TY - JOUR
T1 - Regulatory T Cells in Pregnancy Adverse Outcomes
T2 - A Systematic Review and Meta-Analysis
AU - Green, Samantha
AU - Politis, Marina
AU - Rallis, Kathrine S.
AU - Saenz de Villaverde Cortabarria, Alba
AU - Efthymiou, Athina
AU - Mureanu, Nicoleta
AU - Dalrymple, Kathryn V.
AU - Scottà, Cristiano
AU - Lombardi, Giovanna
AU - Tribe, Rachel M.
AU - Nicolaides, Kypros H.
AU - Shangaris, Panicos
N1 - Funding Information:
PS is funded by an NIHR Clinical Lectureship (CL-2018-17-002). This study was funded by the Fetal Medicine Foundation (KHN, AE&NM) (registered charity 1037116), Tommy’s (RT&KD) (registered charity number 1060508) and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London (IS-BRC-1215–20006).
Publisher Copyright:
Copyright © 2021 Green, Politis, Rallis, Saenz de Villaverde Cortabarria, Efthymiou, Mureanu, Dalrymple, Scottà, Lombardi, Tribe, Nicolaides and Shangaris.
PY - 2021/10/29
Y1 - 2021/10/29
N2 - 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.
AB - 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.
KW - high blood pressure (hypertension)
KW - pre-eclampsia
KW - pre-term birth (PTB)
KW - pregnancy
KW - pregnancy adverse outcomes (PAO)
KW - regulatory T cells (Tregs)
UR - http://www.scopus.com/inward/record.url?scp=85119050392&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.737862
DO - 10.3389/fimmu.2021.737862
M3 - Article
AN - SCOPUS:85119050392
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 737862
ER -