27 June 2023: Review Articles
A Review of the Mechanism of Action and Clinical Applications of Osmotic Dilators for Cervical Ripening in the Induction of Labor and in Gynecology ProceduresMaciej W. Socha 12ABCDEF*, Wojciech Flis 12EF, Mateusz Wartęga 3EF, Aleksandra Kunicka 2F, Martyna Stankiewicz 2ABC
Med Sci Monit 2023; 29:e940127
ABSTRACT: Cervical ripening is defined as the significant softening of the cervical tissue that usually begins before the onset of contractions during labor, and is required for cervical dilation and delivery. Osmotic dilators are medical implements that dilate the uterine cervix by increasing in size as they absorb fluid from the surrounding tissue. This article aims to review the mechanisms and applications of osmotic dilators for cervical ripening in the induction of labor and in gynecology procedures.
Keywords: Cervical Ripening, Labor, Induced, Laminaria, Obstetrics, Dilapan
Despite the fact that the human cervix is a small part of the uterus, it plays an important role in various processes . During the course of pregnancy, the cervix maintains a physical barrier, so the fetal development remains undisturbed. It is also actively involved in parturition by becoming soft and susceptible so the fetus can be delivered . In a non-pregnant state, cervical epithelium provides a structural and immunoprotective barrier mediated by the production of cytokines and antimicrobials . Dilatation of the cervical canal is a component of many obstetric and gynecological procedures. It is required in gynecological procedures such as brachytherapy, preparation for operative hysteroscopy, and preparation for surgical abortion . In obstetrics, cervical ripening is crucial for proper labor preinduction. Suitable labor preinduction can prevent dysfunctional labor. Since the dawn of time, gynecological practitioners have sought to obtain the best method to achieve cervical dilatation through experimentation with various materials. The ideal dilatation agent should be clinically effective, easy to use, cost-effective, and safe for the patient. Over the years, many effective methods to dilatate the cervical canal have been developed . The cervix is often prepared with osmotic or mechanical dilatators (both synthetic and organic) or with pharmacological methods. The latest studies show that no single cervical ripening method is superior, considering safety outcomes and efficiency . Correct and appropriate cervical dilatation is pivotal for the proper and safe conduct of the required diagnostic and therapeutic procedures involving the cervix and the interior of the uterus . In recent years, the role of osmotic dilatators (both synthetic and Laminaria) in gynecological and obstetric procedures has been expanding. Osmotic dilatators are medical implements used to dilatate and soften the cervix by swelling as they absorb fluid from the surrounding cervical tissue. Their composition differs depending on their origin. Therefore, we can distinguish natural or synthetic dilators.
The present study is an in-depth analysis of the available literature using the keywords: labor, induction of labor, cervical ripening, Laminaria, Dilapan, osmotic dilators. An analysis of the literature in the last 15 years was made, also taking into account older papers relating to the biology of the cervix. This article aims to review the mechanisms of action and applications of osmotic dilators for cervical ripening in the induction of labor and in gynecology procedures.
Anatomy of the Cervix
The human uterine cervix is a passive organ located at the lower end of the uterus. It is developed (together with the uterus and vagina) from Mullerian ducts. It can be divided into a supravaginal portion and a lower portion. The cervical canal runs between the internal and external os. The cervix consists of connective tissue, ground substance, and a small amount of smooth muscle that make up about 10% of its dry weight. In addition, fibroblasts and wandering cells can be found in the cervical tissue. The columnar epithelium lines the cervical canal. Its cells are responsible for the production of a large amount of mucus composed mainly of water, enzymes, glycoproteins, and ions. The extracellular matrix (ECM) contains a large amount of collagen (mainly type I and III), glycosaminoglycans (GAGs), and elastin fibers [5–7]. Collagen fibers are cross-linked together by covalent bonds, which provides collagen molecules stability. The ground substance of cervical tissue (cervical stroma) is formed of glycosaminoglycans (GAGs), which are responsible for maintaining cervical tissue hydration and strength. GAGs chains create covalent bonds with the protein core, leading to creation of proteoglycans. Proteoglycans subsequently create bonds with collagen fibers . This close association plays a pivotal role in providing cervical strength. The composition of the cervical stroma is determined by fibroblasts, which synthesize and degrade the major extracellular matrix elements .
In general, the process of cervical ripening is the result of an inflammatory process accompanied by enzymatic breakdown of the extracellular matrix. The whole process is under strict regulation by hormonal factors . The main mediator of these changes are metalloproteinases (MMPs), which digest ECM components, leading to significant loosening of the previously tightly packed structure of the cervical stroma . The main sources of MMPs are neutrophils and macrophages, and their concentration in the cervical tissue significantly increases at term [10,11]. The activity of these cells (and the activity of MMPs) is significantly stimulated by pro-inflammatory cytokines, nitric oxide, and prostaglandins [11–14]. The most important cytokines involved in this process are interleukin-1 (IL-1) and interleukin-8 (IL-8) [15,16]. IL-1 directly stimulates the activity of cyclooxygenase 2 (COX-2), which enhances the production of prostaglandins (PGs) and increases the activity of MMPs . IL-8 is an extremely strong chemotactic factor for neutrophils, which increases their concentration in the cervical tissue . Additionally, IL-8 greatly enhances secretion of nitric oxide (NO). Nitric oxide strongly induces local vasodilation (which intensifies inflow of inflammatory cells), increases the activity of pro-inflammatory cytokines, and stimulates PGs production in cervical stroma [6,18–21]. Hormones such as ACTH and CRH are extremely important factor regulating the whole process [22–24].
Overall, this process consists of a series of complex biochemical pathways that results in rearrangement of the cervical ECM. Subsequently, the cervix significantly relaxes and becomes more susceptible, which makes the cervix prone to dilation.
Osmotic dilatators are medical devices used to dilatate the cervix. They are dehydrated rods that can be placed in the cervical canal. The 2 types of osmotic dilatators currently available differ in origin: Laminaria and Dilapan-S. A Laminaria stick (of natural origin) is made from seaweed (
Although both types of osmotic dilators (Dilapan and Laminaria) are safe and highly effective, there are several dissimilarities between them , related mainly to the origins of Laminaria and their processing. They are created without modifications and result in properties depending on the portion of the plant from which the dilator is made . Therefore, Laminaria has been reported to have several differences from synthetic osmotic dilators. Firstly, using Laminaria may be associated with an increased risk of infection because bacterial spores can remain in the tents despite sterilization of Laminaria [39,40]. Secondly, use of Laminaria can be associated with hypersensitivity reactions and anaphylaxis [41,42], believed to be mediated by IgE . Finally, compared with Laminaria, synthetic dilators are entirely sterile, achieve larger cervical dilatation in a shorter timeframe, and swell more rapidly [44–47]. Additional advantages of synthetic dilators are the consistency of length and shape and, therefore, more predictable results (Table 1). The main disadvantage of the synthetic dilator is that Dilapan-S shortens as it swells (unlike Laminaria). Therefore, there is a theoretical possibility of dilator entrapment or fracture in the cervical canal . Considering the above, we believe that synthetic dilators are more suitable and preferable, with fewer adverse effects in medical procedures involving cervical dilatation.
Mechanism of Action
The mechanism of action of osmotic dilators has been known for years. However, recent studies clearly show that their mechanism of action is vastly more complex and multi-step than previously assumed. The basic principle of operation of osmotic dilators results from their hygroscopic nature. After application, these dilators absorb moisture (through their hygroscopic properties), drawing fluid from surrounding cervical tissue, which softens the tissue. As the dilators absorb fluid, axial expansion occurs, which applies a radial force to the walls of the cervical canal , subsequently leading to mechanical dilatation of the cervical canal. However, their impact on cervical tissue is not limited to a mechanical effect; ripening of the cervix is a process by which the cervix transforms from closed and rigid to soft and susceptible, and the cervical maturation process is complex, involving enzymatic breakdown, inflammatory reaction (accompanied by an infiltration of leukocytes), and endocrine regulation. Cervical remodeling is possible because of the reactions mediated by specific factors: nitric oxide, prostaglandins, and inflammatory cytokines. Osmotic dilators affect cervical tissue composition through the above factors . Research has unequivocally shown that insertion of Laminaria in the cervical canal significantly increases the concentration of IL-1, IL-8, and PGE2, and elastase activity in cervical mucus [48–50]. IL-1 and IL-8 are basic factors involved in cervical ripening. IL-1 (occurring in 2 isoforms – IL-1α and IL-1β) can upregulate COX-2, which in turn increases the production of prostaglandins . Additionally, IL-1 stimulates the production of other inflammatory cytokines involved in cervical ripening and enhances the expression of matrix metalloproteinases (MMPs), which can cleave collagen cross-links [1,6]. IL-8 is another important player in cervical ripening; it is a powerful neutrophil chemotactic agent that releases MMPs and inflammatory cytokines [6,52]. Moreover, IL-8 can increase vascular permeability, which subsequently increases the inflow of inflammatory cells [53,54]. IL-8 also stimulates fibroblasts to produce hyaluronic acid, which is another pivotal regulatory factor in cervical ripening [55,56]. Prostaglandins (PGs) are another important factor significantly participating in cervical maturation. PGs (mainly PGE2) can strongly stimulate (mainly via EP4 receptor) MMPs activity, upregulate IL-8 synthesis, and stimulate vasodilatation [47,56–58]. Apart from their impact on the cervical tissue, PGs also strongly affect uterus contractions. A possible explanation for the phenomenon of increased pro-inflammatory cytokines and PGs production during the use of Laminaria tents is that mechanical stretching of fetal membranes and myometrial cells (caused by Laminaria tent placement) dramatically increase secretion of factors such as PGs, IL-8, and hyaluronic acid (HA) [48,58–61] (Figure 1). Although the hygroscopic properties of osmotic dilators are considered the principal mechanism promoting cervical dilatation, osmotic dilators can drastically increase the production and release of PGs. Therefore, biochemical as well as mechanical factors may enhance cervical dilatation in women treated with osmotic dilators.
Brachytherapy is an extremely important part of oncological treatment, especially in gynecological oncology. It is a form of radiation therapy in which the radiation source is placed directly in or in close proximity to a malignant tumor . Proper cervix preparation can significantly influence the brachytherapy procedure. Inadequate and forcible dilatation of the unprepared cervix can perforate the uterus or rupture the cervix, leading to life-threatening hemorrhage. Moreover, inadequate dilatation of the cervix before planned brachytherapy can result in incorrect placement of the applicator, which can significantly affect the effectiveness of the entire therapy . Proper placement of the applicator is crucial for homogenous distribution of the radiation dose throughout the pelvis, ensuring adequate tumor coverage and sparing adjacent organs . Theoretically, using osmotic dilators to dilate the cervical canal before planned brachytherapy can positively affect the correct placement of the applicator, resulting in the proper administration of radiation to diseased tissue. Research has shown that cervical osmotic dilation with a synthetic osmotic agent before planned brachytherapy can reduce treatment-associated morbidity and allow the delivery of adequate radiation therapy. Moreover, it can minimize discomfort associated with the procedure and thus eliminate the need for general or local anesthesia, which is highly important, especially in patients for whom anesthesia is contraindicated . Finally, the absence of the need to use anesthesia significantly reduces the duration of the entire cervical brachytherapy procedure [65,66]. Additionally, placement of a Laminaria tent during pre-planning MRI for cervical cancer brachytherapy can improve the accuracy of image fusion with planning computed tomography (CT), which helps to delineate a more accurate brachytherapy profile . Considering the above, we believe that using osmotic dilators prior to the cervical brachytherapy applicator placement can significantly improve the overall course of radiation therapy. However, this topic requires further studies.
Hysteroscopy is a very important diagnostic and therapeutic tool in managing patients with infertility, suspected intrauterine cavity, and abnormal uterine bleeding . It gained immense popularity due to its minimally invasive approach to intrauterine lesions. Adequate dilation of the cervical canal during operative hysteroscopy is one of the key elements of the entire procedure . Cervical dilation can be challenging, particularly in nulligravidae, postmenopausal women, and women with cervical stenosis. Furthermore, some lengthy hysteroscopic operations (such as myomectomy) require proper cervical dilation to facilitate repeated insertions of the resectoscope. Inadequate cervical dilation prior to the hysteroscopy can lead to cervical laceration, uterine perforation, and the creation of a false passage during attempts to dilate the cervix . Additionally, a proper degree of cervical dilation is required to extract previously excised lesions in the uterine cavity. In conclusion, proper cervical preparation is essential for conducting operative hysteroscopy and avoiding dangerous complications. Various agents have been tried to achieve cervical ripening of the cervix prior to operative hysteroscopy. These agents include osmotic dilators and prostaglandins (eg, misoprostol). However, it is still debatable which of the agents is superior in terms of cervical dilatation efficiency, safety of use, and possible adverse effects [71–74]. Recent studies clearly show that an osmotic dilator is more effective than misoprostol at achieving cervical ripening prior to operative hysteroscopy and has a lower percentage of adverse effects than vaginal misoprostol [73,75]. Moreover, an osmotic dilator achieved greater spontaneous dilation of the cervix than the vaginal misoprostol . On the other hand, vaginal misoprostol seems to have an advantage due to its easy application, reduced cost, convenience, and patient acceptability . However, using vaginal misoprostol in preoperative cervical ripening is associated with an increased rate of adverse effects such as febrile episodes, diarrhea, abdominal pain, and vaginal bleeding [75–78]. It has also been shown that intravaginal administration of misoprostol is more effective than oral administration in achieving preoperative cervical ripening . Considering the above, we believe that osmotic dilators may be the superior tool to achieve cervical ripening prior to the operative hysteroscopy, with fewer adverse effects. Despite misoprostol’s advantages, it has a much higher percentage of adverse effects than osmotic dilators. It is advisable to explore this topic further to determine the appropriate dose of misoprostol with the fewest possible adverse effects.
Induced surgical abortion is one of the most common surgeries performed worldwide. The vast majority of abortions are performed in the first trimester [79,80]. The entire procedure consists of curettage or evacuation preceded by dilatation of the cervical canal . Proper cervical ripening before pregnancy termination by dilatation and suction curettage (D&C) greatly improves the procedure course and safety. Adequate cervical preparation is pivotal to safe abortion practice across all gestations. Forceful cervical dilatation is associated with cervical or uterine trauma with possible subsequent hemorrhage, infection, or adverse reproductive outcomes such as pregnancy loss, cervical insufficiency, and preterm birth . Possible complications from D&C increase with advancing gestational age . Therefore, the safety and success of the procedure largely depends on adequate cervical ripening. The cervix may be prepared with osmotic agents, pharmacological agents, or both. However, so far, it has not been possible to clearly establish which of the agents used to ripen the cervix has the best effectiveness and safety profile . The most common pharmacological agent used to ripen the cervix prior to a surgical abortion is misoprostol. Its superiority lies in its effectiveness, low costs, and convenience of use with multiple routes of administration. The major disadvantage of misoprostol is its adverse effects, such as nausea, vomiting, and abdominal pain [82,83]. On the other hand, osmotic dilators are well-known cervical ripening agents with high efficiency and a small percentage of adverse effects. Their major drawbacks are the prolonged time required for cervical preparation and the need for vaginal examination with a speculum for proper application of the rod . The main risks associated with using osmotic agents are pain, vasovagal reactions, allergic reactions, infection (rather when using Laminaria than synthetic dilators), and the possibility of dilator entrapment leading to intra-abdominal perforation [44,55,84,85–88]. Research shows that both Laminaria and misoprostol provide sufficient dilatation of the cervical canal for surgical abortion [87,88]. However, Laminaria seems to be a more effective cervical dilator (achieving greater dilatation of the cervix) than vaginal misoprostol for surgical abortion [87,90]. Moreover, using Laminaria is associated with a lower percentage of adverse effects such as nausea, vomiting, and vaginal bleeding [3,89–90]. Other studies comparing buccal misoprostol and osmotic dilators before surgical abortion have shown that either buccal misoprostol or osmotic dilator provides adequate preoperative dilatation of the cervical canal. However, the use of buccal misoprostol was associated with more pain . Taking the above into account, we believe that although misoprostol has a similar effectiveness and a much easier route of administration, osmotic dilators appear to be slightly more effective due to the greater dilatation of the cervical canal and have a lower percentage of adverse effects in the maturation of the cervix before surgical abortion. Also noteworthy is the comparison of the effectiveness of natural (Laminaria) and synthetic (Dilapan-S) osmotic dilators. Research has unequivocally shown that Dilapan-S is superior to Laminaria in cervical ripening prior to surgical abortion. Moreover, the use of synthetic dilators allows greater dilatation of the cervix in a shorter time [44,45,88,89]. A puzzling issue is the simultaneous use of Laminaria and misoprostol for the induction of abortion. Interestingly, concurrent insertion of Laminaria and vaginal misoprostol did not improve the abortifacient effect of misoprostol . Moreover, the addition of misoprostol to osmotic dilators was not found to increase cervical dilation . Considering all the above, we believe that cervical preparation with osmotic dilators or misoprostol before surgical abortion is safe and effective. However, we suggest that osmotic dilators may be superior to misoprostol for cervical dilation and have fewer adverse effects.
Over 20% of pregnant women undergo labor induction, and approximately half of them require a ripening agent due to an unfavorable cervix [92,93]. Cervical ripening is a process involving physically detectable softening, shortening, and dilatation of the uterine cervix . The ripening process is a multifactorial process governed by endocrine changes, inflammatory response (accompanied by infiltration of leukocytes), and other biological changes. Research is ongoing to better understand this process’s molecular and biochemical basis . Currently, prostaglandins, progesterone antagonists, and mechanical devices (eg, Foley catheter) have been used to ripen the cervix. Each of the above methods has a different degree of effectiveness and safety. No single cervical ripening method seems to be superior in safety and efficacy . Prostaglandins are highly effective in cervical ripening. However, using prostaglandins (mainly misoprostol) is associated with significant adverse effects such as uterine hyperstimulation, uterine rupture (especially in previous cesarean sections), fetal heart rate changes, and fetal hypoxia. Additionally, use of prostaglandins is associated with nausea, vomiting, and abdominal pain . Inflatable balloon catheters are also known to be strongly effective in cervical ripening, with fewer adverse effects, but they can cause cervical tissue injury and scarring. Moreover, the application of balloon catheters (eg, Foley catheter) can be associated with an increased risk of umbilical cord prolapse [96–98]. The role of osmotic dilators (both synthetic and natural) in labor preinduction has been constantly growing. Recent studies show that using osmotic dilators in labor preinduction is highly effective, with a small number of adverse effects and with minimal potential to cause uterine hyperstimulation [99–103]. As mentioned earlier, there are significant differences between Laminaria and synthetic osmotic dilators, with a possible higher rate of adverse effects when using Laminaria. In labor preinduction, the use of synthetic osmotic dilators (eg, Dilapan-S) appears to be preferable because it can shorten the induction-to-delivery interval, with fewer devices required to obtain significant cervical dilatation and with fewer adverse effects . Patient satisfaction is an important factor determining the effectiveness of a cervical ripening agent. Compared to the Foley balloon, patients were more satisfied with a synthetic osmotic dilator in terms of time to relaxation and performance of daily activities . Osmotic dilators are extremely effective in preinduction of labor after cesarean section. Additionally, their use reduces the risk of uterine hyperstimulation and rupture, which is of great importance in the preinduction of labor after cesarean sections [105–107]. Combining a synthetic osmotic dilator with vaginal prostaglandins or a progesterone antagonist (mifepristone) may lead to more effective cervical ripening and more rapid induction-to-delivery interval than prostaglandins or mifepristone alone . However, the benefits of the combined use of vaginal prostaglandins and synthetic osmotic dilators are outweighed by an increased incidence of intrauterine infections .
Considering all the above, we believe that osmotic dilators are highly effective in labor preinduction. Thanks to their properties, they have a low percentage of adverse effects and are well tolerated by patients, which is a pivotal factor in the proper preinduction of labor.
This article aims to review the mechanisms of action and applications of osmotic dilators for cervical ripening in the induction of labor and in gynecology procedures.
The main emphasis was placed on the role of osmotic dilators in specific clinical situations (both gynecological and obstetrical), detailing the safety profile and efficiency of using dilators. We limited the information on the anatomy and molecular biology of the cervix to the minimum necessary to understand the mechanism of action of osmotic dilators. The data presented above indicate that osmotic dilators are extremely effective in preparing the cervix for planned diagnostic and therapeutic procedures. We suggest that their effectiveness is mainly due to their dual action. Firstly, due to the ability to absorb water from surrounding tissues (thanks to their hygroscopic properties), they can apply a radial force to the cervical canal, leading to cervical dilatation. Secondly, mechanical stretching of myometrial cells and fetal membranes can increase the secretion of PGs and IL-8, which are strong cervical ripening factors.
Natural osmotic dilators (Laminaria) are a puzzling issue that requires special attention. Although they are less effective and have a greater number of adverse effects compared to synthetic dilators, they may be useful in other situations. Taking all the above information into account, we believe that using synthetic osmotic dilators (in comparison with natural osmotic dilators) is more effective and much safer for the patient, with fewer adverse effects. Considering surgical abortion, the available data unequivocally suggest that osmotic dilators are more effective cervical dilators than are pharmacological agents. However, using osmotic dilators may also be associated with a small spectrum of adverse effects (as are other cervical ripening agents), the possibility of dilator entrapment, and the prolonged time required to achieve proper cervical dilatation. Further research is necessary to accurately assess the risk of adverse effects and impact on quality of life regarding cervical preparation and the patient’s preferences for using osmotic dilators and pharmacological agents. It is also worth noting that when comparing synthetic and natural osmotic dilators, it is possible to achieve greater cervical dilatation with a much shorter time using synthetic dilators. Therefore, we believe that the use of synthetic osmotic dilators prior to a surgical abortion is not only more effective but also has fewer adverse effects. The concurrent insertion of Laminaria and vaginal misoprostol did not improve the abortifacient effect of misoprostol. However, no data are available on the simultaneous use of a synthetic osmotic dilator with a pharmacological agent (eg, misoprostol). Bearing in mind the effectiveness of using a synthetic dilator, further research should evaluate the effect of the concurrent use of misoprostol with a synthetic osmotic dilator (Dilapan-S).
An extremely interesting topic is the use of osmotic dilators in the preinduction of labor. Presented data clearly indicate that osmotic dilators (in particular synthetic dilators) are highly effective in cervical ripening, with a small number of adverse effects (especially with minimal potential to cause uterine hyperstimulation). Moreover, the simultaneous application of a synthetic osmotic dilator with vaginal prostaglandins (or progesterone antagonist) may lead to much more effective cervical ripening.
Detailed knowledge of the mechanisms responsible for the maturation of the cervix is pivotal for the safe and proper preparation of the cervix. Therefore, understanding the events that lead to cervical ripening can lead to the development of more effective and safer labor induction methods. Moreover, comprehensive knowledge of cervical biology and selecting the appropriate cervical ripening agent can significantly influence delivery success and may prevent women from having dysfunctional labor. Therefore, we believe that it is necessary to further expand the (already extensive) knowledge in the field of cervical biology.
We also believe that synthetic osmotic dilators are a highly effective form of cervical ripening agents, as proven by many studies. Moreover, it is important to realize that brown algae (a natural dilator) are not constant in their biomass composition. The harvesting season of brown algae significantly affects their composition, which may affect their effectiveness and possibly cause adverse effects. However, further clinical trials and studies are required to more accurately assess the effect of changes in brown algae biomass on their effectiveness. As mentioned, Laminaria is composed mainly of cellulose, laminarin, and ions. Laminarin is a mucopolysaccharide that has versatile biomedical potential. Recent studies show that laminarin has antioxidant properties and can be used in cancer therapy or tissue engineering . However, this requires more careful research to clearly define the effects of this substance on the tissues of the female reproductive system. Moreover, the use of Laminaria probably contributes to some extent to the detachment of placenta . We believe that the substances contained in Laminaria can influence the fibrinolytic activity. However, this topic requires further, in-depth research to determine the exact effect of Laminaria on hemostasis and their possible applications.
According to the presented data, osmotic dilators are effective cervical ripening agents and therefore can be effectively used in gynecological and obstetric procedures. They can be successfully used in the induction of labor, preparation for surgical abortion, or as a preparation for elective brachytherapy in the case of endometrial cancer or cervical cancer.
We suggest that more research is needed to carefully compare the efficacy, possible adverse effects, and patient satisfaction of using the most commonly used cervical maturation (such as pharmacological agents or Foley catheter) with osmotic dilators. Careful study of this topic will allow selection of the most appropriate cervical ripening agent (with the best possible safety profile) and may significantly influence the success of delivery and prevent women from experiencing dysfunctional labor.
FiguresFigure 1. Diagram showing the molecular and biomechanical mechanism of action of osmotic dilators. Swelling of osmotic dilator leads to applying a radial force to the walls of cervical canal. These events lead to mechanical dilation. Mechanical stretching of cervical tissue and surrounding membranes leads to enhanced secretion of IL-1, IL-8, PGs, and HA (which are the main cervical ripening mediators). Increased concentrations of the above substances lead to total rearrangement of the cervical extracellular matrix, thus significantly softening the cervix. PGs – prostaglandins; IL-1 – Interleukin-1; IL-8 – Interleukin-8; HA – hyaluronic acid. Created using MS Word software.
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