1. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth Produced in cooperation with: American Academy of Pediatrics The American College of Obstetricians and Gynecologists Association of Women’s Health, Obstetric and Neonatal Nurses © March of Dimes 2006

2. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Objectives  At the completion of this section, participants should be able to: –Demonstrate four major pathophysiologic pathways involved in the progression to preterm delivery Inflammation Activation of the maternal/fetal hypothalamic-pituitary- adrenal axis Decidual hemorrhage Pathologic distension of the uterus –Identify the common final pathway to preterm birth –Describe possible areas for research related to the pathways

3. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Complex Interactions in Preterm Birth Source: Green NS et al., AJOG 2005 ;193:626-35.

4. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Pathways to Preterm Birth Source: Lockwood CL. Unpublished data, 2002. proteases PTD Uterine Contractions Cervical Change Infection: - Chorion-Decidual - Systemic Decidual Hemorrhage CRH E1-E3 Thrombin Thrombin Rc Pathological Uterine Distention Multifetal Pregnancy Polyhydramnios Uterine Abnormality Inflammation Maternal-Fetal Stress Premature Onset of Physiologic Initiators Activation of Maternal-Fetal HPA Axis CRH + Chorion Decidua uterotonins Mechanical Stretch Gap jct PG synthase Oxt recep PPROM Ils, Fas L TNF + Abruption

5. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006  Inflammation  Infection - ~40%  Activation of the maternal-fetal hypothalamic– pituitary–adrenal (HPA) Axis  Stress - ~30%  Decidual hemorrhage  Abruption - ~20%  Uterine distension  Stretching - ~10% Pathways to Preterm Birth Sources: Lockwood CJ, Iams JD. Preterm labor and delivery. In: Precis: Obstetrics, 3rd ed. ACOG, 2005; Lockwood CJ, Kuczynski E. Paediatr Perinat Epidemiol 2001;15:78-89.

6. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Iams JD. Unpublished figure, 2003. Inflammation, Preterm Birth & Neonatal Outcomes Pro- Inflammatory Maternal Factors Anti- Inflammatory Maternal Factors Bacteria Fetal Response Maternal Response Normal Neonatal Mortality Morbidity Long-Term Morbidities Gestational Age 

7. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Pathway to Preterm Birth  Inflammation –Maternal and fetal cytokine response (interleukin-1  and tumor necrosis factor  ) Stimulates prostaglandin production –  Uterine contractions Enhanced protease and cytokine production (Matrix metalloproteinases and interleukin-8) –  Breakdown of fetal membranes and cervix

8. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. Copyright 1999 by Walter de Gruyter and Company. Reproduced with permission of Walter de Gruyter and Company via Copyright Clearance Center. Inflammation Amniochorionic-decidual systemic inflammation TNF/IL-1 Proteases/apoptosis rupture of membranes cervical change IL-6 CRH Uterotonins (PG, endothelin) contractions + + + FasL

9. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Infections Associated with Preterm Birth  Sexually transmitted infections  Bacterial vaginosis  Genitourinary infections –Asymptomatic bacteriuria –Pyelonephritis  Pneumonia  Peritonitis  Periodontal disease

10. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Pathway to Preterm Birth  Maternal/fetal HPA axis activation –  Corticotropin-releasing hormone (CRH)  Maternal and fetal adrenal cortisol –  Prostaglandin production  Fetal adrenal dehydroepiandrosterone sulfate (DHEAS) production –  Placental estrogen production

11. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. Copyright 1999 by Walter de Gruyter and Company. Reproduced with permission of Walter de Gruyter and Company via Copyright Clearance Center. HPA Axis Activation: The Role of CRH Maternal/Fetal HPA Axis glucocorticoid placental/membrane/decidual CRH PGs CRH-BP + + contractions cervical change rupture of membranes

12. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. Copyright 1999 by Walter de Gruyter and Company. Reproduced with permission of Walter de Gruyter and Company via Copyright Clearance Center. HPA Axis Activation: The Role of Estrogens & Cortisol Activation of Fetal HPA Axis UPV abnormality Early onset physiologic initiators ACTH Adrenal cortisolDHEA/16-OH DHEA Placenta, Decidua Fetal Membrane Placenta ? membranes CRHE1-E3 PG + Myometrial oxytocin receptors, gap jct, MLCK calmodulin, PG synthase + + contractionscervical changerupture of membranes

13. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Risk Factors Associated With HPA Axis Activation  Maternal psychosocial stress –Domestic violence –Racism  Fetal physiological stress –Compromised uteroplacental blood flow –Placental pathology

14. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Pathway to Preterm Birth  Decidual hemorrhage –Release of decidual tissue factor –Initiation of coagulation cascade and thrombin production causing: Cervical ripening Fetal membrane damage  PPROM Uterine contractions

15. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. Copyright 1999 by Walter de Gruyter and Company. Reproduced with permission of Walter de Gruyter and Company via Copyright Clearance Center. Decidual Hemorrhage FVIIa/TF FXa Thrombin uPA + tPA plasmin Extravasation of clotting factors Active MMPs ECM Degradation clot contractionscervical change rupture of membranes

16. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Risk Factors for Decidual Hemorrhage  Placental abruption –Maternal smoking –Maternal cocaine use –Chronic hypertension with superimposed preeclampsia –Maternal trauma –IUGR –Hereditary coagulopathies

17. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Pathway to Preterm Birth  Abnormal uterine distension –Mechanical stretching  Myometrial gap junctions Activation of oxytocin receptors Prostaglandin synthesis

18. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Source: Lockwood CJ, Kuczynski E. Markers of risk for preterm delivery. J Perinat Med 1999;27:5-20. Copyright 1999 by Walter de Gruyter and Company. Reproduced with permission of Walter de Gruyter and Company via Copyright Clearance Center. Abnormal Uterine Distension Uterine distention Uterine expansile capacity Myometrial activation Fetal membrane cytokine activation contractionsrupture of membranescervical change 

19. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Risk Factors for Abnormal Uterine Distension  Multifetal pregnancy  Polyhydramnios  Structural uterine anomalies

20. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006  Inflammation –Interleukin-1 –Tumor necrosis factor  Activation of the maternal / fetal hypothalamic– pituitary–adrenal (HPA) axis –Corticotropin-releasing factor (CRH) –Estradiol  Decidual hemorrhage –Thrombin activation  Uterine distension –Myometrial stretch Source: Lockwood CJ, Iams JD. In: Precis: Obstetrics, 3rd ed. ACOG, 2005. Summary of Mediators for Preterm Birth

21. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Common Final Pathway to Preterm Birth  Increase in uterotonins –Prostaglandins –Endothelin –Oxytocin  Increase in protease expression –Matrix metalloproteinases (MMP-1 and MMP-9) –Plasminogen activator –Plasmin –Elastase

22. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006 Clinical Research Strategies  Prevention of ascending genital tract infections  Control of cytokine responses  Prophylactic heparin therapy for thrombophilias  Refinement of infertility practices