Courtesy of Dr. Pete Peterson, Ob/Gyn, Michigan ‘59

Placental

Pathology

Lithopedion

Placental Evaluation in the Investigation of Fetal Demise

Richard W. Lieberman, MD, FCAP, FACOG University of Michigan Health System

Department of Pathology

Department of Obstetrics & Gynecology

2

Intrauterine Fetal Demise Cases –

Sometimes the Answer is in the Placenta

Listen to the history

perhaps it contributes, but if it doesn’t seem to

fit the histopathology…

keep in mind the gestational age dependent

differential diagnoses

every so often you need to as “should the

Medical Examiner get involved?”

3

Case: Clinical Scenario

23 y/o woman, G1P0, 17 weeks pregnant Extreme abdominal cramping and nausea following a

prepared meal that she described as “tasting funny”

“Water broke” in hospital parking lot

FOB did not want a child

Concerned about “morning-after pill” poisoning FOB had many friends who are doctors, could get

“anything he wanted”

4

Stillbirth or Miscarriage?

Michigan Definition

Miscarriage

death of fetus prior to 20 weeks OR

fetus < 400 grams

Stillbirth = IUFD (intrauterine fetal demise)

death after gestation of 20 weeks or more (by LMP)

OR fetus > 400grams

…know your own State’s definition

5 CDC: 1997 State Definitions and Reporting Requirements

Is this a...

Stillbirth: General Statistics

~26,000 per year

0.6% of all births

nearly equal to infant mortality infant mortality = death prior to 1st birthday

stillbirth rates ”stable” for several decades

Detailed analytical study is limited

state-to-state variability in definitions and reporting requirements

risk factor assessment a challenge

6

Certificate

of Fetal

Death

7 NCHS Fetal Death Manual - 2012

State Reporting of Fetal Death

8

All products of human

conception = fetal death:

American Samoa

Arkansas

Colorado

Georgia

Hawaii

New York City

New York State

Northern Mariana Islands

Rhode Island

Virginia

Virgin Islands

The 1992 Revision of the Model State Vital Statistics Act and

Regulations:

‘‘Each fetal death of 350 grams or more, or if weight is

unknown, of 20 completed weeks gestation or more,

calculated from the date last normal menstrual period began

to the date of delivery, which occurs in this state shall be reported

within 5 days after delivery to the (Office of Vital Statistics) or as

otherwise directed by the State Registrar.’’

Eleven areas report all periods of gestation as a fetal death;

25 20 weeks or more; [Montana]

13 350 grams or more or >20 weeks;

1 400 grams or more or >20 weeks; [Michigan]

1 500 grams or more or >20 weeks;

1 350 grams or more;

3 500 grams or more;

1 >16 weeks; and

1 > 5 months.

CDC: 1997 State Definitions and Reporting Requirements

Montana Definitions

(15) (a) "Stillbirth" means a fetal death occurring

after a minimum of 20 weeks of gestation.

(b) The term does not include an abortion, as

defined in 50-20-104.

http://codes.lp.findlaw.com/mtcode/50/15/1/50-15-

101#sthash.rTOoFjNf.dpuf

9

Case – Suspected

Abortifacient Poisoning

23 y/o woman, G1P0, 17 weeks gestation

Extreme abdominal cramping and nausea

following alleged administration of “morning

after pill” by disinterested boyfriend

presents to emergency room

No fetal heart tones on admission

ß-hCG: 73,000 IU/ml

10

Case (cont’d)

D&C one day later

Case reported to Medical Examiner

Maternal and fetal toxicology samples

collected with fetal remains & placenta

11

Case: Placenta

Fragmented placenta

with “grape-like”

vesicles

Three vessel cord

12

Case: Autopsy

Fragments of:

calvarium

left hand, portion right hand

rib cage and shoulder girdle…

Not enough to make a morphological

assessment, but tissue sent for “genetic

analysis”

13

14

15

16

Case: Atypical villous morphology

Variable size and shape of villi

Villous scalloping and notching

Trophoblastic inclusions

trophoblastic hyperplasia

17

Case: Results

Toxicology

Maternal and fetal blood negative for

mifepristone and norgestrel

Chromosome analysis

69XXX

Diagnosis…

18

Case: Diagnosis?

Partial hydatidiform mole

Conclusions:

miscarriage/abortion imminent

later presentation than usual

no association with “purposeful” administration

of abortifacient

19

Initial : All Stillbirths

Inspection of fetus and

placenta

photographs

document any anomalies

weights

trimmed placenta weight

fetal measurements

HC, CR, Foot length

Consent for cytologic

specimens, may include:

amniotic fluid if delivery is

not imminent

fresh placental tissue

1x1cm below cord insertion

umbilical cord segment

internal fetal tissue

chondroid or patella

not skin

collect sterilely store in LR

at room temp 20 ACOG Practice Bulletin #102, May 2009

Initial Evaluation: All Stillbirth (cont’d)

Maternal History

smoking, drugs

diabetes, autoimmune

FH: hereditary conditions

Ob Hx: recurrent AB,

prior demise, SGA babies

Current Pregnancy

AMA, HTN, TTTS, bleeding

alloimunization

Maternal Laboratory Eval

Kleihauer-Betke

(immediate)

parvovirus

syphilis (RPR/VDRL)

MTHFR gene mutation

anti-cardiolipin antibodies

thrombophilias

Factor V Leiden, Protein C

or S

antithrombin III

21 ACOG Practice Bulletin #102, May 2009

Fetal Autopsy in Stillbirth

Obtain parental

consent, unless

deemed indicated by

Medical Examiner

Placental exams

covered by insurance

extremely valuable in

identifying underlying

etiologies

Despite

recommendations of

both fetal and

placental exam, only

15-40% are done

<50% of parents

consent for fetal

autopsy

22

ACOG Practice Bulletin #102, May 2009

Etiology of Stillbirth

Unknown in 25 – 60% of cases

Cause of Stillbirth can be related to one or more

of the following:

Maternal conditions

Fetal conditions

Placental conditions

23

Partial Hydatidiform Mole

triploid fetal

morphology 24

dispermy fertilization

triploid chromosome

25-45% of molar gestations

Normal to elevated hCG

GTN?

persistent HCG <5%

choriocarcinoma NO!

Case: Questions…

Fetal Death?

but not at the hand of another

Miscarriage or “stillbirth”?

Reportable case?

How would you Classify this pregnancy loss?

classification of stillbirth… have you heard about this?

25

Difficulties in Stillbirth Classification Systems

not utilized nor easy to use

definition of stillbirth varies

investigators, states,

countries, and systems

no International approach

“unexplained” ranges from

15-71%

Two “Best”:

ReCoDe (Relevant

Condition at Death)

PSANZ-PDC

(Perinatal Society of

Austrailia-New

Zealand Perinatal

Death Classification)

26 BMC Pregnancy & Childbirth 9: 24-37, 2009

both stillbirth & neonatal

death have overlapping, but

distinct sets of disease

ReCoDe:

relevant conditions @ death

Fetal lethal anomaly

infection

hydrops

F-M hemorrhage

IUGR

Umbilical cord prolapse

constricting loop/knot

Maternal diabetes

hypertension

cholestasis

drugs

Idiopathic

Placenta abruption

placenta previa

vasa previa

insufficiency

Amniotic Fluid infection

oligo- or poly-

Uterus

Intrapartum “asphyxia”

birth trauma

External trauma

Unclassified

27 BMC Pregnancy and Childbirth 2013, 13:182

http://www.biomedcentral.com/1471-2393/13/182

Next case…

28

Case: IUFD after “kick” in abdomen

21 y/o G2P1:24 weeks decreased fetal movement

5 year old child kicked her in the abdomen days earlier

noted leaking of “greenish” fluid AM of admission

NO signs of maternal trauma noted

U/S: no fetal movement or cardiac activity

DIAGNOSIS: Intrauterine fetal demise (IUFD) 29

Case: IUFD (cont’d) Antenatal history:

chlamydia 1st trimester

ER visit one month earlier for abdominal cramps

declined pelvic or cervical exam

marijuana use twice a day since age 17

did not stop after discovery of this pregnancy

DID cut back from 8 cigarettes to 2-3/day

PMH:

cholecystectomy – age 15

SVD at term – age 16

30

Case IUFD

Clinical Course:

delivery of a non-viable female infant

further details of fetal demise not provided

autopsy refused by mother

placenta pale and edematous (weight not given)

31

Pale edematous placenta:

appears “large” for 24 weeks

32

33

34

35

36

Numerous Erythroblasts with

Eosinophilic Nuclear Inclusions

37

Parvo B19 Immunohistochemistry

38

Human parvovirus B19

commonly infects children

causing erythema infectiosum (fifth disease)

TORCH: it’s the “other” or the 5th disease

a significant adult population has not been

exposed to the virus

many adults are non-immune

susceptible to infection

30-50% of pregnant women have not been exposed

39 BJOG 118:175-86, 2011

Human Parvovirus B19 in Pregnancy

Maternal Acute Infection

~1-2% incidence in pregnancy

50% asymptomatic

vertical transmission may still occur

fetal effects:

anemia

edema (hydrops)

congestive heart failure

myocarditis

fetal demise

40 BJOG 118:175-86, 2011

Fetal Effects from Parvo Infection Consequences of Infection

3% of all spontaneous AB

fetal death ≈ age at infection

1st trimester – 19%

2nd trimester – 15%

3rd trimester – 6%

no increase in malformations

over background incidence

IgM positive infants imply

resolution of infection

Mechanism of injury

primarily anemia due to

red cell destruction

evidence of virus in cell

eosinophilic nuclear

inclusion

also…

myocarditis

hepatitis

hypoalbuminemia

placentitis/villitis

most prominent injury

noted in 2nd trimester

41

Case Summary Based upon placental evaluation alone:

marked increase in NRBCs

eosinophilic intranuclear inclusions

parvovirus b19 infection (confirmed with IHC).

immature, enlarged, hypercellular villi with increased stromal histiocytes and edema

red-cell destruction and other adverse fetal effects cannot be assessed in the absence of fetopsy (hydrops etc)

Conclusions: the claim “a kick in the stomach” by the 5 year old caused the

demise is not possible

it may indeed be true that the child exposed the patient to parvovirus infection that did ultimately result in IUFD

42

Differential Diagnosis: Pale ± Heavy Placenta

Immune-hydrops

RhD antigen (most common)

ABO incompatibility

lesser common blood group

antigens

Non-immune hydrops

15-35% genetically transmitted disease

~10% alpha-thalassemia chronic blood loss (occasionally acute blood loss)

trauma: massive or chronic fetal-maternal hemorrhage

large chorangiomas

cystic adenomatoid malformation

congenital malformations

congenital heart disease

congenital nephrotic syndrome

infectious parvovirus

adenovirus

43

Hydrops=ascites + generalized edema + hydramnios (+/-) + fluid accumulation (i.e. pleural)

24 - 27 weeks 28 - 37 weeks 37+ weeks

Infection

(19%)

Unexplained

(26%)

Unexplained

(40%)

Abruptio placenta

(14%)

Fetal growth

restriction (19%)

Fetal growth

restriction (14%)

Anomalies

(14%)

Abruptio placenta

(18%)

Abruptio placenta

(12%)

Most Frequent Types of Stillbirth

Based on Gestational Age

Fretts et al. Ob Gyn 1992;79:35-9

Fretts and Usher. Contem Rev Ob Gyn 1997;9:173-9

44

SCRN: Causes of Death Among Stillbirths

(n=663)

75% agreed to fetal autopsy (best in literature)

racial disparity: 2.3 risk for non-Hispanic black

Placental Disease (26%)

maternal decidual vasculopathy (8%)

uteroplacental insufficiency (5%)

umbilical cord abnormalities (10%)

vasa previa, cord entrapment (prolapse) &

occlusion (nuchal cord alone not a cause)

more common after 32 weeks

46 JAMA 306(22):2459-2468, 2011

N.B.: Fetal Death Following Maternal

Trauma

Maternal Trauma

with maternal death

medical examiner

case

post-mortem emergent

cesarean

autopsy

mother

placenta

…and baby

Maternal Trauma

with maternal survival

placental examination

?medical examiner?

…fetal autopsy?

informed consent

or, a medical examiner

case

?fetal homicde?

47

Evaluation of Stillbirth: Conclusions

Understanding Requires:

diligent protocols for

evaluation

with or without concurrent

maternal death/trauma

the fetal “cause of death”

increased knowledge risk

reduction

standardize reporting is

desirable, but not likely

Team Approach

medical examiners

and investigators

maternal-fetal

specialist

perinatologists

placental pathology

48

References for Stillbirth Evaluation:

Stillbirth Collaborative Research Network

Postmortem Evaluation

Am J Perinatology 29(3):187-202, 2012

Placenta and Umbilical Cord

Am J Perinatology 28(10):781-792, 2011

Neuropathological Examination

Am J Perinatology 28(10):793-802, 2011

49

50

The

“Scream”

of the

Placenta

Assorted Causes of Fetal

Demise – Stillbirth

Cord Anomalies

Two Vessel Cord

Three Vessel Cord

False Knot in Cord

True Knot in Cord 52

Cord: “Loss of Spiral”

Growth Delayed small placenta

small baby decreased fetal

movement

Possible Etiologies

drugs & EtOH

smoking

congenital

infection

anomalies

etc…..

54

Placental Insufficiency

Umbilical Coiling: Too many or too few

Umbilical coiling index

Defined: 1 /(over the) #coils

per length of cord

Hypercoiled > 0.31 coils/ cm

Hypocoiled < 0.065 coils/ cm

Controversial association

with poor outcome

55

Hint: Photograph cord fully extended;

you can count the coils later as needed.

Stillbirth: Umbilical Cord Stricture

56

True “Cord Accident”

57

Cord Accidents Nuchal cord present in 25% of normal pregnancies

~2.5% of stillbirths in autopsy case series

Strict criteria for “causation”

Cord occlusion and hypoxic tissue

placenta with compensatory mechanisms (chorangiosis…)

fetal ischemic changes (hard to differentiate from post-mortem)

Exclusion of other causes

Actual proportion remains uncertain

58

Placental

Variations

Abnormal Shapes lobar variations

number, shape

cord implantation location on disc

membranous implant

membrane anomalies circumvallate

amnionic bands

59

Velamentous Insertion & Vasa Previa

60

Placenta Percreta ~

“Chronic” Rupture of LUS

61

Multifetal Gestation

62

Twin-Twin Transfusion

Syndrome

63

Monoamnionic Twin Gestation

64

Placental Infarction

65 from www.pathguy.com

…and one more

66

Ectopic Pregnancy

67

Where life imitates art… Placental Histopathology

Gromit (from Wallace & Gromit)

Ultrasound

68

Case: Placenta

69

Retroplacental

hematoma

Three vessel cord

Maternal Surface… clot doesn’t appear significant

70

Traumatic Uterine Rupture,

2nd Trimester

71