Plasma phospholipid n-3 and n-6 polyunsaturated fatty acids in relation to cardiometabolic markers and gestational diabetes: A longitudinal study within the prospective NICHD Fetal Growth Studies
Open accessAbstract
BACKGROUND: Despite dietary recommendations of polyunsaturated fatty acids (PUFAs) for cardiometabolic health, n-3 and n-6 PUFAs and their interplay in relation to diabetes risk remain debated. Importantly, data among pregnant women are scarce. We investigated individual plasma phospholipid n-3 and n-6 PUFAs in early to midpregnancy in relation to subsequent risk of gestational diabetes mellitus (GDM). METHODS AND FINDINGS: Within the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort (n = 2,802), individual plasma phospholipid n-3 and n-6 PUFAs levels were measured at gestational weeks (GWs) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used, adjusting for major risk factors for GDM. After adjusting for covariates, individual n-3 eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were inversely correlated with insulin-resistance markers, whereas individual n-6 dihomo-gamma-linolenic acid (DGLA) was positively correlated with insulin-resistance markers. At GW 15-26, a standard deviation (SD) increase in total n-3 PUFAs and individual n-3 DPA was associated with a 36% (adjusted odds ratio 0.64; 95% CI 0.42-0.96; P = 0.042) and 33% (0.67; 95% CI 0.45-0.99; P = 0.047) lower risk of GDM, respectively; however, the significance did not persist after post hoc false-discovery rate (FDR) correction (FDR-corrected P values > 0.05). Associations between total n-6 PUFAs and GDM were null, whereas associations with individual n-6 PUFAs were differential. Per SD increase, gamma-linolenic acid (GLA) at GWs 10-14 and DGLA at GWs 10-14 and 15-26 were significantly associated with a 1.40- to 1.95-fold higher risk of GDM, whereas docosatetraenoic acid (DTA) at GW 15-26 was associated with a 45% (0.55; 95% CI 0.37-0.83) lower risk of GDM (all FDR-corrected P values < 0.05). Null associations were observed for linoleic acid (LA) in either gestational window in relation to risk of GDM. Women with high (≥median) n-3 PUFAs and low (<median) n-6 PUFAs levels had a 64% (95% CI 0.14-0.95; P value = 0.039) lower risk of GDM versus women with low n-3 and high n-6 PUFAs. Limitations include the inability to distinguish between exogenous and endogenous influences on circulating PUFA levels and the lack of causality inherent in observational studies. CONCLUSIONS: Our findings may suggest a potential role of primarily endogenously metabolized plasma phospholipid n-6 PUFAs including GLA, DGLA, and DTA in early to midpregnancy in the development of GDM. Null findings on primarily diet-derived n-3 EPA and DHA and n-6 LA do not provide strong evidence to suggest a beneficial role in prevention of GDM, although not excluding the potential benefit of EPA and DHA on glucose-insulin homeostasis given the inverse associations with insulin-resistance markers. Our findings highlight the importance of assessing individual circulating PUFAs to investigate their distinct pathophysiologic roles in glucose homeostasis in pregnancy.
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Omega-6 consumption is associated with increased GDM risk.
“However, a longitudinal study reported increased GDM risk with omega-6 consumption [117].”
From Medical Nutrition Therapy for Women with Gestational Diabetes: Current Practice and Future Perspectives (2025) · cites this paper as [117]
The Results section reports higher GDM risk with higher plasma levels of two individual omega-6 fatty acids, GLA and DGLA. But it reports no significant association for total plasma omega-6 fatty acids, and the Discussion says the primarily diet-derived omega-6 fatty acid LA was not significantly associated with GDM risk. The study measured circulating fatty acids, not omega-6 consumption, so the citation does not support the claim as phrased. (LLM, conf=0.87)
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- Authors
- Zhu, Y., Li, M., Rahman, M. L., Hinkle, S. N., Wu, J., Weir, N. L., Lin, Y., Yang, H., Tsai, M. Y., Ferrara, A., & Zhang, C.
- Affiliations
- Kaiser Permanente (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Harvard University (US)
- Glotech (United States) (US)
- University of Minnesota (US)
- Indiana University Indianapolis (US)
- Peking University First Hospital (CN)
- Corresponding author
- Zhu, Yeyi
- Zhang, Cuilin
- ORCID
- Venue
- PLOS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2019-09-13
- Volume
- 16
- Issue
- 9
- Pages
- e1002910
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- PMC
- PMC6743768
- OpenAlex
- W2972623323
- Cited by
- 79
- References
- 60
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 7 · 2023: 17 · 2022: 12 · 2021: 14 · 2020: 9
- FWCI
- 6.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- creativecommons.org/publicdomain/zero/1.0/ (vor)
- Locations
- PLoS Medicine (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HHSN275200800013C, HHSN275200800002I, HHSN27500006, HHSN275200800003IC, HHSN275200800014C, HHSN275200800012C, HHSN275200800028C, HHSN275201000009C, and HHSN275201000001Z)
- National Institutes of Health (NIH) Building Interdisciplinary Research Careers in Women’s Health Program (5K12HD052163)
- National Institute of Diabetes and Digestive and Kidney Diseases (K01DK120807)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Health Sciences › Medicine › Obstetrics and Gynecology › Gestational Diabetes Research and Management
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- gestational diabetes mellitus, plasma phospholipid fatty acids, omega-3 fatty acids, omega-6 fatty acids, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid, insulin resistance, cardiometabolic risk, pregnancy
- MeSH terms
- Adolescent, Adult, Blood Glucose, Female, Gestational Age, Humans, Insulin, Insulin Resistance, Longitudinal Studies, Nutritional Status, Phospholipids, Pregnancy, Prospective Studies, Risk Factors, Biomarkers, Fatty Acids, Omega-3, Case-Control Studies, Diabetes, Gestational, Risk Assessment, Maternal Nutritional Physiological Phenomena, Fatty Acids, Omega-6, Young Adult
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