Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis

Abstract

Background: Several studies report the role of Regulatory T-cells (Tregs) in the pathophysiology of pregnancy adverse outcomes.

Objective: The aim of this systematic review and meta-analysis was to determine whether there is an association between regulatory T cell levels and pregnancy adverse outcomes (PAOs), including pre-eclampsia and preterm birth (PTB).

Method: Literature searches were conducted in PubMed/MEDLINE, Embase, and Cochrane CENTRAL databases. Inclusion criteria were original articles (clinical trials, case-control studies and cohort studies) comparing Tregs, sampled from the decidua or maternal blood, in healthy pregnant women versus women with pre-eclampsia or PTB. The outcome was standardised mean difference (SMD) in Treg numbers. The tau-squared (Tau²), inconsistency index (I²), and chi-squared (χ²) test quantified heterogeneity among different studies. Analyses were performed in RevMan software V.5.4.0 for Mac using a random-effects model with outcome data reported with 95% confidence intervals (CI). This study was prospectively registered with PROSPERO (CRD42020205469). PRISMA guidelines were followed.

Results: From 4,085 unique studies identified, 36 were included in qualitative synthesis, and 34 were included in quantitative synthesis (meta-analysis). In total, there were 1,783 participants in these studies: healthy controls=964, pre-eclampsia=759, PTB=60. Thirty-two studies compared Tregs in healthy pregnant women and women with pre-eclampsia, and 30 of these sampled Tregs from peripheral blood showing significantly higher Treg numbers in healthy pregnancies (SMD; 1.46; 95% CI, 1.03-1.88; I²=92%). Four studies sampled Tregs from the maternal decidua showing higher Tregs in healthy pregnancies (SMD, 0.76; 95% CI, -0.13-1.65; I²=84%). No difference was found in the number of Tregs between early versus late pre-eclampsia (SMD,-1.17; 95% CI, -2.79-0.44; I²=94%). For PTB, two studies compared Tregs sampled from the peripheral blood with a tendency for higher Tregs in healthy pregnancies but this did not reach significance (SMD, 2.18; 95% CI, -1.34-5.70; I²=96%). Subcohort analysis using Treg analysis (flow cytometry vs. qPCR vs. immunofluorescence tissue staining) showed similar associations.

Conclusion: Lower Tregs in pregnancy, sampled from the maternal peripheral blood, are associated with pre-eclampsia. There is a need for further studies to confirm a relationship between low Tregs and PTB. As the precise mechanisms by which Tregs may mediate pre-eclampsia and PTB remain unclear, further fundamental research is necessary to elucidate the underlying processes and highlight the causative link.

Systematic review registration: PROSPERO, identifier CRD42020205469.

Keywords: high blood pressure (hypertension); pre-eclampsia; pre-term birth (PTB); pregnancy; pregnancy adverse outcomes (PAO); regulatory T cells (Tregs).

Figure 1

PRISMA flowchart of study selection.

Figure 2

Standardized mean difference of T regulatory cell numbers in the peripheral blood of healthy pregnant women and women with pre-eclampsia, in subgroups according to ethnicity, age and method of analysis. CI, confidence interval; SD, standard deviation; Std. Mean Difference, standardised mean difference; IV, inverse variance.

Figure 3

Standardized mean difference of T regulatory cell numbers in the decidua of healthy pregnant women and women with pre-eclampsia. CI, confidence interval; SD, standard deviation; Std. Mean Difference, standardised mean difference; IV, inverse variance.

Figure 4

Standardized mean difference of T regulatory cell numbers in the maternal blood of women with early and late pre-eclampsia. CI, confidence interval; SD, standard deviation; Std. Mean Difference, standardised mean difference; IV, inverse variance.

Figure 5

Standardized mean difference of T regulatory cell numbers in the peripheral blood of healthy pregnant women and women who underwent preterm birth (PTB). PTB, preterm birth; CI, confidence interval; SD, standard deviation; Std. Mean Difference, standardised mean difference; IV, inverse variance.

Figure 6

Funnel plot for studies looking at the number of Tregs in the maternal blood included in the subgroup meta-analysis (n=30). SE, standard error; SMD, standardised mean difference.