Selected Immunological Indicators and Microbiota in Patients With Premature Birth and Preeclampsia

NCT06281262 | Recruiting

• 1 other identifier: GIP-23-L-04-223
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The goal is to demonstrate the relationship of the circulating pool of T-regulatory lymphocytes in the mother's peripheral blood with populations in the placentas and to compare with controls, what is the difference in the expression of individual regulatory molecules of T-regulatory lymphocytes according to new paradigms. The proportional and functional characteristics of T-regulatory lymphocytes will be correlated with the composition of the intestinal and vaginal microbiota.

Conditions

Preterm Birth; Preeclampsia

Keywords

Preterm labor; Regulatory T cells; Early pregnancy; Immunology; Maternal-fetal interface

Outcome Measures

Primary Outcomes (2)

• Changes in selected T cell subpopulations in the first trimester associated with subsequent spontaneous preterm birth

  The phenotypic characteristics of leukocytes will be compared between the two groups of pregnant women to identify immunological markers of preterm delivery. Peripheral blood from age-matched healthy nonpregnant women (N=20) will also be collected to define a baseline for the measured leukocyte populations. Furthermore, the composition of placenta infiltrating lymphocytes will be compared between groups and following delivery.

  3 years

• Changes in selected T cell subpopulations in the first trimester associated with subsequent pre-eclampsia

  The phenotypic characteristics of leukocytes will be compared between the two groups of pregnant women to identify immunological markers of pre-eclampsia. Peripheral blood from age-matched healthy nonpregnant women (N=20) will also be collected to define a baseline for the measured leukocyte populations. Furthermore, the composition of placenta infiltrating lymphocytes will be compared between groups and following delivery.

  3 years

Secondary Outcomes (1)

• Association of maternal microbiota and maternal T regulatory cell populations.

  3 years

Study Arms (1)

Pregnant women

Singletone pregnancy, gestational age 9+0 - 12+0, history of preeclampsia (PE) or spontaneous preterm birth (PTL = preterm labour) or pPROM (preterm premature rupture of membranes).

Diagnostic Test: Peripheral blood collection; Diagnostic Test: Swab sample collection

Interventions

Peripheral blood collection DIAGNOSTIC_TEST

The phenotypic characteristics of leukocytes will be compared between the groups to identify immunological markers of women at risk of preterm delivery. Samples from the controls will be taken to define a baseline for the measured leukocyte populations.

Pregnant women

Swab sample collection DIAGNOSTIC_TEST

Oral, vaginal and rectal swabs will be collected and stored for analysis of microbiota at the time of inclusion. At birth, oral, vaginal and rectal swabs and part of the placenta (placental tissue) will be collected for further analysis.

Pregnant women

Eligibility Criteria

• Age: 19 Years - 40 Years
• Sex: female
• Age Groups: Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Pregnant women

You may qualify if:

• singletone pregnancy
• gestational age 9+0 - 12+0
• history of preeclampsia (PE)
• history of spontaneous preterm birth (PTL = preterm labour)
• history of pPROM (preterm premature rupture of membranes).

You may not qualify if:

• uterine malformations
• gestational age out of 9+0 - 12+0
• age out of 19-40

Sponsors & Collaborators

• General University Hospital, Prague: lead
• Charles University, Czech Republic: collaborator
• Institute of Hematology and Blood Transfusion, Czech Republic: collaborator

Study Sites (1)

Department of Gynaecology, Obstetrics and Neonatology of the First Faculty of Medicine of the Charles University and General University Hospital in Prague

Prague, 128 08, Czechia

RECRUITING

Related Publications (38)

• Perin J, Mulick A, Yeung D, Villavicencio F, Lopez G, Strong KL, Prieto-Merino D, Cousens S, Black RE, Liu L. Global, regional, and national causes of under-5 mortality in 2000-19: an updated systematic analysis with implications for the Sustainable Development Goals. Lancet Child Adolesc Health. 2022 Feb;6(2):106-115. doi: 10.1016/S2352-4642(21)00311-4. Epub 2021 Nov 17.

  PMID: 34800370 BACKGROUND

• Ohuma EO, Moller AB, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, Okwaraji YB, Mahanani WR, Johansson EW, Lavin T, Fernandez DE, Dominguez GG, de Costa A, Cresswell JA, Krasevec J, Lawn JE, Blencowe H, Requejo J, Moran AC. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023 Oct 7;402(10409):1261-1271. doi: 10.1016/S0140-6736(23)00878-4.

  PMID: 37805217 BACKGROUND

• Manuck TA. Racial and ethnic differences in preterm birth: A complex, multifactorial problem. Semin Perinatol. 2017 Dec;41(8):511-518. doi: 10.1053/j.semperi.2017.08.010. Epub 2017 Sep 21.

  PMID: 28941962 BACKGROUND

• Chawanpaiboon S, Vogel JP, Moller AB, Lumbiganon P, Petzold M, Hogan D, Landoulsi S, Jampathong N, Kongwattanakul K, Laopaiboon M, Lewis C, Rattanakanokchai S, Teng DN, Thinkhamrop J, Watananirun K, Zhang J, Zhou W, Gulmezoglu AM. Global, regional, and national estimates of levels of preterm birth in 2014: a systematic review and modelling analysis. Lancet Glob Health. 2019 Jan;7(1):e37-e46. doi: 10.1016/S2214-109X(18)30451-0. Epub 2018 Oct 30.

  PMID: 30389451 BACKGROUND

• Ream MA, Lehwald L. Neurologic Consequences of Preterm Birth. Curr Neurol Neurosci Rep. 2018 Jun 16;18(8):48. doi: 10.1007/s11910-018-0862-2.

  PMID: 29907917 BACKGROUND

• Green ES, Arck PC. Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus. Semin Immunopathol. 2020 Aug;42(4):413-429. doi: 10.1007/s00281-020-00807-y. Epub 2020 Sep 7.

  PMID: 32894326 BACKGROUND

• Gomez-Lopez N, Arenas-Hernandez M, Romero R, Miller D, Garcia-Flores V, Leng Y, Xu Y, Galaz J, Hassan SS, Hsu CD, Tse H, Sanchez-Torres C, Done B, Tarca AL. Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes. Cell Rep. 2020 Jul 7;32(1):107874. doi: 10.1016/j.celrep.2020.107874.

  PMID: 32640239 BACKGROUND

• Robertson SA, Care AS, Moldenhauer LM. Regulatory T cells in embryo implantation and the immune response to pregnancy. J Clin Invest. 2018 Oct 1;128(10):4224-4235. doi: 10.1172/JCI122182. Epub 2018 Oct 1.

  PMID: 30272581 BACKGROUND

• Xue L, Gyles SL, Wettey FR, Gazi L, Townsend E, Hunter MG, Pettipher R. Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells. J Immunol. 2005 Nov 15;175(10):6531-6. doi: 10.4049/jimmunol.175.10.6531.

  PMID: 16272307 BACKGROUND

• Tsuda S, Zhang X, Hamana H, Shima T, Ushijima A, Tsuda K, Muraguchi A, Kishi H, Saito S. Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans. Front Immunol. 2018 Aug 24;9:1934. doi: 10.3389/fimmu.2018.01934. eCollection 2018.

  PMID: 30197648 BACKGROUND

• Rowe JH, Ertelt JM, Xin L, Way SS. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature. 2012 Oct 4;490(7418):102-6. doi: 10.1038/nature11462. Epub 2012 Sep 26.

  PMID: 23023128 BACKGROUND

• Schober L, Radnai D, Schmitt E, Mahnke K, Sohn C, Steinborn A. Term and preterm labor: decreased suppressive activity and changes in composition of the regulatory T-cell pool. Immunol Cell Biol. 2012 Nov;90(10):935-44. doi: 10.1038/icb.2012.33. Epub 2012 Jul 3.

  PMID: 22751216 BACKGROUND

• Tilburgs T, Roelen DL, van der Mast BJ, de Groot-Swings GM, Kleijburg C, Scherjon SA, Claas FH. Evidence for a selective migration of fetus-specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol. 2008 Apr 15;180(8):5737-45. doi: 10.4049/jimmunol.180.8.5737.

  PMID: 18390759 BACKGROUND

• Krop J, Heidt S, Claas FHJ, Eikmans M. Regulatory T Cells in Pregnancy: It Is Not All About FoxP3. Front Immunol. 2020 Jun 23;11:1182. doi: 10.3389/fimmu.2020.01182. eCollection 2020.

  PMID: 32655556 BACKGROUND

• Green S, Politis M, Rallis KS, Saenz de Villaverde Cortabarria A, Efthymiou A, Mureanu N, Dalrymple KV, Scotta C, Lombardi G, Tribe RM, Nicolaides KH, Shangaris P. Regulatory T Cells in Pregnancy Adverse Outcomes: A Systematic Review and Meta-Analysis. Front Immunol. 2021 Oct 29;12:737862. doi: 10.3389/fimmu.2021.737862. eCollection 2021.

  PMID: 34777347 BACKGROUND

• Tsuda S, Nakashima A, Shima T, Saito S. New Paradigm in the Role of Regulatory T Cells During Pregnancy. Front Immunol. 2019 Mar 26;10:573. doi: 10.3389/fimmu.2019.00573. eCollection 2019.

  PMID: 30972068 BACKGROUND

• Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011 May;241(1):260-8. doi: 10.1111/j.1600-065X.2011.01018.x.

  PMID: 21488902 BACKGROUND

• Yadav M, Stephan S, Bluestone JA. Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front Immunol. 2013 Aug 7;4:232. doi: 10.3389/fimmu.2013.00232. eCollection 2013.

  PMID: 23966994 BACKGROUND

• Elkord E. Helios Should Not Be Cited as a Marker of Human Thymus-Derived Tregs. Commentary: Helios(+) and Helios(-) Cells Coexist within the Natural FOXP3(+) T Regulatory Cell Subset in Humans. Front Immunol. 2016 Jul 8;7:276. doi: 10.3389/fimmu.2016.00276. eCollection 2016. No abstract available.

  PMID: 27456241 BACKGROUND

• Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S, Kastner P, Haining WN, Cantor H. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015 Oct 16;350(6258):334-9. doi: 10.1126/science.aad0616.

  PMID: 26472910 BACKGROUND

• Yu WQ, Ji NF, Gu CJ, Wang YL, Huang M, Zhang MS. Coexpression of Helios in Foxp3+ Regulatory T Cells and Its Role in Human Disease. Dis Markers. 2021 Jun 22;2021:5574472. doi: 10.1155/2021/5574472. eCollection 2021.

  PMID: 34257746 BACKGROUND

• Shevyrev D, Tereshchenko V. Treg Heterogeneity, Function, and Homeostasis. Front Immunol. 2020 Jan 14;10:3100. doi: 10.3389/fimmu.2019.03100. eCollection 2019.

  PMID: 31993063 BACKGROUND

• Zhao H, Bo C, Kang Y, Li H. What Else Can CD39 Tell Us? Front Immunol. 2017 Jun 22;8:727. doi: 10.3389/fimmu.2017.00727. eCollection 2017.

  PMID: 28690614 BACKGROUND

• Svensson-Arvelund J, Mehta RB, Lindau R, Mirrasekhian E, Rodriguez-Martinez H, Berg G, Lash GE, Jenmalm MC, Ernerudh J. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages. J Immunol. 2015 Feb 15;194(4):1534-44. doi: 10.4049/jimmunol.1401536. Epub 2015 Jan 5.

  PMID: 25560409 BACKGROUND

• Wang S, Zhu X, Xu Y, Zhang D, Li Y, Tao Y, Piao H, Li D, Du M. Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface. Hum Reprod. 2016 Apr;31(4):700-11. doi: 10.1093/humrep/dew019. Epub 2016 Feb 16.

  PMID: 26908841 BACKGROUND

• Wang W, Sung N, Gilman-Sachs A, Kwak-Kim J. T Helper (Th) Cell Profiles in Pregnancy and Recurrent Pregnancy Losses: Th1/Th2/Th9/Th17/Th22/Tfh Cells. Front Immunol. 2020 Aug 18;11:2025. doi: 10.3389/fimmu.2020.02025. eCollection 2020.

  PMID: 32973809 BACKGROUND

• Travis OK, White D, Pierce WA, Ge Y, Stubbs CY, Spradley FT, Williams JM, Cornelius DC. Chronic infusion of interleukin-17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats. Physiol Rep. 2019 Apr;7(7):e14038. doi: 10.14814/phy2.14038.

  PMID: 30963715 BACKGROUND

• Wang WJ, Hao CF, Yi-Lin, Yin GJ, Bao SH, Qiu LH, Lin QD. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol. 2010 Mar;84(2):164-70. doi: 10.1016/j.jri.2009.12.003. Epub 2010 Jan 27.

  PMID: 20106535 BACKGROUND

• van der Zwan A, Bi K, Norwitz ER, Crespo AC, Claas FHJ, Strominger JL, Tilburgs T. Mixed signature of activation and dysfunction allows human decidual CD8+ T cells to provide both tolerance and immunity. Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):385-390. doi: 10.1073/pnas.1713957115. Epub 2017 Dec 19.

  PMID: 29259116 BACKGROUND

• Jabrane-Ferrat N. Features of Human Decidual NK Cells in Healthy Pregnancy and During Viral Infection. Front Immunol. 2019 Jun 28;10:1397. doi: 10.3389/fimmu.2019.01397. eCollection 2019.

  PMID: 31379803 BACKGROUND

• Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. 2002 Sep;2(9):656-63. doi: 10.1038/nri886.

  PMID: 12209134 BACKGROUND

• Thomsen SF. Epidemiology and natural history of atopic diseases. Eur Clin Respir J. 2015 Mar 24;2. doi: 10.3402/ecrj.v2.24642. eCollection 2015.

  PMID: 26557262 BACKGROUND

• Hagihara Y, Yoshimatsu Y, Mikami Y, Takada Y, Mizuno S, Kanai T. Epigenetic regulation of T helper cells and intestinal pathogenicity. Semin Immunopathol. 2019 May;41(3):379-399. doi: 10.1007/s00281-019-00732-9. Epub 2019 Mar 19.

  PMID: 30891628 BACKGROUND

• Berni Canani R, Paparo L, Nocerino R, Di Scala C, Della Gatta G, Maddalena Y, Buono A, Bruno C, Voto L, Ercolini D. Gut Microbiome as Target for Innovative Strategies Against Food Allergy. Front Immunol. 2019 Feb 15;10:191. doi: 10.3389/fimmu.2019.00191. eCollection 2019.

  PMID: 30828329 BACKGROUND

• Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175-91. doi: 10.3758/bf03193146.

  PMID: 17695343 BACKGROUND

• Nakashima A, Ito M, Shima T, Bac ND, Hidaka T, Saito S. Accumulation of IL-17-positive cells in decidua of inevitable abortion cases. Am J Reprod Immunol. 2010 Jul 1;64(1):4-11. doi: 10.1111/j.1600-0897.2010.00812.x. Epub 2010 Mar 4.

  PMID: 20219063 BACKGROUND

• Vanikova S, Koladiya A, Musil J. OMIP-080: 29-Color flow cytometry panel for comprehensive evaluation of NK and T cells reconstitution after hematopoietic stem cells transplantation. Cytometry A. 2022 Jan;101(1):21-26. doi: 10.1002/cyto.a.24510. Epub 2021 Oct 24.

  PMID: 34693626 BACKGROUND

• Kratochvil M, Koladiya A, Vondrasek J. Generalized EmbedSOM on quadtree-structured self-organizing maps. F1000Res. 2019 Dec 18;8:2120. doi: 10.12688/f1000research.21642.2. eCollection 2019.

  PMID: 32518625 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Flow cytometry includes a live/dead discriminator dye and markers for identification of major T cells and NK cell lineages as well as functional markers. Data will be analyzed using a hybrid approach combining manual gating in FlowJo and unsupervised clustering using the GQT-SOM dimensionality reduction algorithm collaboratively developed between IHBT and IOCB. Flow cytometry will be used to test Treg suppressive function by measuring the suppression of target cell proliferation in carboxyfluorescein succinimidyl ester (CFSE) dilution assay, coculturing CFSE-stained target cells (CBMC or CD4+CD25-). Bacterial DNA will be isolated from oral, vaginal, rectal swabs and piece of placenta for determination of bacterial species according to bacterial 16S rRNA. We will utilise Illumina MiSeq platform, where specific region of 16S rRNA (region V4) will be sequenced and followed by sophisticated analysis (LEfSe). Sequencing will be outsourced to Laboratory of Environmental Microbiology.

MeSH Terms

Conditions

Premature Birth; Pre-Eclampsia; Obstetric Labor, Premature

Condition Hierarchy (Ancestors)

Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Hypertension, Pregnancy-Induced

Study Officials

• Zdeněk Laštůvka, MD, PhD

  General University Hospital, Prague

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Zdeněk Laštůvka, MD, PhD

CONTACT

+420224967432; zdenek.lastuvka@vfn.cz

Michal Koucký, MD, assoc. prof.

CONTACT

+420224967432; michal.koucky@vfn.cz

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator, MD

Study Record Dates

• First Submitted: February 20, 2024
• First Posted: February 28, 2024
• Study Start: June 30, 2023
• Primary Completion: March 30, 2025
• Study Completion: March 30, 2025
• Last Updated: March 1, 2024

Record last verified: 2024-02

Locations

CZ (1)