Decreased placental and maternal serum TRAIL-R2 levels are associated with placenta accreta
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
References (30)
- et al.
IFPA Meeting 2010 Workshops Report II: Placental pathology; trophoblast invasion; fetal sex; parasites and the placenta; decidua and embryonic or fetal loss; trophoblast differentiation and syncytialisation
Placenta
(2011) - et al.
Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy
Placenta
(1980) - et al.
Factors regulating trophoblast migration and invasiveness: possible derangements contributing to pre-eclampsia and fetal injury
Placenta
(2003) - et al.
Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes
Am. J. Obstet. Gynecol.
(2003 Oct) - et al.
Apoptosis and its role in the trophoblast
Am. J. Obstet. Gynecol.
(2006) - et al.
A placental protective role for trophoblast-derived TNF-related apoptosis-inducing ligand (TRAIL)
Placenta
(2009) - et al.
Placental apoptosis in normal human pregnancy
Am. J. Obstet. Gynecol.
(1997) - et al.
Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5
Mol. Cell
(1999) - et al.
Identification and characterization of a new member of the TNF family that induces apoptosis
Immunity
(1995) - et al.
Localization and variation of TRAIL and its receptors in human placenta during gestation
Life Sci.
(2004)