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

Author summaryWhy was this study done? Dietary guidelines promote intakes of polyunsaturated fatty acids (PUFAs) for cardiometabolic health, whereas evidence on PUFAs for pregnant women is scarce. Experimental and observational studies have linked both dietary and circulating fatty acids to the risk of developing type 2 diabetes, insulin resistance, and beta-cell dysfunction, but only a few studies did for the risk of developing gestational diabetes mellitus (GDM). In particular, evidence is missing for the associations of individual plasma phospholipid PUFAs, rather than total PUFAs conventionally via dietary assessment, with the risk of subsequent GDM. What did the researchers do and find? In this longitudinal study of 107 women with GDM and 214 matched non-GDM women within the prospective National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort in the United States, we evaluated the associations of individual plasma phospholipid PUFAs in early to midpregnancy with a panel of glucose metabolism and cardiometabolic markers and subsequent risk of GDM. Total and individual plasma phospholipid n-3 PUFAs-specifically, diet-derived eicosapentaenoic acid and docosahexaenoic acid-were inversely correlated with insulin-resistance markers but not associated with the risk of GDM. Associations of individual plasma phospholipid n-6 PUFAs with GDM risk were differential, with no associations for the major diet-derived n-6 PUFAs (linolenic acid and arachidonic acid) comprising over 80% of total n-6 PUFAs and with null, positive, or negative associations for minor n-6 PUFAs recognized to be primarily produced from endogenous metabolism of linolenic acid. What do these findings mean? No significant associations of major diet-derived n-6 PUFAs and significant findings for the other minor n-6 PUFAs known to reflect endogenous metabolism suggest a potential role of circulating levels of plasma phospholipid n-6 PUFAs in pathophysiology of GDM. Furthermore, our findings do not provide strong evidence to suggest beneficial roles of primarily diet-derived n-3 PUFAs in prevention of GDM, although also not excluding the possibility of benefit on glucose-insulin homeostasis given their inverse correlations with insulin-resistance markers. Similarly, our findings suggest neither a harmful nor a beneficial role of diet-derived n-6 PUFA linolenic acid in GDM pathophysiology. Our findings among pregnant women highlight the need to recognize the heterogeneous associations of individual circulating PUFAs with subsequent GDM risk and to investigate the underlying metabolism. 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 (