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- Pathways and Barriers to Parenthood
- Pathways to Pregnancy and Parturition
- Follow the Author
- Pathways to Pregnancy and Parturition 3rd Edition
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Pathways and Barriers to Parenthood
Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. Preterm birth has usually been treated as a single entity, for epidemiological and statistical purposes. This traditional empiric approach, however, presupposes a single pathologic process for which treatment could be uniform. This approach has met with only limited success in the treatment and prevention of preterm labor. It is now clear that the causes of preterm labor are multifactorial and vary according to gestational age.
Important common pathways leading to preterm birth include stress, systemic or maternal genital tract infections, placental ischemia or vascular lesions, and uterine overdistension.
These pathways differ in their initiating factors and mediators, but ultimately, they share many common features that result in preterm uterine contractions and birth. Appropriate animal models have been very useful in describing the temporal events leading to preterm birth and the neonatal sequelae of prematurity, particularly in the setting of intrauterine infection. The use of animal models to answer specific questions related to prematurity and to describe the pathophysiological events associated with preterm birth will contribute to the development of rational and efficacious treatment and prevention strategies for preterm birth.
The process of normal spontaneous parturition can be divided into four stages see the reviews of Challis  and Challis et al. During most of pregnancy, the uterus remains relatively quiescent, and this corresponds to Phase 0 quiescence of parturition.
Phase 1 activation involves uterine stretch and fetal hypothalamic-pituitary-adrenal HPA activation. Phase 2 stimulation refers to stimulation of the activated uterus by various substances, including corticotropin-releasing hormone CRH , oxytocin, and prostaglandins. These different processes lead to a common pathway to parturition involving increased uterine contractility, cervical ripening, and decidual and fetal membrane activation Romero et al.
Phase 3 involution corresponds to postpartum involution of the uterus. These unique phases are described below and are summarized in Figure Following implantation, more than 95 percent of gestation is spent in Phase 0, uterine quiescence.
During quiescence, myometrial contractility is inhibited by a variety of biological substances, including progesterone. Phase 1, myometrial activation, is characterized by increased expression of contraction-associated proteins, receptors for oxytocin, and prostaglandins, and increased placental estrogen biosynthesis.
The signal for myometrial activation is controlled by the fetal HPA axis, which, in turn, is up-regulated by endogenous placental CRH production. Phase 2, myometrial stimulation, involves a progressive cascade of events, beginning with myometrial activation, which results in myometrial contractility, cervical ripening, and decidua and membrane activation. It is likely initiated by the same events of fetal HPA activation that initiate Phase 1.
Phase 3, involution, involves placental separation and contraction of the uterus. It is primarily effected by maternal oxytocin. Throughout most of pregnancy the uterus remains relatively quiescent. Myometrial activity is inhibited during pregnancy by various substances, including progesterone, prostacyclin PGI2 , nitric oxide, relaxin, and parathyroid hormone-related peptide. These substances function by different mechanisms, but in general they increase intracellular levels of cyclic nucleotides cyclic adenosine monophosphate [cAMP] or cyclic guanosine monophosphate , which in turn inhibit the release of calcium from intracellular stores or reduce the activity of the enzyme myosin light-chain kinase MLCK.
Calcium and MLCK are central to uterine contractility. Calcium is required to activate calmodulin, which in turn induces a conformational change in MLCK, allowing the enzyme to phosphorylate myosin and initiate the coupling of actin and myosin, which leads to myometrial contraction. Rare uterine contractions that occur during the quiescent phase are of low frequency and amplitude and are poorly coordinated; these are commonly referred to as contractures in animals and Braxton-Hicks contractions in women.
The poor coordination of these contractions is primarily due to an absence of gap junctions in the pregnant myometrium Garfield, Gap junctions and their associated proteins, called connexins allow cell-to-cell coupling. With the onset of labor, there is a massive increase in the numbers of gap junctions, resulting in significantly enhanced electrical coupling and synchronized high-amplitude contractions throughout the myometrium. Phase 1 myometrial activation is characterized by increased levels of expression of contraction-associated proteins CAPs , including connexin43 CX; the major protein of myometrial gap junctions , and receptors for oxytocin and stimulatory prostaglandins Lye et al.
Normally, the signals for myometrial activation can come from uterine stretch as a result of fetal growth or from activation of the fetal HPA axis as a result of fetal maturation, or both. Uterine stretch has been shown in animal models to increase CAP and oxytocin receptor gene expression in the myometrium, but the ability to do so is highly dependent on the endocrine environment.
Progesterone blocks stretch-induced increases in the levels of CX expression. However, with progesterone withdrawal at term see below , uterine stretch is associated with significant increases in the levels of CX expression.
It is currently thought that once fetal matu-. Fetal androgens are then aromatized into estrogens by the placenta. Phase 2 involves a progressive cascade of events that lead to a common pathway of parturition involving uterine contractility, cervical ripening, and decidual and fetal membrane activation.
These events are characterized by fetal HPA activation, functional progesterone withdrawal, increasing maternal and fetal estrogens, and rising prostaglandins. The cascade may begin with the placental production of CRH and eventually leads to a functional progesterone withdrawal in the myometrium. The progesterone withdrawal causes increased levels of expression of estrogen receptors and promotes estrogen activity.
The increased action of estrogen leads to the formation of many estrogen-dependent CAPs, such as CX, oxytocin receptors, and prostaglandins, that promote uterine contractility. CRH, a neuropeptide of predominantly hypothalamic origin, is also expressed in the human placenta and membranes and is released into maternal and fetal compartments in exponentially increasing amounts over the course of gestation.
The trajectory of the rise in CRH levels has been associated with the length of gestation Hobel et al. Specifically, women destined to preterm delivery have higher concentrations of maternal CRH in plasma as early as 16 weeks of gestation and a more rapid rise in CRH levels than women who deliver at term. Placental CRH synthesis is stimulated by glucocorticoids, in contrast to the inhibitory effect of glucocorticoids on hypothalamic CRH synthesis.
Placental CRH, in turn, promotes fetal cortisol and DHEA-S production, and this positive-feedback loop is progressively amplified, thereby driving the process forward from fetal HPA activation to parturition. CRH, in turn, enhances prostaglandin production by increasing the levels of expression of prostaglandin H2 synthase PGHS chorion and amnion cells, creating yet another positive-feedback loop that drives the process of parturition.
Paradoxically, during uterine quiescence CRH may act as a myometrial relaxant rather than as a promoter of parturition. Functional progesterone withdrawal. For most of pregnancy, uterine quiescence is maintained by the action of progesterone. It does so by blocking CAP gene expression and gap junction formation within the myometrium; inhibiting placental CRH secretion; opposing the activity of estrogen see below ; up-regulating systems e.
At the end of pregnancy in most mammals, maternal progesterone levels fall and estrogen levels rise. In women, however, progesterone and estrogen concentrations continue to rise throughout pregnancy until delivery of the placenta. Recent data suggest that functional progesterone withdrawal may occur in women and nonhuman primates by alterations in the levels of progesterone receptor PR isoforms Smith R et al. In women, the PR-B receptor isoform functions predominantly as an activator of progesterone-responsive genes, whereas the PR-A receptor isoform acts as a repressor of PR-B function and other nuclear receptors.
In the term myometrium, the onset of labor is associated with increased levels of PR-A expression relative to the levels of PR-B expression. Because PR-A suppresses the action of progesterone, the increased level of PR-A expression relative to that of PR-B decreases the responsiveness of the myometrium to progesterone, resulting in a functional progesterone withdrawal that enables parturition to proceed.
Unlike the placentas of most other species, the human placenta cannot convert progesterone to estrogen because it is deficient in hydroxylase, which is required for this conversion. Estrogen production in the placenta depends largely on precursor androgens synthesized in the fetal zone of the fetal adrenal; approximately 50 percent of circulating maternal estrone and estradiol are derived from placental aromatization of the fetal androgen, DHEA-S.
Estrogens, in turn, enhance the expression of many estrogen-dependent CAPs, including CX gap junctions , oxytocin receptor, prostaglandin receptors, cyclooxygenase-2 COX-2; which results in prostaglandin production , and MLCK which stimulates myometrial contractility and labor Challis, Extensive evidence supports a central role for prostaglandins in promoting uterine contractiity Challis et al.
The actions of prostaglandin are effected through specific receptors. PGE2 induces myometrial contractions by binding to EP-1 and EP-3 receptors, which mediate contractions through mechanisms that lead to increased calcium mobilization and reduced levels of production of inhibition of intracellular cAMP. Prostaglandins also enhance the production of matrix metalloproteinases MMP in the cervix and decidua to promote cervical ripening and decidual and fetal membrane activation.
Prostaglandins are formed from arachidonic acid by PGHS. In turn, prostaglandins are metabolized to inactive forms by the actions of PGDH. Thus, increases in fetal steroid hormone production following fetal HPA activation leads to a net increase in prostaglandin levels. In summary, these events initiated by fetal HPA activation and resulting in increased fetal and placental steroid biosynthesis result in a progressive cascade of biological processes lead to a common pathway of parturition involving cervical ripening, uterine contractility and decidual and fetal membrane activation.
Cervical ripening. Cervical changes precede the onset of labor, are gradual, and develop over several weeks. Cervical ripening is characterized by a decrease in the total collagen content, an increase in collagen solubility, and an increase in collagenolytic activity that results in the remodeling of the extracellular matrix of the cervix Romero et al.
Prostaglandins, estrogens, progesterones, and inflammatory cytokines e. PGE2 stimulates collagenolytic activity and the synthesis of subtypes of proteoaminoglycans. Progesterone blocks estrogen-induced collagenolysis in vitro and down-regulates IL-8 production by the uterine cervix.
In addition to these hormones, nitric oxide may play a role in cervical ripening in some circumstances. Nitric oxide accumulates at sites of inflammation and can act as an inflammatory mediator at high concentrations. Nitric oxide donors e. Uterine contractility. Uterine contraction results from the coupling of actin and myosin, which depends on the phosphorylation of myosin by MLCK.
MLCK is activated by calcium-calmodulin after an increase in intracellular calcium levels. This increase in generated by the actions of various uterotonins, including oxytocin and prostaglandins. Cell-to-cell coupling, which allows the myometrium to develop synchronous high-amplitude contractions during labor, is facilitated by the formation of gap junctions and their associated proteins e. Their formation is highly dependent on estrogen; estrogen activation, in turn, is induced by a functional progesterone withdrawal at term.
Decidual and fetal membrane activation. Decidual and fetal membrane activation refers to a complex set of anatomical and biochemical events that result in the separation of the lower pole of the membranes from the deciduas of the lower uterine segment and, eventually, in the spontaneous rupture of membranes.
The precise mechanism of membrane and decidual membrane activation remains to be elucidated, but extracellular matrix-degrading enzymes such as MMP type 1 MMP-1 , interstitial collagenase, MMP-8 neutrophil collagenase , MMP-9 gelatinase B , neutrophil elastase, and plasmin have been implicated. These enzymes degrade extracellular matrix proteins e. Phase 3 begins with the third stage of labor and involves placental separation and uterine contraction.
Placental separation occurs by cleavage along the plane of the decidua basalis. Uterine contraction is essential to prevent bleeding from the large venous sinuses that are exposed after delivery of the placenta and is primarily affected by oxytocin. Parturition in women involves a progressive cascade of events initiated by HPA activation and increased placental CRH expression, leading to a functional progesterone withdrawal and estrogen activation, which in turn results in the expression and activation of CAPs including oxytocin receptors , oxytocin, and prostaglandins.
This biological cascade eventually leads to a common pathway involving cervical ripening, uterine contractility, decidual and fetal membrane activation, and, in the second stage, increases in maternal oxytocin. It has been hypothesized that both preterm and term labor share this common pathway and that the pathologic stimuli of parturition, as described in the following sections, may act in concert with the normal physiological preparation for labor, especially after 32 weeks of gestation.
Before 32 weeks of gestation, a greater degree of pathologic stimulus may be required to initiate labor.
Pathways to Pregnancy and Parturition
Multiple processes are capable of activating the onset of parturition; however, the specific contributions of the mother and the fetus to this process are not fully understood. Together, the results of this study demonstrate that the fetal lungs produce signals to initiate labor in the mouse. This work underscores the importance of the fetus as a contributor to the onset of murine, and potentially human, parturition. In fact, according to the World Health Organization, preterm birth is the leading cause of death in children under five years of age 1. Unfortunately, the ability to intervene to delay parturition delivery is limited. For example, tocolytics, which are used to acutely inhibit uterine contractions, are ineffective for long-term pregnancy maintenance.
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Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. Preterm birth has usually been treated as a single entity, for epidemiological and statistical purposes. This traditional empiric approach, however, presupposes a single pathologic process for which treatment could be uniform. This approach has met with only limited success in the treatment and prevention of preterm labor. It is now clear that the causes of preterm labor are multifactorial and vary according to gestational age. Important common pathways leading to preterm birth include stress, systemic or maternal genital tract infections, placental ischemia or vascular lesions, and uterine overdistension.
Follow the Author
It provides detailed specimen and full color graphics targeted specifically to students. The ultimate goal of Pathways to Pregnancy and Parturition — 3rd Edition is to enable people to understand the principles of reproductive physiology. This discipline is a visual one and requires image of anatomical structures and physiologic processes.
Skip to search form Skip to main content You are currently offline. Some features of the site may not work correctly. Senger Published Biology. Obstructed labour the s heart cardio sensor is reached! The placenta nmr was in the increased relaxation and use this naturally.
Наконец Нуматака спросил: - Где ключ. - Вам нужно знать только одно: он будет найден.
Pathways to Pregnancy and Parturition 3rd Edition
Повисла тишина. Фонтейн, видимо, размышлял. Сьюзан попробовала что-то сказать, но Джабба ее перебил: - Чего вы ждете, директор. Позвоните Танкадо.
Мы должны вырубить питание главного банка данных. - Это невозможно, - сказал директор. - Вы представляете, каковы будут последствия. Джабба отлично знал, что директор прав. Более трех тысяч узлов Независимой цифровой сети связывают весь мир с базой данных агентства.
Она сейчас наверняка уже над Атлантикой. Беккер взглянул на часы. Час сорок пять ночи. Он в недоумении посмотрел на двухцветного. - Ты сказал - в два ночи.
The ultimate goal of Pathways to Pregnancy and Parturition – 3rd Edition is to enable people to understand the principles of reproductive physiology.
Maternal control of gestational length
Камера вдруг повернулась к укрытию Халохота. Убийцы там уже не. Подъехал полицейский на мотоцикле. Женщина, наклонившаяся над умирающим, очевидно, услышала полицейскую сирену: она нервно оглянулась и потянула тучного господина за рукав, как бы торопя. Оба поспешили уйти. Камера снова показала Танкадо, его руку, упавшую на бездыханную грудь. Кольца на пальце уже не .
Я понимаю, но… - Сегодня у нас особый день - мы собирались отметить шесть месяцев. Надеюсь, ты помнишь, что мы помолвлены. - Сьюзан - вздохнул он - Я не могу сейчас об этом говорить, внизу ждет машина. Я позвоню и все объясню. - Из самолета? - повторила. - Что происходит.
Судя по той увлеченности, с которой молодой профессор говорил о преподавательской работе, из университета он не уйдет. Сьюзан решила не заводить деловых разговоров, чтобы не портить настроение ни ему ни. Она снова почувствовала себя школьницей. Это чувство было очень приятно, ничто не должно было его омрачить. И его ничто не омрачало. Их отношения развивались медленно и романтично: встречи украдкой, если позволяли дела, долгие прогулки по университетскому городку, чашечка капуччино у Мерлутти поздно вечером, иногда лекции и концерты.
И все же… секрет Цифровой крепости будет служить Хейлу единственной гарантией, и он, быть может, будет вести себя благоразумно. Как бы там ни было, Стратмор знал, что Хейла можно будет всегда ликвидировать в случае необходимости. - Решайтесь, приятель! - с издевкой в голосе сказал Хейл. - Мы уходим или нет? - Его руки клещами сжимали горло Сьюзан.
Скоро, подумал он, совсем. Как хищник, идущий по следам жертвы, Халохот отступил в заднюю часть собора, а оттуда пошел на сближение - прямо по центральному проходу. Ему не было нужды выискивать Беккера в толпе, выходящей из церкви: жертва в ловушке, все сложилось на редкость удачно. Нужно только выбрать момент, чтобы сделать это тихо. Его глушитель, самый лучший из тех, какие только можно было купить, издавал легкий, похожий на покашливание, звук.
Три строки по пять, семь и снова пять слогов. Во всех храмах Киото… - Довольно! - сказал Джабба. - Если ключ - простое число, то что с .
Все зависит от того, что ударило в голову автору. - Он привлек внимание к тексту на экране.