Randomised clinical trials of fish oil supplementation in high risk pregnancies
Corresponding Author
Sjúrour F. Olsen
Senior Scientist
Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark
Correspondence: Dr S. F. Olsen (email: [email protected]), Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark
Correspondence: Professor N. J. Secher (email: [email protected]), Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
Search for more papers by this authorCorresponding Author
Niels J. Secher
Professor
Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Denmark
Correspondence: Dr S. F. Olsen (email: [email protected]), Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark
Correspondence: Professor N. J. Secher (email: [email protected]), Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
Search for more papers by this authorAnn Tabor
Chief Physician
Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Copenhagen, Denmark
Search for more papers by this authorTom Weber
Chief Physician
Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Copenhagen, Denmark
Search for more papers by this authorJames J. Walker
Professor
St James University Hospital, Leeds, West Yorkshire
Search for more papers by this authorChristian Gluud
Chief Physician
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Institute of Preventive Medicine, Copenhagen University Hospital, Denmark
Search for more papers by this authorCorresponding Author
Sjúrour F. Olsen
Senior Scientist
Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark
Correspondence: Dr S. F. Olsen (email: [email protected]), Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark
Correspondence: Professor N. J. Secher (email: [email protected]), Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
Search for more papers by this authorCorresponding Author
Niels J. Secher
Professor
Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Denmark
Correspondence: Dr S. F. Olsen (email: [email protected]), Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark
Correspondence: Professor N. J. Secher (email: [email protected]), Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
Search for more papers by this authorAnn Tabor
Chief Physician
Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Copenhagen, Denmark
Search for more papers by this authorTom Weber
Chief Physician
Department of Obstetrics and Gynaecology, Hvidovre University Hospital, Copenhagen, Denmark
Search for more papers by this authorJames J. Walker
Professor
St James University Hospital, Leeds, West Yorkshire
Search for more papers by this authorChristian Gluud
Chief Physician
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Institute of Preventive Medicine, Copenhagen University Hospital, Denmark
Search for more papers by this authorFor a list of all members of the Fish Oil Trials In Pregnancy (FOTIP) Team see page 393
Abstract
Objective To test the postulated preventive effects of dietary n-3 fatty acids on pre-term delivery, intrauterine growth retardation, and pregnancy induced hypertension.
Design In six multicentre trials, women with high risk pregnancies were randomly assigned to receive fish oil (Pikasol) or olive oil in identically-looking capsules from around 20 weeks (prophylactic trials) or 33 weeks (therapeutic trials) until delivery.
Setting Nineteen hospitals in Europe.
Samples Four prophylactic trials enrolled 232, 280, and 386 women who had experienced previous pre-term delivery, intrauterine growth retardation, or pregnancy induced hypertension respectively, and 579 with twin pregnancies. Two therapeutic trials enrolled 79 women with threatening pre-eclampsia and 63 with suspected intrauterine growth retardation.
Interventions The fish oil provided 2.7 g and 6.1 g n-3 fatty acids/day in the prophylactic and therapeutic trials, respectively.
Main outcome measures Preterm delivery, intrauterine growth retardation, pregnancy induced hypertension.
Results Fish oil reduced recurrence risk of pre-term delivery from 33% to 21% (odds ratio 0.54 (95% CI 0.30 to 0.98)) but did not affect recurrence risks for the other outcomes (OR 1.26; 0.74 to 2.12 and 0.98; 0.63 to 1.53, respectively). In twin pregnancies, the risks for all three outcomes were similar in the two intervention arms (95% CI for the three odds ratios were 0.73 to 1.40, 0.90 to 1.52, and 0.83 to 2.32, respectively). The therapeutic trials detected no significant effects on pre-defined outcomes. In the combined trials, fish oil delayed spontaneous delivery (proportional hazards ratio 1.22; 1.07 to 1.39, P= 0.002).
Conclusions Fish oil supplementation reduced the recurrence risk of pre-term delivery, but had no effect on pre-term delivery in twin pregnancies. Fish oil had no effect on intrauterine growth retardation and pregnancy induced hypertension, affecting neither recurrence risk nor risk in twin pregnancies.
References
- 1 Dyerberg J, Bang HO, Hjθrne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr 1975; 28: 958–966.
- 2 Bang HO, Dyerberg J, Hjθrne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand 1976; 200: 69–73.
- 3 Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapen-taenoic acid and prevention of thrombosis and atherosclerosis. Lancet 1978; 2: 117–119.
- 4 Sanders TAB. Marine oils: metabolic effects and role in human nutrition. Proc Nutr Soc 1993; 52: 457–472.
- 5 Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr 1990; 52: 1–28.
- 6 Hansen HS. New biological and clinical roles for the n-6 and n-3 fatty acids. Nutr Rev 1994; 52: 162–167.
- 7 Harris WS, Rothrock DW, Fanning A et al. Fish oils in hypertriglyc-eridemia: a dose-response study. Am J Clin Nutr 1990; 51: 399–406.
- 8 Crawford MA. The role of essential fatty acids in neural development: implications for perinatal nutrition. The role of essential fatty acids in neural development: implications for perinatal nutrition 1993; 57: 703S–709S.
- 9 Uauy R, Hoffman DR, Birch EE, Birch DG, Jameson DM, Tyson J. Safety and efficacy of omega-3 fatty acids in the nutrition of very low birth weight infants: soy oil and marine oil supplementation of formula. J Pediatr 1994; 124: 612–620.
- 10 Carlson SE, Werkman SH. A randomized trial of visual attention of pre-term infants fed docosahexaenoic acid until two months. Lipids 1996; 31: 85–90.
- 11 Olsen SF, Hansen HS, Sθrensen TI et al. Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation. Lancet 1986; 2: 367–369.
- 12 Olsen SF, Hansen HS. Marine fat, birthweight, and gestational age: a case report. Agents Actions 1987; 22: 373–374.
- 13 Olsen SF. Marine n-3 fatty acids ingested in pregnancy as a possible determinant of birth weight: A review of the current epidemiologic evidence (Erratum appeared in American Journal of Epidemiology 1994; 139: 856). Epidemiol Rev 1993; 15: 399–413.
- 14 Andersen HJ, Andersen LF, Fuchs AR. Diet, pre-eclampsia, and intrauterine growth retardation [letter]. Lancet 1989; 1: 1146.
- 15 Olsen SF, Olsen J, Frische G. Does fish consumption during pregnancy increase fetal growth? A study of the size of the newborn, placental weight and gestational age in relation to fish consumption during pregnancy. Int J Epidemiol 1990; 19: 971–977.
- 16 Dyerberg J, Bang HO. Pre-eclampsia and prostaglandins. Lancet 1985; 1: 1267.
- 17 England MJ, Atkinson PM, Sonnendecker EW. Pregnancy induced hypertension: will treatment with dietary eicosapentaenoic acid be effective Med Hypotheses 1987; 24: 179–186.
- 18 Secher NJ, Olsen SF. Fish-oil and pre-eclampsia. Br J Obstet Gynaecol 1990; 97: 1077–1079.
- 19 Pipkin FB. Fish-oil and pre-eclampsia. Br J Obstet Gynaecol 1991; 98: 737–738.
- 20 Secher NJ, Olsen SF, Sθrensen JD. Fish-oil and pre-eclampsia. Br J Obstet Gynaecol 1991; 98: 738–740.
- 21 Secher NJ, Hansen PK, Lenstrup C et al. Birthweight-for-gestational age charts based on early ultrasound estimation of gestational age. Br J Obstet Gynaecol 1986; 93: 128–134.
- 22 Andersen PK. Conditional power calculations as an aid in the decision whether to continue a clinical trial. Clinical Controlled Trials 1987; 8: 67–74.
- 23 Eriksen PS, Secher NJ, Weis-Bentzon M. Normal growth of the fetal biparietal diameter and the abdominal diameter in a longitudinal study. An evaluation of the two parameters in predicting fetal weight. Acta Obstet Gynecol Scand 1985; 64: 65–70.
- 24 Olsen SF, Sθrensen JD, Secher NJ et al. Randomised controlled trial of effect of fish-oil supplementation on pregnancy duration. Lancet 1992; 339: 1003–1007.
- 25 Olsen SF, Secher NJ. A possible preventive effect of low-dose fish oil on early delivery and pre-eclampsia: indications from a 50-year-old controlled trial. Br J Nutr 1990; 64: 599–609.
- 26 People's League of Health. The nutrition of expectant and nursing mothers in relation to maternal and infant mortality and morbidity. J Obstet Gynaecol Br Emp 1946; 53: 498–509.
- 27
People's League of Health.
Nutrition of expectant and nursing mothers.
BMJ
1942; 2: 77–78.
10.1136/bmj.2.4254.77 Google Scholar
- 28 Olsen SF, Hansen HS, Sommer S et al. Gestational age in relation to marine n-3 fatty acids in maternal erythrocytes: a study of women in the Faroe Islands and Denmark. Am J Obstet Gynecol 1991; 164: 1203–1209.
- 29
Olsen SF,
Hansen HS,
Jensen B,
Sθrensen TIA.
Pregnancy duration and the ratio of long-chain n-3 fatty acids to arachidonic acid in erythrocytes from Faroese women.
J Intern Med Suppl
1989; 225: S185–S189.
10.1111/j.1365-2796.1989.tb01454.x Google Scholar
- 30 Olsen SF, Hansen HS, Secher NJ, Jensen B, Sandstrom B. Gestation length and birth weight in relation to intake of marine n-3 fatty acids. Br J Nutr 1995; 73: 397–404.
- 31 Olsen SF, Hansen HS, Sandström M, Jensen B. Erythocyte levels compared with reported dietary intake of marine n-3 fatty acids in pregnant women. Br J Nutr 1995; 73: 387–395.
- 32 Olsen SF, Grandjean P, Weihe P, Videro T. Frequency of seafood intake in pregnancy as a determinant of birth weight: evidence for a dose dependent relationship. J Epidemiol Community Health 1993; 47: 436–440.
- 33 Lange AP. Induction of labour. Dan Med Bull 1984; 31: 89–108.
- 34 Ellwood DA et al. The in-vitro production of prostaglandins by the human cervix during pregnancy: preliminary observations. Br J Obstet Gynaecol 1980; 87: 210–214.
- 35 Olson D, Zakar T, Mitchell B. Prostaglandin synthesis regulation by intrauterine tissues. In: G Rice, Brennecke, editors. Molecular aspects of placental and fetal membrane autacoids. Boca Raton ( Florida ) : CRC Press; 1993: 55–95.
- 36 Geirsson RT, Greer IA. Prostaglandins: a key factor in human labor. Acta Obstet Gynecol Scand 1990; 69: 371–373.
- 37 Mitchell MD, Bibby JG, Hicks BR, Turnbull AC. Possible role for prostacyclin in human parturition. Prostaglandins 1978; 16: 931–1030.
- 38 Williams KI, Dembinska-Kiec A, Zmuda A, Gryglewski RJ. Prostacyclin formation by myometrial and decidual fractions of the pregnant rat uterus. Prostaglandins 1978; 15: 343–349.
- 39 Wikland M, Lindblom B, Hammarstrom S, Wiqvist N. The effect of prostaglandin I on the contractility of the term pregnant human myometrium. Prostaglandins 1983; 26: 905–916.
- 40 Omini C, Folco GC, Pasargiklian R, Fano M, Berti F. Prostacyclin (PG12) in pregnant human uterus. Prostaglandins 1979; 17: 113–120.
- 41 Wilhelmsson L, Wikland M, Wiqvist N. PGH2, TxA2 and PGI2 have potent and differentiated actions on human uterine contractility. Prostaglandins 1981; 21: 277–286.
- 42 Hansen HS, Olsen SF. Dietary (n-3)-fatty acids, prostaglandins, and prolonged gestation in humans. Prog Clin Biol Res 1988; 282: 305–317.
- 43 Olsen SF, Hansen HS, Jensen B. Fish oil versus arachis oil food supplementation in relation to pregnancy duration in rats. Prostaglandins Leukot Essent Fatty Acids 1990; 40: 255–260.
- 44 Baguma-Nibasheka M, Brenna JT, Nathanielsz. Delay of pre-term delivery in sheep by omega-3 long-chain polyunsaturates. Biol Reprod 1999; 60: 698–701.
- 45 Olsen SF. Further on the association between retarded fetal growth and adult cardiovascular diease. Could low intake of marine diets be a common cause J Clin Epidemiol 1994; 47: 565–569.
- 46 Dagnelie PC, van Staveren WA, van Klaveren JD, Burema J. Do children on macrobiotic diets show catch-up growth? A population-based cross-sectional study in children aged 0–8 years. Eur J Clin Nutr 1988; 42: 1007–1016.
- 47 Dar E, Kanarek MS, Anderson HA, Sonzognu WC. Fish consumprion and reproductive outcomes in Green Bay Wisconsin. Environ Res 1992; 59: 189–201.
- 48 Sørensen JD, Olsen SF, Pedersen AK, Boris J, Secher NJ, FitzGerald GA. Effect of fish oil supplementation in the third trimester of pregnancy on prostacyclin and thromboxane production. Am J Obstet Gynecol 1993; 168: 915–922.
- 49 Schiff E, Baruch GB, Barkai G, Peleg E, Rosenthal T, Mashiach S. Reduction of thromboxane A synthesis in pregnancy by polyunsaturated fatty acid supplements. Am J Obstet Gynecol 1993; 168: 122–124.
- 50 Salvig JD, Olsen SF, Secher NJ. Effects of fish oil supplementation in late pregnancy on blood pressure: a randomised controlled trial. Br J Obstet Gynaecol 1996; 103: 529–533.
- 51 Onwude JL, Lilford RJ, Hjartardottir H, Staines A, Tuffnell D. A randomised double blind placebo controlled trial of fish oil in high risk pregnancy. Br J Obstet Gynaecol 1995; 102: 95–100.
- 52 Bulstra-Ramakers MT, Huisjes HJ, Visser GHA. The effects of 3 g eicosapentaenoic acid daily on recurrence of intrauterine growth retardation and pregnancy induced hypertension. Br J Obstet Gynaecol 1995; 102: 123–126.
- 53 Starling MB, McCowan L, Stewart F, Gunn T. Fish-oil and preeclampsia [correspondence]. Br J Obstet Gynaecol 1992; 99: 351–352.
- 54 England MJ, Chetty N, Dukes IAF, Reavis S, Arkinson P, Sonnendecker EWW. Eicosapentaenoic acid in pre-eclampsia: a randomized trial. Proceedings of the Silver Jubilee Congress of Obstetrics and Gynaecology 1989 [abstract].
- 55 Williams MA, Zingheim RW, King IB, Zebelman AM. Omega-3 fatty acids in maternal erythrocytes and risk of preeclampsia. Epidemiology 1995; 6: 232–237.
- 56 Popeski D, Ebbeling LR, Brown PB, Hornstra G, Gerrard JM. Blood pressure during pregnancy in Canadian Inuit: community differences related to diet. Can Med Assoc J 1991; 145: 445–454.
- 57 Pocock SJ. Statistical and ethical issues in monitoring clinical trials. Statistics in Medicine 1993; 12: 1459–1469.
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