Preterm Birth Causes, Consequences, and Prevention (2007) / Chapter Skim
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6 Biological Pathways Leading to Preterm Birth
6 Biological Pathways Leading to Preterm Birth
Pages 169-206
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From page 169... ...
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.
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From page 170... ...
170 PRETERM BIRTH MECHANISMS OF PARTURITION Parturition The process of normal spontaneous parturition can be divided into four stages (see the reviews of Challis [2000] and Challis et al.
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From page 171... ...
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-43 expression.
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From page 172... ...
. 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.
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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., 2002)
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Thus, increases in fetal steroid hormone production following fetal HPA activation leads to a net increase in prostaglandin levels. Similarly, proinflammatory cytokines such as IL-1 and tumor necrosis factor alpha (TNF-α)
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175 BIOLOGICAL PATHWAYS LEADING TO PRETERM BIRTH that are less stabilizing. Estrogen stimulates collagen degradation in vitro, and intravenous administration of 17β-estradiol induces cervical ripening.
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From page 176... ...
The traditional empirical approach to preterm labor presupposed a single pathologic process for which treatment could be uniform. It is now clear that the causes of preterm labor are multifactorial and vary according to gestational age.
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From page 177... ...
Stress and the Placental Clock Stress is increasingly being recognized as an important risk factor for preterm delivery. Stress may be simply defined as any challenge -- psychological or physical -- that threatens or that is perceived to threaten homeostasis (i.e., the stability of the internal milieu of the organism)
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From page 178... ...
Activation of Maternal/Fetal Inflammation/Infection Ischemia Pathologic Uterine Distension 178 • Intra-amniotic • Multifetal pregnancy HPA Axis Decidual Hemorrhage • Cervical/decidual • Polyhydramnios • Stress • Abruptio placentae • Systemic • Uterine structural anomaly • Premature activation physiologic effectors Pro-inflammatory cytokines Thrombin Fetal inflammatory response syndrome CRH Gap junctions Fetal adrenal androgens Contraction-associated proteins Placental Oxytocin receptors Estrogens/progesterone Decidua & Fetal Membranes Maternal oxytocin Matrix metalloproteinases Prostaglandins Proteases Other uterotonins Cervical ripening Uterine Rupture of membranes contractions Preterm labor FIGURE 6-2 Overview of commonly occurring pathways to preterm birth. Although the causes of preterm birth are multiple and there are many unique upstream regulatory initiators of preterm birth, there are few downstream effectors that lead to preterm birth.
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From page 179... ...
A negative-feedback loop exists between the HPA axis and the immune system; proinflammatory cytokines (e.g., IL-1β, TNF-α, and IL-6) stimulate the HPA axis, resulting in the secretion of glucocorticoids.
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Most epidemiological studies of maternal stress and birth outcomes have treated risk behaviors as confounders, although a few clinic-based studies have found that behaviors may play a mediating role between maternal psychosocial stress and lower birth weight (see Chapter 3)
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The mechanisms by which uterine overdistension might lead to preterm labor are not well understood. Uterine stretch induces the expression of gap junction proteins, such as CX-43 and CX-26 (Ou et al., 1997)
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From page 182... ...
. Vascular lesions of the placenta have been reported in 34 percent of women with preterm delivery, 35 percent of women with PPROM, and 12 percent of uncomplicated deliveries at term (Arias et al., 1993)
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A prospective cohort study found that pregnant women with preterm labor who delivered within 3 weeks of admission had significantly elevated TAT levels compared with those in control subjects (Elovitz et al., 2001)
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From page 184... ...
: elevated concentrations of cytokines and prostaglandins in amniotic fluid are found in patients with intra-amniotic infection and preterm labor; in vitro, bacterial products stimulate the production of proinflammatory cytokines by human decidua; these cytokines, in turn, stimulate the production of prostaglandins by the amnion and the decidua; the administration of IL-1 to pregnant mice or nonhuman primates induces preterm labor, which can be prevented by the administration of IL-1 receptor antagonist protein.
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From page 185... ...
have demonstrated that IL-6 is neither a sufficient nor a necessary component of this cascade to stimulate preterm labor but that IL-1β is sufficient. Thus, animal models, as discussed below, have contributed greatly to providing an understanding of the pathophysiology of infection-induced preterm birth.
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From page 186... ...
. Several studies have demonstrated reductions in the rates of preterm delivery or pregnancy loss among women at increased risk of prematurity by antibiotic treatment and eradication of bacterial vaginosis, whereas others have not (Hauth et al., 1995; McDonald et al., 1997b; Morales et al., 1994; Ugwumadu et al., 2003)
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From page 187... ...
. A growing body of evidence now suggests that complications that become apparent relatively late in pregnancy, including preterm delivery, may actually reflect errors that occurred much earlier in placental development, beginning with implantation of the blastocyst in the uterus.
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From page 188... ...
A direct causal link between implantation problems and spontaneous preterm delivery has not been established in animal or human studies; nonetheless, indirect evidence suggests that this may be an important area for further research. The nonpregnant endometrial cavity is frequently colonized by microorganisms (Arechavaleta-Velasco et al., 2002; Romero et al., 2004b)
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From page 189... ...
. PREMATURE RUPTURE OF MEMBRANES Regardless of the etiology or mechanistic pathway to spontaneous preterm labor, preterm birth is usually preceded by PPROM.
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MMP-9 levels are increased in the amniotic fluid of women with intrauterine infections (Fortunato et al., 1999)
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Women with PPROM had higher levels of proapoptotic proteins such as p53, Bax, and caspase, whereas the membranes of women with preterm labor had higher levels of Bcl2, an antiapoptotic protein. Investigators have also found that FAS and TNF-α-mediated apoptotic pathways are up-regulated in PPROM but not in preterm labor without premature rupture of membranes (reviewed by Menon and Fortunato, 2004)
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Animal Models of Preterm Birth Spontaneous preterm birth occurs infrequently in most species. This has limited research in this area to specific pharmacological or environmen
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begins. This schema indicates that maturation of the lungs and cerebrum, two organs with important contributions to neonatal morbidity and mortality, in sheep and nonhuman primates most closely parallel development in humans.
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Pharmacological administration of RU-486, a progesterone antagonist, leads to preterm delivery in rodents but not in nonhuman primates (Dudley et al., 1996; Garfield et al., 1987; Haluska et al., 1994)
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From page 195... ...
Research with nonhuman primates has demonstrated that following experimental intraamniotic fluid infection, sequential increases in the levels of proinflammatory cytokines, prostaglandins, and MMPs precede the onset of preterm labor by 24 to 48 hours (Gravett et al., 1994; Vadillo-Ortega et al., 2002)
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From page 196... ...
Periventricular Leukomalacia and Cerebral White Matter Lesions PWMD is detected in a significant proportion of premature infants and is strongly associated with adverse outcomes, including motor, perceptual, visual, behavioral, and cognitive disorders (see Chapter 10 for a further discussion of PWMD)
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. A physiological correlate of these anatomic factors is the observation of extremely low level of blood flow to the cerebral white matter in premature infants compared with that in term infants and adults (Altman et al., 1988; Greisen, 1986)
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From page 198... ...
Again, a minimal margin of safety may exist, leading to ischemia in the watershed areas of the white matter. In a child or an adult, an intact cerebrovascular regulation system is in place that keeps the cerebral blood flow constant over a wide range of blood pressures through appropriate compensatory vessel dilation and vasoconstriction (Volpe, 2001)
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From page 199... ...
. Maternal or Fetal Infection or Inflammation and Cerebral White Matter Lesions Recently, the role of intrauterine infections in the pathogenesis of periventricular leukomalacia and cerebral palsy has become a major focus
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From page 200... ...
observed cerebral white matter damage in association with maternal intrapartum fever or chorioamnionitis. A recent meta-analysis of 30 human observational studies by use of a random-effects model reported that clinical chorioamnionitis was significantly associated with both cerebral palsy (relative risk [RR]
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From page 201... ...
) and chronic or progressive lung injury (bronchopulmonary dysplasia [BPD]
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From page 202... ...
Further studies are necessary to test this hypothesis. Disruption of Alveolarization Recent pathologic analyses of very low birth weight human infants who have died of BPD demonstrate an arrest of alveolar development, with the
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. Mechanical Ventilation and Lung Injury Diffuse atelectasis and decreased compliance lead to alveolar hypoventilation and an imbalance in ventilation-perfusion.
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From page 204... ...
If only a small portion of the lung is being ventilated, a normal tidal volume for weight will be too large and will result in the disruption of structural elements, such as the pulmonary capillary endothelium, the alveolar and airway epithelia, and the basement membrane. This concept has been tested in studies with preterm lambs, in which as few as six manual inflations of 35 to 40 milliliters per kilogram of body weight before surfactant treatment and mechanical ventilation led to increased lung injury and a decrease in the response to surfactant therapy (Bjorklund et al., 1997)
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From page 205... ...
An additional source of free radicals in the lungs is thought to be phagocyte activation. The increases in phagocyte numbers and interleukin concentrations and the increased levels of free radical release seen in the bronchoalveolar fluid of premature infants with both acute and chronic lung disease indicate that oxygen toxicity and inflammation are involved in the development of lung injury (Zoban and Cerny, 2003)
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From page 206... ...
These include the use of • nonhuman primates to describe the temporal or longitudinal relationships among the mediators of preterm labor; • genetically altered mice to ascertain the roles that putative mediators of preterm birth has in leading to prematurity; and • sheep or nonhuman primates to ascertain the relationships among the various pathways to preterm birth and their sequelae in neonates, such as cerebral white matter injury and bronchopulmonary dysplasia.
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