inflammation and risk for prematurity
TRANSCRIPT
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Inflammation and Risk for Prematurity
Amy P. Murtha, MDDuke University Medical Center
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Outline
• Preterm delivery• Inflammation in preterm delivery• Polymorphisms in inflammatory cytokines• Obstetrics and cytokine polymorphisms
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Preterm Delivery
• 6-8% of all pregnancies deliver preterm• No improvement in preterm delivery rates
with current management strategies• Causes include
– Preterm premature rupture of membranes– Preterm labor– Maternal or fetal complications
• Rates of LBW continue to rise
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Risk Factors for Preterm Delivery
• Previous obstetric history • Race/ethnicity• Vaginal bleeding• Multiple gestation• Incompetent cervix• Infection
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Risk Factors for Preterm Delivery
• Marital Status• Substance use• Pre-Pregnancy Weight• Stress• Maternal Age• Congenital Anomalies
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Racial Disparity for Preterm Birth and Infant Mortality
• LBW in singletons-– 11.4% in blacks – 5% in whites
• #1 contributor to disparity in infant mortality
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Infant Mortality Rates by Maternal Race andEthnicity, 1997 U.S. Death Cohort
1368.5
868.5
604.6 595.4497.7
0
200
400
600
800
1000
1200
1400
1600
Black Am/Ind White Hispanic Asian/Pas
Race and Ethnicity of Mother
Deaths per 100,000 live
births
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Preterm Birth and Family History
• Data from linked database of birth certificates of two generational cohorts
• Risk of PTD for preterm mothers was higher than those that had been born at term (OR 1.18)
• If preterm mother delivered <30 weeks OR increased to 2.38
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Preterm Birth and Inflammatory Response
• Increased TNF production in whole blood stimulated by LPS in patients with history of PTB (Amory et al, Am J Obstet Gynecol, 2001)
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Infection as a Noxious Stimuli
• BV is 2 times more prevalent among African Americans
• Higher prevalence not explained by known behaviors or risk factors
• High BV rates in African American women may account for up to 30% excess risk of PTD
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The Effects of Stress
• Endocrine system (CRH production)• Immune system response• Maternal behaviors
– smoking – nutritional status– substance abuse
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The Pathogeneses of Preterm Birth
• Decidual-chorioamniotic or systemic inflammation (40%)
• Activation of the maternal or fetal HPA (30%)
• Decidual hemorrhage (20%)• Pathologic overdistention (10%)
Lockwood and Kuczynski, Pediatric and Perinatal Epidemiology, 2001
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Inflammatory Mediators and Preterm Birth
• Produced by choriodecidual tissues in response to infectious stimuli
• Elevated in maternal serum, amniotic fluid, cord blood, cervical/vaginal secretions in PTL and PPROM
• FIRS- elevated IL-6 by cordocentesisassociated with serious neonatal complication (Gomez, 1998)
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Inflammatory Mediators and Intra-amniotic Infection
• Not always possible to document intra-amniotic infection
• Similar outcome in preterm patients with intra-amniotic inflammation and proven infection
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Interleukin-6
• Elevated in maternal serum in chorioamnionitis (Greig, 1996)
• Elevated in fetal cord blood with funisitis (Swamy, 2002)
• Elevated in PPROM with FIRS• In amniotic fluid of PPROM, PTL
especially in presence of infection
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Polymorphisms
• Common sequence variations that occur at a frequency greater than 1% – (Mutations occur <1%)
• Single nucleotide Polymorphism– occur every 500-1000 bases throughout the
genome– IL-6 gene polymorphism
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Polymorphisms
• VNTR- common polymorphism that result form slippage during DNA replication– several copies of a repeated unit
• GAGAGAGAGA
• Depending on location may result in alterations in protein production– exon may alter the protein– promoter region alter amount produced
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Cytokine Polymorphisms and Systemic Disease
• TNF: septic shock, RA, AIDs, MS, diabetes, lupus, graft versus host disease, cardiac and renal transplant rejection
• IL-6: JCA, cardiac disease, graft versus host disease and lupus
• IL-10: lupus, RA, asthma, cardiac and renal transplant rejection, graft versus host disease
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Polymorphism and Transplantation
• Bronciolitis Obliterans in lung transplant patients with IL-6 -174G/C and IFN-gamma(+874) (Lu, Transplantation, 2002)
• Carriers of IL-6 -174C allele had inferior graft survival with RR of 3.7 for graft loss (Muller-Steinhardt, Kidney Int, 2002)
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Cytokine Polymorphism and GVHD
• Acute GVHD independently associated with IL-10 gene polymorphisms– from the recipient (RR 7.9) and the donor (RR
3.5)
• Chronic GVHD independently associated with IL-6 gene polymorphism from recipient (RR 4.2, P=0.02)
(Socie, Transplantation, 2001)
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Interleukin-6 Polymorphisms• -174G/C, -597G/A, -572G/C
– named for location in the gene in relation to start codon
• -174 located in the promoter region of IL-6 gene– Guanine replaced by cytosine
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Interleukin-6 -174 G/C Polymorphism
• -174CC has been associated with elevated plasma levels in CABG patients (Brull, Arterioscler Thromb Vasc Biol, 2002)
• -174CC genotype is more responsive to statins (Basso, Arterioscler Thromb Vasc Biol, 2002)
• -174C allele associated with higher CRP, fibrinogen and IL-6 levels in CVD (Jenny, Arterioscler Throm Vasc Biol, 2002)
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Interleukin-6 and CRP
• Vickers (Cardiovascular Research, 2002)
– 98 Caucasian families in the UK (4-7 members)– Log CRP was strongly associated with the C
allele (as a dominant gene)– CRP levels are highly heritable phenotype
associated with IL-6 -174G/C polymorphism
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IL-6 -174G/C and Race
Race GG GC CCC Allele
FrequencyWhite 169 (40%) 188 (44%) 67 (16%) 38%
AfricanAmerican
182 (85%) 33 (15%) 0 (0%) 8%
(Jenny, Arterioscler Thromb Vasc Biol, 2002)
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IL-6 -174G/C and Race
Race GG GC CCC AlleleFrequency
White 46 (41%) 40 (39%) 16 (16%) 55%
AfricanAmerican
35 (81%) 8 (19%) 0 (0%) 19%
(Cox, Transplantation, 2000)
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Problems with Polymorphisms
• Many different polymorphisms– effect of polymorphism may be different
depending on the exposures• So many different candidate genes
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Obstetrics and Cytokine Polymorphisms
• Little available data• Will need to consider both environmental
exposures as well as genetic predisposition
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Tumor Necrosis Factor
• Case control study- 55 cases with 110 controls
• Cases included PTL and PPROM• TNF-308 more common in PPROM
compared to controls (OR 3.18, 95% CI 1.33-7.83)
(Roberts, Am J Obstet Gynecol, 1999)
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Interleukin-1
• IL-1 +3953, IL-1RN • 52 pregnancies that resulted in PTD<34
weeks 197 controls– IL-1 +3953 was associated with PTD in African
American– IL-1RN associated with PTD in Hispanics
Genc, Am J Obstet Gynecol, 2002)
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Interleukin-1 Receptor Antagonist
• Cohort study• 207 women in first trimester• 62% of the homozygote for allele 2
cultured positive for Ureaplasma– 47% of heterozygotes– 34% of homozygotes for the normal allele
• Vaginal concentrations of IL-1RA correlated with zygosity
(Barton, Infect Immun, 2003)
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Obstetric evidence for link
• Ongoing study examining 500 preterm birth trios and 500 controls (Wang et al, Paediatr PerinatEpidemiol, 2001)
– candidate genes- IL-1, IL-6, TNF, CRH, MTHFR, and susceptibility to environmental toxins
• Polymorphism in metabolic genes altered association between smoking and birthwieght
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Summary
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Now What?
• Preterm delivery is a highly heterogeneous complex syndrome determined by both genetic and environmental factors
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