Key Points
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Pathological examination of the placenta may provide useful information regarding the underlying mechanisms of a range of pregnancy complications that may guide future management and improve understanding of disease pathophysiology.
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Placentas should be submitted for examination by specialist pathologists in all complicated pregnancies according to national and local guidelines.
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Interpretation of the clinical significance of many placental histologic changes remains difficult, and novel approaches are required for future development in addition to traditional histologic evaluation.
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Paraffin-embedded tissue blocks are stable for many years at room temperature and thus may be transferred to tertiary pathology centres if required for reassessment, using additional histologic or DNA methods, and may also be used for medicolegal assessment of disease causation.
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Placental evaluation should be encouraged in all cases of intrauterine death, regardless of whether formal postmortem fetal examination is requested.
Introduction
It has long been recognised that a wide range of disorders of pregnancy are related to changes affecting the placenta, and our understanding of the underlying mechanisms of many obstetric diseases, such as fetal growth restriction (FGR) and preeclampsia, is largely derived from pathological studies of the delivered placenta. With this in mind, the potential benefits of a specialised placental pathology service include improved evaluation of pathophysiological processes in specific cases, which may affect subsequent management and recurrence risk, and as a source of material for subsequent research. This chapter provides an overview of the role of placental pathological assessment in modern fetal medicine, with examples in relation to antenatal diagnosis, and suggests how this area may develop in the near future. Extensive literature is available regarding details of specific placental pathologies in specialist texts.
Placental Pathological Assessment
The yield of significant abnormal findings from placental pathology examination is related to the underlying clinical circumstances, and there are therefore several recommendations published regarding indications for formal placental pathological evaluation. These largely include all preterm deliveries and otherwise complicated pregnancies, either associated with maternal or fetal diseases, acute compromise to fetal health or admission to the neonatal intensive care unit (NICU). This policy results in examination of around 10% of placentas from unselected low-risk pregnancies, a proportion that will obviously be much greater in tertiary referral fetal medicine centres. In addition, protocols exist describing the suggested examination approach, including macroscopic assessment, tissue sampling and subsequent histologic evaluation to form an overall diagnostic opinion.
In the majority of cases examined as part of clinical practice, sampling of the umbilical cord, membranes and placental parenchyma (normal and abnormal), including any lesions, takes place after a period of fixation, with subsequent processing and histologic evaluation of haematoxylin and eosin–stained slides from each tissue sample. Large placental tissue diagnostic archives are therefore available but are limited by being composed primarily of formalin-fixed paraffin-embedded (FFPE) blocks and slides rather than frozen material that is typically obtained from fresh tissue. With the introduction of novel methods of future investigation, it is likely that routine storage of fresh placenta samples taken immediately at delivery may be required for analysis (typically for protein, metabolite or RNA studies), with obvious resource implications.
Placental histologic sections are evaluated and the findings interpreted in the context of details in the clinical history such as gestational age, pregnancy complications, birth details and the initial gross placental findings ( Fig. 9.1 ). In this regard, placental pathology reporting is in many ways more challenging than other areas such as tumour pathology because there are few placental histologic changes that are pathognomonic of a specific disease; rather, interpretation is based upon constellations of features in relation to the clinical features that are statistically associated with particular clinical presentations. Placental features are therefore helpful for determining the broad mechanisms of underlying pathological processes leading to overt clinical manifestations so as to improve our understanding of the pathogenesis of a variety of complications of pregnancy (e.g., early- and late-onset preeclampsia, in which maternal factors can considerably affect the risk for disease).
However, because histologic evaluation involves subjective assessment, a relationship exists between pathologist expertise or experience and placental reporting utility; 40% of placental cases reported by nonspecialist pathologists were erroneous compared with subspecialty assessment, including omissions and false-positive findings. It is therefore recommended that multidisciplinary placental teams are established in specialist centres, with close interaction of the obstetric and perinatal pathology reporting staff, and regular discussion of findings in relation to both antenatal ultrasound findings and clinical outcomes. It is hoped that recent efforts regarding consensus statements for placental reporting will reduce interpathologist variability and allow improved studies of interpretation.
Prenatal Assessment of Specific Placental Pathologies
The ability to identify pregnancies with, or at risk for, a range of placental pathologies has advanced considerably over the past 30 years, with the application of both real-time and colour Doppler ultrasound to evaluate both the placenta and its maternal and fetal circulations. The definitive placenta is formed by the end of the first trimester, such that many aspects of gross anatomy, such as shape, size, cord insertion and implantation site, can be determined from the first trimester, using either simple two-dimensional methods or three-dimensional volume assessment. During the second trimester, the placenta is larger and thus easier to assess using abdominal ultrasound imaging including Doppler assessment of the uteroplacental circulation ( Figs. 9.2 to 9.4 ).
Because maternal vascular malperfusion (MVM) is the most common type of placental pathology associated with early-onset preeclampsia and FGR, screening programs to identify women at most risk have focused on incorporating uterine artery Doppler studies into screening algorithms that include clinical risk scores and biomarkers, such as serum placenta growth factor (PlGF). This combined approach has the potential to provide improved precision in screening for both preventable stillbirth caused by placental disease and FGR, although to date, no interventions have delivered improved perinatal outcome.
Many large-scale research screening programs such as those referenced lack placental pathology findings, which is understandable because of the associated cost per case. However, the inherent variability in underlying placental pathophysiology associated with stillbirth and FGR has the potential to confound the accuracy of screening. Uterine artery Doppler may predict the placental features associated with MVM; however, in a study of severe early-onset FGR pregnancies with abnormal umbilical artery Doppler, 10% had normal uterine artery Doppler studies; these had a greater risk for placental diseases unrelated to MVM but with significant recurrence rates (e.g., chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition).
It has further been suggested that many placentas from early-onset FGR or preeclampsia exhibit abnormalities of size, shape, cord insertion or parenchyma, which may be detectable antenatally. For example, ‘chorion regression’ may be associated with a ‘jelly-like’ hyperinflated placenta, and several specific placental pathologies have sonographically identifiable features. However, the role of ‘placental sonography’ beyond individual case assessment remains uncertain. Illustrative examples of the role of placental sonography in identifying pathologies of the placenta, umbilical cord and membranes are provided ( Figs. 9.5 and 9.6 and 
).
Classification of Placental Lesions
One of the historical difficulties of interpreting literature relating to placental pathology has been inconsistent use of terminologies by clinicians, scientists and pathologists and use of multiple labels for the same entity. To address this issue, there have been recent collaborative approaches to unify the use of terminology. The currently recommended classification system is being used in this chapter ( Box 9.1 ).
Interpretation of Lesions
Some placental lesions demonstrate characteristic and unique histologic features, allowing definitive diagnosis regardless of clinical circumstances or other factors. However, such entities represent only a minority of histologic changes identified in the placenta, with the majority of lesions also being encountered in clinically uncomplicated normal pregnancies, although being more or less frequent in association with specific pregnancy complications. This overlap results in consistent data describing risks or odds ratios for the strength of association among specific histologic features and specific obstetric disorders on a population basis, but accurate interpretation of the clinical significance of specific findings in an individual case is fraught with difficulties. The details provided summarise the available data but should be interpreted with these above in mind.
Categories of Placental Pathologies
In this section, entities which are relatively common or important are described, focusing particularly on their relationship to antenatal detection and management of common clinical conditions. Extensive literature is available providing details of the full spectrum of pathologies. The categories broadly map to Box 9.1 but for ease of discussion are described in terms of their mechanisms and clinical significance.
Placental vascular processes
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Maternal stromal-vascular lesions
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Malperfusion (including distal villous hypoplasia, accelerated villous maturation and infarct)
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Loss of integrity (including abruptio placenta and marginal abruption)
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Fetal stromal-vascular lesions
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Developmental (including delayed villous maturation and dysmorphic villi)
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Malperfusion (including global and segmental lesions)
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Loss of integrity (including fetal haemorrhage and fetomaternal haemorrhage)
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Placental inflammatory-immune processes
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Infectious inflammatory lesions
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Acute (including maternal and fetal inflammatory responses)
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Chronic (including villitis and intervillositis)
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Immune or idiopathic inflammatory lesions
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Including villitis of unknown aetiology (chronic villitis, chronic chorioamnionitis, lymphoplasmacytic deciduitis, eosinophil T-cell fetal vasculitis) and chronic histiocytic intervillositis
Other placental processes
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Massive perivillous fibrin(oid) deposition (maternal floor infarction)
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Morbidly adherent placentas (accreta)
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Meconium-associated changes
Abnormalities of Placental Development
The details of normal placental development are described in Chapter 7 . There are a range of macroscopically identifiable disorders which are believed to be a consequence of gross abnormalities of the process of initial implantation or subsequent growth of the placental disk, resulting in abnormalities in placental shape, architecture or umbilical cord insertion site. These lesions are not usually associated with specific histologic abnormalities (although it has been suggested that abnormal placental regression may also be related to villous changes) but may be associated with increased risk for certain pregnancy complications.
Eccentric or velamentous insertion and vasa praevia
The umbilical cord normally inserts into the central portion of the placental disk chorionic plate. Minor degrees of peripheral insertion are usually of no clinical significance, but because of rarefaction of the process of dichotomous branching of the surface chorionic plate arteries, the opposite side of the placenta from a marginal cord may be hypovascularized, thus reducing placental efficiency. At the extremes, umbilical cord–derived vessels may leave the margins of the placenta, found in around 1% of pregnancies, termed velamentous insertion ; a variant of this is when vessels from a marginal cord insertion traverse within the membranes to accessory, or succenturiate, lobes, so as to connect them in a functional sense, to the fetus. The term vasa previa describes this arrangement when the vessels run closer to, or over, the internal os of the cervix. The fetus is then at risk for hypovolemic shock during vaginal delivery because these vessels may be damaged as labour advances, especially at the time of membrane rupture. Antenatal screening using ultrasound (for variants of placental and cord anatomy) and diagnosis (using transvaginal colour Doppler ultrasound) are lifesaving for the fetus because elective caesarean section increases fetal survival to more than 95% ( Figs. 9.7 and 9.8 and 
).
Bilobata, succenturiata and other shape abnormalities
Although the normal human placenta is discoid, there are numerous variations in shape, most of which are not associated with significant or consistent clinical complications. These include placenta membranacea, in which placental villous tissue persists extensively around the gestational sac; placenta fenestrate, in which there is focal deficiency of parenchyma; placenta bilobata, in which two distinct disks are present usually with central cord insertion between the two; and placenta succenturiata, in which one of more accessory lobes is present joined to the main disk by intramembranous vessels. These deviations from a spherical placenta and central cord insertion have been suggested to reduce efficiency in some studies but do not threaten fetal survival unless additional pathologies are present. However, because of the abnormal anatomy, either placental parenchymal tissue or chorionic vessels may be present over the cervical os, with associated risks of trauma and haemorrhage.
Circummarginate or circumvallate placenta
As part of normal placental development, the edge of the placental parenchymal disk (basal plate) corresponds to the edge of the chorionic plate and hence the smooth junction of the amniotic cavity with the placenta. If this process is defective the edge of the chorionic plate may no longer be sited over the placental parenchymal edge, resulting in either a smooth or ridged, abnormally sited junction (circummarginate and circumvallate placentation, respectively). To some degree, this affects around 1% to 5% of placentas with little functional significance but has been associated with increased rates of antepartum haemorrhage and preterm delivery. The normal marginal sinus, where intervillous blood reenters the uteroplacental veins, can be imaged by ultrasound and may on occasion be prominent. This is of no consequence unless sited close to the internal os but can be mistaken for marginal abruption.
Abnormalities of Placental Perfusion
To function normally, maternal blood must flow, at the appropriate rate and pressure, into and through the intervillous space (uteroplacental circulation) surrounding the chorionic villi; this blood supply is arranged as functional units, each centrally perfused by a spiral artery branch. These functional units may be termed placentomes , and up to 50 exist in a normal-term placenta. Effective transplacental diffusion also requires adequate perfusion from the fetus (fetoplacental circulation). It will be apparent therefore that these processes may be defective at any level, resulting in chronic fetal hypoxia and impaired fetal growth, and it is therefore logical to discuss these according to the anatomical area predominantly affected.
Abnormalities of Uteroplacental Flow
Fetal growth restriction and preeclampsia
Pathological studies of products of conception, delivered placentas and placental bed biopsies have demonstrated that abnormalities of normal establishment of the uteroplacental circulation are associated with, and likely the underlying pathophysiological process responsible for, a range of pregnancy complications ranging from early pregnancy failure (miscarriage), preeclampsia and FGR. It is now generally accepted that in the first trimester decidual vessels become occluded by extravillous endovascular trophoblast to protect the early conceptus from pressure and oxygen-related damage, with failure of such ‘plugging’ one of the causes of miscarriage, for example, in association with antiphospholipid antibodies. After initial endovascular invasion, during the second trimester, the trophoblast masses recanalize, and both endovascular and interstitial extravillous trophoblast of the implantation site combine to convert the distal muscular spiral artery branches into poorly muscularised, low-resistance, high-flow uteroplacental vessels supplying the intervillous space. Failure of this phase of development is associated with abnormally reactive uteroplacental vessels with increased flow resistance and reduced and abnormally pulsatile intervillous flow. These changes have secondary effects on chorionic villus structure and function, the combination of which results in FGR, preeclampsia or both. Although in most cases, the cause of the defective implantation remains unknown, in a minority, there may be underlying conditions, such as maternal connective tissue diseases, which are associated with identical features.
Pathological evaluation of the delivered placenta in such cases may demonstrate a range of histologic features, which are now recognised as ‘typical’ changes of FGR or preeclampsia described collectively as MVM. These changes include reduced placental size and surface area, presence of decidual vasculopathy (fibrinoid necrosis or macrophages and inflammatory cells within the vessel wall (atherosis)), villous infarction, fetoplacental vasoconstriction, reduced villous branching and hypovascularity, accelerated maturation and a range of functional alterations. Although many such changes are subjective and may be identified to some degree in clinically uncomplicated pregnancies at term, the constellation of all features, especially in iatrogenic preterm deliveries, is highly suggestive of underlying MVM. The alterations in maternoplacental flow or placental shape and size are detectable antenatally based upon uterine artery Doppler and placental morphology assessment, and the secondary changes in fetoplacental flow, especially maldevelopment of the gas exchanging peripheral villi, result in changes detectable using umbilical artery Doppler sonography ( Fig. 9.9 ).
Abruption and retroplacental haemorrhage
The placenta is normally firmly adherent to the uterus at the basal plate until the third stage of labour. If abnormally premature separation occurs, either centrally or at the margin, the consequence is retroplacental haemorrhage, which most often tracks along the uteroplacental junction, resulting in vaginal bleeding, but is occasionally ‘concealed’, being retained retroplacentally. In addition, because separation has occurred, no functional uteroplacental circulation remains in these areas, with associated complete loss of functional capacity of the supplied villous areas, which may result in ischaemic necrosis (infarction) of the overlying placenta. It should be noted that although in some cases, unequivocal abnormal retroplacental haemorrhage with secondary overlying changes may be identified in the delivered placenta, in other cases, especially with marginal separation and vaginal bleeding, the delivered placenta may not demonstrate characteristic changes of abruption even in the presence of a typical clinical history. Ultrasound may occasionally diagnose chronic abruption, although often abruption is such an acute event in labour and delivery that clinical management and delivery override the utility of ultrasound imaging ( Fig. 9.10 ).
