Clinical Correlates of Histopathological Entities of the Placenta

Clinical

Clinical correlates of histopathological entities of the placenta

Admire Matsika PLACENTAL EXAMINATION has a critical research on the understanding of the role in understanding adverse fetal clinical implications of placental lesions in and maternal outcomes in pregnancy. obstetric and neonatal care. Background General and allied health practitioners However, progress in correlating placental This review provides medical caring for pregnant women and neonates pathology with clinical phenotypes has practitioners with an update on new often encounter placental histopathological been hampered by methodological issues terminology and status quo of research on reports with esoteric diagnostic entities of in many studies published.1 Additionally, placental entities of clinical significance contentious clinical significance such as there appears to be a knowledge disparity that may recur in subsequent pregnancy chronic villitis, massive perivillous fibrin between perinatal pathologists reporting and for which alteration of obstetric care deposition, chronic histiocytic intervillositis, microscopic changes seen in the organ and may improve outcomes. With the advent materno-fetal vascular malperfusion and delayed villous maturation. These lesions understanding of the clinical significance of the electronic My Health Record may recur in subsequent pregnancies. of placental histopathological diagnoses by system implemented Australia-wide, obstetric care providers.2 When reported patients will have direct access to their Objective and interpreted correctly, the placenta histopathological reports online. As a The aim of this article is to review the provides useful information that may result, it is likely that general practitioners status quo of placental pathology and research with an emphasis on clinical explain adverse pregnancy outcomes as will find themselves explaining the management implications for some of well as guide further management of the clinical significance of placental pathology these most often reported but less mother, newborn or future pregnancy.3 reports to their patients more frequently understood recurrent clinicopathological Table 1 lists the most important and than before. entities of the placenta. An update on the recurrent histopathological diagnoses This article focuses on the clinical current nomenclature and classification of the placenta with some of the clinical significance of recurrent placental of placental conditions is also provided. steps that may be taken, based on expert entities diagnosable on microscopic Discussion opinion as well as anecdotal and limited examination. Readers are referred to the When reported adequately and interpreted scientific evidence available to date.4 aforementioned Amsterdam Workshop correctly, placental histopathology Other hurdles to a full understanding Group article5 for definitions and provides useful information that may of the clinical significance of placental histological descriptions of these lesions. explain adverse pregnancy outcomes and guides further management of the mother, pathology in obstetric care include the lack Neoplasms of the placenta are extremely newborn or future pregnancy. Empirical of standardisation in nomenclature and rare, often sporadic and non-recurrent and treatments for immune-mediated diagnostic criteria as well as interobserver are not discussed in this article. placental conditions with prednisolone, variability among pathologists.1 To address aspirin, heparin and intravenous these issues, a panel of international immunoglobulins have been reported. expert placental pathologists formulated Ascending intrauterine infection However, evidence-based guidelines for the 2014 Amsterdam classification, Ascending intrauterine infection or management of these conditions are lacking, and more research, including terminology and definitions of placental amniotic fluid infection (AFI) sequence 5 clinical trials, is in order. lesions. Table 2 is a comprehensive list of complicates up to 50% of preterm placental pathology entities incorporating deliveries and is seen in 5–10% of term the new Amsterdam Placental Workshop placentas. Acute chorioamnionitis or Group terminology. This consensus acute subchorionitis imply a maternal nosology is expected to accelerate inflammatory response to ascending

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infection in the genital tract that has grade loosely correlates with clinical to identify for the specific organism reached the amniotic sac (Figure 1A). severity. Grade 1 AFI is often subclinical, involved. For example, Listeria spp. Conversely, acute funisitis, chorionic while grade 2 lesions are more likely to infection often causes acute villitis vasculitis and umbilical vasculitis be clinically apparent, with higher risk of (Figure 1B) in addition to high-grade implies a fetal response to ascending perinatal morbidity and mortality.6 Stages acute chorioamnionitis, while acute intrauterine infection. The recommended 2 and 3 AFI with fetal inflammatory funisitis due to Candida spp. is typically histopathological grading of AFI is binary response significantly correlate with focal, necrotising and peripherally (grade 1 = mild, and grade 2 = severe), perinatal morbidity and are associated located. Candidal hyphae can be and the staging is three-tiered: stage 1 with increased likelihood of various highlighted with fungal stains by the (early), 2 (intermediate) and 3 (advanced) neonatal conditions including culture- histopathologist; this is considered a for both maternal and fetal inflammatory positive sepsis, respiratory distress and critical result to be conveyed urgently responses.6 neurological impairment.7 to the treating team so that antifungal Studies show some correlation between Some bacteria and fungi elicit therapy may be prescribed in lieu of histopathological stage and duration characteristic patterns of inflammatory the empirical standard triple-antibiotic of clinical AFI, while histopathological response that may direct the pathologist therapy.8

Table 1. Clinical significance of placental histopathological diagnoses

Placental diagnosis Suggested clinical action postpartum and in future pregnancy

Ascending intrauterine infection (acute subchorionitis, • Correlate with microbiology, culture and sensitivity studies acute chorioamnionitis, acute fetal vasculitis, acute funisitis) • Consider or review antimicrobial treatment for mother and baby • Cervical cerclage in future pregnancy if complicated by recurrent preterm labour

Chronic inflammatory condition (chronic villitis, chronic • Screen for viral, treponemal and protozoal (syphilis, toxoplasmosis, deciduitis, chronic chorioamnionitis, chronic histiocytic rubella, cytomegalovirus, herpes simplex [‘STORCH’]) infection intervillositis, eosinophilic T-cell vasculitis • Malarial screen if chronic histiocytic intervillositis predominant

High-grade villitis of unknown aetiology (VUE) • Maternal autoimmunity screen • Consider low-dose aspirin, prednisolone, intravenous immunoglobulin in future pregnancy • Specialist obstetric care for possible fetal growth restriction with early delivery in future pregnancy if indicated

Idiopathic chronic histiocytic intervillositis • As for VUE • Also consider low molecular weight heparins, hydroxychloroquine in future pregnancy

Massive perivillous fibrin deposition and maternal • Consider pravastatin, low-dose aspirin, low molecular weight heparins, floor infarction immunoglobulin

Fetal vascular malperfusion • Maternal diabetes screen • Neurological assessment and thrombophilia screen of the neonate • Treat underlying cause where possible

Maternal vascular malperfusion • Maternal blood pressure, weight, glucose, liver and renal function assessments • Consider aspirin, specialist obstetric care, early delivery • Long-term maternal cardiovascular disease risk assessment • Specialist obstetric care with early delivery in future pregnancy if indicated

Delayed villous maturation • Maternal diabetes screen and review of previous tests • Advice to avoid excessive weight gain in future pregnancy • Fetal movements monitoring in third trimester • Specialist obstetric care with early delivery in future pregnancy if indicated

Chronic inflammatory to exclude viral and protozoal (eg are due to infections in the developed conditions of the placenta cytomegalovirus, rubella, toxoplasmosis) world.9 In the majority of cases, no A histopathological diagnosis of chronic infections in both mother and fetus. infection is found; this inflammation villitis (Figure 1C) requires the clinician Fewer than 5% of cases of chronic villitis is termed villitis of unknown aetiology (VUE). A binary grading system for chronic villitis and deciduitis is also in use.5 Low-grade chronic villitis, after Table 2. Classification of placental clinicopathological disorders incorporating exclusion of infections, does not have a 2014 Amsterdam Working Group nosology known clinical significance. Conversely, Disease category Placental entity high-grade VUE shows consistent association with adverse pregnancy Infectious conditions • Acute: outcomes including fetal growth of placenta – Maternal inflammatory response: (sub)chorionitis, restriction, recurrent pregnancy loss and chorioamnionitis intrauterine fetal death.9,10 Severe VUE – Fetal inflammatory response: funisitis, chorionic vasculitis may be accompanied by thrombosis in or umbilical vasculitis fetal vasculature, in which case the risks • Chronic: of neurological deficits in the neonatal – Villitis (syphilis, toxoplasmosis, rubella, cytomegalovirus, period and long-term cerebral palsy herpes simplex [‘STORCH’]; other) are high. Studies show recurrence rates – Histiocytic intervillositis (protozoal, malaria, other) of VUE of up to 37% in subsequent 9,10 Vascular conditions • Maternal vascular malperfusion: pregnancy for some individuals. of placenta – Distal villous hypoplasia/accelerated villous maturation Evidence on how best to manage VUE – Decidual arteriopathy in subsequent pregnancy is lacking because of a dearth of randomised – Villous infarction control studies comparing potential – Infarction haematoma/intervillous haemorrhage treatment options suggested from – Retroplacental haemorrhage case reports and laboratory studies. • Fetal vascular malperfusion: Anecdotal and limited experimental – Fetal vascular thrombosis evidence from one French group – Avascular sclerotic villi suggest that use of aspirin 100 mg/d – Delayed villous maturation combined with prednisolone 20 mg/d from early second trimester may reduce Immune-mediated/ • Villitis of unknown aetiology the recurrence rate of VUE and possibly idiopathic inflammatory • Chronic deciduitis conditions improve outcomes in future pregnancy • Chronic chorioamnionitis for affected individuals.11 Weekly • Chronic (histiocytic) intervillositis maternal intravenous immunoglobulin • Eosinophilic T-cell fetal vasculitis (1 g/kg) from late first trimester Other placental disorders • Massive perivillous fibrin deposition (‘maternal floor significantly reduced the occurrence infarction’) of VUE associated with neonatal • Chorangiosis alloimmune thrombocytopaenia 12 • Chorangiomatosis (NAIT) in one small study. • Placenta accreta, increta and percreta Chronic inflammation involving other • Umbilical cord abnormalities placental structures – such as the decidua • Macroscopic anomalies of placental disc and membranes (chronic deciduitis), fetal membranes (chronic chorioamnionitis), intervillous Placental tumour-like • Chorangioma space (chronic histiocytic intervillositis lesions and neoplasms • Placental pseudocyst (extravillous trophoblastic cyst) [Figure 1D]) and fetal vessels (eosinophilic • Intraplacental choriocarcinoma T-cell vasculitis) – can occur either in • Placental site trophoblastic tumour isolation or accompanying high-grade • Other (eg ALK-rearranged inflammatory myofibroblastic VUE and is also thought to have an tumour) immune-mediated pathogenesis. • Metastases – maternal origin For all forms of high-grade chronic • Metastases – fetal origin inflammatory conditions of the placenta, expert recommendations for subsequent ALK, anaplastic lymphoma kinase management include a maternal

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thrombophilia and autoimmunity screen, FVM shows a strong correlation with in life after acute atherosis has recently neonatal screen for NAIT and neurological neurological impairment in the fetus or been highlighted.20 Maternal diabetes and deficits, review of the clinical history for newborn, neonatal stroke, seizures and obesity,21 antiphospholipid syndrome22 a possible viral or protozoal cause, and long-term neurological deficits.18 Severe and smoking23 have been shown to be review of any previous placentas and FVM is also associated with a higher associated with variable combinations of products of conception for recurrent likelihood of perinatal death. these lesions, the extent of which likely chronic inflammation.3,4 Specialist Suggested clinical management of depends on the severity of disease and antenatal care with intensive monitoring an FVM diagnosis includes neurological antenatal treatment administered. Thus, and elective early delivery are also assessment and thrombophilia work-up a finding of MVM lesions in a placenta is recommended for future pregnancy. of the neonate, together with diabetes a surrogate for evidence of the impact of screening for the mother.4 A placental systemic maternal conditions and may diagnosis of FVM may help account for be useful in assessing effectiveness of Massive perivillous fibrin otherwise unexplained abnormal Doppler antenatal management as well as how deposition and maternal ultrasonography findings, fetal distress, to better manage affected individuals in floor infarction a neurologically impaired neonate that subsequent pregnancies. Severe MVM is Massive perivillous fibrin deposition requires intensive care admission and a risk factor for perinatal death, neonatal (MPFVD) and the associated entity perinatal death. Treatment of, and bronchopulmonary dysplasia24 and maternal floor infarction (Figure 1E) monitoring for, any underlying cause, neurological impairment in the neonate.25,26 are rare, complicating up to 0.5% where present, may prevent recurrences of pregnancies. They are clinically in subsequent pregnancies. associated with otherwise unexplained Delayed villous maturation fetal growth restriction and, sometimes, Delayed villous maturation (DVM; fetal demise.13 Recurrence rates for these Maternal vascular malperfusion ‘villous dysmaturity’) occurs in 2–5% of lesions are very high, with rates of up to Maternal vascular malperfusion (MVM) pregnancies and is most often seen in 89% reported in some series.14 Clinical is the currently recommended umbrella pregnancies complicated by gestational management implications, including term for pathological placental findings diabetes, hypercoiled cord, obesity, and empirical treatment of recurrent MPFVD, that are manifestations of chronic excessive weight gain during pregnancy.27 are the same as for VUE. Pravastatin has under- or overperfusion due to any cause. An idiopathic form of DVM (Figure 2E) also been used successfully in one patient Histopathological lesions of MVM include occurs in the absence of known gestational with recurrent MPFVD.15 small placental disc (<10th percentile or chronic diabetes, and recent research for gestational age), pathological villous suggests abnormal growth factor infarction (all pre-term infarcts [Figures 2A expression or an underlying delay in gene Fetal vascular malperfusion and 2B], multiple infarcts at any gestational expression to be potential causes.28 Fetal vascular malperfusion (FVM) is age, and term infarcts >5% by volume; a The most common setting of idiopathic the currently preferred term for lesions small isolated peripheral focus at term is DVM in clinical practice is an initially previously called fetal thrombotic excluded), infarction haematoma, distal unremarkable pregnancy, with normal vasculopathy. It affects 4–6% of placentas villous hypoplasia (Figure 2C), accelerated growth parameters during the first and sent to pathologists for examination.16 villous maturation, decidual vasculopathy second trimesters, that is complicated The syndrome encompasses the following (Figure 2D) and laminar decidual necrosis.5 by sudden and unexplained fetal distress histopathological lesions and terms: MVM lesions are caused by maternal or perinatal death at or near term avascular villi (global and segmental), systemic conditions that compromise (>35 weeks). Autopsy often reveals a occlusive and non-occlusive thrombosis blood flow to the placenta and fetus. normally grown fetus with no congenital in fetal vasculature (Figure 1F), vascular Hypertensive disorders (pre-eclampsia; anomaly and a large placenta with intramural fibrin deposition, endothelial eclampsia; chronic hypertension; DVM features. Idiopathic DVM causes cushions, vascular ectasia, haemorrhagic hemolysis, elevated liver enzymes, low intrauterine fetal demise in up to 2% of endovasculitis, villous stromal-vascular platelet count [HELLP] syndrome) are the pregnancies, and its recurrence rate is karyorrhexis, fibrinous vasculosis, most common and most studied.19 Acute approximately 10%.27 thrombosclerosing placentitis, endarteritis atherosis – the constellation of intramural Recommendations for clinical obliterans and fibromuscular sclerosis.17 fibrinoid deposition in decidual vessels management of subsequent pregnancies in Risk factors for FVM include gestational with foamy histiocytic and perivascular the setting of idiopathic DVM complicated diabetes, hypercoiled umbilical cord and lymphoplasmacytic infiltration – is almost by fetal distress or perinatal death cord accident. pathognomonic for severe pre-eclampsia includes a diabetes screen, avoidance of A grading system for FVM has been complicated by intrauterine growth excessive weight gain, third trimester fetal proposed.5 Low-grade FVM may not have restriction (Figure 2D). An increased risk movement monitoring and earlier delivery clinical significance, whereas high-grade of maternal cardiovascular disease later before full term.4

A B

C D

E F

Figure 1. Inflammatory and other lesions of the placenta a. Stage 3 acute chorioamnionitis with early necrotising inflammation of the amniotic basement membrane;b. Acute villitis in a case of fetal demise due to in utero Listeria monocytogenes infection; c. Chronic villitis of unknown aetiology involving terminal villi in the centre at low power; note the reduced vasculature, broad outlines and hypercellularity; d. Chronic histiocytic intervillositis (CHIV): histiocytic and lymphocytic cells aggregate between uninvolved chorionic villi. Malarial infection and idiopathic CHIV elicit similar histopathological features; e. Massive perivillous fibrin deposition; pink fibrinoid material encases the majority of chorionic villi in the placenta, rendering them non-functional for nutrient supply and oxygenation; f. Segmental fetal vascular malperfusion; occlusive thrombosis of stem villous vasculature associated with fibrotic and avascular distal terminal villi

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A B

C D

E F

Figure 2. Maternal vascular malperfusion a. Cut surface of a 32 weeks’ gestation placenta showing an off-white solid focus of villous infarction;b. Corresponding microscopy of the edge of the villous infarct shown in Figure 2A, showing ghost outlines of villi that are clumped together into a solid mass. Chorionic villi to the left of the infarct show features of accelerated villous maturation for 32 weeks; c. Distal villous hypoplasia at 35 weeks’ gestation: chorionic villi are smaller than normal, widely spaced with slender outlines and prominent, wavy syncytiotrophoblasts; d. Acute atherosis in a spiral artery of the uterine decidua. There is intramural fibrinoid necrosis with foamy histiocytic aggregates and surrounding lymphocytes;e. Delayed villous maturation in a 38 weeks’ gestation pregnancy complicated by otherwise unexplained sudden intrauterine fetal demise at term. Villous maturation resembles that seen in early second trimester. Villi are broad with increased stroma and reduced vasculo-syncytial membranes; f. Normal villous maturation at term for comparison

Conclusion Health Services, Qld; Senior Associate Lecturer, Am J Obstet Gynecol 2005;193(3 Pt 2):1100–04. Biomedical Sciences, Faculty of Medicine, University doi: 10.1016/j.ajog.2005.06.043. A lack of universally accepted diagnostic of Queensland, Qld 13. Devisme L, Chauvière C, Franquet-Ansart H, et al. criteria, terminology and grading systems Competing interests: None. Perinatal outcome of placental massive perivillous has hindered the full potential of placental Funding: None. fibrin deposition: A case-control study. Prenat Diagn 2017;37(4):323–28. doi: 10.1002/pd.5013. histopathology in fetomaternal care.1 The Provenance and peer review: Not commissioned, externally peer reviewed. 14. He M, Migliori A, Maari NS, Mehta ND. Follow-up universal adoption of the Amsterdam and management of recurrent pregnancy Correspondence to: criteria by reporting pathologists and losses due to massive perivillous fibrinoid [email protected] obstetricians is a positive and welcome step deposition. 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