Summary of evidence
This systematic review summarizes the available data on the association of circulating omega 3, 6, and 9 fatty acids with GDM. Most included studies have revealed correlations between metabolites and GDM risk factors, especially age, pre-pregnancy BMI, family history of T2D, smoking, ethnicity, systolic blood pressure, and parity. Just one of the included studies evaluated the frequency of physical activity during pregnancy. Studies mostly used Carpenter–Coustan criteria and then IADPSG criteria as diagnostic criteria. GC-MS was the most applied analytical technique.
Mammals can make saturated and omega-9 monounsaturated fatty acids but are unable to synthesize precursors required to produce omega-3 and omega-6 fatty acids which are needed for the body cells to function properly, so these fatty acids, called essential fatty acids, must be supplied through food. However, mammals can produce some longer-chain unsaturated fatty acids through unsaturation and elongation processes. Linoleic acid as an essential omega 6 fatty acid, is a precursor of dihomogamma linoleic acid, arachidonic acid (20:4 n-6, AA), and α-linoleic acid as an essential omega 3 fatty acid, is a precursor of EPA and docosaexahenoic acid (DHA) which are their long-chain metabolites (long-chain PUFAs, LC-PUFAs) [29]. AA and DHA are important components of the cell membranes. For instance, AA is used in the phospholipid part of the membrane of all cells and DHA is an important part of the phospholipids that make up the membrane of the central nervous system [30]. Also, prostaglandins and prostacyclins are among the eicosanoid metabolites of LC-PUFAs that play a key role in placental growth and development, gestational length, and initiation of labor [31].
Pregnancy is associated with changes in the mother’s metabolism to provide the fetus’ needs for proper growth. This period is associated with increased accumulation of lipids in maternal tissue and the later development of maternal hyperlipidemia [32]. During the first months of pregnancy, LC-PUFAs stored in the mother’s adipose tissue acts as the only source of LC-PUFAs for fetal growth [31].
Dietary intake
Studies conducted on the connection between fatty acids received via dietary and their amounts (that is reflected in the blood) revealed that n-3 and n-6 PUFA, in comparison with saturated and monounsaturated fatty acids, have reliable diagnostic worthiness [10]. Omega-6 / omega-3 ratio is an important criterion for determining health. A balance in the consumption of omega 3 and 6 fatty acids is necessary to maintain health throughout the lifecycle as well as a successful pregnancy. An imbalance in this ratio leads to auto-immune and mental disorders, chronic inflammation, and diabetes. Over the past few decades, consumption of Western diets which consist of large amounts of omega-6 fatty acids has increased, leading to a loss of fatty acid balance [30]. A summary of national nutrition studies shows a reduction in the consumption of PUFA, especially omega-3 PUFA, derived from seafood on a global scale [10]. This issue is important and noteworthy in maintaining the health of people in the community, especially pregnant women who are carriers of the next generation.
Insulin resistance
On the other hand, in pregnancy, to ensure the supply of nutrients needed for fetal growth, insulin resistance, and hyperinsulinemia can develop to some extent, which in some women leads to gestational diabetes [33]. The main pathophysiological causes of GDM are considered to be decreased insulin secretion and abnormal insulin resistance, which are associated with impaired fatty acid metabolism [30]. The amount of fat received through the diet and the type of fatty acids that make up the structure of these fats are among the factors that are effective in moderating insulin resistance.
Chen XH et al. reported when Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and C-peptide increased, GDM risk has increased by twofold to fourfold. There was a negative relationship between palmitoleic, oleic, linolenic acids, and HOMA-IR and C-peptide levels. In contrast, arachidonic, dihomo-γ-linolenic (DGLA), and DHAs were positively associated with HOMA-IR and C-peptide [12]. As reported by Muñoz-Nava MA et al., HOMA-IR positively correlated with dihomo-gamma linolenic acids, and negatively with oleic and linoleic acids. Beta-cell function in the GDM group positively correlated with linolenic acid and negatively with oleic acid [24]. In Zhu YY et al. study, among plasma phospholipid n-3 PUFAs at gestational weeks 10–14, EPA inversely correlated with insulin and HOMA-IR [18].
Inflammatory markers
Diabetes is a metabolic disorder caused by increased Inflammation. Fatty acids in the diet are among the factors that can affect the inflammatory pathways [34]. Adipose tissue has a considerable role in GDM development through the synthesis and secretion of a great number of adipocytokines and biologically active materials such as proinflammatory cytokines, acute phase reactants, leptin, resistin, adiponectin, and others. These compounds can lead to insulin resistance when synthesized at high levels. There is a basic connection between fatty acids and inflammation, especially as precursors to eicosanoids as modifiers of inflammation [32]. Plasma total antioxidant capacity could be adjusted by the administration of omega-3 fatty acids and vitamin E in women with GDM [35].
In a study by Chen XH et al., cytokine or adipokine levels could be predicted by the individual FFAs. For instance, women with increased DGLA levels were twice as likely to have higher interleukin (IL)-8. Conversely, women who had higher oleic, palmitoleic, and linolenic acid, had decreased odds for having higher Interleukin-6 (IL-6), Interleukin-8 (IL-8), or tumor necrosis factor-alpha (TNF-α) [12]. Results of a study by Burlina S et al. show that all the inflammatory parameters considered (TNFa, IL6, IL-10, and C-reactive protein) were significantly higher in GDM women than in the NGT group, both during the pregnancy and after delivery [16]. In another study by Zhu YY et al., DHA correlated positively with adiponectin, among plasma phospholipid n-3 PUFAs at gestational weeks 10–14 [18].
BMI
Pre-pregnancy BMI is a considerable risk factor of GDM by which the risks for developing GDM are 2–6 folds greater in women with either pre-pregnancy obesity or extensive gestational weight gain (GWG) [36]. In most obese individuals, elevated plasma FFA concentrations are observed because extended and stressed adipose cells release more FFA and FFA elimination may be diminished. Moreover, elevated FFA can prevent insulin’s antilipolytic action which leads to releasing more FFA into the blood circulation [37]. By characterizing the relationship between maternal BMI and GDM with maternal metabolites and neonatal or cord blood metabolites, the theory of the transgenerational cycle of obesity and diabetes can be verified [38].
In a study by White SL et al., it was indicated that obese GDM women exhibited overstated dyslipidaemic profiles compared with obese non-GDM women, which integrated the effects of insulin resistance in the lipid metabolism pathways and subsequently reduced insulin sensitivity from an earlier gestation in pregnant women [11]. De La Garza Puentes A et al. reported a BMI ≥ 25 in GDM women with a higher rate of LCn6 to LCn3 fatty acids [23]. Wijendran V et al. showed that in women with GDM, maternal plasma phospholipid DHA and n-3 long-chain PUFAs were significantly lower in overweight (BMI: > 25.5 to < 30) than in normal-weight (BMI > 19.8 to ≤25.5) subjects [17].
Physiologic mechanisms of omega fatty acids
Omega-3 PUFA administration result in improvement of lipid profile, inflammatory markers, and glycemic state in GDM through PPAR-gamma which is the members of the nuclear receptors family that control various genes related to fatty acid metabolism [39]. The activity of PPAR-gamma in peripheral blood mononuclear cells (PBMCs) affected by Omega-3 PUFA, enhanced expression of LDL receptor, and decreased inflammatory markers. These accomplish were continued by reduction of fasting glucose, LDL, and triglycerides and rise of HDL levels. Regulation of lipid profile in GDM patients involved of diverse mechanisms. The normal transportation of fatty acids and their suitable concentration mediates by the placenta. The abnormal progress and function of the placenta underlie disturb of Omega-3 and Omega-6 PUFAs balance. Free fatty acid receptor 4 (FFAR4) is one of the factors that expresses in the placenta and has role in the insulin resistance mediation and adipocyte differentiation. The FFAR4 expression may be influenced by polymorphisms, so, they can influence the therapeutic consequences of Omega-3 PUFA administration. Supplementation with Omega-6 PUFAs indicated an increase in the AA levels in GDM which is associated with improved insulin sensitivity, glucose levels, and reducing obesity [40]. The beneficial effect of ω-3 and ω-6 FAs in GDM patients and their offspring have been reported while their role in GDM prevention is unclear. In some of the included studies the changes in levels of these fatty acids were associated with the risk of GDM with inconsistent results. Some others conducted metabolic profiling and it is not obvious the changes in fatty acids are the cause of GDM or these changes are the consequence of GDM. There is a need for cohort studies, especially cohorts in women from pre-pregnancy to postpartum to evaluate this issue.