Defective deep placentation is characterised by defective remodelling of the utero-placental arteries. Under certain conditions, it is also characterised by the presence of arterial lesions, such as acute atherosis and the persistence of endovascular trophoblast. The condition has been associated with a spectrum of complications during pregnancy, including pre-eclampsia, intrauterine growth restriction, pre-term birth, pre-term premature rupture of membranes, late sporadic miscarriage and abruptio placentae. Criteria are proposed for the classification of defective deep placentation into three types based on the degree of restriction of remodelling and the presence of obstructive lesions in the myometrial segment of the spiral arteries. Although the underlying mechanisms are not understood, evidence is emerging that the origin of defective deep placentation may not lie in primary defect of the trophoblast, but in abnormalities of the endometrium and inner myometrium before or during the early stages of placentation.
Introduction
Research into the transformation of small spiral arterioles into large utero-placental arteries during pregnancy began in the 1950s. Investigators conducting radioangiographic studies suggested that maternal blood probably enters the intervillous space of the haemochorial placenta in the form of discrete ‘spurts’. In their monumental work on the human placenta, Boyd and Hamilton vaguely described that the functional communications between the spiral arteries and the intervillous space is considerably increased in size during the last 3 months of pregnancy both by an actual increase in calibre of the vessels and by a diminution in the amount of cytotrophoblastic plug. Measurements of the amount of maternal blood flowing through the uterus and the intervillous space were made by Assali et al., which showed that maternal blood flows through the uterus and placenta during the third trimester at an approximate rate of 750 ml min −1 and 600 ml min −1 , respectively. Browne and Veall found a significant decrease of flow in the presence of maternal hypertension, which seemed to relate to the severity of the hypertension.
These observations prompted Dixon and Robertson and Renaer and Brosens to introduce the technique of placental bed biopsy to study the pathology of spiral arteries in late pregnancy in the presence of maternal hypertension. They introduced the concept of the placental bed as the area of decidua and myometrium controlling the formation of the utero-placental arteries. However, the study of the vascular pathology of the placental bed on biopsy material was criticised (Hamilton W.J., personal communication) for the risk of confusing placentation changes with pathology. The study of hysterectomy specimens with placenta in situ was recommended to identify the spiral arteries from their origin in the inner myometrium. Unfortunately, the hysterectomy specimens with placenta in situ collected by Boyd in Cambridge, UK, and Hamilton in London, UK, were not useful. In most of the cases, the specimens were obtained by coroners at the time of fatal road accidents when no clinical data were available.
In addition to placental bed biopsies, Brosens et al. collected a series of caesarean hysterectomy specimens with the placenta at least partially in situ from women with normal pregnancy and pre-eclampsia with and without intrauterine growth restriction. Large serial histological sections of the specimens allowed them to trace the origin of the utero-placental vessels in the myometrium and to follow the individual utero-placental arteries in their course from the inner myometrium, through the decidua and basal plate until the opening in the intervillous space of the placenta. With these specimens, they were able to show that, in normal pregnancy, the remodelling extends from the decidual terminations of the spiral arteries as far as the radial arteries in the myometrium, except in some spiral arteries at the periphery of the placenta. Deep placentation involves remodelling of the decidual and myometrial segments of about 90% of the utero-placental arteries (see Pijnenborg R, Chapter 3). The changes are associated with trophoblast invasion, disintegration and loss of the elastic elements and the smooth muscle cells. The vessel no longer represents an artery, but is transformed into a grossly distended vessel with a fibro-fibrinoid wall infiltrated by trophoblastic cells.
In early studies, the clinical conditions associated with defective deep placentation included chronic hypertension, pre-eclampsia and pre-eclampsia with intrauterine growth restriction.
Defective spiral artery remodelling
The seminal observation that physiological vascular changes were absent in the myometrial segments of spiral arteries in pre-eclampsia provided an explanation for the reduced blood flow to the intervillous space seen in pre-eclampsia compared with normal pregnancy. The retrograde endovascular trophoblast migration fails to extend beyond the deciduo-myometrial junction. Consequently, instead of the fibrinoid matrix with embedded endovascular trophoblast within the wall of the transformed utero-placental artery, these segments of the spiral arteries retain their muscular and elastic tissue, rendering them vasoreactive as well as being narrower in diameter (200 μm) than the utero-placental arteries (500 μm).
Further observations showed that this defect is also seen in normotensive intrauterine growth restriction and in pre-eclampsia superimposed on essential hypertension, with vessels in the latter also showing intimal hyperplastic changes as a result of the essential hypertension.
Not all pre-eclamptic pregnancies are complicated by intrauterine growth restriction and, therefore, the absence of physiological vascular changes in the myometrial segments of the spiral arteries is insufficient to explain the growth restriction. It is now clear that the failure of trophoblastic invasion into the spiral arteries is not confined just to the intramyometrial segments. One-third to one-half of the spiral arteries in the placental bed lack the physiological changes in pre-eclampsia ( Fig. 1 ). This absence of remodelling of the spiral artery at the level of the decidual segments is also seen in intrauterine growth restriction. Furthermore, the lack of physiological change may also be confined to part of the circumference of the vessel with the remaining portion of the circumference showing physiological change.
Spiral arteries terminate as openings into the intervillous space in the basal plate of the placenta; therefore, the absence of physiological change in the decidual segments of the spiral arteries can be detected in sections of the basal plate. Slices of the basal plate taken perpendicular to the maternal surface, as en face sections, increase the frequency of observing these vessels. The disadvantage of this sectioning lies in the abundant fibrinoid material within the Rohr’s and Nitabuch layer in the basal plate, which can mislead the unwary in interpreting the fibrinoid change in vascular changes and, as will be discussed later, the fibrinoid necrosis in acute atherosis.
Defective spiral artery remodelling
The seminal observation that physiological vascular changes were absent in the myometrial segments of spiral arteries in pre-eclampsia provided an explanation for the reduced blood flow to the intervillous space seen in pre-eclampsia compared with normal pregnancy. The retrograde endovascular trophoblast migration fails to extend beyond the deciduo-myometrial junction. Consequently, instead of the fibrinoid matrix with embedded endovascular trophoblast within the wall of the transformed utero-placental artery, these segments of the spiral arteries retain their muscular and elastic tissue, rendering them vasoreactive as well as being narrower in diameter (200 μm) than the utero-placental arteries (500 μm).
Further observations showed that this defect is also seen in normotensive intrauterine growth restriction and in pre-eclampsia superimposed on essential hypertension, with vessels in the latter also showing intimal hyperplastic changes as a result of the essential hypertension.
Not all pre-eclamptic pregnancies are complicated by intrauterine growth restriction and, therefore, the absence of physiological vascular changes in the myometrial segments of the spiral arteries is insufficient to explain the growth restriction. It is now clear that the failure of trophoblastic invasion into the spiral arteries is not confined just to the intramyometrial segments. One-third to one-half of the spiral arteries in the placental bed lack the physiological changes in pre-eclampsia ( Fig. 1 ). This absence of remodelling of the spiral artery at the level of the decidual segments is also seen in intrauterine growth restriction. Furthermore, the lack of physiological change may also be confined to part of the circumference of the vessel with the remaining portion of the circumference showing physiological change.
Spiral arteries terminate as openings into the intervillous space in the basal plate of the placenta; therefore, the absence of physiological change in the decidual segments of the spiral arteries can be detected in sections of the basal plate. Slices of the basal plate taken perpendicular to the maternal surface, as en face sections, increase the frequency of observing these vessels. The disadvantage of this sectioning lies in the abundant fibrinoid material within the Rohr’s and Nitabuch layer in the basal plate, which can mislead the unwary in interpreting the fibrinoid change in vascular changes and, as will be discussed later, the fibrinoid necrosis in acute atherosis.
Vascular lesions
The prototypical vascular lesion in placental bed pathology is acute atherosis, although it is best seen in maternal vessels outwith the placental bed in the decidua parietalis. It is generally agreed that it can be seen in pre-eclampsia, hypertensive disease not complicated by pre-eclampsia, normotensive intrauterine growth restriction and systemic lupus erythematosus. Its presence in uncomplicated diabetes mellitus or gestational diabetes, however, is disputed.
In its earliest form, fibrinoid necrosis of the arterial wall occurs. In established cases, a perivascular lymphocytic infiltrate and lipid-laden macrophages within the lumen and the damaged vessel wall are seen in addition to the fibrinoid necrosis ( Fig. 2 ). The reason why acute atherosis is best seen within maternal vessels in the decidua parietalis is that it affects vessels that have not undergone the physiological changes of pregnancy. Vessels in the placental bed that have undergone physiological changes will have a fibrinoid matrix within their wall, which may be mistaken for the fibrinoid necrosis of acute atherosis. However, the vessels in the decidua parietalis remain unadulterated by fibrinoid deposition normally, as they do not undergo physiological changes.
The fibrinoid necrosis has two unwelcome consequences: (1) it results in endothelial disruption, which predisposes the vessel to thrombosis, and (2) the weakening of the vessel wall can result in aneurysmal formation.
The incidence of acute atherosis ranged from 41% to 48% in a study examining placental bed biopsies, placental basal plates and amniochorial membranes in pre-eclampsia and intrauterine growth restriction. The correlation between acute atherosis and birthweight, degree of proteinuria and severity or duration of the hypertension is unclear.
A less well-recognised abnormality in the maternal placental bed spiral arteries is the presence of endovascular trophoblast within the lumina of the spiral arteries in the third trimester ( Fig. 3 ). Their presence is physiological in the first and second trimester as part of the vascular response to pregnancy; however, in the third trimester, it is pathological and is seen in the context of pre-eclampsia or intrauterine growth restriction. This has two effects. First, it disrupts the vascular endothelium and adds to the thrombogenicity of the vessel. Second, although not proven, it may present a physical impediment to blood flow not dissimilar to the reduction of blood flow into the intervillous space in the first trimester as a result of the intravascular plugging by endovascular trophoblast.
Relationship with placental pathology
Defects in the maternal blood supply to the placenta can result in pathological lesions in the placenta.
Placental infarcts
The utero-placental arteries act effectively as end arteries to their servant organ, namely the placenta, as there is little cross-circulation in the intervillous space in which the villi are immersed. Brosens and Renaer showed that a reduction in the blood flow through these arteries due to a defect in spiral arterial remodelling was a significant cause of placental infarction. Similarly, other vascular defects that can diminish utero-placental blood flow, such as acute atherosis or other pathology, can also result in placental infarction. The placental bed and the supplying arteries of the infarct show a range of pathology. The absence of the physiological vascular changes may be seen in the decidual and, more often, in the myometrial segments of the spiral arteries, and trophoblastic invasion is absent. In the basal plate, what is more often seen is thrombosis within maternal utero-placental arteries ( Fig. 4 ).
Infarcts are seen in about 10–25% of placentas, and it is generally agreed that infarcts occupying less than 10% of the parenchyma or peripheral infarcts are clinically insignificant. Those occurring in small placentas (which would have less functional reserve) would, however, be clinically significant. The infarcts vary in shape and can be irregularly shaped, but are most often wedge shaped with the base oriented in the basal plate. A fresh infarct is dark red and is more easily palpable than it is to visualise. With increasing age, the infarct becomes firmer and paler, changing from brown-red to yellow-white ( Fig. 5 ).
