Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lipids and cardiovascular disease

Impact of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring neurodevelopment: 5-year follow-up of a randomized controlled trial

Abstract

Background/Objectives:

Evidence regarding the effect of n-3 long-chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on offspring’s neurodevelopment is not conclusive.

Subjects/Methods:

In this analysis, the effect of a reduced n-6:n-3 LCPUFA ratio in the diet of pregnant/lactating women (1.2 g n-3 LCPUFA together with an arachidonic acid (AA)-balanced diet between 15th wk of gestation-4 months postpartum vs control diet) on child neurodevelopment at 4 and 5 years of age was assessed. A child development inventory (CDI) questionnaire and a hand movement test measuring mirror movements (MMs) were applied and the association with cord blood LCPUFA concentrations examined.

Results:

CDI questionnaire data, which categorizes children as ‘normal’, ‘borderline’ or ‘delayed’ in different areas of development, showed no significant evidence between study groups at 4 (n=119) and 5 years (n=130) except for the area ‘letters’ at 5 years of age (P=0.043). Similarly, the results did not strongly support the hypothesis that the intervention has a beneficial effect on MMs (for example, at 5 years: dominant hand, fast: adjusted mean difference, −0.08 (−0.43, 0.26); P=0.631). Children exposed to higher cord blood concentrations of docosahexaenoic acid, eicosapentaenoic acid and AA, as well as a lower ratio of n-6:n-3 fatty acids appeared to show beneficial effects on MMs, but these results were largely not statistically significant.

Conclusions:

Our results do not show clear benefits or harms of a change in the n-6:n-3 LCPUFA ratio during pregnancy on offspring’s neurodevelopment at preschool age. Findings on cord blood LCPUFAs point to a potential influence on offspring development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kapur A . Pregnancy: a window of opportunity for improving current and future health. Int J Gynaecol Obstet 2011; 115 (Suppl 1), S50–S51.

    Article  Google Scholar 

  2. Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF . The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res 2001; 40: 1–94.

    Article  CAS  Google Scholar 

  3. Innis SM . Dietary (n-3) fatty acids and brain development. J Nutr 2007; 137: 855–859.

    Article  CAS  Google Scholar 

  4. Rogers LK, Valentine CJ, Keim SA . DHA supplementation: current implications in pregnancy and childhood. Pharmacol Res 2013; 70: 13–19.

    Article  CAS  Google Scholar 

  5. Lauritzen L, Carlson SE . Maternal fatty acid status during pregnancy and lactation and relation to newborn and infant status. Matern Child Nutr 2011; 7 (Suppl 2), 41–58.

    Article  Google Scholar 

  6. Koletzko B, Lien E, Agostoni C, Bohles H, Campoy C, Cetin I et al. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. J Perinat Med 2008; 36: 5–14.

    CAS  PubMed  Google Scholar 

  7. Hibbeln JR, Davis JM, Steer C, Emmett P, Rogers I, Williams C et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet 2007; 369: 578–585.

    Article  Google Scholar 

  8. Oken E, Radesky JS, Wright RO, Bellinger DC, Amarasiriwardena CJ, Kleinman KP et al. Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol 2008; 167: 1171–1181.

    Article  Google Scholar 

  9. Mendez MA, Torrent M, Julvez J, Ribas-Fito N, Kogevinas M, Sunyer J . Maternal fish and other seafood intakes during pregnancy and child neurodevelopment at age 4 years. Public Health Nutr 2009; 12: 1702–1710.

    Article  Google Scholar 

  10. Steer CD, Lattka E, Koletzko B, Golding J, Hibbeln JR . Maternal fatty acids in pregnancy, FADS polymorphisms, and child intelligence quotient at 8 y of age. Am J Clin Nutr 2013; 98: 1575–1582.

    Article  CAS  Google Scholar 

  11. Cheruku SR, Montgomery-Downs HE, Farkas SL, Thoman EB, Lammi-Keefe CJ . Higher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Am J Clin Nutr 2002; 76: 608–613.

    Article  CAS  Google Scholar 

  12. Krabbendam L, Bakker E, Hornstra G, van Os J . Relationship between DHA status at birth and child problem behaviour at 7 years of age. Prostaglandins Leukot Essent Fatty Acids 2007; 76: 29–34.

    Article  CAS  Google Scholar 

  13. Bakker EC, Hornstra G, Blanco CE, Vles JS . Relationship between long-chain polyunsaturated fatty acids at birth and motor function at 7 years of age. Eur J Clin Nutr 2009; 63: 499–504.

    Article  CAS  Google Scholar 

  14. Jacobson JL, Jacobson SW, Muckle G, Kaplan-Estrin M, Ayotte P, Dewailly E . Beneficial effects of a polyunsaturated fatty acid on infant development: evidence from the inuit of arctic Quebec. J Pediatr 2008; 152: 356–364.

    Article  CAS  Google Scholar 

  15. Meldrum S, Dunstan JA, Foster JK, Simmer K, Prescott SL . Maternal fish oil supplementation in pregnancy: a 12 year follow-up of a randomised controlled trial. Nutrients 2015; 7: 2061–2067.

    Article  CAS  Google Scholar 

  16. Campoy C, Escolano-Margarit MV, Anjos T, Szajewska H, Uauy R . Omega 3 fatty acids on child growth, visual acuity and neurodevelopment. Br J Nutr 2012; 107 (Suppl 2), S85–106.

    Article  CAS  Google Scholar 

  17. Dziechciarz P, Horvath A, Szajewska H . Effects of n-3 long-chain polyunsaturated fatty acid supplementation during pregnancy and/or lactation on neurodevelopment and visual function in children: a systematic review of randomized controlled trials. J Am Coll Nutr 2010; 29: 443–454.

    Article  CAS  Google Scholar 

  18. Hadders-Algra M . Prenatal and early postnatal supplementation with long-chain polyunsaturated fatty acids: neurodevelopmental considerations. Am J Clin Nutr 2011; 94 (6 Suppl), 1874s–1879s.

    Article  CAS  Google Scholar 

  19. Gould JF, Smithers LG, Makrides M . 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. Am J Clin Nutr 2013; 97: 531–544.

    Article  CAS  Google Scholar 

  20. Hauner H, Vollhardt C, Schneider KT, Zimmermann A, Schuster T, Amann-Gassner U . The impact of nutritional fatty acids during pregnancy and lactation on early human adipose tissue development. Rationale and design of the INFAT study. Ann Nutr Metab 2009; 54: 97–103.

    Article  CAS  Google Scholar 

  21. Hauner H, Much D, Vollhardt C, Brunner S, Schmid D, Sedlmeier EM et al. Effect of reducing the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on infant adipose tissue growth within the first year of life: an open-label randomized controlled trial. Am J Clin Nutr 2012; 95: 383–394.

    Article  CAS  Google Scholar 

  22. Much D, Brunner S, Vollhardt C, Schmid D, Sedlmeier EM, Bruderl M et al. Effect of dietary intervention to reduce the n-6/n-3 fatty acid ratio on maternal and fetal fatty acid profile and its relation to offspring growth and body composition at 1 year of age. Eur J Clin Nutr 2013; 67: 282–288.

    Article  CAS  Google Scholar 

  23. Much D, Brunner S, Vollhardt C, Schmid D, Sedlmeier EM, Bruderl M et al. Breast milk fatty acid profile in relation to infant growth and body composition: results from the INFAT study. Pediatr Res 2013; 74: 230–237.

    Article  CAS  Google Scholar 

  24. Brei C, Stecher L, Much D, Karla MT, Amann-Gassner U, Shen J et al. Reduction of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring body composition: follow-up results from a randomized controlled trial up to 5 y of age. Am J Clin Nutr 2016; 103: 1472–1481.

    Article  CAS  Google Scholar 

  25. Ireton H Child Development Inventory Manual. Behavior Science Systems, Inc: Minneapolis, MN, USA, 1992, 1–39.

  26. Brandstetter G, Siebler V, Schneider H, Grässle A, Steinmacher J, Bode H . Elternfragebogen zur Entwicklung im Kleinkindalter (EFkE) - ein Screeninginstrument: I. Normierung. Kinderarztl Prax 2002; 5: 338–344.

    Google Scholar 

  27. Brandstetter G, Bode H, Ireton HR Elternfragebogen zur kindlichen Entwicklung (EFkE) Manual, 1st edn. Verlag Alexander Möckl: Augsburg, Germany, 2003..

  28. Hermsdörfer J, Mai N, Marquardt C . Evaluation of precision grip using pneumatically controlled loads. J Neurosci Methods 1992; 45: 117–126.

    Article  Google Scholar 

  29. Uttner I, Mai N, Esslinger O, Danek A . Quantitative evaluation of mirror movements in adults with focal brain lesions. Eur J Neurol 2005; 12: 964–975.

    Article  CAS  Google Scholar 

  30. Uttner I, Kraft E, Nowak DA, Muller F, Philipp J, Zierdt A et al. Mirror movements and the role of handedness: isometric grip forces changes. Motor Control 2007; 11: 16–28.

    Article  Google Scholar 

  31. Doig KB, Macias MM, Saylor CF, Craver JR, Ingram PE . The child development inventory: a developmental outcome measure for follow-up of the high-risk infant. J Pediatr 1999; 135: 358–362.

    Article  CAS  Google Scholar 

  32. Brandstetter G . Manualeinlage - Ergänzung zum Kapitel 3.3. Reliabilität und Validität, 2005. In: Brandstetter G, Bode H, Ireton HR. Elternfragebogen zur kindlichen Entwicklung (EFkE), Manual, 1st edn. Verlag Alexander Möckl: Augsburg, Germany, 2003.

  33. Meldrum SJ, Smith MA, Prescott SL, Hird K, Simmer K . Achieving definitive results in long-chain polyunsaturated fatty acid supplementation trials of term infants: factors for consideration. Nutr Rev 2011; 69: 205–214.

    Article  Google Scholar 

  34. D'Agati E, Casarelli L, Pitzianti MB, Pasini A . Overflow movements and white matter abnormalities in ADHD. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 441–445.

    Article  Google Scholar 

  35. Barnea-Goraly N, Menon V, Eckert M, Tamm L, Bammer R, Karchemskiy A et al. White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. Cereb Cortex 2005; 15: 1848–1854.

    Article  Google Scholar 

  36. Kuratko CN, Barrett EC, Nelson EB, Salem N Jr. . The relationship of docosahexaenoic acid (DHA) with learning and behavior in healthy children: a review. Nutrients 2013; 5: 2777–2810.

    Article  CAS  Google Scholar 

  37. Koerte I, Eftimov L, Laubender RP, Esslinger O, Schroeder AS, Ertl-Wagner B et al. Mirror movements in healthy humans across the lifespan: effects of development and ageing. Dev Med Child Neurol 2010; 52: 1106–1112.

    Article  Google Scholar 

  38. Janssen CI, Kiliaan AJ . Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration. Prog Lipid Res 2014; 53: 1–17.

    Article  CAS  Google Scholar 

  39. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA . Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics 2003; 111: e39–e44.

    Article  Google Scholar 

  40. Helland IB, Smith L, Blomen B, Saarem K, Saugstad OD, Drevon CA . Effect of supplementing pregnant and lactating mothers with n-3 very-long-chain fatty acids on children's IQ and body mass index at 7 years of age. Pediatrics 2008; 122: e472–e479.

    Article  Google Scholar 

  41. Escolano-Margarit MV, Ramos R, Beyer J, Csabi G, Parrilla-Roure M, Cruz F et al. Prenatal DHA status and neurological outcome in children at age 5.5 years are positively associated. J Nutr 2011; 141: 1216–1223.

    Article  CAS  Google Scholar 

  42. Campoy C, Escolano-Margarit MV, Ramos R, Parrilla-Roure M, Csabi G, Beyer J et al. Effects of prenatal fish-oil and 5-methyltetrahydrofolate supplementation on cognitive development of children at 6.5 y of age. Am J Clin Nutr 2011; 94 (6 Suppl), 1880S–1888S.

    Article  CAS  Google Scholar 

  43. Makrides M, Gould JF, Gawlik NR, Yelland LN, Smithers LG, Anderson PJ et al. Four-year follow-up of children born to women in a randomized trial of prenatal DHA supplementation. JAMA 2014; 311: 1802–1804.

    Article  CAS  Google Scholar 

  44. Gould JF, Treyvaud K, Yelland LN, Anderson PJ, Smithers LG, McPhee AJ et al. Prenatal supplementation with DHA improves attention at 5 y of age: a randomized controlled trial. JAMA 2017; 317: 1173–1175.

    Article  Google Scholar 

  45. Ramakrishnan U, Gonzalez-Casanova I, Schnaas L, DiGirolamo A, Quezada AD, Pallo BC et al. Prenatal supplementation with DHA improves attention at 5 y of age: a randomized controlled trial. Am J Clin Nutr 2016; 104: 1075–1082.

    Article  CAS  Google Scholar 

  46. Dunstan JA, Simmer K, Dixon G, Prescott SL . Cognitive assessment of children at age 2(1/2) years after maternal fish oil supplementation in pregnancy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2008; 93: F45–F50.

    Article  CAS  Google Scholar 

  47. Ghys A, Bakker E, Hornstra G, van den Hout M . Red blood cell and plasma phospholipid arachidonic and docosahexaenoic acid levels at birth and cognitive development at 4 years of age. Early Hum Dev 2002; 69: 83–90.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We kindly thank Karina Pusch for her support in data collection and trial management. We also thank all families and their children for participating in the study. The study was supported by grants from the Else Kröner-Fresenius Foundation, Bad Homburg; the European Union-funded Early Nutrition Programming Project (EARNEST) consortium (FOOD-CT-2005-007036); and the German Ministry of Education and Research via the Competence Network Obesity (Kompetenznetz Adipositas, 01GI0842). HH has received grants from Riemser and Weight Watchers for clinical trials and payment for lectures from Novartis, Roche Germany and Sanofi-Aventis.

Disclaimer

The analysis of fatty acids was performed by the Laboratory of Lipid Research, Danone Research—Center for Specialised Nutrition using coded samples. There was no intervention from any sponsor with any of the research aspects of the study, including study design, intervention, data collection, data analysis and interpretation, as well as writing of the manuscript.

Author contributions

HH designed the research; RE and FH were involved in the methodological design and gave scientific advice; CB and SB were responsible for the data collection and trial management; PDW and JH developed the algorithm for the mirror movement analysis, provided scientific advice regarding the analysis and edited previous versions of the manuscript; CB analyzed the data; CB and LS were responsible for statistical analysis; CB wrote the manuscript; and all authors contributed to the critical revision of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H Hauner.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on European Journal of Clinical Nutrition website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brei, C., Stecher, L., Brunner, S. et al. Impact of the n-6:n-3 long-chain PUFA ratio during pregnancy and lactation on offspring neurodevelopment: 5-year follow-up of a randomized controlled trial. Eur J Clin Nutr 71, 1114–1120 (2017). https://doi.org/10.1038/ejcn.2017.79

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2017.79

This article is cited by

Search

Quick links