Characteristics of the inflammatory response in pregnant women with very early preterm premature rupture of membranes

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Abstract

BACKGROUND: Premature rupture of the membranes in the very early stages of pregnancy is an irreversible complication of pregnancy, leading in 100% of cases to premature delivery and the birth of children with extremely low (up to 1000 g) and low (up to 1500 g) birth weight. The course of pregnancy depends on the consequential outcomes of the genetically determined inflammatory response in the female body.

AIM: The aim of this study was to determine the characteristics of pro- and anti-inflammatory cytokine gene polymorphism, as well as local and systemic cytokine profiles in pregnant women with preterm premature rupture of membranes at 22–27 weeks 6 days of gestation.

MATERIALS AND METHODS: This prospective case-control study enrolled 120 pregnant women with a gestation period of 22–28 weeks. Group 1 consisted of 80 pregnant women with preterm premature rupture of membranes, and group 2 included 40 women with normal pregnancy. All pregnant women were analyzed for gene polymorphism of pro- and anti-inflammatory cytokines (IFNG: 874Т>А, IL10: −1082G>A, IL10: −592A>C, IL10: 819C>T, IL12B: −1188C>A, IL18: 137G>С, IL18: −607G>T, IL18: −656А>С, IL1β: −31T>C, IL1β: 3953C>T, IL1β: −511C>T, IL6: −174G>C, IL8: −251А>T, TNF: −238G>A, TNF: −308G>A), as well as local (in the lower reproductive tract: inflammation index level; IL1β, IL10, IL18, TNFα, TLR4, B2M messenger RNA expression levels) and systemic (blood interleukin-1β, -2, -6, -8, -10, -12β, -18, interferon gamma, tumor necrosis factor alpha levels) cytokine profiles.

RESULTS: In women with preterm premature rupture of membranes, the CC genotype is more often registered for the −137G>С polymorphism of the IL18 gene (χ2 = 37.4, р < 0.0001). In the blood of women in this group, interleukin-18, interferon gamma, and tumor necrosis factor alpha levels were higher [interleukin-18: 334 (267–384) pg/ml in group 1 and 209 (143–304) pg/ml in group 2 (р = 0.001); interferon gamma: 5.85 (4.8–7.0) pg/ml in group 1 and 3.4 (2.0–6,9) pg/ml in group 2 (р = 0.005); tumor necrosis factor alpha: 15.4 (13.5–23.7) pg/ml in group 1 and 12.6 (10.6–16.0) pg/ml in group 2 (р = 0.001)], while interleukin-10 levels were lower (6.8 (4.7–9.7) pg/ml in group 1 and 9.0 (6.6–13.6) pg/ml in group 2 (р = 0.016) compared to the control group. In the lower reproductive tract, pregnant women with preterm premature rupture of membranes had higher messenger RNA expression levels of pro-inflammatory cytokine genes (IL1β, TNFα), as well as TLR4 and B2M as compared to apparently healthy pregnant women. IL1β level was 5.83 (5.0–6.1) in group 1 and 4.69 (4.0–5.1) in group 2 (р = 0.034). TNFα level was 4.28 (3.8–4.9) in group 1 and 2.17 (1.9–3.2) in group 2 (р = 0.001). TLR4 level was 3.36 (2.6–4.3) in group 1 and 1.9 (1.4–2.2) in group 2 (р = 0.042). B2M level was 5.7 (5.0–6.3) in group 1 and 3.77 (2.9–4.3) in group 2 (р = 0.002).

CONCLUSIONS: Molecular genetic determination of preterm labor associated with very early preterm premature rupture of membranes was established, expressed in a selective potentiation increase in the production of a number of pro-inflammatory cytokines in the second trimester of pregnancy, which creates conditions that ensure the formation of morphofunctional disorders in the membranes with their subsequent failure.

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About the authors

Natalya B. Kuznetsova

Rostov State Medical University

Email: lauranb@inbox.ru

MD, Dr. Sci. (Med.)

Russian Federation, Rostov-on-Don

Maria P. Grishchuk (Dmitriyeva)

Pskov Clinical Perinatal Center

Email: dr.dmitrieva@inbox.ru
ORCID iD: 0000-0003-2155-6668
SPIN-code: 2854-6366

MD, Cand. Sci. (Med.)

Russian Federation, Pskov

Natalia G. Pavlova

Academician I.P. Pavlov First Saint Petersburg State Medical University

Email: ngp05@mail.ru

MD, Dr. Sci. (Med.), Professor

Russian Federation, St. Petersburg

Elena V. Mashkina

D.I.Ivanovsky Academy of Biology and Biotechnology, Southern Federal University

Author for correspondence.
Email: lenmash@mail.ru

Dr. Sci. (Biol.), Assistant Professor

Russian Federation, Rostov-on-Don

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2. Figure. Genotypic frequencies of the pro- and anti-inflammatory cytokine single nucleotide polymorphism genes in patients of the study groups

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