The Effect of Dietary Supplements on Oxidative Stress in Pregnant Women with Gestational Diabetes Mellitus: A Network Meta-Analysis

Background: Gestational diabetes mellitus (GDM) exacerbates the oxidative stress status of the pregnant women. Τo improve the oxidative stress status, several therapeutic interventions have been suggested. The aim of this network meta-analysis is to assess the effect of different dietary supplements on the oxidative stress status in pregnant women with GDM. Methods: A network meta-analysis of randomized control trials was performed comparing the changes delta (Δ) in total antioxidant capacity (TAC) and concentration of malondialdehyde (MDA) as primary outcomes, following different therapeutic interventions with dietary supplements in pregnant women with GDM. Four electronic databases and grey literature sources were searched. The secondary outcomes were other markers of oxidative stress. Results: The meta-analysis included 16 studies of 1173 women with GDM. Regarding ΔTAC: probiotics and omega-3 with vitamin E were superior to placebo/no intervention. Regarding ΔMDA: vitamin D with calcium, omega-3, vitamin D, omega-3 with vitamin E, magnesium with zinc and calcium, and probiotics were superior to placebo/no intervention. Conclusions: Administration of dietary supplements in women with GDM can be helpful in limiting the oxidative stress which develop in these pregnancies.


Introduction
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during the second or third trimester of pregnancy excluding cases of clearly overt diabetes [1]. It is estimated that 17 million or 13.2% of live births to women in 2019 were affected from gestational diabetes mellitus (GDM) [2]. Despite the abundance of management strategies against diabetes, there is still need for both effective and harmless treatments in GDM.
Oxidative stress is defined as an imbalanced equilibrium between the production of reactive oxygen species (ROS) and antioxidant defenses [3]. Increased levels of free radicals and lipid peroxides constitute a normal phenomenon during pregnancy [4,5]. However, excessive oxidation is reported in pregnancies complicated with GDM, mainly due to hyperglycaemia. Excess glucose is responsible for increased free radical production by activating several metabolic mechanisms, such as the polyol pathway, formation of AGE, activation of protein kinase C (PKC), the hexosamine pathway and directly by encouraging the ROS production in the placental mitochondria [3,4,6,7]. Increased levels of oxidative    One oral synbiotic capsule containing Lactobacillus acidophilus strain T16, L. casei strain T2 and Bifidobacterium bifidum strain T1 (2 × 10 9 CFU/g each) plus 800 mg inulin 6 weeks Primary outcomes were inflammatory markers (hs-CRP). The secondary outcomes were biomarkers of oxidative stress (TAC, NO, GSH, MDA) and pregnancy outcomes (c-section, preterm delivery, pre-eclampsia, polyhydramnios, maternal hospitalization, macrosomia > 4000 g, gestational age, newborns' weight, newborns' length, newborns' head circumference, Apgar score, newborns' hyperbilirubinemia, newborns' hypoglycemia)
The network plot for the changes in the MDA is presented in Figure 2b. All interventions were pairwise tested in 10 studies. The most common comparison was probiotic supplementation vs. no intervention (two studies) [25,28]. The most studied patients were included in probiotics vs. placebo (120 patients, two studies) [25,28] and Omega-3 versus placebo (114 patients, two studies) [31,33]. Placebo/no intervention was given in 299 patients (ten studies) [23,25,[28][29][30][31][32][33]35,36]. Network plots for the primary outcomes of (a) ΔTAC (changes in total antioxidant capacity) and (b) ΔMDA (changes in malondialdehyde). Interventions are represented by nodes and head-to-head comparisons with edges. The size of the nodes is proportional to the number of the patients, while the thickness of the edges is proportional to the number of studies. The color of the edges represents the average risk of bias for each head-to-head comparison, green for low risk of bias, yellow for uncertain risk of bias, and red for high risk of bias.

Risk of Bias
The risk of bias is presented in Table 2. The randomization procedure was not described in one study [37]. The exercise study used a diet modification as intervention (soy protein as part of total protein), therefore blindness was not possible [35]. However, the effect of lack of blinding of the assessors is likely to be limited, as the outcomes (effects on metabolic profile, inflammatory factors and biomarkers of oxidative stress) are objectively Network plots for the primary outcomes of (a) ∆TAC (changes in total antioxidant capacity) and (b) ∆MDA (changes in malondialdehyde). Interventions are represented by nodes and head-to-head comparisons with edges. The size of the nodes is proportional to the number of the patients, while the thickness of the edges is proportional to the number of studies. The color of the edges represents the average risk of bias for each head-to-head comparison, green for low risk of bias, yellow for uncertain risk of bias, and red for high risk of bias.

Risk of Bias
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Deviations from Intended Interventions
Missing Outcome Data

Overall
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Assessment of Transitivity and Inconsistency
No discrepancies in study and participant characteristics or the definition of interventions and outcomes were detected among studies which compared more than one dietary supplements (Table 1). Transitivity was examined by assessing inconsistency. No such inconsistency was detected.
Furthermore, the result of the leave one out analysis, showed that there was no study diverting from the average estimate ( Figure S1).  Table 3). Regarding relative ranking, among all supplements administrated, omega-3 with vitamin E had the highest SUCRA value (95.5%), followed by soy (72.3%) and probiotics (67.2%), while placebo/no intervention was the least effective ( Figure 4a).  Table 4). Regarding relative ranking: among all supplements administrated omega-3 had the highest SUCRA value (66.6%), closely followed by zinc (65.2%), while placebo/no intervention was the least effective ( Figure 4b).       Table 5). In terms of relative ranking, omega-3 with vitamin E had the highest SUCRA value (77.3%), followed by omega-3 with vitamin D (73.6%) and probiotics (69.3%); vitamin D with calcium were the least effective (Table S2).   Table 4). Regarding relative ranking: among all supplements administrated omega-3 had the highest SUCRA value (66.6%), closely followed by zinc (65.2%), while placebo/no intervention was the least effective ( Figure 4b).

Small-Study Effects
Comparison-adjusted funnel plots were symmetric for all outcomes, indicating a lack of significant small study effect ( Figure 5).

Quality of the Evidence
The overall quality of the evidence as per GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria adapted for network meta-analysis was moderate to high and is presented in detail in Tables S3 and S4 [38].
Study limitations: the contributions of direct and indirect data to the network estimate are presented in Figure S4. The evidence in all network estimates was downgraded (a) by one level, if >50% of the information came from studies at "some concerns" or "high risk" of bias, (b) by two levels, if >50% of the information came from studies at "high risk" of bias.
Indirectness: There were no differences in the baseline patient characteristics (including the BMI at randomization) among the studies. Thus, no downgrading took place.
Inconsistency: Due to the lack of closed loops, the point estimates of direct and indirect comparisons were evaluated. The evidence was downgraded by one level, if the prediction intervals extended across the line of no effect. Imprecision: The evidence was downgraded by one level, if the prediction intervals extended across the line of no effect.
Publication bias: The comparison-adjusted funnel plot was symmetric for all outcomes ( Figure 5). Thus, no downgrading took place.

Summary of the Evidence
Following analysis from 16 RCTs which studied pregnant women with (1173) GDM, we found that several dietary supplements are superior to placebo/no intervention regarding improvement of oxidative stress status in women with GDM. The majority of dietary supplements studied led to decrease and increase in concentrations of pro-and anti-oxidation biomarkers, respectively.

Interpretation
In normal pregnancy, the metabolic adaptations and secretion of placental hormones leads to the development of "physiological" insulin resistance, which, ultimately, serves Indirectness: There were no differences in the baseline patient characteristics (including the BMI at randomization) among the studies. Thus, no downgrading took place.
Inconsistency: Due to the lack of closed loops, the point estimates of direct and indirect comparisons were evaluated. The evidence was downgraded by one level, if the prediction intervals extended across the line of no effect. Imprecision: The evidence was downgraded by one level, if the prediction intervals extended across the line of no effect.
Publication bias: The comparison-adjusted funnel plot was symmetric for all outcomes ( Figure 5). Thus, no downgrading took place.

Summary of the Evidence
Following analysis from 16 RCTs which studied pregnant women with (1173) GDM, we found that several dietary supplements are superior to placebo/no intervention regarding improvement of oxidative stress status in women with GDM. The majority of dietary supplements studied led to decrease and increase in concentrations of pro-and anti-oxidation biomarkers, respectively.

Interpretation
In normal pregnancy, the metabolic adaptations and secretion of placental hormones leads to the development of "physiological" insulin resistance, which, ultimately, serves to ensuring the transfer of the appropriate amounts of glucose to the fetus [39,40]. Gestational diabetes mellitus develops in women whose pancreatic function is insufficient to overcome this pregnancy-associated insulin resistance, resulting in increased concentrations of blood glucose [41]. The hyperglycemic environment in GDM is strongly associated with the emergence of oxidative stress, which is characterized by increased and decreased concentrations of pro-and anti-oxidation biomarkers [42][43][44][45][46][47][48][49][50]. Increased blood glucose concentrations lead to interaction of blood glucose with proteins, forming advanced glycation end-products (AGEs) [51][52][53][54]. This modification of proteins alters their function [55][56][57][58]. Extracellular AGEs bind to the receptor of AGEs (RAGE) and activate different intracellular signaling molecules such as nuclear factor-kappa B (NF-kB), an intra-cytoplasmic molecule whose activation leads to the formation of reactive oxygen species (ROS) via NADPH oxidase activity [3,59] Furthermore, increased blood glucose concentrations result in lipid peroxidation. The resulting products damage cell membranes and lead to the production of end-products such as MDA [60,61]. In addition, increased blood glucose concentrations activate the hexosamine biosynthetic pathway to produce glucosamine-6-phosphate, an inhibitor of the glucose-6-phosphate dehydrogenase (G6PD), which holds a crucial role in the pentose phosphate pathway [62][63][64][65]. The latter produces an important amount of the NADPH in cells. Activated G6PD converts glucose-6-phosphate into glucose-6phosphogluconate and, subsequently, via formation of NADPH to ribose-5-phosphate. Therefore, inhibition of G6PD will result in decreased production of NADPH [66]. The latter is instrumental in anti-oxidation due to its action as electron donor in the reduction in glutathione disulfide (GSSG) to glutathione (GSH), which reduces free hydrogen peroxides to water ( Figure S5) [67][68][69][70].
Omega-3 fatty acids either alone or in combination with other interventions, are consistently score in the first most effective interventions for the primary outcomes and for the majority of the secondary outcomes. Administration of omega-3 fatty acids in pregnant women with GDM is justified by their capacity to improve the oxidative status in various ways. Previous studies have shown that administration of omega-3 fatty acids increase the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) resulting thus, to inhibition of NF-kB activation and subsequent secretion of proinflammatory cytokines [71][72][73]. In addition, administration of omega-3 fatty acids leads to the increase in glutathione concentrations, an antioxidant [74][75][76]. Moreover, omega-3 fatty acids prevent oxidation of plasma lipids [77][78][79]. Indeed, in this metanalysis we found that administration of omega-3 fatty acids was superior to placebo/no intervention regarding the increase and decrease in GSH and MDA, respectively.
Similarly, administration of probiotics in pregnant women with GDM is justified by their capacity to attenuate the negative effects of oxidative stress. Their administration results in production of metabolites with anti-oxidation capacity such as glutathione (GSH) [80]. In addition, probiotics increase expression of PPAR-γ which inhibits activation of NF-kB and secretion of proinflammatory cytokines [81,82]. Furthermore, probiotics prevent oxidation of plasma lipids [80,83]. Indeed, in this metanalysis we have shown that administration of probiotics was superior to placebo/no intervention regarding production of GSH and MDA.
Vitamin E and vitamin C exert their anti-oxidation capacity either by reducing or by preventing oxidative damage. Vitamin E prevents lipid peroxidation chain reactions in cellular membranes by interfering with propagation of lipid radicals. Vitamin C even in small amounts, can protect proteins, lipids, carbohydrates, and nucleic acids from damage due to pro-oxidants generated physiologically. Vitamin C is also responsible for restoration of oxidized glutathione (GSSG) back to its reduced isoform GSH [84][85][86]. Administration of vitamin D has been shown to decrease peroxidation of lipids, production of AGEs and to increase activity of glutathione enzymes [87][88][89].

Strengths and Limitations
This is the first metanalysis assessing the effect of different dietary supplements upon pro-or anti-oxidation status of women with GDM. The present network metanalysis provides a global comparison and ranking of these interventions. Network metanalysis allows assessment of dietary supplements not directly compared in the same study [90,91] and ranks the compared interventions to identify the optimal one, based on their probability to be the most effective, as expressed by the SUCRA values [12] (References [92][93][94][95][96][97][98][99][100][101][102][103] are cited in the supplementary materials). Furthermore, this is the first study providing, via GRADE, an overview of the quality of the current evidence for the dietary interventions in women with GDM. This methodological approach evaluates evidence according to combinations of outcomes and comparisons. The moderate-to-high quality evidence analyzed in this metanalysis is translated into moderate-to-high confidence in the results adding to the strengths of the study. An inherent limitation of any network metanalysis is that ranking can be misleading, if interpreted "as it is". The assessment of the differences in the effect estimates among ranks should consider the clinical implications of the ranking Nutrients 2021, 13, 2284 23 of 27 difference between two interventions. In addition, a potential limitation of the present network meta-analysis is that there is no correlation between the improvement of oxidative stress status in women with GDM and clinical maternal and fetal/neonatal outcomes. However, the clinical outcomes are not in the scope of the present study and an additional study which will address this issue may follow.

Conclusions
In conclusion, this network metanalysis provides convincing evidence that the use of dietary supplements in women with GDM can be helpful in limiting the deleterious oxidative effects which develop in these pregnancies.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/nu13072284/s1, Figure S1: Leave one out analysis for the baseline values of A) TAC and B) MDA, investigating the influence of each individual study on the overall meta-analysis summary estimate, Figure S2: Network plots for the secondary outcomes of A) TAC B) MDA, C) ∆GSH, D) GSH. Treatments are represented by nodes and head-to-head comparisons with edges. The size of the nodes is proportional to the number of the patients, while the thickness of the edges is proportional to the number of studies. The color of the edges represents the average risk of bias for each head-to-head comparison, green for low risk of bias, yellow for uncertain risk of bias, and red for high risk of bias, Figure S3: Mean difference (MD) for A) TAC, B) MDA, C) ∆GSH and D) GSH as estimated from the network meta-analysis for every possible pair of interventions. Solid lines represent 95% Confidence Intervals (Cis), Figure S4: The contributions of direct and indirect data to the network estimate, Figure S5: Pathophysiology between hyperglycemia and impairment of antioxidant mechanisms, Table S1: Excluded studies, Table S2: SUCRA values of different antibiotic treatments for the primary and secondary outcomes, Table S3: GRADE for the ∆TAC outcome, Table S4: GRADE for the ∆MDA outcome.
Author Contributions: C.C. and A.S. Performed the literature search, C.C. and E.T. performed the extraction of data and M.P. and G.M. performed the risk of bias assessment. C.C. and K.D. performed the statistical analysis. All authors contributed to the writing of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding from funding agencies in the public, commercial, or not-for-profit sectors.