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The Journal of Maternal-Fetal & Neonatal Medicine
ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: https://www.tandfonline.com/loi/ijmf20
Increased levels of serum IL-33 is associated with
adverse maternal outcomes in placenta previa
accreta
Sibel Ozler, Efser Oztas, Basak Gumus Guler & Ali Turhan Caglar
To cite this article: Sibel Ozler, Efser Oztas, Basak Gumus Guler & Ali Turhan Caglar (2019): Increased levels of serum IL-33 is associated with adverse maternal outcomes in placenta previa accreta, The Journal of Maternal-Fetal & Neonatal Medicine, DOI: 10.1080/14767058.2019.1679766To link to this article: https://doi.org/10.1080/14767058.2019.1679766
Published online: 24 Oct 2019.
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ORIGINAL ARTICLE
Increased levels of serum IL-33 is associated with adverse maternal
outcomes in placenta previa accreta
Sibel Ozlera , Efser Oztasb, Basak Gumus Gulerc and Ali Turhan Caglard
a
Department of Perinatology, Selcuk University Medical School, Konya, Turkey;bDepartment of Perinatology, Eskisehir City Hospital, Eskisehir, Turkey;cDepartment of Health Sciences, Istinye University, Istanbul, Turkey;dDepartment of Pathology, University of Health Sciences Ankara City Hospital, Ankara, Turkey
ABSTRACT
Purpose: IL-33 is associated with invasion, proliferation, and metastasis of various cancers. The trophoblastic cells of placenta previa accreta (PPA) invade into the myometrium in a similar way to the invasion of cancers. We studied the role of IL-33 in PPA and also aimed to investigate its relation with adverse maternal outcome in this placental disorder.
Methods: A total of 87 pregnant patients were enrolled in this prospective case-control study [27 with PPA, 30 with placenta previa totalis (PPT; nonadherent placenta previa), and 30 con-trols]. IL-33 and IL-6 levels were studied in maternal serum at late preterm gestation weeks. Multiple logistic regression analyses analyzed the risk factors which are associated with PPA and adverse maternal outcomes. Adjusted odds ratios and 95% confidence intervals were also calcu-lated. Enzyme-linked immunosorbent assay (ELISA) method was used to determine maternal serum IL-33 and IL-6 levels.
Results: Serum IL-33 levels were significantly higher in PPA patients when compared with both nonadherent PPT and the control groups (p ¼ .011, p ¼ .010). Serum IL-6 and neutrophil/lympho-cyte ratio levels were significantly higher than the control group’s (p ¼ .045, p ¼ .028). IL-33 lev-els and history of previous cesarean section were found to be significantly associated with PPA (OR: 1.039, 95% CI: 1.004–1.075; p ¼ .030 and OR: 0.067, 95% CI: 0.014–0.309, p ¼ .001, respect-ively). Serum IL-33 levels were positively correlated with previous cesarean section history in PPA. Increased maternal serum IL-33 levels were found to be independently associated with a cesarean hysterectomy and massive transfusion in PPA patients (OR: 1.098, 95% CI: 0.998–1.207; p ¼ .049 and OR: 1.162 95% CI: 1.010–1.337; p ¼ .036).
Conclusion: Increased levels of maternal serum IL-33 and history of previous cesarean section were found to be significantly associated with PPA, and also increased maternal serum IL-33 lev-els were related to cesarean hysterectomy and massive blood transfusion in PPA. We suggest that IL-33 may have a role in abnormal placental invasion.
ARTICLE HISTORY Received 5 September 2019 Accepted 9 October 2019 KEYWORDS Cesarean hysterectomy; interleukin 33; interleukin 6; massive blood transfusion; nonadherent placenta previa totalis; placenta previa accreta
Introduction
Placenta previa accreta (PPA) is defined as abnormal penetration of decidua basalis by placental chorionic villi and invasion of myometrium [1]. It may lead to maternal bleeding in the antenatal period, massive blood transfusion, hysterectomy in cesarian section, and maternal death [2]. It is mostly associated with pla-centa previa totalis (PPT) in which plapla-centa is partially and/or wholly located on internal cervical opening [3]. Its incidence has been increasing in the last 50 years, due to increasing cesarian rates, and has reached 1 in 2500 pregnancies [4]. Previous uterine surgeries increased PPA risk but did not always cause PPA [5]. Cytokines, growth factors, adhesion molecules, and proteases are affective in trophoblast invasion [6–9].
Trophoblastic proliferation and invasion start at the implantation stage and continue up to 12th gestational week on average [10]. In healthy implantation, human extravillous trophoblasts (EVT) invade the maternal decidua and reconstruct maternal spiral arterioles dur-ing early placentation stage. But EVT invasion of myo-metrium continues in PPA [11]. Although this situation is found to be associated with many factors, the molecular basis of trophoblast invasion remains poorly understood.
IL-33, which is a member of the IL-1 family, is an immunomodulatory cytokine. It affects the prolifer-ation and invasion of trophoblastic cells via ST2/IL-4R [12]. Recently, new proofs suggesting the action of IL-33 in decidual trophoblast proliferation and invasion via CCL2/CCR2, NF-jB, and ERK1/2 signal pathways,
CONTACTSibel Ozler sibel2ozler@gmail.com Department of Perinatology, Selcuk University Medical School, Alaeddin Keykubat Campus, Akademi Mahalle, New Istanbul Street No. 369, Postal Code 42130, Konya, Turkey
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
and its help in achieving a healthy pregnancy have been found [13]. Besides, new data are supporting the role of other proinflammatory cytokines, like IL-6, in migration and invasion of trophoblasts [14]. However, the presence and potential roles of IL-33 and IL-6 at the fetal–maternal interface are unknown.
In light of these findings, we aimed to investigate if there were any differences in maternal serum levels of IL-33 and IL-6 of patients having PPA when they were compared to healthy controls. We also studied the relation of these parameters with maternal complica-tions like hysterectomy, massive blood transfusion, and need for intensive care unit (ICU) admission.
Materials and methods
Patients
A prospective case-control study, including 27 patients with PPA, 30 patients with PPT (nonadherent), and 30 healthy controls was conducted. The study was carried out in the perinatology department of Konya Education and Research Hospital. Diagnosis of PPT depended on the following criteria; (a) whole of the placenta placed on internal cervical opening, (b) part of a placenta, the central part of which was placed on anterior/posterior/lateral uterine wall, closes the internal cervical opening. Fifty-seven white female pregnant patients having singleton pregnancy with live fetus>26 weeks of gestation (gestational age was determined from the date of the last menstrual period and confirmed by means of ultrasound in the first tri-mester) were diagnosed to have PPT according to before mentioned criteria, by ultrasonography (Samsung HS70A, Samsung Medison Diagnostic Ultrasound System, Medison Co., Ltd., Seoul, Korea). Suspicion of PPA was defined as the presence of find-ings of placental lacunae or the loss of a clear zone in sonographic examination [15]. Cervical vascularity was defined as the sponge-like appearance of the cervix, namely, the presence of five or more hypoechogenic areas>5 mm in diameter [5]. Nevertheless, 27 patients included in the study were diagnosed with PPA during cesarean section, and all cases were histologically con-firmed according to previously established criteria as the abnormal adherence of placenta involving all layers of the underlying uterine wall [4].
Patients were excluded if any of the following dis-orders were present: preeclampsia, gestational hyper-tension, preterm premature rupture of membranes (PPROM), gestational diabetes, type 1 diabetes, auto-immune diseases (systemic lupus erythematosus, hypothyroidism, hyperthyroidism), gestational
cholestasis, acute trauma leading oxidative stress, seiz-ure, eclampsia, sepsis, chronic kidney or liver disease, fetuses diagnosed to have physical or cytogenetic abnormality, twin pregnancies, alcohol or cigarette consumption, a history of known liver or thrombo-embolic disease.
Thirty healthy controls, who were matched to the patient group by age and body mass index (BMI), were recruited among the patients of our clinic. They were later confirmed to have no adhesion abnormal-ities during cesarean section or vaginally delivery at term. The following criteria were met to choose healthy controls: pregnants of 20–35 years of age; absence of any acquired or congenital uterine abnor-malities (unicorn, didelphys, bicornuate uterus, etc.); no history of assisted reproductive technique, endo-metriosis and/or Asherman syndrome; absence of pre-term labor and/or PPROM, or any disease-causing increase in inflammatory markers (like rheumatoid arthritis, collagen vascular disease, urinary infection, respiratory infection etc.).
Assessment of clinic and laboratory parameters
All participants provided written informed consent. The study protocol was performed according to the principles of the Declaration of Helsinki and was approved by the local Ethical Committee (approval date/number: 2018/77). All participants of the study were evaluated at the initial admission. Clinical exam-ination was performed (obstetric ultrasonography, maternal age, gestational age at delivery) and anthropometric measurements (BMI), as well as the previous obstetric and medical history (parity, previous cesarean section, previous uterine surgery (laparo-scopic or open myomectomy), previous curettage), were recorded. Gestational age was calculated accord-ing to the last menstrual period and verified by ultra-sonography. The blood samples of study and control groups were collected from the participants who were not in any labor in the late preterm or PPROM period (between<34th gestational week and >36 weeks and 6 days). Blood samples were obtained by venipuncture and processed within 30 min to 1 h after withdrawal, by centrifugation at 5000 revolutions/minute for 15 min. All serum samples were stored at80C until the day of analysis.
The IL-33 and IL-6 levels in the maternal serum were analyzed using an interleukin-33 (IL-33) enzyme-linked immunosorbent assay (ELISA) kit and human interleukin-6 (IL-6) ELISA (USCN, Wuhan USCN Business Co., Ltd. China) with an immunoassay (ALISEI) device,
and the results are presented as pg/mL. The detection range of IL-33 and IL-6 were 15.6–1.000 pg/mL and 7.8–500 pg/mL, respectively. Routine laboratory auto-mated techniques were used to determine serum C-reactive protein (CRP) and complete blood count (CBC) levels. CBC parameters were measured with LH780 hematological analyzer (Beckman Coulter, Fullerton, CA). The proportioning absolute neutrophil count calculated the neutrophil-to-lymphocyte ratio (NLR) to total lymphocyte count. CRP measurements were obtained by using an automated clinical chemis-try analyzer (Cobas 501; Roche Diagnostics, Mannheim, Germany) and the results were obtained in mg/L.
Society for Maternal-Fetal Medicine (SMFM) recom-mends delivery by elective cesarian at 36–37 weeks of pregnancy, due to antenatal bleeding risk in patients suffering PPT, without the concern of fetal lung matur-ation [2]. We also planned the delivery of the patients, whose clinical and laboratory parameters were normal and who did not have any bleeding, at the 37th week. Nonstress test and/or biophysical profile, assessment of antepartum vaginal bleeding were used to follow up in the antenatal period. If vaginal bleeding had occurred in the included PPT patients before the 37th week, two doses of betamethasone were applied for fetal lung maturation [5].
The presence of any of cesarean hysterectomy, massive blood transfusion, or need for ICU admission was accepted as an adverse maternal outcome. Massive blood transfusion criteria were as follows: anticipated need to replace 50% or more of blood vol-ume within 2 h, continuous bleeding even after trans-fusion of 4 units of packed red blood cells within a short period of time (1–2 h), systolic blood pressure less than 90 mm Hg and the heart rate more than 120 beats per minute in the presence of uncontrolled bleeding [16]. The patients to be followed in ICU in the postpartum period were selected according to cri-teria of Critical Care in Pregnancy [17].
Statistical analysis
BM SPSS Statistics for Windows, version 22.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. Data were shown as mean (95% confidence interval) or sev-eral cases and (percentage), where applicable. Variables were tested for normality by the Kolmogorov–Smirnov test. The descriptive analyses for normally distributed variables were expressed as the mean ± standard deviation. For variables that were not normally distributed, the median (min–max) values were used. We used one-way ANOVA and
Kruskal–Wallis H tests for the comparison of multiple groups. The non-parametric post hoc test and LSD test were used for the post hoc analysis. Pearson’s chi-square test analyzed nominal data.
The optimal cutoff points of IL-33 were evaluated by ROC analysis calculating area under the curve (AUC) as giving the maximum sum of sensitivity and specificity for the significant test. Sensitivity and speci-ficity values for IL-33 were also calculated at the best cutoff point for PPA. The best predictors of IL-33, to differ PPA groups, were determined by multiple logis-tic regression analysis. Each maternal complication was evaluated to find a relation with IL-33, and other clinical and laboratory parameters by multiple logistic regression analysis. Any variable, whose univariable test had ap-value < .05, was accepted as a candidate for the multivariable model along with all variables of known clinical importance. Spearman rank correlation analyses calculated degrees of association between continuous and metric discrete variables. Adjusted odds ratios and 95% confidence intervals were calcu-lated for each variable, for each specific adverse maternal outcome (hysterectomy, massive blood trans-fusion, and ICU). A p-value less than < .05, was con-sidered statistically significant.
Results
The baseline demographic, clinical, and obstetric parameters of all groups
The baseline characteristics of PPA, PPT, and control patients are given inTable 1. There was no statistically significant difference for gravity, history of previous curettages, delivery week, and fetal birth weight among the groups.
The rate of previous cesarean section was signifi-cantly higher in the PPA group when compared to the other groups (p < .001 and p < .001). PPT (nonadherent previa) group also had a higher cesarean rate when compared to the control group (p ¼ .005) (Table 1).
The levels of IL-33, IL-6, m-CRP, and baseline inflammatory markers of all groups
The maternal serum IL-33 levels of the PPA group were significantly higher than those of the other groups (mean 60.97 ± 5.82 versus 46.04 ± 9.54;p ¼ .011, and mean 60.97 ± 5.82 versus 45.99 ± 9.91; p ¼ .010), but no significant difference was observed between the nonadherent previa and the control groups. The maternal serum IL-6 and NLR levels in PPA group were significantly higher than control group’s (mean
17.51 ± 5.24 versus 11.36 ± 4.84; p ¼ .045 and mean 5.98 ± 3.72 versus 4.24 ± 1.53; p ¼ .028, respectively), but no significant difference was observed when PPA and PPT (nonadherent previa), and PPT and the con-trol groups were compared separately (Table 2).
Best cutoff value, specificity, sensitivity, and AUC for IL-33 in PPA
Serum IL-33 and IL-6 levels were reevaluated with ROC analysis; cutoff levels were determined, and AUC was calculated (Figure 1). According to the ROC analysis performed for the predictive value of IL-33 and IL-6 levels for PPA, the AUC were 0.666 (95% CI: 0.539–0.793; p ¼ .020). In association with PPA,
47.26 pg/mL was the best cut-off value for IL-33 (with 79% specificity and 51% sensitivity) (Table 3).
Factors related to PPA in patients of PPT
Odds ratios for each specific factor were calculated by multivariable logistic regression analysis. Increased serum levels of IL-33 (>47.26 pg/ML) and previous cesarean section were found to be independently associated with PPA in PPT patients (OR: 1.039, 95% CI: 1.004–1.075; p ¼ .030 and OR: 0.067, 95% CI: 0.014–0.309, p ¼ .001). None of the other variables (clinical or laboratory) were associated with PPA (Table 4).
Table 2. The levels of IL-33, IL-6, m-CRP, and baseline inflammatory markers of all groups.
PPA (n ¼ 27) PPT (non-adherens) (n ¼ 30) Control (n ¼ 30) p-Valuea p-Valueaa
IL-33 (pg/mL) 60.97 ± 5.82 46.04 ± 9.54 45.99 ± 9.91 p(ab) 5 .011 p(ac) 5 .010 p(bc) ¼ ns .014 IL-6 (pg/mL) 17.51 ± 5.24 15.70 ± 1.78 11.36 ± 4.84 p(ab) ¼ ns p(ac) 5 .045 p(bc) ¼ ns .158 CRP (mg/L) 0.96 ± 0.168 0.99 ± 0.22 0.91 ± 0.058 p(ab) ¼ ns p(ac) ¼ ns p(bc) ¼ ns .182 WBC (mm3) 10.17 ± 2.52 10.82 ± 2.68 10.51 ± 2.37 p(ab) ¼ ns p(ac) ¼ ns p(bc) ¼ ns .685
Neutrophil/Lymphocyte ratio 5.98 ± 3.72 5.02 ± 2.83 4.24 ± 1.53 p(ab) ¼ ns p(ac) 5 .028 p(bc) ¼ ns
.089
Results were analyzed by OneWay ANOVA (Brown–Forsythe), Post-hoc test (LSD-Games Howell), Mean ± SD, p-value;abetween groups,p-value;aawithin
groups,p-value. p-Values < .05 are statistically significant and are indicated as bold text. NS: not significant. Statistically significant p-values are marked as bold text. IL-33: interleukin-33; IL-6: interleukin-6; CRP: C-reactive protein; WBC: white blood cells.
Table 1. The baseline demographic, clinical, and obstetric parameters for all groups.
PPA (n ¼ 27) PPT (non-adherens) (n ¼ 30) Control (n ¼ 30) p-Value p-Value††
Age (year) 30.30 ± 5.58 30.72 ± 5.56 29.97 ± 6.18 p(ab) ¼ ns
p(ac) ¼ ns p(bc) ¼ ns .892 BMI (kg/m2) 29.30 ± 3.76 30.36 ± 3.86 29.45 ± 4.01 p(ab) ¼ ns p(ac) ¼ ns p(bc) ¼ ns .570 Gravida Nulligravida 4 (14.8%) 4 (13.3%) 8 (26.7%) p(ab) ¼ .372 p(ac) ¼ .222 p(bc) ¼ .073 .174 Multigravida 23 (85.2%) 26 (86.66%) 22 (73.3%) Previous curettages 0 22 (81.5%) 27 (90%) 28 (93.3%) p(ab) ¼ .261 p(ac) ¼ .170 p(bc) ¼ .605 .319 1 5 (18.5%) 3 (10%) 2 (6.7%)
Gestational birth week 36.59 ± 1.64 37.08 ± 1.16 37.10 ± 1.04 p(ab) ¼ ns p(ac) ¼ ns p(bc) ¼ ns
.273
Previous cesarean section† 1.59 [0–4] 0.81 [0–2] 0.31 [0–1] p(ab) < .001 p(ac) < .001 p(bc) ¼ .005
<.001 Total fetal birth weight 2878.89 ± 656.97 3138.08 ± 360.11 3162.76 ± 481.54 p(ab) ¼ ns
p(ac) ¼ .043 p(bc) ¼ ns
.085
Results were analyzed by OneWay ANOVA (Brown-Forsythe), Post-hoc Test (LSD-Games Howell), Kruskal Wallis Test, Mean ± SD, ; Median [min-max], ; Pearson chi-square test, p-value †; between groups, p-value ††; with in groups. p < .05 statistically significant, NS; not significant, Statistically significant p values are marked as bold text. BMI; body mass index.
Correlation between clinical and laboratory parameters, IL-6 and serum IL-33 levels in PPA
Correlation analyses between IL-33 and other variables in PPA were given inTable 5. Only serum IL-33 levels and previous cesarean section rates were significantly correlated to PPA (r ¼ 0.576, p ¼ .041) (Table 5).
Logistic regression analysis of the possible risk factors for cesarean hysterectomy, massive blood transfusion and ICU admission in PPA
Odds ratios for each specific maternal complication in PPA were calculated by multivariable logistic regres-sion analysis. Increased serum levels of IL-33 (>47.26 pg/mL) were found to be independently asso-ciated with a cesarean hysterectomy and massive blood transfusion in PPA (OR: 1.098, 95% CI: 0.998–1.207; p ¼ .049 and OR: 1.162 95% CI: 1.010–1.337; p ¼ .036). None of the other laboratory or clinical variables was associated with cesarean hyster-ectomy, massive blood transfusion, and ICU admission in PPA (Table 6).
Figure 1. ROC curve for IL-33.
Table 3. Best cutoff value, specificity, sensitivity, and AUC of IL-33 in PPA.
Cutoff Specificity Sensitivity AUC (95% CI) p-Value IL-33 (pg/mL) 47.26 79% 51% 0.666 (0.539–0.793) .020 AUC: area under curve; CI: confidence interval.p-Values < .05 are statistic-ally significant and are indicated as bold text. IL-33: interleukin-33. Table 4. Factors related to PPA in all patients of PPT.
PPA Multivariate OR (95% CI) p-Value Age (year) 1.000 (0.922–1.084) .992 BMI (kg/m2) 0.962 (0.852–1.086) .533 Previous curettages 1 1.175 (0.554–2.490) .674 Previous cesarean section 0.067 (0.014–0.309) .001 IL-33 (pg/mL) 1.039 (1.004–1.075) .030 IL-6 (pg/mL) 1.021 (0.998–1.046) .077
CRP (mg/L) 1.532 (0.104–22.492) .756
WBC (mm3) 1.000 (1.000–1.000) .446
Neutrophil/Lymphocyte ratio 1.184 (0.977–1.433) .085 Logistic regression analysis.p-Values < .05 are statistically significant and are marked as bold text. BMI: body mass index; IL33: interleukin-33; IL6: interleukin-6; CRP: C-reactive protein; WBC: white blood cells; OR: Odds Ratio; CI: confidence interval.
Table 5. Correlation between clinical and laboratory parame-ters, IL-6, and serum IL-33 levels in PPA.
IL-33 (pg/mL)
r p
Age (year) 0.156 .457
BMI (kg/m2) 0.201 .335
Previous curettages 0.088 .674
Previous cesarean section 0.576 .041
IL-6 (pg/mL) 0.261 .217
CRP (mg/L) 0.138 .484
WBC (mm3) 0.339 .143
Neutrophil/Lymphocyte ratio 0.007 .977
Pearson’s correlation test and Spearman’s rho test were used. p-Values < .05 are statistically significant and are marked as bold text. r: correl-ation coefficient; BMI: body mass index; IL33: interleukin-33; IL6: interleu-kin-6; CRP: C-reactive protein; WBC: white blood cells.
Discussion
IL-33 is one of the members of IL-1 superfamily and is a ligand for a transmembrane form of ST2. It has recently been discovered and have a role in the pathogenesis of rheumatoid arthritis, asthma, and cardiovascular disease via regulating macrophage function [18]. It has recently been shown that placen-tal and decidual macrophages produce IL-33, and increase EVT proliferation and invasion and via regulating NF-kB and ERK1/2 signal and CCL2/CCR2 pathway [19].
As far as our current knowledge, our study is the only one investigating the role of IL-33 in PPA, which is a placental invasion anomaly; and demonstrating its increase in PPA patients when compared to healthy controls. IL-33 is related to proliferation and metastasis of tumoral cells in many studies [20,21]. IL-33 is known to be expressed in human endometrium, mucosal, and epithelial barriers [22,23]. Hu et al. [20] demonstrated a decreased level of IL-33/ST2 gene expression in decidual cells of patients having a miscarriage when they were compared to healthy controls. Topping et al. , showed expression of IL-33 in endothelial cells of the placenta and CD14þ macrophages of Wharton jelly, and its increased expression in patients suffering acute chorioamnionitis.
IL-33 was shown to be decreased in obese preg-nant patients suffering preeclampsia when they were compared to their non-preeclamptic companions and negatively correlated to uterine artery pulsatility index [24]. IL-33 gene polymorphism was shown to be related to recurrent miscarriage [25]. Granne et al. [26], studied IL-33/ST2 expression in preeclampsia patients and reported no difference in its levels when they were compared to healthy controls [27].
We observed that increased serum IL-33 levels were related to serious maternal complications like hyster-ectomy during the cesarian section, massive blood transfusion, and ICU admission in PPA patients, in our
study. In PPA, need for cesarian hysterectomy, and massive blood transfusion is increased due to myome-trial invasion and angiogenesis [11]. IL-33 is related to angiogenesis, but we have not observed any report mentioning its effect on placental angiogenesis. He et al. reported an important role of IL-33 in the devel-opment of neovascularization and wound epitheliza-tion in diabetic rats [28]. Theodoropoulou et al. [29], observed IL-33 increase tissue remodeling and endo-thelial cell migration in retinal microvessels, in macular degeneration patients. IL-33 was also shown to be increased in colorectal cancer and induce angiogenesis via changing tumoral microenvironment [30].
We observed a positive correlation of IL-33 with a previous cesarian section in PPA patients. Increased maternal serum IL-33 and number of previous cesarian operation was related to PPA risk. Cesarian section, myomectomy operation, curettage procedure, uterine septum resection, and endometrial ablation increase PPA risk by causing endometrial damage [31]. Endometrial damage increases inflammation and vas-cularization in the tissue, just like the other wounds. The impairment in the feto-maternal surface may cause unlimited EVT myometrial invasion [32].
IL-6 increases the expression of subunits of integrin in pregnancy and causes trophoblastic migration and invasion. Jovanovic et al. [14], reported that both exogenous and endogenous IL-6 stimulated tropho-blast cell migration and invasion. However, Umumera et al. [6], observed no relation of trophoblastic inva-sion to IL-6 or IL-8 in PPA patients. We saw increased IL-6 in PPA group, but there was no relation of it in PPA prediction or adverse maternal outcome.
In conclusion, we can, for the first time, provide evi-dence that IL-33 is associated with PPA together with the increased previous cesarean count. We might sug-gest that elevated IL-33 levels, together with the increased count of the previous cesarean section, can be used to determine the risk of PPA in PPT patients.
Table 6. Logistic regression analysis of the possible risk factors for cesarean hysterectomy, massive blood transfusion and ICU admission in PPA.
Cesarean hysterectomy Massive transfusion ICU
OR (95% CI) p-Value OR (95% CI) p-Value OR (95% CI) p-Value
Age (year) 1.019 (0.880–1.179) .804 0.982 (0.855–1.129) .982 0.952 (0.826–1.096) .496 BMI (kg/m2) 0.910 (0.721–1.148) .424 0.863 (0.687–1.082) .202 0.856 (0.683–1.072) .175 Previous curettages1 2.286 (0.216–4.140) .492 4.000 (0.383–7.441) .247 1.500 (0.208–10.807) .687 Previous cesarean section 1.279 (0.381–4.287) .690 1.340 (0.428–4.192) .615 1.530 (0.485–4.826) .468 IL-33 (pg/mL) 1.098 (0.998–1.207) .049 1.162 (1.010–1.337) .036 1.127 (0.997–1.274) .056 IL-6 (pg/mL) 0.995 (0.963–1.027) .740 1.042 (0.992–1.095) .098 1.042 (0.992–1.095) .098 CRP (mg/L) 3.110 (0.041–6.233) .309 2.605 (0.021–3.175) .369 5.527 (0.022–10.914) .412 WBC (mm3) 1.000 (1.000–1.000) .758 1.000 (0.999–1.000) .116 1.000 (0.999–1.000) .408 Neutrophil/Lymphocyte ratio 0.770 (0.445–1.331) .349 0.516 (0.231–1.149) .105 0.642 (0.353–1.168) .146 Logistic regression analysis.p-Values < .05 are statistically significant. Statistically significant p-values are marked as bold text. BMI: body mass index; IL33: interleukin-33, IL6: interleukin-6; CRP: C-reactive protein; WBC: white blood cells; ICU: Intensive Care Unit; OR: odds ratio; CI: confidence interval. 6 S. OZLER ET AL.
We also found that increased levels of IL-33 were asso-ciated with a cesarean hysterectomy and massive blood transfusion in PPA patients. We suggest that increased IL-33 levels can be used to predict the risk of cesarean hysterectomy and massive blood transfu-sion in PPA patients. Because of a low dataset of the study, it must be validated with larger cohorts and with immunohistochemical and RT-PCR studies.
Ethical approval
Informed consent was obtained from all patients for being included in the study.
Disclosure statement
No potential conflict of interest was reported by the authors. The authors alone are responsible for the content and writ-ing of the paper.
ORCID
Sibel Ozler http://orcid.org/0000-0003-4577-8185
Basak Gumus Guler http://orcid.org/0000-0002-0182-6774
References
[1] Royal College of Obstetricians and Gynaecologists (RCOG). Placenta praevia, placenta praevia accreta and vasa praevia: diagnosis and management (Green-top Guideline No 27). London (UK): Royal College of Obstetricians and Gynaecologists. 2011.
[2] Spong CY, Mercer BM, D’alton M, et al. Timing of indi-cated late-preterm and early-term birth. Obstet Gynecol. 2011;118(2):323–333.
[3] Schneiderman M, Balayla J. A comparative study of neonatal outcomes in placenta previa versus cesarean for other indication at term. J Matern Fetal Neonatal Med. 2013;26(11):1121–1127.
[4] Committee on Obstetric Practice. ACOG committee opinion. Placenta accreta. Number 266, January 2002. American College of Obstetricians and Gynecologists. Int J Gynecol Obstet. 2002;77(1):77–78.
[5] Publications Committee, Society for Maternal-Fetal Medicine. Placenta accreta. Am J Obstet Gynecol. 2010;203(5):430–439.
[6] Umemura K, Ishioka S, Endo T, et al. Roles of microRNA-34a in the pathogenesis of placenta accreta. J Obstet Gynaecol Res. 2013;39(1):67–74. [7] Uyanıkoglu H, _Incebıyık A, Turp AB, et al. Serum
angiogenic and anti-angiogenic markers in pregnant women with placenta percreta. Balkan Med J. 2018; 35(1):55–60.
[8] Bartels HC, Postle JD, Downey P, et al. Placenta accreta spectrum: a review of pathology, molecular biology, and biomarkers. Dis Markers. 2018;3:1507674. [9] Plaisier M. Decidualisation and angiogenesis. Best
Pract Res Clin Obstet Gynaecol. 2011;25(3):259–271.
[10] Burton GJ, Jauniaux E, Watson AL. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd col-lection revisited. Am J Obstet Gynecol. 1999;181(3): 718–724.
[11] Marcellin L, Delorme P, Bonnet MP, et al. Placenta percreta is associated with more frequent severe maternal morbidity than placenta accreta. Am J Obstet Gynecol. 2018;219(2):193.e1–193.e9.
[12] Chen H, Zhou X, Han TL, et al. Decreased IL-33 pro-duction contributes to trophoblast cell dysfunction in pregnancies with preeclampsia. Mediators Inflamm. 2018;15:9787239–9787211.
[13] Hu WT, Li MQ, Liu W, et al. IL-33 enhances prolifer-ation and invasiveness of decidual stromal cells by up-regulation of CCL2/CCR2 via NF-jB and ERK1/2 signaling. Mol Hum Reprod. 2014;20(4):358–372. [14] Jovanovic M, Vicovac L. Interleukin-6 stimulates cell
migration, invasion and integrin expression in HTR-8/ SVneo cell line. Placenta. 2009;30(4):320–328.
[15] Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol. 2006;107(4): 927–941.
[16] Committee on Obstetric Practice. Committee Opinion No. 713: Antenatal corticosteroid therapy for fetal maturation. Obstet Gynecol. 2017;130(2):e102–e109. [17] Pacheco LD, Saade GR, Costantine MM, et al. An
update on the use of massive transfusion protocols in obstetrics. Am J Obstet Gynecol. 2016;214(3):340–344. [18] American College of Obstetricians and Gynecologists. Practice Bulletin No. 170: Critical Care in Pregnancy. Obstet Gynecol. 2016;128(4):e147–e154.
[19] Fock V, Mairhofer M, Otti GR, et al. Macrophage-derived IL-33 is a critical factor for placental growth. J Immunol. 2013;191(7):3734–3743.
[20] Hu W-T, Huang L-L, Li M-Q, et al. Decidual stromal cell-derived IL-33 contributes to Th2 bias and inhibits decidual NK cell cytotoxicity through NF-jB signaling in human early pregnancy. J Reprod Immunol. 2015; 109:52–65.
[21] Tong X, Barbour M, Hou K, et al. Interleukin-33 pre-dicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways. Mol Oncol. 2016;10(1): 113–125.
[22] Mager LF, Riether C, Sch€urch CM, et al. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J Clin Invest. 2015;125(7):2579–2591. [23] Palmer G, Gabay C. Interleukin-33 biology with
poten-tial insights into human diseases. Nat Rev Rheumatol. 2011;7(6):321–329.
[24] Topping V, Romero R, Than NG, et al. Interleukin-33 in the human placenta. J Matern Fetal Neonatal Med. 2013;26(4):327–338.
[25] Beneventi F, Locatelli E, De Amici M, et al. Maternal and fetal leptin and interleukin 33 concentrations in pregnancy complicated by obesity and preeclampsia. J Matern Fetal Neonatal Med. 2019;27:1–7.
[26] Soheilyfar S, Nikyar T, Fathi Maroufi N, et al. Association of IL-10, IL-18, and IL-33 genetic polymor-phisms with recurrent pregnancy loss risk in Iranian women. Gynecol Endocrinol. 2019;35(4):342–345.
[27] Granne I, Southcombe JH, Snider JV, et al. ST2 and IL-33 in pregnancy and pre-eclampsia. PLoS ONE. 2011; 6(9):e24463.
[28] He R, Yin H, Yuan B, et al. IL-33 improves wound heal-ing through enhanced M2 macrophage polarization in diabetic mice. Mol Immunol. 2017;90:42–49. [29] Theodoropoulou S, Copland DA, Liu J, et al.
Interleukin-33 regulates tissue remodelling and inhib-its angiogenesis in the eye. J Pathol. 2017;241(1): 45–56.
[30] Zhang Y, Davis C, Shah S, et al. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol Carcinog. 2017;56(1):272–287. [31] Carusi DA. The placenta accreta spectrum:
epidemi-ology and risk factors. Clin Obstet Gynaecol. 2018; 61(4):733–742.
[32] Tantbirojn P, Crum CP, Parast MM. Pathophysiology of placenta creta: the role of decidua and extravillous trophoblast. Placenta. 2008;29(7):639–645.
