Mechanisms of Premature Delivery
Premature delivery occurs in almost 7% of all births in Ukraine and 10% of all births in the United States. The premature delivery rate in developed countries has recently increased due to advanced maternal age and multiple pregnancies with the help of assisted reproductive technology (ART). There are several risk factors for premature delivery such as infection, low socioeconomic status, low body mass index, previous premature birth, obesity, cigarette smoking, maternal malnutrition, young or elderly age, periodontal disease, and poverty and genital bleeding in the first and second trimester.
Infection is considered the main cause of premature delivery. Bacteria are recognized by pattern recognition receptors, such as toll-like receptors, which induce the release of inflammatory chemokines and cytokines. Adenomyosis is considered as another important risk factor for premature delivery due to an increase in the synthesis of prostaglandins. Recent advances in molecular biology have revealed a new mechanism for premature delivery, but the vast majority remain unknown.
Stress-Related Premature Delivery
Maternal stresses, such as depression, anxiety and chronic stress, are associated with premature delivery. In addition, the risk of preterm delivery is increased in women who work for many hours. In the hypothalamus, glucocorticoids inhibit the release of corticotropin-releasing hormone (CRH). This reduces the expression of adrenal glucocorticoids in order to establish a classical negative feedback. During pregnancy, on the contrary, glucocorticoids stimulate the release of CRH from the placenta and embryonic membrane, and increased CRH increases the production of prostaglandins from the embryonic membrane, which play a decisive role in the birth of a newborn by stimulating cervical ripening, contraction of the myometrium and fetal membrane.
Maternal stress is caused by social factors, so it would be possible to reduce the level of preterm delivery by improving the living conditions of low-income people, reducing the working hours for pregnant women and providing psychological help to mitigate maternal mental stress.
Premature Delivery Associated With Infection
Intrauterine infection is an important cause leading to premature delivery, which accounts for approximately 25% of cases of premature delivery. Infection can occur between maternal decidua and fetal chorion (choriodecidual space) by bacteria that go back from the vagina. The most frequently identified bacteria are Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis, Peptostreptococcus and Bacteroides – all vaginal organisms with relatively low virulence.
The prevalence of the vaginal community living with Lactobacillus is inversely correlated with the gestational age at birth. Almost a third of women with the vaginal community of Lactobacillus-poor delivered very premature babies. In contrast, at least three-quarters of the women who underwent pregnancy before the term had a lactobacillus-dominant vaginal microbiota. The risk of preterm delivery was more pronounced for patients with a higher content of Gardnerella or Ureaplasma. It is interesting that hyaluronic acids play an important role in protecting the epithelial barriers of the lower reproductive tract from bacteria. Thus, maintaining a healthy vaginal microbiota is the key to a successful pregnancy.
Myometrial Conquest and Reduction
For most of the pregnancy, the uterine generation is supported by increased progesterone acting through the progesterone receptor (PR). In humans, serum progesterone concentrations do not decrease as they approach work, so reducing local concentrations of progesterone or the number of receptors is a plausible mechanism for reducing PR function. When pregnancy approaches terms, levels of circulating estradiol-17β (E2) increase, and the enhanced activity of the estrogen receptor α (ERα) increases, which contributes to a pro-inflammatory cascade that reduces PR function and initiates a contraction of the myometrium. Estrogens also induce the influx of macrophages and neutrophils into the uterus and further increase the pro-inflammatory event. Expressions of these reduction-related genes are low throughout most of the pregnancy, but with a high degree of regulation in terms.
Premature Rupture of Membrane (pPROM)
pPROM is associated with approximately one-third of premature delivery cases and occurs in 1-3% of all pregnancies. The primary carrier structure of fetal membranes is the amnion, which consists of a single layer of epithelial cells and a lower layer of mesenchymal cells.
Mesenchymal cells are the main source of collagen and matrix support in the amnion. Interstitial collagens (types I, III and V) support the mechanical integrity of the amnion. Fetal membrane rupture precedes the degradation of collagen, which is mainly mediated by matrix metalloproteinase (MMP) in the amnion. Ehlers-Danlos Syndrome, an inherited connective tissue disease, is a risk factor for PROM due to a defect in the structure, production or processing of collagen or proteins that interact with collagen.
Intrauterine Bleeding, Thrombin and Risk of Premature Delivery
Intrauterine bleeding or hematoma during early pregnancy is correlated with an increased risk of adverse complications in the mother and newborns. Scientists reported a two-fold increase in premature delivery in the hematoma group. In addition, hypertension caused by pregnancy, preeclampsia, placental abruption and restriction of fetal growth also often occurred in this group. These reports show that intrauterine bleeding during pregnancy is a strong risk factor for perinatal complications, especially premature delivery.
In conclusion, the bacterial infection, presumably due to the vaginal community of Lactobacillus, activates the pattern recognition receptors, which induce the release of inflammatory chemokines and cytokines. Chemokines and cytokines lead to a decrease in the function of the progesterone receptor (PR), and an increase in the activity of estrogen receptors in the uterus initiates a contraction of the myometrium. Placental CRH exponentially increases during pregnancy, acting as a “placental clock”, which further increases in the glucocorticoid of the mother and fetus as a feedback loop. CRH enhances the synthesis of prostaglandins.
Together, these events converge to rupture of the membrane, maturation of the cervix and a reduction in the myometrium of preterm delivery and pPROM.
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