placental potpourri: the pernicious, picayune, and...

Placental Potpourri: the

Pernicious, Picayune, and

Pervasive

Phyllis C. Huettner, M.D.

Washington University Medical Center

St. Louis

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

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

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.

Etiology of Stillbirth

Cause 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

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

Pathogenesis of Intrauterine Infection

• Ascending - typically bacterial → chorioamnionitis

• Transplacental - viral, protozoal, bacterial → villitis

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

Intrauterine Infection

Common

• See in 10% to 20% of term deliveries

• Up to two-thirds of preterm deliveries

Important associations

• Preterm delivery

• Neonatal sepsis

• Cerebral palsy

• Chronic lung disease

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

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

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

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.

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

Cerebral Palsy and FIR Syndrome

Role 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

Cerebral Palsy and FIR Syndrome

Possible 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

Proposed Pathogenesis

Bacterial

infection↑ cytokines

Permeability of

blood brain barrier

passage of bacteria,

cytokines

Cell destruction,

abnormal proliferation

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

Fetal Inflammatory Response

Chorioamnionitis 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

Ascending Infection

Better standardization of diagnostic terminology is needed

• Degree, location of inflammation related to outcome

• Stratification of prognosis

• Stratification of treatment

• Facilitate studies between institutions

Redline RW et al. have proposed a scheme for staging and grading the maternal and fetal response

Pediatr Develop Pathol 6:435-448, 2003

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

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


Stage 1- Acute Chorionitis

Neutrophils in membrane trophoblast


Stage 1- Early Acute Chorionitis

Neutrophils in fibrin beneath chorionic plate


Stage 2


• Acute chorioamnionitis

• Definition

• Neutrophils in chorionic plate or membranous chorionic connective tissue and/or amnion



Stage 2 – Acute Chorioamnionitis

Scattered neutrophils in chorion and amnion


Stage 3


• Necrotizing chorioamnionitis

• Definition

• Neutrophil karyorrhexis, amnion necrosis and/or amniotic basement membrane thickening/hypereosinophilia



Stage 3

Neutrophils with karyorrhexis

Maternal Inflammatory Response Stage

3 – Necrotizing Chorioamnionitis

Amniotic epithelial necrosis; thickened, eosinophilic basement membrane


Grade 1 – Mild-Moderate


• Mild or moderate

• Definition

• Individual or small clusters of neutrophils



Grade 1- Mild-Moderate

Scattered neutrophils


Grade 2 - Severe


• Severe acute chorioamnionitis or with

subchorionic microabscesses

• Definition

• Confluent neutrophils between chorion

and decidua; > or equal to 3 isolated foci

or continuous bandRedline RW et al. Pediatr Dev Pathol 6:435-448, 2003


Grade 2 - Severe

Confluent band of neutrophils


Stage 1


• With chorionic vasculitis or umbilical

phlebitis

• Definition

• Intramural neutrophils in chorionic vessels

and/or umbilical vein



Stage 1 - Phlebitis

Neutrophils in smooth muscle of umbilical vein wall


Stage 1 - Chorionic Vasculitis

Neutrophils in wall of large chorionic vessels on fetal plate


Stage 2


• 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


Stage 2 - Arteritis

Neutrophils in smooth muscle of wall of umbilical artery


Stage 3


• With necrotizing funisitis or with concentric

umbilical perivasculitis

• Definition

• Neutrophils +/- debris in concentric bands-

rings-halos around one or more umbilical

vesselsRedline RW et al. Pediatr Dev Pathol 6:435-448, 2003


Stage 3 - Necrotizing Funisitis

Neutrophils and debris ring the umbilical vessels


Stage 3 - Necrotizing Funisitis


Grade 1 - Mild-Moderate


• Mild – moderate

• Definition

• Scattered neutrophils



Grade 2 - Severe


• 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

Chorionic Vasculitis with Thrombi

Ascending Infection

• Rarely see causative organisms in sections

• Exceptions:

• Group B beta-hemolytic streptococcus

• Fusobacterium

• Candida

Group B beta-hemolytic strep

Bacterial colonies with no inflammatory response

Hematogenous Infection

• Virus – CMV, Rubella, Varicella, Parvovirus, HSV

• Bacteria – Treponema pallidum, Listeria

• Parasites – Toxoplasma gondii

• Unknown – > 95%, ? abnormal immune reaction

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

Villitis

Type acute, chronic, granulomatous

Composition lymphs, histiocytes, plasma

cells, neutrophils

Necrosis necrotizing, non-necrotizing

Distribution focal, diffuse, basal

Severity very mild, mild, mod, severe

Villitis

Collections of abnormally agglutinated villi

Villitis

Necrotizing villitis

Villitis

Non necrotizing villitis

Villitis

Granulomatous villitis

Villitis

Basal villitis

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

Infectious Villitis

Confirm with

• Special stains

• Molecular techniques

• Maternal/infant serology

• Detailed clinical history

Congenital CMV Infection

0.2% 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

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


• Recent evidence that decidual cells or

decidual macrophages are reservoir for

CMV

• Reactivation is more likely after

inflammatory response to bacterial

infections


• Usually infected women are asymptomatic

• No guidelines for treating CMV during

pregnancy

• Role of screening pregnant women for

CMV is unclear

CMV Placentitis

• Lymphoplasmacytic villitis

• Necrotizing vasculitis

• Vessel occlusion

• Stromal hemosiderin

• Viral inclusions – 20%

CMV

Necrotizing villitis

CMV

Numerous plasma cells – important clue to CMV

CMV

Vascular sclerosis

CMV

Stromal sclerosis

CMV

Stromal hemosiderin and sclerosis

CMV

Inclusions in stromal cells

CMV

Inclusions in endothelial cells

CMV

Eosinophilic nuclear and basophilic cytoplasmic inclusions

CMV Placentitis

Immunohistochemistry, in situ

hybridization and PCR will detect CMV in

cases of congential infection

• When placenta is normal

• When infection is sub clinical

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


• Most cases are necrotizing

• Most are lymphohistiocytic

• Most cases are focal

• May be associated with vasculitis of fetal

stem vessels

• Avascular downstream terminal villi


Theories of pathogenesis

• Result of unidentified pathogen

• Immunologic phenomenon


• Inflammatory cells

• Maternal

• T helper cells

• Ia antigen-bearing macrophages

• incidence in women with autoimmune

disorders

• Tendency to recur


Clinical 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


Which cases to work up for infection?

• Suspicious maternal history

• Suspicious clinical findings in neonate

• Not mild

• Pattern besides lymphohistiocytic

Villitis

Basic work up

• IHC for CMV

• IHC for toxoplasma

• Warthin-Starry or IHC for spirochetes

• Gram stain if lots of neutrophils or abscesses

Important Circulatory Disorders

• Abnormal fibrin deposition

• Massive perivillous fibrin

• Maternal floor infarct

• Infarction

• Retroplacental hematoma

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%)

Normal Fibrin Deposition

Normal Fibrin Deposition

Above basal plate

Fibrin Deposition

Gross

• Firm, tan, yellow or white

• Fuzzy border

• Interspersed red villous tissue

• Not as well circumscribed as infarct

• Often in periphery

Perivillous Fibrin Deposition

Massive Perivillous Fibrin

Deposition


Not as well circumscribed as infarcts


Expansion of intervillous space


Cytotrophoblast proliferation


Differential diagnosis

• Infarct

• Also firm, white if not recent

• Well circumscribed

• Collapse, not expansion, of intervillous space

• No trophoblast proliferation


• Involves the basal villi and decidua


Clinically significant if:

• Entraps 20% of terminal villi

• Central-basal location

Clinical significance

• Intrauterine growth retardation

• Low placental weight

• Fetal death in utero

Redline RW, Patterson P. Arch Pathol Lab Med 1994; 18:698


Katzman 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


Katzman 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


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 vascular diseases, coagulopathy

• Aspirin, dipyridamole prevents perivillous fibrin and SGA

Fuke Y et al Gyn Obstet Invest 38:5-9, 1994

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



• 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%

Subchorionic Fibrin Deposition

Not clinically significant

Subchorionic Fibrin

Layers of blood and fibrin beneath chorionic plate

Subchorionic Fibrin

• Not clinically significant

• May reflect damage to fetal plate by fetal

movements

• Less common in infants with disorders that

restrict movement

Infarcts

Firm, well circumscribed, often pale

Infarcts

Well circumscribed

Usually abut the maternal surface

May be red, tan, or white

Extensive Infarction

Infarcts

Loss of intervillous space

Infarcts

Ghost villi with thick trophoblast membranes

Infarcts

Differential diagnosis

• Perivillous fibrin deposition

• Intervillous thrombohematoma

• Also well circumscribes, white if not recent

• Often laminated

• Contain no villi, only blood

Intervillous Thrombohematoma

Well circumscribed, laminated, red if early, white if older

Infarcts

Pathogenesis

• Decreased blood supply to group of villi

• Vessel narrowing (hypertension)

• Atherosis (preeclampsia)

• Physical separation (retroplacental

hematoma)

Normal Vascular Remodeling

• Replacement of smooth muscle and elastic by

fibrinoid material

• Vessels become flaccid, low resistance tubes

• Increases blood flow 10-fold

Decidual Vasculopathy

Two forms

• Lack of physiologic transformation

• Acute atherosis

• Both are associated with

• Preeclampsia

• IUGR

• Small for gestational age infants

• Collagen vascular disease

Implantation Site Vessels

Prominent endovascular trophoblast

Acute Atherosis

Prominent fibrinoid necrosis, very narrow lumens

Acute Atherosis

Infarcts

Normal

• See in 10-25% of term placentas

• Small, located in periphery

Clinically significant if:

• Multiple, central

• Large (>3 cm)

• Preterm

Infarcts

Clinical significance for fetus

• Hypoxia

• Intrauterine growth restriction

• Periventricular leukomalacia (preterm)

• Intrauterine fetal demise

Infarcts

Clinical significance for the mother

• Extensive implies significant maternal disease

• Preeclampsia - severity related to extent of

infarction

• Maternal thrombophilic conditions

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

Low Flow Changes

Small, thin, unbranched villi

Increased syncytial knots

Retroplacental Hematoma

Densely adherent clot indents surface, underlying infarction


Blood clot indents placenta, underlying infarction


Villous stromal hemorrhage may be seen beneath, especially

in the 2nd trimester


Incidence ~ 5%


• Preeclampsia

• Heavy smoking, cocaine

• Trauma

• Acute chorioamnionitis

• Maternal thrombophilic conditions

• Prior abruption


Postulated pathogenesis

• Atherosis (preeclampsia) – weakened

vessels

• Cocaine, cigarettes – spasm

• Thrombophilia - thrombosis

Placental Abruption

A clinical syndrome

• Vaginal bleeding

• Increased uterine tone

• Uterine tenderness

• Decreased fetal heart tones

• Maternal hypotension, DIC


• 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)

Marginal Hematoma

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

Circulatory Disorders

Disorders of maternal circulation

• Perivillous fibrin deposition


• Infarct

• Intervillous thrombohematoma

• Retroplacental hematoma

• Marginal hematoma

Fetal Vascular Obstruction

May occur at any level

• Umbilical cord vessels

• Chorionic plate vessels

• Small vessels in villi


• 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


Well circumscribed, pale but not firm


Well circumscribed area of pale, fibrotic villi


Thrombosis of larger vessels, downstream avascular terminal villi


Sclerosis 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


Pathogenesis

• Stasis

• Hypercoagulability

• Vascular damage


Clinical Associations

• Maternal diabetes

• Maternal thrombophilia (but

not fetal thrombophilia)

• Chorioamnionitis

Fetal Thrombotic Vasculopathy

Unanswered questions:

• Incidence from prospective data

• Predictive value

• Clinically significant amount

• Appropriate work up

• Role of treatment in next pregnancy

• Pathogenesis

Maternal Thrombophilic Conditions

• Antithrombin III deficiency

• Protein C deficiency

• Protein S deficiency

• Factor V mutation (Leiden)

• Prothrombin 20120A

• MTHFR C677T- hyperhomocysteinemia

Maternal Thrombophilic Conditions


• Controversial

• Preeclampsia

• Late pregnancy loss

• Intrauterine growth restriction

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


• Cord abnormalities

• Long cord

• Velamentous insertion

• Excess twisting

• Nuchal cord


Consequences for fetus if extensive:

• Fetal growth restriction

• Chronic monitoring abnormalities

• Stillbirth

• Neurologic impairment

• Hepatic failure

• Vascular compromise involving kidneys, GI


84 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


125 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


• 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

1

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 in

structure to supply the needs of the rapidly growing fetus for the crucial first 40 weeks of

development. During life in utero, the circulation of the fetus and the circulation of the placenta

form one continuous unit. Examination of the placenta, which is easily accessible, may provide

valuable information about events during gestation affecting the fetus.

I’ll begin by discussing the importance of placental examination. The remainder of the

talk will focus on those placental abnormalities that are clinically important for the infant, the

mother 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 have

made important new discoveries in terms of pathophysiology with important implications for

fetal and maternal health.

Why Examine the Placenta? Placental examination can be very rewarding in determining the cause of an intrauterine

or 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% of

cases. The cause of death was a placental or cord abnormality in almost a third of cases and in

16% of cases was a contributing factor.1 In more recent studies of structurally normal stillborn

infants, examination of the placenta significantly increased the percentage of cases in which a

cause of death could be determined.2,3

Examination of the placenta may help explain the etiology of a preterm delivery, a

congenital anomaly or other adverse neonatal outcome. Obstetrical management of subsequent

pregnancies 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 placental

examination. Information that may help explain the outcome of a neurologically impaired child

and be useful in the legal defense of these cases may be obtained from placental examination.4,5

In a general way, examination of placentas has provided and will continue to provide insights

into the pathophysiology of various important maternal and neonatal disorders potentially

improving diagnosis and therapy for these conditions.

The information obtained from placental examination may be immediately useful in the

care of a sick neonate and may be very helpful to parents and pediatricians caring for impaired

children later in life. In order to maximize the value of placental examination, pathologists and

informaticians need to develop better ways to ensure that the results of the placental examination

reach and are understood by the neonatologists and general pediatricians caring for children and

communicating with parents, in addition to the obstetrician who sent the placenta for

examination. This is challenging because mothers and babies frequently have different last

names 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 neurologic

deficits including cerebral palsy, mental retardation, blindness, deafness and learning disabilities.

2

There are two broad patterns of placental infection - ascending infections and

hematogenous infections, each associated with a characteristic type and pattern of inflammation

within the placenta as well as characteristic organisms. In general, ascending infections, the most

common pattern, are caused by bacteria that pass from the vagina or cervix into the uterus and

cause acute inflammation of the fetal membranes (acute chorioamnionitis) and umbilical cord

(acute funisitis). In hematogenous infections, a less common pattern, organisms are passed

hematogenously from the mother to the placenta and fetus. This is the pattern typically seen in

TORCH infections and may be caused by viral organisms (CMV, Rubella and others), protozoa

(Toxoplasma gondii) and some bacteria (Listeria monocytogenes, Treponema pallidum). The

placenta usually shows chronic inflammation of the villi (villitis) but may also have a component

of chorioamnionitis. Infants may also be infected with bacterial or viral agents after passing

through an infected birth canal, a common form of infection with HIV and HSV, but this form of

transmission does not involve the placenta.

Ascending Infection and Acute Chorioamnionitis

Chorioamnionitis is the most common form of inflammation in the placenta. It is found in

the placentas of about 10 to 20% of term deliveries.6

Chorioamnionitis is strongly correlated with

prematurity; about two-thirds of infants born before 24 weeks gestation will have evidence of

chorioamnionitis.6

The prevalence is also increased in women of low socioeconomic status and

African-American women.7

A distinction needs to be made between clinical and histologic

chorioamnionitis. Clinical chorioamnionitis is characterized by some combination of fever,

elevated maternal white count, premature rupture of membranes and foul vaginal discharge. The

gold standard for diagnosis, however, remains histologic chorioamnionitis with the presence of

neutrophils in the chorion and/or amnion. There is very poor correlation between the clinical

diagnosis of chorioamnionitis and histologic chorioamnionitis; 72% of cases with histologic

chorioamnionitis don’t meet the clinical diagnosis and 9% of cases with clinical chorioamnionitis

don’t have histologic chorioamnionitis.8

It is now clear that infection causes acute chorioamnionitis. The implicated organisms

may be aerobic or anaerobic and are typically normal flora or gastrointestinal contaminants of

the vagina and cervix. Factors such as rupture of membranes, cervical dilatation, and the

presence of an IUD or cerclage may facilitate spread to the amnionic cavity. There is a strong

relationship between rupture of membranes and chorioamnionitis, the risk of chorioamnionitis

increasing with increasing duration of membrane rupture.9 This relationship is particularly strong

at term. In other cases, chorioamnionitis may precede rupture of membranes actually causing

premature rupture of membranes and/or preterm birth.10

The organisms seen in preterm labor

with intact membranes are typically low virulence vaginal and enteric organisms.11

There is

increasing evidence that some of these organisms may ascend from the lower GYN tract weeks

or even months before acute chorioamnionitis develops and reside in the uterine tissues including

the decidua due to decreased local immunity secondary to pregnancy.10

Pathologic Features and Grading of Acute Chorioamnionitis

The fetal membranes in chorioamnionitis are typically normal on gross examination but

in cases of severe or longstanding infection, may be discolored, friable and foul smelling. Both

the 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 maternal

blood vessel, and accumulate in the fibrin layer beneath the chorion. From here they pass

through the connective tissue of the chorion and eventually into the amnion of the fetal plate of

the placenta in response to chemotactic factors generated by bacteria in the amnionic fluid.

3

Maternal neutrophils also migrate from maternal blood vessels in the decidua, through the

decidua, 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) and

may also migrate from the umbilical cord vessels, typically first from the umbilical vein then by

the artery. Neutrophils are first seen in the clear spaces between smooth muscle cells but

eventually migrate completely through the vessel wall to involve the surrounding Wharton’s

jelly. If severe, rings or arcs of degenerating neutrophils will surround the umbilical vessels.

Typically, causative organisms are not seen on histologic sections. Important exceptions

include Group B streptococcus, Candida and fusobacterium. When organisms are identified, it is

important to consider post delivery overgrowth in unfixed specimens, especially those without

inflammation.

Because of the increasingly clear relationship between acute chorioamnionitis and

adverse fetal outcomes, including long-term sequelae such as cerebral palsy and chronic lung

disease (see below), standardized grading and staging of chorioamnionitis and funisitis may

facilitate study and potentially even treatment of this common condition. While many schemes

for grading and staging chorioamnionitis have been proposed, none is completely reproducible or

prospectively validated for correlation with outcomes. The scheme proposed by Redline and his

colleagues in the Society for Pediatric Pathology has good reproducibility and can serve as a start

toward standardization.12

In this system both the stage (localization) and grade (severity) are

determined for the maternal inflammatory response (chorioamnionitis) and the fetal

inflammatory response (chorionic vasculitis and funisitis). Maternal inflammatory response

(MIR) stage 1 represents acute subchorionitis and/or acute chorionitis in which neutrophils are

seen in the subchorionic fibrin layer or at the junction of decidua and chorion in the free

membranes. MIR stage 2 represents acute chorioamnionitis in which neutrophils extend into the

amnionic connective tissue or epithelium. MIR stage 3 represents necrotizing chorioamnionitis

characterized by karyorrhexis of neutrophils, hypereosinophilia of the amnionic basement

membrane and at least focal necrosis of the amnionic epithelium. MIR grade two is

characterized by chorionic microabscesses composed of 10 to 20 neutrophils; less inflammation

than this represents MIR grade 1. Fetal inflammatory response (FIR) stage 1 represents

inflammation around the large vessels of the chorionic plate (chorionic vasculitis) or the

umbilical vein. FIR stage 2 represents umbilical arteritis with or without chorionic vasculitis or

umbilical vein inflammation and FIR stage 3 represents necrotizing funisitis. Grade 2 is severe

inflammation and inflammation less than this is grade 1.

Clinical Consequences of Acute Chorioamnionitis and the Fetal Inflammatory Response

Syndrome

The pathogenesis of acute chorioamnionitis is likely different in term and preterm

gestations. In term gestations there is a strong relationship between the presence of ruptured

membranes and the duration of membrane rupture, and the likelihood of developing acute

chorioamnionitis. In contrast, in many preterm gestations, it appears that chorioamnionitis

precedes and, in fact causes premature membrane rupture and frequently preterm labor. In this

situation, low virulence organisms such as Ureaplasma and Mycoplasma ascend into uterine

tissues, perhaps very early in pregnancy, and eventually extend from decidua to chorion to

amnion and eventually into the amniotic fluid. Uterine contractions can be induced by

inflammatory cytokines such as IL-1, IL-6 and tumor necrosis factor produced as a result of the

inflammatory response.10, 13, 14

The inflammatory response also releases other factors such as

metalloproteases that degrade the extracellular matrix of the membranes and remodel cervical

collagen leading to premature cervical ripening and membrane rupture.15

4

In the past, it was thought that the adverse outcomes experienced by many infants with

acute chorioamnionitis were largely the result of the associated preterm labor, preterm delivery

and prematurity. We have now come to understand that acute chorioamnionitis leads to a fetal

reaction pattern known as the fetal inflammatory response syndrome (FIRS) and that this

reaction pattern is important in the pathogenesis of many of the adverse outcomes these infants

experience.16

The FIRS is defined by systemic inflammation and elevated levels of fetal

inflammatory cytokine IL-6.17

FIRS correlates with a variety of adverse clinical outcomes

including respiratory distress syndrome, neonatal sepsis, pneumonia, bronchopulmonary

dysplasia, intraventricular hemorrhage, perventricular leukomalacia and necrotizing

enterocolitis.16

The morphologic correlates of this fetal systemic inflammatory response are

funisitis and chorionic vasculitis. Inflammation of the umbilical artery is better correlated with

elevated IL-6 levels and adverse outcomes than inflammation of the umbilical vein.18, 19

Fetal

vascular inflammation with associated thrombosis is even more strongly correlated with poor

prognosis.20

One of the most devastating long term complications associated with chorioamnionitis is

cerebral palsy. Eastman and DeLeon noted in 1955 that infants born to mothers with fever have

a seven-fold increased risk of cerebral palsy.21

Others have noted a relationship between

histologic acute chorioamnionitis and cerebral palsy, particularly among preterm low and very

low birth weight infants.22-25

There is experimental evidence linking infection to white matter

lesions.26

Evidence that the FIRS is involved include the relationship between increased

amnionic fluid cytokines and fetal plasma cytokines with intraventricular hemorrhage, white

matter damage and cerebral palsy.25, 27

The morphologic correlates of the FIRS, acute funisitis

and 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 more

specific predictor of poor neurologic outcomes in newborns than IL-6 levels in cord venous

blood.31

Leviton proposed several mechanisms by which inflammatory cytokines released during

intrauterine infection might cause damage to the developing brain in the form of periventricular

leukomalacia. These include: 1). fetal hypotension leading to brain ischemia 2). Stimulation of

tissue factor production and release which may activate hemostasis resulting in coagulation

necrosis of white matter 3). Release of platelet activating factor which acts as a membrane

detergent to directly damage brain tissue and 4). TNF a directly damages oligodendrocytes and

disrupts myelinization.32

Others have noted that cytokines increase the permeability of the blood

brain barrier allowing microbial products and cytokines themselves into the brain.33

Certain

cytokines such as IL1 and TNFα activate astrocytic populations which further disrupts the

programmed sequence of normal development.33

An individual’s response may be modified by

various factors. For example genetic polymorphisms in the inflammatory cytokine genes appear

to increase the risk for cerebral palsy.34-36

An equivalent cytokine response may have very

different 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 chronic

lung disease and the FIRS, which though more common in premature infants, is not explained by

prematurity and treatment of respiratory distress alone. Very low birthweight infants who

develop BPD have an increased incidence of chorioamnionitis but less respiratory distress.37

The

risk of BPD is increased with antenatal exposure to inflammatory cytokines.38

Those preterm

infants with intact membranes who had the highest IL-6, IL-8, and IL1b levels were at the

greatest 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

5

apoptosis of lung cells, decreased proliferation of certain lung cell populations, inhibition of

microvascular development, and decreased expression of numerous growth.16

Administration of

an antagonist to IL-1 prior to endotoxin administration prevents many of these changes.16

Hematogenous 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 this

pattern of spread may be seen with some bacterial infections, such as Listeria and syphilis and

parasitic infections such as toxoplasmosis. The morphologic manifestation of infections that

reach 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 apparent

on gross examination.

Microscopic features

Microscopically, the hallmark of a hematogenous infection is an inflammatory infiltrate in

the villi. The inflammatory cells may be lymphocytes, histiocytes, plasma cells and,

occasionally, neutrophils or a mixture of these. Rarely, villitis may be composed of

granulomatous inflammation. Despite their location within the villi, studies have shown that the

lymphocytic inflammatory cells are predominantly of maternal origin.40

There is often associated

necrosis of the villous trophoblast and prominent villous agglutination with eosinophilic

fibrinoid material; however, in some cases the inflammatory cells infiltrate the villi without

destruction. 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 active

inflammation, resolving villitis and healed villitis with prominent fibrosis are scattered in a

patchy distribution throughout the placenta. Often cases with an infectious etiology have

associated chorioamnionitis. Sometimes the villitis is localized to a particular area such as stem

villi 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 such

outcomes 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 a

particular infectious etiology that may be confirmed with immunohistochemistry, PCR, infant

and 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 be

identified on histologic sections, culture or ancillary techniques. These cases represent villitis of

unknown etiology or VUE (see below). While a detailed discussion of the pathology of all the

various infectious agents that may infect the placenta and fetus is beyond the scope of this

discussion, I would like to examine the features of the most common infectious agent in the US

to infect the infant by the hematogenous route: cytomegalovirus.

6

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 are

lymphoplasmacytic inflammatory infiltrates, stromal hemosiderin, necrotizing vasculitis,

occluded villous vessels and villous necrosis.41

In about 20% of cases the characteristic

eosinophilic intranuclear and basophilic cytoplasmic inclusions can be identified in stromal,

endothelial, Hofbauer or trophoblast cells. Immunohistochemistry, in situ hybridization and PCR

will detect CMV in the placenta of cases of congenital CMV infection even in cases that are

normal histologically or in which the infection is.42-44

In a study of 94 term placentas sent for

examination for reasons other than infection, that were normal histologically, 11.7% had CMV

detected by PCR; 90% of these were also positive by in situ hybdridization.45

By in situ

hybridization, CMV DNA localizes to the cytotrophoblast, syncytiotrophoblast, fetal capillaries

and villous stromal cells.45

Clinical features

CMV usually infects the fetus in utero. This may occur as a result of a primary maternal

infection 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 lower

socioeconomic status.46

Usually infected women are asymptomatic. Primary maternal infection is

more likely to infect the fetus and these fetuses are more likely to be symptomatic.46

There is

evidence that decidual cells or decidual macrophages may serve as a reservoir for CMV and that

reactivation from these cells is enhanced as a result of the inflammatory response to concomitant

bacterial infections.47

In the United States, CMV is the most commonly identified infectious agent in cases of

villitis where an etiology is identified. About 1% of infants are born with congenital CMV

infection.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 clinically

unrecognized disease and about 5% to15% of these will have long-term sequelae such as mental

retardation, learning disabilities and sensorineural hearing loss.48

These figures indicate that

congenital CMV infection represents an important public health problem. It is estimated that

nearly two billion dollars is spent annually in the U.S. on the care of symptomatic infants with

congenital CMV infection.49

Treatment of congenitally infected infants shortly after birth may decrease the severity of

neurologic damage and improve long-term outcome, therefore it is important for pathologists to

have a high level of suspicion for CMV and convey positive results immediately to the

pediatrician caring for these infants.50

There are no guidelines for treating CMV that occurs in

pregnancy, making the role of screening women for CMV infection unclear.49, 50

Villitis of Unknown Etiology (VUE)

The vast majority of cases of villitis represent villitis of unknown etiology (VUE) in

which an infectious etiology cannot be established. VUE will be seen in about 5% to 15% of

third trimester placentas.51

Nearly all cases occur after 32 weeks and 80% occur after 37 weeks

therefore villitis earlier than 32 weeks is more likely to have an infectious etiology.51

Gross and microscopic features

7

Placentas from most cases of VUE are normal on gross examination. Studies have shown

that the detection rate peaks at four blocks of tissue and that about 90% of cases are found with

sampling of two to three blocks.52

Villitis can be graded based on the amount of placental

parenchyma affected or on the number of villi involved per focus. Redline has proposed a

scheme in which the term low grade is applied to cases in which 10 or fewer villi are involved

per focus and high grade to cases with greater than 10 involved villi per focus. Focal describes

those 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 villi

involved and diffuse with more than 5% involvement.51

The vast majority of cases of VUE are

focal. 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 decidual

inflammation.51

Most cases are necrotizing and the inflammatory cells are lymphocytes and

histiocytes. Plasma cells are not seen in VUE and their presence should suggest CMV or other

infectious etiologies. VUE may be associated with vasculitis of fetal stem vessels with

downstream avascular terminal villi.

Pathogenesis

There are two schools of thought about the pathogenesis of VUE. One proposes that VUE

is the result of an as yet unidentified infectious pathogen. Against this theory are the lack of

symptoms in patients, the lack of seasonal variation, and failure to identify a consistent pattern of

infection despite diligent searching with increasingly sophisticated techniques for several

decades.51

Another theory proposes that VUE is an immunologic phenomenon. This seems more

likely. The cells in foci of villitis have been demonstrated to be primarily maternal in origin and

to represent T cells with a CD4/CD8 ratio of in the range of 0.1 to 0.5, and macrophages that

exhibit up regulation of class II major histocompatability complex antigens.51

The findings

suggest a delayed hypersensitivity type or T-helper-1-type response as would be expected in an

allograft reaction, in this case host versus graft, between maternal and fetal tissues.51, 53

This

theory is also in keeping with clinical features such as an increased incidence of maternal

autoimmunity in women with placental VUE and the tendency for VUE to recur in some patients

in 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 been

significantly associated with intrauterine growth restriction, oligohydramnios and chronic

monitoring abnormalities including abnormal non stress tests, abnormal pulsed flow Doppler

studies and abnormal biophysical profiles, diffuse perivillous fibrin deposition, and perinatal

mortality.51, 55

The more extensive and severe the villitis, the more likely that it will be associated

with adverse outcomes.51

Circulatory Disorders Circulatory disorders of the placenta are common and are frequently clinically important

for both the mother and the baby. It is important to keep in mind that the placenta has a dual

circulation. Maternal blood enters the intervillous space surrounding the villi through the uterine

spiral arteries. The blood percolating through this intervillous space provides nutrients to the

fetus. Deoxygenated fetal blood enters the placenta through the umbilical arteries which branch

over the chorionic plate and continue branching into the villous tree, ending in a capillary

network in the terminal villi. After nutrient exchange, oxygen-rich blood climbs up the villous

8

tree and is taken to the fetus via the umbilical vein. Disorders of the maternal circulation give

rise to one set of abnormalities and clinical problems while disorders of the fetal circulation give

rise to another.

Infarct

Gross Features

Placental infarcts are common lesions seen in about 10% to 25% of placentas from

normal term pregnancies.56, 57

Infarcts can vary in size and shape but are usually somewhat

triangular with the broad edge abutting the basal plate. They are commonly found in the

peripheral regions of the placenta. All infarcts are firmer than the surrounding placental tissue

and are typically very well circumscribed. Recent infarcts are dark red, firm and granular. With

age they become yellow and eventually white. Occasionally, central hemorrhage with cavitation

is seen.

Microscopic Features

In early infarction the villi are crowded together with narrowing or loss of the intervillous

space. The fetal vessels in the affected area are dilated and congested. The syncytiotrophoblast

nuclei show signs of degeneration such as nuclear pyknosis and karyorrhexis. With time, the

villous stroma and syncytiotrophoblast degenerate and eventually only "ghosts" of villi remain.58

The intervillous space no longer contains maternal red cells. Neutrophils and macrophages may

be seen at the periphery of a longstanding infarct but no true organization occurs, as occurs in

infarcts in other organs.

Differential Diagnosis

On gross examination, the differential diagnosis for infarcts includes perivillous fibrin

deposition 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 villous

tissue interspersed with the white fibrin. Microscopically, there is expansion of the intervillous

space and proliferation of trophoblast within the fibrin. Intervillous thrombohematomas are well

circumscribed and firm like infarcts but they have a smooth, not granular cut surface, and are

usually 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 the

blood supply to a portion of the placenta. It is maternal blood, percolating in the intervillous

space that supplies and nourishes the placenta. When this blood supply is cut off, the relatively

well circumscribed area of villous tissue supplied by a particular maternal vessel or group of

vessels undergoes infarction. This can occur because of vascular narrowing or occlusion of the

vessel as in atherosis (preeclampsia), with or without superimposed acute thrombosis, or because

the supplying maternal vessel is physically separated from the placenta, as in retroplacental

hematoma (placental abruption). Histologic sections of the decidua beneath an infarct may

demonstrate these pathologic changes. Often the decidua is extensively necrotic indicating that

the involved vessel is deep, near the myometrial-decidual junction. McDermott and Gillian have

presented evidence that infarcts are also accompanied by a concomitant reduction in fetal blood

flow to the villi in the infarcted area, manifesting as increased mineralization of the trophoblast

membrane.59

9

Clinical Significance

Extensive infarction, large infarcts (>3 cm), infarcts involving the central area of the

placenta, and infarcts in the first and second trimester are thought to be associated with

significant underlying maternal disease and interruption in the normal uteroplacental blood

flow.58, 60

Preeclampsia represents a major risk factor for infarction. There is a strong relationship

between the severity of preeclampsia and the extent of infarction.61

Increased rates of placental

infarction have also been reported in a variety of thrombophilic conditions including factor V

Leiden mutation heterozygosity, prothrombin gene variants, hyperhomocyteinemia, and

antiphospholipid antibodies.62-65

Extensive infarction may have serious consequences for the fetus including intrauterine

fetal demise, hypoxia, and intrauterine growth retardation both at term and in preterm infants.66-67

It is thought that the normal placenta can withstand the loss of as much as 15 to 20% of the

villous tissue without adversely affecting the fetus, but in conditions in which there is already

poor uteroplacental perfusion, such as preeclampsia, even lesser degrees of infarction may be

detrimental to the fetus. Lesions which cause a disturbance of uteroplacental circulation,

including extensive infarction, in the placentas of preterm infants has been significantly

associated with periventricular leukomalacia.68

High rates of infarction and low flow changes

were also noted in a series of stillborn infants with ischemic cerebral injury.69

However, this

association has not been found by all.70

Massive Perivillous Fibrin Deposition

Some fibrin is seen normally in most placentas and is particularly common beneath the

chorionic plate, around stem villi, and above the basal plate. This type of fibrin deposition is

thought to be due to local stasis and eddy currents in these areas and may actually reflect good

intraplacental blood flow, as this type of fibrin deposition is seen less commonly in placentas

from abnormal pregnancies such as those complicated by preterm delivery and diabetes.71

Gross Features

Large amounts of fibrinoid material can be appreciated grossly as firm white, yellow or

brown plaques. These may be slightly granular or smooth. Often they are located in the periphery

of the placenta where they fill in the angle where the fetal membranes meet the basal plate. Much

less commonly the fibrinoid material forms thick white or grey strands that replace much of the

placental parenchyma leaving only small pockets of interspersed red villous tissue.


Microscopically, the terminal villi are widely separated and enmeshed in an abundant

amount of eosinophilic fibrinoid material that obliterates the intervillous space. In early lesions,

the syncytiotrophoblast shows signs of degeneration and eventually disappears leaving behind a

thickened trophoblastic basement membrane. The trophoblast show a marked degree of

proliferation and extends out into the perivillous fibrin in clusters. The villous stroma becomes

progressively more fibrotic and eventually there is obliteration of fetal vessels.

In order to separate the normal amount of fibrin seen in the placenta from fibrin

deposition that is likely to be clinically significant, Katzman and Genest have proposed some

quantitative definitions.72

They define transmural massive perivillous fibrin deposition (MFD)

as perivillous fibrinoid material that extends from the maternal to the fetal surface encasing

greater than or equal to 50% of the villi on at least one slide.72

Borderline MFD is transmural or

nearly transmural and encases 25% to 50% of the villi on at least one slide.72

10


The differential diagnostic considerations include maternal floor infarct, placental infarct,

fibrin associated with chronic villitis and fibrinoid deposition after fetal death with retained

placenta. Maternal floor infarct overlaps significantly with massive perivillous fibrin deposition

and these entities are likely part of the same spectrum. Maternal floor infarct has similar

microscopic features, shares similar clinical features and often is associated with massive

perivillous fibrin deposition. By definition, maternal floor infarct involves the villi, and often the

decidua, 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 be

yellow or white and firm. Infarcts tend to be more sharply circumscribed and abut the maternal

surface of the placenta. Microscopically, infarcts show collapse rather than expansion of the

intervillous space, no trophoblast hyperplasia, and necrosis rather than fibrosis of the villous

stroma. Fibrin deposition associated with chronic villitis can be distinguished from massive

perivillous fibrin deposition because it usually has associated areas of active villitis. The clinical

history of intrauterine fetal demise will point to the correct diagnosis of villous fibrosis on this

basis. This is usually diffuse.

Clinical Features

Extensive perivillous fibrin deposition, while quite rare, involving less than 1% of

examined placentas, is an important lesion for pathologists to recognize because it is associated

with a high rate of adverse fetal outcome.72

What is likely to be clinically significant is the

location of the perivillous fibrin and the number of villi that are ischemic as a result of it. Redline

and Patterson observed that perivillous fibrin that entrapped more than 20% of the terminal villi

in the central basal portion of the placenta, which is thought to be the major nutrient-exchanging

region of the placenta, was significantly associated with intrauterine fetal growth retardation and

low placental weight.55

Although not as carefully localized or quantitated, a study by Fuke et al

also found a significant relationship between massive perivillous fibrin deposition and

intrauterine growth retardation.73

These workers observed that the combination of intrauterine

growth retardation and MFD could recur in subsequent pregnancies and could be prevented with

anticoagulant therapy.73

Katzman and Genest reported a 31% incidence of IUGR in cases with

MFD.72

About 14% of their cases had recurrent MFD or maternal floor infarct in subsequent 2nd

or 3rd

trimester placentas and 50% had increased perivillous fibrin or maternal floor infarct in 1st

trimester placentas.72

Kumazaki et al found a significant relationship between lesions which

cause a disturbance of uteroplacental circulation, including MFD, in the placentas of preterm

infants and periventricular leukomalacia.68

Retroplacental Hematoma/Placental Abruption

Gross Features

A retroplacental hematoma is a blood clot that lies between the basal plate of the placenta

and the uterine wall and indents the overlying placental parenchyma. It may be large, covering

most of the maternal surface, or small, best visualized on serial sections. A recent retroplacental

hematoma will be soft and red and will easily separate from the placenta. An indentation, a

disrupted maternal surface, a large amount of clot in the specimen container, the delivering

physician's impression of the placenta when delivered or at the time of Cesarean section may all

point 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 is

infarcted, particularly if the hematoma is not very recent. Occasionally a hematoma may rupture

11

and dissect into adjacent villous tissue. In a very recent retroplacental bleed there may be no clot

adherent to the placenta and no deformation of the maternal surface.


Early hematomas are composed of red cells while older ones contain varying amounts of

fibrin, degenerated red cells, hemosiderin-laden macrophages and neutrophils. The overlying

decidua may be necrotic. Villous stromal hemorrhage and villous edema may be seen adjacent to

retroplacental hematoma, particularly when the hematoma occurs in the second trimester.74

Retroplacental hematomas, particularly large hematomas and those that are not recent, may be

associated with infarction.

Clinical Features

Retroplacental hematomas are common, occurring in as many as 4.5% of placentas.75

The

most consistently identified risk factors for retroplacental bleeding include preeclampsia with a

three fold increased risk, abdominal trauma, cigarette smoking, both maternal and of the male

partner, a previous history of abruption, extremes of maternal age, multiparity, poor nutrition,

low socioeconomic status, acute chorioamnionitis, severe fetal growth retardation, maternal

thrombophilic conditions, and cocaine abuse.75-79

Retroplacental hematoma is related to, but not synonymous with, the clinical syndrome of

placental abruption (abruptio placentae). The features of this clinical syndrome include vaginal

bleeding, increased uterine tone, uterine tenderness, diminished fetal heart tones and if severe,

maternal hypovolemia, consumptive coagulopathy, and fetal death.80

The incidence of abruption

is about 11.5/1000 deliveries.76

It is associated with a 20% to 40% fetal mortality rate and

accounts for 10% of all stillbirths and 6% of all maternal deaths in developed countries.76

The

rate 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 and

a clear distinction between them has not always been made in the literature. There is poor

concordance between the clinical and pathologic criteria for abruption/retroplacental

hematoma.81

In only about a third of the cases with a clinical diagnosis of abruption can a

retroplacental hematoma be demonstrated on placental examination, probably because of the

rapidity of development and subsequent delivery.82

Conversely, in only about a third of cases in

which the pathologist identifies a retroplacental hematoma will the clinical syndrome of

placental abruption have been diagnosed.82

These probably represent smaller, clinically

insignificant hematomas.

The clinical significance of retroplacental hematoma is largely dependant on the size and

the amount of placenta that is infarcted, keeping in mind that in a background of chronic

uteroplacental ischemia, such as with preeclampsia, the functional reserve of the placenta will be

exceeded with lesser degrees of infarction. Gross lesions with disturbance of uteroplacental

circulation, including massive retroplacental hematoma has been associated with periventricular

leukomalacia in preterm infants.68

Extensive retroplacental hematoma with infarction may also

cause fetal death.83

Pathogenesis

The pathogenesis of retroplacental hematoma is not well understood. It is thought that in

cases of preeclampsia the associated atherosis may weaken the vessels increasing the likelihood

of rupture. Cigarette smoking and cocaine abuse may also damage vessels walls.

Hyperhomocysteinemia and hereditary deficiencies in various factors involved in normal

coagulation may also lead to repeated thrombosis and possibly vascular damage.

12

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 fetal

vessels within the chorionic villi. During gestation there is one continuous circulation between

the fetus and the placenta. The term fetal vascular obstruction used in this discussion refers to

thrombi, or related downstream lesions, in the fetal portion of the placental circulation. It has

become increasingly clear that thrombotic lesions in the placental part of this fetal circulation

may be associated with, and could serve as a marker for, thrombotic or embolic lesions in the

circulation of the fetus itself, sometimes with devastating consequences for the fetus. For this

reason, it is important for pathologists to become familiar with the gross and microscopic

appearance of fetal vascular obstructive lesions in the placenta.

Gross and Microscopic Features

Areas of avascular terminal villi downstream from vascular obstruction in the placenta or

cord form well circumscribed, pale areas with the same spongy consistency as the surrounding

placental tissue. The affected villi are sharply demarcated, both grossly and microscopically,

from adjacent normal villi. Microscopically, the villi are avascular and the villous stroma

exhibits an increased amount of bland eosinophilic stromal hyaline fibrosis. The villi are

normally spaced within the intervillous space.

Redline et al. recently proposed diagnostic terminology with precise, reproducible

definitions for lesions of fetal vascular obstruction.20

The term uniformly avascular villi is used

when three or more foci of two terminal villi show avascularity. Another form of fetal vascular

obstruction 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 karyorrhexis

of fetal cells either endothelium, stromal cells or blood cell elements.20

Often the villi are

hypovascular with degenerating capillaries and fragmented red cells. This lesion has been termed

hemorrhagic endovasculitis in the past. It is now thought to represent part of the spectrum of

changes in fetal vascular obstruction as both patterns may coexist, both share the same

predisposing risk factors and both carry similar implications for the fetus.20

All of these villous

changes are considered severe when there are more than two foci that average 15 or more villi

per focus per slide.20

It is recommended that the term fetal thrombotic vasculopathy be reserved

for those cases in which the villous vascular obstruction is this extensive. Massive thrombosis

may 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 extensive

avascular villi are present.85

The distal villous changes may be more sensitive and reproducible

evidence of fetal thrombotic vasculopathy than thrombotic lesions in large vessels.86


The differential diagnosis on gross examination is primarily with an infarct. Both an

infarct and an area of avascular terminal villi will be well circumscribed and all but very recent

infarcts will be pale. In contrast to areas of avascular villi which have the same spongy

consistency as the surrounding placental tissue, infarcts are always more firm than surrounding

tissue. 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

13

exhibit ischemic necrosis whereas those in fetal vascular obstruction show dense, eosinophilic

stromal fibrosis.

Another differential diagnostic consideration, especially on microscopic examination, is

with the villous changes associated with intrauterine fetal demise. The microscopic changes may

be very similar to fetal vascular obstruction, but with intrauterine fetal demise, the process is

generalized involving all villi and all vessels of a similar size to the same degree, in contrast to

the sharply demarcated areas of avascularity in fetal vascular obstruction.

A third process in the differential diagnosis is villitis of unknown etiology with stem

villitis and avascular villi.20

In this condition, the placenta will show areas of active and healed

villitis with villitis involving the stem villi, including the vessels which show obliteration and

downstream 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 factor

abnormalities or hereditary thrombophilias in the fetus alone probably explain very few of these

cases but may provide a substrate that when combined with other factors can tip the balance

towards thrombosis.87, 88

There is an association between fetal thrombotic vasculopathy and a

variety of cord abnormalities including velamentous cord insertion, excessive cord twisting,

nuchal cord, other encirclements, and very long cords.85

These cord abnormalities promote

vascular stasis and the development of clot which may be propagated with downstream effects or

embolize downstream or into the circulation of the fetus itself. There is also an association

between fetal vascular obstruction and chorioamnionitis. The mediators of the inflammatory

process trigger the coagulation cascade at several points. The incidence of thrombosis in the

placental part of the fetal circulation is also increased in the placentas of diabetic mothers for

reasons that are not well understood.89

Clinical Features

Very extensive avascular villi, involving 40 to 60% of the placental tissue, may cause

sudden intrauterine or intrapartum fetal death due to massive placental dysfunction.90

Fetal

thrombotic vasculopathy as defined above, is associated with cerebral palsy, perinatal liver

disease, fetal and neonatal thromboembolic disease and discordant growth in twins.85

Fetal vascular obstructive lesions in fetal circulation of the placenta may be associated

with thrombotic lesions in the fetus itself or with fetal conditions such as cerebral palsy that may

have thrombosis as part of its pathogenesis. Redline and Pappin, using avascular villi as a

marker of this process, found that cases with extensive areas of avascular villi were significantly

associated with fetal growth retardation, oligohydramnios in the absence of membrane rupture

and acute and chronic monitoring abnormalities.86

In a subset of this group that was over 34

weeks, did not have malformations and did not have other major placental pathology, the

presence of very large areas of avascular villi, diffuse platelet aggregates or intravascular fibrin

strands 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 thrombotic

vasculopathy, as well as funisitis and accelerated villous maturation were all independently and

significantly associated with neonatal encephalopathy.91

Kraus has described a high rate of

downstream avascular villi and thrombi in fetal placental vessels in a selected group of infants

with cerebral palsy referred for the purpose of litigation.92

Redline et al, studying a similar

population, also found extensive avascular villi in about 18% of term cases with long-term

neurologic impairment.93

Potentially obstructing umbilical cord abnormalities were much more

14

likely in infants with fetal thrombotic vasculopathy. In a study of 84 consecutive perinatal

autopsies, Kraus found fetal vascular obstructive lesions in the placentas of 16 cases.94

The areas

of fetal vascular obstructive lesions were extensive in the placentas of all cases and occupied 25

to 40% of the placenta in four cases. In these four cases, the extensive fetal vascular obstructive

lesions were the only explanation for the fetal death. Six of these cases had thrombi in fetal

organs including the brain, kidney and lungs. Eight of the mothers had an extensive work up for

coagulopathy and five had one or more coagulation abnormalities.94

These findings indicate that fetal vascular obstructive lesions in the placenta, particularly

if extensive, may be a reliable indicator of the potential for thrombi in the circulation of the fetus

or newborn and may explain adverse perinatal outcomes and some perinatal deaths. It should be

clear that the process of thrombosis occurs well before labor and delivery. Prospective studies

will be needed to determine the predictive value of fetal vascular obstructive lesions for various

adverse fetal outcomes such as neurologic impairment. Further studies are also needed to

determine the clinically significant amount of avascular villi, the appropriate work up for this

finding, and what role, if any, there is for treatment in subsequent pregnancies.

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placental potpourri: the pernicious, picayune, and...

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