Providing clinically relevant placental diagnoses in 2018

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

3. Distinct Pathophysiologic Events Specific Placental Lesions Adverse Pregnancy Outcome

4. 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

5. 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

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

7. 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

8. 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

9. 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)

10. Current CAP Indications for PlacentalExam 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

11. 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:

12. 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) villitis intervillositis 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)

13. Case 1: clinical history18 yo G1P0 with chronic renal disease presents at 34 weeks with elevated blood pressure, fetal growth restriction, and abnormal pulsed flow DopplerElective C-section following betamethasone of 1510 gram SGA female infant with Apgars 8 and 8

14. 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) • Maternal vascular malperfusion • Chronic villitis, noninfectious (VUE) • Fetal vascular malperfusion

15. Findings Case 1: small elongated placenta with firm lesions

16. Findings Case 1: villous infarcts

17. Findings Case 1: villous agglutination and increased syncytial knots

18. Findings Case 1: distal villous hypoplasia

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

20. 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.

21. Maternal supply line: the “extended” placenta

22. MVM is due to abnormal trophoblastic arterial remodeling Normal Abnormal

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

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

25. 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

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

27. 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

28. Case 2: clinical history25 yo G3 P2002 with decreased fetal movements at 41 2/7 weeks gestationIntrauterine fetal demise (stillbirth) of slightly autolyzed 3400 G male fetus

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

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

31. Findings Case 2: venous ectasia, large fetal veins

32. Findings Case 2: intramural fibrin, fetal stem vessels

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

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

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

36. Case 2: placental report PLACENTA: --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

37. 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

38. 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

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

40. 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

41. Case 3: clinical history31 yo G2 P1001 37 wks admitted in labor with nonreactive nonstress test (decreased BTBV, no accelerations). Outlet forceps delivery. 2900 gram female. Apgars 0/7/7CNS Injury: Neonatal seizures x 3 in first 6 hrs. Developed microcephaly and spastic quadriplegia

42. 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

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

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

45. Findings Case 3: stem villous vasculitis/ vascular obliteration

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

47. Case 3: placental report PLACENTA: --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.

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

49. 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

50. 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)