Providing clinically relevant placental diagnoses in 2018 Raymond Redline Department of Pathology University Hospitals Cleveland Medical Center Case Western Reserve University 1

Distinct Pathophysiologic Events Specific Placental Lesions Adverse Pregnancy Outcome

Distinct Pathophysiologic Events Usually relate to 3 underlying imperatives 1. Vascular: Transport maternal and fetal blood to the interhemal membrane for efficient nutrient exchange 2. Immunologic: Protect the fetal allograft in a region susceptible to infection 3. Developmental: Adjust to meet fetal demand under constraint of maternal and fetal environmental and genetic factors

Big 5: 1. Fetal growth restriction (FGR) Adverse Pregnancy Outcomes Big 5: 1. Fetal growth restriction (FGR) 2. Stillbirth (IUFD) 3. CNS injury 4. Preterm birth 5. Recurrent pregnancy loss Other: - Later cardiovascular disease (mother and child) - Neonatal problems - Genetic/ chromosomal disorders - Morbidly adherent placenta

Purposes of Placental Pathology Identify immediately treatable processes Determine cause of adverse outcomes Estimate recurrence risk Guide subsequent management Quality assurance and risk management

Historical overview Phase 1: Major concepts (1960-1980) e.g. Amniotic fluid infection, Maternal supply line Phase 2: Additional important lesions (1980-2000) e.g. Villitis of unknown etiology, fetal thrombotic vasculopathy, maternal floor infarction Phase 3: Standardization (reproducible criteria for grading and staging) 2004: SPP Nosology projects 2015 Amsterdam Placental Pathology Workshop 2018 Dublin Placental Pathology Consensus Meeting Phase 4: Utilizing placental data (Human Placenta Project) in utero biomarkers and imaging for placental disease therapeutic interventions for future pregnancies

Placental Pathology: Problems Lack of familiarity with placental lesions by many pathologists Failure to understand placental diagnoses by many clinicians Absence of a framework for using placental data to improve clinical care

Placental Pathology: Solutions Clinicians must value pathology and demand high quality reports At least one designated perinatal pathologist per center Appropriate placentas are submitted promptly Relevant history and specific questions are provided Pathology results are reported: Using standardized nomenclature In a timely manner To the responsible clinicians (for mother and infant)

Current CAP Indications for Placental Exam Maternal: Delivery at <37 wks or more than 42 wks (alternative: <34 wks only) Unexplained or recurrent pregnancy complications Systemic disorders, gestational or underlying, with concern for mother or infant Peripartum fever or infection Excessive third trimester bleeding Thick or prolonged meconium Severe oligohydramnios/ polyhydramnios Fetal/ neonatal Stillbirth or neonatal death NICU admission SGA/ LGA (birthweight <10th or > 90th percentile for gestational age) Birth depression/ pH < 7.0 / Apgar5 < 7/ Assisted ventilation > 10 min Neonatal hematocrit <35 Neonatal seizures Suspected infection or sepsis Hydrops fetalis of unknown etiology Multiple pregnancy (alternative: fused placentas, same sex twins, and/or twins with discordant fetal growth) Placental Structural abnormalities of the placental disc, umbilical cord, or membranes Abnormal size for gestational age Fragmented, possibly incomplete placenta Reference: Arch Pathol Lab Med 121: 449-472, 1997

Clinical Data Needed for Placental Evaluation Sheet filled out by M.D. (Printed Name) ______________ Gestational Age (best estimate) ____________________ Ob Index: G ____ Term____ Prem ____ Ab ____ Lvg ___ Maternal History: Baby (weight, Apgars, malformations, other): Reason for submission/ Specific questions:

Current Classification (Amsterdam system) 1. Maternal uterine/ trophoblastic Maldevelopment: decidual arteriopathy superficial implantation Malperfusion: partial global: accelerated villous maturation complete segmental: infarct, infarction-hematoma Loss of Integrity: abruptio placenta marginal abruption, acute or chronic 3. Inflammatory, infectious Acute: chorioamnionitis villitis intervillositis Chronic (TORCH) deciduitis 4. Inflammatory, idiopathic Villitis/ VUE Chronic deciduitis Fetal vasculitis, eosinophilic T cell Intervillositis, histiocytic 2. Fetal stromal-vascular Maldevelopment: delayed villous maturation villous capillary lesions Malperfusion: partial global: umbilical cord compromise complete segmental: fetal thrombosis Loss of integrity: small vessel hemorrhage large vessel hemorrhage edema 5. Pathogenesis incompletely understood Perivillous fibrin(oid) deposition, diffuse or localized 6. Other Malformations/ deformations/ disruptions Tumors and heterotopias Morbidly adherent placenta Genetic/ chromosomal abnormalities Secondary/ extrinsic: meconium effects increased nucleated red cells (NRBC) Consensus for the entities highlighted in red: 2014 Amsterdam Conference (Arch Pathol Lab Med 2016; 140(7): 698-713) ; highlighted in green: 2018 Dublin Conference (February 8-10, 2018, textbook to follow, 2019) 12

Case 1: clinical history 18 yo G1P0 with chronic renal disease presents at 34 weeks with elevated blood pressure, fetal growth restriction, and abnormal pulsed flow Doppler Elective C-section following betamethasone of 1510 gram SGA female infant with Apgars 8 and 8

Fetal growth restriction: known placental associations Preterm (<34 weeks) Maternal vascular malperfusion Chronic abruption Increased perivillous fibrin deposition Abnormal placental shape Term/ late preterm (34-42 weeks) Chronic villitis, noninfectious (VUE) Fetal vascular malperfusion

Findings Case 1: small elongated placenta with firm lesions

Findings Case 1: villous infarcts

Findings Case 1: villous agglutination and increased syncytial knots

Findings Case 1: distal villous hypoplasia

Findings Case 1: fibrinoid necrosis and foamy macrophages (acute atherosis), decidual arterioles

Case 1: pathology report A. PLACENTA: --RELATIVELY SMALL, HISTOLOGICALLY MATURE PLACENTA (155 G; LESS THAN 3RD PERCENTILE FOR 34 WEEKS). --ELEVATED FETOPLACENTAL WEIGHT RATIO: 9.7 --FINDINGS CONSISTENT WITH MATERNAL VASCULAR MALPERFUSION: MULTIPLE VILLOUS INFARCTS, ACCELERATED VILLOUS MATURATION --DECIDUAL ARTERIOPATHY: ACUTE ATHEROSIS, SEE NOTE. Note: The findings suggest fetal growth restriction secondary to early onset preeclampsia and associated severe maternal vascular malperfusion.

Maternal supply line: the “extended” placenta

MVM is due to abnormal trophoblastic arterial remodeling 22

MVM- Superficial implantation Persistent muscularization, Large basal plate arteries Increased placental site giant cells in free decidua

MVM: Small placenta with altered lobular architecture (alternating areas of crowding and paucity)

Maternal Vascular Malperfusion (MVM): Differential Diagnosis: Dysmorphic villi (aneusomy, especially Trisomy 16 confined placental mosaicism) Distal villous hypoplasia without MVM Perivillous fibrin plaque/ normal intervillous fibrin

Dysmorphic villi Perivillous fibrin plaque Distal villous hyplasia without MVM Normal intervillous fibrin

Maternal Vascular Malperfusion: Clinical Implications: Recurrence rate: 10-25%, severe preterm Early monitoring and aspirin treatment of next pregnancy Increased risk of cardiovascular disease, mother and child

Case 2: clinical history 25 yo G3 P2002 with decreased fetal movements at 41 2/7 weeks gestation Intrauterine fetal demise (stillbirth) of slightly autolyzed 3400 G male fetus

Stillbirth (IUFD): known placental associations Preterm Occult chromosomal abnormality Congenital infection (TORCH) Hydrops fetalis Term Feto-maternal hemorrhage Delayed villous maturation (often with Diabetes) Both Fetal vascular malperfusion/ “umbilical cord accident” Maternal vascular malperfusion Abruptio placenta 29

Findings Case 2: long, macerated, and hypoercoiled umbilical cord 30

Findings Case 2: venous ectasia, large fetal veins 31

Findings Case 2: intramural fibrin, fetal stem vessels

Findings Case 2: scattered small (less than 5) foci of avascular villi

Findings Case 2: fetal stem vessel obliteration and villous stromal vascular karyorrhexis

Findings Case 2: large (>5) foci of avascular villi

Case 2: placental report --SLIGHTLY IMMATURE PLACENTA (486 G) --HIGH GRADE FETAL VASCULAR MALPERFUSION (MIXED TYPE): GLOBAL: SCATTERED SMALL FOCI OF AVSCULAR VILLI AND STEM VESSEL MURAL FIBRIN DEPOSITION SEGMENTAL: LARGE FOCI OF AVASCULAR VILLI WITH STEM VESSEL OBLITERATION AND CHORIONIC VESSEL THROMBI --LONG, HYPERCOILED UMBILICAL CORD, 97 CM, SEE NOTE NOTE: The findings suggest chronic partial intermittent umbilical cord obstruction leading to stasis and fetal thrombosis. High grade = more than one focus, average of more than 15 affected villi per slide

FETAL VASCULAR MALPERFUSION BY SITE Fetal blood flow CORD OBSTRUCTION Global partial: Chronic partial intermittent UC obstruction UMBILICAL CORD Segmental complete: Fetal thrombosis CHORIONIC PLATE PROXIMAL VILLI Stem vessel obliteration DISTAL VILLI Avascular villi/ Villous stromal Vascular karyorhhexis Courtesy of Theonia Boyd, Boston Children’s Hospital

Potentially obstructive umbilical cord (UC) i. abnormal UC length a. excessively long UC b. excessively short UC ii. abnormal UC conformation a. thin UC b. hypercoiled UC c. UC stricture iii. abnormal umbilical cord insertion site a. membranous insertion of UC b. marginal insertion of UC c. furcate insertion of UC e. tethered insertion of UC

Potentially obstructive UC lesions, examples Tight nuchal cord True knot Membranous insertion Furcate and tethered 39

Fetal Vascular Malperfusion: Differential Diagnosis: Involutional changes of IUFD VUE with stem vessel occlusion and avascular villi TORCH infection, especially CMV Clinical Implications: Recurrence rate: less than 5% Reassurance, institute fetal movement counts next pregnancy Consider coagulopathy workup for thromboembolic disease if positive maternal history or fetal thrombosis

Case 3: clinical history 31 yo G2 P1001 37 wks admitted in labor with nonreactive nonstress test (decreased BTBV, no accelerations). Outlet forceps delivery. 2900 gram female. Apgars 0/7/7 CNS Injury: Neonatal seizures x 3 in first 6 hrs. Developed microcephaly and spastic quadriplegia

known placental associations CNS Injury: known placental associations Preterm Maternal vascular malperfusion, severe Diffuse villous edema Term Fetal vascular malperfusion, high grade Chronic villitis, high grade and/or obliterative vasculopathy Prolonged meconium exposure with fetal vascular necrosis Both Multiple placental lesions Sentinel events (abruption, UC accidents, fetal hemorrhage) Chorioamnionitis with severe fetal inflammatory response

Findings Case 3: slightly firm placental parenchyma (perivillous fibrin)

Findings Case 3: High grade chronic villitis, noninfectious (VUE) (greater than 10 contiguous villi with lymphocytic infiltrate

Findings Case 3: stem villous vasculitis/ vascular obliteration

Findings Case 3: High grade villitis and intervillositis with associated avascular villi

Case 3: placental report --RELATIVELY SMALL, MATURE PLACENTA (340 GMS; LESS THAN 10TH PERCENTILE FOR 37 WEEKS). --CHRONIC VILLITIS, HIGH GRADE, DIFFUSE, WITH STEM VESSEL OBLITERATION AND EXTENSIVE AVSCULAR VIILI NOTE: High grade chronic villitis with obliterative vascular changes has been associated with neonatal encephalopathy and seizures, as seen in this case.

X-chromosome signals) Chronic villitis, noninfectious = ? graft versus host reaction Fetoplacental Antigens Maternal Immune Response Maternal T cells (Blue with two X-chromosome signals) Scott Hyde

Chronic villitis, noninfectious (“VUE”) Classification scheme Location: Exclusively basal vs. parenchymal Extent: Low Grade (<10 villi/ focus) Focal: > 1 focus, 1 slide Multifocal: >1 slide High Grade (>10 villi/ focus) Patchy: >1 focus Diffuse: >5% of all villi Associated lesions: lymphoplasmacytic deciduitis extensive perivillous fibrin fetal stem vessel obliteration large foci of avascular villi

Chronic villitis, noninfectious (“VUE”) Differential Diagnosis Increased villous Hofbauer cells, nonspecific TORCH infections, most common CMV, Syphilis, ZIKV Recent fetal vascular malperfusion with villous stromal vascular karyorrhexis 4. Fetal lymphoma/ leukemia (rare)

VUE- differential diagnosis (no lymphocytes) increased Hofbauer cells stromal vascular karyorrhexis Congenital syphilis Fetal lymphoma/ leukemia

Chronic villitis, noninfectious (“VUE”) Clinical Implications Recurrence rate: 25-30%, high grade Early monitoring of subsequent pregnancies Consider immunosuppression for recurrent cases

Case 4: clinical history 19 yo G2 P1001 26 wks with history of LEEP conization and retained IUD Admitted in labor with prolonged PPROM x 7 days Preterm delivery of 650 gram infant with a skin rash

Spontaneous premature birth: known placental associations Early (23-34 weeks) Acute chorioamnionitis Marginal abruption (acute or chronic) Chronic lymphoplasmacytic deciduitis Late (34-37 weeks) Maternal vascular malperfusion Abruptio placenta Chronic villitis/ chorioamnionitis

Findings Case 4: diffuse erythematous rash with desquamation

Findings Case 4: Acute necrotizing chorioamnionitis (maternal stage 3/3) 56

Findings Case 4: concentric umbilical perivasculitis (necrotizing funisitis), fetal stage 3/3 57

Findings Case 4: small yellow spots on the umbilical cord

peripheral funisitis (umbilical surface abscesses) Findings Case 4: peripheral funisitis (umbilical surface abscesses) GMS stain positive for fungal hyphae, c/w candida infection

Case 4: placental report --GREEN STAINED, IMMATURE PLACENTA (190 G). --NECROTIZING CHORIOAMNIONITIS WITH UMBILICAL PANVASCULITIS/ PERIVASCULITIS (MATERNAL STAGE 3; FETAL STAGE 3) --CANDIDAL PERIPHERAL FUNISITIS WITH MICROABSCESSES NOTE: GMS stain for fungi is positive. Prolonged PPROM and pregnancy with an IUD in place are both risk factors for Candida chorioamnionitis. Neonatal nursery notified.

Potential routes of placental infection Blanc 1977

Gross Placental Features of Acute Chorioamnionitis Twin B: Milder Twin A: Severe

Histologic chorioamnionitis Separate maternal and fetal inflammatory responses to amniotic fluid infection

Histologic Chorioamnionitis Maternal Inflammatory Response Stage = Duration 1. Chorionitis (precursor: subchorionitis) 2. Chorioamnionitis (amnion + chorion) 3. Necrotizing (necrosis of >25% amniocytes)

Histologic Chorioamnionitis Fetal Inflammatory Response Stage = f (duration x fetal maturity) 1. Chorionic Vasculitis/ Umbilical Phlebitis 2. Umbilical Arteritis 3. Umbilical Perivasculitis (concentric rings), “Necrotizing Funisitis”

Premature delivery - role of chorioamnionitis 1. Premature labor with intact membranes = 45% 14-21% positive for histologic chroioamnionitis 2. Premature rupture of membranes = 30% 26-50% with histologic chorioamnionitis 3. Indicated preterm births = 25% <5% with histologic CA Histologic Chorioamnionitis: Overall attributable risk for PTD = 25% (Guzick, Obstet Gynecol 1985)

Acute chorioamnionitis Differential Diagnosis: Ischemic decidual necrosis, premature separation or retromembranous hemorrhage Fetal inflammatory response, due to meconium in term infant Clinical Implications: Identify infants requiring antifungal therapy High recurrence rate, less than 32 weeks Next pregnancy: treat bacterial vaginosis, vaginal ultrasound for cervical length, 17 OH-P, cerclage

Case 5: clinical history 37 yo G6 P2021 with prior history of recurrent pregnancy loss (2 miscarriages followed by male IUFD, female with mild FGR in last pregnancy) on aspirin and LMW heparin presents with mild FGR at 38 1/7 weeks gestation. Elective induction: 2870 gram female infant with Apgars 8/9.

Recurrent pregnancy loss: known placental associations Common: Chronic villitis, noninfectious, high grade, 25-50% Severe preterm maternal vascular malperfusion, 10-25% Early preterm birth with histologic chorioamnionitis, 10-25% Rare: Diffuse perivillous fibrin(oid) deposition (“maternal floor infarction”), 40-60% Chronic histiocytic intervillositis, 70-90%

Findings Case 5: Large thin placenta with diffuse firm areas

Findings Case 5: Diffuse perivillous fibrin deposition

Findings Case 5: Chronic intervillositis

Composed of monocyte-macrophages Findings Case 5: Composed of monocyte-macrophages CD68 immunostain

Case 5: placental report A. PLACENTA: MATURE PLACENTA (422 G) DIFFUSE PERIVILLOUS FIBRIN(OID) DEPOSITION WITH A MINOR COMPONENT OF CHRONIC HISTIOCYTIC INTERVILLOSITIS, FOCALLY ACTIVE, SEE NOTE NOTE: The findings are interesting when taken in context with the previous pregnancies (first three with severe chronic histiocytic intervillositis (CHI) and the fourth with mild focal CHI).  The present placenta also shows mild CHI, but this is now associated with diffuse perivillous fibrin(oid) deposition (PVF).  CHI and PVF share certain characteristics: adverse pregnancy outcomes, high recurrence rates, and the suggestion of an immune pathogenesis.  While PVF usually occurs alone, up to 30-40% of CHI have a significant component of PVF.

Chronic Histiocytic Intervillositis Diffuse infiltration of intervillous space by CD68+ histiocytes, some T cells Associated perivillous fibrin common (chronic villitis not allowed) Recurrent miscarriage, FGR, IUFD, maternal autioimmunity Biomarker: ↑ maternal serum PLAP Rx: aspirin, corticosteroids, LMWH, hydroxychloroquine

Differential Dx #1: Diffuse perivillous fibrin(oid) deposition (“maternal floor infarction”) Pathology: Small for GA. Thickening of the maternal surface. Firm, marbled cut surface. Perivillous fibrin(oid) surrounds > 20% of terminal villi Clinical associations: autoimmunity, thrombophilia, some infections, fetal LCHAD heterozygosity Pathogenesis: ? Injury with villous to extravillous trophoblast metaplasia and fibrinoid matrix secretion ? Activation of coagulation cascade

Placental Malaria Differential Dx #2: Histiocytic intervillositis Trophoblast necrosis Malarial parasites and pigment Primiparous patients without previous exposure

Chronic Villitis with intervillositis Differential Dx: Etiology: Infectious (<5%) Gram negative bacilli Nonsyphilitic spirochetes Rickettsia, tularemia Coccidiomycosis HSV, VZV, measles virus Noninfectious (>95%) VUE