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

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. 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

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 ( )
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 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: , 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)
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): ) ; highlighted in green: 2018 Dublin Conference (February 8-10, 2018, textbook to follow, 2019) 12

13. 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

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)
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 remodeling22

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

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 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

29. 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

30. Findings Case 2: long, macerated, and hypoercoiled umbilical cord30

31. Findings Case 2: venous ectasia, large fetal veins31

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
--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 39

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

42. 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

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
--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. 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

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)

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

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

53. Case 4: clinical history 19 yo G2 P 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

54. 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

55. Findings Case 4: diffuse erythematous rash with desquamation

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

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

58. Findings Case 4: small yellow spots on the
umbilical cord

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

60. 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.

61. Potential routes of placental infection
Blanc 1977

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

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

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

65. 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”

66. 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)

67. 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

68. 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: gram female infant with Apgars 8/9.

69. 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%

70. Findings Case 5:
Large thin placenta with diffuse firm areas

71. Findings Case 5:
Diffuse perivillous fibrin deposition

72. Findings Case 5: Chronic intervillositis

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

74. 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.

75. 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

76. 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

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

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