Inflammation and Risk for Prematurity

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Inflammation and Risk for Prematurity

• Amy P. Murtha, MD
• Duke 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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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 lt30 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 cordocentesis associated
  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 lt1)
• 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, P0.02)

(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
(Jenny, Arterioscler Thromb Vasc Biol, 2002)
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IL-6 -174G/C and Race
(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 PTDlt34 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 Perinat
  Epidemiol, 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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