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Meta-Analysis
. 2023 Dec 4:14:1226617.
doi: 10.3389/fimmu.2023.1226617. eCollection 2023.

Regulatory T cells in the peripheral blood of women with gestational diabetes: a systematic review and meta-analysis

Hania Arain  1 , Tina Patel  1 , Nicoleta Mureanu  1   2 , Athina Efthymiou  1   2 , Giovanna Lombardi  3 , Timothy Tree  3 , Kypros H Nicolaides  1   2 , Panicos Shangaris  1   2   3
Affiliations
Meta-Analysis

Regulatory T cells in the peripheral blood of women with gestational diabetes: a systematic review and meta-analysis

Hania Arain et al. Front Immunol. .

Abstract

Background: Gestational diabetes (GDM) affects approximately 14% of pregnancies globally and is associated with short- and long-term complications for both the mother and child. In addition, GDM has been linked to chronic low-grade inflammation with recent research indicating a potential immune dysregulation in pathophysiology and a disparity in regulatory T cells.

Objective: This systematic review and meta-analysis aimed to determine whether there is an association between GDM and the level of Tregs in the peripheral blood.

Methods: Literature searches were conducted in PubMed, Embase, and Ovid between the 7th and 14th of February 2022. The inclusion criteria were any original studies published in the English language, measuring differentiated Tregs in women with GDM compared with glucose-tolerant pregnant women. Meta-analysis was performed between comparable Treg markers. Statistical tests were used to quantify heterogeneity: τ 2, χ 2, and I 2. Study quality was assessed using a modified version of the Newcastle-Ottawa scale.

Results: The search yielded 223 results: eight studies were included in the review and seven in the meta-analysis (GDM = 228, control = 286). Analysis of Tregs across all trimesters showed significantly lower Treg numbers in women with GDM (SMD, -0.76; 95% CI, -1.37, -0.15; I 2 = 90%). This was reflected in the analysis by specific Treg markers (SMD -0.55; 95% CI, -1.04, -0.07; I 2 = 83%; third trimester, five studies). Non-significant differences were found within subgroups (differentiated by CD4+FoxP3+, CD4+CD127-, and CD4+CD127-FoxP3) of both analyses.

Conclusion: GDM is associated with lower Treg numbers in the peripheral maternal blood. In early pregnancy, there is clinical potential to use Treg levels as a predictive tool for the subsequent development of GDM. There is also a potential therapeutic intervention to prevent the development of GDM by increasing Treg populations. However, the precise mechanism by which Tregs mediate GDM remains unclear.

Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022309796.

Keywords: chronic low-grade inflammation; gestational diabetes mellitus (GDM); immune dysregulation; regulatory T-cells (Tregs); systematic review & meta-analysis; treg markers.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
PRISMA flow diagram.
Figure 2
Figure 2
Forest plot of the SMD of women with GDM vs. control subgrouped by trimesters. The figure shows that overall Treg populations are found to be lower in women with GDM. Individually by trimester, significant differences were shown in the studies of women in the first (p = 0.004; SDM = −0.83; CI: −1.40, −0.26) and second trimesters (p = 0.004; SDM = −2.50; CI: −3.23, −1.78) reflective of the published individual study findings. However, when comparing studies in the third trimester only, the overall SDM was −0.43 (95% CI: −0.99, 0.14; I 2 = 84%). As the CI crosses the null value, there is no overall significance. In the third trimester, only one study reported a significantly lower number of Tregs in women with GDM with the other four reporting and showing a non-significant difference.
Figure 3
Figure 3
Forest plot of GDM vs. control subgrouped by the Treg markers Foxp3+, CD127−, and CD127−Foxp3+. The figure shows that overall Treg populations are found to be lower in women with GDM.
Figure 4
Figure 4
Forest plot of women with GDM vs. control done for sensitivity analysis excluding studies that included overweight/obese women only. The figure shows that overall Treg populations remain lower in women with GDM with CI below the null value.
Figure 5
Figure 5
A visual aid of the factors showing a link between GDM and low Treg levels. This shows that though there may be an association between low Treg levels and GDM, current evidence does not allow a conclusion on the causal relationship between the two.
Figure 6
Figure 6
A visual aid constructed to explore some of the potential future work and clinical applications based on our research.
See this image and copyright information in PMC

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