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Central Biological Mechanism

A. Hemorrhage into the tissue factor-rich decidua (abruption) generates thrombin which binds to its protease-activated receptors (1 and 3) to enhance COX-2 expression triggering increased prostaglandin F2 alpha (PGF2alpha) synthesis, as well as matrix metalloproteinases (MMPs), and the potent neutrophile chemoattractant, interleukin (IL)-8.
B. Thrombin-PAR interactions also activate the ERK1/2 MAPK pathway to inhibit decidual cell progesterone receptor (PR) expression and activity, further promoting prostaglandin, protease, and inflammatory cytokine release to cause fetal membrane rupture, cervical change, and myometrial contractions resulting in preterm birth (PTB).
C. Changes in the vaginal microbiome can trigger an ascending genital tract infection (chorioamnionitis) resulting in increased IL-1beta production which in turn induces COX-2 (and prostaglandins), MMPs and IL-8 (with neutrophile infiltration) in the cervix, decidua, and ultimately the myometrium, and amnion-chorion. IL-1beta also activates ERK1/2 MAPK to inhibit PR expression, exacerbating prostaglandin and protease production to cause PTB with or without fetal membrane rupture.
PAR: protease-activated receptors; ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase; MMP: matrix metalloproteinase; COX-2: cyclooxygenase 2; IL: interleukin; PGF2alpha: prostaglandin F2-alpha; PR: progesterone receptor; GR: glucocorticoid receptor; CRH: corticotropin-releasing hormone; FKBP51: FK506-binding protein 51; PTB: preterm birth.
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PathogenesisspontPTB.gif
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D. Maternal and/or fetal stress-induced and idiopathic premature activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis enhances fetal cortisol production which increases placental CRH expression to create a feed-forward loop of fetal HPA axis activation and cortisol production. CRH has direct proparturition effects and cortisol increases decidual cell production of FKBP51 which inhibits PR action to trigger the parturition cascade and cause PTB.
E. Uterine stretch associated with polyhydramnios and multifetal gestation induces formation of myometrial gap junctions, oxytocin receptors and myosin light chain kinase, and produces amnion-chorion and cervical derived inflammatory cytokines, prostaglandins, and proteases to promote PTB. Patients may have multiple pathogenic pathways active simultaneously.



Table
Name
Mechanisms
Potential Drug Classes
Targetable Therapeutic Mechanisms
1
Inflammation
Intra-amniotic inflammation, caused by infection or damage-associated molecular patterns (DAMPs), is a significant contributor to sPTB.
Key points:
Infection-induced sPTB may involve different pathways than premature HPA axis activation.
Systemic and genitourinary tract pathogens, as well as altered microbiomes, are associated with sPTB.
Asymptomatic bacteriuria is independently associated with PTB.
Clinical and subclinical chorioamnionitis are more common in preterm than term deliveries.
The prevalence of Lactobacillus-poor vaginal communities is inversely correlated with gestational age at delivery.
Microbial invasion of the amniotic cavity can lead to inflammation and activation of the innate immune system.
Bacterial degradation of membranes and direct uterotonic effects.
Bacterial induction of maternal-fetal inflammatory responses, leading to uterotonic effects.
Increased levels of proinflammatory mediators have been found in amniotic fluid, vaginal-cervical secretions, and serum of patients with preterm labor, which can contribute to sPTB. Some examples of these mediators include:
Interleukin (IL) 1, 6, and 8
Tumor necrosis factor (TNF)
Granulocyte colony-stimulating factor (G-CSF)
Colony-stimulating factor 2 (CSF-2)
Matrix metalloproteinases (MMPs)
Prostaglandins cause uterine contractions and cervical ripening, while MMPs degrade the extracellular matrix, leading to membrane weakening and rupture.
​
tumor necrosis factor (TNF) inhibitors
interleukin (IL)-6 inhibitors
IL-1 receptor antagonists.
2
Pathological Uterine Distension
Multiple gestation, polyhydramnios, and other causes of excessive uterine distention are well-described risk factors for sPTB.
Myometrial and fetal membrane distention contribute to myometrial activation, preterm cervical ripening, and PPROM.
As the uterus expands due to fetal growth, mechanical stretch on the myometrium can trigger preterm labor.
Stretch-induced activation of mechanosensitive ion channels leads to increased intracellular calcium levels, which in turn stimulate uterine contractions.

Inhibitors of mechanosensitive ion channels, calcium channel blockers, and oxytocin receptor antagonists.
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3
Decidual Activation
Decidual cells play a critical role in maintaining pregnancy
activated by factors such as infection or inflammation, they can produce cytokines, chemokines, and MMPs, promoting uterine contractions and membrane rupture
Decidual hemorrhage, specifically decidual vasculopathy and retroplacental hematoma, has been implicated in the pathogenesis of spontaneous preterm birth (sPTB).
Decidual vasculopathy is characterized by the presence of atherosis in the spiral arteries, resulting in reduced blood flow to the intervillous space and placental hypoxia.
Vascular Factors
Impaired placental perfusion and abnormal angiogenesis
Release of factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)
Retroplacental hematoma, a blood clot between the placenta and uterine wall, is believed to result from hemorrhage of these compromised vessels.
Decidual vasculopathy and retroplacental hematoma can lead to placental infarction, ischemia, and hypoxia, which are associated with sPTB.
The exact mechanisms underlying the relationship between decidual hemorrhage and sPTB are not fully understood, but they may involve inflammation, oxidative stress, and activation of the maternal and fetal immune systems.
Decidual hemorrhage (placental abruption) is associated with a high risk of preterm labor and PPROM.
Hormonal factors, such as progesterone, play a modulatory role.
Thrombin activation contributes to various mechanisms leading to sPTB.
Angiogenesis modulators, antioxidants, agents that improve uteroplacental perfusion
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4
Genetic factors
Genetic predisposition and variations in genes related to inflammation, coagulation, and extracellular matrix remodeling can increase the risk of preterm labor.
sPTB demonstrates familial aggregation.
Genetic factors may be involved in the risk of sPTB.
Ethnic differences in risk of sPTB suggest a genetic component.
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5
Stress Pathway
Fetal stress caused by uteroplacental vascular insufficiency.
Relationship between fetal stress and sPTB or indicated PTB.
Impact of major maternal psychosocial stress on sPTB risk.
Relationship between Stress and Hormonal Changes Leading to sPTB
Fetal or maternal stress can induce premature activation of the fetal HPA axis.
Hormonal changes involved in sPTB: CRH, ACTH, cortisol, prostaglandins, and glucocorticoids.
Placental Clock and CRH
Role of stress-induced increases in placental CRH in programming the placental clock for labor and delivery.
Accelerated process leading to PTB marked by elevated maternal CRH levels.
Positive and Negative Feedback Loops in Hormonal Regulation
Increasing levels of CRH, glucocorticoids, and prostaglandins during gestation.
High concentrations of CRH in maternal and fetal blood and amniotic fluid by term.
Role of prostaglandins in cervical maturation and uterine contractility.
Estrogens and sPTB
Conversion of DHEA and DHEA-S to estrone (E1), estradiol (E2), and estriol (E3) in the placenta.
Elevated circulating estrogens as a marker for sPTB.
Impact of elevated estrogens on gap junction formation, oxytocin receptors, prostaglandin activity, and muscle contraction.
FKBP51 and Functional Progesterone Withdrawal
Glucocorticoids induce FKBP51, which inhibits PR and GR activity.
Increased FKBP51 expression in decidual cells during human labor at term.
Stress-induced functional intracellular progesterone withdrawal mediated by increased decidual FKBP51 expression and FKPB51-PR binding to promote sPTB.
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6
Cervical Insufficiency
Cervical insufficiency may lead to previable pregnancy loss and sPTB.
Cervical cerclage may be helpful in select instances.
Inherited pathogenic variants may play a role in sPTB.
​
​
7
Hormonal Factors
Column 5 Slide 5: Hormonal Factors * Importance of progesterone and its anti-inflammatory and uterine quiescence effects * Decreased progesterone levels or action leading to preterm labor * Increased levels of corticotropin-releasing hormone (CRH) * Potential drug targets: Progesterone supplementation, progesterone receptor modulators, CRH antagonists
Potential drug targets: Progesterone supplementation, progesterone receptor modulators, and CRH antagonists.
Progesterone, a hormone crucial for maintaining pregnancy, has anti-inflammatory and uterine quiescence effects. A decrease in progesterone levels or its action can lead to preterm labor. Additionally, increased levels of corticotropin-releasing hormone (CRH) can stimulate the production of prostaglandins, leading to uterine contractions.
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Molecular Targets for PreTerm Labor
Name
Mechanism
Column 5
Companies
Notes
1
Progesterone Receptor Modulators: Progesterone is critical for maintaining pregnancy, and its withdrawal is associated with the onset of labor. Targeting the progesterone receptor with modulators, including progesterone, 17-hydroxyprogesterone caproate (17-OHPC), and selective progesterone receptor modulators (SPRMs), could help maintain uterine quiescence and prevent preterm labor.
Progesterone: Crucial for maintaining pregnancy, progesterone withdrawal is associated with the onset of labor (Scurlock et al., 2022). Progesterone supplementation helps maintain uterine quiescence and prevent preterm labor by binding to progesterone receptors.
17-hydroxyprogesterone caproate (17-OHPC): This synthetic progestogen acts similarly to progesterone, maintaining uterine quiescence by binding to progesterone receptors (Scurlock et al., 2022).
Selective progesterone receptor modulators (SPRMs): These modulators selectively target progesterone receptors, promoting uterine quiescence and preventing preterm labor (Scurlock et al., 2022).
​
Open
2
​
​
Tumor necrosis factor (TNF) inhibitors: These drugs inhibit the proinflammatory cytokine TNF, thereby reducing inflammation that contributes to preterm labor (Scurlock et al., 2022).
Interleukin (IL)-6 inhibitors: By inhibiting the proinflammatory cytokine IL-6, these drugs help reduce inflammation associated with preterm labor (Scurlock et al., 2022).
IL-1 receptor antagonists: These antagonists block the IL-1 receptor, thereby reducing inflammation related to preterm labor (Scurlock et al., 2022).
​
Open
3
Targeting Oxytocin Pathway: Oxytocin is a critical hormone involved in uterine contractions. Drugs that target the oxytocin pathway, such as oxytocin receptor antagonists (atosiban and nolasiban), may help reduce uterine contractions and prevent preterm labor.
​
Oxytocin receptor antagonists: Atosiban and nolasiban inhibit oxytocin receptors, reducing oxytocin-induced uterine contractions and preventing preterm labor (Scurlock et al., 2022).
​
Open
4
Targeting Prostaglandin Pathway: Prostaglandins are key mediators of inflammation and uterine contractions. Inhibiting the prostaglandin pathway with drugs like cyclooxygenase-2 (COX-2) inhibitors, prostaglandin F2α receptor (FP) antagonists, or prostaglandin E2 receptor (EP) antagonists could help prevent preterm labor.
​
Cyclooxygenase-2 (COX-2) inhibitors: These drugs inhibit COX-2, an enzyme involved in prostaglandin synthesis, thereby reducing inflammation and uterine contractions (Scurlock et al., 2022).
Prostaglandin F2α receptor (FP) antagonists: By blocking FP receptors, these antagonists reduce the action of prostaglandin F2α on uterine contractions (Scurlock et al., 2022).
Prostaglandin E2 receptor (EP) antagonists: These drugs inhibit EP receptors, reducing the action of prostaglandin E2 on uterine contractions (Scurlock et al., 2022).
​
Open
5
Targeting Calcium Channels: Calcium channels play a crucial role in uterine muscle contraction. Drugs like calcium channel blockers (nifedipine) can help inhibit uterine contractions and reduce the risk of preterm birth.
​
Calcium channel blockers (e.g., nifedipine): These drugs inhibit the influx of calcium into uterine smooth muscle cells, reducing uterine contractions and preventing preterm labor (Scurlock et al., 2022).
​
Open
6
Targeting Gap Junctions: Gap junctions facilitate cell-to-cell communication and are involved in the coordination of uterine contractions. Inhibiting gap junctions, specifically connexin 43, could help disrupt the synchronization of uterine contractions and delay labor.
​
Connexin 43 inhibitors: By inhibiting connexin 43, a key component of gap junctions in uterine smooth muscle cells, these drugs disrupt the synchronization of uterine contractions and delay labor (Scurlock et al., 2022).
​
Open
7
Relaxin: Relaxin is a hormone that plays a role in the relaxation of uterine smooth muscle. Targeting the relaxin pathway with relaxin receptor agonists may help maintain uterine quiescence and prevent preterm labor.
​
Relaxin receptor agonists: These drugs activate relaxin receptors, promoting the relaxation of uterine smooth muscle and preventing preterm labor (Scurlock et al., 2022).
​
Open
8
Prolactin Receptor Modulation: Prolactin receptor modulators, such as bromocriptine, are being investigated for their potential role in maintaining uterine quiescence and preventing preterm labor.
​
Bromocriptine: A dopamine agonist that inhibits prolactin secretion, bromocriptine is being investigated for its potential role in maintaining uterine quiescence and preventing preterm labor (Scurlock et al., 2022).
​
Open
9
Targeting the Endothelin Pathway: Endothelins are potent vasoconstrictors and play a role in uterine contractility. Drugs targeting the endothelin pathway, such as endothelin receptor antagonists (macitentan), could help prevent preterm labor by reducing uterine contractions.
​
Endothelin receptor antagonists (e.g., macitentan): These drugs block endothelin receptors, reducing the action of potent vasoconstrictors (endothelins) on uterine contractility and potentially preventing preterm labor (Scurlock et al., 2022).
​
Open
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"Preterm birth: emerging therapies"

Title: Preterm birth: emerging therapies
Authors: Laura J. Scurlock, Lila K. Knight, and Tracy A. Manuck
Journal: American Journal of Obstetrics and Gynecology
Publication Date: 2022
PMCID: PMC8268657
Summary:
This review article discusses emerging therapies for preterm birth (PTB) and provides an overview of potential drug targets. Here are the primary drug targets identified in the paper:
Progesterone Receptor Modulators: Progesterone is critical for maintaining pregnancy, and its withdrawal is associated with the onset of labor. Targeting the progesterone receptor with modulators, including progesterone, 17-hydroxyprogesterone caproate (17-OHPC), and selective progesterone receptor modulators (SPRMs), could help maintain uterine quiescence and prevent preterm labor.
Inhibition of Inflammatory Pathways: Inflammation plays a significant role in PTB. Several drug targets focus on inhibiting inflammatory pathways, including tumor necrosis factor (TNF) inhibitors, interleukin (IL)-6 inhibitors, and IL-1 receptor antagonists.
Targeting Oxytocin Pathway: Oxytocin is a critical hormone involved in uterine contractions. Drugs that target the oxytocin pathway, such as oxytocin receptor antagonists (atosiban and nolasiban), may help reduce uterine contractions and prevent preterm labor.
Targeting Prostaglandin Pathway: Prostaglandins are key mediators of inflammation and uterine contractions. Inhibiting the prostaglandin pathway with drugs like cyclooxygenase-2 (COX-2) inhibitors, prostaglandin F2α receptor (FP) antagonists, or prostaglandin E2 receptor (EP) antagonists could help prevent preterm labor.
Targeting Calcium Channels: Calcium channels play a crucial role in uterine muscle contraction. Drugs like calcium channel blockers (nifedipine) can help inhibit uterine contractions and reduce the risk of preterm birth.
Targeting Gap Junctions: Gap junctions facilitate cell-to-cell communication and are involved in the coordination of uterine contractions. Inhibiting gap junctions, specifically connexin 43, could help disrupt the synchronization of uterine contractions and delay labor.
Relaxin: Relaxin is a hormone that plays a role in the relaxation of uterine smooth muscle. Targeting the relaxin pathway with relaxin receptor agonists may help maintain uterine quiescence and prevent preterm labor.
Prolactin Receptor Modulation: Prolactin receptor modulators, such as bromocriptine, are being investigated for their potential role in maintaining uterine quiescence and preventing preterm labor.
Targeting the Endothelin Pathway: Endothelins are potent vasoconstrictors and play a role in uterine contractility. Drugs targeting the endothelin pathway, such as endothelin receptor antagonists (macitentan), could help prevent preterm labor by reducing uterine contractions.
In summary, the article identifies various drug targets for emerging therapies to prevent preterm birth. These targets include progesterone receptor modulators, inhibitors of inflammatory pathways, oxytocin and prostaglandin pathway modulators, calcium channel blockers, gap junction inhibitors, relaxin, prolactin receptor modulators, and endothelin pathway inhibitors.

Detailed list of molecular targets identified in the paper "Preterm birth: emerging therapies" (Scurlock, Knight, & Manuck, 2022) along with their mechanisms of action:
Progesterone Receptor Modulators
Progesterone: Crucial for maintaining pregnancy, progesterone withdrawal is associated with the onset of labor (Scurlock et al., 2022). Progesterone supplementation helps maintain uterine quiescence and prevent preterm labor by binding to progesterone receptors.
17-hydroxyprogesterone caproate (17-OHPC): This synthetic progestogen acts similarly to progesterone, maintaining uterine quiescence by binding to progesterone receptors (Scurlock et al., 2022).
Selective progesterone receptor modulators (SPRMs): These modulators selectively target progesterone receptors, promoting uterine quiescence and preventing preterm labor (Scurlock et al., 2022).
Inhibition of Inflammatory Pathways
Tumor necrosis factor (TNF) inhibitors: These drugs inhibit the proinflammatory cytokine TNF, thereby reducing inflammation that contributes to preterm labor (Scurlock et al., 2022).
Interleukin (IL)-6 inhibitors: By inhibiting the proinflammatory cytokine IL-6, these drugs help reduce inflammation associated with preterm labor (Scurlock et al., 2022).
IL-1 receptor antagonists: These antagonists block the IL-1 receptor, thereby reducing inflammation related to preterm labor (Scurlock et al., 2022).
Targeting Oxytocin Pathway
Oxytocin receptor antagonists: Atosiban and nolasiban inhibit oxytocin receptors, reducing oxytocin-induced uterine contractions and preventing preterm labor (Scurlock et al., 2022).
Targeting Prostaglandin Pathway
Cyclooxygenase-2 (COX-2) inhibitors: These drugs inhibit COX-2, an enzyme involved in prostaglandin synthesis, thereby reducing inflammation and uterine contractions (Scurlock et al., 2022).
Prostaglandin F2α receptor (FP) antagonists: By blocking FP receptors, these antagonists reduce the action of prostaglandin F2α on uterine contractions (Scurlock et al., 2022).
Prostaglandin E2 receptor (EP) antagonists: These drugs inhibit EP receptors, reducing the action of prostaglandin E2 on uterine contractions (Scurlock et al., 2022).
Targeting Calcium Channels
Calcium channel blockers (e.g., nifedipine): These drugs inhibit the influx of calcium into uterine smooth muscle cells, reducing uterine contractions and preventing preterm labor (Scurlock et al., 2022).
Targeting Gap Junctions
Connexin 43 inhibitors: By inhibiting connexin 43, a key component of gap junctions in uterine smooth muscle cells, these drugs disrupt the synchronization of uterine contractions and delay labor (Scurlock et al., 2022).
Relaxin
Relaxin receptor agonists: These drugs activate relaxin receptors, promoting the relaxation of uterine smooth muscle and preventing preterm labor (Scurlock et al., 2022).
Prolactin Receptor Modulation
Bromocriptine: A dopamine agonist that inhibits prolactin secretion, bromocriptine is being investigated for its potential role in maintaining uterine quiescence and preventing preterm labor (Scurlock et al., 2022).
Targeting the Endothelin Pathway
Endothelin receptor antagonists (e.g., macitentan): These drugs block endothelin receptors, reducing the action of potent vasoconstrictors (endothelins) on uterine contractility and potentially preventing preterm labor (Scurlock et al., 2022).
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