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 Unpublished data, 2002.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

Compendium on Preterm BirthPathophysiologic 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