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Journal of Diabetes and Metabolic Disorders logoLink to Journal of Diabetes and Metabolic Disorders
. 2020 Jun 6;19(2):1685–1699. doi: 10.1007/s40200-020-00558-5

The effects of omega-3 fatty acids supplementation on metabolic status in pregnant women: a systematic review and meta-analysis of randomized controlled trials

Elaheh Amirani 1, Zatollah Asemi 1, Omid Asbaghi 2, Alireza Milajerdi 3,4, Željko Reiner 5, Mohammad Ali Mansournia 6, Jamal Hallajzadeh 7,✉, Bahram Moazzami 8, Shahla Chaichian 8,✉
PMCID: PMC7843696  PMID: 33520859

Abstract

Background and objective

Data regarding the effects of omega-3 polyunsaturated fatty acids (PUFA) supplementation on metabolic status of pregnant women are limited. This systematic review and meta-analysis were done based on randomized controlled trials (RCTs) dealing with the effects of omega-3 PUFA supplementation on glycemic control, lipoproteins, inflammation and oxidative stress in pregnant women.

Methods

Following databases were searched for eligible studies published from inception to until 2019: MEDLINE, EMBASE, Web of Science, PubMed, Scopus, Cochrane Library, and Google scholar. Studies that evaluated the effect of omega-3 PUFA supplementation on parameters of glycemic control, lipoproteins, inflammation and oxidative stress in pregnant women were found by using the key MeSH. A study quality assessment was performed using the Cochrane Collaboration risk of bias tool and heterogeneity between studies was statistically computed using Cochrane’s Q test and I-square (I2). Data were pooled using a random-effects model and weighted mean difference (WMD) was considered as the overall effect size.

Results

No significant effects of omega-3 PUFA supplementation on FPG, insulin, insulin resistance, total cholesterol, triglycerides, LDL-cholesterol, total cholesterol/HDL-cholesterol, interleukin 6 (IL-6), IL-8, and malondialdehyde were found. However, omega-3 PUFA significantly increased serum concentrations of HDL-cholesterol (WMD: 3.10; 95% CI: 0.18, 6.03) and reduced C-reactive protein (WMD: -1.85; 95% CI: -2.61, -1.09).

Conclusion

Based on the results of this meta-analysis omega-3 PUFA supplementation during pregnancy has a significant beneficial effect on HDL-cholesterol, and C-reactive protein.

Keywords: Omega 3 fatty acids, Insulin resistance, Lipoproteins, Inflammation, Oxidative stress, Pregnant woman

Introduction

Pregnancy is associated with a variety of physiological changes in maternal metabolism including maternal insulin resistance, dyslipidemia [1], a moderate inflammation [2], and increased oxidative stress [3]. In pregnancies complicated by obesity, gestational diabetes mellitus (GDM) and pre-eclampsia these changes are even more expressed [4]. Impaired metabolic function in pregnant women probably also affects fetal growth and development [5]. In recent years, attention has been focused on maternal supplementation with different nutrients in order to support additional nutritional demands during pregnancy, improving mother's health and fetal development, and preventing metabolic disorders and adverse pregnancy outcomes [6, 7].

Omega-3 fatty acids are long chain polyunsaturated fatty acids (PUFA). The most important are alpha linoenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).The sources of ALA are vegetable oils like flaxseed and canola, while EPA and DHA are found in fish oils [8]. EPA and DHA are important for brain and retinal development of fetus [9]. Lower levels of omega-3 PUFA have been reported in a number of pregnancy complications such as intrauterine growth restriction (IUGR), pre-eclampsia and GDM [10]. It has been shown that taking omega-3 PUFA during pregnancy increased mean gestational length and decreased the risk of preterm birth and low birthweight [11]. Zhong et al.[12] in a meta-analysis concluded that omega-3 PUFA supplementation in women with GDM was associated with decreased fasting plasma glucose (FPG) levels, insulin resistance and C-reactive protein (CRP) concentrations, but it did not change the pregnancy outcomes. Since omega-3 PUFA have anti-inflammatory effects and participate in the regulation of metabolic pathways, a number of studies have investigated the efficacy of these PUFA on metabolic status in different conditions. A meta-analysis by AbuMweis et al. [13] indicated that taking EPA and DHA supplements decreased plasma levels of CRP and improved some serum lipoproteins. Zhang et al. [14], have found in their meta-analysis that omega-3 PUFA supplementation in overweight and obese adult's decreased serum triglycerides (TG) but did not change total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) levels and FPG.

The efficacy of omega-3 PUFAs supplementation during pregnancy has not been well stablished and the results of studies have been inconclusive. Several randomized controlled trials (RCTs) indicated that omega-3 supplementation in pregnant women might improve some metabolic parameters [15, 16], while several others have not shown beneficial effects [17, 18]. Discrepancies between studies may be due to difference in study design, length of treatment, bioavailability and doses of omega-3 supplements, whether they were performed in healthy or sick pregnant women, previous PUFAs status of mother and the existence of pregnancy complications. We have performed a meta-analysis of RCTs to determine the effects of omega-3 PUFA supplementation on glycemic status, serum lipoproteins concentrations, as well as biomarkers of inflammation and oxidative stress in healthy and sick pregnant women.

Methods

Search strategy

Eligible RCTs were identified using Cochrane Library, Embase, Medline, Scopus, Web of Science, PubMed and Google scholar databases for relevant articles published from inception until 2019, and by manually searching the reference list of the located articles. Studies that evaluated the effects of omega-3 PUFA supplementation on parameters of glycemic control, lipoproteins, inflammation and oxidative stress were found by using MeSH and the following text words: intervention ["omega 3" OR "omega-3" OR "n-3 fatty acid*" OR "polyunsaturated fatty acid" OR PUFA OR "n-3 oil" OR "eicosapentaenoic acid" OR "alpha-linolenic acid" OR "alpha linolenic acid" OR "docosahexaenoic acid" OR "fish oil" OR "cod liver oil"], outcomes ["glycemic control" OR "glucose" OR "fasting plasma glucose" OR "fasting blood glucose" OR "FPG" OR "FBG" OR "FBS" OR "HbA1c" OR "insulin" OR "HOMA" OR "homeostatic model of insulin resistance" OR "lipid profile*" OR "lipoprotein" OR "triglyceride*" OR "cholesterol " OR "LDL" OR "HDL" OR "inflammation" OR "inflammatory markers" OR "C-Reactive Protein" OR "CRP" OR "Interleukin*" "IL" OR "oxidative stress" OR "malondialdehyde" OR "MDA"] and population ["gestation" OR "pregnancy" OR "pregnant" OR "gestational"]. Additional manual searches including reference lists of related studies as well as n reviews were reviewed to increase sensitivity of the search strategy. Studies included in this meta-analysis had to meet the following criteria: 1) original trials, 2) trials on humans, 3) intervention and control groups receiving omega-3 supplementation, and placebo or control, respectively and 4) the trials that reported mean changes or mean difference of metabolic parameters with standard deviation (SD) for the intervention and control groups. The search was restricted to clinical RCTs on humans and those published in English. In this study we did not include trials investigating the effects of flax seed oil supplementation or combined therapy of fish oil with other nutrients.

Data extraction and quality assessment

Two authors (EA and OA) independently extracted the data and assessed its quality using standard forms and the Cochrane Collaboration risk of bias tool [19, 20], respectively. This tool is based on information on the following domains: randomization generation, allocation concealment, blinding of subjects and outcome assessment, incomplete outcome data, and selective outcome reporting, and other sources of bias. When there was a disagreement between them, it was resolved by third author (JH). From eligible studies the following data were obtained: 1) first authors’ name 2) publication year 3) age, sex, and anthropologic parameters and/or metabolic parameters of study participants 4) study location 5) number of subjects in the intervention and control groups 6) study design 7) duration of the intervention.

Data analysis

Heterogeneity and publication biases

The statistical heterogeneity of the results of the included studies was tested using chi-square test [21], and quantified by the I2 statistic [22]. Publication bias was assessed by the funnel plot and tested for statistical significance using the Egger's test [23].

Results

14 Studies with 15 effect sizes were included in this systematic review and meta-analysis. Flow-diagram of studies selection is presented in Fig. 1. Included studies were published from 2006 to 2019. 1468 subjects, including 718 controls, were enrolled in these studies. Participants were healthy, overweight or obese, and allergic pregnant women or those with gestational diabetes mellitus or at risk of depression. Studies were done in Australia, Norway, Germany, USA, Iran, Spain, New Mexico, and Finland. The trials used different doses of omega 3 fatty acids ranging from 1 g/day to 10 ml/day. The duration of intervention varied from 6 to 25 weeks. Studies reported no significant difference concerning side effects between intervention and control groups. TC, LDL-C, HDL-C, TG, TC/HDL-C ratio, FPG, insulin, HOMA-IR, MDA, CRP, IL-6 and IL-8 were measured as outcome in these studies. General characteristics of included studies are summarized in Table 1.

Fig. 2.

Fig. 2

Fig. 2

Fig. 2

Fig. 2

Fig. 2

Fig. 2

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A-H. Meta-analysis metabolic profiles weighted mean difference estimates for A) FPG, B) Insulin, C) HOMA-IR, D) Triglycerides, E) Total cholesterol, F) LDL-cholesterol, G) HDL-cholesterol, H) Total cholesterol/HDL-cholesterol, I) C-reactive protein, J) Interleukin-6, K) Interlukin-8, I) Malondialdehyde in the omega-3 and placebo groups (CI = 95%)

Fig. 1.

Fig. 1

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Literature search and review flowchart for selection of studies

Table 1.

Characteristics of included studies

Authors (Ref) Publication year Sample size (control/
intervention)		 Country/population Intervention (name and daily dose) Duration Age (y)
(control vs. intervention)		 Presented data
Barden et al. [17] 2006 43/40 Australia/ Pregnant women with allergic disease

4 g/d fish oil (56% DHA

 + 27.7% EPA)

≈ 16 weeks

(20 wk until delivery)

 32.4 ± 3.27, 31.0 ± 3.7 TC, LDL-C, HDL-C
Helland et al. [24] 2006 154/160 Norway/ Pregnant women 10 ml/d cod liver oil (1183 mg DHA + 803 mg EPA)

17 weeks

(18 wk until 35)

 19–35 TG, TC, HDL-C, TC/HDL-C
Franke et al. [18] 2010 59/57 Germany/ Pregnant women Modified fish oil in form of milk-based supplements (500 mg DHA + 150 mg EPA)

≈ 20 weeks

(20 wk until delivery)

 31.4 ± 4.7, 30.8 ± 4.8 TG, TC, MDA
Haghiac et al. [15] 2015 24/25 USA/ Overweight or obese pregnant women 2 g/d fish oil (800 mg DHA + 1200 mg EPA) 25 weeks (before 16 wk until delivery) 27 ± 5 FPG, insulin, CRP, IL-6, IL-8
Samimi et al. [25] 2015 28/28 Iran/ Pregnant women with GDM 1 g/d fish oil (120 mg DHA + 180 mg EPA)

6 weeks

(24–28 wk until 6 wk later)

 30.3 ± 5.5, 29.8 ± 5

FPG, insulin, HOMA-IR,

TG, TC, LDL-C, HDL-C, TC/HDL-C
Faraji et al. [26] 2016 47/45 Iran/ Pregnant women with GDM 1 g/d fish oil (120 mg DHA + 180 mg EPA)

≈ 20 weeks

(21 wk until delivery)

 27.3 ± 4.2, 25.6 ± 4.7 TG, TC, LDL-C, HDL-C
Jamilian et al. [16] 2016 27/27 Iran/ Pregnant women with GDM 1 g/d fish oil (120 mg DHA + 180 mg EPA)

6 weeks

(24–28 wk until 6 wk later)

 30.0 ± 5.5, 30.1 ± 5.3 CRP, MDA
Jamilian et al. [27] 2017 35/35 Iran/ Pregnant women with GDM 2 g/d fish oil (240 mg DHA + 360 mg EPA)

6 weeks

(24–28 wk until 6 wk later)

 30.7 ± 4.1, 30.7 ± 3.5 FPG, insulin, HOMA-IR, TG, TC, LDL-C, HDL-C, TC/HDL-C
Razavi et al. [28] 2017 30/30 Iran/ Pregnant women with GDM 2 g/d fish oil (240 mg DHA + 360 mg EPA)

6 weeks

(24–28 wk until 6 wk later)

 29.2 ± 3.4, 29.7 ± 3.6 CRP, MDA
Jamilian et al. [29] 2018 20/20 Iran/ Pregnant women with GDM 2 g/d fish oil (240 mg DHA + 360 mg EPA)

6 weeks

(24–28 wk until 6 wk later)

 30.8 ± 2.4, 30.5 ± 3.8

FPG, insulin, HOMA-IR

TG, TC, LDL-C, HDL-C

CRP
Kajarabille et al. [30] 2018 46/44 Spain/ Pregnant women Fish oil enriched dairy drink (320 mg DHA + 72 mg EPA)

≈ 12 weeks

(28 wk until delivery)

 29.9 ± 4.7, 30.5 ± 4.8 Insulin, IL-6
Mozurkewich et al. (a) [31] 2018 20/37 New Mexico/ Pregnant women at risk for depression

EPA-rich fish oil

(1060 mg EPA + 274 mg DHA)

 minimum: 14 weeks (between 12–20 wk and 34–36 wk) 18–40 IL-6, IL-8
Mozurkewich et al. (b) [31] 2018 20/36 New Mexico/ Pregnant women at risk for depression

DHA-rich fish oil

(900 mg DHA + 180 mg EPA)

 minimum: 14 weeks (between 12–20 wk and 34–36 wk) 18–40 IL-6, IL-8
Vahedi et al. [32] 2018 75/75 Iran/ Pregnant women

1 g fish oil

(120 mg DHA + 180 mg EPA)

20 weeks

(6–10 wk until 26–30)

 26.9 ± 4.5, 25.9 ± 4.8 FPG
Pellonpera et al. [33] 2019 91/90 Finland/ Overweight and obese pregnant women Fish oil containing 2.4 g W3 (1900 mg DHA + 220 mg EPA)

≈ 21 weeks

(14 wk until 35)

 30.4 ± 4.1, 30.4 ± 4.8 FPG, insulin, HOMA-IR
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HOMA IR, homeostasis model assessment of insulin resistance; TG, triglyceride; TC, total cholesterol; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; CRP, C-Reactive Protein; NO, nitric oxide; TAC, total antioxidant capacity; GSH, glutathione; MDA, malondialdehyde; TNF-a, tumor necrosis factor α; IL, interleukin

The effects of omega-3 PUFA on glycemic control

Our meta-analysis showed no significant effects of omega-3 PUFA supplementation on serum concentrations of FPG [Weighted Mean Difference (WMD): 0.11; 95% Confidence Interval (CI): -2.52, 2.74)] and insulin (WMD: -0.79; 95% CI: -2.24, 0.66), and on HOMA-IR (WMD: -0.56; 95% CI: -1.38, 0.26) (Table 2). Different findings were obtained in subgroup analyses. A significant reduction was found in serum levels of FPG following omega-3 PUFA supplementation in studies which lasted ≤ 6 weeks and were performed on patients with GDM. However, omega-3 PUFA supplementation resulted in a significant increase in FPG in studies with a duration of > 6 weeks and those performed on healthy subject. On the other hand, omega-3 PUFA supplementation had a significant effect on reducing insulin level in studies which lasted ≤ 6 weeks, and those using intervention dosage < 1 g/day which were performed on both healthy and GDM subjects. However, duration of intervention for > 6 weeks decreased the insulin levels significantly (Table 3).

Table 2.

Effect of omerga-3 on glycemic control, lipid profile, inflammatory biomarkers and oxidative stress biomarkers

Variables Number of effect sizes Weighted Mean Difference Confidence Interval 95% P-value Heterogeneity
I-squared (%) P-value
Glycemic control FPG 6 0.11 -2.52, 2.74 0.935 71.8% 0.003
Insulin 6 -0.79 -2.24, 0.66 0.285 54.3% 0.053
HOMA-IR 4 -0.56 -1.38, 0.26 0.181 80.3% 0.002
Lipid profile TC 7 5.36 -2.83, 13.56 0.200 77.3% < 0.001
TG 6 -8.38 -27.01, 10.24 0.378 88.4% < 0.001
LDL-C 5 11.98 -0.04, 24.00 0.051 78.1% 0.001
HDL-C 6 3.10 0.18, 6.03 0.038 87.2% < 0.001
TC/HDL 3 -0.15 -0.35, 0.06 0.157 73.0% 0.025
oxidative stress and Inflammatory biomarkers CRP 4 -1.85 -2.61, -1.09 < 0.001 28.0% 0.244
IL-6 4 -5.40 -13.87, 3.08 0.212 98.7% < 0.001
IL-8 3 0.09 -0.54, 0.71 0.780 0.0% 0.855
MDA 3 -0.39 -1.43, 0.66 0.470 90.1% < 0.001
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FPG, fasting plasma glucose; HOMA IR, homeostasis model assessment of insulin resistance; QUICKI, quantitative insulin-sensitivity check index; TC, total cholesterol; TG, triglyceride; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; CRP, C-Reactive Protein; IL, interleukin; MDA, malondialdehyde

Table 3.

Subgroup analysis of omerga-3 on glycemic control, lipid profile

Number of effect sizes Weighted Mean Difference Confidence Interval 95% P-value Heterogeneity
I-squared (%) P-value Between-study I2 (%)
Effect of omerga-3 on FPG
Study duration (week)
> 6 3 2.38 1.28, 3.48 < 0.001 0.0% 0.432 < 0.001
≤ 6 3 -3. 39 -6.28, -0.49 0.022 24.8% 0.265
Dosage (EPA + DHA)
≥ 1 g/d 2 2.20 -0.02, 4.43 0.053 39.3% 0.199 0.587
< 1 g/d 4 1.50 0.35, 2.66 0.011 81.0% 0.001
Health status
Healthy 3 2.38 1.28, 3.48 < 0.001 0.0% 0.432 < 0.001
GDM 3 -3.39 -6.28, -0.49 0.022 24.8% 0.265
Effect of omerga-3 on insulin
Study duration (week)
> 6 3 -0.31 -0.46, -0.15 < 0.001 29.3% 0.243 0.010
≤ 6 3 -3.11 -5.22, -0.99 0.004 0.0% 0.496
Dosage (EPA + DHA)
≥ 1 g/d 2 1.11 -0.74, 2.96 0.240 0.0% 0.457 0.127
< 1 g/d 4 -0.33 -0.48, -0.18 < 0.001 62.7% 0.045
Health status
Healthy 3 -0.31 -0.46, -0.15 < 0.001 29.3% 0.243 0.010
GDM 3 -3.11 -5.22, -0.99 0.004 0.0% 0.496
Effect of omerga-3 on TG
Study duration (week)
> 6 3 -15.31 -22.79, -7.84 < 0.001 94.9% < 0.001 0.878
≤ 6 3 -14.34 -24.19, -4.49 0.004 52.8% 0.120
Dosage (EPA + DHA)
≥ 1 g/d 1 -35.40 -45.18, -25.61 < 0.001 - - < 0.001
< 1 g/d 5 -2.94 -10.44, 4.56 0.442 75.8% 0.002
Health status
Healthy 3 -15.31 -22.79, -7.84 < 0.001 94.9% < 0.001 0.878
GDM 3 -14.34 -24.19, -4.49 0.004 52.8% 0.120
Effect of omerga-3 on TC
Study duration (week)
> 6 4 1.42 -2.73, 5.58 0.501 87.4% < 0.001 0.561
≤ 6 3 3.80 -3.04, 10.65 0.276 12.6% 0.319
Dosage (EPA + DHA)
≥ 1 g/d 2 -3.52 -8.41, 1.37 0.158 89.5% 0.002 0.001
< 1 g/d 5 8.31 3.14, 13.49 0.002 36.1% 0.181
Health status
Healthy 4 1.42 -2.73, 5.58 0.501 87.4% < 0.001 0.561
GDM 3 3.80 -3.04, 10.65 0.276 12.6% 0.319
Effect of omerga-3 on LDL-C
Study duration (week)
> 6 2 28.82 14.60, 43.04 < 0.001 81.8% 0.019 0.002
≤ 6 3 4.20 -1.39, 9.81 0.141 29.0% 0.245
Dosage (EPA + DHA)
≥ 1 g/d 1 47.95 26.53, 69.36 < 0.001 - - < 0.001
< 1 g/d 4 4.96 -0.40, 10.34 0.070 18.9% 0.296
Health status
Healthy 2 28.82 14.60, 43.04 < 0.001 81.8% 0.019 0.002
GDM 3 4.20 -1.39, 9.81 0.141 29.0% 0.245
Effect of omerga-3 on HDL-C
Study duration (week)
> 6 3 4.96 3.75, 6.16 < 0.001 93.9% < 0.001 0.023
≤ 6 3 2.62 1.01, 4.24 0.001 0.0% 0.672
Dosage (EPA + DHA)
≥ 1 g/d 2 5.23 3.99, 6.48 < 0.001 96.7% < 0.001 0.006
< 1 g/d 4 2.45 0.93, 3.98 0.002 0.0% 0.748
Health status
Healthy 3 4.96 3.75, 6.16 < 0.001 93.9% < 0.001 0.023
GDM 3 2.62 1.01, 4.24 0.001 0.0% 0.672
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FPG, fasting plasma glucose; HOMA IR, homeostasis model assessment of insulin resistance; TC, total cholesterol; TG, triglyceride; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; GDM, gestational diabetes mellitus

The effects of omega-3 PUFA on serum lipoproteins

Supplementation with omega-3 PUFA had no significant effects on serum concentrations of TC (WMD: 5.36; 95% CI: -2.83, 13.56), TG (WMD: -8.38; 95% CI: -27.01, 10.24), LDL-C (WMD: 11.98; 95% CI: -0.04, 24.00), and TC/HDL-C (WMD: -0.15; 95% CI: -0.35, 0.06). However, omega-3 PUFA supplementation had a significant effect on increasing HDL-C levels (WMD: 3.10; 95% CI: 0.18, 6.03). Subgroup analysis demonstrated that omega-3 PUFA supplementation increased TC level in studies which used dosage < 1 g/day. All subgroups showed that TG level was significantly reduced after omega-3 PUFA supplementation, except when dosage was less than 1 g/day. LDL-C level was significantly increased in studies with the duration > 6 weeks, when the dosage was ≥ 1 g/day and in those which were performed on healthy women. However, findings of the subgroup analysis did not change the results concerning HDL-C (Table 3).

The effects of omega-3 PUFA on MDA and inflammatory biomarkers

Supplementation with omega-3 PUFA reduced serum CRP concentrations (WMD: -1.85; 95% CI: -2.61, -1.09), but had no significant effect on IL-6 (WMD: -5.40; 95% CI: -13.87, 3.08), IL-8 (WMD: 0.09; 95% CI: -0.54, 0.71) and MDA (WMD: -0.39; 95% CI: -1.43, 0.66) concentrations (Table 2).

Publication bias

Findings from Egger’s regression test demonstrated that there was no considerable publication bias for FPG (P = 0.051), Insulin (P = 0.124), HOMA-IR (P = 0.068), TC (P = 0.233), TG (P = 0.137), LDL-C (P = 0.279), HDL-C (P = 0.085), TC/HDL (P = 0.350), CRP (P = 0.703), IL-6 (P = 0.841), IL-8 (P = 0.623), and MDA (P = 0.213).

Discussion

In this study, for the first time, the data of RCTs with omega-3 PUFA supplementation in pregnant women were analyzed. This meta-analysis showed that taking omega-3 PUFA supplements during pregnancy might increase HDL-C levels and decrease serum CRP concentrations.

Effects on parameters of glycemic control and serum lipoproteins

During the pregnancy different physiologic changes occur in metabolic status, including increased insulin resistance, dyslipidemia, increased inflammatory markers and decreased antioxidant defense system. Exacerbation of these changes is supposed to play an important role in pregnancy complications and negatively affects maternal and infant outcomes [4, 34]. The findings of this meta-analysis suggest that taking omega-3 PUFA supplements during pregnancy significantly increases HDL-C values while does not affect markers related to glycemic status including FPG, serum insulin levels, HOMA-IR, but neither TG, TC, LDL-C and total/HDL-C ratio. Several meta-analyses investigated the effects of omega-3 PUFAs intake in different populations. A meta-analysis by Gao et al.[35], indicated that fish oil supplementation could improve insulin sensitivity in individuals with metabolic disorders. Zhong et al.[12] reported that omega-3 PUFA supplementation decreased FPG and HOMA-IR in women with GDM. Another study demonstrated that taking EPA and DHA containing supplements resulted in a significant increase of both HDL-C and LDL-C levels [13]. A meta-analysis by Choi et al.[36] indicated that combination therapy with omega-3 PUFA and statins in patients with dyslipidemia improved lipid profiles except LDL-C when compared with statin monotherapy. Abdelhamid et al.[37] found that increased intake of fish and plant based omega-3 PUFAs in RCTs that lasted 12 months or more did not change lipid profiles and that increasing EPA and DHA has little or no effect on cardiovascular (CV) risk or mortality. Increased maternal insulin resistance plays a central role in the pathogenesis of GDM which is not a rare complication of pregnancy [38]. On the other hand, a recent study suggested that maternal lipid concentrations were associated with offspring DNA methylation metabolites and developmental epigenetic programming which might have an impact on lifelong disease risk [39]. Decreased insulin sensitivity can be associated with an altered lipid metabolism [40], and both are involved in the development of CV disease in mother and affect offspring health in later life [41, 42]. Omega-3 PUFA may promote insulin sensitivity and lipid profiles by regulation of transcription factors related to carbohydrate and lipid metabolism such as peroxisome proliferator-activated receptor (PPAR) alpha and gamma and sterol regulatory element binding protein-1c (SREBP-1c) [43], increased glucose transporter-4 (GLUT-4) and insulin receptor substrate-1 (IRS-1) expression [44], increased adiponectin secretion and anti-inflammatory functions [45]. Despite the established fact that omega-3 PUFA have TG-lowering effects in appropriate doses, conflicting results of different studies caused uncertainity whether they can prevent CV disease and events, particularly CV deaths [46]. Recently two studies were published analyzing the effects of omega-3 PUFA on serum lipoproteins and CV events on a large number of subjects. The first study was performed on 15,480 patients with diabetes who were treated with 1 g/day of omega-3 PUFA and no significant effect on reducing CV events could be seen [47]. However, in another study on 8,179 patients with elevated triglycerides and either diabetes or CV disease a much higher dose of 4 g/day resulted with a significant reduction of CV events [48, 49].

Effects on inflammation and oxidative stress markers

Our meta-analysis showed that omega-3 PUFA supplementation in pregnant women had a significant effect on CRP plasma levels but did not improve IL-6, IL-8 and MDA. An earlier meta-analysis by AbuMweis et al.[13] indicated that EPA and DHA was effective in reducing CRP levels. Two other meta-analyses also demonstrated that omega-3 PUFA supplementation was associated with a significant decrease in inflammatory markers in patients with T2DM [50] and GDM [12]. According to some studies fish oil supplementation in patients on hemodialysis reduced CRP concentrations without changing IL-6 and TNF-α levels [51]. Sepidarkis et al. [52] in a meta-analysis suggested that co-administration of omega-3 PUFA and vitamin E decreased MDA but did not improve other markers of oxidative stress. Ren et al.[53] reported that taking flaxseed and its derivatives could not improve CRP levels except in obese populations. Another study reported that omega-3 PUFA supplementation did not affect CRP levels in patients with chronic kidney disease [54]. During pregnancy inflammatory state and oxidative stress are associated with an imbalance between angiogenic and antiangiogenic factors which leads to low-flow uteroplacental circulation and chronic fetal hypoxia. This consequently increases the risk of placental abruption, premature rupture of membranes, fetal growth restriction, preeclampsia and stillbirth [55, 56]. Modulation of maternal immune system function and anti-oxidant defense system may be a potential therapeutic target to reduce these adverse pregnancy outcomes [57, 58]. Probable mechanisms by which omega-3 PUFA might achieve anti-inflammatory and antioxidant effects most probably include suppression of generation of pro-inflammatory eicosanoids by competition for active sites of cyclooxygenase and lipoxygenase enzymes, inhibition of nuclear factor kappa B (NF-kB), decreased cytokines production, activation of anti-inflammatory transcription factor PPAR gamma, modulation of cell membrane phospholipids composition, participating in nitric oxide (NO) synthesis, increasing resolvins and protectins production and restored antioxidant capacity [59–61].

This meta-analysis has some limitations. One of the most important is that subjects in the included studies had different clinical characteristics, and the studies were performed on healthy, overweight or obese, and allergic pregnant women as well as those with gestational diabetes mellitus or at risk of depression which might have an influence on the results. Moreover, due to the heterogeneity between the studies concerning variations in duration of omega-3 PUFA intake, the dosage and frequency of omega-3 PUFA used, the results of this meta-analysis should be interpreted with caution. The number of studies and sample size of participant's that finally were included in this meta-analysis was relatively low.

Conclusions

Based on the results of this meta-analysis, it could be concluded that omega-3 PUFA supplementation during pregnancy has a significant beneficial effect on HDL-C and CRP levels. Therefore, omega-3 PUFA intake might play an indirect role in improved pregnancy outcomes due to its effect on HDL-C and CRP levels.

Abbreviations

HOMA IR

homeostasis model assessment of insulin resistance

TG

triglyceride

TC

total cholesterol

HDL-C

HDL cholesterol

LDL-C

LDL cholesterol

CRP

C-Reactive Protein

MDA

malondialdehyde

IL

interleukin

Author contributions

JH and SC contributed in conception, design, statistical analysis and drafting of the manuscript. EA, ZA, OA, AM, MAM, ZR and BM contributed in conception, data collection and manuscript drafting. The final version was confirmed by all authors for submission.

Availability of data and material

The primary data for this study is available from the authors on direct request.

Compliance with ethical standards

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.

Consent for publication

Not applicable.

Competing interests

The authors declare no conflict of interest.

Footnotes

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Contributor Information

Elaheh Amirani, Email: elahe.amirani@rocketmail.com.

Zatollah Asemi, Email: asemi_r@yahoo.com.

Omid Asbaghi, Email: omid.asbaghi@gmail.com.

Alireza Milajerdi, Email: Alimila66@gmail.com.

Željko Reiner, Email: zeljko.reiner@kbc-zagreb.hr.

Mohammad Ali Mansournia, Email: mansournia_ma@yahoo.com.

Jamal Hallajzadeh, Email: jamal.hallaj@yahoo.com.

Bahram Moazzami, Email: bahrammoazzami@gmail.com.

Shahla Chaichian, Email: shchaichian@gmail.com.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The primary data for this study is available from the authors on direct request.

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