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Evaluation of Stillbirth. Katy Kemnetz , PGY2. objectives. Evaluation of stillbirth. Objectives. The participant will be able to: Identify the conditions that have been best demonstrated to cause stillbirth Evaluate a stillbirth using the most effective workup

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evaluation of stillbirth

Evaluation of Stillbirth

Katy Kemnetz, PGY2

objectives
objectives

Evaluation of stillbirth

objectives1
Objectives

The participant will be able to:

  • Identify the conditions that have been best demonstrated to cause stillbirth
  • Evaluate a stillbirth using the most effective workup
  • Accurately formulate an etiology for a stillbirth, when possible
  • Employ the recmomended hospital policies for management of stillbirth
outline
Outline
  • Definitions
  • Causes of stillbirth
  • Workup of stillbirth
  • Other considerations
  • Conclusions
definitions

Definitions

Evaluation of Stillbirth

definitions1
Spontaneous abortion

Intrauterine fetal demise

  • Miscarriage
  • <20 weeks gestation or <500g
  • “Stillbirth”
  • >20 weeks gestation or >350g—state dependent
    • 350g is 50%ile for 20 weeks gestation
    • Illinois: >20 weeks gestation
  • “Delivery of a fetus showing no signs of life as indicated by the absence of breathing, heart beats, pulsation of the umbilical cord, or definite movements of voluntary muscles”
  • Does not include terminations of pregnancy or IOL for previable PPROM
Definitions
causes

Causes

Evaluation of stillbirth

causes of stillbirth
Causes of stillbirth
  • >30 classification systems exist
  • Important to distinguish between
    • Underlying cause of death
    • Mechanism of death
    • Risk factors
classification of stillbirth
Classification of stillbirth

The National Institute of Child Health and Human Development

classification of stillbirth1
Classification of Stillbirth
  • Eunice Kennedy Shriver workshop 2007
  • National Institute of Child Health and Human Development
  • “An optimal classification system would identify the pathophysiological entity initiating the chain of events that irreversibly lead to death”
criteria for cause
Criteria for “cause”
  • Epidemiologic data demonstrate an excess of stillbirth associated with that condition
  • Biologic plausibility that the condition causes stillbirth
  • Either rarely seen in association with live births or, when seen in live births, results in a significant increase in neonatal death
  • A dose-response relationship exists
    • The greater the “dose” of the condition, the greater the risk of fetal death
  • Associated with evidence of fetal compromise
  • The stillbirth likely would not have occurred if that condition had not been present
causes of stillbirth1
Causes of stillbirth

Reddy, UM et al. “Stillbirth Classification—Developing an International Consensus for Research.” Obstetrics and Gynecology, Vol 114, No 4, October 2009.

infection
Infection
  • Associated with 10-20% of stillbirths in developed countries
  • Higher association with preterm birth
  • Sometimes difficult to prove causality
infection1
Infection
  • Ascending infectionamniotic fluid or fetusfetalpneumonitis
  • Hematogenousspreadvillitis

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

mechanism of fetal death
Mechanism of fetal death
  • Severe maternal illness
  • Placental infection that prevents oxygen/ nutrients from crossing to the fetus
  • Fetal infection that causes a lethal congenital deformity
  • Fetal infection that damages a vital organ
  • Precipitation of preterm labor, with intrapartum fetal death
infections must be proven
Infections must be proven
  • Signs of infection in the fetus
    • Evidence on autopsy of extensive organ involvement
  • Positive fetal cultures
  • Positive maternal cultures plus chorioamnionitis/ funisitis

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

causes of iufd spirochetes
Causes of IUFD: Spirochetes

Severe placental dysfunction

protozoa
Protozoa

Severe placental dysfunction

viruses
Viruses

Causes lethal fetal anomalies

bacteria
Bacteria

Damage to vital organs (brain, heart)

Severe placental dysfunction

Goldenberg RL, Thompson C. The infectious origins of stillbirth. Am J Obstet Gynecol

2003;189:861–73

slide23

Hypertensive disorders

Simpson, LL. Maternal medical disease: Risk of Antepartum Fetal Death. SeminPerinatol, 2002, 26, 47.

hypertensive disorders
Mechanism of fetal demise:

To consider cause of death:

  • Placental insufficiency
    • IUGR
    • Abruption
  • If it progresses to eclampsia
  • If it is associated with placental abruption or fetal growth restriction
Hypertensive disorders
slide25

Diabetes

Simpson, LL. Maternal medical disease: Risk of Antepartum Fetal Death. SeminPerinatol, 2002, 26, 47.

diabetes
Mechanism of fetal demise:

To consider cause of death:

  • Congenital abnormality
  • Placental dysfunction
  • Obstructed labor and intrapartum death
  • Macrosomia
    • Fetal hyperglycemiafetal insulin productionexcessive fetal growthmetabolic acidosis
  • Signs of intrauterine or intrapartum asphyxia
  • LGA fetus
  • SGA fetus
  • Severe malformation
  • Placenta demonstrates characteristic histologic findings
    • Large edematous villi
    • Increased prominence of cytotrophoblasts
Diabetes
slide27

Thyroid/renal disorders

Simpson, LL. Maternal medical disease: Risk of Antepartum Fetal Death. SeminPerinatol, 2002, 26, 47.

thyroid renal disorders
Thyroid disorders

Renal disorders

  • Graves disease, where thyroid-stimulating hormone receptor antibody causes fetal toxicosis
  • Untreated thyroid disorders
  • Linear relationship between maternal creatinine and risk of fetal demise

Systemic Lupus Erythematosus

  • Stillbirth rates are higher in the presence of HTN, nephritis, or APL
  • Circulating auto-antibodies, anti-Ro, anti-La
    • Congenital heart block, hydrops
Thyroid/renal disorders
maternal medical conditions1
Maternal medical conditions
  • Risk is a continuum

Reddy, UM et al, 2009

thrombophilias1
Antiphospholipid syndrome

Inherited thrombophilias

  • Inflammation, thrombosis, and infarction in the placenta
  • Clear histopathological or clinical evidence of placental insufficiency
  • Factor V Leiden mutation, antithrombin III deficincy, prothrombin gene mutation, protein C deficiency, protein S deficiency
  • Placental infarction and thrombosis
  • Thrombophilias should only be considered as the cause of stillbirth with:
    • Evidence of placental insufficiency such as fetal growth restriction or infarction and
    • Recurrent fetal loss

Two large prospective cohort studies found no association between factor V Leiden mutation and pregnancy loss or placental insufficiency

Thrombophilias are common in healthy women with normal outcomes

Thrombophilias
alloimmunization1
Red cell alloimmunization

Platelet alloimmunization

  • Anti-Rhesus D, anti-Rhesus C, anti-Kell
  • Must have a positive indirect Coombs test
  • Antibody titers more than 1:16 (or 1:8 for anti-Kell)
  • Evidence of fetal anemia with hydrops
  • Evidence of fetal extramedullaryhematopoeisis
  • HPA-1a, HPA-5a, HPA-4
  • Maternal antibodies against paternal and fetal platelet antigens
  • Parental platelet incompatibility for the pertinent antigen
  • Fetal thrombocytopenia
  • Massive intracranial hemorrhage
Alloimmunization
criteria
Criteria
  • Epidemiologic data demonstrating an excess of intrauterine mortality
  • Seen rarely in liveborn neonates
  • When seen in liveborn neonates, it frequently results in neonatal death
  • Biologic plausibility that it can result in death
slide36

Congenital malformations

Reddy, UM et al. “Stillbirth Classification—Developing an International Consensus for Research.” Obstetrics and Gynecology, Vol 114, No 4, October 2009.

chromosomal abnormalities
Incidence
  • Cytogenetic abnormalities account for 6-13% of all stillbirths
  • This may be higher because 40-50% attempted karyotypes fail to grow
  • 23% monosomy X, 23% trisomy 21, 21% trisomy 18, 8% trisomy 13
Chromosomal abnormalities

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

chromosomal abnormalities1
Autosomal recessive disorders

Autosomal dominant disorders

  • Alpha thalessemia, Smith LemliOpitz
  • Phenotype in lethal cases may differ from live cases
  • Skeletal dysplasias
  • More often spontaneous mutations
Chromosomal abnormalities

Firestein: Kelley’s Textbook of Rheumatology, 9th ed. Saunders 2012

fetomaternal hemorrhage1
Fetomaternal hemorrhage
  • The cause 4% of all stillbirths
  • Risk factors:
    • Placental abruption
    • Abdominal trauma
    • Multiple gestation
    • Abnormal fetal testing
fetomaternal hemorrhage2
Fetomaternal hemorrhage
  • Risk of stillbirth depends on
    • Amount of hemorrhage
    • Acute/chronic
    • Gestational age
  • A threshold of 20 mL/kg of fetal bleeding is associated with increased risk of stillbirth
  • Autopsy confirmation of fetal anemia and hypoxia
placental causes1
Placental causes
  • Placenta previa, vasaprevia, neoplasms
  • Placental abruption has 8.9 relative risk of stillbirth
    • May be considered the cause of death if >30% of the placenta shows signs of abruption

Reddy, UM et al, 2009

placental causes2
Placental causes
  • Any disease that causes an SGA placenta may result in stillbirth
    • <5% expected weight for gestational age
    • Preeclampsia, DM, HTN, renal, chronic infections
  • Any disease that causes an LGA placenta may result in stillbirth
    • >95% expected weight for gestational age
    • Hydropsfetalis, DM, syphilis
umbilical cord pathology1
Umbilical cord pathology
  • Account for 3.4-15% of stillbirths
  • Velamentous insertion
    • If it leads to a vasaprevia or bleeding during labor
  • Umbilical cord prolapse
    • Associated with prematurity, malpresentation, mutiparity, obstetric manipulation
  • Umbilical cord occlusion
    • Cord prolapse, entanglement (mono-mono twins)
    • Torsion
    • Rupture, strictures, hematomas
umbilical cord pathology2
Umbilical cord pathology

Isolated finding of a nuchal cord or a true knot at the time of delivery is insufficient evidence that cord accident is the cause of stillbirth

  • Nuchal cord
    • Occurs in up to 30% of normal pregnancies
    • Not associated with an increased risk of stillbirth in study of 14,000 deliveries
  • True knot
    • Also common in live births
    • Grooving of the cord, constriction of the umbilical vessels, edema, congestion, thrombosisrequired to claim it is the etiology
  • Exclude other relevant causes of stillbirth
  • Find evidence of hypoxia and cord occlusion on postmortem examination
complications of multifetal gestation
Complications of multifetal gestation
  • Monochorionicplacentation
    • Twin-twin transfusion syndrome occurs in 9% of mono-di twins
    • Mortality can be 90% in untreated cases
complications of multifetal gestation1
Complications of multifetal gestation
  • Mono-mono twins
    • Cord entanglement, preterm birth, growth impairment, malformations, genetic abnormalities, vascular anastomoses

Gabbe: Obstetrics: normal and problem pregnancies, 6th ed. Saunders 2012

uterine complications1
Uterine complications
  • Uterine rupture
    • Evidence of obstructed circulation
  • Uterine abnormalities
    • There is an increased risk of uterine abnormalities in women with recurrent pregnancy loss/stillbirth
    • Possibly due to poorly vascularized uterine tissue or space constraints
    • Increased risk of PPROM, cervical insufficiency, preterm labor
    • Septate uterus has highest risk of stillbirth and placental abruption
workup

Workup

Evaluation of stillbirth

importance
importance

Workup of stillbirth

importance of a stillbirth evaluation
Importance of a stillbirth evaluation
  • Counseling for risk of recurrence
  • Possible intervention to reduce recurrence risk
  • Facilitate emotional closure and healing
most stillbirths remain unexplained
Most stillbirths remain unexplained
  • Incomplete evaluation
    • Lack of clinician awareness
    • Concerns of the family
  • Lack of single universally accepted classification scheme
    • Difficult to assign a definitive cause
  • Unknown cause
    • Sometimes despite thorough evaluation
overview
overview

Workup of stillbirth

overview1
Overview

Silver et al, 2010

how do we know what works
How do we know what works?
  • “Evaluation of 1025 fetal deaths: proposed diagnostic workup.” Korteweg FJ, Erwich JJHM, Timmer A, et al. AJOG 2012.
  • Prospective cohort study in 50 Dutch hospitals
  • Singleton IUFDs at >=20wks gestation, excluding pregnancy terminations and intrapartum deaths
  • Cause of death determined by a multidisciplinary panel (2 obstetricians, an OB resident, perinatal pathologist, neonatologist, genetics, microbiologist)
    • Initial demonstratablepathophysiological entity initiating the chain of events that irreversibly led to death
  • Contribution of each diagnostic test for determination of cause of death was determined by the panel
    • Valuable for “establishing cause of death” or “excluding cause of death”
medical history
Medical history

Workup of stillbirth

thorough medical obstetrical history
Thorough medical/obstetrical history

Maternal medical history

Genetic abnormalities

Pregnancy complications

Family history

Substance use

Pregnancy history

physician s exam
Physician’s exam
  • Weight, head circumference, length
  • Photographs
    • Frontal and profie
    • Whole body, face, extremeties, palms, abnormalities

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

slide66

Time of demise

“Estimating the time of death in stillborn fetuses: III. External fetal examination; a study of 86 stillborns.” Genest DR, Singer DB. Obstet and Gynecol, 1992; 80(4), 593

autopsy
Autopsy
  • New information that influences counseling in 26-51% of cases
  • Dutch study: valuable in 72% of cases
  • However, it is performed in <50% of cases
    • Clinician hesitation to recommend autopsy
    • Patient reservations
autopsy1
Autopsy
  • Ask about patient reservations
  • Emphasize potential benefits to family
  • Allow the family ample time to hold the baby and perform religious/cultural activities first
autopsy2
Autopsy
  • Medical autopsies require consent of next-of-kin
  • Consent should be explicit enough that parents can limit the autopsy procedure
illinois masonic policy
Illinois Masonic Policy
  • “An autopsy is an option for fetuses 20 weeks or greater, but if clinically indicated or requested by the family, an autopsy can be offered before 20 weeks.”
  • If an autopsy is not requested, a Surgical Pathology examination can be performed
components of an autopsy
Components of an autopsy
  • Review of the clinical history, laboratories, antenatal imaging
  • External examination:
    • Weight, crown-rump length, foot length, crown-heel length, occipital-frontal circumference
    • Joint mobility, facial features, hands, feet, genitalia
  • Intraoral examination:
    • Pharynx, soft palate, uvula
  • Take into consideration changes from maceration
  • Photographs
external examination
External examination

Lentz: Comprehensive Gynecology, 6th ed

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

components of an autopsy1
Components of an autopsy
  • Internal examination
    • Y or T shaped incision on anterior trunk
    • Organs examined in situ
    • Heart sometimes opened in situ, sometimes removed and fixed
      • Vascular connections, septal defects
    • Organs removed in bloc for detailed dissection
    • Spinal cord removed
components of an autopsy2
Components of an autopsy
  • Brain
    • Coronal scalp incision extending to behind the ears
    • Skull is opened along cranial sutures
    • Can extend into posterior neck for posterior fossa (Dandy-Walker, Chiari) by removing occipital bone and cervical vertebrae
    • Brain is placed in formalin for 10 days before examination
brain
Brain

Chiari malformation—downward displacement of medulla

Fligner 2011

components of an autopsy3
Components of an autopsy
  • Samples of tissue for
    • Microscopic evaluation
    • Viral cultures
    • Bacterial cultures
  • Metabolic studies (Guthrie card)
histologic exam
Histologic exam

Extramedullaryhematopoeisis in fetal liver in fetus with non-immune hydrops

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

what autopsy can identify
What autopsy can identify
  • Markers of IUGR
    • Head circumference percentile higher than weight percentile
    • Brain weight appropriate for gestation while other organs are appropriate for body weight
    • Altered brain weight:liver weight
  • Kidneys
    • Polycystic kidney disease
  • Certain brain pathologies
  • Congenital anomalies
kidneys
Kidneys

A: 28 wks, suspicious for autosomal recessive polycystic kidney disease

B: confirmed on autopsy

C: 22 wks, suspicious for ARPKD

D: Autopsy showed diffuse renal cystic dysplasia

autopsy can provide evidence
Autopsy can provide evidence
  • Infection
  • Anemia
  • Hypoxia

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

alternatives to autopsy
Alternatives to autopsy
  • Partial autopsy
    • Head-sparing autopsy (may miss CNS pathology)
  • External examination by a trained pathologist
    • Can identify syndromes, congenital anomalies, timing of death, growth anomalies
    • Will likely miss fetal infections and internal anomalies
  • External examination with selected biopsies
    • More likely to identify fetal infections
alternatives to autopsy mri
Alternatives to autopsy: MRI
  • Very good for CNS pathology
    • Sometimes better than autopsy, because fetal brain has high water content and liquefies
  • Fluid collections and effusions in the body

Advantages

Disadvantages

  • May miss cardiac anomalies, bowel anomalies
  • Cannot diagnose infections or metabolic disease
slide83
MRI

24 wks, massive bilateral intraventricular hemorrhage

Fligner 2011

slide84
MRI
  • Image-guided percutaneous biopsies
    • <50% success rate at obtaining tissue in one study
    • Somewhat inferior to autopsy:
      • 12 cases where “minimally invasive autopsy” provided equivalent information to autopsy
      • 12 cases where “minimally invansive autopsy” provided inferior information than autopsy
      • 2 cases where MRI and biopsy provided superior information
      • However, 73% of minimally invasive autopsies provided Information of equivalent clinical significance to autopsy

Fligner 2011

alternatives to autopsy1
Alternatives to autopsy
  • X ray
    • Useful for skeletal dysplasias
    • Ribs/vertebrae as part of diagnosis of VACTERL or diabetic fetopathy
x ray
X ray

Achondrogenesis 1b (absence of vertebral bodies)

Fligner 2011

x ray1
X ray

Hemivertebrae (VACTERL)

Fligner 2011

examination of the placenta1
Examination of the placenta
  • The most valuable diagnostic test in most studies
    • Dutch study showed it to be valuable in 95% of cases
  • Provides additional information in 30% of cases
examination of the placenta2
Examination of the placenta
  • Weight in relation to norms for gestational age
  • Evidence of abruption, infarction, thrombophilias
  • Hemosiderindepositschronic abruption
    • Perivillious and marginal fibrin deposition
    • Decidual necrosis
    • Evidence of infarction
examination of the placenta3
Examination of the placenta
  • Multiples: chorionicity, vascular anastomoses in multifetal gestations
  • Cord: thrombosis, velamentous cord insertion, vasaprevia
  • Evidence of infections
    • More common in preterm stillbirth
    • Viral nuclic acid amplification
    • Bacterial cultures
examination of the placenta4
Examination of the placenta

Kumar: Robbins pathologic basis of disease, 8th edition. 2009

genetics
genetics

Workup of stillbirth

karyotype
Karyotype
  • Abnormal fetal karyotype noted in 8-13% of all stillbirths and in >20% of those with morphologic abnormalities or IUGR
  • Dutch study: 11.9% prevalence of a chromosomal abnormality in the 362 IUFDs who underwent karyotyping
    • 37% trisomy 21, 16% monosomy X, 4% trisomy 13
  • Karyotypewas valuable in 29% of cases
cell culture
Cell culture
  • Successful in only ~50% of cases
  • Cells must be cultured in vitro—need metaphase chromosomes
  • Only 1% of cells are dividing at any time
cell culture1
Cell culture
  • Acceptable cytologic specimens:
    • Amniotic fluid (yield is 84%) obtained by amniocentesis at the time of prenatal diagnosis of demise, 20-30mL
    • 1x1cm placental block from below the cord insertion site on an unfixed placenta
    • 1.5cm segement of umbilical cord
    • Internal fetal tissue specimen (costochondral junction, patella, lung, kidney, gonad, not skin)
cell culture2
Cell culture
  • Collect the specimen in a sterile manner
    • Prokaryotic cells outcompete and overgrow any human cells
  • Transport to the laboratory as soon as possible
  • Blood, amniotic fluid, chorionic villi at room temperature
  • Solid tissue transported on wet ice
    • Lysosomalenzyme activity is inhibited at 4 C and viability is maintained
cell culture3
Cell culture
  • Monolayer in situ
  • Up to 2 weeks for solid tissue culture
  • Cells are swelled hypotonically, ruptured (blowing on the coverslip) and metaphase chromosomes are spread
  • Automatic robotic harvesters
  • Stained with Giemsa or Wright
    • Results in banding pattern unique to each chromosome
karyotype1
Karyotype
  • Count the chromosomes in each cell
    • Technologist at a microscope
  • Must analyze 15-20 cells to get karyotype
  • Photograph of karyogram or computer-assisted imaging
    • Manipulate/move chromosomes
    • Pattern-recognition software to generate karyogram
    • Computer must be double-checked by a technologist

Stein 2011

if culture is unsuccessful
If culture is unsuccessful
  • Flourescent in-situ hybridization (FISH)
    • Can test for the most common aneuploidies
    • Can test for specific mutations
slide102
FISH
  • Molecular probe
    • Fluorescent dye
    • Visualized using fluorescence microscopy
  • Molecular probes can be
    • Specific to certain mutations
    • A cocktail that coats the whole chromosome
  • FISH can be performed on metaphase or interphase chromosomes—cell culture not required for FISH
slide103
FISH
  • DNA is denatured and allowed to hybridize with the probe
  • Nonhybridized DNA is then counterstained
slide104
FISH

X, X

Normal chromosome 21

Trisomy 21

Stein 2011

slide105
FISH

Microdeletion in chromosome 22 associated with DiGeorge syndrome

Stein 2011

slide106
FISH

Advantages

Disadvantages

  • Probes must be known genes/mutations
  • Limited number of colors can be seen with fluorescent microscope
  • Does not require metaphase chromosomes
  • Can obtain karyotype and information about mutations
fish with computer assisted system
FISH with computer-assisted system
  • Fluorochromes can be mixed
  • Too subtle for human eye, but computer assisted systems allow detection of all 24 chromosomes
  • Karyotype in interphase

Trisomy18 and XXY

Stein 2011

if live cells are not available microarray
If live cells are not available: Microarray
  • Screens the genome for copy number variations (CNPs)
    • BAC arrays provide overview of genome
    • SNP arrays provide more detailed coverage with probes on every 100-1000 base pairs
    • Detects deletions, duplications, aneuploidies, unbalanced translocations with a gain/loss of sequences
  • Good for small deletions or cryptic changes
    • Cytogenetics resolution is only 5-10Mb
microarray
Microarray

Stein 2011

limitations
Limitations
  • Many copy number changes are of uncertain clinical significance
    • More CNVs are being identified every day
  • It will not detect balanced translocations or inversions
microarray versus karyotyping
Microarray versus karyotyping
  • Reddy UM et al, 2012: Prospective population-based study of 532 stillbirths over 2 years
  • Patients with IUFD underwent:
    • Interview, chart abstraction, postpartum examination, placental pathology, karyotype analysis, and specimen collection
  • DNA analyzed with an SNP microarray with data aligned to Human Genome release 18
microarray versus karyotyping1
Microarray versus karyotyping
  • Benign CNV: full length listed in any of three databases of unaffected persons
  • Pathogenic CNV:
    • Evidence of pathogenicityin literature
    • Agene listed in the OMIM database that is known to cause developmental/lethal disease
    • In a pathogenic database
  • Probably benign CNV: no evidence of pathogenicity in literature
  • Unknown CNV
microarray versus karyotyping2
Microarray versus karyotyping
  • Microarray analysis yielded a result in 87.4% stillbirths compared to 70.5% for karyotype
  • 85.2% of these were benign, too small, or probably benign
  • 2.6% were pathogenic, 6.9% were aneuploid
  • Microarray detected CNV consistent with DiGeorge syndrome not detected by karyotypein 3 cases
conclusions microarray
Conclusions: microarray
  • Can detect mutations too small for FISH
  • Higher chance of obtaining a result

Genetic workup should be guided by family history and presence of congenital anomalies

Consider microarray when karyotypefails to grow in culture

Disadvantages

Advantages

  • More expensive
maternal workup
Maternal workup

Workup of stillbirth

laboratories recommended
Laboratories (Recommended)
  • CBC
  • Kliehauer-Betke
  • Human parvovirus B-19 IgG and IgM
  • Lupus anticoagulant, anticardiolipin antibodies
  • Indirect Coombs
    • If not already done antepartum
  • Toxicology screen
kliehauer betke
KliehauerBetke
  • Recommended to do before induction of labor
  • However, given that only massive hemorrhage is likely to cause fetal death, can also be done up to 2-3 weeks after delivery
  • In Dutch study, FMH was a contributing factor in 10.6% of the total cohort
kliehauer betke1
KliehauerBetke

Reddy et al 2009

antiphospholipid antibodies
Antiphospholipid antibodies
  • One fetal death satisfies criteria for testing
  • Confirm with repeat testing in 6-12 weeks
  • More likely positive if stillbirth was accompanied by IUGR or severe preeclampsia
  • Two dutch studies (750 fetal deaths in Korteweg et al 2010, 1025 fetal deaths in Korteweg et al 2012) showed that neither testing for acquired nor inherited thrombophilia is valuable
    • Unless the patient has a family or personal history of thrombophilia

Given significant implications for future pregnancies and future health of the mother, testing is generally recommended

laboratories sometimes useful
Laboratories (Sometimes useful)
  • Syphilis
  • TSH
  • Inherited thrombophilia workup
    • Factor V Leiden, prothrombin gene mutation, antithrombin III, fasting homocysteine
  • Glucose screening
  • Sonohysterogram
    • Especially if loss associated with preterm labor, PPROM, cervical insufficiency, previable gestations, fetal malpresentation

Guided by maternal history and risk factors

inherited thrombophilia
Inherited thrombophilia
  • Korteweg et al 2010. Multicenter, prospective study. 750 singleton fetal deaths >=20 wks, excluding terminations
  • Tested for vWF, antithrombin, protein C, total and free protein S, prothrombin gene mutation, factor V Leiden
  • Cause of death classified by a panel
  • “Except for vWF and paternal free protein S, acquired and thrombophilic defects were not more prevalent after fetal death.”
  • However, many case-control studies show an association

Consider it in cases of severe placental pathology, IUGR, or a history of thrombosis

However, remember that most women with these conditions will have uncomplicated pregnancies

laboratories unproven benefit
Laboratories (unproven benefit)
  • Toxoplasmosis, rubella, CMV, HSV, other infections
    • Viruses for which vaccines are prevalent are uncommon in developed countries
    • However, if autopsy, pathology, or history is suggestive, take maternal/neonatal serology, special tissue staines, testing for nucleic acids
  • ANA
routine torch
Routine TORCH
  • Dutch study: of the women tested for TORCH, 17.0% had positive IgM for TORCH, parvo, syphilis, or hepatitis B
  • However only 1.8% of the total cohort had infection as the cause of death
in selected cases
In selected cases
  • Paternal karyotype
  • Protein S and C activity
  • Kliehauer-Betke
considerations

Considerations

Evaluation of stillbirth

aimmc protocol
AIMMC protocol
  • All intact fetal remains are sent to the morgue within 4 hours of expiration, UNLESS a Surgical Pathology examination is requested
  • If a Surgical Pathology examination is requested
    • Remains with a Surgical Pathology requisition to the Histology Laboratory
    • Central Transport and Nursing are responsible for the initial transport of the body to the morgue and filling out the morgue census sheet
aimmc protocol1
AIMMC protocol
  • If autopsy is requested, the fetus is obtained from the morgue
  • An autopsy is an option for fetuses >=20 weeks
    • But if clinically indicated or requested by the family, an autopsy can be offered before 20 weeks
aimmc protocol2
AIMMC protocol
  • Autopsies are performed by AIMMC pathologists
    • Trained in fetal/neonatal autopsies
    • Consult specialists when needed
  • Preliminary result in 24 hours; final result in 30 days
  • Genetic and molecular testing at ACL
  • A fetus that undergoes an autopsy can still receive private burial
fetal death disposition notification
Fetal death disposition notification
  • Within 24 hours after an abortion/miscarriage the mother must be informed of her right to determine the final disposition of the remains
    • Private burial
    • Cremation
    • Hospital disposition
fetal death disposition notification1
Fetal death disposition notification

http://www.idph.state.il.us/vitalrecords/pdf/Fetal%20Death%20Disposition%20Notification.pdf

fetal death disposition notification2
Fetal death disposition notification
  • If patient is unclear, sign the form without making a selection
    • RN notes “undecided at discharge”
  • Fax a copy to Mission and Spiritual Care at 773-296-5010 and place a copy in the chart
  • Mission and Spiritual Care or the Perinatal Loss Coordinator will follow up with the family
  • If the family can not be reached within 2 weeks, Pathology will initiate the procedure for hospital disposition
private burial
Private burial
  • Perinatal loss coordinator has a list of funeral homes
  • Cremation or burial
  • Only a licensed funeral director can pick up the fetus
    • Parents provide the name to Health Information Management
  • Cost: some funeral home directors reduce the rate
    • Medicaid pays for modest funeral and burial
  • For very young fetuses, parents advised that there might not be many remains after autopsy
hospital disposition
Hospital disposition
  • St Luke’s Cemetery
    • 5300 N. Pulaski Road, Chicago, IL 60630
  • “Babyland,” exact location not identified
  • No charge
perinatal loss coordinator
Perinatal loss coordinator
  • Always notifiy Anna Zieba (pager 61-7656, phone 61-7127)
  • Always notify Mission and Spiritual Care 61-5005
    • Can provide religious services from most religions
considerations1
Considerations
  • Parents benefit from seeing/holding the infant
    • Warn them about how the baby will appear
  • Use the term “baby”
  • Encourage parents to name the infant
    • Knowing the sex is important
  • Fetal loss can be devastation at any gestational age
  • Different cultures grieve in different ways
considerations2
Considerations
  • Keepsakes and memory boxes
  • Child Life specialist can aid with siblings
  • For a loss in the ER, consider consulting crisis if parents show signs of depression
  • Bereavement care track after discharge
conclusions

Conclusions

Evaluation of stillbirth

conclusions1
Conclusions
  • The cause of a stillbirth is the initial pathophysiologic entity that irreversibly led to fetal death
  • Cause must be proven with evidence of fetal harm
  • There are many benefits to finding a cause
  • Encourage patients to allow an evaluation within the boundaries of their personal and cultural values
conclusions2
Conclusions
  • Recommended laboratories are CBC, Kliehauer-Betke, parvovirusB-19 IgG and IgM, lupus anticoagulant, anticardiolipinantibodies, and toxicology screen
  • Only perform other labs as indicated by maternal history
  • Encourage patients to receive an autopsy
    • Partial autopsy and MRI are alternatives
  • Always send the placenta to pathology
conclusions3
Conclusions
  • Encourage karyotyping
  • Base evaluation for other chromosomal abnormalities on family history and results of other studies
  • Consider FISH or microarray if low likelihood of getting a result from cell culture
  • Utilize hospital resources for perinatal loss
sources

Sources

Evaluation of stillbirth

slide145

ACOG Practice Bulletin Number 102. “Management of Stillbirth.” American College of Obstetricians and Gynecologists. March 2009. acog.org

  • Fligner CL, Dighe M. “Fetal and Perinatal Death Investigation: Redefining the Autopsy and the Role of Radiologic Imaging.” Ultrasound Clin 6, 2011 (105-117).
  • Illinois Masonic Medical Center Perinatal Loss Policy. Policy 20.118.044
  • Korteweg FJ, Erwich JJHM, Timmer A, et al. “Evaluation of 1025 fetal deaths: proposed diagnostic workup.” Am J ObstetGynecol 2012; 206:53.e1-12.Korteweg FJ, Erwich JJHM, et al. “Prevalence of Parental Thrombophilic Defects after Fetal Death and Relation to Cause.” Obstet and Gynecol. August 2010, Vol 116, No 2, part 1.
  • Kumar: Robbins and Coltran Pathologic Basis of Disease, Professional Edition, 8th ed. 2009 Saunders, an imprint of Elsevier.
  • Reddy UM, Goldenburg R, et al. “Stillbirth Classification—Developing an International Consensus for Research.” Obstet and Gynecol. Oct 2009, Vol 114, No 4.
  • Reddy UM, Page GP, Saade GR. “Karyotype versus Microarray testing for Genetic Abnormalities after Stillbirth.” N Engl J med 367; 23, December 2012
  • Silver R, Heuser C. “Stillbirth Workup and Delivery Management.” ClinObstet and Gynecol 2010; 53, 3.
  • Stein, CK. “Applications of cytogenetics in Modern Pathology.” McPherson: Henry’s Clinical Diagnosis and Management by Laboratory Methods, 22nd ed. 2011 Saunders, an imprint of Elsevier.