Elsevier

Placenta

Volume 39, March 2016, Pages 1-6
Placenta

Decreased placental and maternal serum TRAIL-R2 levels are associated with placenta accreta

https://doi.org/10.1016/j.placenta.2016.01.004Get rights and content

Highlights

  • TRAIL-R2, also known as death receptor-5, induces apoptotic signalling.

  • We examine placental and maternal serum TRAIL-R2 levels in placenta accreta.

  • Lower levels of placental TRAIL-R2 are associated with placenta accreta.

  • Maternal serum and placental TRAIL-R2 levels are well-correlated.

  • Previous history of cesarean section is significantly associated with placenta accreta.

Abstract

Objectives

TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) is produced both by decidual and trophoblast cells during pregnancy and known to participate in apoptosis. In this study, we aimed to determine and to compare maternal serum and placental TRAIL-R2 levels in patients with placenta accreta, non-adherent placenta previa and in healthy pregnancies. We also aimed to analyze the association of placenta accreta with the occurrence of previous C-sections.

Study design

A total of 82 pregnant women were enrolled in this case–control study (27 placenta accreta patients, 26 non-adherent placenta previa patients and 29 age-, and BMI-matched healthy, uncomplicated pregnant controls). TRAIL-R2 levels were studied in both maternal serum and placental tissue homogenates. Determining the best predictor(s) which discriminate placenta accreta was analyzed by multiple logistic regression analyses. Adjusted odds ratios and 95% confidence intervals were also calculated.

Results

Both placental and serum TRAIL-R2 levels were significantly lower in placenta accreta group (median 34.82 pg/mg and 19.85 pg/mL, respectively) when compared with both non-adherent placenta previa (median 39.24 pg/mg and 25.99 pg/mL, respectively) and the control groups (median 41.62 pg/mg and 25.87 pg/mL, respectively) (p < 0.05). Placental TRAIL-R2 levels and previous cesarean section were found to be significantly associated with placenta accreta (OR: 0.934 95% CI 0.883–0.987, p = 0.016 and OR:7.725 95% CI: 2.717–21.965, p < 0.001, respectively). Placental and serum TRAIL-R2 levels were positively correlated.

Conclusion

Decreased levels of placental TRAIL-R2 and previous history of cesarean section were found to be significantly associated with placenta accreta, suggesting a possible role of apoptosis in abnormal trophoblast invasion.

Introduction

In a normal, healthy pregnancy, there is a perfect organisation of trophoblastic invasion, maternal decidual defence barrier and placental angiogenesis. An imbalance within these well-designed processes may cause inadequate or excessive trophoblastic invasion leading to many pregnancy associated disorders. The most common examined risk factor of abnormal placental invasion is the disturbance of the fine balance between the pro- and anti-invasive factors at the placentation site [1], [2]. Previous reports indicated that the most important risk factor for placenta accreta is placenta previa in the presence of an uterine scar, and the remaining risk factors reported are multiparity, maternal age, any prior uterine surgery or curettage, uterine irradiation, endometrial ablation, Asherman syndrome or other uterine anomalies [1]. When all these associated risk factors are considered, it is clear that the common feature is the disruption of the fetal–maternal interface by the alterations in the local microenvironment [2]. Because abnormal placental invasion is commonly located in the area of the previous hysterotomy, and because the incidence of placenta accreta appears to be increasing parallel to the increasing number of cesarean deliveries, the scarring of the uterine wall, particularly by previous cesarean deliveries, is hypothesized as the most important risk factor leading to placental hyperinvasiveness [1], [2].

Extravillous trophoblast cell (EVT) invasion of the maternal decidua is critical for the maintenance of a successful pregnancy. During normal placental development, EVT invade maternal tissues via two routes, the interstitial route, which proceeds through the decidua to the inner third of the myometrium, and the endovascular route, which includes the invasion of decidual spiral arteries [3]. EVT invasion is tightly regulated, unlike the uncontrolled invasion of neoplastic cells [4]. Deficient invasion of EVT has been shown to be related with miscarriage, preeclampsia, intrauterine growth restriction and preterm delivery [5], [6], [7]. Conversely, excessive trophoblast invasion together with decidual deficiency are the main mechanisms proposed for the pathophysiology of morbidly adherent placenta, placenta accreta [8]. A number of fetomaternal mechanisms work together in the regulation of trophoblastic invasion, and one mechanism is the balance between EVT proliferation and cell death, mediated through apoptotic mechanisms [9]. Apoptosis, programmed cell death, is a crucial factor in normal placental development and also for mediating immune privilege of the fetus during pregnancy [10], [11]. Any disturbance of the balance between cell proliferation and apoptosis may also cause alterations in trophoblastic invasion. Although a number of mechanisms have been proposed, the molecular basis of trophoblast invasion remains poorly understood.

Apoptosis continues to increase throughout pregnancy and can be initiated either intrinsically by the mitochondrial pathway or extrinsically via membrane-associated death receptors [10], [12]. In the extrinsic pathway, the members of the tumour necrosis factor (TNF) family, such as TNF-α, Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL), are the most relevant factors that trigger apoptosis by binding to receptors on the cell surface [13]. TRAIL belongs to the TNF superfamily and was first identified in 1995. TRAIL is a type II membrane protein and can also exist as a soluble fragment (sTRAIL) following proteolytic cleavage [14]. Both membrane-expressed TRAIL and the soluble form have been shown to induce apoptosis in various cell lines. TRAIL can interact with five different receptors. Among these five receptors, TRAIL-R1 (DR4) and -R2 (DR5) are also known as death receptors (DR) and induce apoptotic signalling [10], [15]. EVT was previously shown to express both TRAIL and its receptors. Additionally, TRAIL-R1 and R2 can be detected in the placenta throughout pregnancy, and the immunohistochemical analysis by Chen et al. showed that staining of both these receptors was gradually increased parallel to placental development [15]. Therefore, it would not be wrong to say that as both apoptosis and the immunoreactivity of death receptors increase throughout gestation, TRAIL receptors may be implicated in altered trophoblastic invasion. In addition to the trophoblastic expression of TRAIL-R2, it has been shown that human decidual stromal cells also express TRAIL-R2, but not TRAIL and TRAIL-R1 [16]. So, as TRAIL-R2 is produced both by decidual and trophoblast cells during pregnancy and known to participate in apoptosis, we suggested that it may be associated with altered trophoblast invasion in placenta accreta.

In the present study, we aimed to determine and to compare maternal serum and placental TRAIL-R2 levels in patients with placenta accreta, non-adherent placenta previa and those with healthy pregnancies. We also aimed to evaluate whether the placental and serum levels of TRAIL-R2 are correlated. Another purpose of the study was to determine the other possible risk factors, such as scarring of the uterine wall by previous cesarean deliveries, which may be associated with placental invasion anomalies.

Section snippets

Design and study population

A prospective case–control study was performed between August 2013 and September 2014 in the Perinatology Department of Zekai Tahir Burak Women's Health Education and Training Hospital. A total of eighty-two participants were included in the study. Twenty-seven patients were diagnosed as placenta previa prenatally by grey-scale ultrasonography and later histologically diagnosed as placenta accreta according to previously established criteria defined as the abnormal adherence of the placenta

The baseline characteristics, maternal serum and placental TRAIL-R2 levels of the groups

A total of 82 pregnant women were enrolled in the study (27 placenta accreta patients, 26 non-adherent placenta previa patients and 29 age-, gestational age- and BMI-matched healthy, uncomplicated pregnant controls). The baseline demographic, clinical and laboratory characteristics of all groups are given in Table 1. There were no statistically significant differences among age, parity, BMI and previous history of curettages between groups. There was a significant difference for the mean birth

Discussion

In the present prospective case–control study of placenta accreta, decreased levels of placental TRAIL-R2 and a previous history of cesarean section were significantly associated with placenta accreta.

Placenta accreta is defined as the complete or partial adhesion of the placenta in the myometrium and the incidence has increased to 3 per 1000 deliveries in the last decade, parallel with the increasing rate of cesarean delivery [1]. Placenta accreta is an obstetric life-threatening clinical

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