Chapter 49 Augustine T. Peter Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana, USA The placenta, an arrangement of transporting epithelia between the fetal and maternal circulations, created and owned by the fetus, protected by the dam, and escaping antigenic rejection, loses its purpose immediately after the rupture of the umbilical cord and is expelled after the delivery of the fetus. Bovine placenta fascinated the early farmers, excited many scholars to create more than 1500 documents since 1910,1 and continues to provide remuneration for veterinarians all over the globe because of its retention. Failure of placental expulsion constitutes retained placenta. Much has been documented about retained placenta in theriogenology textbooks2–7 based on these authors’ own vast clinical experience and information gleaned from scientific publications. Excellent review articles by leading veterinary clinical investigators have more vividly encapsulated the various aspects of this clinical condition.8–26 What is known about its clinical signs and negative influence on postpartum reproductive performance has not changed in the last two centuries. However, over the years, many hypotheses with regard to its occurrence (particularly at the tissue and cellular levels), risk factors, preventive measures, and treatment plans have been proposed. The headings for this topic include definitions, developmental morphology of placenta to better understand the process of detachment and etiology, pathogenesis, treatment, and prevention. It will become very apparent on reading this chapter that there are many instructive similarities among these topics. The fetal part of the placenta, namely the fetal membrane (allantochorion), normally separates from its maternal moorings during the process of parturition. The process of parturition is marked by vascular, contractile, and mechanical dynamics designed to expel the fetus and its membranes (allantochorion and amnion). The fetal and maternal parts of the placenta have equal regulatory roles in the timely separation of the fetal part of the placenta. Hence use of the term “placenta” in this chapter will point to a collective structure created by the dam and the fetus. Retention is primarily due to failure of the villi of the fetal cotyledon to detach themselves from the maternal crypts of the caruncle. The process of separation and inversion of allantochorion (allantoic surface faces outside) is completed on average within 8 hours of initiation of parturition, depending on the parity and age of the patient. In general, all parts of the allantochorion and amnion need to be expelled within 0.5–12 hours after calving. Thus retention of fetal membranes is referred to as retained placenta or, more correctly, as retained fetal membranes (RFM), with the term “fetal membranes” referring to both the allantochorion and amnion. While the use of “fetal membrane” (singular) for allantochorion is accepted, to avoid confusion the term “allantochorion” will be used here. Presently, bovine placenta is described as cotyledonary synepitheliochorial based on the morphology that is established around 40–50 days into pregnancy. Earlier classification as syndesmochorial was based on a misunderstanding of the number and form of the layers intervening between the fetal and maternal circulation. This classification needed correction because of new evidence. The earlier assumption that the uterine epithelium is lost in the process of placentation resulting in direct apposition of trophectoderm to the maternal connective tissue is no longer tenable. Now it is known that the uterine epithelium persists although initially modified to a variable degree into patches of a hybrid fetomaternal syncytium formed by the migration and fusion of a particular type of trophectodermal cells with uterine epithelial (UE) cells. These trophoblast binucleate/giant cells (TGC) migrate and modify the uterine epithelium by apical fusion to form fetomaternal hybrid syncytial plaques with up to eight nuclei at the junction of the fetal and maternal tissue. These syncytial plaques are replaced by regrowth of uterine epithelial cells by day 40, and subsequently TGC–UE fusion produces only transient trinucleate minisyncytia throughout the remainder of pregnancy. Research findings have necessitated a change in the morphological terminology of placentation and defined the bovine placenta as synepitheliochorial. The prefix “syn” indicates the contribution of TGC to the fetomaternal syncytium and contrasts with the simple microvillar interdigitation between trophoblast and uterine epithelium (epitheliochorial) over the rest of the placenta. Cotyledonary refers to the presence of localized areas of trophectodermal proliferation forming “cotyledons” in the placenta and each cotyledon is the fetal part of a placentome. The placentome is formed by the tuft of branching chorionic villi from the cotyledon that grow and enmesh with corresponding maternal caruncular crypts, providing a finger-in-glove arrangement. These crypts develop from the preformed flat endometrial caruncles (Figure 49.1), present in the nonpregnant cow, which are aligned along the uterine horns. Normally, the placenta consists of 80–90 of these placentomes. The placentomes are linked together by areas of flat apposition between trophoblast and caruncular epithelium (CE). The CE cells are similar to UE cells and are homogeneous in population unlike the trophoblast. The placentomes guarantee a firm anchorage by the complementary interdigitation of fetal villous trees with maternal crypts and by the interdigitation of the apical microvilli from uninucleate trophoblast cells (UTC) and CE directly by cell–cell contact or indirectly by cell–matrix contact. Secondly, placentome formation with a synepitheliochorial interhemal barrier provides the vast increase in surface area necessary for the continuously increasing substance exchange between the dam and the fetus. It is important to note that placentomal gross morphology and the pattern of fetomaternal interdigitation (villus/crypt architecture of the mid to late pregnant placenta) differ considerably between bovid species but the detailed cellular structure of the maternofetal interface is the same throughout pregnancy. It is pertinent to point out that no maternal tissue is shed in the afterbirth (secundines) of cattle. On the other hand, a few fetal villi may be caught and left in the maternal crypts. Figure 49.1 Caruncles are arranged in four rows with approximately 15 in each row. Courtesy of Maarten Drost. Placentomal maturation coupled with appropriate structural, endocrinological, and immunological changes result in easy separation and expulsion of the fetal membranes. Furthermore, vascular, contractile, and involution changes that occur in the uterus before and during parturition also help in the separation and expulsion of the fetal membranes. It should be very well recognized that the process of maturation and timely separation and expulsion of the fetal membranes involves well-orchestrated regulation by both the maternal and fetal components of the placenta. It has been established that a physiological parturition occurs on the face of mature placental structures. The fact that induction of parturition is followed by RFM in most cases supports the observation that immaturity of placentome may be one of the contributing factors for RFM since parturition is initiated before term in such cases. Similarly, that RFM has been an issue in most abortion cases lends credence to the notion that a mature placentome is a prerequisite for the separation of the allantochorion. Maturation of placenta is followed by specific endocrine changes. These changes are important to bring about contractile and apoptotic events, and expression of genes for matrix metalloproteinases and their inhibitors. Although a mature placenta is capable of initiating favorable steroidogenic and arachidonic cascades, altered expression of antioxidative defense mechanisms at this juncture can interfere with steroidogenesis at the cellular metabolic level. Poor expression of the antioxidative defense mechanisms against reactive oxygen species (ROS) can result in an imbalance between production and neutralization of ROS, preventing proper detachment of the allantochorion. Closer to parturition, increases in peripheral estradiol concentrations and less perceptible changes in progesterone are observed. Progesterone perfuses into placentomes which may contribute to its imbibition within the placentome, enabling structural and functional changes. These changes facilitate the contraction of myometrium by estradiol along with other hormones including oxytocin and specific prostaglandins. It is important to note that these structural changes can possibly occur only in a mature placentome that has been exposed to adequate duration and quantity of estradiol. Regarding prostaglandins, the type and quantity of prostaglandins produced can influence the contractility of the myometrium. For example, a lower ratio of prostaglandin (PG)E2 to PGF2α within the fetomaternal compartments of the placentome and an elevated steroid hormone receptor status possibly reduces the rate of apoptosis occurring in the chorionic epithelium before calving. There may be other unknown factors involved in the regulation of apoptosis; nevertheless, it is recognized that dysfunctional expression of apoptotic regulating factors can contribute to failure of separation. Expression of matrix metalloproteinases and counteracting tissue inhibitors of metalloproteinases in the fetal compartment are essential to balance extracellular matrix formation and degradation, critical in the separation of the allantochorion. Specifically, they are responsible in breaking down collagen within the villi and assisting in the separation of villi from the crypts. Finally, it should be remembered that despite the complexity of various prostaglandins and their production and our incomplete understanding of their specific roles, the use of prostaglandins to prevent the occurrence of RF in induced parturition has yielded inconclusive results. Although the tight connection within the placentome is essential during pregnancy, it has to cease to allow allantochorion separation. Indeed, distinct remodeling and loosening of adherence occurs within the placentome during late pregnancy. Transformations that occur in the placental epithelium and connective tissue during the last month of pregnancy prepare the placentome for the critical loosening of the tissues involved in the fetomaternal interdigitation. This process has to proceed undisturbed and has to culminate in separation of the allantochorion at the right time. The changes include progressive collagenization of maternal and fetal connective tissues, flattening of the maternal epithelium lining of the crypts nearest to the caruncular stalk, and the appearance of TGC that become polynuclear shortly before the detachment process. Expression of the major histocompatibility complex (MHC) class I in bovine trophoblast cells and their tight regulation are biologically relevant. Early in pregnancy, a complete shutdown of major MHC class I expression by trophoblast cells appears to be critical for normal placental development and fetal survival. This immunological camouflage is vital to avoid recognition by the multifactorial array of cellular and hormonal mechanisms that mediate rejection. In a mature placenta, maternal immunological recognition of fetal MHC class I proteins triggers immune and inflammatory responses that contribute to rejection of the allantochorion at parturition. It is interesting to note that in these situations there is a clear adaptation of the immune system for a function distinct from protection against pathogens. In summary, MHC compatibility has significant molecular consequences and can result in an increased incidence of RFM. The inflammatory response is followed by the maternal immune response. Two characteristic actions are evident in the inflammatory process, namely production of neutrophil-activating factors and the chemotactic activity to neutrophils. These are important for successful immune-assisted detachment of the allantochorion. It has been suggested that the function of peripheral leukocytes may be reduced, which may be a cause for, or an effect of, retention leading to other complications such as mastitis in RFM cases. During contractions of the uterus, uterine pressure is constantly changing and this leads to alternating anemic and hyperemic conditions and temporary changes on the surface of the fetal chorionic villi. As a result, the attachment of the chorionic epithelium in the maternal crypts becomes impaired. Further, the subsequent rupture of the umbilical cord shuts down the blood supply to the fetal villi and helps in the separation process by reducing the size of the villi. The anemic changes that occur to the fetal villi after calving because of rupture of the umbilical cord are essential and these mechanical processes of detachment should not be underestimated. Identical changes occur in the caruncles due to uterine contractions. The uterine contractions that continue reduce the amount of blood directed to the uterus. Consequently, the caruncles become smaller in size due to reduced blood supply, resulting in the dilation of maternal crypts.
Retained Fetal Membranes
Introduction
Definitions
Developmental morphology
Etiology
Placentome maturation
Endocrine changes
Structural changes
Immunological changes
Vascular changes
Contractile changes
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