Post on 29-Dec-2015
Compendium on Preterm BirthCompendium on Preterm Birth
Pathophysiologic Pathways Pathophysiologic Pathways to Preterm Birthto Preterm Birth
Produced in cooperation with:American Academy of PediatricsAmerican Academy of Pediatrics
The American College of Obstetricians and GynecologistsThe American College of Obstetricians and Gynecologists
Association of Women’s Health, Obstetric and Neonatal NursesAssociation of Women’s Health, Obstetric and Neonatal Nurses
© March of Dimes 2006
Compendium on Preterm BirthPathophysiologic 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
Compendium on Preterm BirthPathophysiologic Pathways to Preterm Birth © March of Dimes 2006
Complex Interactions in Preterm Birth
FA
CT
OR
S
External Environment
Immune Status
Nutrition
Behaviors
Medical Conditions
Medical Interventions
Psychosocial
Oth
ers: Ho
rmo
nes?
Toxin
s?
Bleed
ing
/ Th
rom
bo
ph
ilias
Ab
no
rmal U
terine D
istentio
n
Matern
al / Fetal S
tress
Inflam
matio
n / In
fection
PRETERM BIRTH
OUTCOMES
Preterm Labor / pPROM
Racial / Ethnic Disparities
Genetics / Family History
Source: Green NS et al., AJOG 2005 ;193:626-35.
Compendium on Preterm BirthPathophysiologic Pathways to Preterm Birth © March of Dimes 2006
Pathways to Preterm Birth
Source: Lockwood CL. Unpublished data, 2002.
proteases
PTDUterine
ContractionsCervical Change
• Infection: - Chorion-Decidual - Systemic
DecidualHemorrhage
CRHE1-E3
ThrombinThrombin Rc
Pathological UterineDistention
• Multifetal Pregnancy• Polyhydramnios• Uterine Abnormality
Inflammation
• Maternal-Fetal Stress
• Premature Onset of Physiologic Initiators
Activation of Maternal-Fetal
HPA Axis
CRH+
ChorionDecidua
uterotonins
Mechanical StretchGap jctPG synthaseOxt recep
PPROM
Ils, Fas LTNF
+
Abruption
Compendium on Preterm BirthPathophysiologic 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.
Compendium on Preterm BirthPathophysiologic 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
MaternalFactors
Bacteria
FetalResponse
Maternal Response
Normal
NeonatalMortalityMorbidity
Long-TermMorbidities
Gestational Age
Compendium on Preterm BirthPathophysiologic 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 BirthPathophysiologic 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-6CRH
Uterotonins(PG, endothelin)
contractions
++
+FasL
Compendium on Preterm BirthPathophysiologic Pathways to Preterm Birth © March of Dimes 2006
Infections Associated withPreterm Birth
Sexually transmitted infections
Bacterial vaginosis
Genitourinary infections– Asymptomatic bacteriuria– Pyelonephritis
Pneumonia
Peritonitis
Periodontal disease
Compendium on Preterm BirthPathophysiologic 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 BirthPathophysiologic 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/decidualCRH
PGs CRH-BP+
+
contractions cervical change
rupture of membranes
Compendium on Preterm BirthPathophysiologic 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
ACTHAdrenal
cortisol DHEA/16-OH DHEA
Placenta, Decidua Fetal Membrane
Placenta? membranes
CRH E1-E3
PG+ Myometrial oxytocin receptors, gap jct,
MLCK calmodulin, PG synthase
+
+
contractions cervical change rupture of membranes
Compendium on Preterm BirthPathophysiologic 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 BirthPathophysiologic 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 BirthPathophysiologic 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
Decidual Hemorrhage
FVIIa/TF
FXa
Thrombin
uPA + tPA
plasmin
Extravasation of clotting factors
Active MMPs
ECM Degradation
clot
contractions cervical changerupture of membranes
Compendium on Preterm BirthPathophysiologic 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 BirthPathophysiologic 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 BirthPathophysiologic 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
contractions rupture of membranescervical change
Compendium on Preterm BirthPathophysiologic Pathways to Preterm Birth © March of Dimes 2006
Risk Factors for Abnormal Uterine Distension
Multifetal pregnancy
Polyhydramnios
Structural uterine anomalies
Compendium on Preterm BirthPathophysiologic 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
Compendium on Preterm BirthPathophysiologic 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