. For example, socioeconomic disadvantage and smoking are known factors associated with increased risk of adverse birth outcomes in the general population [6,7]. DHA supplementation may improve outcomes for these women, whilst women who are socially advantaged may not benefit as much from supplementation. Thus, the overall effect of a DHA intervention may depend on the relative proportions of heterogeneous subgroups recruited in a given trial. Understanding if subgroups respond differently to DHA will allow tailoring interventions to women who will benefit the most, however consideration of this is largely absent in the context of RCT's [8] of prenatal DHA supplementation. Here we present our secondary analyses of our DOMInO trial [2] to investigate whether maternal smoking and social disadvantage affect the response to DHA supplementation on a range of outcomes.
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2. Patients and methods 2.1. Participants and study design The DOMInO trial, previously published in detail, was a multicentre RCT in which n ¼2399 women less than 21 weeks’ gestation were randomly assigned to receive three capsules of either DHArich fish oil (providing 800 mg DHA/day, treatment, Incromega 500 TG, Croda Chemicals, UK) or vegetable oil (placebo) per day from study entry until delivery [2]. Women were excluded if they were already taking a supplement containing DHA, their fetus had a known major abnormality, they had a bleeding disorder in which fish oil was contraindicated, were taking anticoagulant therapy, had a documented history of drug or alcohol abuse, were participating in another fatty acid trial, were unable to give written informed consent or if English was not the main language spoken at home. Written informed consent was obtained from all participants and all procedures were conducted in accordance with the approval of the relevant Human Research Ethics Committees at each site involved in the trial. Women were assigned to the treatment or control group through a computer driven telephone randomization service according to an independently generated randomization schedule, with balanced variable-sized blocks. Stratification was by center and parity (first birth vs. subsequent birth). Compliance with the intervention was assessed through participant interview at 28 weeks gestation, return of unused capsules after birth and cord blood plasma phospholipid DHA concentrations [2]. All study personnel were blinded to treatment group allocation for the duration of the trial and follow-up assessments. Women were blinded until the 18-month child development follow-up was complete. After this time, women could request their group allocation; however the majority of families (92%) remained blinded throughout the follow-up studies that have been conducted to 7 years of age. 2.2. Definition of subgroup populations The data used to define subgroups were collected at enrolment, along with age, parity, previous history of depression, and family history of allergic disease. 2.2.1. Smoking Mothers were defined as smokers if they smoked at trial entry (mid pregnancy) or in the 2–3 months leading up to pregnancy, and non-smokers otherwise. 2.2.2. Educational achievement The level of maternal educational achieved was used as a proxy measure of the mother's relative SES [9]. Maternal completion of further education was defined as completion of a degree, diploma, certificate or trade. Women that had started further education but not finished, were categorized as having not completed that aspect of their education. 2.3. Outcome assessments 2.3.1. Maternal and infant pregnancy outcomes Information was collected from medical records and included: gestational age at birth, birth weight, birth length, and birth head circumference. Gestational age at birth was used to define early preterm birth (o34 weeks' gestation), preterm birth (o37 weeks' gestation) and post-term birth (440 weeks' gestation) requiring obstetric intervention (induction or pre-labour caesarean due to associations with
increased perinatal mortality and morbidity in both infants and mothers). Low birth weight was defined as o2500 g and high birth weight 44000 g. Small for gestational age (SGA) was defined as below the 10th percentile for weight and large for gestational age (LGA) was defined as above the 90th percentile for weight for the corresponding gestational age and sex [10]. 2.3.2. Maternal postpartum depression Postpartum depression (PPD) was assessed using the Edinburgh Postnatal Depression Scale (EPDS) questionnaire in English at six weeks and six months post-partum [11]. The EPDS has been shown to have both high sensitivity (68–95%) and high specificity (78–96%) against a clinical psychiatric diagnosis of depression [11– 13]. A score of 12 or more on the EPDS is widely used to indicate a probable depressive disorder [14,15]. For the purpose of statistical analyses, EPDS scores r12 were classified as “no depression” and EPDS scores 412 were classified as “depression”. 2.3.3. Child neurodevelopment outcomes Psychologists assessed neurodevelopment outcomes in 96 preterm infants and 630 randomly selected term infants from two centres in Adelaide [16]. Neurodevelopment was assessed at 18 months of age (corrected for premature birth) with the Bayley Scales of Infant and Toddler Development, Third Edition (BayleyIII) Cognitive and Language subscales [16]. The Bayley-III is the international test of choice in assessing developmental functioning in young children. Child development was assessed again in the same group of randomly selected term and preterm children at four years of age (corrected for premature birth), using the Differential Ability Scales, Second Edition (DAS II) [17]. The DAS II evaluates conceptual and reasoning abilities and equates to a standard Development Quotient (DQ) score of general cognitive functioning ability. Both the DAS II and the Bayley-III provide standardized scores with a mean of 100 and SD of 15, where a score 41 SD below the mean indicates impaired performance. 2.3.4. Child allergic disease Pregnant women from the Adelaide centres were included in the allergy follow-up if the unborn baby had a mother, father or sibling with a history of any medically diagnosed allergic disease (asthma, allergic rhinitis, eczema) [4,5]. There were n¼ 706 families who consented to appointments at one and three years of age with nurses and medical staff who assessed child allergy with skin prick testing and allergy symptoms. Allergic sensitization was defined as a positive skin prick test to at least one of the food allergens or aeroallergens tested. Glycerine and histamine (10 mg/mL) were used as negative and positive controls, respectively. Diagnosis of immunoglobulin E (IgE) associated allergic disease was made by one of six specifically trained medical practitioners following standardized history, clinical examination and skin prick testing of the child, as described previously [4,5]. IgE eczema was defined as sensitization, and the presence on medical review of eczema [4,5]. IgE food allergy was defined as a history of immediate skin rash with or without respiratory symptoms and/or gastrointestinal symptoms and/or cardiovascular symptoms following ingestion of a food, and a positive skin prick test to the implicated food [4,5]. 2.4. Statistical methods Analyses were performed on the available data with participants included in the treatment group assigned at randomization. Interaction tests were conducted to assess whether the response to DHA supplementation varied according to smoking/education status and subgroup analyses were performed to estimate the
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effect of DHA supplementation by smoking/education status. The results of the subgroup analyses should be interpreted with caution where the interaction test is not statistically significant. Continuous outcomes were analysed using linear regression models with treatment effects expressed as mean differences (MD) and interactions were assessed on the additive scale. Binary outcomes were analysed using log binomial regression models with treatment effects expressed as RR and interactions were assessed on the multiplicative scale. Additional analyses were performed using an identity binomial model to investigate interactions on the additive scale. For outcomes measured at multiple time points, analyses were performed at each time point separately and on a combined outcome of any occurrence across all time points. Regression models included treatment group, smoking/education status and their interaction, with or without adjustment for the stratification variables (centre and parity). All analyses were performed using SAS v9.3 (Cary, NC, USA) and no adjustment was made for multiple comparisons.
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fewer children with a Bayley-III cognitive composite score more than 1 SD below the mean (adjusted RR ¼0.23 95% CI 0.10–0.53, po 0.01) compared with non-smoking controls. DHA treatment could prevent one low birth weight baby by supplementing 33 non-smoking women (95% CI 20–88, po 0.01). In contrast, women who were classified as smokers at baseline did not appear to respond to DHA supplementation, although the infants of smokers were smaller on average than the infants of non-smokers. These conclusions were unaltered based on interaction tests on the additive scale (data not shown). Consistent with these findings, there was some evidence to suggest that DHA supplementation in non-smoking women resulted in lower risk of early preterm birth, and higher risk of postterm birth, high birth weight and LGA, compared with controls. However, these subgroup findings should be interpreted with caution, as there was no evidence to suggest that the effect of DHA depended on smoking status for these outcomes. 3.2. Maternal education
3. Results Participant flow is presented in Fig. 1. Participants’ characteristics at baseline were well balanced between treatment groups within the overall sample and in the allergy and neurodevelopment follow-up subgroups (Table 1). Women were compliant with the intervention, with 36% of women reporting not missing any capsules, 35% reporting missing r3 out of 21 capsules per week, and less than 2% reporting not taking any capsules. Follow-up was greater than 90% for each outcome. 3.1. Maternal smoking Maternal smoking appeared to modify the effect of DHA intervention on birth weight (p ¼0.01), low birth weight (p ¼0.01) and Bayley-III cognitive composite score more than 1 SD below the mean (p ¼0.02) (Table 2). Among women who were classified as non-smokers at study entry, the DHA group had heavier babies (adjusted MD¼99 g 95% CI 45–153, po 0.01), fewer low birth weight babies (adjusted RR ¼0.43 95% CI 0.25–0.74, po 0.01) and
The effect of the DHA intervention was significantly modified by maternal further education for Bayley-III cognitive composite score (po0.01), Bayley-III language composite score (p¼0.04), and DAS II score (p¼ 0.02) (Table 3). DHA treatment resulted in higher BayleyIII cognitive composite scores at 18 months (adjusted MD¼ 3.15 95% CI 0.93–5.37, p¼0.01) in children from women who had not completed further education, while no such effect was present among women who had completed further education. Language composite scores at 18 months were lower in the DHA group among women who had completed further education (adjusted MD 2.82 95% CI 4.90 to 0.73, p¼ 0.01) but did not appear to be influenced by the intervention among women who had not completed further education. There was some evidence to suggest that the effect of DHA supplementation on DAS II score was positive among women who had not completed further education (adjusted MD 2.43 95% CI 0.50 to 5.37, p¼0.10) and negative among women who had (adjusted MD 1.76 95% CI 3.72 to 0.20, p¼0.08). There were some additional outcomes where the effect of DHA appeared to relate to maternal education subgroups. In particular, DHA supplementation reduced the risk of early preterm birth,
Fig. 1. Flow Diagram of mother-child pairs through the DOMInO trial and follow-ups. 1 DHA to Optimize Mother Infant Outcomes. Birth Outcomes: early preterm birth ( o 34 weeks'), preterm birth ( o 37 weeks'), post term birth ( 440 weeks') and intervention, birth weight, low birth weight ( o 2500 g), high birth weight ( 44000 g), small for gestational age, large for gestational age, Depression: the Edinburgh Postnatal Depression Scale at 6 weeks and 6 months post-partum. 18 month neurodevelopment cohort outcomes: the Bayley Scales of Infant and Toddler Development, Third Edition Cognitive Score and Language Score. 4 year neurodevelopment cohort outcome: the Differential Ability Scales developmental quotient. Allergy cohort outcomes at 1 year: IgE allergic disease, sensitization, eczema. Allergy cohort outcomes at 3 years: IgE allergic disease, sensitization, eczema.
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Table 1 Participant characteristics at baseline.a,b
Characteristics
All Participants n¼ 2399
Neurodevelopment Subgroup n¼726
Allergy Subgroup n¼ 706
DHAc n¼1197
Control n¼ 1202
DHA n¼351
DHA n¼ 368
Control n¼ 338
838 (70.0) 358 (29.9)
792 (65.9) 407 (33.9)
254 (72.4) 97 (27.6)
269 (73.1) 99 (26.9)
232 (68.6) 106 (31.4)
816 380 28.9 605 471 298
824 375 28.9 591 474 287
230 121 29.0 176 155 89
255 113 29.6 169 150 110
241 97 29.5 168 131 85
Control n¼ 375
Maternal smoking Non-smoker Smoker Maternal further education Completed Not completed Maternal age (years) mean (SD) Infant male sex Maternal parity of 0 Previous history of depression
(68.2) (31.7) (5.7) (50.5) (39.3) (24.9)
(68.6) (31.2) (5.6) (49.2) (39.4) (23.9)
(65.5) (34.5) (5.7) (50.1) (44.2) (25.4)
241 (64.3) 133 (35.5) 254 121 28.5 189 166 96
(67.7) (32.3) (6.0) (50.4) (44.3) (25.6)
(69.3) (30.7) (5.7) (45.9) (40.8) (29.9)
(71.3) (28.7) (5.6) (49.7) (38.8) (25.1)
a
Values are n(%) unless otherwise stated. Data are missing for n ¼1 DHA group participant and n ¼3 control group participants for all characteristics except infant sex (n ¼11 DHA group participants and n ¼18 control group participants). c DHA¼ docosahexaenoic acid. b
sensitization at 1 year, and having a Bayley-III cognitive composite score more than 1 SD below the mean, and increased the mean birth weight in the subgroup of women who did not complete further education. The DHA intervention also increased the risk of high infant birth weight and having a DAS II score more than 1 SD below the mean, among women who completed further education. While these subgroup findings are generally consistent with the effect of DHA on all participants as previously reported, [3] they should not be taken as evidence that the effect of DHA varies according to maternal education for these outcomes, due to the non-significant interactions.
4. Discussion and conclusions Our study highlights the fact that there are subgroups who respond differently to prenatal DHA supplementation during pregnancy, and this was particularly evident in those women who smoked in the periconceptional period. The fact that these women had a higher risk of poorer outcomes than women who did not smoke is not surprising. However, rather than benefitting from the intervention, the adverse effects of smoking appeared to nullify the benefits of DHA supplementation that were evident among nonsmoking women. In fact, the adverse effect of smoking on the mean birth weight among control group women (decrease of 75 g) was of a similar magnitude to the increase in mean birth weight from DHA supplementation among non-smoking women (increase of 95 g). Interestingly, there were no differential responses in smokers on non-smokers with the duration of gestation. This indicates that the effects noted on infant birth weight are independent of the duration of gestation. However, the effects of DHA supplementation seen among non-smoking women, and their direction, are consistent with the findings of the overall trial [2] and suggest that the inclusion of smokers in the DOMInO trial might have reduced the ability to detect an effect of supplementation. The proportion of women who reported smoking during pregnancy was higher in our sample (32%) than in the general Australian population at the time of recruitment (18%) [18,19]. Smokers have previously been shown to have lower DHA levels when compared with non-smokers, [20] although it is unclear whether this is due to a biological effect of smoking, or lifestyle factors associated with smoking, or both. We recommend that smoking, as a baseline characteristic, should be reported in trials of DHA supplementation, and that future efficacy trials consider stratifying the randomization on smoking status, or considering the outcomes of smokers and non-smokers separately in pre-specified subgroup analyses.
Maternal DHA supplementation had mixed results for developmental outcomes of children depending on maternal education. DHA supplementation appeared to increase the 18 month cognitive scores of children among women who had not completed further education, but unexpectedly may have led to a decrease in the 18 month language scores among children of women who had completed further education. Additionally, child cognitive development at 4 years was higher in the DHA group if women had not completed further education, but lower than controls if they had completed further education. We explored further education rather than secondary education, as completion of further education is optional and involves a qualification and training for a specific vocation whereas partial completion of secondary education is compulsory in Australia. We expected that non-completion of education would serve as a proxy for social disadvantage, and that these women would benefit from supplementation. While education is considered by many to be a good indicator of social disadvantage and health behaviour, our results highlight the complexity of measuring social advantage or disadvantage through a single variable. We had an ideal sample for exploring the interaction of prenatal DHA supplementation with education as the proportion of women who had completed further education was lower in our sample than in the general population (63% vs. 77%, respectively) [21]. The limitations of the results presented here stem from the nature of the analysis in the available sample. Although the largest trial of DHA in pregnancy, we were powered to detect the effect of DHA supplementation in the overall sample, rather than in specific subgroups. Our exploration of the effect of maternal social characteristics on responses to DHA supplementation may be underpowered and was not planned in the design of the trial, limiting our ability to identify subgroups who may benefit most from supplementation. Furthermore, the sample used to explore allergy excluded children who were not defined as having a high genetic risk of, or predisposition to allergy development, meaning that the results may have limited generalizability. Whilst caution is warranted in the interpretation of these results, there are several key advantages of this study. The DOMInO trial a large sample of women with the broadest inclusion criteria among trials investigating DHA supplementation in pregnancy [22]. The dose of DHA administered and the level of compliance with the intervention resulted in an increased cord blood DHA concentration in the treatment group that was adequate to induce a benefit of supplementation [2]. Furthermore, a comprehensive range of outcomes were assessed with gold-standard measures and minimal attrition. All of these advantages mean that the
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Table 2 Effect modification by maternal smoking status for pregnancy outcomes, and child allergy and neurodevelopment outcomes in a randomized controlled trial of docosahexaenoic acid (DHA)-rich tuna oil supplementation in pregnancy. Outcome
Subgroup
DHAa frequency (%)
Placebo frequency (%)
Unadjb RRc (95% Unadj p CI) value
Unadj Int pd value
Adje RR (95% CI)
Early preterm birth ( o 34 wks) Preterm birth ( o 37 wks)
Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker
6/831 (1) 7/353 (2) 40/831 (5) 25/353 (7) 146/831(18) 63/353 (18)
17/775 (2) 9/406 (2) 52/775 (7) 32/406 (8) 103/775 (13) 60/406 (15)
0.33 (0.13, 0.83) 0.89 (0.34, 2.38) 0.72 (0.48, 1.07) 0.90 (0.54, 1.49) 1.32 (1.05, 1.67) 1.21 (0.87, 1.67)
0.02 0.82 0.10 0.68 0.02 0.25
0.15 – 0.49 – 0.66 –
0.33 (0.13, 0.82) 0.90 (0.34, 2.40) 0.72 (0.48, 1.07) 0.90 (0.54, 1.49) 1.31 (1.04, 1.65) 1.23 (0.89, 1.69)
0.02 0.84 0.10 0.68 0.02 0.21
0.14 – 0.49 – 0.76 –
Non-smoker 3536 (538)
3441 (555)
o 0.01
0.01
0.01
3337 (601)
3366 (573)
Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker
19/830 (2) 21/352 (6) 150/830(18) 43/352 (12) 37/830 (4) 35/352 (10) 155/830(19) 46/352 (13) 111/828(13) 63/353 (18) 22/261 (8) 8/96 (8) 36/242 (15) 13/91 (14) 42/269 (16) 16/99 (16) 37/255 (15) 14/94 (15) 57/221 (26) 20/82 (24) 70/269 (26) 26/99 (26) 102 (101, 103)
41/774 (5) 18/405 (4) 103/774 (13) 49/405 (12) 46/773 (6) 35/405 (9) 116/773 (15) 53/405 (13) 125/767 (16) 74/401 (18) 30/224 (13) 11/100 (11) 41/214 (19) 12/91 (13) 52/232 (22) 19/106 (18) 47/220 (21) 16/97 (16) 55/198 (28) 19/81 (23) 77/232 (33) 29/106 (27) 103 (101, 104)
o 0.01 0.35 0.01 0.96 0.18 0.54 0.05 0.99 0.11 0.83 0.08 0.53 0.22 0.83 0.05 0.74 0.05 0.76 0.65 0.89 0.08 0.86 0.73
Smoker
101(99,102)
101 (99, 102)
0.43 (0.25, 0.74) 1.34 (0.73, 2.48) 1.36 (1.08, 1.71) 1.01 (0.69, 1.48) 0.75 (0.49, 1.14) 1.15 (0.74, 1.80) 1.24 (1.00, 1.55) 1.00 (0.69, 1.44) 0.82 (0.65, 1.04) 0.97 (0.71, 1.31) 0.63 (0.37, 1.06) 0.76 (0.32, 1.80) 0.78 (0.52, 1.17) 1.08 (0.52, 2.25) 0.70 (0.48, 1.01) 0.90 (0.49, 1.65) 0.68 (0.46, 1.00) 0.90 (0.47, 1.74) 0.93 (0.68, 1.27) 1.04 (0.60, 1.80) 0.78 (0.60, 1.03) 0.96 (0.61, 1.51) 0.30 ( 2.06, 1.46) 0.14 ( 2.07, 2.34) 0.22 (0.10, 0.52) 0.97 (0.38, 2.48) 0.90 ( 3.03, 1.23) 3.08 ( 5.85, 0.32) 1.02 (0.75, 1.38) 1.02 (0.61, 1.70) 0.08 ( 2.16, 1.99) 1.74 ( 4.33, 0.85) 1.32 (0.89, 1.96) 1.85 (0.94, 3.63)
98.89 (44.65, 153.14) 32.78 ( 111.89, 46.33) 0.43 (0.25, 0.74) 1.34 (0.73, 2.47) 1.37 (1.09, 1.73) 1.00 (0.68, 1.47) 0.74 (0.49, 1.13) 1.17 (0.75, 1.82) 1.26 (1.02, 1.57) 1.00 (0.69, 1.44) 0.83 (0.65, 1.04) 0.96 (0.71, 1.29) 0.63 (0.38, 1.06) 0.75 (0.31, 1.77) 0.78 (0.52, 1.17) 1.08 (0.52, 2.24) 0.70 (0.48, 1.01) 0.90 (0.49, 1.65) 0.68 (0.46, 1.01) 0.89 (0.46, 1.72) 0.93 (0.68, 1.28) 1.05 (0.60, 1.81) 0.78 (0.60, 1.03) 0.96 (0.61, 1.51) 0.30 ( 2.06, 1.46) 0.13 ( 2.08, 2.33) 0.23 (0.10, 0.53) 0.97 (0.39, 2.52) 0.93 ( 3.06, 1.20) 3.15 ( 5.93, 0.38) 1.02 (0.75, 1.38) 1.03 (0.62, 1.72) 0.08 ( 2.16, 2.00) 1.84 ( 4.43, 0.74) 1.32 (0.89, 1.95) 1.89 (0.96, 3.72)
o 0.01
Smoker
95.46 (40.73, 150.20) 28.78 ( 108.60, 51.05)
Post-term birth ( 440 wks) þ intervention Birth weight (g)f
Low birthweight ( o 2500 g) High birthweight ( 44000 g) Small for gestational age Large for gestational age EPDS 412 overallg IgE allergic disease at 1 Yr IgE allergic disease at 3 Yrs IgE allergic disease at 1 or 3 Yrs Sensitisation at 1 Yr Sensitisation at 3 Yrs Sensitisation at 1 or 3 Yrs Cognitive composite scoreh
Cognitive composite score 41 SD below meani Language composite scoreh
Non-smoker 1.7 (0.8, 3.5) Smoker 4.4 (2.3, 8.4) Non-smoker 97 (96, 98)
7.5 (5.2, 10.6) 4.6 (2.3, 8.8) 98 (96, 99)
Smoker
99 (97, 101)
96 (94, 98)
Non-smoker 18.6 (15.0, 22.9) 18.3 (14.8, 22.6) Language composite 14.9 (10.0, 21.7) 14.6 (10.4, 20.1) score41 SD below meani Smoker DAS DQ at 4 Yrsh Non-smoker 100(98,101) 100 (99, 101) Smoker DAS DQ at 4 Yrs4 1 SD below meani
99 (97, 101)
Non-smoker 15.7 (12.1, 20.0) Smoker 12.3 (7.8. 19.0)
101 (99, 102) 11.8 (8.7, 15.9) 6.7 (4.0, 11.0)
0.48
0.90 o 0.01 0.95 0.41
–
0.01 – 0.20 – 0.17 – 0.32 – 0.41 – 0.72 – 0.44 – 0.48 – 0.47 – 0.73 – 0.45 – 0.76 – 0.02 0.22
0.03
–
0.92 0.94 0.94
0.99
0.19
–
0.17 0.08
0.40
0.33
Adj p value Adj Int p value
0.42
o 0.01 0.34 0.01 0.995 0.16 0.49 0.04 0.98 0.11 0.78 0.08 0.51 0.23 0.83 0.06 0.73 0.06 0.73 0.66 0.87 0.08 0.86 0.74 0.91 o 0.01 0.98 0.39
–
0.01 – 0.17 – 0.14 – 0.27 – 0.45 – 0.75 – 0.44 – 0.49 – 0.50 – 0.72 – 0.45 – 0.77 – 0.02 0.21
0.03
–
0.93 0.91 0.94
0.97
0.16
–
0.17 0.07
0.36
0.30
a
DHA ¼docosahexaenoic acid. Unadj ¼unadjusted. c RR ¼Relative Risk (DHA/Control). d Int p¼ Interaction p value. e Adj¼Adjusted (adjustment for stratification variables centre and parity). f Mean (SD) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-Control. g EPDS 412 overall indicates whether EPDS was 412 at 6 weeks and/or 6 months. h Weighted mean (95% CI) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-control. i Weighted percentage (95% CI) instead of frequency (percentage), and group comparison is relative risk (95% CI) for DHA/Control. b
DOMInO trial is the only trial to date to provide an overall picture of the effect of maternal DHA supplementation in pregnancy with results that can be applied to a more generalized population. 4.1. Conclusion The present study provides the first exploration of differential responses to maternal DHA supplementation in pregnancy in the
context of a clinical trial. Our results lend support to the argument that subgroups may vary in their response to DHA intervention, however further RCT's will need to collect characteristics that may identify responders in order to better target interventions with potential therapeutic applications. In the meantime, we recommend that RCT's with comparable DHA dosage and outcome measures pool data to evaluate SES factors in a more diverse sample with greater power to explore the possibility of identifying
10 Table 3 Effect modification by maternal further education for pregnancy outcomes, and child allergy and neurodevelopment outcomes in a randomized controlled trial of docosahexaenoic acid (DHA)-rich tuna oil supplementation in pregnancy. Outcome
Subgroup
DHAa frequency (%)
Placebo frequency (%)
Unadjb RRc (95% CI)
Unadj p value
Unadj Int pd value
Adje RR (95% CI)
Early preterm birth ( o 34 wks)
Completed Not completed Completed Not complete Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed
10/806 (1) 3/378 (1)
15/811 (2) 11/370 (3)
0.67 (0.30, 1.48) 0.27 (0.08, 0.95)
0.32 0.04
0.23 –
0.67 (0.30, 1.48) 0.27 (0.08, 0.95)
0.32 0.04
0.23 –
43/806 (5) 22/378 (6) 133/806 (17) 76/378 (20)
58/811 (7) 26/370 (7) 108/811 (13) 55/370 (15)
0.75 (0.51, 1.09) 0.83 (0.48, 1.43) 1.24 (0.98, 1.57) 1.35 (0.99, 1.86)
0.13 0.50 0.07 0.06
0.76 – 0.66 –
0.75 (0.51, 1.09) 0.83 (0.48, 1.44) 1.24 (0.98, 1.56) 1.35 (0.99, 1.85)
0.13 0.51 0.07 0.06
0.74 – 0.65 –
3486 (567) 3458 (561)
3437 (563) 3367 (559)
48.97 ( 5.92, 103.87) 0.08 90.98 (10.28, 171.68) 0.03
0.40 –
50.46 ( 3.89, 104.81) 89.18 (9.27, 169.08)
0.07 0.03
0.43 –
25/805 (3) 15/377 (4)
36/809 (4) 23/370 (6)
0.70 (0.42, 1.15) 0.64 (0.34, 1.21)
0.16 0.17
0.83 –
0.70 (0.42, 1.15) 0.65 (0.35, 1.23)
0.15 0.18
0.87 –
137/805 (17) 56/377 (15)
109/809 (13) 43/370 (12)
1.26 (1.00, 1.59) 1.28 (0.88, 1.85)
0.05 0.19
0.96 –
1.28 (1.02, 1.61) 1.26 (0.87, 1.82)
0.04 0.22
0.94 –
46/805 (6) 26/377 (7)
51/808 (6) 30/370 (8)
0.91 (0.62, 1.33) 0.85 (0.51, 1.41)
0.61 0.53
0.85 –
0.90 (0.61, 1.33) 0.85 (0.52, 1.41)
0.60 0.54
0.87 –
140/805 (17) 61/377 (16)
122/808 (15) 47/370 (13)
1.15 (0.92, 1.44) 1.27 (0.90, 1.81)
0.21 0.18
0.64 –
1.17 (0.93, 1.45) 1.27 (0.90, 1.81)
0.17 0.17
0.67 –
115/803 (14) 59/378 (16)
141/799 (18) 59/369 (16)
0.81 (0.65, 1.02) 0.98 (0.70, 1.36)
0.07 0.89
0.37 –
0.82 (0.65, 1.02) 0.96 (0.69, 1.34)
0.08 0.82
0.42 –
24/250 (10) 6/107 (6)
31/231 (13) 10/93 (11)
0.72 (0.43, 1.18) 0.52 (0.20, 1.38)
0.19 0.19
0.57 –
0.72 (0.43, 1.18) 0.52 (0.20, 1.37)
0.19 0.18
0.56 –
42/233 (18) 7/100 (7)
40/221 (18) 13/84 (15)
1.00 (0.67, 1.47) 0.45 (0.19, 1.08)
0.98 0.08
0.11 –
1.00 (0.67, 1.47) 0.45 (0.19, 1.09)
0.99 0.08
0.11 –
49/255 (19) 9/113 (8)
55/241 (23) 16/97 (16)
0.84 (0.60, 1.19) 0.48 (0.22, 1.04)
0.33 0.06
0.20 –
0.84 (0.60, 1.19) 0.48 (0.22, 1.04)
0.33 0.06
0.120 –
43/245 (18) 8/104 (8)
46/228 (20) 17/89 (19)
0.87 (0.60, 1.27) 0.40 (0.18, 0.89)
0.47 0.02
0.09 –
0.87 (0.60, 1.26) 0.40 (0.18, 0.89)
0.46 0.02
0.08 –
63/212 (30) 14/91 (15)
55/205 (27) 19/74 (0.26)
1.11 (0.82, 1.50) 0.60 (0.32, 1.11)
0.51 0.11
0.08 –
1.11 (0.82, 1.51) 0.60 (0.33, 1.12)
0.50 0.11
0.08 –
79/255 (31) 17/113 (15)
81/241 (34) 25/97 (26)
0.92 (0.71, 1.19) 0.58 (0.34, 1.01)
0.53 0.06
0.14 –
0.92 (0.71, 1.19) 0.58 (0.34, 1.02)
0.53 0.06
0.14 –
102 (101, 103) 102 (101, 104)
103 (102, 105) 99 (98, 101)
1.51 ( 3.25, 0.23) 3.14 (0.91, 5.37)
0.09 0.01
o 0.01 –
1.52 ( 3.26, 0.22) 3.15 (0.93, 5.37)
0.09 0.01
o0.01 –
2.7 (1.5, 4.7) 1.9 (0.6, 5.3)
4.9 (3.2, 7.7) 9.8 (6.1, 15.3)
0.54 (0.26, 1.11) 0.19 (0.06, 0.60)
0.09 0.01
0.13
0.54 (0.26, 1.12) 0.19 (0.06, 0.60)
Preterm birth ( o 37 wks)
Birth weight (g)f
Low birthweight ( o 2500 g)
High birthweight ( 44000 g)
Small for gestational age
Large for gestational age
EPDS 412 overallg
IgE allergic disease at 1 Yr
IgE allergic disease at 3 Yrs
IgE allergic disease at 1 or 3 Yrs
Sensitisation at 1 Yr
Sensitisation at 3 Yrs
Sensitisation at 1 or 3 Yrs
Cognitive composite score,h
Cognitive composite score 4 1 SD below meani
0.10 o 0.01
0.13
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
Post-term birth ( 440 wks) þ intervention
Adj p value Adj Int p value
0.05 1.93 (1.23, 3.02) 0.96 (0.56, 1.64) 0.05
Conflict of interest
0.01 0.85
RAG and MM receive honoraria (payable to their institutions) for scientific advisory board contributions to Fonterra (RAG, MM), and Nestle Nutrition Institute (MM). All honoraria are used to support conference travel and continuing education for postgraduate students and early career researchers. No other authors have any conflicts of interest to declare.
c
b
DAS DQ at 4Yrs 41 SD below meani
DAS DQ at 4 Yrsi
Language composite score41 SD below meani
a
1.93 (1.23, 3.03) 0.95 (0.55, 1.63) 7.8 (5.4, 11.1) 15.2 (10.3, 21.9) 15.0 (11.4, 19.4) 14.4 (9.7, 20.9)
0.09 0.11 1.72 ( 3.67, 0.24) 2.45 ( 0.53, 5.43) 102 (101, 103) 96 (93, 98) 101 (99, 102) 98 (96, 100)
0.38 0.44 1.16 (0.84, 1.59) 0.84 (0.54, 1.31) 15.6 (12.4, 19.5) 20.1 (14.8, 26.7) 18.1 (14.3, 22.5) 16.9 (12.0, 23.2)
0.50 95 (93, 98) 96 (95, 98)
Not completed Completed Not completed Completed Not completed Completed Not completed
0.01
2.76 ( 4.84, 0.67) 1.00 ( 1.92, 3.91) 99 (98, 101) 97 (95, 98) Completed Language composite scoreh
DHA ¼docosahexaenoic acid. Unadj¼ unadjusted. RR ¼Relative Risk (DHA/Control). d Int p¼ Interaction p value. e Adj ¼Adjusted (adjustment for stratification variables centre and parity). f Mean (SD) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-Control. g EPDS 412 overall indicates whether EPDS was 4 12 at 6 weeks and/or 6 months. h Weighted mean (95% CI) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-control. i Weighted percentage (95% CI) instead of frequency (percentage) and group comparison is relative risk (95% CI) for DHA/Control.
1.76 ( 3.72, 0.20) 2.43 ( 0.50, 5.37) 0.02 –
0.01 0.87
0.02 –
0.26
MM, RAG, and LNY were supported by Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowships and an Early Career Fellowship, respectively (MM: 1061704, RAG: 1046207 LNY: 1052388). The DOMInO Trial was supported by a grant from the NHMRC (ID: 349301). The contents of the published material are solely the responsibility of the authors and do not reflect the views of the NHMRC. The funding bodies had no role in the study design or conduct, data collection, management, analysis, or interpretation; or in the writing, review or approval of the report.
–
1.16 (0.84, 1.60) 0.85 (0.55, 1.32)
0.08 0.10
Sources of support
0.25
0.37 0.47
–
responders to DHA supplementation. In particular, the potential to prevent one low birth weight baby by supplementing 33 nonsmoking women should be verified so that appropriate changes to clinical practice and public policy can be made.
2.82 ( 4.90, 0.73) 1.00 ( 1.87, 3.87)
0.49
11
0.04
0.01
0.04
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
Acknowledgements We thank Efamol UK for donating the treatment and placebo capsules used in the DOMInO trial; the families and their children who generously participated; Jennie Louise for assistance with statistical analyses and the DOMInO Trial Steering Committee for management of the DOMInO Trial (Chair: Maria Makrides, Deputy chair: Robert A. Gibson, members: Andrew J. McPhee, Lisa Yelland, Julie Quinlivan, Phillip Ryan).
References [1] R. De Giuseppe, C. Roggi, H. Cena, n-3 LC-PUFA supplementation: effects on infant and maternal outcomes, Eur. J. Nutr. 53 (5) (2014) 1147–1154 (PubMed PMID: 24448975. Epub 2014/01/23). [2] M. Makrides, R.A. Gibson, A.J. McPhee, L. Yelland, J. Quinlivan, P. Ryan, et al., Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial, J. Am. Med. Assoc. 304 (15) (2010) 1675–1683 (PubMed PMID: 20959577). [3] M. Makrides, J.F. Gould, N.R. Gawlik, L.N. Yelland, L.G. Smithers, P.J. Anderson, et al., Four-year follow-up of children born to women in a randomized trial of prenatal DHA supplementation, J. Am. Med. Assoc. 311 (17) (2014) 1802–1804 (PubMed PMID: 24794375. Epub 2014/05/06. eng). [4] D.J. Palmer, T. Sullivan, M.S. Gold, S.L. Prescott, R. Heddle, R.A. Gibson, et al., Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants' allergies in first year of life: randomised controlled trial, BMJ 344 (2012) e184 (PubMed PMID: 22294737. Pubmed Central PMCID: 3269207). [5] D.J. Palmer, T. Sullivan, M.S. Gold, S.L. Prescott, R. Heddle, R.A. Gibson, et al., Randomized controlled trial of fish oil supplementation in pregnancy on childhood allergies, Allergy 68 (11) (2013) 1370–1376 (PubMed PMID: 24111502). [6] P. Blumenshine, S. Egerter, C.J. Barclay, C. Cubbin, P.A. Braveman, Socioeconomic disparities in adverse birth outcomes: a systematic review, Am. J. Prev. Med. 39 (3) (2010) 263–272 (PubMed PMID: 20709259). [7] W. Hofhuis, J.C. de Jongste, P.J. Merkus, Adverse health effects of prenatal and postnatal tobacco smoke exposure on children, Arch. Dis. Child. 88 (12) (2003) 1086–1090 (PubMed PMID: 14670776. Pubmed Central PMCID: 1719394). [8] J.P. Ioannidis, Implausible results in human nutrition research, BMJ 347 (2013) f6698 (PubMed PMID: 24231028). [9] B. Galobardes, J. Lynch, G.D. Smith, Measuring socioeconomic position in
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health research, Br. Med. Bull. 81–82 (2007) 21–37 (PubMed PMID: 17284541). [10] P.J. Beeby, T. Bhutap, L.K. Taylor, New South Wales population-based birthweight percentile charts, J. Paediatr. Child Health 32 (6) (1996) 512–518 (PubMed PMID: 9007782. Epub 1996/12/01.eng). [11] J.L. Cox, J.M. Holden, R. Sagovsky, Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale, Br. J. Psychiatry: J. Ment. Sci. 150 (1987) 782–786 (PubMed PMID: 3651732). [12] P. Boyce, J. Stubbs, A. Todd, The Edinburgh Postnatal Depression Scale: validation for an Australian sample, Aust. NZ J. Psychiatry 27 (3) (1993) 472–476 (PubMed PMID: 8250792). [13] L. Murray, A.D. Carothers, The validation of the Edinburgh Post-natal Depression Scale on a community sample, Br. J. Psychiatry 157 (1990) 288–290 (PubMed PMID: 2224383). [14] H. Hiscock, M. Wake, Infant sleep problems and postnatal depression: a community-based study, Pediatrics 107 (6) (2001) 1317–1322. [15] L. Murray, The impact of postnatal depression on infant development, J. Child Psychol. Psychiatry 33 (3) (1992) 543–561. [16] N. Bayley, Bayley Scales of Infant and Toddler Development, third ed., Pearson Education Inc., San Antonio, Texas, 2006.
[17] C.D. Elliott, Differential Ability Scales, Second ed., Pearson Education Inc., San Antonio, Texas, 2007. [18] A. Chan, J. Scott, A.-M. Nguyen, P. Green, Pregnancy outcome in South Australia 2006, Pregnancy Outcome Unit, Epidemiology Branch, Department of Health, Adelaide, 2007. [19] A. Chan, J. Scott, A.-M. Nguyen, P. Green, Pregnancy outcome in South Australia 2007, Pregnancy Outcome Unit, Epidemiology Branch, Department of Health, Adelaide, 2008. [20] C. Agostoni, E. Riva, M. Giovannini, F. Pinto, C. Colombo, P. Rise, et al., Maternal smoking habits are associated with differences in infants’ long-chain polyunsaturated fatty acids in whole blood: a case-control study, Arch. Dis. Child. 93 (5) (2008) 414–418 (PubMed PMID: 18426936. Epub 2008/04/23. eng). [21] B. Pink, Australian Social Trends 2008, Australian Bureau of Statistics, Commonwealth of Australia, Australia, 2008. [22] J.F. Gould, L.G. Smithers, M. Makrides, The effect of maternal omega-3 (n-3) LCPUFA supplementation during pregnancy on early childhood cognitive and visual development: a systematic review and meta-analysis of randomized controlled trials, AJCN 9 (3) (2013) 531–544 (PubMed PMID: 23364006. Epub 2013/02/01. Eng).
Contents lists available at ScienceDirect
Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
Maternal characteristics influence response to DHA during pregnancy J.F. Gould a,b, A.J. Anderson a,b, L.N. Yelland a,b,c, R.A. Gibson b,d, M. Makrides a,b,e,n a
Women's and Children's Health Research Institute, 72 King William Road, North Adelaide, Australia South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia School of Public Health, University of Adelaide, Adelaide, Australia d FOODplus Research Centre, School of Agriculture, Food & Wine, University of Adelaide, Waite Campus, Adelaide, Australia e Discipline of Paediatrics, University of Adelaide, Adelaide, Australia b c
art ic l e i nf o
a b s t r a c t
Article history: Received 6 October 2015 Received in revised form 15 March 2016 Accepted 15 March 2016
We explored the degree to which maternal and offspring outcomes resulting from consuming prenatal docosahexaenoic acid (DHA, 800 mg/day) in a clinical trial were influenced by maternal characteristics. Among non-smokers, women who received DHA had heavier babies (adjusted mean difference (MD) ¼ 99 g 95% CI 45–153, po 0.01; interaction p¼0.01) and fewer low birth weight babies than control women (adjusted relative risk ¼ 0.43 95% CI 0.25–0.74, po 0.01; interaction p¼ 0.01). From women who had not completed further education, children in the DHA group had higher cognitive scores at 18 months compared with control children (adjusted MD ¼3.15 95% CI 0.93–5.37, p ¼0.01; interaction po 0.01). Conversely, the children of women who completed further education in the DHA group had lower language scores than control children (adjusted MD 2.82 95% CI 4.90 to 0.73, p ¼0.01; interaction p¼ 0.04). Our results support the notion that responsiveness to prenatal DHA may depend on the characteristics of specific population subgroups. & 2016 Elsevier Ltd. All rights reserved.
Keywords: DHA Omega-3 fatty acids Pregnancy Supplementation
1. Introduction The omega-3 long chain polyunsaturated fatty acid docosahexaenoic acid (DHA) has many postulated roles during pregnancy including extending the gestational period, increasing birth weight, enhancing child neurodevelopment and reducing the risk of child allergic disease early in postnatal life [1]. However, the extent of benefit for prenatal DHA supplementation for general populations has been difficult to elucidate. This may be partly explained by the fact that many trials were specifically designed to address the effect of DHA on a single outcome. For example, almost all of the trials that focussed on allergy outcomes only included women carrying fetus’ at high risk of allergies, while other trials that addressed the effect of prenatal DHA on developmental outcomes excluded preterm births, making generalizations across outcomes difficult. The largest randomized controlled trial (RCT) to date of maternal DHA supplementation in pregnancy (n ¼ 2399), the DHA to Optimize Maternal Infant Outcome (DOMInO) trial is relatively unique because it had broad inclusion criteria and assessed a range of birth and longer-term outcomes [2]. DHA supplementation did n Correspondence to: Women's and Children's Health Research Institute, Level 7, Clarence Rieger Building, Women's and Children's Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. E-mail address: [email protected] (M. Makrides).
http://dx.doi.org/10.1016/j.plefa.2016.03.011 0952-3278/& 2016 Elsevier Ltd. All rights reserved.
not affect the risk of development of postpartum depression at six weeks and six months after birth or have an effect on child cognitive development at 18 months or 4 years of age [2,3]. However, DHA supplementation in this RCT reduced the incidence of early preterm birth, increased the incidence of post-term inductions or post-term pre-labour caesarean sections, increased the mean birth weight by 68 g, and reduced the risk of atopic eczema at one but not three years of age [2,4,5]. Although broad inclusion criteria improve the generalizability of trial results, heterogeneity of the sample may mask the benefits of the intervention in certain subgroups. For example, socioeconomic disadvantage and smoking are known factors associated with increased risk of adverse birth outcomes in the general population [6,7]. DHA supplementation may improve outcomes for these women, whilst women who are socially advantaged may not benefit as much from supplementation. Thus, the overall effect of a DHA intervention may depend on the relative proportions of heterogeneous subgroups recruited in a given trial. Understanding if subgroups respond differently to DHA will allow tailoring interventions to women who will benefit the most, however consideration of this is largely absent in the context of RCT's [8] of prenatal DHA supplementation. Here we present our secondary analyses of our DOMInO trial [2] to investigate whether maternal smoking and social disadvantage affect the response to DHA supplementation on a range of outcomes.
6
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
2. Patients and methods 2.1. Participants and study design The DOMInO trial, previously published in detail, was a multicentre RCT in which n ¼2399 women less than 21 weeks’ gestation were randomly assigned to receive three capsules of either DHArich fish oil (providing 800 mg DHA/day, treatment, Incromega 500 TG, Croda Chemicals, UK) or vegetable oil (placebo) per day from study entry until delivery [2]. Women were excluded if they were already taking a supplement containing DHA, their fetus had a known major abnormality, they had a bleeding disorder in which fish oil was contraindicated, were taking anticoagulant therapy, had a documented history of drug or alcohol abuse, were participating in another fatty acid trial, were unable to give written informed consent or if English was not the main language spoken at home. Written informed consent was obtained from all participants and all procedures were conducted in accordance with the approval of the relevant Human Research Ethics Committees at each site involved in the trial. Women were assigned to the treatment or control group through a computer driven telephone randomization service according to an independently generated randomization schedule, with balanced variable-sized blocks. Stratification was by center and parity (first birth vs. subsequent birth). Compliance with the intervention was assessed through participant interview at 28 weeks gestation, return of unused capsules after birth and cord blood plasma phospholipid DHA concentrations [2]. All study personnel were blinded to treatment group allocation for the duration of the trial and follow-up assessments. Women were blinded until the 18-month child development follow-up was complete. After this time, women could request their group allocation; however the majority of families (92%) remained blinded throughout the follow-up studies that have been conducted to 7 years of age. 2.2. Definition of subgroup populations The data used to define subgroups were collected at enrolment, along with age, parity, previous history of depression, and family history of allergic disease. 2.2.1. Smoking Mothers were defined as smokers if they smoked at trial entry (mid pregnancy) or in the 2–3 months leading up to pregnancy, and non-smokers otherwise. 2.2.2. Educational achievement The level of maternal educational achieved was used as a proxy measure of the mother's relative SES [9]. Maternal completion of further education was defined as completion of a degree, diploma, certificate or trade. Women that had started further education but not finished, were categorized as having not completed that aspect of their education. 2.3. Outcome assessments 2.3.1. Maternal and infant pregnancy outcomes Information was collected from medical records and included: gestational age at birth, birth weight, birth length, and birth head circumference. Gestational age at birth was used to define early preterm birth (o34 weeks' gestation), preterm birth (o37 weeks' gestation) and post-term birth (440 weeks' gestation) requiring obstetric intervention (induction or pre-labour caesarean due to associations with
increased perinatal mortality and morbidity in both infants and mothers). Low birth weight was defined as o2500 g and high birth weight 44000 g. Small for gestational age (SGA) was defined as below the 10th percentile for weight and large for gestational age (LGA) was defined as above the 90th percentile for weight for the corresponding gestational age and sex [10]. 2.3.2. Maternal postpartum depression Postpartum depression (PPD) was assessed using the Edinburgh Postnatal Depression Scale (EPDS) questionnaire in English at six weeks and six months post-partum [11]. The EPDS has been shown to have both high sensitivity (68–95%) and high specificity (78–96%) against a clinical psychiatric diagnosis of depression [11– 13]. A score of 12 or more on the EPDS is widely used to indicate a probable depressive disorder [14,15]. For the purpose of statistical analyses, EPDS scores r12 were classified as “no depression” and EPDS scores 412 were classified as “depression”. 2.3.3. Child neurodevelopment outcomes Psychologists assessed neurodevelopment outcomes in 96 preterm infants and 630 randomly selected term infants from two centres in Adelaide [16]. Neurodevelopment was assessed at 18 months of age (corrected for premature birth) with the Bayley Scales of Infant and Toddler Development, Third Edition (BayleyIII) Cognitive and Language subscales [16]. The Bayley-III is the international test of choice in assessing developmental functioning in young children. Child development was assessed again in the same group of randomly selected term and preterm children at four years of age (corrected for premature birth), using the Differential Ability Scales, Second Edition (DAS II) [17]. The DAS II evaluates conceptual and reasoning abilities and equates to a standard Development Quotient (DQ) score of general cognitive functioning ability. Both the DAS II and the Bayley-III provide standardized scores with a mean of 100 and SD of 15, where a score 41 SD below the mean indicates impaired performance. 2.3.4. Child allergic disease Pregnant women from the Adelaide centres were included in the allergy follow-up if the unborn baby had a mother, father or sibling with a history of any medically diagnosed allergic disease (asthma, allergic rhinitis, eczema) [4,5]. There were n¼ 706 families who consented to appointments at one and three years of age with nurses and medical staff who assessed child allergy with skin prick testing and allergy symptoms. Allergic sensitization was defined as a positive skin prick test to at least one of the food allergens or aeroallergens tested. Glycerine and histamine (10 mg/mL) were used as negative and positive controls, respectively. Diagnosis of immunoglobulin E (IgE) associated allergic disease was made by one of six specifically trained medical practitioners following standardized history, clinical examination and skin prick testing of the child, as described previously [4,5]. IgE eczema was defined as sensitization, and the presence on medical review of eczema [4,5]. IgE food allergy was defined as a history of immediate skin rash with or without respiratory symptoms and/or gastrointestinal symptoms and/or cardiovascular symptoms following ingestion of a food, and a positive skin prick test to the implicated food [4,5]. 2.4. Statistical methods Analyses were performed on the available data with participants included in the treatment group assigned at randomization. Interaction tests were conducted to assess whether the response to DHA supplementation varied according to smoking/education status and subgroup analyses were performed to estimate the
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
effect of DHA supplementation by smoking/education status. The results of the subgroup analyses should be interpreted with caution where the interaction test is not statistically significant. Continuous outcomes were analysed using linear regression models with treatment effects expressed as mean differences (MD) and interactions were assessed on the additive scale. Binary outcomes were analysed using log binomial regression models with treatment effects expressed as RR and interactions were assessed on the multiplicative scale. Additional analyses were performed using an identity binomial model to investigate interactions on the additive scale. For outcomes measured at multiple time points, analyses were performed at each time point separately and on a combined outcome of any occurrence across all time points. Regression models included treatment group, smoking/education status and their interaction, with or without adjustment for the stratification variables (centre and parity). All analyses were performed using SAS v9.3 (Cary, NC, USA) and no adjustment was made for multiple comparisons.
7
fewer children with a Bayley-III cognitive composite score more than 1 SD below the mean (adjusted RR ¼0.23 95% CI 0.10–0.53, po 0.01) compared with non-smoking controls. DHA treatment could prevent one low birth weight baby by supplementing 33 non-smoking women (95% CI 20–88, po 0.01). In contrast, women who were classified as smokers at baseline did not appear to respond to DHA supplementation, although the infants of smokers were smaller on average than the infants of non-smokers. These conclusions were unaltered based on interaction tests on the additive scale (data not shown). Consistent with these findings, there was some evidence to suggest that DHA supplementation in non-smoking women resulted in lower risk of early preterm birth, and higher risk of postterm birth, high birth weight and LGA, compared with controls. However, these subgroup findings should be interpreted with caution, as there was no evidence to suggest that the effect of DHA depended on smoking status for these outcomes. 3.2. Maternal education
3. Results Participant flow is presented in Fig. 1. Participants’ characteristics at baseline were well balanced between treatment groups within the overall sample and in the allergy and neurodevelopment follow-up subgroups (Table 1). Women were compliant with the intervention, with 36% of women reporting not missing any capsules, 35% reporting missing r3 out of 21 capsules per week, and less than 2% reporting not taking any capsules. Follow-up was greater than 90% for each outcome. 3.1. Maternal smoking Maternal smoking appeared to modify the effect of DHA intervention on birth weight (p ¼0.01), low birth weight (p ¼0.01) and Bayley-III cognitive composite score more than 1 SD below the mean (p ¼0.02) (Table 2). Among women who were classified as non-smokers at study entry, the DHA group had heavier babies (adjusted MD¼99 g 95% CI 45–153, po 0.01), fewer low birth weight babies (adjusted RR ¼0.43 95% CI 0.25–0.74, po 0.01) and
The effect of the DHA intervention was significantly modified by maternal further education for Bayley-III cognitive composite score (po0.01), Bayley-III language composite score (p¼0.04), and DAS II score (p¼ 0.02) (Table 3). DHA treatment resulted in higher BayleyIII cognitive composite scores at 18 months (adjusted MD¼ 3.15 95% CI 0.93–5.37, p¼0.01) in children from women who had not completed further education, while no such effect was present among women who had completed further education. Language composite scores at 18 months were lower in the DHA group among women who had completed further education (adjusted MD 2.82 95% CI 4.90 to 0.73, p¼ 0.01) but did not appear to be influenced by the intervention among women who had not completed further education. There was some evidence to suggest that the effect of DHA supplementation on DAS II score was positive among women who had not completed further education (adjusted MD 2.43 95% CI 0.50 to 5.37, p¼0.10) and negative among women who had (adjusted MD 1.76 95% CI 3.72 to 0.20, p¼0.08). There were some additional outcomes where the effect of DHA appeared to relate to maternal education subgroups. In particular, DHA supplementation reduced the risk of early preterm birth,
Fig. 1. Flow Diagram of mother-child pairs through the DOMInO trial and follow-ups. 1 DHA to Optimize Mother Infant Outcomes. Birth Outcomes: early preterm birth ( o 34 weeks'), preterm birth ( o 37 weeks'), post term birth ( 440 weeks') and intervention, birth weight, low birth weight ( o 2500 g), high birth weight ( 44000 g), small for gestational age, large for gestational age, Depression: the Edinburgh Postnatal Depression Scale at 6 weeks and 6 months post-partum. 18 month neurodevelopment cohort outcomes: the Bayley Scales of Infant and Toddler Development, Third Edition Cognitive Score and Language Score. 4 year neurodevelopment cohort outcome: the Differential Ability Scales developmental quotient. Allergy cohort outcomes at 1 year: IgE allergic disease, sensitization, eczema. Allergy cohort outcomes at 3 years: IgE allergic disease, sensitization, eczema.
8
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
Table 1 Participant characteristics at baseline.a,b
Characteristics
All Participants n¼ 2399
Neurodevelopment Subgroup n¼726
Allergy Subgroup n¼ 706
DHAc n¼1197
Control n¼ 1202
DHA n¼351
DHA n¼ 368
Control n¼ 338
838 (70.0) 358 (29.9)
792 (65.9) 407 (33.9)
254 (72.4) 97 (27.6)
269 (73.1) 99 (26.9)
232 (68.6) 106 (31.4)
816 380 28.9 605 471 298
824 375 28.9 591 474 287
230 121 29.0 176 155 89
255 113 29.6 169 150 110
241 97 29.5 168 131 85
Control n¼ 375
Maternal smoking Non-smoker Smoker Maternal further education Completed Not completed Maternal age (years) mean (SD) Infant male sex Maternal parity of 0 Previous history of depression
(68.2) (31.7) (5.7) (50.5) (39.3) (24.9)
(68.6) (31.2) (5.6) (49.2) (39.4) (23.9)
(65.5) (34.5) (5.7) (50.1) (44.2) (25.4)
241 (64.3) 133 (35.5) 254 121 28.5 189 166 96
(67.7) (32.3) (6.0) (50.4) (44.3) (25.6)
(69.3) (30.7) (5.7) (45.9) (40.8) (29.9)
(71.3) (28.7) (5.6) (49.7) (38.8) (25.1)
a
Values are n(%) unless otherwise stated. Data are missing for n ¼1 DHA group participant and n ¼3 control group participants for all characteristics except infant sex (n ¼11 DHA group participants and n ¼18 control group participants). c DHA¼ docosahexaenoic acid. b
sensitization at 1 year, and having a Bayley-III cognitive composite score more than 1 SD below the mean, and increased the mean birth weight in the subgroup of women who did not complete further education. The DHA intervention also increased the risk of high infant birth weight and having a DAS II score more than 1 SD below the mean, among women who completed further education. While these subgroup findings are generally consistent with the effect of DHA on all participants as previously reported, [3] they should not be taken as evidence that the effect of DHA varies according to maternal education for these outcomes, due to the non-significant interactions.
4. Discussion and conclusions Our study highlights the fact that there are subgroups who respond differently to prenatal DHA supplementation during pregnancy, and this was particularly evident in those women who smoked in the periconceptional period. The fact that these women had a higher risk of poorer outcomes than women who did not smoke is not surprising. However, rather than benefitting from the intervention, the adverse effects of smoking appeared to nullify the benefits of DHA supplementation that were evident among nonsmoking women. In fact, the adverse effect of smoking on the mean birth weight among control group women (decrease of 75 g) was of a similar magnitude to the increase in mean birth weight from DHA supplementation among non-smoking women (increase of 95 g). Interestingly, there were no differential responses in smokers on non-smokers with the duration of gestation. This indicates that the effects noted on infant birth weight are independent of the duration of gestation. However, the effects of DHA supplementation seen among non-smoking women, and their direction, are consistent with the findings of the overall trial [2] and suggest that the inclusion of smokers in the DOMInO trial might have reduced the ability to detect an effect of supplementation. The proportion of women who reported smoking during pregnancy was higher in our sample (32%) than in the general Australian population at the time of recruitment (18%) [18,19]. Smokers have previously been shown to have lower DHA levels when compared with non-smokers, [20] although it is unclear whether this is due to a biological effect of smoking, or lifestyle factors associated with smoking, or both. We recommend that smoking, as a baseline characteristic, should be reported in trials of DHA supplementation, and that future efficacy trials consider stratifying the randomization on smoking status, or considering the outcomes of smokers and non-smokers separately in pre-specified subgroup analyses.
Maternal DHA supplementation had mixed results for developmental outcomes of children depending on maternal education. DHA supplementation appeared to increase the 18 month cognitive scores of children among women who had not completed further education, but unexpectedly may have led to a decrease in the 18 month language scores among children of women who had completed further education. Additionally, child cognitive development at 4 years was higher in the DHA group if women had not completed further education, but lower than controls if they had completed further education. We explored further education rather than secondary education, as completion of further education is optional and involves a qualification and training for a specific vocation whereas partial completion of secondary education is compulsory in Australia. We expected that non-completion of education would serve as a proxy for social disadvantage, and that these women would benefit from supplementation. While education is considered by many to be a good indicator of social disadvantage and health behaviour, our results highlight the complexity of measuring social advantage or disadvantage through a single variable. We had an ideal sample for exploring the interaction of prenatal DHA supplementation with education as the proportion of women who had completed further education was lower in our sample than in the general population (63% vs. 77%, respectively) [21]. The limitations of the results presented here stem from the nature of the analysis in the available sample. Although the largest trial of DHA in pregnancy, we were powered to detect the effect of DHA supplementation in the overall sample, rather than in specific subgroups. Our exploration of the effect of maternal social characteristics on responses to DHA supplementation may be underpowered and was not planned in the design of the trial, limiting our ability to identify subgroups who may benefit most from supplementation. Furthermore, the sample used to explore allergy excluded children who were not defined as having a high genetic risk of, or predisposition to allergy development, meaning that the results may have limited generalizability. Whilst caution is warranted in the interpretation of these results, there are several key advantages of this study. The DOMInO trial a large sample of women with the broadest inclusion criteria among trials investigating DHA supplementation in pregnancy [22]. The dose of DHA administered and the level of compliance with the intervention resulted in an increased cord blood DHA concentration in the treatment group that was adequate to induce a benefit of supplementation [2]. Furthermore, a comprehensive range of outcomes were assessed with gold-standard measures and minimal attrition. All of these advantages mean that the
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
9
Table 2 Effect modification by maternal smoking status for pregnancy outcomes, and child allergy and neurodevelopment outcomes in a randomized controlled trial of docosahexaenoic acid (DHA)-rich tuna oil supplementation in pregnancy. Outcome
Subgroup
DHAa frequency (%)
Placebo frequency (%)
Unadjb RRc (95% Unadj p CI) value
Unadj Int pd value
Adje RR (95% CI)
Early preterm birth ( o 34 wks) Preterm birth ( o 37 wks)
Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker
6/831 (1) 7/353 (2) 40/831 (5) 25/353 (7) 146/831(18) 63/353 (18)
17/775 (2) 9/406 (2) 52/775 (7) 32/406 (8) 103/775 (13) 60/406 (15)
0.33 (0.13, 0.83) 0.89 (0.34, 2.38) 0.72 (0.48, 1.07) 0.90 (0.54, 1.49) 1.32 (1.05, 1.67) 1.21 (0.87, 1.67)
0.02 0.82 0.10 0.68 0.02 0.25
0.15 – 0.49 – 0.66 –
0.33 (0.13, 0.82) 0.90 (0.34, 2.40) 0.72 (0.48, 1.07) 0.90 (0.54, 1.49) 1.31 (1.04, 1.65) 1.23 (0.89, 1.69)
0.02 0.84 0.10 0.68 0.02 0.21
0.14 – 0.49 – 0.76 –
Non-smoker 3536 (538)
3441 (555)
o 0.01
0.01
0.01
3337 (601)
3366 (573)
Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker Smoker Non-smoker
19/830 (2) 21/352 (6) 150/830(18) 43/352 (12) 37/830 (4) 35/352 (10) 155/830(19) 46/352 (13) 111/828(13) 63/353 (18) 22/261 (8) 8/96 (8) 36/242 (15) 13/91 (14) 42/269 (16) 16/99 (16) 37/255 (15) 14/94 (15) 57/221 (26) 20/82 (24) 70/269 (26) 26/99 (26) 102 (101, 103)
41/774 (5) 18/405 (4) 103/774 (13) 49/405 (12) 46/773 (6) 35/405 (9) 116/773 (15) 53/405 (13) 125/767 (16) 74/401 (18) 30/224 (13) 11/100 (11) 41/214 (19) 12/91 (13) 52/232 (22) 19/106 (18) 47/220 (21) 16/97 (16) 55/198 (28) 19/81 (23) 77/232 (33) 29/106 (27) 103 (101, 104)
o 0.01 0.35 0.01 0.96 0.18 0.54 0.05 0.99 0.11 0.83 0.08 0.53 0.22 0.83 0.05 0.74 0.05 0.76 0.65 0.89 0.08 0.86 0.73
Smoker
101(99,102)
101 (99, 102)
0.43 (0.25, 0.74) 1.34 (0.73, 2.48) 1.36 (1.08, 1.71) 1.01 (0.69, 1.48) 0.75 (0.49, 1.14) 1.15 (0.74, 1.80) 1.24 (1.00, 1.55) 1.00 (0.69, 1.44) 0.82 (0.65, 1.04) 0.97 (0.71, 1.31) 0.63 (0.37, 1.06) 0.76 (0.32, 1.80) 0.78 (0.52, 1.17) 1.08 (0.52, 2.25) 0.70 (0.48, 1.01) 0.90 (0.49, 1.65) 0.68 (0.46, 1.00) 0.90 (0.47, 1.74) 0.93 (0.68, 1.27) 1.04 (0.60, 1.80) 0.78 (0.60, 1.03) 0.96 (0.61, 1.51) 0.30 ( 2.06, 1.46) 0.14 ( 2.07, 2.34) 0.22 (0.10, 0.52) 0.97 (0.38, 2.48) 0.90 ( 3.03, 1.23) 3.08 ( 5.85, 0.32) 1.02 (0.75, 1.38) 1.02 (0.61, 1.70) 0.08 ( 2.16, 1.99) 1.74 ( 4.33, 0.85) 1.32 (0.89, 1.96) 1.85 (0.94, 3.63)
98.89 (44.65, 153.14) 32.78 ( 111.89, 46.33) 0.43 (0.25, 0.74) 1.34 (0.73, 2.47) 1.37 (1.09, 1.73) 1.00 (0.68, 1.47) 0.74 (0.49, 1.13) 1.17 (0.75, 1.82) 1.26 (1.02, 1.57) 1.00 (0.69, 1.44) 0.83 (0.65, 1.04) 0.96 (0.71, 1.29) 0.63 (0.38, 1.06) 0.75 (0.31, 1.77) 0.78 (0.52, 1.17) 1.08 (0.52, 2.24) 0.70 (0.48, 1.01) 0.90 (0.49, 1.65) 0.68 (0.46, 1.01) 0.89 (0.46, 1.72) 0.93 (0.68, 1.28) 1.05 (0.60, 1.81) 0.78 (0.60, 1.03) 0.96 (0.61, 1.51) 0.30 ( 2.06, 1.46) 0.13 ( 2.08, 2.33) 0.23 (0.10, 0.53) 0.97 (0.39, 2.52) 0.93 ( 3.06, 1.20) 3.15 ( 5.93, 0.38) 1.02 (0.75, 1.38) 1.03 (0.62, 1.72) 0.08 ( 2.16, 2.00) 1.84 ( 4.43, 0.74) 1.32 (0.89, 1.95) 1.89 (0.96, 3.72)
o 0.01
Smoker
95.46 (40.73, 150.20) 28.78 ( 108.60, 51.05)
Post-term birth ( 440 wks) þ intervention Birth weight (g)f
Low birthweight ( o 2500 g) High birthweight ( 44000 g) Small for gestational age Large for gestational age EPDS 412 overallg IgE allergic disease at 1 Yr IgE allergic disease at 3 Yrs IgE allergic disease at 1 or 3 Yrs Sensitisation at 1 Yr Sensitisation at 3 Yrs Sensitisation at 1 or 3 Yrs Cognitive composite scoreh
Cognitive composite score 41 SD below meani Language composite scoreh
Non-smoker 1.7 (0.8, 3.5) Smoker 4.4 (2.3, 8.4) Non-smoker 97 (96, 98)
7.5 (5.2, 10.6) 4.6 (2.3, 8.8) 98 (96, 99)
Smoker
99 (97, 101)
96 (94, 98)
Non-smoker 18.6 (15.0, 22.9) 18.3 (14.8, 22.6) Language composite 14.9 (10.0, 21.7) 14.6 (10.4, 20.1) score41 SD below meani Smoker DAS DQ at 4 Yrsh Non-smoker 100(98,101) 100 (99, 101) Smoker DAS DQ at 4 Yrs4 1 SD below meani
99 (97, 101)
Non-smoker 15.7 (12.1, 20.0) Smoker 12.3 (7.8. 19.0)
101 (99, 102) 11.8 (8.7, 15.9) 6.7 (4.0, 11.0)
0.48
0.90 o 0.01 0.95 0.41
–
0.01 – 0.20 – 0.17 – 0.32 – 0.41 – 0.72 – 0.44 – 0.48 – 0.47 – 0.73 – 0.45 – 0.76 – 0.02 0.22
0.03
–
0.92 0.94 0.94
0.99
0.19
–
0.17 0.08
0.40
0.33
Adj p value Adj Int p value
0.42
o 0.01 0.34 0.01 0.995 0.16 0.49 0.04 0.98 0.11 0.78 0.08 0.51 0.23 0.83 0.06 0.73 0.06 0.73 0.66 0.87 0.08 0.86 0.74 0.91 o 0.01 0.98 0.39
–
0.01 – 0.17 – 0.14 – 0.27 – 0.45 – 0.75 – 0.44 – 0.49 – 0.50 – 0.72 – 0.45 – 0.77 – 0.02 0.21
0.03
–
0.93 0.91 0.94
0.97
0.16
–
0.17 0.07
0.36
0.30
a
DHA ¼docosahexaenoic acid. Unadj ¼unadjusted. c RR ¼Relative Risk (DHA/Control). d Int p¼ Interaction p value. e Adj¼Adjusted (adjustment for stratification variables centre and parity). f Mean (SD) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-Control. g EPDS 412 overall indicates whether EPDS was 412 at 6 weeks and/or 6 months. h Weighted mean (95% CI) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-control. i Weighted percentage (95% CI) instead of frequency (percentage), and group comparison is relative risk (95% CI) for DHA/Control. b
DOMInO trial is the only trial to date to provide an overall picture of the effect of maternal DHA supplementation in pregnancy with results that can be applied to a more generalized population. 4.1. Conclusion The present study provides the first exploration of differential responses to maternal DHA supplementation in pregnancy in the
context of a clinical trial. Our results lend support to the argument that subgroups may vary in their response to DHA intervention, however further RCT's will need to collect characteristics that may identify responders in order to better target interventions with potential therapeutic applications. In the meantime, we recommend that RCT's with comparable DHA dosage and outcome measures pool data to evaluate SES factors in a more diverse sample with greater power to explore the possibility of identifying
10 Table 3 Effect modification by maternal further education for pregnancy outcomes, and child allergy and neurodevelopment outcomes in a randomized controlled trial of docosahexaenoic acid (DHA)-rich tuna oil supplementation in pregnancy. Outcome
Subgroup
DHAa frequency (%)
Placebo frequency (%)
Unadjb RRc (95% CI)
Unadj p value
Unadj Int pd value
Adje RR (95% CI)
Early preterm birth ( o 34 wks)
Completed Not completed Completed Not complete Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed Completed Not completed
10/806 (1) 3/378 (1)
15/811 (2) 11/370 (3)
0.67 (0.30, 1.48) 0.27 (0.08, 0.95)
0.32 0.04
0.23 –
0.67 (0.30, 1.48) 0.27 (0.08, 0.95)
0.32 0.04
0.23 –
43/806 (5) 22/378 (6) 133/806 (17) 76/378 (20)
58/811 (7) 26/370 (7) 108/811 (13) 55/370 (15)
0.75 (0.51, 1.09) 0.83 (0.48, 1.43) 1.24 (0.98, 1.57) 1.35 (0.99, 1.86)
0.13 0.50 0.07 0.06
0.76 – 0.66 –
0.75 (0.51, 1.09) 0.83 (0.48, 1.44) 1.24 (0.98, 1.56) 1.35 (0.99, 1.85)
0.13 0.51 0.07 0.06
0.74 – 0.65 –
3486 (567) 3458 (561)
3437 (563) 3367 (559)
48.97 ( 5.92, 103.87) 0.08 90.98 (10.28, 171.68) 0.03
0.40 –
50.46 ( 3.89, 104.81) 89.18 (9.27, 169.08)
0.07 0.03
0.43 –
25/805 (3) 15/377 (4)
36/809 (4) 23/370 (6)
0.70 (0.42, 1.15) 0.64 (0.34, 1.21)
0.16 0.17
0.83 –
0.70 (0.42, 1.15) 0.65 (0.35, 1.23)
0.15 0.18
0.87 –
137/805 (17) 56/377 (15)
109/809 (13) 43/370 (12)
1.26 (1.00, 1.59) 1.28 (0.88, 1.85)
0.05 0.19
0.96 –
1.28 (1.02, 1.61) 1.26 (0.87, 1.82)
0.04 0.22
0.94 –
46/805 (6) 26/377 (7)
51/808 (6) 30/370 (8)
0.91 (0.62, 1.33) 0.85 (0.51, 1.41)
0.61 0.53
0.85 –
0.90 (0.61, 1.33) 0.85 (0.52, 1.41)
0.60 0.54
0.87 –
140/805 (17) 61/377 (16)
122/808 (15) 47/370 (13)
1.15 (0.92, 1.44) 1.27 (0.90, 1.81)
0.21 0.18
0.64 –
1.17 (0.93, 1.45) 1.27 (0.90, 1.81)
0.17 0.17
0.67 –
115/803 (14) 59/378 (16)
141/799 (18) 59/369 (16)
0.81 (0.65, 1.02) 0.98 (0.70, 1.36)
0.07 0.89
0.37 –
0.82 (0.65, 1.02) 0.96 (0.69, 1.34)
0.08 0.82
0.42 –
24/250 (10) 6/107 (6)
31/231 (13) 10/93 (11)
0.72 (0.43, 1.18) 0.52 (0.20, 1.38)
0.19 0.19
0.57 –
0.72 (0.43, 1.18) 0.52 (0.20, 1.37)
0.19 0.18
0.56 –
42/233 (18) 7/100 (7)
40/221 (18) 13/84 (15)
1.00 (0.67, 1.47) 0.45 (0.19, 1.08)
0.98 0.08
0.11 –
1.00 (0.67, 1.47) 0.45 (0.19, 1.09)
0.99 0.08
0.11 –
49/255 (19) 9/113 (8)
55/241 (23) 16/97 (16)
0.84 (0.60, 1.19) 0.48 (0.22, 1.04)
0.33 0.06
0.20 –
0.84 (0.60, 1.19) 0.48 (0.22, 1.04)
0.33 0.06
0.120 –
43/245 (18) 8/104 (8)
46/228 (20) 17/89 (19)
0.87 (0.60, 1.27) 0.40 (0.18, 0.89)
0.47 0.02
0.09 –
0.87 (0.60, 1.26) 0.40 (0.18, 0.89)
0.46 0.02
0.08 –
63/212 (30) 14/91 (15)
55/205 (27) 19/74 (0.26)
1.11 (0.82, 1.50) 0.60 (0.32, 1.11)
0.51 0.11
0.08 –
1.11 (0.82, 1.51) 0.60 (0.33, 1.12)
0.50 0.11
0.08 –
79/255 (31) 17/113 (15)
81/241 (34) 25/97 (26)
0.92 (0.71, 1.19) 0.58 (0.34, 1.01)
0.53 0.06
0.14 –
0.92 (0.71, 1.19) 0.58 (0.34, 1.02)
0.53 0.06
0.14 –
102 (101, 103) 102 (101, 104)
103 (102, 105) 99 (98, 101)
1.51 ( 3.25, 0.23) 3.14 (0.91, 5.37)
0.09 0.01
o 0.01 –
1.52 ( 3.26, 0.22) 3.15 (0.93, 5.37)
0.09 0.01
o0.01 –
2.7 (1.5, 4.7) 1.9 (0.6, 5.3)
4.9 (3.2, 7.7) 9.8 (6.1, 15.3)
0.54 (0.26, 1.11) 0.19 (0.06, 0.60)
0.09 0.01
0.13
0.54 (0.26, 1.12) 0.19 (0.06, 0.60)
Preterm birth ( o 37 wks)
Birth weight (g)f
Low birthweight ( o 2500 g)
High birthweight ( 44000 g)
Small for gestational age
Large for gestational age
EPDS 412 overallg
IgE allergic disease at 1 Yr
IgE allergic disease at 3 Yrs
IgE allergic disease at 1 or 3 Yrs
Sensitisation at 1 Yr
Sensitisation at 3 Yrs
Sensitisation at 1 or 3 Yrs
Cognitive composite score,h
Cognitive composite score 4 1 SD below meani
0.10 o 0.01
0.13
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
Post-term birth ( 440 wks) þ intervention
Adj p value Adj Int p value
0.05 1.93 (1.23, 3.02) 0.96 (0.56, 1.64) 0.05
Conflict of interest
0.01 0.85
RAG and MM receive honoraria (payable to their institutions) for scientific advisory board contributions to Fonterra (RAG, MM), and Nestle Nutrition Institute (MM). All honoraria are used to support conference travel and continuing education for postgraduate students and early career researchers. No other authors have any conflicts of interest to declare.
c
b
DAS DQ at 4Yrs 41 SD below meani
DAS DQ at 4 Yrsi
Language composite score41 SD below meani
a
1.93 (1.23, 3.03) 0.95 (0.55, 1.63) 7.8 (5.4, 11.1) 15.2 (10.3, 21.9) 15.0 (11.4, 19.4) 14.4 (9.7, 20.9)
0.09 0.11 1.72 ( 3.67, 0.24) 2.45 ( 0.53, 5.43) 102 (101, 103) 96 (93, 98) 101 (99, 102) 98 (96, 100)
0.38 0.44 1.16 (0.84, 1.59) 0.84 (0.54, 1.31) 15.6 (12.4, 19.5) 20.1 (14.8, 26.7) 18.1 (14.3, 22.5) 16.9 (12.0, 23.2)
0.50 95 (93, 98) 96 (95, 98)
Not completed Completed Not completed Completed Not completed Completed Not completed
0.01
2.76 ( 4.84, 0.67) 1.00 ( 1.92, 3.91) 99 (98, 101) 97 (95, 98) Completed Language composite scoreh
DHA ¼docosahexaenoic acid. Unadj¼ unadjusted. RR ¼Relative Risk (DHA/Control). d Int p¼ Interaction p value. e Adj ¼Adjusted (adjustment for stratification variables centre and parity). f Mean (SD) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-Control. g EPDS 412 overall indicates whether EPDS was 4 12 at 6 weeks and/or 6 months. h Weighted mean (95% CI) instead of frequency (percentage), and group comparison is difference in means (95% CI) for DHA-control. i Weighted percentage (95% CI) instead of frequency (percentage) and group comparison is relative risk (95% CI) for DHA/Control.
1.76 ( 3.72, 0.20) 2.43 ( 0.50, 5.37) 0.02 –
0.01 0.87
0.02 –
0.26
MM, RAG, and LNY were supported by Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowships and an Early Career Fellowship, respectively (MM: 1061704, RAG: 1046207 LNY: 1052388). The DOMInO Trial was supported by a grant from the NHMRC (ID: 349301). The contents of the published material are solely the responsibility of the authors and do not reflect the views of the NHMRC. The funding bodies had no role in the study design or conduct, data collection, management, analysis, or interpretation; or in the writing, review or approval of the report.
–
1.16 (0.84, 1.60) 0.85 (0.55, 1.32)
0.08 0.10
Sources of support
0.25
0.37 0.47
–
responders to DHA supplementation. In particular, the potential to prevent one low birth weight baby by supplementing 33 nonsmoking women should be verified so that appropriate changes to clinical practice and public policy can be made.
2.82 ( 4.90, 0.73) 1.00 ( 1.87, 3.87)
0.49
11
0.04
0.01
0.04
J.F. Gould et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 108 (2016) 5–12
Acknowledgements We thank Efamol UK for donating the treatment and placebo capsules used in the DOMInO trial; the families and their children who generously participated; Jennie Louise for assistance with statistical analyses and the DOMInO Trial Steering Committee for management of the DOMInO Trial (Chair: Maria Makrides, Deputy chair: Robert A. Gibson, members: Andrew J. McPhee, Lisa Yelland, Julie Quinlivan, Phillip Ryan).
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