Stillbirth

We Can Do Better!

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 2015as 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: USA6/1000 (1:165)

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

WHOdefinition≥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

Classification Systems

• Investment to prevent stillbirth also improve women’s health, generating substantial economic & social benefits

• The cost of averting stillbirth in LMIC is returned almost 25 times by the economic and social value theselive children would provide their families, communities and nations

Quadruple return …..fewer stillbirths, fewer maternal & newborn deaths, improved child development

Return on investment

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

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

Classification Systems

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

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

University of Utah

NICHD / 5 Clinical Sites / Data Center

Emory University

NICHD

RTI International

Brown University

University of Texas Medical Branch atGalveston

University of TexasSan Antonio

Study Hospitals by Clinical SiteBROWN Grady Memorial Hermann Jordan ValleyWomen & Infants Northside St. Luke's Episcopal LDSKent Emory U Midtown UTHSC SAN ANTONIO Pioneer ValleyMemorial Piedmont Baptist Medical Center St. Mark'sNewport Atlanta Christus Santa Rosa Salt Lake RegionalSouth County DeKalb at Hillandale Metropolitan Methodist University of UtahWesterly UTMB GALVESTON North Central Baptist North DavisLandmark UTMB Galveston Northeast Baptist American ForkCharlton Clear Lake Regional Southeast Baptist Orem CommunityGood Samaritan Women's Hospital of Tx Southwest General Utah Valley RegionalMorton Mainland SW Texas Methodist Ogden RegionalSt. Luke's Brazosport Memorial St. Luke’s Baptist McKay-DeeSturdy Christus St. John’s University IntermountainTobey Memorial Hermann SE Wilford Hall

Brockton Angleton Danbury UTAH N=59 HospitalsEMORY Methodist Alta ViewDeKalb Medical Christus St. Joseph’s Cottonwood

Study Design

Population-based case-control study

• SBs and LBs enrolled at delivery • All SBs (residents of catchment areas)• Representative sample of LBs• Goal:Examine risk factors for and causes of SB

Case-control Protocol

• In-hospital maternal interview• Medical record abstraction• Standardized postmortem (SBs) and

placental pathology (SBs and LBs)• Clinically indicated tests (SBs)• Biospecimen collection fetal samples (SBs)maternal and cord blood, placental samples

(SBs and LBs)

Enrollment of Eligible Women

958 Eligible SBs 3,084 Eligible LBs

70%enrolled

63%enrolled

17% refused

13% not approached

24% refused

13% not approached

663 Enrolled SBs 1,932 Enrolled LBs

Stillbirths Livebirths

Stillbirths (Cases): Results

• 663 stillbirths enrolled (03/06 – 08/08)• 512 – complete postmortem exams425 (83%) antepartum stillbirth87 (17%) intrapartum stillbirth

• RaceWhite / Non-Hispanic: 35.7%Black / Non-Hispanic: 22.5%Hispanic: 34.4%Other: 7.2%

SCRN; JAMA 2011;306:2459-68

Timing in Gestation of Stillbirths

0

10

20

30

40

50

60

70

80

90

20-24 25-28 29-32 33-36 37+

Percent

Weeks Gestation

AntepartumIntrapartum

Overallp < 0.0001

SCRN; JAMA 2011;306:2459-68

Timing of Stillbirths by Race / Ethnicity

0102030405060708090

100

White Black Hispanic Other

Percent

AntepartumIntrapartum

p < 0.0001

SCRN; JAMA 2011;306:2459-68

INCODEInitial 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

INCODECauses of Death

• Probable: high likelihood • Possible: reasonable certainty -

involved in a pathophysiologicsequence

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

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

INCODECauses 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

INCODECauses 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 or probable cause

SCRN; JAMA 2011;306:2459-68

Probable / Possible Cause of DeathBroad Categories

0

5

10

15

20

25

30

35

40

Placental Obstetric Fetal Infection Medical Cord HTN

Percent

SCRN; JAMA 2011;306:2459-68

Probable / Possible Cause of Death by Timing of Death

0102030405060708090

100

Placental Obstetric Fetal Infection Medical Cord HTN

Percent

AntepartumIntrapartum

p < 0.0001

P = 0.0001

p < 0.002

P = 0.0007

SCRN; JAMA 2011;306:2459-68

Probable / Possible Cause of Deathby Race / Ethnicity

05

101520253035404550

Obstetric Infection HTN Medical

Percent

WhiteBlackHispanic

P = 0.006

P = 0.0004

SCRN; JAMA 2011;306:2459-68

05

101520253035404550

Placental Fetal Cord None

Percent

WhiteBlackHispanic

Probable / Possible Cause of Deathby Race / Ethnicity

P = 0.03

SCRN; JAMA 2011;306:2459-68

Probable / Possible Cause of Deathfor Gestational Age Groups

Percent

05

101520253035404550

Placenta Obstetric Infection

20-2425-2829-3233-3637+

p < 0.0001

p < 0.0001

p < 0.0001

Summary

• Systematic and thorough evaluation leads to a probable or possible cause in a majority of cases

• The most common causes of stillbirth were placental and obstetric conditions

• A higher proportion of stillbirths in non-Hispanic Blacks are intrapartum and due to obstetric complications and infections

Stillbirth: Risk FactorsCondition Prevalence SB Rate /

1,000 SB: OR

1.5 – 5.6

1.2 – 4.0

1.8 – 4.4

1.2 – 2.4

6 – 25

9 - 51

12 - 29

6 - 10

6 – 10%

5.8 – 7.7%

1.3 – 3.3%

Chronic HTN

Mild PIH

Severe PIH

Diabetes (diet)

1.7 – 7.06 - 35Diabetes (insulin)

2.5 – 5.0%

2.4%

Fretts; Am J Obstet Gynecol 2005;193:1923-35Reddy; Obstet Gynecol 2010;116:1119-26

SCRN, JAMA 2011;306:2469-79

Stillbirth: Risk FactorsCondition Prevalence SB Rate /

1,000 SB: OR

6 - 20

2.2 - 30

2.2 – 3.0

2.8 – 5.0

40 - 150

15 - 200

12 - 20

18 - 40

< 1%

< 1%

0.2 – 2%

SLE

Renal Disease

Thyroid Disorders

Thrombophilia

Fretts; Am J Obstet Gynecol 2005;193:1923-35

1.8 – 4.412 - 30Cholestasis

1 – 5%

< 0.1%

Stillbirth: Risk FactorsCondition Prevalence SB Rate /

1,000 SB: OR

1.3 – 3.0

1.1 – 2.7

1.3 – 2.8

1.3 – 2.0

10 - 15

12 - 15

13 - 18

10 - 13

10 – 20%

21%

20%

Smoking

BMI 25 – 29.9

BMI > 30

< 12 years education

2.0 – 4.612 - 30Prior FGR

30%

6.7%

Fretts; Am J Obstet Gynecol 2005;193:1923-35Reddy; Obstet Gynecol 2010;116:1119-26

SCRN, JAMA 2011;306:2469-79

Stillbirth: Risk FactorsCondition Prevalence SB Rate /

1,000 SB: OR

1.0 – 2.8

2.8 – 3.2

1.3 – 2.2

1.6 – 2.2

12

34

11 - 14

11 - 21

2.7%

0.14%

15 - 18%

Twins

Triplets

35 – 39 yrs

≥ 40 yrs

1.4 – 2.212 - 14Non-Hispanic Black

2%

15%

Fretts; Am J Obstet Gynecol 2005;1923-35

Reddy; Obstet Gynecol 2010;116:1119-26SCRN, JAMA 2011;

306:2469-79

Genetic ConditionsMicroarray

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

• Does not require live cells!

• Identification of abnormalities not ascertained by conventional cytogenetics

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

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 of Loss

OMIMLoci

SNPsCNPs

Chr. Band

Genes

Region of Gain

OMIMLoci

SNPSCNPS

Chr. Band

Panel B1

Panel B2

Panel C1

Panel C3Panel C2

Array Data

Copy # x2

Copy # x1

Copy Number State

50 Genes

7 OMIM loci

25 MB Deletion in q-arm, chro 4

6 OMIM loci

Unbalanced translocation

20 Genes

Copy Number State

Array Data2.5 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 Data2.5 MB Deletionin q-arm, chro 22

Copy # x2

Copy # x1

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 of 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

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 autopsyPlacental pathologyMaternal 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 probableor possible INCODE cause of deathPertinent 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

JAMA. 2011;306(22):2459-2468

0%

10%

20%

30%

40%

50%

60%

70%

% U

sefu

lTest 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%

% U

sefu

lFetal Growth Restriction: Helpful Tests

(n = 53)

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

100%

% U

sefu

lHypertensive Disorders: Helpful Tests

(n = 50)

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

% U

sefu

lPreterm Labor, Chorioamnionitis,

PPROM: Helpful Tests (n = 77)

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

100%

% U

sefu

lSuspected Fetal Anomalies: Helpful

Tests (n = 31)

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

% U

sefu

lNo 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

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 of 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

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

We Can Do Better!

The Lancet’s Series onEnding

preventable stillbirths

Phot

o: S

uzan

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e/Sa

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Indi

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