Omega-3 supplementation to prevent recurrent preterm birth: a systematic review and metaanalysis of randomized controlled trials

Published:March 07, 2015DOI:
      The purpose of this study was to evaluate the efficacy of omega-3 supplementation for the prevention of recurrent preterm birth (PTB) in asymptomatic singleton gestations with previous PTB. We searched fish oil, long chain polyunsaturated fatty acids, pregnancy, and omega-3 in MEDLINE, OVID, Scopus,, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, and the Cochrane Central Register of Controlled Trials from inception of each database to December 2014 with no limit for language. In addition the reference lists of all identified articles were examined to identify studies that were not captured by electronic searches. We performed a metaanalysis of randomized controlled trials of asymptomatic singleton gestations with previous PTB who were assigned randomly to prophylactic omega-3 supplementation vs control (either placebo or no treatment). The primary outcome was predefined as PTB at <37 weeks of gestation. The pooled results were reported as relative risk (RR) with 95% confidence interval (95% CI). The protocol of this review was registered with PROSPERO (registration number: CRD42015016371). Two randomized controlled trials that included 1080 women were analyzed. The mean gestational age at randomization was approximately 134 days in both groups (mean difference, 0.01 days; 95% CI, –0.13 to 0.14). Women who received omega-3 had similar rates of PTB at <37 weeks of gestation (34.5% vs 39.8%; RR, 0.81; 95% CI, 0.59–1.12) and PTB at <34 weeks of gestation (12.0% vs 15.4%; RR, 0.62; 95% CI, 0.26–1.46) compared with control subjects. The omega-3 groups had a statistically significantly longer latency (mean difference, 2.10 days; 95% CI, 1.98–2.22) and higher birthweight (mean difference, 102.52 g; 95% CI, 20.09–184.95) compared with control subjects; the other secondary outcomes (which included gestational age at delivery, spontaneous PTB at <37 and 34 weeks of gestation, admission to the intensive care unit, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and perinatal death) were similar. Omega-3 supplementation during pregnancy does not prevent recurrent PTB in asymptomatic singleton gestations with previous PTB. The benefits in longer latency and higher birth weight may deserve further study.

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        • Hamilton B.E.
        • Martin J.A.
        • Ventura S.J.
        Births: preliminary data for 2011.
        Natl Vital Stat Rep. 2012; 61: 1-20
        • Spong C.Y.
        Prediction and prevention of recurrent spontaneous preterm birth.
        Obstet Gynecol. 2007; 110: 405-415
        • Karim S.M.
        The role of prostaglandins in human parturition.
        Proc R Soc Med. 1971; 64: 10-12
        • Toppozada M.
        • el Ghazzawi E.
        • Gaweesh S.
        • el Abd M.
        • Samaha A.
        Effect of prostaglandins E2 and 15-methyl F2 alpha on human pregnant and non-pregnant cervix.
        Eur J Obstet Gynecol Reprod Biol. 1987; 26: 27-32
        • Olsen S.F.
        • Hansen H.S.
        • Sorensen T.I.
        • et al.
        Intake of marine fat, rich in n-3-polyunsaturated fatty acids may increase birthweight by prolonging gestation.
        Lancet. 1986; 2: 367
        • Olsen S.F.
        • Secher N.J.
        • Tabor A.
        • Weber T.
        • Walker J.J.
        • Gluud C.
        Randomised clinical trials of fish oil supplementation in high risk pregnancies: Fish Oil Trials in pregnancy (FOTIP).
        BJOG. 2000; 107: 382-395
        • Harper M.
        • Thom E.
        • Klebanoff M.A.
        • et al.
        Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial.
        Obstet Gynecol. 2010; 115: 234-242
      1. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, version 5.1.0 (update March 2011). The Cochrane Collaboration, 2011. Available at: Accessed Dec. 30, 2014.

        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        J Clin Epidemiol. 2009; 62: 1006-1012
        • Olsen S.F.
        • Sorensen J.D.
        • Secher N.J.
        • et al.
        Randomized controlled trial of effect of fish oil supplementation on pregnancy duration.
        Lancet. 1992; 339: 1003-1007
        • Bulstra-Ramakers M.T.E.W.
        • Huisjes H.J.
        • Visser G.H.A.
        The effects of 3g eicosapentaenoic acid daily on recurrence of intrauterine growth retardation and pregnancy induced hypertension.
        BJOG. 1994; 102: 123-126
        • Onwude J.L.
        • Lilford R.J.
        • Hjartardottir H.
        • Staines A.
        • Tuffnell D.
        A randomized double blind placebo controlled trial of fish oil in high risk pregnancy.
        BJOG. 1995; 102: 95-100
        • Malcolm C.A.
        • Hamilton R.
        • McCulloch D.L.
        • Montgomery C.
        • Weaver L.T.
        Scotopic electroretinogram in term infants born of mothers supplemented with docosahexaenoic acid during pregnancy.
        Invest Ophthalmol Vis Sci. 2003; 44: 3685-3691
        • Sanjuro P.
        • Ruiz-Sanz J.I.
        • Jimeno P.
        • et al.
        Supplementation with docosahexaenoic acid in the last trimester of pregnancy: maternal-fetal biochemical findings.
        J Perinat Med. 2004; 32: 132-136
        • Decsi T.
        • Campoy C.
        • Koletzko B.
        Effect of n-3 polyunsaturated fatty acid supplementation in pregnancy: the Nuheal trial.
        Adv Exp Med Biol. 2005; 569: 109-113
        • Tofail F.
        • Kabir I.
        • Hamadani J.D.
        • et al.
        Supplementation of fish-oil and soy-oil during pregnancy and psychomotor development of infants.
        J Health Popul Nutr. 2006; 24: 48-56
        • Makrides M.
        • Gibson R.A.
        • McPhee A.J.
        • Yelland L.
        • Quinlivan J.
        • Ryan P.
        Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial.
        JAMA. 2010; 304: 1675-1683
        • Escolano-Margarit M.V.
        • Ramos R.
        • Beyer J.
        • et al.
        Prenatal DHA status and neurological outcome in children at age 5.5 years are positively associated.
        J Nutr. 2011; 141: 1216-1223
        • Colombo J.
        • Kannass K.N.
        • Shaddy D.J.
        • et al.
        Maternal DHA and the development of attention in infancy and toddlerhood.
        Child Dev. 2004; 75: 1254-1267
        • Boris J.
        • Jensen B.
        • Salving J.D.
        • Secher N.K.
        • Olsen S.F.
        A randomized controlled trial of the effect of fish oil supplementation in late pregnancy and early lactation on the n-3 fatty acid content in human breast milk.
        Lipids. 2004; 39: 1191-1196
        • Borod E.
        • Atkinson R.
        • Barclay W.R.
        • Carlson S.E.
        Effects of third trimester consumption of eggs high in docosahexaenoic acid on docosahexaenoic acid status and pregnancy.
        Lipids. 1999; 34: S231
        • Van Houwelingen A.C.
        • Sorensen J.D.
        • Hornstra G.
        • et al.
        Essential fatty acid status in neonates after fish oil supplementation during late pregnancy.
        Br J Nutr. 1995; 74: 723-731
        • Montgomery C.
        • Speake B.K.
        • Cameron A.
        • Sattar N.
        • Weaver L.T.
        Maternal docosahexaenoic acid supplementation and fetal accretion.
        Br J Nutr. 2003; 90: 135-145
        • Salving J.D.
        • Olsen S.F.
        • Secher N.J.
        Effect of fish oil supplementation in late pregnancy on blood pressure: a randomized controlled trial.
        BJOG. 1996; 103: 529-533
        • Smuts C.M.
        • Huang M.
        • Mundy D.
        • Plasse T.
        • Major S.
        • Carlson S.E.
        A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy.
        Obstet Gynecol. 2003; 101: 469-479
        • D’Almeida A.
        • Carter J.P.
        • Anatol A.
        • Prost C.
        Effects of a combination of evening primrose oil (gamma linolenic acid) and fish oil (eicosapentaenoic + docosahexaenoic acid) versus magnesium, and versus placebo in preventing preeclampsia.
        Women Health. 1992; 19: 117-131
        • De Groot R.H.
        • Hornstra G.
        • van Houwelingen A.C.
        • Roumen F.
        Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome.
        Am J Clin Nutr. 2004; 79: 251-260
        • Herrera J.A.
        • Arevalo-Herrera M.
        • Herrera S.
        Prevention of preeclampsia by linoleic acid and calcium supplementation: a randomized controlled trial.
        Obstet Gynecol. 1998; 91: 585-590
        • Colombo J.
        • Carlson S.E.
        • Cheatham C.L.
        • et al.
        Long-term effects of LCPUFA supplementation on childhood cognitive outcomes.
        Am J Clin Nutr. 2013; 98: 403-412
        • Olsen S.F.
        • Secher N.J.
        A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: indication from a 50-year-old controlled trial.
        Br J Nutr. 1990; 64: 599-609
        • Laivuori H.
        • Hovatta O.
        • Viinikka L.
        • Ylikorkala O.
        Dietary supplementation with primrose oil or fish oil does not change urinary excretion of prostacyclin and thromboxane metabolites in pre-eclamptic women.
        Prostaglandins Leukot Essent Fatty Acids. 1993; 49: 691-694
        • Helland I.B.
        • Saugstad O.D.
        • Smith L.
        • et al.
        Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women.
        Pediatrics. 2001; 108: E82
        • Knudsen V.K.
        • Hansen H.S.
        • Osterdal M.L.
        • Mikkelsen T.B.
        • Mu H.
        • Olsen S.F.
        Fish oil in various doses or flax oil in pregnancy and timing of spontaneous delivery: a randomized controlled trial.
        BJOG. 2006; 113: 536-543
        • Gould J.F.
        • Makrides M.
        • Colombo J.
        • Smithers L.G.
        Randomized controlled trial of maternal omega-3 long-chain PUFA supplementation during pregnancy and early childhood development of attention, working memory, and inhibitory control.
        Am J Clin Nutr. 2014; 99: 851-859
        • Mulder K.A.
        • King D.J.
        • Innis S.M.
        Omega-3 fatty acid deficiency in infants before birth identified using a randomized trial of maternal DHA supplementation in pregnancy.
        PloS One. 2014; 9: e83764
        • Smuts C.M.
        • Borod E.
        • Peeples J.M.
        • Carlson S.E.
        High-DHA eggs: feasibility as a means to enhance circulating DHA in mother and infant.
        Lipids. 2003; 38: 407-414
        • Saccone G.
        • Berghella V.
        Omega-3 long chain polyunsaturated fatty acids to prevent preterm birth: a systematic review and meta-analysis.
        Obstet Gynecol. 2015; 3: 663-672
        • Szajewska H.
        • Horvath A.
        • Koletzko B.
        Effect of n-3 long-chain polyunsaturated fatty acid supplementation of women with low-risk pregnancies on pregnancy outcome and growth measures at birth: a meta-analysis of randomized controlled trials.
        Am J Clin Nutr. 2006; 83: 1337-1344
        • Makrides M.
        • Duley L.
        • Olsen S.F.
        Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction.
        Cochrane Database Syst Rev. 2006; 19: CD003402
        • Iams J.D.
        • Berghella V.
        Care for women with prior preterm birth.
        Am J Obstet Gynecol. 2010; 203: 89-100
        • Sargi S.C.
        • Dalalio M.M.
        • Moraes A.G.
        • Visentainer J.E.
        • Morais D.R.
        • Visentainer J.V.
        Role of omega-3 polyunsaturated fatty acids in the production of prostaglandin E2 and nitric oxide during experimental murine paracoccidioidomycosis.
        Biomed Res Int. 2013; 2013: 947687
        • James M.J.
        • Gibson R.A.
        • Cleland L.G.
        Dietary polyunsaturated fatty acids and inflammatory mediator production.
        Am J Clin Nutr. 2000; 71: 343S-348S
        • Zhang P.
        • Smith R.
        • Chapkin R.S.
        • McMurray D.N.
        Dietary (n-3) polyunsaturated fatty acids modulate murine Th1/Th2 balance toward the Th2 pole by suppression of Th1 development.
        J Nutr. 2005; 135: 1745-1751