**1. Introduction**

Premature birth is a pathological condition that requires high-quality medical care due to the infants' low body mass and gestational age, as well as morphofunctional immaturity. Moreover, such children are at great risk for retardation of mental development; metabolic, cardiovascular, and malignant diseases; and many other health problems at a later age [1, 2]. Early and late complications of preterm birth depend significantly on the gestational age at birth and the intrauterine development conditions of the fetus [3, 4]. Due to the more severe and complicated course of perinatal pathologies, premature babies with fetal growth retardation syndrome constitute a larger risk group. Approximately 50–70% of these children receive long-term treatment in the neonatal intensive care unit after birth. Furthermore, 70% of them face behavioral and memory problems in later life [5, 6].

Children with extreme small mass comprise a significant risk group due to developmental and behavioral anomalies. The main problems faced by these children in the neonatal period are related to nutrition and infection [7]. Thus, not only satisfying

the energy demand, but also the oral and parenteral intake of the necessary nutrients and microelements leads to the prevention of a number of psychosocial problems at later ages [8, 9]. Additionally, the correct use of antibiotics, the timely implementation of measures to protect against hospital bacterial strains, and the minimization of damage to the integrity of the skin and mucous membranes lead to the reduction of infectious complications [10, 11]. One of the factors leading to the violation of early adaptation in children born prematurely is the immaturity of the painful stimuli response. It is believed that because gestational age and the degree of morphofunctional maturity of the body are low, the cumulative reaction formed in the body against pain stimulus causes not only behavioral disorders but also dysfunctional changes in all organs and systems [12, 13].

Premature birth is the most important medical and social problem of modern times, accounting for 12% of all live births [14]. The rate of prematurity in child mortality varies according to the level of neonatal care in a given region [15]. According to the Institute of Children's Health and Development, this problem ranks first among causes of child mortality in the African-American zone and second in the Caucasian zone [15, 16]. Despite the improvement of preventive and treatment measures in this field, the fact that the frequency of premature birth is increasing all over the world can be explained by the low level of neonatal care in some regions and the increase in the number of multi-fetal pregnancies as a result of the widespread use of assisted reproductive technologies in developed countries [17, 18]. Statistical studies have shown that even in developed countries, pregnancy ending with premature birth has increased from 9 to 9.4% to 12.7–14% compared to the 1980s [1, 19]. An estimated 75% of the 500,000 preterm births that occur worldwide each year are between 34 and 36 weeks of gestational age, with 25% at a lower gestational age [20–22]. Studies have shown that 50% of all preterm births occur spontaneously without any specific cause, 40% are medically induced, and 10% occur due to the premature rupture of fetal membranes [23].

Among the risk factors leading to premature birth, in recent years, a history of complicated incomplete birth, multiple pregnancy, and short cervical length have become increasingly relevant. It is believed that women whose previous pregnancies ended prematurely have a higher risk of stillbirth. The recurrent risk depends on the gestational age of the child born during the previous pregnancy and the number of premature births in the history of the woman. Thus, in 50–70% of cases, incomplete birth is repeated at the same gestational age. As well, the risk of repeated preterm birth is 16% in women who have given birth to one child at a gestational age of less than 35 weeks and 41–67% in women who have had multiple pregnancies [24, 25]. Due to the widespread use of assisted reproductive technologies, the number of multiple pregnancies has increased significantly in the last 20 years. Although in vitro fertilization is more successful at achieving and sustaining pregnancy, most twin and multiple pregnancies result in preterm birth [26, 27]. A number of studies have confirmed the association of short cervix size with preterm birth. Some authors have even proposed predicting the time of childbirth based on this indicator [28, 29]. Randomized clinical trials have shown that vaginal progesterone treatment to reduce the risk of premature termination of pregnancy with short cervical length had a positive effect in 45% of cases [25, 30].

Investigations into the possible causes of spontaneous births have found that the intrauterine inflammatory process, mother's psychosocial stress, fetal psychological stress, uterine overstretching, and uterine bleeding are of significant note [31–34]. These causes manifest themselves with different frequency depending on the duration

#### *Preterm Birth and Postnatal Developmental Outcomes DOI: http://dx.doi.org/10.5772/intechopen.108061*

of pregnancy. For example, births stimulated by intrauterine bacterial colonization usually occur at a gestational age of less than 34 weeks, while pregnancies that end due to psychosocial problems occur at a gestational age of 34–36 weeks. Preeclampsia, fetal distress, and retardation of fetal development are the main pregnancy pathologies that cause premature birth. According to the data of the International Institute for Child Health and Development, 40% of premature births due to medical intervention are related to women with preeclampsia [35–37]. Premature rupture of fetal membranes occurs mainly as a result of exacerbation of chronic inflammation, accounting for 21% and 8% of early and late preterm births, respectively [38]. Studies have shown that placental inflammation caused by the impaired protective capacity of the antioxidant protein heme oxygenase-1 plays a fundamental role in the pathogenesis of both preeclampsia and the premature rupture of fetal membranes. Therefore, some scientific studies have been conducted on the effectiveness of drugs with heme oxygenase activity to prolong pregnancy when there is a risk of premature birth [39, 40]. Parturition is a complex biological process regulated by numerous signaling molecules and biologically active substances from the mother, mate, and fetal tissue. A number of preventive measures are implemented to identify and prevent the risk of premature birth. Studies have shown that the placental corticotropin-releasing hormone is the main endocrine mediator of preterm labor [41, 42]. Determination of this factor in pregnancies with a gestation period of less than 33 weeks can be a prognostic indicator of the level of fetal development and premature birth [43–45]. In recent years, the use of special portable monitors that monitor children's activity at home has been proposed, but this method is not widely used due to the high economic costs required. The dynamic monitoring of women to prevent any problems that may occur during pregnancy, tocolytic therapy to reduce uterine contractions if necessary, and antibiotic therapy in case of infectious complications are believed to be more effective. Of course, since women whose previous pregnancies ended in premature birth are at greater risk, they should be monitored more actively. The most successful results in the prevention of recurrent premature births have been obtained via the administration of 12 alpha-hydroxyprogesterone injections. Thus, prescribing this drug to women whose previous pregnancies ended in premature birth at 16–20 weeks of gestation significantly reduces the risk of premature birth [46–48].

Fetal inflammatory response is the main pathogenetic link to preterm birth. The process is due to the influence of microorganisms and is accompanied by chorioamnionitis, funisitis, or intraamnial inflammation [49, 50]. Acute intraventricular hemorrhage, periventricular leukomalacia (PVL), necrotic enterocolitis, bronchopulmonary dysplasia, myocardial dysfunction, and sepsis are more common during the inflammatory process of the fetoplacental system [51–54]. During the fetal inflammatory response, preterm birth is associated with the effects of cytokines, matrix metalloproteinases, and prostaglandins. In cases of high bacterial colonization, the levels of TNF-α, IL-6, and IL-8 in umbilical cord blood increase significantly [55, 56]. The main clinical manifestations of inflammatory changes that lead to premature birth are uterine prolapse, changes in the cervix, and the premature rupture of the fetal membranes. Unfortunately, during the inflammatory process occurring in the fetoplacental system, the risk of similar inflammation in the mother's body is very low. Therefore, it is not possible to predict preterm birth based on the inflammatory indicators in the peripheral blood of pregnant women. The cultivation of microbial colonization determined during the examination of the contents taken from the birth canal also does not provide an idea of the level of intraamniotic inflammation [32, 57, 58]. The decrease in the probability of premature birth against

the background of antibiotic therapy is also explained by the inhibition of the bacterial infectious process due to the effect of antibacterial drugs [59]. However, there are conflicting and controversial opinions on the use of antibiotic therapy to reduce the probability of premature termination of pregnancy [60–62]. A group of studies has shown that routine treatment of asymptomatic microbial invasion reduces perinatal morbidity and mortality but has no effect on the incidence of preterm birth [63–65]. Other studies have shown that bacterial colonization increases the risk of premature birth, although it is not manifested by a specific infectious process. In cervical and vaginal secretions, a membrane protein called fetal fibronectin is found at a frequency 50 times higher in women with the possibility of premature birth than in those with normal pregnancies [66, 67]. The Maternal-Fetal Medicine Union states that the reduction of fetal fibronectin does not occur against the background of antibiotic therapy [68–70]. As well, despite the weakening of intrauterine colonization against the background of antibacterial therapy, against the background of the use of broad-spectrum antibiotics, no significant improvement in spontaneous births or perinatal and neonatal outcomes has been shown [62, 70]. Therefore, for more accurate diagnosis and data, the contents obtained directly from the fetal membranes rather than from the birth canal should be examined. Elevation of IL-6 and matrix metalloproteinase 8 and 9 levels in amniotic fluid is also considered a more sensitive indicator for amniotic infection [71, 72]. However, because obtaining amniotic fluid is invasive and poses a risk for subsequent infection, this diagnostic method is not widely used. In recent years, it has been considered more appropriate to differentiate inflammatory processes in the amniotic cavity, chorion, and placenta through vaginal cervicometry [73, 74]. Thus, when intraamniotic microbial colonization increases, in 80% of cases, the length of the cervix is shortened, which is called cervical insufficiency [75–77]. This method is safer and is now widely used in predicting the occurrence of premature birth. Another group of studies has shown that fetal damage during microbial colonization depends on the activity of anti-inflammatory factors in the fetoplacental system. It was determined that as a result of the effect of oxidative stress products, the activation of specific soluble and transmembrane RAGE receptors occurs in macrophages, monocytes, and endothelial cells [78]. This directly leads to the activation of cytokine and growth factor genes [79, 80]. The activation of RAGE receptors during the acceleration of the inflammatory process have been proven to have a protective nature, causing the inhibition of inflammation [81]. Another group of studies has shown that the progress and activity of the inflammatory process depends on the degree of activation of the RAGE and Toll-like receptors [82, 83]. Taketoshi Noguchi and co-authors showed that activation of Toll-like receptors induces preterm labor by leading to a more acute inflammatory process in the fetoplacental system [84]. The activation of RAGE receptors causes the inhibition of the acute process, and the process becomes chronic [85, 86]. A group of studies proved that the polymorphism of Toll-like receptors and the genetic structure of different alleles play an important role in the occurrence of premature birth [87, 88]. Hopefully, large-scale scientific research is being conducted on the genetic basis of the occurrence of premature birth. According to the obtained results thus far, premature pregnancy depends on cytokine, Toll-like receptors, and RAGE polymorphism regulated at the genetic level. Depending on this polymorphism, the inflammatory response of the fetoplacental system is formed. This response, in turn, not only causes premature birth but also significantly affects the course of perinatal pathologies [89]. Uteroplacental ischemia is primarily formed during the inflammatory process in the mother-couple-fetus system [89, 90]. At this time,

#### *Preterm Birth and Postnatal Developmental Outcomes DOI: http://dx.doi.org/10.5772/intechopen.108061*

generalized endothelial dysfunction leads to premature termination of pregnancy and various intrauterine developmental pathologies of the fetus [91]. The pathogenetic mechanisms of the formation of endothelial dysfunction during uteroplacental ischemia have not yet been fully investigated. However, numerous scientific studies have proven that inflammatory processes occurring in the fetoplacental system are often accompanied by thrombophilic conditions [1, 92, 93]. Thrombophilia factors that lead to premature birth are grouped into two categories—congenital and acquired. Congenital thrombophilia is mainly caused by the Leiden mutation and coagulation factor II - prothrombin mutation [94]. Antiphospholipid syndrome is the main acquired factor [95]. The violation of placental microcirculation during thrombophilia can cause thromboembolism, intrauterine death of the fetus, intrauterine growth retardation, premature separation of the pair, acute preeclampsia, and spontaneous abortions [52, 96, 97].

In recent scientific literature, there have been many reports on the increased incidence of preterm birth in women with mutations of the methylenetetrahydrofolate reductase gene and disorders of folic acid metabolism [98]. It is believed that as a result of mutation, folic acid cannot be activated and transformed into tetrahydrafolate-metafolin. As the latter provides the remethylation of homocysteine, its deficiency leads to disruption of homocysteine transformation and its excessive accumulation in the body [99]. Hyperhomocysteinemia causes generalized damage to the endothelium, atherosclerotic changes, placental microcirculation disorders, premature birth, sudden intrauterine death, as well as congenital developmental anomalies of the neural tube, heart, and a number of organs [100–102].

One of the main reasons for premature termination of pregnancy is the improper adjustment of the contraction capacity of the uterine muscle depending on the period of gestation. Contraction of the uterus is regulated by the interaction of actin and myosin proteins in myocytes [103]. Myocytes, which create special connections, ensure the synchrony and coordination of contractions of the uterus. The interaction of the actin and myosin complex is realized by the phosphorylation of myosin by the enzyme myosinkinase. The homeostasis of calcium ions plays a key role in myocyte activity. The increase in calcium ions inside the cell is carried out through membrane receptors stimulated by ovarian and placental steroids. Progesterone activates beta adrenergic receptors, and estradiol activates alpha adrenergic, cholinergic, and prostaglandin receptors [104, 105]. The passage of calcium ions into the cell membrane is carried out by alpha adrenergic receptor agonists, and its return is carried out by beta adrenergic receptor agonists. The contraction and relaxation of the uterine muscle depends on the entry of calcium ions from the sarcoplasmic reticulum into the cytoplasm and the amount of agonists and antagonists of multiple receptors involved in this process [106, 107]. Depending on their balance, inadequate contraction of the uterine muscle, loss of synchrony prompts the onset of premature labor. It has been established that uterine contractions during childbirth and labor pains are initiated through the expression of contraction-related protein genes [108, 109]. These genes regulate the synthesis of Connexin-43, the main protein of ion channels and receptors [110]. The role of a number of factors in the regulation of the synchrony of uterine contractions has been indicated—notably, progesterone, nitric oxide, relaxin, prostacyclin, and the corticotropin-releasing hormone (CRH) [110–112]. These biologically active substances, called hestagens, prevent the release of calcium ions from the sarcoplasmic reticulum by inhibiting cyclic AMF inside the cell. Since numerous experimental studies have shown that these compounds reduce inadequate uterine contractions, they are now widely used in clinical practice to prevent premature birth.

#### *Maternal and Child Health*

There are many theories about the immunological incompatibility between the mother and the fetus in the etiopathogenesis of premature birth. Increased tolerance of the mother to the fetus depends on the balance of the histological compatibility of complex antigens. While class I HLA-A and HLA-B antigens can be inactivated by the trophoblast, HLA-G antigens expressed during pregnancy protect the fetus from the maternal immune response [102, 113]. Inadequate recognition of fetal antigens by the mother can lead to miscarriage. In animal studies, reduction of galectin-1, a specific immunoregulatory protein, has been shown to stimulate preterm labor [114]. Additionally, in the case of a number of autoimmune diseases (systemic lupus erythematosus, ulcerative colitis, immunopathologies of the thyroid gland, etc.), there is a high probability of premature birth, and the severity of immunological incompatibility between the mother and the fetus significantly affects the gestation period at which the birth ends [106, 115]. In a number of studies, opinions have been expressed about the allergic reaction of the mother to fetal tissues during pregnancy [116, 117]. According to relevant sources, the amount of eosinophilic granulocytes in the amniotic fluid increases in cases of premature birth. As well, the number of mast cells, more sensitive to allergic processes, is greater in the uterine muscle, and due to the effect of prostaglandin, they easily degranulate and accelerate the accumulation of the uterus. Currently, scientific studies are being conducted to study the effectiveness of antihistamine drugs in preventing premature birth [118].

Congenital anomalies of the uterus, polyhydramnios, and the high risk of premature birth during multiple pregnancy indicate that uterine muscle tension plays an important role in pregnancy disruption. Although the size of the uterus increases as the pregnancy period increases, the intrauterine tension remains constant. Progesterone and endogenous myometrial relaxants, especially nitric oxide, are important in maintaining this stability [119, 120]. Prostaglandins and neuromuscular junction proteins, especially connexin-43, increase during uterine strain [121]. Amniochorial strain, on the other hand, causes the premature rupture of membranes and premature birth. Because of this, premature birth is more difficult to control and is regarded as an almost unavoidable process.

Thus, although numerous concepts of the causes and pathophysiology of premature birth have been put forward and various developmental mechanisms have been determined, it is not possible to completely prevent perinatal pathologies caused by premature termination of pregnancy or incomplete birth. Although inflammation has been identified as the main pathogenetic mechanism in the occurrence of premature birth, the pathophysiology of the process has not yet been fully studied. The inflammatory process in the fetoplacental system is stimulated both by the effect of bacterial colonization and by the effect of hypoxia, accompanied by an inflammatory response in the maternal and fetal bodies. However, since the response to fetal infection is often not manifested by noticeable pathological changes in a pregnant woman, it can be overlooked by specialists or identified late. Even if it does not cause a pathological process in the mother's body, the fetal inflammatory response causes premature birth, increased perinatal morbidity, and mortality. In modern times, despite the improvement of perinatal medical care technologies, methods for the effective prevention of premature birth have not been developed. The specificity and sensitivity of clinicalinstrumental examinations and laboratory markers are very low. Therefore, in recent years, numerous scientific studies have been conducted with the aim of finding new sensitive markers of premature birth and identifying women from the risk group by involving pregnant women in screening examinations.
