孕期补充DHA 有用吗？---美国医学会研究结果

current as of October 27, 2010. Online article and related content http://jama.ama-assn.org/cgi/content/full/304/15/1675 . 2010;304(15):1675-1683 (doi:10.1001/jama.2010.1507) JAMA Maria Makrides; Robert A. Gibson; Andrew J. McPhee; et al. Children: A Randomized Controlled Trial Maternal Depression and Neurodevelopment of Young Effect of DHA Supplementation During Pregnancy on Supplementary material http://jama.ama-assn.org/cgi/content/full/304/15/1675/DC1 eTables Correction Contact me if this article is corrected. Citations Contact me when this article is cited. This article has been cited 2 times. Topic collections Contact me when new articles are published in these topic areas. Outcomes Health; Pregnancy and Breast Feeding; Randomized Controlled Trial; Prognosis/ Malnutrition; Pediatrics; Child Development; Psychiatry; Depression; Women's Nutritional and Metabolic Disorders; Lipids and Lipid Disorders; Nutrition/ http://pubs.ama-assn.org/misc/permissions.dtl permissions@ama-assn.org Permissions http://jama.com/subscribe Subscribe reprints@ama-assn.org Reprints/E-prints http://jamaarchives.com/alerts Email Alerts at University of California - San Francisco on October 27, 2010 www.jama.comDownloaded from ORIGINAL CONTRIBUTION Effect of DHA Supplementation During Pregnancy on Maternal Depression and Neurodevelopment of Young Children A Randomized Controlled Trial Maria Makrides, BSc, BND, PhD Robert A. Gibson, BSc, PhD Andrew J. McPhee, MBBS Lisa Yelland, BSc Julie Quinlivan, MBBS, PhD Philip Ryan, MBBS, BSc and the DOMInO Investigative Team EPIDEMIOLOGICAL INVESTIGA-tions from theUnited States andEurope demonstrate that higherintakes of n-3 long-chain poly- unsaturated fatty acids (LCPUFA) from fish and seafood during pregnancy are associated with a reduced risk of de- pressive symptoms in the postnatal pe- riod,1 as well as improved developmen- tal outcomes in the offspring.2,3 Of the n-3 LCPUFA, it is hypothesized that docosahexaenoic acid (DHA) may be responsible for the observed associa- tions based on estimates of dietary re- quirements during pregnancy and the results of experimental animal stud- ies.4 However, n-3 LCPUFA interven- tion trials in human pregnancy have re- portedmixed results and have not been conclusive largely because of method- ological limitations. Studies focused on perinatalmood have had open-label de- signs, small sample sizes, or large at- trition, andmost did not analyze by in- tention-to-treat.5 Similarly, trials focused on the developmental out- comes of the children have made post- See also p 1717 and Patient Page. Author Affiliations: Child Nutrition Research Centre, Women’s and Children’s Hospital, Flinders Medical Cen- tre, and Women’s and Children’s Health Research In- stitute, Adelaide (Drs Makrides and Gibson); Schools of Pediatrics and Reproductive Health (Dr Makrides), Agriculture, Food and Wine (Dr Gibson), and Popula- tion Health and Clinical Practice (Dr Ryan and Ms Yel- land), University of Adelaide, Adelaide; Department of Neonatal Medicine, Women’s and Children’s Hospi- tal, Adelaide (Dr McPhee); and School of Medicine, University of Notre Dame Australia, and Sunshine Hos- pital, Melbourne (Dr Quinlivan), Australia. The DOMInO Investigative Teammembers and their author affiliations are listed at the end of this article. Corresponding Author: Maria Makrides, BSc, BND, PhD, Child Nutrition Research Centre, Women’s and Children’s Health Research Institute, Women’s and Children’s Hospital, 72 King William Rd, North Ad- elaide SA 5006, Australia (maria.makrides@health.sa .gov.au). Context Uncertainty about the benefits of dietary docosahexaenoic acid (DHA) for pregnant women and their children exists, despite international recommendations that pregnant women increase their DHA intakes. Objective To determine whether increasing DHA during the last half of pregnancy will result in fewer women with high levels of depressive symptoms and enhance the neurodevelopmental outcome of their children. Design, Setting, and Participants A double-blind, multicenter, randomized con- trolled trial (DHA to Optimize Mother Infant Outcome [DOMInO] trial) in 5 Austra- lian maternity hospitals of 2399 women who were less than 21 weeks’ gestation with singleton pregnancies and who were recruited between October 31, 2005, and Janu- ary 11, 2008. Follow-up of children (n=726) was completed December 16, 2009. Intervention Docosahexaenoic acid–rich fish oil capsules (providing 800 mg/d of DHA) or matched vegetable oil capsules without DHA from study entry to birth. Main Outcome Measures High levels of depressive symptoms in mothers as indi- cated by a score of more than 12 on the Edinburgh Postnatal Depression Scale at 6 weeks or 6 months postpartum. Cognitive and language development in children as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition, at 18 months. Results Of 2399 women enrolled, 96.7% completed the trial. The percentage of women with high levels of depressive symptoms during the first 6 months postpar- tum did not differ between the DHA and control groups (9.67% vs 11.19%; adjusted relative risk, 0.85; 95% confidence interval [CI], 0.70-1.02; P=.09). Mean cognitive composite scores (adjusted mean difference, 0.01; 95% CI, −1.36 to 1.37; P=.99) and mean language composite scores (adjusted mean difference, −1.42; 95% CI, −3.07 to 0.22; P=.09) of children in the DHA group did not differ from children in the con- trol group. Conclusion The use of DHA-rich fish oil capsules compared with vegetable oil cap- sules during pregnancy did not result in lower levels of postpartum depression in moth- ers or improved cognitive and language development in their offspring during early childhood. Trial Registration anzctr.org.au Identifier: ACTRN12605000569606 JAMA. 2010;304(15):1675-1683 www.jama.com ©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, October 20, 2010—Vol 304, No. 15 1675 at University of California - San Francisco on October 27, 2010 www.jama.comDownloaded from randomization exclusions,6,7 had high attrition rates, and lacked power.6-9 De- spite the paucity of evidence, recom- mendations exist to increase intake of DHA in pregnancy,4,10 and the nutri- tional supplement industry success- fullymarkets prenatal supplementswith DHA to optimize brain function of mother and infant. Before DHA supple- mentation in pregnancy becomeswide- spread, it is important to knownot only if there are benefits, but also of any risks for either themother or child. TheDHA to Optimize Mother Infant Outcome (DOMInO) trial was designed primar- ily to assess whether DHA supplemen- tation during the last half of preg- nancy reduced the risk of depressed maternal mood during the postpar- tum period and improved early cogni- tive development in the offspring. METHODS Study Design We conducted a double-blind, multi- center, randomized controlled trial in 5 Australian perinatal centers. Ap- proval was granted by the local insti- tutional review boards (human re- search ethics committees) of each center and written informed consent was ob- tained from each participant. An inde- pendent serious adverse event commit- tee reviewed all deaths, admissions to level III care, and major congenital abnormalities. Women with singleton pregnancies at less than 21weeks’ gestationwere ap- proached by study research assistants while attending routine antenatal ap- pointments to participate in the trial. Women were excluded if they were al- ready taking a prenatal supplementwith DHA, their fetus had a knownmajor ab- normality, they had a bleeding disor- der in which tuna oil was contraindi- cated, were taking anticoagulant therapy, had a documented history of drug or alcohol abuse, were participat- ing in another fatty acid trial, were un- able to give written informed consent, or if English was not the main lan- guage spoken at home. Recruitment for the trial began October 31, 2005, and ended January 11, 2008. Randomization and Trial Entry Women were randomly assigned a unique study number and treatment group allocation through a computer- driven telephone randomization ser- vice according to an independently gen- erated randomization schedule, with balanced variable-sized blocks. Strati- fication was by center and parity (first birth vs subsequent birth). Baseline characteristics, includingmaternal age, medical diagnosis of previous or cur- rent depression, current treatment for depression, social support using theMa- ternal Social Support Index,11 weight, highest level of education, occupa- tion, and smoking status, were re- corded. Dietary Treatments Women allocated to the DHA group were asked to consume three 500- mg/d capsules of DHA-rich fish oil con- centrate, providing 800 mg/d of DHA and 100mg/d of eicosapentaenoic acid (EPA, 20:5n-3; Incromega 500 TG, Croda Chemicals, East Yorkshire, En- gland); andwomen in the control group were asked to take three 500-mg/d veg- etable oil capsules without DHA. The dose of 800 mg/d was chosen because this was above the estimated thresh- old associated with lower risk of de- pressed maternal mood and higher scores on developmental outcomes of children,1 as well as being consistent with the estimated requirement to cover 97% of the population.12 The veg- etable oil capsules contained a blend of 3 nongenetically modified oils (rape- seed, sunflower, and palm) in equal proportions. This blend of oils was de- signed to match the polyunsaturated, monounsaturated, and saturated fatty acid profile of the average Australian diet.13Womenwere asked to take their assigned capsules daily, from study en- try until birth of their child. All cap- sules were similar in size, shape, and color and donated by Efamol, Surrey, England. Treatment Phase Monitoring During the intervention period, trial as- sistants telephonedwomen 2weeks af- ter enrollment (approximately 22 weeks’ gestation) and at 28 and 36 weeks’ gestation to document adverse gastrointestinal or bleeding events and to monitor and encourage adherence. The concentration of DHA in cord bloodwasmeasured using capillary gas chromatography14 to provide an inde- pendent biomarker of adherence. An- tenatal hospitalizations, antenatal hem- orrhage, pregnancy andbirth outcomes, and postpartum hemorrhage were re- corded from a review of medical rec- ords. Outcome Assessments Women completed a self-adminis- tered Edinburgh Postnatal Depression Scale (EPDS) at 6 weeks and 6months postpartum, and the primary mater- nal outcomewas a high level of depres- sive symptoms documented as a score ofmore than 12 on the EPDS at 6weeks or 6 months postpartum. Although a high EPDS score cannot in itself con- firm a diagnosis of depression, a score of more than 12 is widely used to in- dicate a probable depressive disorder. Validation studies indicate high sensi- tivity (68%-95%) and high specificity (78%-96%) of the EPDS against a clini- cal psychiatric diagnosis of depres- sion.15-17 Women with a score of more than 12 on the EPDS were referred to their general practitioners formore for- mal medical assessment. Secondary analyses compared the percentage of women medically diagnosed with de- pression or receiving treatment for de- pression, as reported by women dur- ing pregnancy and at 6 weeks and 6 months postpartum, between the 2 groups. The primary childhood outcome of neurodevelopment at 18 months was assessed by 1 of 4 study psychologists using the Cognitive and Language Composite Scales of the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). The cogni- tive scale evaluates abilities, such as sen- sorimotor development, exploration and manipulation, object relatedness, concept formation,memory, and simple problem solving, and the language scale DHA SUPPLEMENTATION DURING PREGNANCY AND MATERNAL DEPRESSION 1676 JAMA, October 20, 2010—Vol 304, No. 15 (Reprinted) ©2010 American Medical Association. All rights reserved. at University of California - San Francisco on October 27, 2010 www.jama.comDownloaded from is a composite of receptive communi- cation (verbal comprehension, vocabu- lary) and expressive communication (babbling, gesturing, and utterances). Themotor scale, which evaluates both gross and fine motor functioning, as well as the parental report scales of so- cial-emotional behavior and adaptive behavior were assessed as secondary outcomemeasures. The raw scores for each of the scales are standardized to a mean of 100 with an SD of 15 (range, 50-150). The standardized scores were also classified into the categories of ac- celerated performance (�115), within normal limits (85-115), and delayed performance (�85). All 96 preterm children and 630 ran- domly selected term children fromAd- elaide, Australia, were chosen for BSID- III assessment (N=726). The families and trial staff did not knowwhich chil- dren had been randomly selected for follow-up until the infants were 12 months old. At this time, trial assis- tants in each center were supplied with birthday cards for all children, and those selected for follow-up were informed and invited for a BSID-III appoint- ment. The last BSID-III assessment was completed on December 16, 2009. Sample Size and Statistical Analysis Epidemiological data suggest a 7% to 8% absolute reduction (from approxi- mately 16% to 9%) in the prevalence of high levels of depressive symptoms when n-3 LCPUFA intake is increased from the typically low-level intakes commonly observed in Westernized diets to more than 1 g/d.1 Although these data were derived from a well- controlled cohort study, we expected that any effect size of a DHA-rich in- terventionwould be smaller because of possible residual confounding. We therefore powered our trial to detect an absolute reduction of 4.2% (from16.9% to 12.7%) in depressive symptomswith 80%power (�=.05), requiring a sample size of 1121 women per group. The control rate of depressive symptoms was estimated from Australian popu- lation data,18 which was also consis- tent with the epidemiological data from England.1 We planned to enroll 2280 women in total, allowing for 2% loss to follow-up. A minimum clinically meaningful difference in developmental scores is considered to be of the order of 4 points.19 Studies showing differences between nutritional or environment in- terventions of 4 to 5 points or greater have been catalysts for changes inhealth policy.20,21 To detect a difference of 5 points between groups (mean [SD], 100 [15])with 80%power (�=.05) for boys and girls separately, we required a total sample size of 572 children.We there- fore randomly sampled 630 term chil- dren such that half were male, allow- ing for 10% loss to follow-up. The selection process occurred between birth and 1 year. All children born pre- termwere included in the follow-up to enable modeling of the effect of DHA supplementation in pregnancy on all children; those born preterm being more nutritionally and more develop- mentally vulnerable than children born at term.22 All analyses were performed accord- ing to the intention-to-treat principle. Multiple imputation was used to deal with missing data (outcomes and co- variates) and create 50 complete data sets for analysis. Sensitivity analyses were performedon the original data and on imputed data using different seeds for imputation and different imputa- tion models. All produced similar re- sults; therefore, we reported the re- sults of the imputed analyses. Continuous outcomes were ana- lyzed by using linear regression mod- els, following log transformationswhere appropriate, with treatment effects ex- pressed asmeandifferences. Binary out- comes were analyzed using log bino- mial regressionmodels, with treatment effects expressed as relative risks (RRs) or Fisher exact test for rare outcomes. Time-to-event outcomes were ana- lyzed by using stratified log-rank tests. For outcomes measured at multiple time points, dependence was ac- counted for using generalized estimat- ing equations. Models initially in- cluded a treatment� time interaction. Separate estimates of treatment effect are presented at each time point if the interaction was significant or if sepa- rate estimateswere prespecified.Where the interactionwas not significant, this was removed from the model and an overall estimate of treatment effect is presented. Analysis of the primaryma- ternal depression outcome was per- formed on all women and on the sub- group with a previous or current diagnosis of depression at trial entry. Outcomes derived from the BSID-III as- sessment took into account both the sampling design and probability weights, calculated as the inverse of the probability of selection. A priori sec- ondary analyses were performed to test for effect modification by sex and re- sults are presented both overall and by sex, because previous studies suggest that boys and girls may respond differ- ently to DHA supplementation. Both unadjusted and adjusted analy- ses were performed, with adjustment for the stratification variables, center, and parity, as well as any prespecified potential confounders. Statistical sig- nificance was assessed at the 2-sided P� .05 level. No adjustment wasmade formultiple comparisons and results for secondary outcomes should be inter- preted with caution unless they are highly significant. Analyses were per- formed by using SAS version 9.2 (SAS Institute Inc, Cary,NorthCarolina) and Stata Release 11 (Statacorp LP, Col- lege Station, Texas). RESULTS The number of women screened and assessed for the trial, randomly assigned to receive either DHA or con- trol supplementation, are shown in the FIGURE. A total of 2399 women were enrolled and adequate data for the analysis of the primary outcome were available for 2320 women (97.3% in the DHA group and 96.1% in the control group). In addition, 694 ch i ld ren (95 .6% of those selected for follow-up) were assessed at 18 months. Other outcomes and covariates were generally available DHA SUPPLEMENTATION DURING PREGNANCY AND MATERNAL DEPRESSION ©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, October 20, 2010—Vol 304, No. 15 1677 at University of California - San Francisco on October 27, 2010 www.jama.comDownloaded from for more than 95% of participants. The demographic and clinical char- acteristics of the women at random- ization were comparable between the 2 groups, both overall (TABLE 1) and for the subset assessed at 18 months (eTable 1). The families of children se- lected for follow-up also had similar baseline characteristics to those of all other children in the trial (eTable 2). Docosahexaenoic acid concentration in the plasma phospholipids of cord blood from women in the high-DHA group was greater than control (median, 7.22%vs 6.09% total phospholipid fatty acids, P� .001 based on a comparison ofmean log-transformed values). At 28 weeks’ gestation, 35.6% of mothers re- ported that they had not missed tak- ing any capsules and an additional 34.5% reported that they hadmissed 3 or less per week (from a total of 21 cap- sules per week). Fewer than 2% of mothers in each group chose not to take any capsules. Efficacy The percentage of women reporting high levels of depressive symptoms (EPDS score �12) during the first 6 months postpartum did not differ be- tween the DHA and control groups (9.67% vs 11.19%; adjusted RR, 0.85; 95% CI, 0.70-1.02; P=.09) (TABLE 2). Depressive symptomsweremore com- mon among womenwith a previous or current diagnosis of depression at trial entry but did not differ between groups. The percentage of women with a new medical diagnosis for depression dur- ing the trial or a diagnosis requiring treatment also did not differ between groups. Mean cognitive scores of children from women allocated to the DHA group did not differ from mean scores of children of