Placental Pathology

Phyllis C. Huettner, M.D.

Washington University St. Louis
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
 Value of Placental Examination
• Immediately useful to neonatologists caring
for sick infant
• Useful to pediatricians and parents later in
infancy or childhood
• Reports usually go to obstetrician not
pediatrician
 1997 CAP Practice Guideline
All placentas be examined in delivery room
• Cord length, number of vessels, dimension,
weight, integrity of maternal surface and
membranes
Triaged for complete exam if they meet certain
maternal, fetal or placental criteria
• Obstetric history, gestational age, mode of
delivery, birth weight, sex, Apgar scores,
maternal and fetal complications in pregnancy,
labor and delivery, indications for exam
 How well are CAP guidelines followed?

Spencer and Khong Arch Pathol Lab Med

2003;127:205-207
• Records from 1000 deliveries over 3 months
• Less than one-third of requisitions correctly
and completely listed maternal indications
• Less than one-tenth of requisitions correctly
and completely listed neonatal indications
 How well are CAP guidelines
followed?
• 53.8% had CAP “recommended” or “other”
indications for examination
• 17.8% had placental examination
• Indications with lowest examination rates
• Meconium – 9.7%
• Maternal fever – 13.7%
• Suspected neonatal infection – 24.8%
• IUGR – 26.7%
• Maternal diabetes – 29.2%
Gross Examination
Three components
• Membranes
• Cord
• Disk
 Gross Examination
• Placental weight
• Do fresh
• Weigh after examining and removing cord,
membranes and clot
• Compare weight to standard chart
• Low weight (< 10th percentile)
• Preeclampsia, growth retardation,
maternal diseases, intrauterine infection,
trisomy
• Heavy weight (> 90th percentile)
• Anemia, maternal diabetes, infection
(syphilis, toxo), hydrops fetalis
 Gross Examination
Fetal membranes
• Completeness
• Point of rupture
• Shortest distance from end of membranes to disk
• Tells where in uterus placenta implanted
• Type of insertion
• Circummarginate
• Circumvallate
 Gross Examination
Fetal Membranes
• Color – meconium, hemosiderin
• Opacity – chorioamnionitis
• Nodules – squamous metaplasia, amnion
nodosum
• Bands – amnionic band syndrome
• Retromembranous hematoma
 Gross Examination
Umbilical cord
• Length, diameter
• Number of vessels – normal is three
• Don’t take section at insertion site
• Type of insertion
• Marginal
• Velamentous – look for lacerations, thrombi
• Take section of intramembranous vessels
 Gross Examination
Focal cord abnormalities
• Knots – photograph, loose vs. tight, describe
cord color and diameter on either side, sample
vessels on either side for thrombi
• Stricture
• Excess twisting – measure # of twists/10 cm
and compare to a standard chart
• Hematoma
• Edema
 Gross Examination
Fetal surface of placental disk
• Color – meconium, chorioamnionitis
• Bands – amnionic bands
• Nodules – squamous metaplasia,
Amnion nodosum
• Clot – subamnionic hematoma
 Gross Examination

Fetal surface of placental disk

• Chorionic vessels
• Thrombi
• Lacerations
• Calcification – old thrombi, toxoplasmosis
 Gross Examination
Placental Disk – maternal surface
• Assess completeness
• Measure in three dimensions
• Slice disk at 1 cm intervals
• Examine and palpate each slice
• Focal lesions
• Size – measure in 3 dimensions
• Location – central or peripheral
• Shape – well circumscribed, fuzzy borders
• Color - red (recent), white (older)
• Percent of placental parenchyma it occupies
 Gross Examination
Sections
• One with two sections of cord and one of
membrane roll
• Two of central placental tissue
• fetal surface
• maternal surface
• Additional sections if abnormalities
 Quality of Pathology Reports
Khong and Gordijin Ped Devel Pathol 2002;6:54-58
• Scored 218 placental reports for gross, histologic
features and commentary on findings related to
clinical history
• 33% of singleton and 41% of multiple gestations
scored < 75%
• Poorly reported features – completeness of
membranes, zygosity in twins, birth order of twins,
commentary on gross or histologic findings
 Reliability of Diagnoses
Discrepancies occur in about 40% of cases
• Nearly all represent underdiagnosis
• Most commonly underdiagnosed conditions:
• Hemorrhagic endovasculitis
• Fetal thrombotic vasculopathy
• Massive perivillous fibrin deposition
• Maternal floor infarct
• Retroplacental hematoma
• Intervillous thrombohematoma
• Acute atherosis
Normal First Trimester Villi

• stroma makes up most of area

• vessels are randomly distributed
Normal First Trimester Villi

distinct cytotrophoblastic layer

 Third Trimester Villi

• cross sectional area is mostly vessels

• vessels are located in the periphery
Implantation Site Vessels

Prominent endovascular trophoblast

Normal Membranes
 Circulatory Disorders
Disorders of the maternal circulation
• Massive perivillous fibrin deposition
• Maternal floor infarct
• Subchorionic fibrin deposition
• Infarcts
• Retroplacental hematoma
• Marginal hematoma
• Intervillous thrombohematoma
• Subamniotic hematoma
• Massive subchorial thrombosis (Breus’ mole)
 Case 1
The patient is a 25 year old G7P2042
woman at 29 and 6/7 weeks gestation. The
fetus had severe intrauterine growth
restriction and was estimated at less than the
1st percentile for weight. The placenta was
small and firm at delivery.
Massive Perivillous Fibrin
Deposition
Perivillous Fibrin Deposition

Expansion of intervillous space

Perivillous Fibrin Deposition

Cytotrophoblast proliferation
 Perivillous Fibrin
• See some fibrin in most placentas
• Grossly visible fibrin in 22%
• Underneath chorionic plate
• Around stem villi
• Just above basal plate
Normal Fibrin Deposition

•Beneath chorionic plate

•Around stem villi
Normal Fibrin Deposition

Above basal plate

 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%)
 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

Not as well circumscribed as infarcts

Perivillous Fibrin Deposition

Not well circumscribed, fuzzy borders

Perivillous Fibrin Deposition

Surrounds normal, red villous tissue

 Perivillous Fibrin Deposition
Clinically significant if:
• Entraps 20% of terminal villi
• Central-basal location
Clinical significance
• Intrauterine growth retardation
• Low placental weight
• Fetal death in utero
• Periventricular leukomalacia if preterm
 Perivillous Fibrin Deposition

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

 Perivillous Fibrin Deposition
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
Pediatr Dev Pathol 2002;5:159-164
 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
Maternal Floor Infarct
Maternal Floor Infarct
 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
 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%
Subchorionic Fibrin Deposition

Not clinically significant

Subchorionic Fibrin
 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
 Infarcts

Loss of intervillous space

 Infarcts

Ghost villi with thick trophoblast membranes

Placental Perfusion
 Infarcts
Pathogenesis
• Decreased blood supply to group of villi
• Vessel narrowing (hypertension)
• Atherosis (preeclampsia)
• Physical separation (retroplacental
hematoma)
 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

Blood clot indents placenta, underlying infarction

 Retroplacental Hematoma

Densely adherent clot indents surface, underlying infarction

Retroplacental Hematoma
 Retroplacental Hematoma

Villous stromal hemorrhage may be seen beneath, especially

in the 2nd trimester
Retroplacental Hematoma
Incidence ~ 5%
Clinical associations
• Preeclampsia
• Heavy smoking, cocaine
• Trauma
• Acute chorioamnionitis
• Maternal thrombophilic conditions
• Prior abruption
 Retroplacental Hematoma
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
 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)
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
Intervillous Thrombohematoma

Midway between fetal and maternal surfaces

Intervillous Thrombohematoma

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

Intervillous Thrombohematoma

Laminated
Pushes villi to the side
 Intervillous Thrombohematoma
• Common
• 50% of normal placentas
• 78% of placentas from complicated
pregnancies
• Small
• Mean size 1.5 cm
• Often multiple
 Intervillous Thrombohematoma
Clinical significance
• Marker of maternal fetal hemorrhage
• Lesions have maternal and fetal blood
• Fetal anemia, thrombocytopenia
• Fetal death - if large
• Maternal sensitization
 Subamniotic Hematoma

Liquid blood
Laceration of surface vessels with cord traction
 Subamnionic Hematoma

Blood dissects between amnion and chorion

 Subamniotic Hematoma
Bleeding due to laceration of surface vessels
• Traction on cord
• After delivery of baby
• Not clinically significant
• Iatrogenic laceration of surface vessels
• Amniotic fluid sampling for lung maturity
• Intrauterine transfusion
• Could be clinically significant
Massive Subchorial Thrombosis
Breus’ Mole

Red clot, 1 cm thick beneath chorion

 Massive Subchorial Thrombosis
Breus’ Mole

• Rare - 0.53/1000 examined placentas

• Intrauterine growth restriction - 40%
• High rate of stillbirth and neonatal death
 Massive Subchorial Thrombosis
Breus’ Mole
Pathogenesis
• Sudden marked stasis in intervillous space
• Rupture of large chorionic plate or stem
villous vessel
• Clot may impede blood flow through cord
vessels
 Circulatory Disorders
Disorders of the maternal circulation
• Massive perivillous fibrin deposition
• Maternal floor infarct
• Subchorionic fibrin deposition
• Infarcts
• Retroplacental hematoma
• Marginal hematoma
• Intervillous thrombohematoma
• Subamniontic hematoma
• Massive subchorial thrombosis (Breus’ mole)
Circulatory Disorders

Disorders of the fetal circulation

• Fetal vascular obstruction
• Chorangioma
• Chorangiosis
Fetal Vascular Obstruction
May occur at any level
• Umbilical cord vessels
• Chorionic plate vessels
• Small vessels in villi
 Fetal Vascular Obstruction
• Fetal circulation of placenta and of fetus
itself are connected
• Vascular obstruction in fetal circulation of
placenta may be associated with thrombotic
or embolic lesions in circulation of fetus
Fetal Vascular Obstruction

Well circumscribed, pale but not firm

Fetal Vascular Obstruction

Well circumscribed area of pale, fibrotic villi

Fetal Vascular Obstruction
 Fetal Vascular Obstruction

Thrombosis of larger vessels, downstream avascular terminal villi

Fetal Vascular Obstruction
 Fetal Vascular Obstruction

Sclerosis of vessels in higher order villi, avascular terminal villi

 Fetal Vascular Obstruction
Recently proposed terminology
• Uniformly avascular villi
Three or more foci of two or more villi are
avascular

Redline RW et al. Pediatr Dev Pathol 2004; 7:443-452

 Fetal Vascular Obstruction
Recently proposed terminology
• Villous stromal-vascular karyorrhexis
Three or more foci of two or more terminal
villi with karyorrhexis of fetal cells –
endothelium, stroma, nRBCs, or
leukocytes
• Formerly termed hemorrhagic endovasculitis

Redline RW et al. Pediatr Dev Pathol 2004; 7:443-452

Villous Stromal-Vascular Karyorrhexis

Karyorrhexis in fetal vessels, fragmented red cells

 Fetal Vascular Obstruction
Determine severity of uniformly avascular villi or
villous stromal-vascular karyorrhexis:
• Any
• Severe
More than two foci/average of 15 or more
affected villi/slide

Redline RW et al. Pediatr Dev Pathol 2004;7:443-452

 Fetal Vascular Obstruction
• Use the term fetal thrombotic vasculopathy
only when there is severe fetal vascular
obstruction
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 thrombophilia)
• Chorioamnionitis
Fetal Vascular Obstruction
• Cord abnormalities
• Long cord
• Velamentous insertion
• Excess twisting
• Nuchal cord
 Fetal Vascular Obstruction
Consequences for fetus if extensive:
• Fetal growth restriction
• Chronic monitoring abnormalities
• Stillbirth
• Neurologic impairment
• Hepatic failure
• Vascular compromise involving kidneys, GI
Fetal Thrombotic Vasculopathy
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 had coagulation abnormalities

Kraus FT, Archeen V Human Pathol 30:759, 1999

 Fetal Thrombotic Vasculopathy
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
 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
Fetal Thrombotic Vasculopathy
Unanswered questions:
• Incidence from prospective data
• Predictive value
• Clinically significant amount
• Appropriate work up
• Role of treatment
• Pathogenesis
Chorangioma
Chorangioma
 Chorangioma

Small chorangiomas in fresh placenta may be subtle

Chorangioma
Chorangioma
Chorangioma
Chorangioma
 Chorangioma

• Small - see in 1% of placentas

• Large - 1:13,000 placentas
• Usually not clinically significant
 Chorangioma
• If large or numerous may be associated with:
• Cardiomegaly, hydrops fetalis
• Polyhydramnios
• Preterm delivery
• Growth restriction
• Anemia, thrombocytopenia
• Neonatal death
• Recurrence
• Rare, usually multiple, poor fetal outcome
Chorangioma
 Chorangioma
• Probably a hamartoma rather than a
neoplasm
• Pathogenesis
• Left to right shunt causing heart failure
• Returns low oxygen blood to fetus
 Chorangiosis
Definition:
more than 10 capillaries per terminal villus
in 10 terminal villi in at least three different
areas of the placenta
Chorangiosis
 Chorangiosis
• Prevalence is about 5%
• Typically see in term gestations
• Associated pathologic findings
• Large placental size
• Delayed villous maturation
• Chronic villitis
• Ischemic lesions
 Chorangiosis
Associated clinical findings
• Congenital anomalies
• Maternal diabetes
• Maternal anemia
• Maternal smoking
• Twin gestation
• Delivery at high altitude
 Chorangiosis
Pathogenesis theories
Capillaries proliferate in response to :
• Hypoxia
• Increased pressure from venous obstruction
in cord or fetal heart
• Cytokines released from inflammatory cells
#1
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 Placenta in Maternal Diseases
• Preeclampsia
• Lupus, anti-phospholipid antibody syndrome
• Maternal thrombophilic disorders
• Diabetes

Common findings: small placenta, maternal

vascular changes, growth restricted infant
 Case 3
This 27 year old G2P1 woman was admitted
at 28 weeks gestation for severe
oligohydramnios, pregnancy-induced
hypertension and severe intrauterine growth
restriction. The infant was delivered two
weeks later because of decreased fluid
volume, lack of growth and incipient fetal
jeopardy.
 Acute Atherosis

Prominent fibrinoid necrosis, very narrow lumens

 Acute Atherosis

Fibrinoid necrosis, foamy macrophages

Acute Atherosis
Acute Atherosis
 Acute Atherosis
• Preeclampsia
• Presence related to severity
• Only see in ~ 50% with extensive sampling
• Idiopathic intrauterine growth restriction
• Small for gestational age infants
• Collagen vascular diseases
Normal Vascular Remodeling
 Normal Vascular Remodeling

• Replacement of smooth muscle and elastic by

fibrinoid material
• Vessels become flaccid, low resistance tubes
• Increases blood flow 10-fold
In preeclampsia, second wave of remodeling in intramyometrial
segments of spiral arteries doesn’t occur
Decidual Vasculopathy

Lack of physiologic transformation

Decidual Vasculopathy
 Decidual Vasculopathy
Two forms
• Lack of physiologic transformation
• Acute atherosis
• Both are associated with
• Preeclampsia
• IUGR
• Small for gestational age infants
 Low Flow Changes
Gross
• small placenta
Microscopic
• Very small villi
• Increased syncytial knots
• Prominent villous stroma
• Small fetal capillaries
• Thickened trophoblastic membrane
• Cytotrophoblast proliferation
Low Flow Changes
Low Flow Changes
 Preeclampsia
• Most common maternal disease in pregnancy
• Complicates 2% to 7% of all pregnancies
• A leading cause of perinatal and maternal
morbidity and mortality
• Definition
• HTN with proteinuria and/or generalized
edema after 20 weeks gestation
• Eclampsia is preeclampsia with seizures
 Preeclampsia
Placental findings – characteristic but not specific
• Small placenta
• Decidual vasculopathy
• Low flow changes
• Infarcts
• Retroplacental hematomas
• Intervillous thrombohematomas
• Fetal vascular obstruction
 Preeclampsia
Pregnancy-specific
• Delivery is effective treatment
Two stage theory
• Stage 1: reduced placental perfusion
• Insufficient maternal vascular remodeling
• Oxidative stress
• Release of factors that cause clinical sxs
• Stage 2: abnormal maternal vascular response
 Preeclampsia

Final common pathway

Diffuse endothelial dysfunction
• Edema
• Platelet consumption
• Renal effects – hypertension, proteinuria
• CNS effects – hyperreflexia, seizures
• Hepatic effects - ↑ LFTs, abdominal pain
 Preeclampsia
New insights in pathogenesis
• Hypoxic trophoblast secretes fms-like tyrosine
kinase 1 (s-flts-1)
• S-flts-1 binds to VEGF and PlGF anti-
angiogenic effect
• Adenovirus encoding s-flts-1 in rats causes
preeclampsia
• Injection of VEGF reverses preeclampsia in rats
• ? Theraputic role
 Preeclampsia
Retrospective data on humans with
preeclampsia:
• Increased serum s-flts-1
• Decreased active VEGF and PlGF
• Detected weeks before symptoms
• ? Role as diagnostic test
 HELLP Syndrome
hemolysis, elevated liver enzyme levels, low
platelet count
• Complicates 4% to 12% of cases with
preeclampsia
• Most occur late 2nd or early 3rd trimester
• One-third occur post partum
• Placental findings same as preeclampsia
 HELLP Syndrome
• Perinatal mortality rate is 35%
• Maternal mortality rate is 1% to 3%
• Abruption correlates with
• Fetal death
• Maternal renal failure, pulmonary edema
Acute Fatty Liver of Pregnancy
• Less common than HELLP syndrome
• Higher fetal and maternal mortality
• Clinical presentation
• Late 3rd trimester
• Nausea, vomiting, RUQ pain
• Microvesicular steatosis
• Treatment – emergent delivery
 Acute Fatty Liver of Pregnancy

Microvesicular steatosis most pronounced in zone 3

Acute Fatty Liver of Pregnancy and
HELLP
Pathogenesis
• Fetal enzyme deficiency in beta-oxidation of long
chain fatty acids
• Most common is mutation in 3 hydroxyacyl-
coenzyme A dehydrogenase gene
• Deficiency causes infant-childhood
• Hepatic encephalopathy
• Cardiomyopathy
• Peripheral neuropathy
• Skeletal myopathy
Acute Fatty Liver of Pregnancy and
HELLP
• Placenta shares fetal genotype
• Placental enzyme deficiency causes
accumulation of toxic intermediates
• How intermediates cause maternal
disease is unclear
• Two-thirds deliver prematurely
• 40% are growth restricted
 Essential Hypertension
• Little information about placental findings in
isolated essential hypertension
• Hyperplastic arteriosclerosis
• Proliferation of all vessel wall layers
• Intimal hyperplasia
• Luminal narrowing
• Most pronounced in myometrial segments
 Systemic Lupus Erythematosus

SLE associated with significantly increased

• Stillbirth
• IUGR
• Prematurity
Systemic Lupus Erythematosus
SLE alone
• Decreased placental weight
• Low flow changes
• Decidual vasculopathy
• Decidual thrombi
• Fetal vascular obstruction
• Villitis of unknown etiology
May occur in 1st trimester
Do not correlate with disease severity
Systemic Lupus Erythematosus

30% to 40% have antiphospholipid antibodies

• Autoantibodies against phospholipids
• Arterial and venous thromboembolic
events
• Thrombocytopenia
• Fetal loss
Systemic Lupus Erythematosus
SLE and antiphospholipid antibodies
• Significant increase in
• Low flow changes
• Extensive infarction
• Fetal death
 Antiphospholipid Antibodies
If + anticardiolipin and + lupus anticoagulant:
High rate of
• Decidual vasculopathy
• Decidual thrombosis
• Extensive infarction
• Fetal loss

Ogishima D et al. Pathol Int 2000; 5-:224-229

Maternal Thrombophilic Conditions

• Antithrombin III deficiency

• Protein C deficiency
• Protein S deficiency
• Factor V mutation (Leiden)
• Prothrombin 20120A
• MTHFR C677T- hyperhomocysteinemia
Maternal Thrombophilic Conditions

Clinical associations
• 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
 Diabetes
Placental findings are variable, non-specific
• Gross findings
• Sometimes normal
• Over 50% are larger, heavier than normal
• Microscopic findings
• Immature, edematous villi
• Prominent cytotrophoblast
• Irregularly thickened trophoblastic
membranes
• Fibrinoid deposits
 Diabetes

Enlarged, immature villi

Diabetes

Villous edema
 Diabetes

Prominent cytotrophoblast
 Diabetes

Thickened basement membrane

 Diabetes
Associated placental findings
• Chorangiosis
• Uniformly avascular terminal villi
• Single umbilical artery
• Increased cord diameter
 Diabetes

Placental changes do not correlate with:

• Size of infant
• Degree of glycemic control
 Diabetes
Fetal complications
• More common if type 1
• Congenital malformations
• Macrosomia
• “unexplained” fetal death
• Not related to presence or severity of
placental findings
Intrauterine Infection
Complications

• Abortion
• Stillbirth
• Malformation
• Acute infection
• Delayed sequelae
 Pathogenesis of Intrauterine
Infection

• Ascending - typically bacterial → chorioamnionitis

• Transplacental - viral, protozoal → 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
 Chorioamnionitis – Incidence
• Fox and Langley 24% 1,000 consecutive

• Salafia 4% normal term

• Hillier 67% preterm

21% term

• Russell 55% 21-28 weeks

11% 33-36 weeks
4% 37-40 weeks
 Chorioamnionitis – Organisms
• E. coli • Bacteroides fragilis
• Staphylococci • Fusobacterium sp.
• Streptococci • Listeria
• Proteus mirabilis monocytogenes
• Klebsiella • Myoplasma
• Ureaplasma • Candida albicans
Acute Chorioamnionitis

Thick, opaque, granular

May be foul-smelling
 Ascending Infection
• Maternal response – acute chorioamnionitis
• In free membranes polys emigrate from decidual
vessels through chorion and amnion
• In placenta polys emigrate from intervillous space
through chorion and amnion
• Fetal response – funisitis, chorionic vasculitis
• Polys emigrate from umbilical vessels
• Polys emigrate from chorionic vessels
 Ascending Infection
• Because of evidence that inflammation
relates to outcomes, better standardization
of diagnostic terminology is needed
• Redline RW et al. (Pediatr Dev Pathol
6:435-448, 2003) have proposed a scheme
for staging and grading the maternal and
fetal response
 Maternal Inflammatory Response
Stage 1
• Suggested diagnostic terminology
• Acute subchorionitis or acute chorionitis
• Definition
• Polys in subchorionic fibrin and/or
membrane trophoblast

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

Maternal Inflammatory Response
Stage 1- Acute Chorionitis

Polys in membrane trophoblast

Maternal Inflammatory Response
Stage 1- Acute Chorionitis

Polys in fibrin beneath chorionic plate

 Maternal Inflammatory Response
Stage 2

• Suggested diagnostic terminology

• Acute chorioamnionitis
• Definition
• Diffuse-patchy polys in fibrous chorion
and/or amnion

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

Maternal Inflammatory Response
Stage 2 – Acute Chorioamnionitis

Polys in chorion and amnion

Maternal Inflammatory Response
Stage 3
• Suggested diagnostic terminology
• Necrotizing chorioamnionitis
• Definition
• Poly karyorrhexis, amnion necrosis
and/or amniotic basement membrane
thickening/hypereosinophilia

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

Maternal Inflammatory Response
Stage 3

Polys with karyorrhexis

Maternal Inflammatory Response Stage
3 – Necrotizing Chorioamnionitis

Amniotic epithelial necrosis, thickened basement membrane

Maternal Inflammatory Response
Grade 1 – Mild-Moderate

• Suggested diagnostic terminology

• Mild or moderate
• Definition
• Not severe

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

Maternal Inflammatory Response
Grade 1- Mild-Moderate

Scattered polys
 Maternal Inflammatory Response
Grade 2 - Severe
• Suggested diagnostic terminology
• Severe acute chorioamnionitis or with
subchorionic microabscesses
• Definition
• Confluent polys between chorion and
decidua; > or equal to 3 isolated foci or
continuous band
Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
Maternal Inflammatory Response
Grade 2 - Severe

Confluent band of polys

 Fetal Inflammatory Response
Stage 1
• Suggested diagnostic terminology
• With chorionic vasculitis or umbilical
phlebitis
• Definition
• Intramural polys in chorionic vessels and/or
umbilical vein

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

Fetal Inflammatory Response
Stage 1 - Phlebitis

Polys in smooth muscle of umbilical vein wall

 Fetal Inflammatory Response
Stage 1 - Phlebitis

Polys in smooth muscle of umbilical vein wall

 Fetal Inflammatory Response
Stage 1 - Chorionic Vasculitis

Polys in wall of large chorionic vessels on fetal plate

 Fetal Inflammatory Response
Stage 1 - Chorionic Vasculitis

Side of vessel towards amniotic cavity has numerous polys

 Fetal Inflammatory Response
Stage 2
• Suggested diagnostic terminology
• With umbilical vasculitis (one or both arteries
+/- vein) or umbilical panvasculitis (all
vessels)
• Definition
• Intramural polys in umbilical artery or arteries
(+/- vein)
Redline RW et al. Pediatr Dev Pathol 6:435-448, 2003
 Fetal Inflammatory Response
Stage 2 - Arteritis

Polys in smooth muscle of wall of umbilical artery

 Fetal Inflammatory Response
Stage 2 - Arteritis

Polys in smooth muscle of wall of umbilical artery

 Fetal Inflammatory Response
Stage 3
• Suggested diagnostic terminology
• With necrotizing funisitis or with concentric
umbilical perivasculitis
• Definition
• Polys +/- debris in concentric bands-rings-
halos around one or more umbilical vessels

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

Fetal Inflammatory Response
Stage 3 - Necrotizing Funisitis

Polys and debris ring the umbilical vessels

Fetal Inflammatory Response
Stage 3 - Necrotizing Funisitis
 Fetal Inflammatory Response
Grade 1 - Mild-Moderate
• Suggested diagnostic terminology
• Mild – moderate
• Definition
• Not severe

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

 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 polys 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
Chorionic Vasculitis with Thrombi
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

Group B beta-hemolytic strep

Bacterial colonies
 Case 4
Fusobacterium Acute
Chorioamnionitis

This 25 year old G1 woman presented with

a nonviable intrauterine pregnancy at 21
weeks gestational age.
 Fusobacterium Acute
Chorioamnionitis

Necrotizing chorioamnionitis, severe (stage 3 grade 2)

 Fusobacterium Acute
Chorioamnionitis

Necrotizing chorioamnionitis, severe - stage 3, grade 2

 Fusobacterium Acute
Chorioamnionitis

Collections of long, thin, organisms

Fusobacterium Acute
Chorioamnionitis
Fusobacterium Chorioamnionitis
Fusobacterium nucleatum
• Cultured in amniotic fluid of 10 to 30%
of women in preterm labor with intact
membranes
• Cultured in amniotic fluid of 10% with
preterm labor and ruptured membranes
• Rarely cultured from lower genital tract
• May not be ascending infection
Fusobacterium Chorioamnionitis
• Ubiquitous in oral cavity
• Associated with periodontal disease
• seeding from oral plaque may colonize
the amniotic cavity
• Experimental evidence:
• Intravenous injection of fusobacterium
nucleatum colonizes and proliferates in
uterus, spreads to amniotic cavity, and
causes preterm birth
 Ascending Infection

• Rarely see causative organisms in sections

• Exceptions:
• Group B beta-hemolytic streptococcus
• Fusobacterium
• Candida
 Peripheral Funisitis

Yellow-tan plaques on cord surface

 Peripheral Funisitis - Candida

Wedge-shaped collection of polys and debris on cord surface

Peripheral Funisitis - Candida

Hyphal and yeast forms are present

Ascending Infection with Candida
• If Candida funisitis
• Usually see acute chorioamnionitis
• May see fungal forms in membranes
• Qureshi F et al Pediatr Dev Pathol 1998;1:118-24
• 32 cases of Candida funisitis
• 75% premature – mean age 31 weeks
• 16% of infants with congenital candidiasis
• Skin rash at birth
• Risk factors – IUD, cerclage
Chronic Chorioamnionitis
 Chronic Chorioamnionitis

• See mononuclear cell infiltrate

• Often associated with chronic villitis and
preterm delivery
• Rarely seen in TORCH infections
 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
 Long-term Effects of
Chorioamnionitis
• Preterm birth
• High percentage of perinatal mortality
• High percentage of long-term neurologic
morbidity
• Chorioamnionitis is an important cause of
preterm birth
• Effects of chorioamnionitis not just due
to association with prematurity
 Long-term Effects of
Chorioamnionitis
• Cerebral palsy is significantly associated
with acute chorioamnionitis
• Fetal Inflammatory Response Syndrome
• Intrauterine infection leads to cytokine
production by fetus
• 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
 Proposed Pathogenesis

Bacterial Production of
infection cytokines, TNF

↑ Permeability of Cell destruction,

blood brain barrier abnormal proliferation

↑ passage of bacteria,
cytokines
 Cerebral Palsy and
Chorioamnionitis
• Infection and inflammation do not explain the
majority of cases
• 82% with infection and histologic chorio do
not have CP
• Other possible cofactors
• Gestational age at time of infection
• Intensity of fetal response
• Genetic differences in genes that code
cytokines
 Long-term Effects of Acute
Chorioamnionitis
Acute chorioamnionitis and funisitis are
significantly associated with other types of
morbidity
• Sepsis
• Respiratory distress syndrome
• Pneumonia
• Intraventricular hemorrhage
• Broncho-pulmonary dysplasia
• Necrotizing enterocolitis
 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
• Seldom seen on gross examination
• Location does not correlate with etiology
• > 95% is villitis of unknown etiology (VUE)
• Certain features do point to particular
infections as the etiology
 Villitis
Type acute, chronic, granulomatous
Composition lymphs, histiocytes, plasma
cells, polys
Necrosis necrotizing, non-necrotizing
Distribution focal, diffuse, basal
Severity very mild, mild, mod, severe
 Villitis - Grade
• Very mild 1 or 2 foci each with few villi
• Mild up to 6 foci, each up to 20 villi
• Moderate multi foci, each up to ½ LPF
• Severe large areas, involving most
slides
 Villitis

Collections of abnormally agglutinated villi

 Villitis

Necrotizing villitis
 Villitis

Non necrotizing villitis

 Villitis

Granulomatous villitis
 Villitis

Basal villitis
 Infectious Villitis
• < 5% of all villitis
• Subtle changes suggest infection
• Confirm with
• Special stains
• Molecular techniques
• Maternal/infant serology
• Detailed clinical history
 Case 5

Fetal death in utero was detected at 21

weeks gestation in this 20 year old woman.
 CMV

Necrotizing villitis
 CMV

Numerous plasma cells – important clue to CMV

 CMV

Vascular sclerosis
 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
 CMV Placentitis

• Lymphoplasmacytic villitis
• Necrotizing vasculitis
• Vessel occlusion
• Stromal hemosiderin
• Viral inclusions – 20%
 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
 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
 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
 Congenital CMV Infection

• Usually infected women are asymptomatic

• No guidelines for treating CMV during
pregnancy
• Role of screening pregnant women for
CMV is unclear
 Herpes Simplex Virus
• Disseminated HSV infection in newborn is
severe and often lethal
• HSV usually acquired during delivery
• Rarely ascending
• See acute chorioamnionitis,lymphocytes,
plasma cells, rarely viral inclusions
• In situ or immunohistochemistry may be
helpful
Herpes Simplex Virus
 Herpes Simplex Virus
• Hematogenous infection is rare
• Necrotizing lymphocytic villitis
• Syncytiotrophoblast show decreased
expression of 3 HSV entry mediators
• Effectively prevents most HSV from
entering fetal circulation
 Parvovirus B19

Small, single-stranded DNA virus

• Children - erythema infectiosum
• Adults - asymptomatic
• Pregnant - flu-like illness, polyarthralgia
• Sickle cell - aplastic crisis
 Parvovirus B19

• 50% of pregnant women are immune

• ~ 20% of exposed non-immune women will
be infected
• Most fetuses are unaffected
• Fetal death ~ 9%
• Infection occurs before 20 weeks
• Fetus dies between 20 and 28 weeks
 Parvovirus B19

Virus infects
• Erythrocyte precursors
• Cardiac myocytes
• Endothelial cells
Causes fetal anemia, heart failure,
hydrops fetalis
 Parvovirus B19
Placental findings
• Often large and pale
• Edematous villi, increased nucleated RBCs
• No villitis
• Eosinophilic intranuclear inclusions
• Red cell precursors
• Immunohistochemistry, in situ, PCR may help
• PCR difficult to interpret – maternal blood is
viremic
Parvovirus
 Parvovirus

Immunostain for parvovirus

Human Immunodeficiency Virus

• Mechanisms of mother to child transmission

• In utero - transplacental
• During delivery - most common
• Postnatal - breast feeding
Human Immunodeficiency Virus
• Role of placenta in promoting or preventing
HIV passage is not well understood
• By IHC, in situ, PCR can find HIV
antigens/DNA
• Trophoblast, Hofbauer cells, villous
endothelium, amnion
• Does not correlate with infant viral
culture or infant infection
 Human Immunodeficiency Virus
Placental findings
• No consistent pattern
• In one large study placentas from HIV +
• Chorioamnionitis – more likely
• Plasma cell deciduitis – more likely
• Villitis – less likely
• Transmission rate – related to chorioamnionitis
in some studies but not others
 Human Immunodeficiency Virus
Co infection with malaria
• Very common in areas of Africa
• severity of malaria infection in pregnant
women
• rate of mother to child transmission of
HIV
• rate of preterm delivery, low birth weight,
infant mortality
 Syphilis
• Resurgence in 1980’s with decline by late
1990’s
• Serologic diagnosis in neonate is difficult
• CDC requirements for diagnosis - find
spirochetes in
• Fetal/neonatal tissue
• Placenta or cord
 Syphilis
• Gross
• Large, bulky placenta
• Normal
• Micro - classic triad
• Large, hypercellular, immature villi
• Proliferative fetal vascular changes
• Villitis - chronic or active
 Syphilis

• Classic triad – 43%

• Two of three – 47%
• One feature – 10%
• Other helpful features:
• Intra or perivillous polys
• Lymphoplasmacytic deciduitis
• Necrotizing funisitis
 Syphilis

Large, edematous villi

 Syphilis

Proliferative vascular changes

 Syphilis

Destructive villitis with polys

 Syphilis

Proliferative vascular changes

 Syphilis
• Strong association between classic triad and
• Spirochetes on silver stain
• Treponema pallidum DNA on PCR
• PCR may identify DNA when staining is
negative
• Number of organisms in tissue is low
 Syphilis

Best places to find spirochetes

• Cord
• Free membranes
• Decidua
• Sclerotic villi adjacent to villitis
Syphilis
Toxoplasma Gondii

Often big, bulky placenta

 Toxoplasmosis

Immature villi with subtle villitis

 Toxoplasmosis

Cyst with no surrounding inflammation

 Toxoplasmosis

Cyst with tachyzoites inside

 Toxoplasmosis

Lymphocytic villitis in response to tachyzoites

 Toxoplasmosis
Placental findings
• Villitis
• Usually subtle, non-necrotizing
• May be extensive with fibrosis or granulomas
• Plasma cell deciduitis
• Increased nucleated RBCs
• Chronic chorioamnionitis, funisitis
• Thrombosis, calcification of chorionic plate vessels
 Toxoplasmosis
Cysts can be found in
• Cord
• Membranes
• Villi
• Decidua
Immunohistochemistry, immunofluorescence
and PCR may be helpful
 Congenital Toxoplasmosis
• Almost always after primary infection
• Reactivation is rare
• In US only one-third of woman are immune
• Maternal infection occurs from ingesting
• Oocysts in cat feces, unwashed
vegetables, soil (gardening)
• Tissue cysts in undercooked meat
 Congenital Toxoplasmosis
After maternal primary infection
• 35% to 50% of fetuses are infected
Maternal infection late in gestation
• ↑ risk of fetal infection
Maternal infection early in gestation
• ↑ severity of sequelae
Congenital Toxoplasmosis
Congenitally infected infants
• Usually asymptomatic at birth
• Most develop sequelae such as:
• Blindness
• Deafness
• Microcephaly
• ↓ IQ
 Congenital Toxoplasmosis
• Treatment as close to maternal infection
significantly decreases
• Number of infants with sequelae
• Number with severe sequelae
• Optimizing screening programs is important
in high infection areas
Villitis of Unknown Etiology
• Accounts for majority of villitis
• Incidence
• 6% to 26%
• Usually greater than 32 weeks gestation
• No gross abnormalities
• 85% are very mild or mild
• Most randomly distributed
• 20% have basal location
 Villitis of Unknown Etiology
• Most cases are necrotizing
• Most are lymphohistiocytic
• May be associated with vasculitis of fetal
stem vessels
• Avascular downstream terminal villi
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
• ↑ incidence in women with autoimmune
disorders
• Tendency to recur
 Villitis of Unknown Etiology
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
 Villitis of Unknown Etiology
Which cases to work up for infection?
• Suspicious maternal history
• Suspicious clinical findings in neonate
• Moderate or severe villitis
• Pattern besides lymphohistiocytic
 Villitis
Basic work up
• IHC for CMV
• IHC for toxo
• Warthin-Starry for spirochetes
• Gram stain if lots of polys or abscesses
 Sample Villitis Comment
Histologic sections show mild, necrotizing
lymphohistiocytic villitis. No plasma cells
or viral inclusions are seen. In most cases
of villitis an etiology cannot be established,
however, villitis may be seen in infections
spread hematogenously from mother to
fetus such as CMV, toxoplasmosis, syphilis
and others. Infant and maternal serologies
may be helpful if clinically indicated.
Implantation Disorders
• Placenta accreta
• Abnormalities of placental shape
• Extrachorial placentation
 Placenta Accreta
Clinical feature
• Abnormally adherent placenta
Pathologic feature
• Absence of decidua between villi and
myometrium
 Placenta Accreta

Three categories
• Accreta vera
• Villi abut but do not invade myometrium
• Increta
• Villi invade myometrium
• Percreta
• Villi perforate myometrium
 Case 6
The patient is a 35 year old G2P1 woman with
placenta previa.
Placenta Percreta
Placenta Percreta
Placenta Percreta
Placenta Percreta
 Placenta Accreta

Trophoblast between muscle and villi

 Placenta Accreta

Fibrin and trophoblast between muscle and villi

 Placenta Accreta

Trophoblast is CK+ but decidua is CK-

 Placenta Accreta
Incidence
• 1:540 to 1:93,000
• May reflect partial vs. complete
• Cases confirmed by hysterectomy 1:2500
• 10-fold increase in the last decade
 Placenta Accreta
Risk factors
• Major
• Prior Cesarean section
• Placenta previa
• Less important
• Prior D&C, scarring
• Need for prior manual removal
• Implantation in cornu, uterine horn
• Increased maternal age, gravidity, parity
 Placenta Accreta
Clinical findings
• Inability to deliver placenta
• Severe postpartum hemorrhage
• 50% require transfusion
• May require emergency hysterectomy
• Antepartum bleeding - 30%
 Placenta Accreta
Clinical complications
• Uterine rupture - 13.8%
• Uterine inversion - 2%
• Maternal mortality - 7%, from shock, DIC
• Fetal mortality - 1% from uterine rupture,
severe antepartum bleeding
 Placenta Accreta
Pathogenesis theories
• Implantation in areas of uterus with
insufficient decidua
• Early, local hypoxia causes deep
trophoblast invasion
Succenturiate Lobe
 Succenturiate Lobe

Incidence
• 3% to 5%
Complications
• Retention in uterus – bleeding, infection
• Tear, thrombosis of connecting vessels
• Placenta previa
Bilobed Placenta
 Bilobed Placenta
Clinical associations
• Multiparity
• Advanced maternal age
• History of infertility
• First trimester bleeding
• Need for manual extraction
• No increased fetal or maternal morbidity
or mortality
Circummarginate Placentation

• Junction with disc is smooth

• Not clinically significant
Extrachorial Placentation
Circumvallate Placentation

• Junction with disc is thick, rolled

• Preterm bleeding, poor outcome
 Extrachorial Placentation

• May be partial or complete

• May have some circummarginate areas and
some circumvallate areas in same placenta
 Extrachorial Placentation

• Partial circummarginate 13.7%

• Complete circummarginate 3.8%
• Partial circumvallate 4.5%
• Complete circumvallate 2.4%
 Extrachorial Placentation
Clinical associations:
• All types increased with increased parity
• Circummarginate
• Not clinically significant
• Complete circumvallate
• Recurrent antepartum bleeding
• Preterm labor and delivery
• Fetal hypoxia
• Post partum hemorrhage
• Recurrence in subsequent pregnancies
 Multiple Gestation
• 1 in 90 pregnancies (twins)
• Marked ↑ secondary to assisted reproductive
technologies
• 50% of twins conceived through ART
• Dramatic ↑ triplets, higher order multiples
• 75% due to ART
• All twins have ↑ mortality and ↑complications
compared to singletons
 Twin Gestations

Dizygous (fraternal)
• Account for 70% of twins
• Fertilization of two ova
• Rates vary with population
• Genetic tendency to poly ovulation
• Dichorionic placentation
 Twin Gestation
Monozygous (identical)
• Account for 30% of twins
• Fertilization of one ovum with post
fertilization splitting
• Rate is constant
• Any type of placentation
• depends on timing of split
 Monozygotic (30%)
1 ovum, 1 sperm

1-3 days 4-7 days 8-12 days 13+ days

Dizygotic (70%)
Duplication
2 ova, 2 sperm Separation early Duplication Incomplete
embryonic
blastomere inner cell duplication of
rudiment of
mass germ disc
the germ disc
~25% of ~75% of ~1-3% of Conjoined
2 ova monozygotic monozygotic monozygotic twins
twins twins twins

Dichorionic
Dichorionic Monochorionic
diamniotic Monochorionic
diamniotic separate diamniotic monoamniotic
fused
Dichorionic Placentation

Thick, opaque dividing membranes

Dichorionic Placentation

Fused amnion and chorion

 Dichorionic Placentation

Fetal vessels approach but do not cross septum

Monochorionic Placentation

Thin, translucent dividing membranes

Vascular anastomoses
Monochorionic Placentation

Fused amnion only

Monochorionic Placentation

Vascular anastomoses
Monoamniotic Placentation

Single sac, no dividing membranes

Conjoined Twins
Higher Order Multiple Gestations

Quadruplet placenta
 Multiple Gestations
Complications more common in twins vs.
singletons
• Low birth weight
• Prematurity
• Anomalies, malformations
• Cerebral palsy
 Multiple Gestation
Complications
MC DC
Loss < 24 wks 12.2% 1.8%
Perinatal mortality 2.8% 1.6%
Delivery < 32 wks 9.2% 5.6%
Low BW 7.5% 1.7%
Discordant growth 11.3% 12.1%

Monoamniotic twins - 28% to 70% mortality

due to cord accidents, preterm delivery
 Multiple Gestation
Complications specific to twins:
• Twin-twin transfusion syndrome (TTTS)
• Discordant fetal growth
• Acardiac twinning
• Death in utero of one twin
 Case 7
This twin gestation was complicated by the
development of polyhydramnios and
discordant fetal growth documented on
ultrasound at 26 weeks. The infants were
delivered at 33 weeks by Cesarean section.
Twin A weighed 2400 gm (hematocrit
85%). Twin B weighed 2100 gm
(hematocrit 18%). At four years, both twins
are severely handicapped.
 Twin-Twin Transfusion Syndrome
• See in 15% of MC twins
• 90% mortality if untreated
• Chronic imbalance of blood flow
• Donor - hypovolemia, oliguria, oligohydramnios
• Anemia, hypoglycemia, pale organs
• Recipient - polyuria, polyhydramnios, hydrops
• Heart failure, jaundice, thromboses, kernicterus
• Fetuses usually discrepant sizes
Twin-Twin Transfusion Syndrome
 Twin-Twin Transfusion Syndrome

Pathogenesis related to vascular anastomoses

• Artery-artery - superficial, bidirectional
• Vein-vein - superficial, bidirectional
• Artery-vein - deep, unidirectional
• Clue to A-V is unpaired superficial
artery or vein
• Presence of A-A may be protective
Vascular Anastomoses
 Twin-Twin Transfusion Syndrome

Other factors are also important

• Velamentous cord insertion
• Placental dysfunction
• Death of one twin in utero
• Acute shifts in blood flow during delivery
Twin-Twin Transfusions Syndrome
Placental features
• Donor
• Large, bulky, pale
• Edematous villi, ↑ nucleated RBCs
• Recipient
• Small, firm
• Congested villi
Twin-Twin Transfusion Syndrome
Twin-Twin Transfusion Syndrome
Twin-Twin Transfusion Syndrome

Donor with large, edematous villi

Twin-Twin Transfusion Syndrome

Recipient with congested villi

Twin-Twin Transfusion Syndrome

Treatment options - controversial

• Delivery
• Amnioreduction
• Rupture of dividing membranes
• Laser coagulation of anastomotic vessels
• Selective termination
 Discordant Fetal Growth

• Difference in fetal weights > 25%

• Occurs in ~ 12% of MC and DC twins
• Mortality is greater if MC
 Discordant Fetal Growth
Causes of discordant fetal growth:
• Degree of placental sharing
• Quality of implantation in each territory
• Differences in angioarchitecture
• Velamentous cord insertion
Fetal Death In Utero of One Twin

• Vascular resistance of dead twin ↓

• Blood flows from live twin to dead twin
• Sudden hypotension, hypoperfusion of
organs
• Severe morbidity in live twin
Fetal Death In Utero of One Twin

Mummified remnant of early embryo

 Pathology of the Fetal
Membranes

• Changes secondary to meconium

• Diffuse chorioamniotic hemosiderosis
• Squamous metaplasia
• Amnion nodosum
• Amniotic bands
 Case 8
This 20 year old G1 P0 woman had an
intrauterine pregnancy at 35 weeks
gestational age complicated by severe fetal
intrauterine growth restriction and
gastroschisis with small intestine and part of
the stomach located outside the abdominal
wall. She was delivered for non reassuring
fetal parameters.
Gastroschisis
 Gastroschisis
Microscopic findings
• Small vacuoles with central nucleus
• Accompanying meconium
• Vacuoles may involve chorion, decidua
Apparently specific for gastroschisis
Material is lipid by ultrastructure
Meconium staining
Meconium

• Stratified amnion
• Pyknotic nuclei
• Pigmented macrophages
Meconium
 Meconium in membranes

Macrophages in membranes stuffed with meconium

 Gross Features Clinical Features

Acute blue-green usually normal

glistening
residual meconium

Subacute dark mec aspiration syndrome

slippery, edematous

Chronic muddy brown prenatal hypoxia likely

dull
 Meconium

10 to 20% of liveborns pass meconium

• 20 to 30% are depressed at birth
• 5% are severely affected
Meconium Aspiration Syndrome

• Respiratory distress in a meconium-stained

infant
• No other explanation for distress
 Meconium
Meconium passage correlates with parameters
of perinatal distress
• Apgars < 3 at 1 and 5 minutes
• Umbilical artery pH < 7.0
• Seizures
• Delivery room resuscitation
 Meconium
Physiologic – majority do well

Adverse stimuli – require low O2

Meconium Aspiration Syndrome

do poorly
 Meconium
Other effects:
• May induce vasoconstriction
• Meconium-associated vascular necrosis in
umbilical cord and chorionic plate vessels
• May really represent meconium-specific
karyorrhexis
• See in < 1% of meconium-stained placentas
 Membrane Pigments

Meconium
• Gross
• green-blue
• Micro
• yellow-green, waxy
• Associated edema, stratification
 Membrane Pigments
Hemosiderin
• Gross
• Brown, green
• Often associated blood clot
• Micro
• Yellow-brown
• Refractile
• Positive on iron stain
 Hemosiderin

No reactive changes in amnion

Hemosiderin

Refractile pigment
 Hemosiderin

Positive Prussian Blue stain for iron

Hemosiderin
 Diffuse Chorioamniotic
Hemosiderosis
• Associated placental findings
• Old clot
• Circumvallation
• Associated clinical findings
• Oligohydramnios without membrane rupture
• Preterm delivery
• Persistent pulmonary HTN, chronic lung disease
 Squamous Metaplasia

Anywhere on fetal membranes, fetal surface

Difficult to remove
Squamous Metaplasia
 Amnion Nodosum

Associated with oligohydramnios

Renal anomalies, Potter’s syndrome, pulmonary hypoplasia
 Amnion Nodosum

Nodule of squamous cells, hair and vernix caseosum material

Amnion Nodosum
Amnion Nodosum
Amniotic Band Syndrome

• Numerous other names

• Variable defects of limbs, trunk,
craniofacial structures
• Malformations and deformations
Amniotic Band Syndrome
Amniotic Band Syndrome
Amniotic Band Syndrome
Amniotic Band Syndrome
Amnionic Bands
Amniotic Band Syndrome
Amniotic Band Syndrome
Amniotic Band Syndrome
Amniotic Band Syndrome
Amniotic Band Syndrome
 Amniotic Band Syndrome

• 1:2500 to 1:8620 liveborns

• 1:55 previable fetuses
• Black multigravid women < age 20 years
• Often misdiagnosed as an hereditary
syndrome
 Amniotic Band Syndrome

Theories of pathogenesis:
• Amniotic bands cause defects
• Timing of rupture determines severity
• Primary defect in embryo
• Vascular disruption
Amniotic Band Syndrome

• High index of suspicion

• Normal karyotype
• Recurrence is extremely rare
 Case 9
The patient is a 35 year old woman
with an intrauterine pregnancy at 33
weeks gestational age complicated by
pregnancy-induced hypertension and
premature rupture of membranes.
Umbilical Cord Thrombus
 Umbilical Cord Thrombus
•1:250 to 1:1500
• Vessel involved
• Vein only - 71%
• Vein and artery - 18%
• Artery only - 11%
• Outcome
• stillbirth - 2/3
• neonatal distress or death -1/3
 Embryonic Remnants

• Fusion of omphalomesenteric and allantoic

ducts
• Ducts obliterated by end of 1st trimester
• Remnants found in 23%
• More than one remnant in 13%
Allantoic Duct Remnant
Allantoic Duct Remnants
• Most common remnant
• Located between arteries
• Most common at fetal end of the cord
• Transitional-type epithelium
• Rarely form cysts
• Associated with patent urachus
Omphalomesenteric Duct Remnants
Omphalomesenteric Duct Remnants

• Located at cord margin

• Most common at fetal end
• Cuboidal or columnar epithelium
• May see smooth muscle, gastric, pancreatic
differentiation
• Cysts are rare, associated with Meckel’s
Vitelline Vessel Remnants
 Vitelline Vessel Remnants

Located at periphery, most common at fetal end

Single Umbilical Artery
 Single Umbilical Artery

• See in 1% of umbilical cords

• Highest in eastern Europeans
• 3 to 4-fold increase in twins vs. singletons
• Fixed gross or micro finds more SUA
• Umbilical arteries fuse just before disk
 Single Umbilical Artery
• Increase in major malformations
• 21% - 7 fold higher than controls
• No pattern to malformations
• Increase in mortality
• 20% - 5 fold higher than controls
• Most deaths due to malformations
• Associated with low birth weight
and growth restriction
 Single Umbilical Artery
• May play a role in congenital anomalies
• Decreased flow to placenta may increase
fetal cardiac workload
• Decreased flow to tissues could cause
chronic hypoxia
• Smaller twin usually has SUA
 Single Umbilical Artery

Atrophic remnant of other umbilical artery

 Single Umbilical Artery

Atrophic remnant of second umbilical artery

 Single Umbilical Artery
Associated placental abnormalities
• Velamentous cord insertion - 9.3% (con=1.2%)
• Marginal cord insertion – 18% (con=5.9%)
• Extrachorialis
• Bilobation
• Succenturiate lobe
• Placenta previa
• Chorangiomas
• Increased infarction
 Single Umbilical Artery

Maternal associations
• Age, gravidity, prior loss - no relationship
• Diabetes, HTN, toxemia - controversial
Outcome
• External anomalies - ↑ risk of internal anomalies
• No external anomalies, no sx – work up unclear
• No anomalies, +IUGR - will catch up
 Umbilical Cord Length

• Mean length - 55 to 60 cm
• Related to tension
• Maternal height and weight is controversial
 Short Umbilical Cord
• < 40 cm
• See in 6% of cases
• Associated with ↓ fetal movements:
• Amniotic bands, arthrogryposis,
oligohydramnios, body wall defects, fetal
neuromuscular disorders
Short Umbilical Cord
 Short Umbilical Cord

• Post natal associations:

• Low Apgar scores
• Jitters and trembles
• Hypotonia
• Need for positive pressure resuscitation
• Psychomotor abnormalities
Long Umbilical Cord

• > 80 cm
• See in 6% of cases
• Increased risk of
• Nuchal cord
• Other encirclement
• Cord prolapse
• Marked twisting
 Long Umbilical Cord
• Significant association between long cords
and placental abnormalities
• ↑ nucleated RBCs
• Chorangiosis
• Fetal vascular thrombi
• Meconium macrophages
 Long Umbilical Cord
If >90 cm half had:
• Abnormal CNS imaging
• Neurologic abnormalities
• Both
May have long cord in subsequent pregnancy
Umbilical Cord Knot
 Umbilical Cord Knots

• See in 1% of cords
• Develop between 9 and 12 weeks
• Mortality between 5 and 11%
 Umbilical Cord Knots
Acute tightening
• Edema, congestion, thrombi on one side
• Collapse between knot and fetus
Chronic tightening
• Untie and see persistent groove, loss of
Wharton’s jelly, curving
 Umbilical Cord Knots
Clinical associations

Long cords Diabetes

Male gender Growth retardation
Multiparity Genetic amniocentesis
hydramnios Monoamniotic twins
 Abnormal Cord Insertion
• Marginal - 5.9 to 18%
• Velamentous - 1%
• Insertio velamentosa - 75% branch in membranes
• Interposition velamentosa - 25% don’t branch
• Insertio furcata
• Don’t insert in membranes but do branch
Marginal Insertion
 Velamentous Insertion

Sample intramembranous vessels (do a roll)

 Velamentous Cord Insertion
Clinical associations:
• Twins 8.5%
• Monochorionic > fused dichorionic >
separate dichorionic
• Single umbilical artery
• Congenital malformations
• IVF conception
• Maternal smoking, diabetes, advanced age
 Velamentous Cord Insertion
Complications
• Laceration
• Compression and thrombosis
• Deformation anomalies
• Vasa previa - vessels over os
• 1:50 velamentous insertions
• Sudden exsanguination - high mortality
Umbilical Cord Hematoma
 Umbilical Cord Hematoma
• 1:5500 deliveries
• 50% perinatal mortality rate
• Usually involves fetal end
• Causes
• Trauma
• See after 1.5% of US-guided cord sampling
• Little morbidity or mortality
• Inflammation
• Primary vessel defect
Umbilical Cord Stricture
Umbilical Cord Constriction

• Uncommon
• High rate of stillbirth
• Early gestations
• Long cords, excess twisting
Umbilical Cord Constriction
Is it a postmortem artifact?
To attribute a fetal death to constriction
• Edema
• Venous congestion
• Occlusive thrombi
 Umbilical Cord Spiral
• Average 10 turns
• Counter-clockwise
• Established early in gestation
• Function
• ↑ turgor
• ↓ compression
• ↑ venous return
Excess Cord Torsion
 Hypercoiled Cord
• Coiling index > 90th percentile
• Clinical associations
• Fetal death
• Preterm delivery
• Low birth weight
• Abnormal cord insertion
• Maternal cocaine use
• Extremes of maternal age
 Uncoiled Cord
• 5% of cords
• Clinical associations
• ↑ mortality
• C-section for distress
• Meconium
• Preterm delivery
• Abnormal karyotype
• Abnormal heart tracing
 Hypocoiled Cord
• Coiling index < 10th percentile
• Clinical associations
• Preterm delivery
• Growth retardation
• C-section for distress
• Meconium, oligohydramnios
• Abnormal karyotype
• Nuchal cord
Umbilical Cord Hemangioma
Umbilical Cord Hemangioma
Umbilical Cord Hemangioma
Umbilical Cord Hemangioma
Umbilical Cord Hemangioma
Umbilical Cord Hemangioma
• Rare lesion
• Probably hamartoma not neoplasm
• Possible origin
• Cord vessels
• Vestigal vitelline vessels
• Cord mesenchyme
Umbilical Cord Hemangioma
• Come to clinical attention
• Mass on ultrasound
• ↑ maternal AFP
• Found at delivery
• Differential diagnosis
• Hematoma
• Teratoma
• Omphalocele
Umbilical Cord Hemangioma
Fetal complications
• Stillbirth
• Preterm delivery
• Hydrops fetalis
• Severe fetal hemorrhage
• Intrauterine growth restriction
• Hemangiomas elsewhere