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Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes.

ABSTRACT: Regulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive transfer of such cells. Treg depletion does not alter obstetrical parameters in the mother, yet it increases susceptibility to endotoxin-induced preterm birth. The mechanisms whereby depletion of Tregs induces adverse perinatal outcomes involve tissue-specific immune responses and mild systemic maternal inflammation, together with dysregulation of developmental and cellular processes in the placenta, in the absence of intra-amniotic inflammation. These findings provide mechanistic evidence supporting a role for Tregs in the pathophysiology of idiopathic preterm labor/birth and adverse neonatal outcomes.

SUBMITTER: Gomez-Lopez N

PROVIDER: S-EPMC7396155 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes.

Gomez-Lopez Nardhy N Arenas-Hernandez Marcia M Romero Roberto R Miller Derek D Garcia-Flores Valeria V Leng Yaozhu Y Xu Yi Y Galaz Jose J Hassan Sonia S SS Hsu Chaur-Dong CD Tse Harley H Sanchez-Torres Carmen C Done Bogdan B Tarca Adi L AL

Cell reports 20200701 1

Regulatory T cells (Tregs) have been exhaustively investigated during early pregnancy; however, their role later in gestation is poorly understood. Herein, we report that functional Tregs are reduced at the maternal-fetal interface in a subset of women with idiopathic preterm labor/birth, which is accompanied by a concomitant increase in Tc17 cells. In mice, depletion of functional Tregs during late gestation induces preterm birth and adverse neonatal outcomes, which are rescued by the adoptive ...[more]

PMID: 32640239

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Project description:BackgroundPreterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.MethodsProteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.FindingsIL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.InterpretationIL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.FundingNICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Project description:Despite remarkable progress in the reduction of under-five mortality, the rate of perinatal and neonatal mortality is still high especially in developing countries. The adverse outcome associated with preterm birth is one of the major public health challenges in Africa. However, there are limited and inconsistent studies conducted on the effect of preterm birth on adverse perinatal and neonatal outcomes in Ethiopia. Therefore, this systematic review and meta-analysis aimed to investigate the association between preterm birth and its adverse perinatal and neonatal outcomes in Ethiopia. We systematically searched several electronic databases like PubMed, Web of Science, SCOPUS, CINAHL, Google Scholar, African Journals Online databases and Science Direct. All identified observational studies were included. The I1 statistics were used to assess the heterogeneity among the studies. A random-effects model was computed to estimate the pooled effect of preterm birth on adverse perinatal and neonatal outcomes. Thirty-three studies with a total of 20 109 live births were included in the final meta-analysis. Our meta-analysis showed that preterm birth increased the odds of perinatal mortality by 10-folds [POR = 9.56 (95% CI: 5.47, 19.69)] and there was a 5.44-folds risk of stillbirth [Odds Ratio = 5.44 (95% CI: 3.57, 8.28)] among women who gave birth before 37 weeks of gestation. In addition, preterm birth was significantly associated with neonatal hypothermia [OR=3.54 (95% CI: 2.41, 5.21)], neonatal mortality [OR= 3.16 (95% CI: 1.57, 6.34). The sub-group analysis of this meta-analysis showed that there was an increased risk of neonatal sepsis [OR=2.33 (95% CI: 1.15, 4.71)] among preterm babies. Preterm births significantly increased the risk of adverse perinatal and neonatal outcomes in Ethiopia. Therefore, scale-up strategies and improving the quality of maternal and child health care providers should be an area of intervention to reduce adverse outcomes associated with preterm birth. The Federal Ministry of Health and concerned bodies should work towards the prevention of preterm birth and its adverse outcomes.

Project description:ObjectiveTo assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women.MethodsIn this post-hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of < 15 mm or a cervical length of 15-30 mm with a positive fetal fibronectin test. Logistic regression analysis was used to investigate the association of cervical length measured at least 48 h after admission and of the change in cervical length between admission and at least 48 h later, with preterm birth before 34 weeks' gestation and delivery within 7 days after admission.ResultsA total of 164 women were included in the analysis. Women whose cervical length increased between admission for threatened preterm labor and 48 h later (32%; n = 53) were found to have a lower risk of preterm birth before 34 weeks compared with women whose cervical length did not change (adjusted odds ratio (aOR), 0.24 (95% CI, 0.09-0.69)). The risk in women with a decrease in cervical length between the two timepoints was not different from that in women with no change in cervical length (aOR, 1.45 (95% CI, 0.62-3.41)). Moreover, greater absolute cervical length after 48 h was associated with a lower risk of preterm birth before 34 weeks (aOR, 0.90 (95% CI, 0.84-0.96)) and delivery within 7 days after admission (aOR, 0.91 (95% CI, 0.82-1.02)). Sensitivity analysis in women randomized to receive no intervention showed comparable results.ConclusionOur study suggests that the risk of preterm birth before 34 weeks is lower in women whose cervical length increases between admission for threatened preterm labor and at least 48 h later when contractions had ceased compared with women in whom cervical length does not change or decreases. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Dataset Information

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes.

Publications

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes.

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