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Placental Potpourri: thePernicious, Picayune, and        Pervasive     Phyllis C. Huettner, M.D.Washington University Medi...
Outline of This Talk• Value of placental examination• Brief review of placental circulation, histology• Lesions that impac...
Value of Placental Examination• Etiology of intrauterine or perinatal death• Etiology of preterm delivery• Etiology of ano...
Etiology of Stillbirth• Classic study of perinatal autopsies  • 92% of cases had placental abnormalities  • In one-third c...
Etiology of StillbirthCause of death (COD) determination in structurally normal  stillbirths   • Increased from 38.5% to 7...
Value of Placental Examination• Etiology of intrauterine or perinatal death• Etiology of preterm delivery• Etiology of ano...
Pathogenesis of Intrauterine Infection• Ascending - typically bacterial → chorioamnionitis• Transplacental - viral, protoz...
Ascending Infection      • Most common type of infection      • Organisms enter through cervix      • Relationship with ru...
Intrauterine InfectionCommon  • See in 10% to 20% of term deliveries  • Up to two-thirds of preterm deliveriesImportant as...
Chorioamnionitis• At term - related to presence and duration of  membrane rupture• Preterm - likely precedes and causes me...
Intrauterine Infection• Prematurity is leading cause of perinatal morbidity  and mortality in the US   • 70% of neonatal d...
Fetal Inflammatory Response Syndrome   • Intrauterine infection leads to production     of inflammatory cytokines by fetus...
Fetal Inflammatory Response Syndrome  • UC IL-6 and AF IL-6 correlate with CP    and periventricular leukomalacia  • Acute...
Cerebral Palsy and Chorioamnionitis• Infection and inflammation do not explain all  cases of CP• Other possible cofactors ...
Cerebral Palsy and FIR SyndromeRole of cytokine polymorphisms  •   Mannose binding lectin-221, TNF-α-308 and MBL-52, 54, 5...
Cerebral Palsy and FIR SyndromePossible mechanisms  • Direct toxicity to neurons  • impair transition from oligo precursor...
Proposed Pathogenesis Bacterial              ↑ cytokines infection Permeability of                        Cell destructio...
Chronic Lung Disease and FIR Syndrome • Bronchopulmonary dysplasia (BPD) not explained   by prematurity alone • Very LBW i...
Fetal Inflammatory ResponseChorioamnionitis and funisitis  • Presence correlates with outcomes  • Severity correlates with...
Ascending InfectionBetter standardization of diagnostic terminology is  needed   • Degree, location of inflammation relate...
Ascending Infection• Maternal response – acute chorioamnionitis  • In free membranes neutrophils emigrate from    decidual...
Maternal Inflammatory Response               Stage 1• Suggested diagnostic terminology   • Acute subchorionitis or early a...
Maternal Inflammatory Response  Stage 1- Acute Chorionitis  Neutrophils in membrane trophoblast
Maternal Inflammatory ResponseStage 1- Early Acute ChorionitisNeutrophils in fibrin beneath chorionic plate
Maternal Inflammatory Response              Stage 2• Suggested diagnostic terminology   • Acute chorioamnionitis• Definiti...
Maternal Inflammatory ResponseStage 2 – Acute ChorioamnionitisScattered neutrophils in chorion and amnion
Maternal Inflammatory Response             Stage 3• Suggested diagnostic terminology   • Necrotizing chorioamnionitis• Def...
Maternal Inflammatory Response             Stage 3    Neutrophils with karyorrhexis
Maternal Inflammatory Response Stage  3 – Necrotizing ChorioamnionitisAmniotic epithelial necrosis; thickened, eosinophili...
Maternal Inflammatory Response   Grade 1 – Mild-Moderate • Suggested diagnostic terminology    • Mild or moderate • Defini...
Maternal Inflammatory Response   Grade 1- Mild-Moderate         Scattered neutrophils
Maternal Inflammatory Response         Grade 2 - Severe• Suggested diagnostic terminology   • Severe acute chorioamnioniti...
Maternal Inflammatory Response       Grade 2 - Severe     Confluent band of neutrophils
Fetal Inflammatory Response               Stage 1• Suggested diagnostic terminology   • With chorionic vasculitis or umbil...
Fetal Inflammatory Response      Stage 1 - PhlebitisNeutrophils in smooth muscle of umbilical vein wall
Fetal Inflammatory Response   Stage 1 - Chorionic VasculitisNeutrophils in wall of large chorionic vessels on fetal plate
Fetal Inflammatory Response                Stage 2• Suggested diagnostic terminology   • With umbilical vasculitis (one or...
Fetal Inflammatory Response          Stage 2 - ArteritisNeutrophils in smooth muscle of wall of umbilical artery
Fetal Inflammatory Response               Stage 3• Suggested diagnostic terminology   • With necrotizing funisitis or with...
Fetal Inflammatory Response Stage 3 - Necrotizing FunisitisNeutrophils and debris ring the umbilical vessels
Fetal Inflammatory ResponseStage 3 - Necrotizing Funisitis
Fetal Inflammatory Response    Grade 1 - Mild-Moderate• Suggested diagnostic terminology   • Mild – moderate• Definition  ...
Fetal Inflammatory Response         Grade 2 - Severe• Suggested diagnostic terminology  • With a severe fetal inflammatory...
Chorionic Vasculitis with Thrombi
Chorionic Vasculitis with Thrombi
Chorionic Vasculitis with Thrombi
Ascending Infection• Rarely see causative organisms in sections• Exceptions:  • Group B beta-hemolytic streptococcus  • Fu...
Group B beta-hemolytic strepBacterial colonies with no inflammatory response
Hematogenous Infection•   Virus – CMV, Rubella, Varicella, Parvovirus, HSV•   Bacteria – Treponema pallidum, Listeria•   P...
Hematogenous Infection       Clinical Impact•   Spontaneous abortion – Rubella•   Fetal death in utero, stillbirth – Parvo...
VillitisType           acute, chronic, granulomatousComposition    lymphs, histiocytes, plasma               cells, neutro...
VillitisCollections of abnormally agglutinated villi
VillitisNecrotizing villitis
VillitisNon necrotizing villitis
VillitisGranulomatous villitis
VillitisBasal villitis
Villitis• > 95% is villitis of unknown etiology (VUE)• Certain features do point to infections as the  etiology   • Clinic...
Infectious VillitisConfirm with  • Special stains  • Molecular techniques  • Maternal/infant serology  • Detailed clinical...
Congenital CMV Infection0.2% to 2.5% of live births   • 5% to 10% have disseminated disease   • 90% unrecognized at birth ...
Congential CMV Infection• In utero > intra partum, post partum• Caused by 1º or 2º infection• If 1º more likely:   • Sympt...
Congenital CMV Infection• Recent evidence that decidual cells or  decidual macrophages are reservoir for  CMV• Reactivatio...
Congenital CMV Infection• Usually infected women are asymptomatic• No guidelines for treating CMV during  pregnancy• Role ...
CMV Placentitis•   Lymphoplasmacytic villitis•   Necrotizing vasculitis•   Vessel occlusion•   Stromal hemosiderin•   Vira...
CMVNecrotizing villitis
CMVNumerous plasma cells – important clue to CMV
CMVVascular sclerosis
CMVVascular sclerosis
CMVStromal sclerosis
CMVStromal hemosiderin and sclerosis
CMVInclusions in stromal cells
CMVInclusions in endothelial cells
CMVEosinophilic nuclear and basophilic cytoplasmic inclusions
CMV
CMV PlacentitisImmunohistochemistry, in situhybridization and PCR will detect CMV incases of congential infection • When p...
Villitis of Unknown Etiology• Accounts for majority of villitis• Incidence   • 6% to 26% of placentas   • Usually greater ...
Villitis of Unknown Etiology•   Most cases are necrotizing•   Most are lymphohistiocytic•   Most cases are focal•   May be...
Villitis of Unknown Etiology Theories of pathogenesis   • Result of unidentified pathogen   • Immunologic phenomenon
Villitis of Unknown Etiology• Inflammatory cells   • Maternal   • T helper cells   • Ia antigen-bearing macrophages•  inc...
Villitis of Unknown EtiologyClinical associations   Severity of clinical findings generally related     to severity of vil...
Villitis of Unknown EtiologyWhich cases to work up for infection? • Suspicious maternal history • Suspicious clinical find...
VillitisBasic work up  • IHC for CMV  • IHC for toxoplasma  • Warthin-Starry or IHC for spirochetes  • Gram stain if lots ...
Important Circulatory Disorders    • Abnormal fibrin deposition       • Massive perivillous fibrin       • Maternal floor ...
Perivillous Fibrin• See some fibrin in most placentas• Grossly visible fibrin in 22%   • Underneath chorionic plate   • Ar...
Normal Fibrin Deposition
Normal Fibrin Deposition       Above basal plate
Fibrin DepositionGross  • Firm, tan, yellow or white  • Fuzzy border     • Interspersed red villous tissue     • Not as we...
Perivillous Fibrin Deposition
Massive Perivillous Fibrin       Deposition
Perivillous Fibrin Deposition  Not as well circumscribed as infarcts
Perivillous Fibrin Deposition     Expansion of intervillous space
Perivillous Fibrin Deposition     Cytotrophoblast proliferation
Perivillous Fibrin DepositionDifferential diagnosis  • Infarct     • Also firm, white if not recent     • Well circumscrib...
Perivillous Fibrin DepositionClinically significant if:   • Entraps 20% of terminal villi   • Central-basal locationClinic...
Perivillous Fibrin DepositionKatzman and Genest• Transmural massive fibrin deposition (MFD)  • Extends from fetal to mater...
Perivillous Fibrin DepositionKatzman and Genest  • 31% of infants had IUGR  • 14% had MFD or maternal floor infarct    in ...
Perivillous Fibrin• Pathogenesis is unclear• Likely related to stasis and thrombosis of  maternal blood
Perivillous Fibrin• Massive perivillous fibrin in small for  gestational age (SGA) and prior SGA• Preeclampsia, collagen v...
Maternal Floor Infarct
Maternal Floor Infarct
Maternal Floor Infarct
Maternal Floor Infarct•   Infarct is a misnomer - fibrinoid deposition•   Fibrinoid involves decidua basalis•   Encases ad...
Maternal Floor Infarct• Stillbirth – 13% to 50%• Growth retardation - 24 to 100%• Preterm delivery – 26% to 60%• Independe...
Subchorionic Fibrin Deposition       Not clinically significant
Subchorionic FibrinLayers of blood and fibrin beneath chorionic plate
Subchorionic Fibrin• Not clinically significant• May reflect damage to fetal plate by fetal  movements• Less common in inf...
InfarctsFirm, well circumscribed, often pale
InfarctsWell circumscribedUsually abut the maternal surfaceMay be red, tan, or white
Extensive Infarction
InfarctsLoss of intervillous space
InfarctsGhost villi with thick trophoblast membranes
InfarctsDifferential diagnosis  • Perivillous fibrin deposition  • Intervillous thrombohematoma     • Also well circumscri...
Intervillous ThrombohematomaWell circumscribed, laminated, red if early, white if older
InfarctsPathogenesis  • Decreased blood supply to group of villi     • Vessel narrowing (hypertension)     • Atherosis (pr...
Normal Vascular Remodeling• Replacement of smooth muscle and elastic by  fibrinoid material• Vessels become flaccid, low r...
Decidual VasculopathyTwo forms  • Lack of physiologic transformation  • Acute atherosis  • Both are associated with     • ...
Implantation Site Vessels  Prominent endovascular trophoblast
Acute AtherosisProminent fibrinoid necrosis, very narrow lumens
Acute Atherosis
InfarctsNormal   • See in 10-25% of term placentas   • Small, located in peripheryClinically significant if:   • Multiple,...
InfarctsClinical significance for fetus   • Hypoxia   • Intrauterine growth restriction   • Periventricular leukomalacia (...
InfarctsClinical significance for the mother   • Extensive implies significant maternal disease   • Preeclampsia - severit...
Infarcts• Sample areas away from infarcts   • Determine overall perfusion of placenta   • Small, narrow villi, few vessels...
Low Flow Changes Small, thin, unbranched villi Increased syncytial knots
Retroplacental HematomaDensely adherent clot indents surface, underlying infarction
Retroplacental Hematoma
Retroplacental HematomaBlood clot indents placenta, underlying infarction
Retroplacental Hematoma
Retroplacental HematomaVillous stromal hemorrhage may be seen beneath, especially                    in the 2nd trimester
Retroplacental HematomaIncidence ~ 5%Clinical associations   • Preeclampsia   • Heavy smoking, cocaine   • Trauma   • Acut...
Retroplacental HematomaPostulated pathogenesis  • Atherosis (preeclampsia) – weakened    vessels  • Cocaine, cigarettes – ...
Placental AbruptionA clinical syndrome  • Vaginal bleeding  • Increased uterine tone  • Uterine tenderness  • Decreased fe...
Retroplacental Hematoma• 30% with abruption have hematoma• 35% with hematoma have abruption• Clinical significance   • Dep...
Marginal Hematoma
Marginal Hematoma
Marginal Hematoma• Blood clot located between disc edge and  membranes• Often associated with hematoma on membranes• Occur...
Circulatory DisordersDisorders of maternal circulation  •   Perivillous fibrin deposition  •   Maternal floor infarct  •  ...
Fetal Vascular Obstruction   May occur at any level     • Umbilical cord vessels     • Chorionic plate vessels     • Small...
Fetal Vascular Obstruction• Fetal circulation of placenta and of fetus  itself are connected during gestation• Vascular ob...
Fetal Vascular Obstruction Well circumscribed, pale but not firm
Fetal Vascular Obstruction
Fetal Vascular Obstruction Well circumscribed area of pale, fibrotic villi
Fetal Vascular Obstruction
Fetal Vascular ObstructionThrombosis of larger vessels, downstream avascular terminal villi
Fetal Vascular Obstruction
Fetal Vascular ObstructionSclerosis of vessels in higher order villi, avascular terminal villi
Villous Stromal-Vascular Karyorrhexis    Karyorrhexis in fetal vessels, fragmented red cells
Chorionic Plate Vessel Thrombus       with Calcification
Chorionic Plate Vessel Thrombus
Fetal Vascular Obstruction   Pathogenesis     • Stasis     • Hypercoagulability     • Vascular damage
Fetal Vascular Obstruction Clinical Associations    • Maternal diabetes    • Maternal thrombophilia (but      not fetal th...
Fetal Thrombotic VasculopathyUnanswered questions:  • Incidence from prospective data  • Predictive value  • Clinically si...
Maternal Thrombophilic Conditions •   Antithrombin III deficiency •   Protein C deficiency •   Protein S deficiency •   Fa...
Maternal Thrombophilic Conditions   Clinical associations      • Controversial      • Preeclampsia      • Late pregnancy l...
Hereditary Thrombophilic Conditions• Problems   • Poor study design   • Imprecise placental terminology• May be associated...
Fetal Vascular Obstruction  • Cord abnormalities     • Long cord     • Velamentous insertion     • Excess twisting     • N...
Fetal Vascular ObstructionConsequences for fetus if extensive:  • Fetal growth restriction  • Chronic monitoring abnormali...
Fetal Thrombotic Vasculopathy84 consecutive perinatal autopsies   • 16 (19%) had avascular terminal villi   • extensive in...
Fetal Thrombotic Vasculopathy125 cases from children with neurologic deficits  referred for litigation   • 4 vascular lesi...
Fetal Vascular Obstruction• One or more of these seen in 51% of cases  vs. 10% of controls• 52% of CP patients had one of ...
Placental Potpourri: the Pernicious, Picayune, and Pervasive                           Phyllis C. Huettner, M.D.          ...
There are two broad patterns of placental infection - ascending infections andhematogenous infections, each associated wit...
Maternal neutrophils also migrate from maternal blood vessels in the decidua, through thedecidua, the chorion and eventual...
In the past, it was thought that the adverse outcomes experienced by many infants withacute chorioamnionitis were largely ...
apoptosis of lung cells, decreased proliferation of certain lung cell populations, inhibition ofmicrovascular development,...
Cytomegalovirus (CMV)Gross and microscopic features         The placenta may be normal, small, if the fetus is growth rest...
Placentas from most cases of VUE are normal on gross examination. Studies have shownthat the detection rate peaks at four ...
tree and is taken to the fetus via the umbilical vein. Disorders of the maternal circulation giverise to one set of abnorm...
Clinical Significance         Extensive infarction, large infarcts (>3 cm), infarcts involving the central area of theplac...
Differential Diagnosis        The differential diagnostic considerations include maternal floor infarct, placental infarct...
and dissect into adjacent villous tissue. In a very recent retroplacental bleed there may be no clotadherent to the placen...
Fetal Thrombotic Vasculopathy        Occlusion of vessels in the fetal circulatory system can involve vessels at any level...
exhibit ischemic necrosis whereas those in fetal vascular obstruction show dense, eosinophilicstromal fibrosis.          A...
likely in infants with fetal thrombotic vasculopathy. In a study of 84 consecutive perinatalautopsies, Kraus found fetal v...
14. Stallmach T, Hebisch G, Joller-Jemelka HI, Orban P, Schwaller J, Engelmann M. Cytokine    production and visualized ef...
34. Gibson CS, Maclennan AH, Dekker GA, Goldwater PN, Sullivan TR, Munroe DJ, Tsang S,    Stewart C, Nelson KB. Candidate ...
52. Knox WR, Fox H. Villitis of unknown aetiology: its incidence and significance in placentae    from a British populatio...
Placental Potpourri: the Pernicious, Picayune, and Pervasive
Placental Potpourri: the Pernicious, Picayune, and Pervasive
Placental Potpourri: the Pernicious, Picayune, and Pervasive
Placental Potpourri: the Pernicious, Picayune, and Pervasive
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Placental Potpourri: the Pernicious, Picayune, and Pervasive

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Placental Potpourri: the
Pernicious, Picayune, and
Pervasive

Phyllis C. Huettner, M.D.
Washington University Medical Center
St. Louis

LBPC

Published in: Health & Medicine
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Placental Potpourri: the Pernicious, Picayune, and Pervasive

  1. 1. Placental Potpourri: thePernicious, Picayune, and Pervasive Phyllis C. Huettner, M.D.Washington University Medical Center St. Louis
  2. 2. Outline of This Talk• Value of placental examination• Brief review of placental circulation, histology• Lesions that impact neonatal or maternal health • Intrauterine infection • Villitis of unknown etiology • Fibrin deposition • Other circulatory disorders • Fetal thrombotic processes
  3. 3. Value of Placental Examination• Etiology of intrauterine or perinatal death• Etiology of preterm delivery• Etiology of anomaly• Etiology of neurologic impairment• Alter management of future pregnancies• Pathophysiology of maternal or neonatal disorders• Useful in the care of a sick neonate
  4. 4. Etiology of Stillbirth• Classic study of perinatal autopsies • 92% of cases had placental abnormalities • In one-third cause of death involved placenta or cord • 16% placenta or cord contributed to death Driscoll SG. Pediatr Clin North Am. 1965;12:493.
  5. 5. Etiology of StillbirthCause of death (COD) determination in structurally normal stillbirths • Increased from 38.5% to 79.5% (p<.0001) after policy of placental examination instituted • Placental exam provided • Confirmation of COD in 24.6% • New diagnostic information and COD in 44.7% • No additional info in 30.7% Wu X et al. Mod Path 2009;22(sup 1):10A poster 33
  6. 6. Value of Placental Examination• Etiology of intrauterine or perinatal death• Etiology of preterm delivery• Etiology of anomaly• Etiology of neurologic impairment• Alter management of future pregnancies• Pathophysiology of maternal or neonatal disorders• Useful in the care of a sick neonate
  7. 7. Pathogenesis of Intrauterine Infection• Ascending - typically bacterial → chorioamnionitis• Transplacental - viral, protozoal, bacterial → villitis
  8. 8. Ascending Infection • Most common type of infection • Organisms enter through cervix • Relationship with rupture of membranes • Inflammation of fetal membranes and umbilical cord • Neonatal pneumonia, sepsis by swallowing, aspirating infected amnionic fluid
  9. 9. Intrauterine InfectionCommon • See in 10% to 20% of term deliveries • Up to two-thirds of preterm deliveriesImportant associations • Preterm delivery • Neonatal sepsis • Cerebral palsy • Chronic lung disease
  10. 10. Chorioamnionitis• At term - related to presence and duration of membrane rupture• Preterm - likely precedes and causes membrane rupture • inflammatory response produces • prostaglandins, cytokines - trigger labor • metalloproteinases - weaken membrane integrity, remodel cervical tissue
  11. 11. Intrauterine Infection• Prematurity is leading cause of perinatal morbidity and mortality in the US • 70% of neonatal deaths • 50% of cases of cerebral palsy • Chronic lung disease, metal retardation• Amnionic infection is a major cause of preterm deliveries
  12. 12. Fetal Inflammatory Response Syndrome • Intrauterine infection leads to production of inflammatory cytokines by fetus • Inflammatory response correlates with adverse outcomes • Neonatal sepsis • Pneumonia • Bronchopulmonary dysplasia, RDS • Intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy • Necrotizing enterocolitis
  13. 13. Fetal Inflammatory Response Syndrome • UC IL-6 and AF IL-6 correlate with CP and periventricular leukomalacia • Acute funisitis, especially arteritis, may be better predictor of CP than IL-6 levels • Severe fetal outcomes occur more often in infants with arteritis • True after adjusting for gestational age Yoon BH et al. Am J Obstet Gynecol 1997; 177:19. Kim CJ et al. Am J Obstet Gynecol 2001; 185:496.
  14. 14. Cerebral Palsy and Chorioamnionitis• Infection and inflammation do not explain all cases of CP• Other possible cofactors • Gestational age at time of infection • Intensity of fetal response • Genetic differences in genes that code cytokines
  15. 15. Cerebral Palsy and FIR SyndromeRole of cytokine polymorphisms • Mannose binding lectin-221, TNF-α-308 and MBL-52, 54, 57 • These polymorphisms alter levels of circulating cytokines • Any of these polymorphisms increased risk of CP • Any MBL 54- ↑ risk of diplegia • Heterozygous TNFα - ↑ risk of quadraplegia at term • Heterozygous or homozygous TNFα - ↑ risk of hemiplegia at <32 weeks Gibson CS et al. Am J Obstet Gynecol 2006; 194:674
  16. 16. Cerebral Palsy and FIR SyndromePossible mechanisms • Direct toxicity to neurons • impair transition from oligo precursors to mature oligos • Activate endothelial cells, shift to prothombotic state, ? Syngergism with thrombophilic polymorphisms • ↑ permeability of blood brain barrier • ↓ innate response to infection
  17. 17. Proposed Pathogenesis Bacterial ↑ cytokines infection Permeability of Cell destruction,blood brain barrier abnormal proliferation  passage of bacteria, cytokines
  18. 18. Chronic Lung Disease and FIR Syndrome • Bronchopulmonary dysplasia (BPD) not explained by prematurity alone • Very LBW infants with BPD • ↑ incidence of chorioamnionitis • ↓ respiratory distress • BPD correlates with ↑ antenatal cytokines • Infants with highest IL-6, IL-8, IL-1 levels had highest risk of BPD, controlled for gestational age • Animal models – cytokines disrupt lung development by variety of mechanisms Mittendorf R et al. J Perinat Med 2005; 33:428 Yoon BH et al. Am J Obstet Gynecol 1997; 177-825
  19. 19. Fetal Inflammatory ResponseChorioamnionitis and funisitis • Presence correlates with outcomes • Severity correlates with outcomes • Numerous staging and grading systems • All have shortcomings • Reproducibility not perfect • Lack of prospective correlation with outcomes
  20. 20. Ascending InfectionBetter standardization of diagnostic terminology is needed • Degree, location of inflammation related to outcome • Stratification of prognosis • Stratification of treatment • Facilitate studies between institutionsRedline RW et al. have proposed a scheme for staging and grading the maternal and fetal response Pediatr Develop Pathol 6:435-448, 2003
  21. 21. Ascending Infection• Maternal response – acute chorioamnionitis • In free membranes neutrophils emigrate from decidual vessels through chorion and amnion • In placenta neutrophils emigrate from intervillous space through chorion and amnion• Fetal response – funisitis, chorionic vasculitis • Neutrophils emigrate from umbilical vessels • Neutrophils emigrate from chorionic vessels
  22. 22. Maternal Inflammatory Response Stage 1• Suggested diagnostic terminology • Acute subchorionitis or early acute chorionitis• Definition • Neutrophils in subchorionic fibrin and/or membranous trophoblast Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  23. 23. Maternal Inflammatory Response Stage 1- Acute Chorionitis Neutrophils in membrane trophoblast
  24. 24. Maternal Inflammatory ResponseStage 1- Early Acute ChorionitisNeutrophils in fibrin beneath chorionic plate
  25. 25. Maternal Inflammatory Response Stage 2• Suggested diagnostic terminology • Acute chorioamnionitis• Definition • Neutrophils in chorionic plate or membranous chorionic connective tissue and/or amnion Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  26. 26. Maternal Inflammatory ResponseStage 2 – Acute ChorioamnionitisScattered neutrophils in chorion and amnion
  27. 27. Maternal Inflammatory Response Stage 3• Suggested diagnostic terminology • Necrotizing chorioamnionitis• Definition • Neutrophil karyorrhexis, amnion necrosis and/or amniotic basement membrane thickening/hypereosinophilia Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  28. 28. Maternal Inflammatory Response Stage 3 Neutrophils with karyorrhexis
  29. 29. Maternal Inflammatory Response Stage 3 – Necrotizing ChorioamnionitisAmniotic epithelial necrosis; thickened, eosinophilic basement membrane
  30. 30. Maternal Inflammatory Response Grade 1 – Mild-Moderate • Suggested diagnostic terminology • Mild or moderate • Definition • Individual or small clusters of neutrophils Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  31. 31. Maternal Inflammatory Response Grade 1- Mild-Moderate Scattered neutrophils
  32. 32. Maternal Inflammatory Response Grade 2 - Severe• Suggested diagnostic terminology • Severe acute chorioamnionitis or with subchorionic microabscesses• Definition • Confluent neutrophils between chorion and decidua; > or equal to 3 isolated foci or continuous band Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  33. 33. Maternal Inflammatory Response Grade 2 - Severe Confluent band of neutrophils
  34. 34. Fetal Inflammatory Response Stage 1• Suggested diagnostic terminology • With chorionic vasculitis or umbilical phlebitis• Definition • Intramural neutrophils in chorionic vessels and/or umbilical vein Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  35. 35. Fetal Inflammatory Response Stage 1 - PhlebitisNeutrophils in smooth muscle of umbilical vein wall
  36. 36. Fetal Inflammatory Response Stage 1 - Chorionic VasculitisNeutrophils in wall of large chorionic vessels on fetal plate
  37. 37. Fetal Inflammatory Response Stage 2• Suggested diagnostic terminology • With umbilical vasculitis (one or both arteries +/- vein) or umbilical panvasculitis (all vessels)• Definition • Intramural neutrophils in umbilical artery or arteries (+/- vein) Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  38. 38. Fetal Inflammatory Response Stage 2 - ArteritisNeutrophils in smooth muscle of wall of umbilical artery
  39. 39. Fetal Inflammatory Response Stage 3• Suggested diagnostic terminology • With necrotizing funisitis or with concentric umbilical perivasculitis• Definition • Neutrophils +/- debris in concentric bands- rings-halos around one or more umbilical vessels Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  40. 40. Fetal Inflammatory Response Stage 3 - Necrotizing FunisitisNeutrophils and debris ring the umbilical vessels
  41. 41. Fetal Inflammatory ResponseStage 3 - Necrotizing Funisitis
  42. 42. Fetal Inflammatory Response Grade 1 - Mild-Moderate• Suggested diagnostic terminology • Mild – moderate• Definition • Scattered neutrophils Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  43. 43. Fetal Inflammatory Response Grade 2 - Severe• Suggested diagnostic terminology • With a severe fetal inflammatory response or with intense chorionic (umbilical) vasculitis• Definition • Near confluent intramural neutrophils in chorionic and/or umbilical vessels with attenuation/degeneration of vascular smooth muscle • Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
  44. 44. Chorionic Vasculitis with Thrombi
  45. 45. Chorionic Vasculitis with Thrombi
  46. 46. Chorionic Vasculitis with Thrombi
  47. 47. Ascending Infection• Rarely see causative organisms in sections• Exceptions: • Group B beta-hemolytic streptococcus • Fusobacterium • Candida
  48. 48. Group B beta-hemolytic strepBacterial colonies with no inflammatory response
  49. 49. Hematogenous Infection• Virus – CMV, Rubella, Varicella, Parvovirus, HSV• Bacteria – Treponema pallidum, Listeria• Parasites – Toxoplasma gondii• Unknown – > 95%, ? abnormal immune reaction
  50. 50. Hematogenous Infection Clinical Impact• Spontaneous abortion – Rubella• Fetal death in utero, stillbirth – Parvovirus• Malformations – Rubella, Toxo• Active infection – Toxo, CMV• Delayed sequelae – CMV and others • Deafness • Mental retardation • Learning disabilities
  51. 51. VillitisType acute, chronic, granulomatousComposition lymphs, histiocytes, plasma cells, neutrophilsNecrosis necrotizing, non-necrotizingDistribution focal, diffuse, basalSeverity very mild, mild, mod, severe
  52. 52. VillitisCollections of abnormally agglutinated villi
  53. 53. VillitisNecrotizing villitis
  54. 54. VillitisNon necrotizing villitis
  55. 55. VillitisGranulomatous villitis
  56. 56. VillitisBasal villitis
  57. 57. Villitis• > 95% is villitis of unknown etiology (VUE)• Certain features do point to infections as the etiology • Clinical history • Active, resolving, healed areas • Prominent fibrosis • Often associated acute chorioamnionitis • Specific features
  58. 58. Infectious VillitisConfirm with • Special stains • Molecular techniques • Maternal/infant serology • Detailed clinical history
  59. 59. Congenital CMV Infection0.2% to 2.5% of live births • 5% to 10% have disseminated disease • 90% unrecognized at birth • 5% to 15% have long-term effects • Mental retardation • Learning disabilities • Sensorineural hearing loss
  60. 60. Congential CMV Infection• In utero > intra partum, post partum• Caused by 1º or 2º infection• If 1º more likely: • Symptomatic • Late sequelae• Treatment immediately after birth may decrease severity of neurologic damage
  61. 61. Congenital CMV Infection• Recent evidence that decidual cells or decidual macrophages are reservoir for CMV• Reactivation is more likely after inflammatory response to bacterial infections
  62. 62. Congenital CMV Infection• Usually infected women are asymptomatic• No guidelines for treating CMV during pregnancy• Role of screening pregnant women for CMV is unclear
  63. 63. CMV Placentitis• Lymphoplasmacytic villitis• Necrotizing vasculitis• Vessel occlusion• Stromal hemosiderin• Viral inclusions – 20%
  64. 64. CMVNecrotizing villitis
  65. 65. CMVNumerous plasma cells – important clue to CMV
  66. 66. CMVVascular sclerosis
  67. 67. CMVVascular sclerosis
  68. 68. CMVStromal sclerosis
  69. 69. CMVStromal hemosiderin and sclerosis
  70. 70. CMVInclusions in stromal cells
  71. 71. CMVInclusions in endothelial cells
  72. 72. CMVEosinophilic nuclear and basophilic cytoplasmic inclusions
  73. 73. CMV
  74. 74. CMV PlacentitisImmunohistochemistry, in situhybridization and PCR will detect CMV incases of congential infection • When placenta is normal • When infection is sub clinical
  75. 75. Villitis of Unknown Etiology• Accounts for majority of villitis• Incidence • 6% to 26% of placentas • Usually greater than 32 weeks gestation• No gross abnormalities• 85% are focal• Most randomly distributed • 20% have basal location
  76. 76. Villitis of Unknown Etiology• Most cases are necrotizing• Most are lymphohistiocytic• Most cases are focal• May be associated with vasculitis of fetal stem vessels • Avascular downstream terminal villi
  77. 77. Villitis of Unknown Etiology Theories of pathogenesis • Result of unidentified pathogen • Immunologic phenomenon
  78. 78. Villitis of Unknown Etiology• Inflammatory cells • Maternal • T helper cells • Ia antigen-bearing macrophages•  incidence in women with autoimmune disorders• Tendency to recur
  79. 79. Villitis of Unknown EtiologyClinical associations Severity of clinical findings generally related to severity of villitis • Small for gestational age infants • Antenatal growth arrest • Perinatal mortality • Oligohydramnios without membrane rupture • Chronic monitoring abnormalities
  80. 80. Villitis of Unknown EtiologyWhich cases to work up for infection? • Suspicious maternal history • Suspicious clinical findings in neonate • Not mild • Pattern besides lymphohistiocytic
  81. 81. VillitisBasic work up • IHC for CMV • IHC for toxoplasma • Warthin-Starry or IHC for spirochetes • Gram stain if lots of neutrophils or abscesses
  82. 82. Important Circulatory Disorders • Abnormal fibrin deposition • Massive perivillous fibrin • Maternal floor infarct • Infarction • Retroplacental hematoma
  83. 83. Perivillous Fibrin• See some fibrin in most placentas• Grossly visible fibrin in 22% • Underneath chorionic plate • Around stem villi • Just above basal plate• See less in preeclampsia (13%)• See less in preterm (6%)
  84. 84. Normal Fibrin Deposition
  85. 85. Normal Fibrin Deposition Above basal plate
  86. 86. Fibrin DepositionGross • Firm, tan, yellow or white • Fuzzy border • Interspersed red villous tissue • Not as well circumscribed as infarct • Often in periphery
  87. 87. Perivillous Fibrin Deposition
  88. 88. Massive Perivillous Fibrin Deposition
  89. 89. Perivillous Fibrin Deposition Not as well circumscribed as infarcts
  90. 90. Perivillous Fibrin Deposition Expansion of intervillous space
  91. 91. Perivillous Fibrin Deposition Cytotrophoblast proliferation
  92. 92. Perivillous Fibrin DepositionDifferential diagnosis • Infarct • Also firm, white if not recent • Well circumscribed • Collapse, not expansion, of intervillous space • No trophoblast proliferation • Maternal floor infarct • Involves the basal villi and decidua
  93. 93. Perivillous Fibrin DepositionClinically significant if: • Entraps 20% of terminal villi • Central-basal locationClinical significance • Intrauterine growth retardation • Low placental weight • Fetal death in utero Redline RW, Patterson P. Arch Pathol Lab Med 1994; 18:698
  94. 94. Perivillous Fibrin DepositionKatzman and Genest• Transmural massive fibrin deposition (MFD) • Extends from fetal to maternal surface • Entraps > 50% of villi on at least one slide • Rare - 0.28 to 0.5% of examined placentas Pediatr Dev Pathol 2002;5:159-164
  95. 95. Perivillous Fibrin DepositionKatzman and Genest • 31% of infants had IUGR • 14% had MFD or maternal floor infarct in other 2nd or 3rd trimester pregnancies • 50% had MFD or maternal floor infarct in other 1st trimester pregnancies Pediatr Dev Pathol 2002;5:159-164
  96. 96. Perivillous Fibrin• Pathogenesis is unclear• Likely related to stasis and thrombosis of maternal blood
  97. 97. Perivillous Fibrin• Massive perivillous fibrin in small for gestational age (SGA) and prior SGA• Preeclampsia, collagen vascular diseases, coagulopathy• Aspirin, dipyridamole prevents perivillous fibrin and SGAFuke Y et al Gyn Obstet Invest 38:5-9, 1994
  98. 98. Maternal Floor Infarct
  99. 99. Maternal Floor Infarct
  100. 100. Maternal Floor Infarct
  101. 101. Maternal Floor Infarct• Infarct is a misnomer - fibrinoid deposition• Fibrinoid involves decidua basalis• Encases adjacent villi• Katzman and Genest definition • Basal villi of entire maternal floor be encased by fibrinoid at least 3 mm thick on at least one slide Pediatr Dev Pathol 2002;5:159-164
  102. 102. Maternal Floor Infarct• Stillbirth – 13% to 50%• Growth retardation - 24 to 100%• Preterm delivery – 26% to 60%• Independent predictor of neurologic impairment in preterm infants• Recurrence – 12% to 78%
  103. 103. Subchorionic Fibrin Deposition Not clinically significant
  104. 104. Subchorionic FibrinLayers of blood and fibrin beneath chorionic plate
  105. 105. Subchorionic Fibrin• Not clinically significant• May reflect damage to fetal plate by fetal movements• Less common in infants with disorders that restrict movement
  106. 106. InfarctsFirm, well circumscribed, often pale
  107. 107. InfarctsWell circumscribedUsually abut the maternal surfaceMay be red, tan, or white
  108. 108. Extensive Infarction
  109. 109. InfarctsLoss of intervillous space
  110. 110. InfarctsGhost villi with thick trophoblast membranes
  111. 111. InfarctsDifferential diagnosis • Perivillous fibrin deposition • Intervillous thrombohematoma • Also well circumscribes, white if not recent • Often laminated • Contain no villi, only blood
  112. 112. Intervillous ThrombohematomaWell circumscribed, laminated, red if early, white if older
  113. 113. InfarctsPathogenesis • Decreased blood supply to group of villi • Vessel narrowing (hypertension) • Atherosis (preeclampsia) • Physical separation (retroplacental hematoma)
  114. 114. Normal Vascular Remodeling• Replacement of smooth muscle and elastic by fibrinoid material• Vessels become flaccid, low resistance tubes• Increases blood flow 10-fold
  115. 115. Decidual VasculopathyTwo forms • Lack of physiologic transformation • Acute atherosis • Both are associated with • Preeclampsia • IUGR • Small for gestational age infants • Collagen vascular disease
  116. 116. Implantation Site Vessels Prominent endovascular trophoblast
  117. 117. Acute AtherosisProminent fibrinoid necrosis, very narrow lumens
  118. 118. Acute Atherosis
  119. 119. InfarctsNormal • See in 10-25% of term placentas • Small, located in peripheryClinically significant if: • Multiple, central • Large (>3 cm) • Preterm
  120. 120. InfarctsClinical significance for fetus • Hypoxia • Intrauterine growth restriction • Periventricular leukomalacia (preterm) • Intrauterine fetal demise
  121. 121. InfarctsClinical significance for the mother • Extensive implies significant maternal disease • Preeclampsia - severity related to extent of infarction • Maternal thrombophilic conditions
  122. 122. Infarcts• Sample areas away from infarcts • Determine overall perfusion of placenta • Small, narrow villi, few vessels, increased knots indicates poor perfusion• Normally perfused placenta can lose ~20% of villi without harming infant• Less reserve if already poorly perfused
  123. 123. Low Flow Changes Small, thin, unbranched villi Increased syncytial knots
  124. 124. Retroplacental HematomaDensely adherent clot indents surface, underlying infarction
  125. 125. Retroplacental Hematoma
  126. 126. Retroplacental HematomaBlood clot indents placenta, underlying infarction
  127. 127. Retroplacental Hematoma
  128. 128. Retroplacental HematomaVillous stromal hemorrhage may be seen beneath, especially in the 2nd trimester
  129. 129. Retroplacental HematomaIncidence ~ 5%Clinical associations • Preeclampsia • Heavy smoking, cocaine • Trauma • Acute chorioamnionitis • Maternal thrombophilic conditions • Prior abruption
  130. 130. Retroplacental HematomaPostulated pathogenesis • Atherosis (preeclampsia) – weakened vessels • Cocaine, cigarettes – spasm • Thrombophilia - thrombosis
  131. 131. Placental AbruptionA clinical syndrome • Vaginal bleeding • Increased uterine tone • Uterine tenderness • Decreased fetal heart tones • Maternal hypotension, DIC
  132. 132. Retroplacental Hematoma• 30% with abruption have hematoma• 35% with hematoma have abruption• Clinical significance • Depends on size, amount of infarction, how well rest of placenta is perfused • Fetal death • Periventricular leukomalacia (preterm)
  133. 133. Marginal Hematoma
  134. 134. Marginal Hematoma
  135. 135. Marginal Hematoma• Blood clot located between disc edge and membranes• Often associated with hematoma on membranes• Occurs in placentas implanted close to os• Causes bleeding during delivery• Clinically mistaken for “abruption”• Not clinically significant – no associated infarction
  136. 136. Circulatory DisordersDisorders of maternal circulation • Perivillous fibrin deposition • Maternal floor infarct • Infarct • Intervillous thrombohematoma • Retroplacental hematoma • Marginal hematoma
  137. 137. Fetal Vascular Obstruction May occur at any level • Umbilical cord vessels • Chorionic plate vessels • Small vessels in villi
  138. 138. Fetal Vascular Obstruction• Fetal circulation of placenta and of fetus itself are connected during gestation• Vascular obstruction in fetal circulation of placenta may be associated with and serve as a marker for thrombotic or embolic lesions in circulation of fetus
  139. 139. Fetal Vascular Obstruction Well circumscribed, pale but not firm
  140. 140. Fetal Vascular Obstruction
  141. 141. Fetal Vascular Obstruction Well circumscribed area of pale, fibrotic villi
  142. 142. Fetal Vascular Obstruction
  143. 143. Fetal Vascular ObstructionThrombosis of larger vessels, downstream avascular terminal villi
  144. 144. Fetal Vascular Obstruction
  145. 145. Fetal Vascular ObstructionSclerosis of vessels in higher order villi, avascular terminal villi
  146. 146. Villous Stromal-Vascular Karyorrhexis Karyorrhexis in fetal vessels, fragmented red cells
  147. 147. Chorionic Plate Vessel Thrombus with Calcification
  148. 148. Chorionic Plate Vessel Thrombus
  149. 149. Fetal Vascular Obstruction Pathogenesis • Stasis • Hypercoagulability • Vascular damage
  150. 150. Fetal Vascular Obstruction Clinical Associations • Maternal diabetes • Maternal thrombophilia (but not fetal thrombophilia) • Chorioamnionitis
  151. 151. Fetal Thrombotic VasculopathyUnanswered questions: • Incidence from prospective data • Predictive value • Clinically significant amount • Appropriate work up • Role of treatment in next pregnancy • Pathogenesis
  152. 152. Maternal Thrombophilic Conditions • Antithrombin III deficiency • Protein C deficiency • Protein S deficiency • Factor V mutation (Leiden) • Prothrombin 20120A • MTHFR C677T- hyperhomocysteinemia
  153. 153. Maternal Thrombophilic Conditions Clinical associations • Controversial • Preeclampsia • Late pregnancy loss • Intrauterine growth restriction
  154. 154. Hereditary Thrombophilic Conditions• Problems • Poor study design • Imprecise placental terminology• May be associated with • ↑ number, ↑ size of infarcts • Acute atherosis, spiral artery thrombi • Retroplacental hematoma/abruption • Fetal vascular obstruction
  155. 155. Fetal Vascular Obstruction • Cord abnormalities • Long cord • Velamentous insertion • Excess twisting • Nuchal cord
  156. 156. Fetal Vascular ObstructionConsequences for fetus if extensive: • Fetal growth restriction • Chronic monitoring abnormalities • Stillbirth • Neurologic impairment • Hepatic failure • Vascular compromise involving kidneys, GI
  157. 157. Fetal Thrombotic Vasculopathy84 consecutive perinatal autopsies • 16 (19%) had avascular terminal villi • extensive in all 16 • Involved 25 to 50% of placenta in 4 • 6 (37.5%) had fetal somatic thrombi • 5/8 mothers had coagulation abnormalities Kraus FT, Archeen V Human Pathol 30:759, 1999
  158. 158. Fetal Thrombotic Vasculopathy125 cases from children with neurologic deficits referred for litigation • 4 vascular lesions significantly increased • Fetal thrombotic vasculopathy • VUE with obliterative fetal vasculopathy • Chorioamnionitis with fetal vasculitis • Meconium-associated vascular necrosis Redline RW Am J Obstet Gynecol 2005; 192:452-7
  159. 159. Fetal Vascular Obstruction• One or more of these seen in 51% of cases vs. 10% of controls• 52% of CP patients had one of these lesions• Cord abnormalities more common in infants with fetal thrombotic vasculopathy Redline RW Am J Obstet Gynecol 2005; 192:452-7 Redline RW Hum Pathol 2004;35:1494-8
  160. 160. Placental Potpourri: the Pernicious, Picayune, and Pervasive Phyllis C. Huettner, M.D. Washington University Medical Center The placenta is a remarkable organ. It undergoes rapid growth and profound changes instructure to supply the needs of the rapidly growing fetus for the crucial first 40 weeks ofdevelopment. During life in utero, the circulation of the fetus and the circulation of the placentaform one continuous unit. Examination of the placenta, which is easily accessible, may providevaluable information about events during gestation affecting the fetus. I’ll begin by discussing the importance of placental examination. The remainder of thetalk will focus on those placental abnormalities that are clinically important for the infant, themother or both. Some of these abnormalities are common but others are easily overlooked.Several have a risk of recurrence in subsequent pregnancy. Many represent areas where we havemade important new discoveries in terms of pathophysiology with important implications forfetal and maternal health.Why Examine the Placenta? Placental examination can be very rewarding in determining the cause of an intrauterineor perinatal death; investigations of such deaths are incomplete without a placental examination.In a large, classic study of perinatal autopsies, placental abnormalities were found in 92% ofcases. The cause of death was a placental or cord abnormality in almost a third of cases and in16% of cases was a contributing factor.1 In more recent studies of structurally normal stillborninfants, examination of the placenta significantly increased the percentage of cases in which acause of death could be determined.2,3 Examination of the placenta may help explain the etiology of a preterm delivery, acongenital anomaly or other adverse neonatal outcome. Obstetrical management of subsequentpregnancies may be altered if conditions that show a risk of recurrence such as abruption,massive perivillous fibrin deposition, or maternal floor infarct are identified on placentalexamination. Information that may help explain the outcome of a neurologically impaired childand be useful in the legal defense of these cases may be obtained from placental examination.4,5In a general way, examination of placentas has provided and will continue to provide insightsinto the pathophysiology of various important maternal and neonatal disorders potentiallyimproving diagnosis and therapy for these conditions. The information obtained from placental examination may be immediately useful in thecare of a sick neonate and may be very helpful to parents and pediatricians caring for impairedchildren later in life. In order to maximize the value of placental examination, pathologists andinformaticians need to develop better ways to ensure that the results of the placental examinationreach and are understood by the neonatologists and general pediatricians caring for children andcommunicating with parents, in addition to the obstetrician who sent the placenta forexamination. This is challenging because mothers and babies frequently have different lastnames and are often cared for in different hospitals.Infection and the Placenta Intrauterine infections can have important consequences for the fetus including abortion,stillbirth, active infection in the newborn period and long-term sequelae such as neurologicdeficits including cerebral palsy, mental retardation, blindness, deafness and learning disabilities. 1
  161. 161. There are two broad patterns of placental infection - ascending infections andhematogenous infections, each associated with a characteristic type and pattern of inflammationwithin the placenta as well as characteristic organisms. In general, ascending infections, the mostcommon pattern, are caused by bacteria that pass from the vagina or cervix into the uterus andcause acute inflammation of the fetal membranes (acute chorioamnionitis) and umbilical cord(acute funisitis). In hematogenous infections, a less common pattern, organisms are passedhematogenously from the mother to the placenta and fetus. This is the pattern typically seen inTORCH infections and may be caused by viral organisms (CMV, Rubella and others), protozoa(Toxoplasma gondii) and some bacteria (Listeria monocytogenes, Treponema pallidum). Theplacenta usually shows chronic inflammation of the villi (villitis) but may also have a componentof chorioamnionitis. Infants may also be infected with bacterial or viral agents after passingthrough an infected birth canal, a common form of infection with HIV and HSV, but this form oftransmission does not involve the placenta.Ascending Infection and Acute Chorioamnionitis Chorioamnionitis is the most common form of inflammation in the placenta. It is found inthe placentas of about 10 to 20% of term deliveries.6 Chorioamnionitis is strongly correlated withprematurity; about two-thirds of infants born before 24 weeks gestation will have evidence ofchorioamnionitis.6 The prevalence is also increased in women of low socioeconomic status andAfrican-American women.7 A distinction needs to be made between clinical and histologicchorioamnionitis. Clinical chorioamnionitis is characterized by some combination of fever,elevated maternal white count, premature rupture of membranes and foul vaginal discharge. Thegold standard for diagnosis, however, remains histologic chorioamnionitis with the presence ofneutrophils in the chorion and/or amnion. There is very poor correlation between the clinicaldiagnosis of chorioamnionitis and histologic chorioamnionitis; 72% of cases with histologicchorioamnionitis don’t meet the clinical diagnosis and 9% of cases with clinical chorioamnionitisdon’t have histologic chorioamnionitis.8 It is now clear that infection causes acute chorioamnionitis. The implicated organismsmay be aerobic or anaerobic and are typically normal flora or gastrointestinal contaminants ofthe vagina and cervix. Factors such as rupture of membranes, cervical dilatation, and thepresence of an IUD or cerclage may facilitate spread to the amnionic cavity. There is a strongrelationship between rupture of membranes and chorioamnionitis, the risk of chorioamnionitisincreasing with increasing duration of membrane rupture.9 This relationship is particularly strongat term. In other cases, chorioamnionitis may precede rupture of membranes actually causingpremature rupture of membranes and/or preterm birth.10 The organisms seen in preterm laborwith intact membranes are typically low virulence vaginal and enteric organisms.11 There isincreasing evidence that some of these organisms may ascend from the lower GYN tract weeksor even months before acute chorioamnionitis develops and reside in the uterine tissues includingthe decidua due to decreased local immunity secondary to pregnancy.10Pathologic Features and Grading of Acute Chorioamnionitis The fetal membranes in chorioamnionitis are typically normal on gross examination butin cases of severe or longstanding infection, may be discolored, friable and foul smelling. Boththe mother and the fetus (after about 20 weeks) respond to infection in the amniotic cavity.Maternal neutrophils first migrate from the intervillous space, which is essentially a maternalblood vessel, and accumulate in the fibrin layer beneath the chorion. From here they passthrough the connective tissue of the chorion and eventually into the amnion of the fetal plate ofthe placenta in response to chemotactic factors generated by bacteria in the amnionic fluid. 2
  162. 162. Maternal neutrophils also migrate from maternal blood vessels in the decidua, through thedecidua, the chorion and eventually into the amnion of the free membranes (membrane roll).Fetal neutrophils migrate out of large vessels on the chorionic plate (chorionic vasculitis) andmay also migrate from the umbilical cord vessels, typically first from the umbilical vein then bythe artery. Neutrophils are first seen in the clear spaces between smooth muscle cells buteventually migrate completely through the vessel wall to involve the surrounding Wharton’sjelly. If severe, rings or arcs of degenerating neutrophils will surround the umbilical vessels. Typically, causative organisms are not seen on histologic sections. Important exceptionsinclude Group B streptococcus, Candida and fusobacterium. When organisms are identified, it isimportant to consider post delivery overgrowth in unfixed specimens, especially those withoutinflammation. Because of the increasingly clear relationship between acute chorioamnionitis andadverse fetal outcomes, including long-term sequelae such as cerebral palsy and chronic lungdisease (see below), standardized grading and staging of chorioamnionitis and funisitis mayfacilitate study and potentially even treatment of this common condition. While many schemesfor grading and staging chorioamnionitis have been proposed, none is completely reproducible orprospectively validated for correlation with outcomes. The scheme proposed by Redline and hiscolleagues in the Society for Pediatric Pathology has good reproducibility and can serve as a starttoward standardization.12 In this system both the stage (localization) and grade (severity) aredetermined for the maternal inflammatory response (chorioamnionitis) and the fetalinflammatory response (chorionic vasculitis and funisitis). Maternal inflammatory response(MIR) stage 1 represents acute subchorionitis and/or acute chorionitis in which neutrophils areseen in the subchorionic fibrin layer or at the junction of decidua and chorion in the freemembranes. MIR stage 2 represents acute chorioamnionitis in which neutrophils extend into theamnionic connective tissue or epithelium. MIR stage 3 represents necrotizing chorioamnionitischaracterized by karyorrhexis of neutrophils, hypereosinophilia of the amnionic basementmembrane and at least focal necrosis of the amnionic epithelium. MIR grade two ischaracterized by chorionic microabscesses composed of 10 to 20 neutrophils; less inflammationthan this represents MIR grade 1. Fetal inflammatory response (FIR) stage 1 representsinflammation around the large vessels of the chorionic plate (chorionic vasculitis) or theumbilical vein. FIR stage 2 represents umbilical arteritis with or without chorionic vasculitis orumbilical vein inflammation and FIR stage 3 represents necrotizing funisitis. Grade 2 is severeinflammation and inflammation less than this is grade 1.Clinical Consequences of Acute Chorioamnionitis and the Fetal Inflammatory ResponseSyndrome The pathogenesis of acute chorioamnionitis is likely different in term and pretermgestations. In term gestations there is a strong relationship between the presence of rupturedmembranes and the duration of membrane rupture, and the likelihood of developing acutechorioamnionitis. In contrast, in many preterm gestations, it appears that chorioamnionitisprecedes and, in fact causes premature membrane rupture and frequently preterm labor. In thissituation, low virulence organisms such as Ureaplasma and Mycoplasma ascend into uterinetissues, perhaps very early in pregnancy, and eventually extend from decidua to chorion toamnion and eventually into the amniotic fluid. Uterine contractions can be induced byinflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor produced as a result of theinflammatory response.10, 13, 14 The inflammatory response also releases other factors such asmetalloproteases that degrade the extracellular matrix of the membranes and remodel cervicalcollagen leading to premature cervical ripening and membrane rupture.15 3
  163. 163. In the past, it was thought that the adverse outcomes experienced by many infants withacute chorioamnionitis were largely the result of the associated preterm labor, preterm deliveryand prematurity. We have now come to understand that acute chorioamnionitis leads to a fetalreaction pattern known as the fetal inflammatory response syndrome (FIRS) and that thisreaction pattern is important in the pathogenesis of many of the adverse outcomes these infantsexperience.16 The FIRS is defined by systemic inflammation and elevated levels of fetalinflammatory cytokine IL-6.17 FIRS correlates with a variety of adverse clinical outcomesincluding respiratory distress syndrome, neonatal sepsis, pneumonia, bronchopulmonarydysplasia, intraventricular hemorrhage, perventricular leukomalacia and necrotizingenterocolitis.16 The morphologic correlates of this fetal systemic inflammatory response arefunisitis and chorionic vasculitis. Inflammation of the umbilical artery is better correlated withelevated IL-6 levels and adverse outcomes than inflammation of the umbilical vein.18, 19 Fetalvascular inflammation with associated thrombosis is even more strongly correlated with poorprognosis.20 One of the most devastating long term complications associated with chorioamnionitis iscerebral palsy. Eastman and DeLeon noted in 1955 that infants born to mothers with fever havea seven-fold increased risk of cerebral palsy.21 Others have noted a relationship betweenhistologic acute chorioamnionitis and cerebral palsy, particularly among preterm low and verylow birth weight infants.22-25 There is experimental evidence linking infection to white matterlesions.26 Evidence that the FIRS is involved include the relationship between increasedamnionic fluid cytokines and fetal plasma cytokines with intraventricular hemorrhage, whitematter damage and cerebral palsy.25, 27 The morphologic correlates of the FIRS, acute funisitisand chorionic vasculitis, are also associated with increased risk of intraventricular hemorrhage,white matter damage and cerebral palsy.28-30 In fact, funisitis has been found to be a morespecific predictor of poor neurologic outcomes in newborns than IL-6 levels in cord venousblood.31 Leviton proposed several mechanisms by which inflammatory cytokines released duringintrauterine infection might cause damage to the developing brain in the form of periventricularleukomalacia. These include: 1). fetal hypotension leading to brain ischemia 2). Stimulation oftissue factor production and release which may activate hemostasis resulting in coagulationnecrosis of white matter 3). Release of platelet activating factor which acts as a membranedetergent to directly damage brain tissue and 4). TNF a directly damages oligodendrocytes anddisrupts myelinization.32 Others have noted that cytokines increase the permeability of the bloodbrain barrier allowing microbial products and cytokines themselves into the brain.33 Certaincytokines such as IL1 and TNFα activate astrocytic populations which further disrupts theprogrammed sequence of normal development.33 An individual’s response may be modified byvarious factors. For example genetic polymorphisms in the inflammatory cytokine genes appearto increase the risk for cerebral palsy.34-36 An equivalent cytokine response may have verydifferent effects in preterm infants compared to term infants. The FIRS has also been implicated in the development of bronchopulmonary dysplasia(BPD).37 Several lines of evidence support the relationship between this form of severe chroniclung disease and the FIRS, which though more common in premature infants, is not explained byprematurity and treatment of respiratory distress alone. Very low birthweight infants whodevelop BPD have an increased incidence of chorioamnionitis but less respiratory distress.37 Therisk of BPD is increased with antenatal exposure to inflammatory cytokines.38 Those preterminfants with intact membranes who had the highest IL-6, IL-8, and IL1b levels were at thegreatest risk of developing BPD even when controlled for gestational age.38, 39 In animal models,these inflammatory cytokines disrupt lung development by a variety of mechanisms including 4
  164. 164. apoptosis of lung cells, decreased proliferation of certain lung cell populations, inhibition ofmicrovascular development, and decreased expression of numerous growth.16 Administration ofan antagonist to IL-1 prior to endotoxin administration prevents many of these changes.16Hematogenous Infection Infectious agents may reach the placenta by hematogenous spread from the mother.Usually organisms that infect the placenta in this way are viruses (TORCH infections) but thispattern of spread may be seen with some bacterial infections, such as Listeria and syphilis andparasitic infections such as toxoplasmosis. The morphologic manifestation of infections thatreach the placenta by the hematogenous route is typically villitis, or inflammation of the villi.Gross Features Villitis is usually not appreciated on gross examination of the placenta. Occasionally,small foci of necrosis may be seen. Sometimes placentas with villitis are enlarged and pale(syphilis and toxoplasmosis). In some infections, particularly Listeria, abscesses may be apparenton gross examination.Microscopic features Microscopically, the hallmark of a hematogenous infection is an inflammatory infiltrate inthe villi. The inflammatory cells may be lymphocytes, histiocytes, plasma cells and,occasionally, neutrophils or a mixture of these. Rarely, villitis may be composed ofgranulomatous inflammation. Despite their location within the villi, studies have shown that thelymphocytic inflammatory cells are predominantly of maternal origin.40 There is often associatednecrosis of the villous trophoblast and prominent villous agglutination with eosinophilicfibrinoid material; however, in some cases the inflammatory cells infiltrate the villi withoutdestruction. Sometimes the majority of the inflammation is present around the villi(intervillositis). In addition to inflammation, the involved villi may show vascular destruction,stromal hemosiderin and fibrosis. Usually when the etiology is infectious, areas of activeinflammation, resolving villitis and healed villitis with prominent fibrosis are scattered in apatchy distribution throughout the placenta. Often cases with an infectious etiology haveassociated chorioamnionitis. Sometimes the villitis is localized to a particular area such as stemvilli or basal plate. This distribution does not appear to be related to the etiology.Clinical Significance The consequences of a hematogenous infection can be devastating and include suchoutcomes as stillbirth, mental retardation, learning disabilities, blindness and deafness.Therefore, it is very important for pathologists to have a high index of suspicion for infection.The morphologic features of some of the well known infectious agents can sometimes point to aparticular infectious etiology that may be confirmed with immunohistochemistry, PCR, infantand maternal serologies, or even a detailed clinical history. It is important to keep in mind,however, that in the vast majority of cases of villitis (>95%) an infectious agent will not beidentified on histologic sections, culture or ancillary techniques. These cases represent villitis ofunknown etiology or VUE (see below). While a detailed discussion of the pathology of all thevarious infectious agents that may infect the placenta and fetus is beyond the scope of thisdiscussion, I would like to examine the features of the most common infectious agent in the USto infect the infant by the hematogenous route: cytomegalovirus. 5
  165. 165. Cytomegalovirus (CMV)Gross and microscopic features The placenta may be normal, small, if the fetus is growth restricted, or enlarged and pale,if the fetus is anemic. The characteristic microscopic features of CMV villitis arelymphoplasmacytic inflammatory infiltrates, stromal hemosiderin, necrotizing vasculitis,occluded villous vessels and villous necrosis.41 In about 20% of cases the characteristiceosinophilic intranuclear and basophilic cytoplasmic inclusions can be identified in stromal,endothelial, Hofbauer or trophoblast cells. Immunohistochemistry, in situ hybridization and PCRwill detect CMV in the placenta of cases of congenital CMV infection even in cases that arenormal histologically or in which the infection is.42-44 In a study of 94 term placentas sent forexamination for reasons other than infection, that were normal histologically, 11.7% had CMVdetected by PCR; 90% of these were also positive by in situ hybdridization.45 By in situhybridization, CMV DNA localizes to the cytotrophoblast, syncytiotrophoblast, fetal capillariesand villous stromal cells.45Clinical features CMV usually infects the fetus in utero. This may occur as a result of a primary maternalinfection during pregnancy, the pattern typically seen in women of higher socioeconomic status,or after reactivation of latent viral infection, the pattern typical in women of lowersocioeconomic status.46 Usually infected women are asymptomatic. Primary maternal infection ismore likely to infect the fetus and these fetuses are more likely to be symptomatic.46 There isevidence that decidual cells or decidual macrophages may serve as a reservoir for CMV and thatreactivation from these cells is enhanced as a result of the inflammatory response to concomitantbacterial infections.47 In the United States, CMV is the most commonly identified infectious agent in cases ofvillitis where an etiology is identified. About 1% of infants are born with congenital CMVinfection.46 About 5% to10% of these will have disseminated disease with hepatosplenomegaly,jaundice, petechiae or death.46 Ninety percent of congenitally infected infants will have clinicallyunrecognized disease and about 5% to15% of these will have long-term sequelae such as mentalretardation, learning disabilities and sensorineural hearing loss.48 These figures indicate thatcongenital CMV infection represents an important public health problem. It is estimated thatnearly two billion dollars is spent annually in the U.S. on the care of symptomatic infants withcongenital CMV infection.49 Treatment of congenitally infected infants shortly after birth may decrease the severity ofneurologic damage and improve long-term outcome, therefore it is important for pathologists tohave a high level of suspicion for CMV and convey positive results immediately to thepediatrician caring for these infants.50 There are no guidelines for treating CMV that occurs inpregnancy, making the role of screening women for CMV infection unclear.49, 50Villitis of Unknown Etiology (VUE) The vast majority of cases of villitis represent villitis of unknown etiology (VUE) inwhich an infectious etiology cannot be established. VUE will be seen in about 5% to 15% ofthird trimester placentas.51 Nearly all cases occur after 32 weeks and 80% occur after 37 weekstherefore villitis earlier than 32 weeks is more likely to have an infectious etiology.51Gross and microscopic features 6
  166. 166. Placentas from most cases of VUE are normal on gross examination. Studies have shownthat the detection rate peaks at four blocks of tissue and that about 90% of cases are found withsampling of two to three blocks.52 Villitis can be graded based on the amount of placentalparenchyma affected or on the number of villi involved per focus. Redline has proposed ascheme in which the term low grade is applied to cases in which 10 or fewer villi are involvedper focus and high grade to cases with greater than 10 involved villi per focus. Focal describesthose cases with only one slide involved and multifocal those with more than one slide involved.High grade cases can be separated into those that are patchy with less than 5% of all distal villiinvolved and diffuse with more than 5% involvement.51 The vast majority of cases of VUE arefocal. In most cases the villitis is randomly distributed throughout the placenta but about 20%have an exclusive or partial basal/parabasal distribution, often with associated decidualinflammation.51 Most cases are necrotizing and the inflammatory cells are lymphocytes andhistiocytes. Plasma cells are not seen in VUE and their presence should suggest CMV or otherinfectious etiologies. VUE may be associated with vasculitis of fetal stem vessels withdownstream avascular terminal villi.Pathogenesis There are two schools of thought about the pathogenesis of VUE. One proposes that VUEis the result of an as yet unidentified infectious pathogen. Against this theory are the lack ofsymptoms in patients, the lack of seasonal variation, and failure to identify a consistent pattern ofinfection despite diligent searching with increasingly sophisticated techniques for severaldecades.51Another theory proposes that VUE is an immunologic phenomenon. This seems morelikely. The cells in foci of villitis have been demonstrated to be primarily maternal in origin andto represent T cells with a CD4/CD8 ratio of in the range of 0.1 to 0.5, and macrophages thatexhibit up regulation of class II major histocompatability complex antigens.51 The findingssuggest a delayed hypersensitivity type or T-helper-1-type response as would be expected in anallograft reaction, in this case host versus graft, between maternal and fetal tissues.51, 53 Thistheory is also in keeping with clinical features such as an increased incidence of maternalautoimmunity in women with placental VUE and the tendency for VUE to recur in some patientsin subsequent pregnancies.54 The target antigen of maternal attack is still not known.Clinical significance Most cases of VUE are focal and the fetus is unaffected. When diffuse, VUE has beensignificantly associated with intrauterine growth restriction, oligohydramnios and chronicmonitoring abnormalities including abnormal non stress tests, abnormal pulsed flow Dopplerstudies and abnormal biophysical profiles, diffuse perivillous fibrin deposition, and perinatalmortality.51, 55 The more extensive and severe the villitis, the more likely that it will be associatedwith adverse outcomes.51Circulatory Disorders Circulatory disorders of the placenta are common and are frequently clinically importantfor both the mother and the baby. It is important to keep in mind that the placenta has a dualcirculation. Maternal blood enters the intervillous space surrounding the villi through the uterinespiral arteries. The blood percolating through this intervillous space provides nutrients to thefetus. Deoxygenated fetal blood enters the placenta through the umbilical arteries which branchover the chorionic plate and continue branching into the villous tree, ending in a capillarynetwork in the terminal villi. After nutrient exchange, oxygen-rich blood climbs up the villous 7
  167. 167. tree and is taken to the fetus via the umbilical vein. Disorders of the maternal circulation giverise to one set of abnormalities and clinical problems while disorders of the fetal circulation giverise to another.InfarctGross Features Placental infarcts are common lesions seen in about 10% to 25% of placentas fromnormal term pregnancies.56, 57 Infarcts can vary in size and shape but are usually somewhattriangular with the broad edge abutting the basal plate. They are commonly found in theperipheral regions of the placenta. All infarcts are firmer than the surrounding placental tissueand are typically very well circumscribed. Recent infarcts are dark red, firm and granular. Withage they become yellow and eventually white. Occasionally, central hemorrhage with cavitationis seen.Microscopic Features In early infarction the villi are crowded together with narrowing or loss of the intervillousspace. The fetal vessels in the affected area are dilated and congested. The syncytiotrophoblastnuclei show signs of degeneration such as nuclear pyknosis and karyorrhexis. With time, thevillous stroma and syncytiotrophoblast degenerate and eventually only "ghosts" of villi remain.58The intervillous space no longer contains maternal red cells. Neutrophils and macrophages maybe seen at the periphery of a longstanding infarct but no true organization occurs, as occurs ininfarcts in other organs.Differential Diagnosis On gross examination, the differential diagnosis for infarcts includes perivillous fibrindeposition and intervillous thrombohematoma. Perivillous fibrin is firm and yellow or white,like an older infarct, but it is usually not as well circumscribed and often has areas of red villoustissue interspersed with the white fibrin. Microscopically, there is expansion of the intervillousspace and proliferation of trophoblast within the fibrin. Intervillous thrombohematomas are wellcircumscribed and firm like infarcts but they have a smooth, not granular cut surface, and areusually laminated, since they contain only blood and fibrin and lack villous tissue.Pathogenesis Like infarcts elsewhere in the body, placental infarcts are caused by an interruption of theblood supply to a portion of the placenta. It is maternal blood, percolating in the intervillousspace that supplies and nourishes the placenta. When this blood supply is cut off, the relativelywell circumscribed area of villous tissue supplied by a particular maternal vessel or group ofvessels undergoes infarction. This can occur because of vascular narrowing or occlusion of thevessel as in atherosis (preeclampsia), with or without superimposed acute thrombosis, or becausethe supplying maternal vessel is physically separated from the placenta, as in retroplacentalhematoma (placental abruption). Histologic sections of the decidua beneath an infarct maydemonstrate these pathologic changes. Often the decidua is extensively necrotic indicating thatthe involved vessel is deep, near the myometrial-decidual junction. McDermott and Gillian havepresented evidence that infarcts are also accompanied by a concomitant reduction in fetal bloodflow to the villi in the infarcted area, manifesting as increased mineralization of the trophoblastmembrane.59 8
  168. 168. Clinical Significance Extensive infarction, large infarcts (>3 cm), infarcts involving the central area of theplacenta, and infarcts in the first and second trimester are thought to be associated withsignificant underlying maternal disease and interruption in the normal uteroplacental bloodflow.58, 60 Preeclampsia represents a major risk factor for infarction. There is a strong relationshipbetween the severity of preeclampsia and the extent of infarction.61 Increased rates of placentalinfarction have also been reported in a variety of thrombophilic conditions including factor VLeiden mutation heterozygosity, prothrombin gene variants, hyperhomocyteinemia, andantiphospholipid antibodies.62-65 Extensive infarction may have serious consequences for the fetus including intrauterinefetal demise, hypoxia, and intrauterine growth retardation both at term and in preterm infants.66-67It is thought that the normal placenta can withstand the loss of as much as 15 to 20% of thevillous tissue without adversely affecting the fetus, but in conditions in which there is alreadypoor uteroplacental perfusion, such as preeclampsia, even lesser degrees of infarction may bedetrimental to the fetus. Lesions which cause a disturbance of uteroplacental circulation,including extensive infarction, in the placentas of preterm infants has been significantlyassociated with periventricular leukomalacia.68 High rates of infarction and low flow changeswere also noted in a series of stillborn infants with ischemic cerebral injury.69 However, thisassociation has not been found by all.70Massive Perivillous Fibrin Deposition Some fibrin is seen normally in most placentas and is particularly common beneath thechorionic plate, around stem villi, and above the basal plate. This type of fibrin deposition isthought to be due to local stasis and eddy currents in these areas and may actually reflect goodintraplacental blood flow, as this type of fibrin deposition is seen less commonly in placentasfrom abnormal pregnancies such as those complicated by preterm delivery and diabetes.71Gross Features Large amounts of fibrinoid material can be appreciated grossly as firm white, yellow orbrown plaques. These may be slightly granular or smooth. Often they are located in the peripheryof the placenta where they fill in the angle where the fetal membranes meet the basal plate. Muchless commonly the fibrinoid material forms thick white or grey strands that replace much of theplacental parenchyma leaving only small pockets of interspersed red villous tissue.Microscopic Features Microscopically, the terminal villi are widely separated and enmeshed in an abundantamount of eosinophilic fibrinoid material that obliterates the intervillous space. In early lesions,the syncytiotrophoblast shows signs of degeneration and eventually disappears leaving behind athickened trophoblastic basement membrane. The trophoblast show a marked degree ofproliferation and extends out into the perivillous fibrin in clusters. The villous stroma becomesprogressively more fibrotic and eventually there is obliteration of fetal vessels. In order to separate the normal amount of fibrin seen in the placenta from fibrindeposition that is likely to be clinically significant, Katzman and Genest have proposed somequantitative definitions.72 They define transmural massive perivillous fibrin deposition (MFD)as perivillous fibrinoid material that extends from the maternal to the fetal surface encasinggreater than or equal to 50% of the villi on at least one slide.72 Borderline MFD is transmural ornearly transmural and encases 25% to 50% of the villi on at least one slide.72 9
  169. 169. Differential Diagnosis The differential diagnostic considerations include maternal floor infarct, placental infarct,fibrin associated with chronic villitis and fibrinoid deposition after fetal death with retainedplacenta. Maternal floor infarct overlaps significantly with massive perivillous fibrin depositionand these entities are likely part of the same spectrum. Maternal floor infarct has similarmicroscopic features, shares similar clinical features and often is associated with massiveperivillous fibrin deposition. By definition, maternal floor infarct involves the villi, and often thedecidua, near the maternal surface and should involve a large amount of the maternal floor.Infarcts may be difficult to distinguish from perivillous fibrin deposition grossly as both may beyellow or white and firm. Infarcts tend to be more sharply circumscribed and abut the maternalsurface of the placenta. Microscopically, infarcts show collapse rather than expansion of theintervillous space, no trophoblast hyperplasia, and necrosis rather than fibrosis of the villousstroma. Fibrin deposition associated with chronic villitis can be distinguished from massiveperivillous fibrin deposition because it usually has associated areas of active villitis. The clinicalhistory of intrauterine fetal demise will point to the correct diagnosis of villous fibrosis on thisbasis. This is usually diffuse.Clinical Features Extensive perivillous fibrin deposition, while quite rare, involving less than 1% ofexamined placentas, is an important lesion for pathologists to recognize because it is associatedwith a high rate of adverse fetal outcome.72 What is likely to be clinically significant is thelocation of the perivillous fibrin and the number of villi that are ischemic as a result of it. Redlineand Patterson observed that perivillous fibrin that entrapped more than 20% of the terminal villiin the central basal portion of the placenta, which is thought to be the major nutrient-exchangingregion of the placenta, was significantly associated with intrauterine fetal growth retardation andlow placental weight.55 Although not as carefully localized or quantitated, a study by Fuke et alalso found a significant relationship between massive perivillous fibrin deposition andintrauterine growth retardation.73 These workers observed that the combination of intrauterinegrowth retardation and MFD could recur in subsequent pregnancies and could be prevented withanticoagulant therapy.73 Katzman and Genest reported a 31% incidence of IUGR in cases withMFD.72 About 14% of their cases had recurrent MFD or maternal floor infarct in subsequent 2ndor 3rd trimester placentas and 50% had increased perivillous fibrin or maternal floor infarct in 1sttrimester placentas.72 Kumazaki et al found a significant relationship between lesions whichcause a disturbance of uteroplacental circulation, including MFD, in the placentas of preterminfants and periventricular leukomalacia.68Retroplacental Hematoma/Placental AbruptionGross Features A retroplacental hematoma is a blood clot that lies between the basal plate of the placentaand the uterine wall and indents the overlying placental parenchyma. It may be large, coveringmost of the maternal surface, or small, best visualized on serial sections. A recent retroplacentalhematoma will be soft and red and will easily separate from the placenta. An indentation, adisrupted maternal surface, a large amount of clot in the specimen container, the deliveringphysicians impression of the placenta when delivered or at the time of Cesarean section may allpoint to the diagnosis in the absence of adherent clot on the placenta. Older hematomas are firm,brown and adherent. Sometimes the placental parenchyma overlying retroplacental hematomas isinfarcted, particularly if the hematoma is not very recent. Occasionally a hematoma may rupture 10
  170. 170. and dissect into adjacent villous tissue. In a very recent retroplacental bleed there may be no clotadherent to the placenta and no deformation of the maternal surface.Microscopic Features Early hematomas are composed of red cells while older ones contain varying amounts offibrin, degenerated red cells, hemosiderin-laden macrophages and neutrophils. The overlyingdecidua may be necrotic. Villous stromal hemorrhage and villous edema may be seen adjacent toretroplacental hematoma, particularly when the hematoma occurs in the second trimester.74Retroplacental hematomas, particularly large hematomas and those that are not recent, may beassociated with infarction.Clinical Features Retroplacental hematomas are common, occurring in as many as 4.5% of placentas.75 Themost consistently identified risk factors for retroplacental bleeding include preeclampsia with athree fold increased risk, abdominal trauma, cigarette smoking, both maternal and of the malepartner, a previous history of abruption, extremes of maternal age, multiparity, poor nutrition,low socioeconomic status, acute chorioamnionitis, severe fetal growth retardation, maternalthrombophilic conditions, and cocaine abuse.75-79 Retroplacental hematoma is related to, but not synonymous with, the clinical syndrome ofplacental abruption (abruptio placentae). The features of this clinical syndrome include vaginalbleeding, increased uterine tone, uterine tenderness, diminished fetal heart tones and if severe,maternal hypovolemia, consumptive coagulopathy, and fetal death.80 The incidence of abruptionis about 11.5/1000 deliveries.76 It is associated with a 20% to 40% fetal mortality rate andaccounts for 10% of all stillbirths and 6% of all maternal deaths in developed countries.76 Therate of placental abruption in the United States has increased in the last few decades.76 Retroplacental hematoma and placental abruption share many of the same risk factors anda clear distinction between them has not always been made in the literature. There is poorconcordance between the clinical and pathologic criteria for abruption/retroplacentalhematoma.81 In only about a third of the cases with a clinical diagnosis of abruption can aretroplacental hematoma be demonstrated on placental examination, probably because of therapidity of development and subsequent delivery.82 Conversely, in only about a third of cases inwhich the pathologist identifies a retroplacental hematoma will the clinical syndrome ofplacental abruption have been diagnosed.82 These probably represent smaller, clinicallyinsignificant hematomas. The clinical significance of retroplacental hematoma is largely dependant on the size andthe amount of placenta that is infarcted, keeping in mind that in a background of chronicuteroplacental ischemia, such as with preeclampsia, the functional reserve of the placenta will beexceeded with lesser degrees of infarction. Gross lesions with disturbance of uteroplacentalcirculation, including massive retroplacental hematoma has been associated with periventricularleukomalacia in preterm infants.68 Extensive retroplacental hematoma with infarction may alsocause fetal death.83Pathogenesis The pathogenesis of retroplacental hematoma is not well understood. It is thought that incases of preeclampsia the associated atherosis may weaken the vessels increasing the likelihoodof rupture. Cigarette smoking and cocaine abuse may also damage vessels walls.Hyperhomocysteinemia and hereditary deficiencies in various factors involved in normalcoagulation may also lead to repeated thrombosis and possibly vascular damage. 11
  171. 171. Fetal Thrombotic Vasculopathy Occlusion of vessels in the fetal circulatory system can involve vessels at any level -large umbilical cord vessels, their branches on the chorionic plate, or smaller capillary fetalvessels within the chorionic villi. During gestation there is one continuous circulation betweenthe fetus and the placenta. The term fetal vascular obstruction used in this discussion refers tothrombi, or related downstream lesions, in the fetal portion of the placental circulation. It hasbecome increasingly clear that thrombotic lesions in the placental part of this fetal circulationmay be associated with, and could serve as a marker for, thrombotic or embolic lesions in thecirculation of the fetus itself, sometimes with devastating consequences for the fetus. For thisreason, it is important for pathologists to become familiar with the gross and microscopicappearance of fetal vascular obstructive lesions in the placenta.Gross and Microscopic Features Areas of avascular terminal villi downstream from vascular obstruction in the placenta orcord form well circumscribed, pale areas with the same spongy consistency as the surroundingplacental tissue. The affected villi are sharply demarcated, both grossly and microscopically,from adjacent normal villi. Microscopically, the villi are avascular and the villous stromaexhibits an increased amount of bland eosinophilic stromal hyaline fibrosis. The villi arenormally spaced within the intervillous space. Redline et al. recently proposed diagnostic terminology with precise, reproducibledefinitions for lesions of fetal vascular obstruction.20 The term uniformly avascular villi is usedwhen three or more foci of two terminal villi show avascularity. Another form of fetal vascularobstruction that manifests in distal villi has been termed villous stromal-vascular karyorrhexis.This can be diagnosed when three or more foci of two or more terminal villi show karyorrhexisof fetal cells either endothelium, stromal cells or blood cell elements.20 Often the villi arehypovascular with degenerating capillaries and fragmented red cells. This lesion has been termedhemorrhagic endovasculitis in the past. It is now thought to represent part of the spectrum ofchanges in fetal vascular obstruction as both patterns may coexist, both share the samepredisposing risk factors and both carry similar implications for the fetus.20 All of these villouschanges are considered severe when there are more than two foci that average 15 or more villiper focus per slide.20 It is recommended that the term fetal thrombotic vasculopathy be reservedfor those cases in which the villous vascular obstruction is this extensive. Massive thrombosismay involve 25 to 50% of the placental parenchyma.84 A thrombosed large vessel upstream from avascular terminal villi or villous stromal-vascular karyorrhexis can only be demonstrated in about a third of cases when extensiveavascular villi are present.85 The distal villous changes may be more sensitive and reproducibleevidence of fetal thrombotic vasculopathy than thrombotic lesions in large vessels.86Differential Diagnosis The differential diagnosis on gross examination is primarily with an infarct. Both aninfarct and an area of avascular terminal villi will be well circumscribed and all but very recentinfarcts will be pale. In contrast to areas of avascular villi which have the same spongyconsistency as the surrounding placental tissue, infarcts are always more firm than surroundingtissue. Microscopically, infarcts will show crowded villi with collapse of the intervillous space,whereas the villi in fetal vascular obstruction will be normally spaced. The villi in infarcts 12
  172. 172. exhibit ischemic necrosis whereas those in fetal vascular obstruction show dense, eosinophilicstromal fibrosis. Another differential diagnostic consideration, especially on microscopic examination, iswith the villous changes associated with intrauterine fetal demise. The microscopic changes maybe very similar to fetal vascular obstruction, but with intrauterine fetal demise, the process isgeneralized involving all villi and all vessels of a similar size to the same degree, in contrast tothe sharply demarcated areas of avascularity in fetal vascular obstruction. A third process in the differential diagnosis is villitis of unknown etiology with stemvillitis and avascular villi.20 In this condition, the placenta will show areas of active and healedvillitis with villitis involving the stem villi, including the vessels which show obliteration anddownstream avascular villi. This diagnosis should only be made in the setting of active villitis.Pathogenesis Thrombotic vascular obstruction in the fetal circulation may have several mechanisms,including a hypercoagulable state, vascular damage and stasis.85 Fetal coagulation factorabnormalities or hereditary thrombophilias in the fetus alone probably explain very few of thesecases but may provide a substrate that when combined with other factors can tip the balancetowards thrombosis.87, 88 There is an association between fetal thrombotic vasculopathy and avariety of cord abnormalities including velamentous cord insertion, excessive cord twisting,nuchal cord, other encirclements, and very long cords.85 These cord abnormalities promotevascular stasis and the development of clot which may be propagated with downstream effects orembolize downstream or into the circulation of the fetus itself. There is also an associationbetween fetal vascular obstruction and chorioamnionitis. The mediators of the inflammatoryprocess trigger the coagulation cascade at several points. The incidence of thrombosis in theplacental part of the fetal circulation is also increased in the placentas of diabetic mothers forreasons that are not well understood.89Clinical Features Very extensive avascular villi, involving 40 to 60% of the placental tissue, may causesudden intrauterine or intrapartum fetal death due to massive placental dysfunction.90 Fetalthrombotic vasculopathy as defined above, is associated with cerebral palsy, perinatal liverdisease, fetal and neonatal thromboembolic disease and discordant growth in twins.85 Fetal vascular obstructive lesions in fetal circulation of the placenta may be associatedwith thrombotic lesions in the fetus itself or with fetal conditions such as cerebral palsy that mayhave thrombosis as part of its pathogenesis. Redline and Pappin, using avascular villi as amarker of this process, found that cases with extensive areas of avascular villi were significantlyassociated with fetal growth retardation, oligohydramnios in the absence of membrane ruptureand acute and chronic monitoring abnormalities.86 In a subset of this group that was over 34weeks, did not have malformations and did not have other major placental pathology, thepresence of very large areas of avascular villi, diffuse platelet aggregates or intravascular fibrinstrands was highly associated with major thrombotic events in the fetus.86 In a study of term,singleton infants with neonatal encephalopathy, McDonald et al found that fetal thromboticvasculopathy, as well as funisitis and accelerated villous maturation were all independently andsignificantly associated with neonatal encephalopathy.91 Kraus has described a high rate ofdownstream avascular villi and thrombi in fetal placental vessels in a selected group of infantswith cerebral palsy referred for the purpose of litigation.92 Redline et al, studying a similarpopulation, also found extensive avascular villi in about 18% of term cases with long-termneurologic impairment.93 Potentially obstructing umbilical cord abnormalities were much more 13
  173. 173. likely in infants with fetal thrombotic vasculopathy. In a study of 84 consecutive perinatalautopsies, Kraus found fetal vascular obstructive lesions in the placentas of 16 cases.94 The areasof fetal vascular obstructive lesions were extensive in the placentas of all cases and occupied 25to 40% of the placenta in four cases. In these four cases, the extensive fetal vascular obstructivelesions were the only explanation for the fetal death. Six of these cases had thrombi in fetalorgans including the brain, kidney and lungs. Eight of the mothers had an extensive work up forcoagulopathy and five had one or more coagulation abnormalities.94 These findings indicate that fetal vascular obstructive lesions in the placenta, particularlyif extensive, may be a reliable indicator of the potential for thrombi in the circulation of the fetusor newborn and may explain adverse perinatal outcomes and some perinatal deaths. It should beclear that the process of thrombosis occurs well before labor and delivery. Prospective studieswill be needed to determine the predictive value of fetal vascular obstructive lesions for variousadverse fetal outcomes such as neurologic impairment. Further studies are also needed todetermine the clinically significant amount of avascular villi, the appropriate work up for thisfinding, and what role, if any, there is for treatment in subsequent pregnancies.References:1. Driscoll SG. Pathology and the developing fetus. Pediatr Clin North Am. 1965;12:493.2. Wu X, Faye-Petersen OM, Steinkampf JL, Richardson TJ, Reilly SD. The impact of placental examination in the autopsy of the structurally normal stillborn. Mod Pathol 2009; 22(supplement 1): 10A poster 33.3. Heazell AEP, Martindale EA. Can post-mortem examination of the placenta help determine the cause of stillbirth? J Obstet Gynaecol 2009; 29(3): 225-228.4. Lambird PA. Resource allocation and cost of quality. Arch Pathol Lab Med 1990:114:1168- 1172.5. Kraus FT. Perinatal pathology, the placenta, and litigation. Human Pathol 2003; 34(6):517- 520.6. Mueller-Heubach E,.Rubinstein DN, Schwarz SS. Histologic chorioamnionitis and preterm delivery in different patient populations. Obstet Gynecol 1990;75:622-626.7. Naeye RL, Blanc WL. Relation of poverty and race to antenatal infection. N Engl J Med 1965; 283:555-560.8. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental Pathology. Atlas of Nontumor Pathology, American Registry of Pathology. Washington, DC. 2004, p. 78.9. Cooperman NR, Kasim M, Rajashekaraiah KR. Clinical significance of amniotic fluid, amniotic membranes, and endometrial biopsy cultures at the time of cesarean section. Am J Obstet Gynecol 1980; 137:536-542.10. Goldenberg RL, Hauth JC, Andrew WW. Intrauterine infection and preterm delivery. N Engl J Med 2000; 342:1500-1507.11. Gersell DJ, Kraus FT. Diseases of the Placenta. In: Ed. Robert J. Kurman. Blaustein’s Pathology of the Female Genital Tract, 5th Edition. Springer-Verlag, New York, 2002, p. 1199.12. Redline RW, Faye-Petersen O, Heller D, Qureshi R, Savell V, Vogler C, and the Society for Pediatric Pathology, Perinatal Section, Amniotic Fluid Infection Nosology Committee. Pediatr Dev Pathol. 2003; 6:435-448.13. Gomez R, Ghezzi F. Romero R, Munoz H, Tolosa JE, Rojas I. Premature labor and intra- amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 1995; 22:281-342. 14
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