Immunology and preterm labor

Fetal Maternal Placental CRH Estrogen Protease synthesis Prostaglandins Inflammation DHEAS Cortisol Premature activation of the fetal HPA endocrine cascade Preterm labor PROM Myometrial activation Cervical ripening Exposure to bacterial endotoxins Secretion of cytokines and chemokines that activate cascades leading to labor Endotoxin activation of decidual cells/leukocytes

Microbes Evidence: association between some microbes and PTL Microbes detected more commonly in amniotic fluid in PTL Gardnerella vaginalis, Fusobacterium Mycoplasma hominis Ureaplasma urealyticum Intrauterine inflammatory response to infection Ligand (e.g. lipopolysaccharide of a bacteria) Recognized by and activate Toll-like receptors which present in the placenta on trophoblast cells Fixed and invading leukocytes On activation: Release of chemokines, cytokine and prostaglandins IL-1B Increased synthesis of other cytokines e.g. IL-6, IL-8, TNF alfa Proliferation , activation and migration of leukocytes Modifications in extracellular matrix proteins Mitogenic and cytotoxic effects such as fever and acute phase response Promotes prostaglandin formation in many tissues e.g. myometrium, decidua and amnion This cascade of events can result in PTL

Origin of cytokine in intrauterine infection

Cytokines:

Example

IL-1, IL-6, IL-8, TNF alfa

Source of cytokines

Leukocytes (fixed and invading) ( main source)

Stromal cells e.g. trophoblasts

Epithelial cells

The transfer of cytokines such as IL-1 from decidua across the membranes into amniotic fluid is limited

Cytokine produced in maternal decidua and myometrium will have effects on that side

Cytokines produced in the membranes or in cells within amniotic fluid will not be transferred to maternal tissues

Maternal decidua and myometrium cytokines:

At the time of labor, invading leukocytes invade

Cervix

Lower uterine segment

Fundus

Myometrium:

Invading leukocytes are main source

Decidua

Both stromal cells and invading leukocytes are sources

Cervix

epithelial cells ( glandular and surface), stromal cells and invading leukocytes are sources

Epithelial cells produce

IL-6, IL-8 and TNF alfa

IL-8 has critical role in cervical dilatation

Amniotic fluid cytokines

Evidence:

Presence of cytokines in amniotic fluid is associated with PTL

Source:

Amniotic fluid IL-1

Does not arise from amnion tissue, fetal urine or fetal lung secresion

Generated in situ:

Most likely secreted by mononuclear phagocytes or neutrophils activated and recruited into the amniotic fluid

Chemokines:

Example

monocyte Chemotactic protein-1

Function:

Leucocyte infiltration

In term labor:

Increased amniotic fluid concentrations of potent chemotactant and monocyte-macrophage activator, monocyte Chemotactic protein-1

PTL associated with higher level of Chemotactic factors

MCP-1 act as a marker for intra-amniotic infection and inflammation

Risk for preterm birth:

Idiopathic

Multifetal pregnancy

Prematurely ruptured membranes

Environmental factors

Maternal hypertension

Placenta previa

Cervical insufficiency

Fetal growth restriction

Premature cervical dilation

Placental abruption

Intrauterine infection

Maternal diabetes

Reproductive tract anomalies

PPROM

Definition:

Spontaneous rupture of fetal membranes before 37 completed weeks and before labor onset

Aetiology:

Major predisposing event  intrauterine infection

Pathogenesis:

Background:

Tensile strength derived form extracellular matrix

Collagens (mainly type I and III)

Produced by mesenchymal cells

Mechanism:

Collagen degradation:

Matrix metalloproteinase (MMP) family

Action:

collagen degradation

Regulated by

Tissue inhibitors of matrix metalloproteinases (TIMPs)

Expression of MMPs increased by IL-1, TNF alfa and IL-6

May be part of inflammatory process

In PPROM:

++ MMP-2, MMP-3, MMP-9

-- TIMPs

Collagen assembly:

Alteration in:

Proteins involved in synthesis of mature cross-linked collagen

Proteins that bind collagen and promote tensile strength

Apoptosis:

In PPROM

++ apoptosis

++ markers of apoptosis

Regulated by bacterial endotoxin IL-1Beta and TNF-alfa

Research:

Aim at identification of early markers for women at risk for PPROM

Sources of intrauterine infection:

Route:

Transplacental transfer of systemic infection

Retrograde flow of infection into peritoneal cavity via fallopian tubes

Ascending infection with bacteria from vagina and cervix

Four stages of infection:

Stage I:

Bacterial vaginosis

Stage II:

Decidual infection

Stage III:

Amniotic infection

Stage IV:

Fetal systemic infection