Defective deep placentation has been associated with a spectrum of complications of pregnancy including preeclampsia, intrauterine growth restriction, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and abruptio placentae. The disease of the placental vascular bed that underpins these complications is commonly investigated with targeted biopsies. In this review, we critically evaluate the biopsy technique to summarize the salient types of defective deep placentation, and propose criteria for the classification of defective deep placentation into 3 types based on the degree of restriction of remodeling and the presence of obstructive lesions in the myometrial segment of the spiral arteries.
It is now well-established that placentation in humans is associated with unique vascular remodeling. The process of physiologic remodeling of the spiral arteries during gestation involves a decidua-associated and a trophoblast-associated stage. Such processes involve the decidual and junctional zone (JZ) myometrial segments. Deep placentation involves nearly complete transformation of the decidual and myometrial segments of approximately 100 spiral arteries. Defective deep placentation was first described in preeclampsia and intrauterine growth restriction (IUGR) and was characterized by absent or incomplete remodeling of the JZ segment of the spiral arteries. In recent years, defective deep placentation has also been associated with other obstetrical syndromes, including spontaneous abortion, preterm labor with intact membranes, and preterm prelabor rupture of the membranes (PROM).
In this review, we critically evaluate the biopsy techniques to assess placental bed vascular disease, summarize the salient features of defective deep placentation associated with different obstetrical syndromes, and propose a new classification that we hope will contribute to a better understanding of the lesions and their pathophysiologic condition.
The study of the placental bed: the beginning
The study of the placental bed began in the late 1950s by 2 independent groups of investigators who used different biopsy techniques. Dixon and Robertson, working in Jamaica, obtained biopsy samples at the time of cesarean delivery with the use of biopsy forceps. At the time of hysterotomy, biopsy samples were obtained under direct visualization from the implantation site after delivery of the placenta. Using curved scissors, the investigators obtained a disk that was approximately 1 cm in diameter. Renaer and Brosens, in Leuven, Belgium, obtained biopsy samples after vaginal delivery using a sharpened ovum forceps. The transvaginal technique required the manual localization and removal of the placenta to sample the placental bed. Although the placenta was peeled away from the wall, the ovum forceps was guided between the palm of the hand and the uterine wall, and a large biopsy sample that included decidua and a few millimeters of the underlying myometrium was obtained. In other studies, different techniques have been used to obtain placental bed biopsy samples. These techniques result in samples of variable size, depth, and origin.
Robertson et al recommended orienting the biopsy sample so that perpendicular sections of the decidua and myometrium could be obtained. Both groups examined the entire biopsy specimen by using a serial sectioning technique, 1 section being stained for every 5, 10, or 20 sections of the tissue.
Histological confirmation that the biopsy was derived from the placental bed was based on (1) the presence of trophoblast, (2) adherent villi, or (3) transformed spiral arteries. However, the absence of these markers does not necessarily mean that the placental bed was not sampled. In IUGR, a small placental bed may affect the success rate of sampling. Unfortunately, the success rates have not been reported systematically in most studies. This is desirable as research in the placental bed moves forward.
A key step in the understanding of the placental bed was made when Brosens systematically studied the placental bed of 14 patients using cesarean hysterectomy specimens. The uteri were obtained from mothers who had preeclampsia, preeclampsia with IUGR, chronic hypertension, and nephrotic syndrome. In 3 cases, the placenta was in situ, which aided in the precise mapping of the placental bed. However, when the placenta had been detached, the implantation site was identified by the presence of trophoblast. In one specimen obtained from a patient with severe preeclampsia and a fetal death at 31 weeks of gestation, the uterus contained the fetus and placenta in situ. All specimens were processed according to the histologic technique of sectioning the uterus with placenta in situ, previously described by Boyd and Hamilton. The technique allowed tracing of the radial arteries in the myometrium and then identification of the individual spiral arteries as they traveled through the placental bed. In each specimen, 10-25 spiral arteries in the placental bed and a similar number in the nonplacental area were examined. In a large subsequent study of hysterectomy specimens (with the placenta in situ) obtained between 8 and 18 weeks of gestation, Pijnenborg et al examined the transformation of the spiral arteries during the first half of pregnancy.
The uteroplacental blood supply
Spiral artery remodeling
After the physiological changes of the spiral arteries in the placental bed were identified, it was postulated that they resulted from the destructive action of trophoblast on the vascular musculature and the elastic membrane. However, it was soon observed that changes associated with trophoblast invasion were preceded by edema of the wall, disintegration of the elastic elements, and changes in smooth muscle cells, such as rounding of the nucleus, the loss of myofibrils and dense bodies, and the accumulation of glycogen.
Subsequent investigation of hysterectomy specimens from 8-18 weeks that were studied by Pijnenborg et al resulted in 2 major findings. First, vascular changes that included disorganization of the muscular wall could not be attributed exclusively to the presence of trophoblast. It was noted that vascular smooth muscle became disorganized before the arrival of endovascular trophoblast; however, this disorganization was enhanced in the presence of interstitial trophoblast. The second finding was the apparent occurrence of endovascular invasion in the JZ myometrium. This was considered the second “wave” of trophoblast invasion, which occurred after a 4-week period of the trophoblast within the decidua. Although the “2-wave concept” is not accepted universally, it provided a valuable model to consider the possible mechanisms responsible for defective deep placentation.
A key question has been the relative contribution of the trophoblast and the decidua in vascular remodeling of the spiral arteries. Craven et al compared the histologic characteristics of spiral arteries in the secretory phase of the menstrual cycle using endometrial biopsy specimens and decidual arteries from patients who underwent elective termination of pregnancy. They concluded that the initial stages of physiologic change of the spiral arteries occurred without evidence of trophoblast invasion. However, King and Loke noted that “fibrinoid necrosis” of the wall does not occur in the absence of trophoblast invasion. Kam et al compared the blood vessels from the implantation sites of early human pregnancies with specimens in which trophoblast was absent. The results confirmed that true physiologic transformation of the spiral arteries occurred only in the presence of trophoblast. Recently, Smith et al examined samples of the decidua basalis (8-12 weeks of gestation) using immunohistochemistry and provided evidence that uterine natural killer cells and macrophages participate in the remodeling through the induction of apoptosis or extracellular matrix degradation. They also reported that, in the early stages of spiral artery remodeling, vascular smooth muscle cells showed dramatic disruption and disorganization preceding the presence of endovascular trophoblast.
Deep placentation
Two major factors determine the maternal blood flow to the placenta. The first is the size of the placental bed, which is determined by the number of spiral arteries that communicate with the intervillous space. In a study that was undertaken to reconstruct the basal plate of the placenta of normal patients, Brosens and Dixon described an irregular distribution of the arterial openings in the intervillous space. They found that arterial openings frequently clustered in groups of 2 or 3 and were located in close proximity to the placental septa ( Figure 1 ). In a careful and detailed study, 48 arterial openings of the spiral arteries were counted (the total was estimated to be 120 openings, based on the examination of a specimen that represented two-fifths of the basal plate). It was also found that each opening corresponded to 1 spiral artery with a density of 1 artery per 2 cm 2 of basal plate. Serial sections of hysterectomy specimens demonstrated that the radial arteries were divided approximately 0.5 cm beneath the endometrium (ie, myometrial JZ) into 2 or 3 arteries with physiologic changes or transformation. This may explain the clustering of 2 or 3 openings of spiral arteries in the intervillous space ( Figure 1 ).
