Stillbirth: USA 2.6 million stillbirths in 2015, 98% in LMIC - - PowerPoint PPT Presentation

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Stillbirth What you can do

Bob Silver University of Utah Salt Lake City, Utah

Behind each death …. a story

2.6 million stillbirths in 2015, 98% in LMIC

Source: Blencowe et al 2016

10 countries account for two-thirds of stillbirths in 2015 as well as the majority of maternal and neonatal deaths

Highest stillbirth rates (deaths

per 1000 total births)

Highest stillbirth rates (deaths

per 1000 total births)

Highest stillbirth numbers Highest stillbirth numbers

Stillbirth: USA 6/1000 (1:165)

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Stillbirth

Woods, R. Bulletin of the WHO. 2008.

Stillbirth

• Many stillbirths may be preventable

De Bernis L, et al. Lancet. 2016.

Report card for stillbirths in United States of America

WHO definition ≥28 weeks 2015 US national definition (≥20 weeks) 2013

Stillbirth rate per 1000 births (Rank*) 3.0 25/186 6.0 Number of stillbirths per year 11,300 22,800 Av annual rate of reduction 2000 – 2015 (Rank*) 0.4% 155/159

Stillbirth rates and reductions in high-income countries since 2000

Source: Flenady et al. Lancet 2016.

• ~ 46,200 stillbirths

in 2015

• ~ 19,400 avoidable

stillbirths if stillbirth rate were ≤2/1000 in all countries

• Large variation in

progress with 1.8% per year average

YET Netherlands is progressing faster at 6.8% per year so faster progress is possible

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Classification Systems

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Stillbirth: Risk factors and Etiologies

• Stillbirths are categorized by risk

factors and by presumed etiology

• Risk factors defined as maternal

characteristics associated with stillbirth but without a known causal pathway leading to the death

• Risk factors often present in

live births

Stillbirth Classification Systems

• Over 80 systems
• No single “perfect” system
• No gold standard to assess system
• Cause of death hard to define
• May be more than one cause
• May be multiple risk factors
• Granularity versus simplicity
• What is the goal?
• Right tool for the job

Dudley et al. Obstet Gynecol 2010;116:254-60

Classification Systems

• Numerous systems / Problems
• Best depends on goals
• Wigglesworth
• ReCoDe
• TULIP
• CODAC
• INCODE

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Stillbirth Collaborative Research Network (SCRN)

• NICHD - RFA – 2001 workshop
• Population-based study
• 5 geographic catchment areas defined

a priori by county lines

• 59 hospitals averaging

>80,000 deliveries per year

• ≥90% of stillbirths (SBs) and live births

(LBs) born to residents of the catchment areas are delivered in these 59 hospitals

Stillbirths (Cases): Results

• 663 stillbirths enrolled (03/06 – 08/08)
• 512 – complete postmortem exams

425 (83%) antepartum stillbirth 87 (17%) intrapartum stillbirth

• Race

White / Non-Hispanic: 35.7% Black / Non-Hispanic: 22.5% Hispanic: 34.4% Other: 7.2% SCRN; JAMA 2011;306:2459-68

INCODE Initial Causes of Fetal Death

• Intended for research purposes
• Evidence based explicit definitions
• Evolving tool
• Each case reviewed by two MDs
• Multidisciplinary panel for

difficult cases

Dudley et al. Obstet Gynecol 2010;116:254-60

INCODE Causes of Death

• Probable: high likelihood
• Possible: reasonable certainty -

involved in a pathophysiologic sequence

• Present: conditions of interest
• May have ≥ 1 cause

Dudley et al. Obstet Gynecol 2010;116:254-60

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INCODE Causes of Death: Diabetes

• Probable: Macrosomia and poor

control and / or embryopathy

• Possible: Macrosomia or poor

control only

• Present: No macrosomia and

good control

Dudley et al. Obstet Gynecol 2010;116:254-60

INCODE

Causes of Death: Broad Categories

• Placental conditions
• Obstetric complications
• Fetal / genetic abnormalities
• Infections
• Maternal medical conditions
• Umbilical cord abnormalities
• Hypertensive disorders

Stillbirths: Cause of Death?

• 61.1% - probable cause
• 81.5% - possible or

probable cause

• 40% - more than one possible
• r probable cause

SCRN; JAMA 2011;306:2459-68

Genetic Conditions Microarray

• The “

“ “ “future” ” ” ” of genetic testing for pregnancy loss (and everything else)

• Does not require live cells!
• Identification of abnormalities not

ascertained by conventional cytogenetics

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Genetic Analysis Karyotype - Microarray

• Karyotype

– 5 – 10 megabase – Losses and gains

• Microarray

– Coverage at a higher density – 50 – 100 kilobase – Losses and gains (Copy number variants)

Objective To determine if microarray identifies abnormalities in stillbirths not detected by karyotype

Reddy et al, NEJM 2012;367:2185-2193

Results

Overall success rate – Karyotype: 70.5% – Array: 87.4% (p<0.001) Abnormal (aneuploidy + pathogenic CNV) – Karyotype: 5.8% – Abnormal Array: 8.3% (p=0.007) – 42% increased detection rate with array

Reddy et al, NEJM 2012;367:2185-2193

Results

157 Cases with failed karyotype – 74% normal array – 5.7% abnormal array Stillbirths with major anomalies (n=472)

– 19.4% abnormal karyotype (13/67) – 30% abnormal array (20/67) – 53.8% increased detection rate with array

Reddy et al, NEJM 2012;367:2185-2193

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Case #1

27 week stillbirth, 746 grams (AGA) Multiple congenital malformations

– Cranio-facial dysmorphism – Cleft soft palate – Limb deficiencies – Multiple cardiac defects

Case #1

Figure 3a: Case 1 Panel A Genes Region

• f Loss

OMIM Loci SNPs CNPs

• Chr. Band

Genes Region

• f Gain

OMIM Loci SNPS CNPS

• Chr. Band

Panel B1 Panel B2 Panel C1 Panel C3 Panel C2

Array Data

Copy # x2 Copy # x1

Copy Number State

50 Genes 7 OMIM loci

25 MB Deletion in q-arm, chro 4

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6 OMIM loci

Unbalanced translocation

20 Genes Copy Number State

Array Data

2.5 MB Gain in p-arm, chro 17

Copy # x2 Copy # x3

Case #2

37 week stillbirth, 2490 grams (AGA) Multiple minor facial and lower extremity anomalies, no clear recognized syndrome

Case #2

30 Genes 12 OMIM loci

Di George syndrome locus

Copy Number State

Array Data

2.5 MB Deletion in q-arm, chro 22

Copy # x2 Copy # x1

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Conclusions

• Primary benefit of array is the greater

likelihood obtaining a result

– Ability to analyze non-viable tissue

• Higher resolution allowing for

detection of copy number changes not visible on karyotype

Reddy et al, NEJM 2012;367:2185-2193

Conclusions

• Array should be considered in cases
• f karyotype failure or major

anomalies

• Array may prove useful as a first line

screen for genetic abnormalities in stillbirth given higher yield of abnormalities as cost decreases

Reddy et al, NEJM 2012;367:2185-2193

Optimal Evaluation of stillbirth

• CONTROVERSIAL
• Cost versus yield
• Focus on common causes
• Focus on recurrent conditions
• Pay attention to clues
• Emotionally challanging:
• Varied levels of comfort with

autopsy or genetic testing

Optimal Evaluation of stillbirth

• Multicenter prospective cohort
• Netherlands: 2002 – 2008
• 1025 stillbirths ≥ 20 weeks
• Comprehensive evaluation
• Cause of death (COD) determined
• TULIP
• Panel determined if test in “

“ “ “work- up” ” ” ” helped to determine COD

Korteweg et al. Am J Obstet Gynecol 2012;206:e1-12

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Optimal Evaluation of stillbirth

• Placental examination:
• Abnormal 89.2% (87.2 – 91.1)
• Valuable 95.7% (94.2 – 96.8)
• Autopsy:
• Abnormal 51.5% (47.4 – 55.2)
• Valuable 72.6% (69.2 – 75.9)
• Karyotype:
• Abnormal 11.9% (8.7 – 15.7)
• Valuable 29.0% (24.4 – 34.0)

Korteweg et al. Am J Obstet Gynecol 2012;206:e1-12

Clinical narrative Clinical suspicion for potential cause of death Fetal autopsy Placental pathology Maternal lab results

Probable or Possible INCODE classification

Confirm or identify a cause Refute a suspected cause Pertinent positive Pertinent negative

Study Design

Pertinent positive leads to a probable

• r possible INCODE cause of death

Pertinent negative rules out suspected causes based on clinical history

“Useful”: result that identifies a cause or confirms/refutes a clinical suspicion

Results

• 512 stillbirth cases
• 390 (76.2%) - probable or possible

cause of death

• 122 (23.8%) - without cause of death

–105 present conditions only –17 no INCODE conditions identified

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0% 10% 20% 30% 40% 50% 60% 70% % Useful

Test Utility for Stillbirth Cause of Death

Clinical Presentations

• Growth Restriction

– 53 cases

• Hypertensive Disorders

– 50 cases

• PTL/Chorio/PPROM

– 77 cases

• Suspected Fetal Anomalies

– 31 cases

• No Clinical Clues

– 115 cases

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Useful

Fetal Growth Restriction: Helpful Tests (n = 53)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Useful

Hypertensive Disorders: Helpful Tests (n = 50)

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0% 10% 20% 30% 40% 50% 60% 70% 80% 90% % Useful

Preterm Labor, Chorioamnionitis, PPROM: Helpful Tests (n = 77)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% % Useful

Suspected Fetal Anomalies: Helpful Tests (n = 31)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% % Useful

No Clinical Clues: Helpful Tests (n = 115)

Autopsy

• Second most useful step in evaluation
• Autopsy cause of death differed from

the fetal death record in 55% of cases

• New information in 26-51% of cases
• Birth defects and morphologic

abnormalities-genetic or developmental abnormalities

• Confirm infection, anemia, hypoxia,

and metabolic abnormalities

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Autopsy

• Limited use
• Cost
• Lack of trained pathologists
• Perinatal pathologists
• Discomfort by physicians
• Discomfort by patients
• Work with families
• Partial autopsy, X-rays, and/or

post-mortem MRI

Placental, membranes, umbilical cord evaluation

• Infection, genetic abnormalities,

anemia, and thrombophilias

• Trained pathologists
• Scientific, systematic evaluation
• Increasingly advised for medico-legal

purposes in all cases of adverse Perinatal outcome

Karyotype / Microarray

• Blood
• Placenta (chorionic plate)
• Fascia lata
• Skin from the nape of the neck
• Trained pathologist - tissues for

karyotype after evaluation

• f the fetus and placenta.
• DO NOT put placental / fetal tissues

in formalin

• Do microarray if you can!

Fetal-maternal hemorrhage

• Kleihauer-Betke test (KBT)

Elution of adult hemoglobin (HbA) from adult red cells, more acid-resistant fetal hemoglobin (HbF) remains intact in fetal RBC. Remaining hemoglobin is subsequently visualized by staining with erythrosin.

• Flow cytometry

May be more accurate Used by some centers

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Infection

• Autopsy and histologic evaluation of the

placenta, membranes and umbilical cord

• Pathologist: obtain cultures and nucleic acid

specimens (bacteria or viruses) based on histology

• Routine cultures or serology – controversial
• Parvovirus serology ???
• Syphilis screening ???
• Serology for “

“ “ “TORCH” ” ” ” (toxoplasmosis, rubella, CMV, HSV) - low yield

Generally accepted tests:

• Clinical history**
• Fetal autopsy
• Placental evaluation
• Karyotype / Microarray ($)
• Screen for fetal-maternal

hemorrhage

• aPL (FGR / HTN / Placenta)

Targeted tests:

• Toxicology screening
• Thyroid testing
• Diabetes screening
• Testing for specific infections
• Maternal serum
• Fetal tissues (nucleic acids / cultures)
• Bile acids
• Additional genetic testing

http://scrn.rti.org

Stillbirth Collaborative Research Network

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We Can Do Better!

The Lancet’s Series on

Ending preventable stillbirths

Photo: Suzanne lee/Save the Children/India