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

Samantha Green; Marina Politis; Kathrine S. Rallis; Alba Saenz de Villaverde Cortabarria; Athina Efthymiou; Nicoleta Mureanu; Kathryn V. Dalrymple; Cristiano Scottà; Giovanna Lombardi; Rachel M. Tribe; Kypros H. Nicolaides; Panicos Shangaris

doi:10.3389/fimmu.2021.737862

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

Samantha Green, Marina Politis, Kathrine S. Rallis, Alba Saenz de Villaverde Cortabarria, Athina Efthymiou, Nicoleta Mureanu, Kathryn V. Dalrymple, Cristiano Scottà, Giovanna Lombardi, Rachel M. Tribe, Kypros H. Nicolaides, Panicos Shangaris^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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.

Original language	English
Article number	737862
Number of pages	1
Journal	Frontiers in Immunology
Volume	12
Early online date	29 Oct 2021
DOIs	https://doi.org/10.3389/fimmu.2021.737862
Publication status	Published - 29 Oct 2021

Keywords

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

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10.3389/fimmu.2021.737862

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Green, S., Politis, M., Rallis, K. S., Saenz de Villaverde Cortabarria, A., Efthymiou, A., Mureanu, N., Dalrymple, K. V., Scottà, C., Lombardi, G., Tribe, R. M., Nicolaides, K. H., & Shangaris, P. (2021). Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis. Frontiers in Immunology, 12, [737862]. https://doi.org/10.3389/fimmu.2021.737862

@article{07c494d11f454cfcb0e69423d2319823,

title = "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)",

author = "Samantha Green and Marina Politis and Rallis, {Kathrine S.} and {Saenz de Villaverde Cortabarria}, Alba and Athina Efthymiou and Nicoleta Mureanu and Dalrymple, {Kathryn V.} and Cristiano Scott{\`a} and Giovanna Lombardi and Tribe, {Rachel M.} and Nicolaides, {Kypros H.} and Panicos Shangaris",

note = "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{\textquoteright}s (RT&KD) (registered charity number 1060508) and the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy{\textquoteright}s and St Thomas{\textquoteright} National Health Service Foundation Trust and King{\textquoteright}s College London (IS-BRC-1215–20006). Publisher Copyright: Copyright {\textcopyright} 2021 Green, Politis, Rallis, Saenz de Villaverde Cortabarria, Efthymiou, Mureanu, Dalrymple, Scott{\`a}, Lombardi, Tribe, Nicolaides and Shangaris.",

year = "2021",

month = oct,

day = "29",

doi = "10.3389/fimmu.2021.737862",

language = "English",

volume = "12",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media",

}

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)

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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 -

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

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