Compendium on Preterm Birth Pathophysiologic Pathways to Preterm

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

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-pituitaryadrenal 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 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. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

Pathways to Preterm Birth Inflammation Activation of Maternal-Fetal HPA Axis Decidual Hemorrhage Pathological Uterine Distention Abruption • Multifetal Pregnancy • Polyhydramnios • Uterine Abnormality • Infection: - Chorion-Decidual - Systemic • Maternal-Fetal Stress • Premature Onset of Physiologic Initiators Thrombin Rc Ils, Fas L TNF CRH E 1 -E 3 Chorion Decidua Mechanical Stretch Gap jct PG synthase Oxt recep + CRH + proteases uterotonins PPROM Cervical Change PTD Uterine Contractions Source: Lockwood CL. Unpublished data, 2002. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

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

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 Unpublished figure, 2003.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

Inflammation Amniochorionic-decidual systemic inflammation IL-6 CRH TNF/IL-1 + Fas. L + + Uterotonins (PG, endothelin) contractions cervical change Proteases/apoptosis rupture of membranes 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. 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 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 Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

HPA Axis Activation: The Role of CRH Maternal/Fetal HPA Axis glucocorticoid + placental/membrane/decidual CRH PGs contractions cervical change CRH-BP + rupture of membranes 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. Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

HPA Axis Activation: The Role of Estrogens & Cortisol Early onset physiologic initiators UPV abnormality Activation of Fetal HPA Axis ACTH Adrenal + cortisol DHEA/16 -OH DHEA Placenta, Decidua Fetal Membrane CRH + + PG contractions Placenta ? membranes E 1 -E 3 Myometrial oxytocin receptors, gap jct, MLCK calmodulin, PG synthase cervical change rupture of membranes 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. 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 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 Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

Decidual Hemorrhage Extravasation of clotting factors FVIIa/TF FXa Thrombin u. PA + t. PA clot plasmin Active MMPs ECM Degradation contractions cervical change rupture of membranes 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. 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 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 Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

Abnormal Uterine Distension Uterine distention Uterine expansile capacity Myometrial activation contractions Fetal membrane cytokine activation cervical change rupture of membranes 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. 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 Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006

Summary of Mediators for Preterm Birth § 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, 3 rd ed. ACOG, 2005. 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 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 Compendium on Preterm Birth Pathophysiologic Pathways to Preterm Birth © March of Dimes 2006