Preterm delivery and associated negative pregnancy outcome – A tale of faulty progesterone receptor signalling pathway and linked derailed immunomodulation: A study from Northeast India (original) (raw)
Related papers
508: Inflammatory cytokines and recurrent preterm birth
Data Revues 00029378 V204i1ss S0002937810017862, 2011
To determine if peripheral blood mononuclear cell (PBMC) production of the anti-inflammatory cytokine interleukin 10 (IL10) and/or the pro-inflammatory cytokine tumor necrosis factor ␣ (TNF␣) differ between high risk women delivering preterm and those delivering at term. STUDY DESIGN: Ancillary to a randomized trial of omega-3 fatty acid (⍀-3) supplementation for the prevention of recurrent preterm birth. Women (nϭ852) with a history of singleton preterm delivery due to either preterm premature rupture of the membranes or preterm labor and currently pregnant with a singleton received weekly injections of 17-alpha hydroxyprogesterone caproate and were randomized to either an omega-3 supplement (2 gram daily) or placebo. PBMC production of IL10 and TNF␣ were measured without (Ϫ) and with (ϩ) stimulation with lipopolysaccharide (LPS) at baseline (B) randomization at 16-22 weeks gestation and again at follow up (FU) at 25-28 weeks gestation. The following values were recorded for both cytokines: BϪ, Bϩ. FUϪ, FUϩ, ⌬B and ⌬FU (difference between LPS stimulated and unstimulated at B and FU) and ⌬⌬ (⌬FU minus ⌬B). RESULTS: A total of 292 and 319 women had paired assays at both baseline and follow up for IL10 ⌬⌬ and TNF␣ ⌬⌬ respectively. The median IL10 ⌬⌬ value for the group delivering at term was positive and higher than that of the group delivering at 35 to 36 weeks. The median IL10 ⌬⌬ value was negative for the group delivering at Ͻ 35 weeks. Because some studies report an association between smoking and IL10 levels we controlled for smoking. The association between IL10 ⌬⌬ levels and preterm birth Ͻ 37 weeks persisted after controlling for smoking, pϭ0.01. There was no significant difference in TNF␣ ⌬⌬ levels between women delivering at term versus preterm, pϭ0.56. CONCLUSIONS: These data suggest that PBMC production of IL10 is depressed as gestation advances in women delivering preterm compared to women delivering at term.
Journal of Reproductive Immunology, 2009
Spontaneous miscarriage and preterm delivery are common complications of pregnancy. Pro-inflammatory cytokines have been shown to be associated with recurrent spontaneous miscarriage (RSM) and preterm delivery (PTD) and these have led to exploration of ways to downregulate pro-inflammatory cytokines and/or to upregulate anti-inflammatory cytokines. Progesterone-induced blocking factor (PIBF) is a molecule with inhibitory effects on cell-mediated immune reactions. We have ascertained the effects of PIBF on secretion of selected type 1 and type 2 cytokines by peripheral blood mononuclear cells from healthy non-pregnant women, women undergoing normal pregnancy, women with unexplained RSM and women with PTD. Peripheral blood mononuclear cells from 30 women with a history of unexplained RSM, 18 women undergoing PTD, 11 women with normal pregnancy and 13 non-pregnant healthy women were stimulated with a mitogen in the absence and presence of PIBF after which the levels of cytokines released into culture supernatants were determined by ELISA. Production of the type 2 cytokines IL-4, IL-6 and IL-10 by lymphocytes from the RSM and PTD groups and of IL-4 and IL-10 by lymphocytes from healthy pregnant women was significantly increased upon exposure to PIBF, while the levels of type 1 cytokines were not affected. Ratios of type 1:type 2 cytokines were decreased, suggesting a shift towards Th2 bias. PIBF did not affect cytokine production by lymphocytes from non-pregnant women. Thus, PIBF acts on lymphocytes in pregnancy to induce a type 1 to type 2 cytokine shift by upregulating the production of type 2 cytokines.
Reproductive Sciences, 2019
Premature prelabor rupture of the membranes (PPROM) causes one-third of preterm births worldwide and is most likely caused by subclinical intrauterine infection and/or inflammation. We proposed that women with systemic inflammation at the time of PPROM would have shorter latency. Peripheral blood samples were collected from 20 singleton pregnant women with PPROM between 23 + 1 and 33 + 6 weeks. The first sample was drawn within 48 hours of admission, followed by weekly blood draws until delivery. Pregnancies complicated with acute chorioamnionitis, preeclampsia, intrauterine growth restriction, obesity, substance abuse, and chronic maternal disease were excluded. Twenty uncomplicated, gestational age-matched pregnancies served as controls. Plasma concentration of 39 cytokines was measured longitudinally using Luminex assays to investigate their value as predictive biomarkers of latency. Women with PPROM exhibited significantly lower plasma concentration of interferong-inducible protein 10-Chemokine (c-x-c motif; IP10/CXCL10), Chemokine (c-x-c motif) Ligand 9 (MIG/CXCL9), Plateletderived growth factor BB (PDGFbb), and cutaneous T cell-attracting chemokine, also known as CCL27/CCL27 than controls at admission but significantly elevated interleukin (IL)1RA, tumor necrosis factor a, monocyte chemotactic protein-1/CCL2 at delivery compared to admission. Women with PPROM who delivered within 7 days had significantly lower plasma concentration of anti-inflammatory cytokine IL1RA than those with latency periods >7 days. The IL1RA and endotoxin activity in conjunction with clinical parameters results in excellent prediction of latency to delivery (area under the receiver-operating characteristic curve ¼ 0.91). We concluded that higher levels of anti-inflammatory cytokines in women with PPROM were associated with increased latency until delivery, likely due to counterbalancing of proinflammatory load. When used in conjunction with other predictive characteristics of time until delivery, cytokines may further assist clinical decision-making and optimize pregnancy outcomes in women with PPROM.
American Journal of Reproductive Immunology, 2009
Pre-term delivery is a major challenge in perinatal health care. In developed countries, the incidence of pre-term delivery has reached 5-7% of all live births over the past few decades. Several factors have contributed to the overall rise in the incidence of pre-term delivery. These factors Citation Hudić I, Fatuš ić Z, Szekeres-Bartho J, Balić D, Polgar B, Ljuca D, Dizdarević -Hudić L. Progesterone-induced blocking factor and cytokine profile in women with threatened pre-term delivery.
American Journal of Obstetrics and Gynecology, 2021
BACKGROUND: Progesterone, acting via its nuclear receptors called progesterone receptors, promotes myometrial relaxation during pregnancy, and suspension of this activity triggers labor. We previously found that 20α-hydroxysteroid dehydrogenase causes a local withdrawal of progesterone in the term and preterm myometrium by converting the progesterone into an inactive form before it accesses the progesterone receptors. OBJECTIVE: We hypothesized that a selective progesterone receptor modulator called promegestone, which is not metabolized by 20α-hydroxysteroid dehydrogenase, would sustain progesterone receptor signaling and prevent/delay term labor and preterm labor in mice. STUDY DESIGN: In the term labor mouse model, promegestone (0.2 mg/dam) or a vehicle were administered subcutaneously in timed-pregnant CD-1 mice at gestational days 15, 16, and 17 (term gestational days, 19.5). In the inflammation preterm labor model, pregnant mice received promegestone or a vehicle on gestational days 15, 16, and 17, which was 24 hours before, immediately before, and 24 hours after systemic bacterial endotoxin (50 μg intraperitoneal; lipopolysaccharide group) or vehicle (saline) administration. The maternal and fetal tissues were collected on gestational day 16 6 hours after lipopolysaccharide±promegestone injection and at term gestational day 18.75. The protein levels of 10 cytokines were measured by multiplex immunoassay in maternal plasma and amniotic fluid. Myometrial, decidual, and placental messenger RNA levels of multiple cytokines and procontractile proteins were evaluated by realtime polymerase chain reaction and confirmed by immunoblotting.
Regulatory Cytokine Expression and Preterm Birth: Case-Control Study Nested in a Cohort
PloS one, 2016
Currently known risk factors explain only a small fraction of preterm birth (PTB). Previous PTB is one of the most important predictors. However, this information is not available in primiparous women. Few studies have looked at associations between regulatory cytokine expression (RCE) and PTB and the results are conflicting. To investigate the association of RCE-Interleukin 10 (IL-10) and Transforming Growth Factor β (TGF-β)-with PTB, and to assess whether bacterial vaginosis (BV) is involved in this relationship. This was a case-control study nested in a prospective cohort-called BRISA. Women with singleton pregnancies were interviewed from 22 to 25 weeks of gestational age (GA). Women were recruited from health services in São Luís, Brazil. A blood sample was collected and gynecological examination was performed. Serum IL-10 and TGF-β were determined using cytometric bead array. Nugent score >7 and/or the presence of clue cells were used for BV diagnosis. All PTB estimated by ...
BMC Pregnancy and Childbirth, 2009
Background: Preterm delivery (PTD) is a significant public health problem associated with greater risk of mortality and morbidity in infants and mothers. Pathophysiologic processes that may lead to PTD start early in pregnancy. We investigated early pregnancy peripheral blood global gene expression and PTD risk. Methods: As part of a prospective study, ribonucleic acid was extracted from blood samples (collected at 16 weeks gestational age) from 14 women who had PTD (cases) and 16 women who delivered at term (controls). Gene expressions were measured using the GeneChip ® Human Genome U133 Plus 2.0 Array. Student's T-test and fold change analysis were used to identify differentially expressed genes. We used hierarchical clustering and principle components analysis to characterize signature gene expression patterns among cases and controls. Pathway and promoter sequence analyses were used to investigate functions and functional relationships as well as regulatory regions of differentially expressed genes. Results: A total of 209 genes, including potential candidate genes (e.g. PTGDS, prostaglandin D2 synthase 21 kDa), were differentially expressed. A set of these genes achieved accurate prediagnostic separation of cases and controls. These genes participate in functions related to immune system and inflammation, organ development, metabolism (lipid, carbohydrate and amino acid) and cell signaling. Binding sites of putative transcription factors such as EGR1 (early growth response 1), TFAP2A (transcription factor AP2A), Sp1 (specificity protein 1) and Sp3 (specificity protein 3) were over represented in promoter regions of differentially expressed genes. Real-time PCR confirmed microarray expression measurements of selected genes. Conclusions: PTD is associated with maternal early pregnancy peripheral blood gene expression changes. Maternal early pregnancy peripheral blood gene expression patterns may be useful for better understanding of PTD pathophysiology and PTD risk prediction.
A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition
American Journal of Obstetrics and Gynecology, 1998
OBJECTIVE: There is no evidence for the participation of the human fetus in the mechanisms responsible for the onset of preterm labor. We propose that preterm labor in the setting of infection results from the actions of proinflammatory cytokines secreted as part of the fetal and/or maternal host response to microbial invasion. The objective of this study was to determine whether a systemic fetal inflammatory response, defined as an elevation of fetal plasma interleukin-6 concentrations, has a temporal relationship with the commencement of labor.STUDY DESIGN: After informed consent was obtained, amniocentesis and cordocentesis were performed in 41 patients with preterm premature rupture of membranes who were not in labor on admission. Amniotic fluid was cultured for both aerobic and anaerobic bacteria, as well as for mycoplasmas. Fetal plasma interleukin-6 was assayed by a sensitive and specific immunoassay. Statistical analyses included contingency tables and survival analysis with time-dependent Cox regression hazard modeling.RESULTS: Microbial invasion of the amniotic cavity was present in 58.5% (24/41) of patients. Fetuses with fetal plasma interleukin-6 concentrations >11 pg/mL had a higher rate of spontaneous preterm delivery within 48 and 72 hours of the procedure than those with fetal plasma interleukin-6 levels ≤11 pg/mL (88% vs 29% and 88% vs 35%, respectively; P < .05 for all comparisons). Moreover, patients with initiation of labor and delivery within 48 hours of the procedure had a higher proportion of fetuses with plasma interleukin-6 values >11 pg/mL than patients delivered >48 hours (58% [7/12] vs 8% [1/13], respectively; P < .05). Survival analysis indicated that fetuses with elevated fetal plasma interleukin-6 levels had a shorter cordocentesis-to-delivery interval than those without elevated fetal plasma interleukin-6 concentrations (median 0.8 days [range 0.1 to 5] vs median 6 days [range 0.2 to 33.6], respectively; P < .05). Time-dependent Cox regression hazard modeling indicated that fetal plasma interleukin-6 level was the only covariate significantly associated with the duration of pregnancy after we adjusted for gestational age, amniotic fluid interleukin-6 level, and the microbiologic state of the amniotic cavity (P < .01).CONCLUSION: A systemic fetal proinflammatory cytokine response is followed by the onset of spontaneous preterm parturition in patients with preterm premature rupture of membranes. (Am J Obstet Gynecol 1998;179:186-93.)
The effect of progesterone on genes involved in preterm labor
Journal of Reproductive Immunology, 2014
The decidua is known to be a major source of intrauterine PGF2α during late gestation and labor, and inflammatory cytokines, including IL-1β, IL-6, and IL-8, are elevated in spontaneous preterm deliveries. In the present study, to elucidate how progesterone blocks the pathways associated with preterm birth, we determined the effects of P4 on 20 the expression of PTGS-2 and PTGFR mRNA in human decidua fibroblast cells, as well as the genes, using microarray analysis. Senescence was induced in primary cultured human decidual cells treated with IL-1β. The IL-1β treatment implicated by microarray analysis increased gene expression levels of PTGS-2, PTGFR, NFκ-B p65, IL-17, and IL-8. In contrast, P4 + IL-1β decreased the expression levels of all of these genes in 25 comparison to treatment with IL-1β alone (p<0.05). IL-1β also increased the proportion of SA-β-gal-positive cells. Treatment with IL-1β also increased the p21 protein level in comparison to cells treated either with the vehicle or P4. Neither the p21 protein level nor the number of SA-β-gal-positive cells was increased in normal endometrial glandular cells by IL-1β (p<0.05). Our studies demonstrated that P4 changes the level of 30 gene expression in a manner that favors an anti-inflammatory milieu. Because IL-8 appears to be the cytokine whose expression is most significantly modulated by P4, further studies evaluating IL-8 as a therapeutic target are needed.