Racial Disparities in Pregnancy Complications

Racial Disparities in
Pregnancy Complications
Should we design diagnostic tests based on race?
Alison Woodworth, PhD, DABCC, FACB
AACC-SES Audio Conference Series
2/23/11
Infant Mortality
• Infant mortality -death of an infant prior to 1 year
• No significant change has been observed since
2000 (Significant reduction 1995 – 2000)
• In the United States in 2006: Infant mortality 6.7 Infant Deaths / 1000 live births
• Healthy people 2010 –Goal to reduce infant
mortality rates to 4.5% and racial disparity
• Research aimed at reduction of causes
Infant mortality rates
US, 2006
Southeast is
well above
national
average and
4.5% goal!!!
An infant death occurs within the first year of life.
Source: National Center for Health Statistics, final mortality data, 1990-1994 and period linked birth/infant death data, 1995-present.
Retrieved February 23, 2011, from www.marchofdimes.com/peristats.
Infant Mortality Rates by Race
US, 2004-2006 Average
An infant death occurs within the first year of life.
Source: National Center for Health Statistics, period linked birth/infant death data. Retrieved July 21, 2010, from
www.marchofdimes.com/peristats.
Infant Mortality by Cause
US, 2006
SIDS is Sudden Infant Death Syndrome. RDS is Respiratory Distress Syndrome. "Maternal Preg. Comp." stands for "Maternal Complications of Pregnancy." Cause of death for 19961998 is based on the Ninth Revision, International Classification of Diseases (ICD-9); cause of death for after 1998 is based on the Tenth Revision, International Classification of
Diseases (ICD-10).
Source: National Center for Health Statistics, period linked birth/infant death data. Retrieved July 21, 2010, from www.marchofdimes.com/peristats.
Racial Disparities in
Pregnancy Outcomes
Bryant et al. AJOG. 2010
Preeclampsia
• Multisystem disorder due to poor placentation
- 2nd half of pregnancy
•Affects up to 8% of pregnancies
•Leading cause of maternal death
(50,000/yr)
• A major cause of perinatal morbidity
and mortality (900,000/yr) worldwide
• Despite extensive research no methods of
prediction or prevention
Racial Disparities in PE
• PE ~2X higher in African Americans than Caucasians
Mortality Rate per 100
hospitalizations with
delivery
Healy, AJ et al. Obstet and gynecol 107(3): 625 – 31, 2006 and Tanaka, M et al. Am J Public Health. 97(2): 163 – 170, 2007.
4
3.5
3
2.5
2
1.5
1
0.5
0
3.4
2.9
2.1
1.7
White
Black
Hispanic
1999-2002
Other
Adapted from Tanaka, M et al.
Symptoms of Preeclampsia
Maternal Syndrome
• Hypertension, edema, proteinuria
• Thrombocytopenia
• Liver dysfunction
HELLP syndrome
• Seizures, stroke
Eclampsia
Fetal Syndrome
• Intrauterine Fetal Growth Restriction (IUGR)
• oligohydramnios
• abnormal oxygenation
Proposed Etiologies of Preeclampsia
Increased in Maternal Serum
Anti-angiogenic factors
Placental Debris
Reactive O2 species
Proinflammatory cytokines
C. W. Redman et al., Science 308, 1592 -1594 (2005)
Decreased in Maternal Serum
Angiogenic factors
Predictors of Preeclampsia
• Risk factors – Advanced maternal age, primiparity,
obesity, insulin resistance, chronic hypertension, preexisting thrombophilias, and limited sperm exposure
• History of preeclampsia
• Multi-fetal gestation
• Edema, Hypertension, Proteinuria
• Doppler ultrasonography- Uterine artery blood flow
• Circulating biochemical markers:
Angiogenic (VEGF,PlGF) and antiangiogenic (sFlt1, sEng)
sFlt-1 and PlGF
• Antiangiogenic factor sFlt-1sequesters proangiogenic
PlGF and VEGF
• Ratio of sFLT-1/PlGF provides the best Predictive value
• Prospective, multicenter trial
• N= 409 controls (High and low risk)
48 cases
• Method = Beckman Access IA
Ideal Cut-off for Preterm PE =137
Sensitivity = 96%, Specificity = 97%
Sunderji et al AJOG 2010
IL-6 and Preeclampsia
• Increase in systemic inflammation in PEelevated CRP in PE
• IL-6 elevation is maternal serum during PE
• Secreted by decidual cells in response to
inflammation
Lockwood, CJ et al. AJP. 172(6): 1571-1577, 2008.
• A role in the pathobiology of PE - IL-6 infused
pregnant rats developed proteinuria and
increased blood pressure
Orshal and Khalil. Hypertension. 43: 434-444, 2004.
Other Markers for Prediction of
Preeclampsia
Analyte/
Sample
Cutoff
GA (wks) Predictive
Reference
Collection
Values
SEng
> 7.2
ng/mL
21 - 32
OR = 9.4
Levine et al.
NEJM 2006
PP-13
< 0.39
MoM
8 - 13
Sens 100%
Spec 80%
Romero R et al.
Am J Obs Gyn
2008
24 - 33
Sig in PE
Zhong et al. Clin
Chem 2005
Fetal DNA N/A
sLSelectin
< 1414
ng/mL
20
Sens = 84
Spec = 90
Chavarria et al.
Eur J Obs Gyn
Rep Biol. 2007
NO Inh.
(ADMA)
N/A
23 – 25
in PE, IUGR,
abn doppler
Savvidou et al.
Lancet 2003
Prospects for Preeclampsia
Predictive Markers
• Limited knowledge of pathogenesis and genetic basis of
preeclampsia limits identification of good predictive
preeclampsia markers
• Uniform definition of PE since 2000 has allowed for
more accurate studies
• Heterogeneity in results of different studies
• Long-term prospective studies are needed with well
defined patient populations and rigorous laboratory and
study design
• WHO Global Program to Conquer Preeclampsia
mid-2006
Preterm Birth (PTB)
• Delivery before 37 weeks gestation
• Two types – Spontaneous and Induced
• Occurred in 12.7% of births
in 2007 (500,000 births/yr)
• 20% increase since 1990
• Accounts for >75% of fetal & neonatal
deaths in babies w/o anomalies
• The majority of surviving preterm infants
suffer serious morbidity
Racial Disparities in Preterm Birth
National Prevalence (%)
Change
-3%
20%
12%
35%
Adapted from Heron et al. Pediatrics. 125:4-15, 2010.
Etiologies of Preterm Birth
Uterine
Distension
Hematologic
Cervical
Disease
Hormonal/
STRESS
Inflammation
Infection
Unknown
GENETICS ?
(Roberto Romero, MD)
Predictors of Preterm Birth
• Symptoms of labor
• Genetics
• History of preterm delivery
• Multi-fetal gestation
• Cervical Evaluation by sonography
or digital exam
• Biochemical markers:
fFN, Salivary Estriol, Cytokines
Fetal Fibronectin (fFN)
• ECM Glycoprotein with unique
“oncofetal domain” (FDC-6)
• Located at choriodecidual
interface – Key for implantation
• In cervicovaginal fluid (CVF)
prior to term labor –glycosylation
• PTL - mechanical or local
inflammation
Courtesy of Hologic
• Absence of fFN in CVF 24 – 36
weeks gestation good predictor
of those who Won’t deliver
Preterm or w/in 14 days
PPV < 20%, NPV > 95%,
Cytokines in Preterm Delivery
• ~40-50% of preterm labor associated w/ infection
• Chorioamnionitis (CAM) -Infection involving chorion,
amnion, amniotic fluid, placental villi, and decidua
• If CAM present
4X increase in neonatal mortality
• Only 12.5% of those women show clinical evidence
• CAM triggers cytokine production and synthesis and
release of prostaglandins
cervical ripening and uterine contractions
Interleukin-6 in Preterm Delivery
• Interleukin-6 (IL-6) and other in
response to infection or injury.
• >50% of PTL associated w/
infection and/or inflammation
• IL-6 stimulates Delivery (left)
• IL-6 in CVF w/ microbial invasion
of the intra-amniotic cavity
•Absence of IL-6 in CVF = good
predictor of No delivery in 2 weeks
Gomez R et al. Am J Obstet Gynecol 1998
PPV < 40%, NPV > 94%
IL-6 and fFN Predict Delivery <14 Days
N = 725 Left over fFN specimens – Multiple sights
Analyte
(cut-off)
PPV
(%)
NPV
(%)
LR +
LR -
Odds
ratio
95% CI
IL-6
(250 pg/mL)
15
98
4.83
0.52
9.3*
4.1 – 20.8
fFN
(50 ng/mL)
14
99
4.48
0.41
11.1*
4.8 – 25.5
*p <0.0001
Woodworth et. al. Clin Chem 2007
Neither is a strong diagnostic test for prediction of PTB in < 14 days
IL-6 and fFN to Predict Delivery
Clinical Variable
Gestational age @ delivery (wks)
(Pos.-neg.) [95% CI]
Interval-collection to birth (days)
(Pos.-neg.) [95% CI]
Preterm Birth (Del > 37 wks)
(Odds Ratio) [95% CI]
*P<0.001, +P<0.007
fFN
IL-6
(Pos > 50 ng/mL)
(Pos >250 pg/mL)
-2.4
[-3.4, -1.4]*
-1.7
[-2.7, -0.7]+
-20.1
-17.0
[-29.6, -10.6]* [-26.2, -7.8]+
7.5
[2.6, 21.6]*
4.4
[1.6, 12.1]+
N= 127 Patients
Racial Disparities and Genetics
• Evidence of genetic predisposition to PTB: Twin studies,
History (personal or family), and Racial Disparities
• Differences in AF concentrations of cytokines between
Cases and Controls – not universal
Menon, R. Acta Obstet Gynecol Scand. 87: 6, 590 – 600. 2008
SNPs in IL-6 Correlate with
Differential Protein Expression
European American
African American
Menon, R et al. Am J Obs Gynecol. 198:77. e1-7.
Racial/Genetic Differences in
Etiologies of PTB
Genetic Parameter
PTB SNP Pathway(s)
Maternal or Fetal
Influence
IL-6 SNP Expression
AF-IL-6 Expression
African
American
Caucasian
Dermatologic,
Inflammatory Disease Inflammatory, and
Hematologic diseases
Fetal
Maternal
Significant Difference in frequencies of
13/20 tested (Allelic and Genotypic)
Elevated in Term &
PTB
Menon et al Reprod Biol Endocrinol 2009; Velez et al Ann Hum Gen 2009
Elevated in PTB
Diagnostic Utility of IL-6 and fFN
in AA and Caucasian Women
• Retrospective cohort study
• Cervicovaginal samples sent to BJH for fFN testing
collected for 5 years (2001 – 2005)
• Symptomatic and Asymptomatic women (all races)
• 24 0/7 - 34 6/7 weeks of gestation
• Singleton gestation
• C-sections & labor induction <14 days of delivery excluded
• Frozen -70 ºC
®
®
• IL-6 performed using DPC Immulite
Woodworth et al. Clin Chim Acta 2011
Patient Samples
1498 leftover cervicovaginal specimens
773 specimens excluded
(No chart, no race data, induction, twins, cervical
dilation or cerclage, vaginal bleeding, wrong GA,
sexual intercourse, placenta previa, result N/A)
725 samples with fFN and IL-6 testing
343 AA and 324 Caucasian
26 delivered < 14 days
(3.6 %)
17 AA
(5%)
7 Cauc
(2.2%)
2 Other
(3.4%)
699 delivered > 14 days
(96.4%)
326 AA
(95%)
317 Cauc
(97.8%)
56 Other
(96.6%)
Clinical Data Categorized By Race
Clinical Variable
Race
p
AA
(% AA)
Cauc
(% Cauc)
Total Samples (n=667, [% Total Samples])
343
324
Average GA at Sampling (wk, mean + SD)
30.4 + 2.7
29.6 + 2.7
*
Average GA at Delivery (wk, mean + SD)
37.7 + 0.14
37.8 + 0.13
NS
Interval–Sampling to Delivery (wk, mean ± SD)
7.3 + 0.2
8.2 ± 0.2
*
FFN Positive (> 50ng/mL) (n=104 [16%])
68 (20%)
36 (11%)
*
IL-6 Positive (> 250 pg/mL) (n=83 [12%])
51 (15%)
29 (9%)
*
Delivery <7 Days of Sampling (n=16 [2.2%])
11(3.2%)
5(1.5%)
NS
Delivery <14 Days of Sampling (n=26 [3.6%])
17(5%)
7(2.2%)
NS
Total Deliveries (n=580)
316 (52%)
264 (43%)
Preterm Deliveries < 37 Weeks GA (n=101 [17%])
62 (20%)
39 (15%)
NS
Deliveries < 32 Weeks GA (n =14 [2.4%] )
9 (2.8%)
5 (1.9%)
NS
Bacterial Vaginosis or Chorioamnionitis (n=124 [21%])
89 (28%)
35 (13%)
*
ROC Curves- PTB < 14 days
250
250
250
Area Under the Curve
Total Population
0.760
Caucasian
0.749
African American
0.762
Racial Disparity in Diagnostic Markers- Delivery = 14 d
LR +
LR-
Odds
Ratio
95% CI
P
fFN
4.48
0.41
11.1
4.8 – 25.5
<0.0001
IL-6
4.83
0.52
9.3
4.1 – 20.8
<0.0001
fFN
5.66
0.48
11.9
2.5 – 55.5
0.004
IL-6
3.24
0.78
4.1
0.8 – 22.2
0.13
fFN
3.7
0.43
8.7
3.1 – 24.4
<0.0001
IL-6
5.15
0.40
12.7
4.5 – 36.3
<0.0001
Race Analyte
All
Cauc
AA
Woodworth et al. Clin Chim Acta 2011
Racial Disparity in Diagnostic Markers- Delivery = 7 d
LR +
LR-
Odds
Ratio
95% CI
P
fFN
5.8
0.2
23.5
6.8 – 80.9
<0.0001
IL-6
5.6
0.4
13.2
4.7 – 37.4
<0.0001
fFN
6.4
0.2
35.9
3.9 – 331
0.0006
IL-6
4.6
0.7
6.9
1.1 – 43.2
0.07
fFN
4.6
0.2
20.8
4.4 – 99
<0.0001
IL-6
5.5
0.3
17.5
4.5 – 68.3
<0.0001
Race Analyte
All
Cauc
AA
Woodworth et al. Clin Chim Acta 2011
Genetic Influence on Preterm Birth
GENETICS
Uterine
Distension
Cervical
Disease
Hormonal/
Stress
Hematologic
Inflammation
Infection
(Roberto Romero, MD)
Unknown
Racial Disparities in Diagnostic
Markers for PTB - Conclusions
• Racial disparities in PTB rates may be related to
differences in pathobiological pathways associated with
PTB in AA versus Caucasian women
• Cervicovaginal IL-6 and fFN have similar diagnostic
strengths in a racially diverse population (NPV >98%).
• IL-6 in AAs and fFN in Caucasians are the only tests with
sufficient diagnostic strength to rule-in delivery in 14 days.
• Diagnostic testing algorithms based upon race/genetics
and/or etiology may more accurately predict PTB.
Conclusions
• Racial disparities in incidences of preeclampsia and preterm
birth may lead to disparities in infant mortality rates.
• No PE biomarkers are currently recommended for routine use
– sFlt1/PlGF ratio is the most promising
– IL-6 may be involved in pathobiology
• Cervicovaginal IL-6 and fFN have similar diagnostic strengths in
a racially diverse population (NPV >98%).
• IL-6 in AAs and fFN in Caucasians are the only tests with
sufficient diagnostic strength to rule-in delivery within 14 days.
• Diagnostic testing algorithms based upon race may provide a
more accurate prediction of women who will deliver preterm and
those at risk for preeclampsia
Acknowledgments
Vanderbilt University
Elizabeth O’Keeffe
Emily Bishop
Courtney Moffett
Terri Scott
Beckman Coulter
DPC Immulite
Washington University
Ann Gronowski
Jennifer Moore
Christopher G’Sell
Bram Verdoes
University of North Carolina
David Grenache
Jennifer Snyder
Lee Morris
Catherine Wares