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  1. 1. Preterm deliveries are those occurring between fetal viability and 37 completed weeks of gestation (menstrual age).1 Delivery of a previable fetus represents a spontaneous abortion rather than a preterm birth. The precise definition of “viability,” however, is a subject of debate because of the increased frequency of survival at very low gestational ages. Some neonates can survive if born around 24 weeks of gestation, but none at 20 weeks; therefore, we propose that preterm birth be defined as one that occurs between 24 and 36 6/7 weeks of gestation. This definition may need to be revised if future technologic advances allow substantial survival at less than 24 weeks of gestation. A birth weight of 500 g has historically been used to define the lower limit of viability. However, this approach is limited because viable neonates born after 24 weeks may be affected by intrauterine growth restriction (IUGR) and have birth weights of less than 500 g. Conversely, some previable infants may weigh more than 500 g. The threshold of 500 g is valuable if there is uncertainty about gestational age. An accurate definition of preterm birth has implications for the calculation of vital statistics and comparisons of the rates of preterm delivery among different countries and populations, an issue that is often overlooked. Preterm births can be spontaneous or “indicated.” Spontaneous preterm labor can occur with either intact membranes or prelabor (premature) rupture of the fetal membranes (PROM). “Indicated” preterm births are those that result from induced preterm labor or preterm cesarean delivery for maternal or fetal indications, usually because of preeclampsia or IUGR or both. The mechanisms of disease responsible for these two conditions are discussed in other chapters of this text (see Chapter 5). Of all preterm deliveries, some 25% (reported range, 18.7% to 35.2%) are indicated, and the remainder are spontaneous—45% (23.2% to 64.1%) from preterm labor with intact membranes and 30% (7.1% to 51.2%) from preterm labor after PROM.2,3 The rate of preterm delivery in the United States has climbed 14% since 1990; this has been attributed to an increased frequency of indicated preterm birth in singleton gestations, an increased number of multiple gesta- tions, and an increased number of older parturients.4 Overview of the Mechanisms of Labor The Common Pathway The traditional view, which has dominated the study of preterm par- turition, is that term and preterm labor are the same processes, albeit occurring at different gestational ages. Indeed, they do share a common pathway, which includes increased uterine contractility, cervical ripen- ing, and membrane rupture.5 It has been proposed that the fundamen- tal difference between term and preterm labor is that the former results from “physiologic activation” of this common pathway, whereas preterm labor results from a disease process (“pathologic activation”) that extemporaneously activates one or more of the components of the common pathway.6 The common pathway of parturition is defined as the anatomic, biochemical, immunologic, endocrinologic, and clinical events that occur in the mother and fetus in both term and preterm labor.6 Much clinical emphasis has been placed on the uterine components of the pathway (myometrial contractility, cervical ripening, and membrane rupture) (Fig. 28-1). However, there are systemic changes, such as an increase in the plasma concentration of corticotropin-releasing hormone (CRH) and in the caloric metabolic expenditures, that are also part of the common pathway.7-10 Activation of the uterine components of the common pathway of parturition may be synchronous or asynchronous. Synchronous acti- vation results in clinical spontaneous preterm labor. Asynchronous activation results in a different phenotype. For example, predominant activation of the membranes leads to preterm PROM, that of the cervix to cervical insufficiency, and that of myometrium to preterm uterine contractions without cervical change or rupture of membranes (Fig. 28-2). Spontaneous preterm labor with intact membranes, preterm PROM, and cervical insufficiency can be considered syndromes caused Chapter 28 Pathogenesis of Spontaneous Preterm Labor Roberto Romero, MD, and Charles J. Lockwood, MD
  2. 2. 522 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor by multiple etiologies with specific pathogenic pathways. This chapter reviews the pathophysiology of the common pathway of parturition and examines the pathologic mechanisms responsible for its activation. Myometrial Contractility Although myometrial contractility occurs throughout pregnancy, labor is characterized by a dramatic change in the pattern of uterine contractility, which evolves from “contractures” to “contractions.”6 Nathanielsz and Honnebier11 and Hsu and colleagues12 defined con- tractures as epochs of myometrial activity lasting several minutes, asso- ciated with a modest increase in intrauterine pressure and fragmented bursts of electrical activity in the electromyogram. In contrast, contrac- tions are epochs of myometrial activity of short duration associated with dramatic increases in intrauterine pressure and electromyo- graphic activity. The switch from a predominant contracture pattern to a predominant contraction pattern occurs physiologically during normal labor13 or can be induced by pathologic events such as food withdrawal, infection, or intra-abdominal surgery.14-16 Increased cell-to-cell communication is thought to be responsible for the effectiveness of myometrial contractility during labor. Gap junctions develop in the myometrium just prior to labor and disappear shortly after delivery.17-21 Gap junction formation and the expression of the gap junction protein, connexin-43, in human myometrium is similar in both term and preterm labor.22-26 These findings suggest that the appearance of gap junctions and increased expression of connexin- 43 may be part of the underlying series of molecular and cellular events responsible for the switch from contractures to contractions before the onset of parturition. Estrogen, progesterone, and prostaglandins have been implicated in the regulation of gap junction formation, and they also influence the expression of connexin-43.27-29 Lye and others have referred to a set of distinct proteins, called contraction- associated proteins, that are characteristic of this phase of parturition (see Chapter 5).24,30,31 Lye and colleagues32 also proposed that the myometrium undergoes sequential phenotypic remodeling during pregnancy. Their studies were undertaken in rodents but have implications for humans. Three distinct stages of rat gestational myometrial development were recognized: 1. Proliferative, in which the number of myocytes increased, as dem- onstrated by greater proliferation cell nuclear antigen labeling and protein expression in early pregnancy. This phenotype coincided with a higher myometrial expression of antiapoptotic proteins (BCL2 and BCL2L1 [formerly BCL-xL]). 2. Synthetic, in which the myometrial cells underwent hypertrophy, as demonstrated by a higher protein/DNA ratio in the second half of pregnancy. This stage coincided with a higher secretion of extracel- lular matrix (ECM) proteins from the myocytes, in particular col- lagen I and collagen III, as well as a high concentration of caldesmon (a marker of synthetic phenotype) 3. Contractile, which occurred at the end of pregnancy and coincided with low myometrial expression of interstitial matrix proteins and highexpressionofcomponentsofthebasementmembrane(laminin and collagen IV). α-Actin was expressed in the myometrium in early pregnancy, whereas γ-actin was highly expressed by myometrium with a contractile phe- notype. The switch from a proliferative to a synthetic phenotype appeared to be regulated by caspase 3, and a decrease in progesterone was responsible for the switch from the synthetic to the contractile phenotype.32 This view is consistent with the proposal of Csapo about the importance of progesterone in the regulation of myometrial con- tractility at the onset of parturition.33 Microarray experiments of myo- metrium in labor indicate an overexpression of genes involved in Membrane Activation Cervical Dilatation Uterine Contractility FIGURE 28-1 Uterine components of the common pathway of parturition (preterm and term). (From Romero R, Gomez R, Mazor M, et al: The preterm labor syndrome. In Elder MG, Romero R, Lamont RF (eds). Preterm Labor. New York: Churchill Livingstone, 1997, pp 29-49.) Preterm PROM Cervical Insufficiency Preterm Contractions FIGURE 28-2 Clinical manifestations of preterm activation of the common pathway of parturition. Clinical manifestations depend on whether there is synchronous or asynchronous recruitment of the pathway. Cervical insufficiency is the presenting phenotype if activation of the cervix occurs in isolation. Prelabor rupture of membranes (PROM) occurs if decidual/membrane activation is the predominant pathway activated. Isolated activation of the myometrium results in preterm uterine contractions. Synchronous activation of the myometrium and the cervix results in the clinical presentation generally recognized as preterm labor with intact membranes. (From Romero R, Gomez R, Mazor M, et al: The preterm labor syndrome. In Elder MG, Romero R, Lamont RF (eds). Preterm Labor. New York: Churchill Livingstone, 1997, pp 29-49.)
  3. 3. 523CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor control of inflammation (Romero et al., unpublished observations) This is consistent with other studies which used subtraction hybridiza- tion to identify genes differentially expressed during labor. Interleukin 8 (IL-8) and superoxide dismutase have been found to be differentially regulated.34 Cervical Remodeling The changes in the cervix include: (1) softening, (2) ripening, (3) dila- tation, and, after delivery, (4) repair.35 Sonographic studies have dem- onstrated that shortening of the cervix occurs before the dramatic increase in uterine contractility that characterizes term and preterm labor. Hence, the regulation of cervical remodeling has become impor- tant in the understanding of cervical insufficiency and spontaneous preterm labor. The molecular and cellular bases for cervical remodeling during pregnancy and parturition are largely dependent on the regulation of extracellular matrix components.35-41 Softening of the cervix begins in early pregnancy. The tensile strength of the softened cervix appears to be maintained by an increase in collagen synthesis and growth of the cervix. Cervical ripening is characterized by a decreased concentration of collagen and the dispersion of collagen fibrils. The latter has been attributed to glycosaminoglycans, such as decorin and hyaluronan, which promote hydration of cervical tissue and dispersion of the col- lagen fibers.36 Dilation of the cervix is an inflammatory phenomenon in which there is an influx of macrophages and neutrophils and matrix degradation.42-44 Chemokines such as IL-845-49 and S100A950,51 attract inflammatory cells, which, in turn, release proinflammatory cytokines, including IL-1β52,53 and tumor necrosis factor-α (TNF-α),35-54 that can activate the nuclear factor (NF)-κB signaling pathway. NF-κB can block progesterone receptor-mediated actions.55 Progesterone has been implicated in the regulation of cervical remodeling because (1) admin- istration of antiprogestins to women in the mid-trimester and at term induces cervical ripening;35,56-60 and (2) the administration of proges- terone-receptor antagonists such as mifepristone (RU-486) or onapris- tone (ZK 98299) to pregnant guinea pigs,61,62 old-world monkeys,63 and Tupaia belangeri induces cervical ripening.35 Cervical responsiveness to antiprogestins increases with advancing gestational age,35 and the effects of antiprogestins in the cervix are not always accompanied by changes in myometrial activity.35 Indeed, Stys and associates64 demon- strated a dissociation between the effects of progesterone in the myo- metrium and those in the cervix. A frequent observation, in animals62,63 as well as in humans,65 is that antiprogestins induce cervical ripening but not labor. Indeed, labor may be delayed by days or weeks, or it may not begin at all after cervical ripening has been accomplished in humans.35 Collectively, these findings suggest that the cervix is a major site of progesterone action. This realization is important, because much of the emphasis in previous years has been on the effect of pro- gesterone on the myometrium. Yet, recent randomized clinical trials suggest that progesterone may be helpful in preventing preterm birth in women with a short cervix.66-69 Decidual/Membrane Activation We use the term decidual/membrane activation to refer to a complex set of anatomic and biochemical events that lead to separation of the lower pole of the fetal amniochorionic membranes from the decidua of the lower uterine segment and, eventually, to spontaneous rupture of the membranes and delivery of the placenta. During pregnancy, the chorioamnionic membranes fuse with the decidua. In preparation for delivery, biochemical events take place to allow separation and postpartum expulsion of the membranes. Fibro- nectins are a family of important extracellular matrix proteins. The available evidence suggests that degradation of a heavily glycosylated form of cellular fibronectin (i.e., fetal fibronectin) which is present at the chorionic-decidual interface leads to its release into cervical and vaginal secretions immediately before term and preterm parturition.70-73 Beyond proteolytic degradation of the decidual and amniochorionic extracellular matrix by matrix-degrading enzymes, PROM is also asso- ciated with amnion epithelial apoptosis and localized inflammation.74 Therefore, these processes belong to the common terminal pathway of parturition. Enzymatic activity of matrix metalloproteinases (MMPs) and other proteases has been implicated in the process of rupture of membranes and parturition with intact membranes (with and without infection).75-77 Histologic studies of membranes in women with term PROM indi- cate that membranes that rupture prematurely have a decreased number of collagen fibers, disruption of the normal wavy patterns of these fibers, and deposition of amorphous materials among them.78 Similar changes have been observed in the membranes apposed to the cervix in women undergoing elective cesarean delivery at term with intact membranes. The implication is that, although spontaneous rupture of membranes normally occurs at the end of the first stage of labor, the process responsible for this phenomenon begins before the onset of labor. Histologic studies of the site of rupture have demonstrated a zone of altered morphology (ZAM).79,80 A significant decrease in the amount of collagen type I, III, or V and an increased expression of tenascin have been reported in the ZAM. Tenascin is an extracellular matrix characteristically expressed during tissue remodeling and wound healing. Its identification in the membranes thus signifies the presence of injury and a wound healing–like response. Observations by Bell and colleagues81,82 suggested that changes in the ZAM are more extensive in the setting of preterm PROM. These morphologic and biochemical observations are consistent with the results of biophysical studies sug- gesting that rupture of membranes results from the application of acute or chronic stress on localized areas of the membranes that are weaker. The precise mechanism of decidual/membrane activation remains to be elucidated. As noted, roles for extracellular matrix–degrading enzymes such as the MMPs and apoptosis have been proposed. Several studies have demonstrated increased availability of MMP-1 (inter- stitial collagenase),83 MMP-8 (neutrophil collagenase),84 MMP-9 (gelatinase-B),85 and neutrophil elastase86 in the amniotic fluid of women with preterm PROM, compared with women in preterm labor with intact membranes. Plasmin has also been implicated in this process,73 because this enzyme can degrade type III collagen, fibronec- tin, and laminin.87 Other MMPs are likely to be involved, but syste- matic studies have not been conducted to date.88-90 A role for tissue inhibitors of MMPs (TIMPs) has also been postulated.91 Prostaglandins as Key Activators of the Common Pathway of Parturition A central question in the understanding of parturition is whether the signals responsible for activation of the common pathway are similar in term and preterm labor. Prostaglandins have been considered the key mediators for the onset of labor,92-107 because they can induce myometrial contractility,92,96,105,107 changes in extracellular matrix metabolism associated with cervical ripening,94,95,99,100,104 and decidual/ membrane activation.5
  4. 4. 524 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor Descriptive evidence traditionally invoked to support a role for prostaglandins in the initiation of human labor includes the following: (1) administration of prostaglandins can induce early or late termina- tion of pregnancy (abortion or labor)103,108-118 ; (2) treatment with indo- methacin or aspirin can delay spontaneous onset of parturition in animals119-122 ; (3) concentrations of prostaglandins in plasma and amniotic fluid increase during labor123-130 ; (4) intra-amniotic injection of arachidonic acid, the precursor of prostaglandins, induces abor- tion101 ; (5) amniotic fluid concentrations of prostaglandins increase before the onset of spontaneous labor at term in humans and nonhu- man primates131 ; (6) expression of myometrial prostaglandin receptors increases in labor132,133 ; and (7) labor is associated with increased cyclooxygenase-2 (COX-2) expression of messenger RNA (mRNA) and increased activity of this enzyme in amnion (a rate-limiting step in the production of prostaglandins). This increase in amnionic COX- 2 activity is accompanied by decreased expression of the prostaglan- din-metabolizing enzyme, 15-hydroxy-prostaglandin dehydrogenase (PGDH) in the chorion. This would allow prostaglandins produced in the amnion to traverse the chorion and reach the myometrium, where they can stimulate smooth muscle contractions.134 The biochemical mechanisms by which prostaglandins activate the common pathway of parturition are the following: (1) prostaglandins directly promote uterine contractions by increasing sarcoplasmic and transmembrane calcium fluxes and through increased transcription of oxytocin receptors, connexin-43 (gap junctions), and the prostaglan- din receptors EP1 through EP4 and FP27,135,136 ; (2) prostaglandins induce synthesis of MMPs by fetal membranes and cells within the uterine cervix (as noted, MMPs have been implicated in the mechanisms of membrane rupture and also in cervical ripening)137,138 ; and (3) prosta- glandin E2 (PGE2) and PGF2α increase the ratio of expression of the progesterone receptor (PR) isoforms, PR-A/PR-B.139 This may induce a functional progesterone withdrawal. Figure 28-3 describes the molecular mechanisms implicated in the common pathway of parturition. Spontaneous Preterm Parturition as a “Syndrome” The current taxonomy of disease in obstetrics is based on the clinical presentation of the mother and not on the mechanisms of disease responsible for the clinical presentation. Neither the term “preterm labor with intact membranes” nor “preterm prelabor rupture of mem- branes” conveys information about the pathologic process that has led to untimely delivery. This situation is not unique to preterm parturi- tion: it is also the case in preeclampsia, small for gestational age (SGA), fetal death, and other obstetric syndromes. Generally, the diagnostic labels used in clinical obstetrics simply reflect a collection of symptoms and signs (e.g., abdominal pain due to uterine contractions, leakage of fluid) without information about the mechanisms of disease. The lack of recognition of this is respon- sible for the failure of any single diagnostic test or treatment to detect, cure, or prevent preterm delivery. To emphasize that preterm labor has multiple causes, we have used the word “syndrome,” which is defined as a combination of symptoms or signs that form a distinct clinical picture but can be generated by multiple etiologies. The features of the great obstetric syndromes have been described elsewhere.140 We also make a distinction between preterm labor as a multifacto- rial disorder versus a syndrome. We are unaware of any disease in medicine that is unifactorial. For example, even sickle cell anemia, which is caused by the mutation of a single nucleotide, produces a wide range of clinical manifestations, and environmental factors such as infection or hypoxia can influence the phenotype caused by a single discrete genotype. The term “multifactorial” is often used in genetics to refer to common complex disorders in which the genetic predisposi- tion is attributed to several genes and can be altered by environmental factors. Each of the causes of preterm parturition syndrome fits this definition of multifactorial. For example, in the case of infection, microorganisms can be considered an environmental factor, but the intensity and nature of the host inflammatory response is under genetic control. Thus, gene-environment interactions contribute to the phenotype of infection associated preterm parturition. The same is the case for vascular disease or hemorrhage, stress, and so on. The causes of preterm parturition syndrome are presented in Figure 28-4. The mechanisms of disease for each cause are in the following sections. The molecular signaling pathways implicated in four of these mechanisms are displayed in Figure 28-5. The Spontaneous Preterm Parturition Syndromes Infection and Inflammation Infection is a frequent and important mechanism of disease in preterm delivery. Indeed, it is the only pathologic process for which an unequiv- ocal causal link with preterm parturition has been established. Evi- dence for causality includes the following: (1) intrauterine infection or systemic administration of microbial products (bacterial endotoxin) to pregnant animals results in spontaneous preterm labor and birth141-153 ; (2) extrauterine maternal infections (malaria,154,155 pyelonephritis,156-160 pneumonia,161-163 and periodontal disease164-169 ) are associated with preterm delivery; (3) subclinical intrauterine infections are consis- tently associated with preterm labor and preterm birth170 ; (4) pregnant PG PR-A/PR-B, ER-α MMPs and IL-8 Cervical change Preterm PROM Contractions Caϩϩ Oxytocin receptor, connexin-43, COX-2 FP and EP1, 3 PG receptors in fundus FIGURE 28-3 Molecular mechanisms implicated in the common pathway of parturition. COX-2, cyclooxygenase-2; EP1, PTGER1, prostaglandin E receptor type 1; ER-α, estrogen receptor-α; FP, PTGFR, prostaglandin F receptor; IL-8, interleukin 8; MMPs, matrix metalloproteinases; PG, prostaglandins; PR, prostaglandin receptor; PROM, premature rupture of membranes.
  5. 5. 525CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor women with intra-amniotic infection171-173 or inflammation (defined as an elevation of amniotic fluid concentrations of proinflammatory cytokines174,175 and matrix-degrading enzymes176 in the mid-trimester) are at risk for subsequent spontaneous preterm birth; (5) antibiotic treatment of ascending intrauterine infections can prevent preterm parturition in experimental models of chorioamnionitis149,177 ; and (6) treatment of asymptomatic bacteriuria prevents preterm birth.178,179 Because the amniotic cavity is sterile for bacteria in 99% of cases, detection of microorganisms in the amniotic cavity with either cultiva- tion techniques or molecular microbiologic techniques defines micro- bial invasion of the amniotic cavity. Microorganisms or their products can elicit an inflammatory response within the amniotic cavity: intra- amniotic inflammation. Inflammation of the chorioamniotic mem- branes, or histologic chorioamnionitis, can exist without clinical signs of infection (clinical chorioamnionitis). The stages of ascending intra- uterine infection are displayed in Figure 28-6. Microbiologic studies using cultivation techniques suggest that infection may account for 25% to 40% of all preterm births.180,181 Microbial invasion of the amniotic cavity (MIAC) is present in 12.8%180 of women with preterm labor with intact membranes, in 32% of those with preterm PROM,180 and in 51% of patients with acute cervical insufficiency.182,183 Patients with MIAC are more likely to deliver preterm neonates, have spontaneous rupture of membranes, and develop clinical chorioamnionitis than those with sterile amniotic fluid.184 The most common organisms found in the amniotic fluid are genital mycoplasmas.185,186 It is believed that ascending infection is the most common source of microbial invasion of the amniotic cavity, although transplacental infections may also occur. The lower the ges- tational age at which a patient presents with preterm labor and preterm PROM, the higher the frequency of MIAC.187,188 Moreover, many of these infections appear to be chronic in nature, because they have been detected in women having mid-trimester amniocentesis for genetic indications.171-173 Bacterial products such as endotoxin have also been detected in the amniotic cavity of women with preterm labor and preterm PROM.189,190 Endotoxin has powerful proinflammatory effects in maternal and fetal tissues.191-193 Uterine overdistention Cervical disease Abnormal allograft reaction Uterine Ischemia + hemorrhage Allergic phenomena Infection Endocrine disorder FIGURE 28-4 The preterm parturition syndrome. Multiple pathologic processes can lead to activation of the common pathway of parturition. (Modified from Romero R, Espinoza J, Mazor M, Chaiworapongsa T: The preterm parturition syndrome. In Critchely H, Bennett P, Thornton S (eds): Preterm Birth. London: RCOG Press, 2004, pp 28-60.) Inflammation Thrombin PTL or PPROM CRH Estrogen Stretch Integrins Abruption Stress COX2 PGDH PR-B MMPs IL-6 and 8 IL-1β TNF-α FIGURE 28-5 Principal biochemical mechanisms responsible for the main pathways of preterm parturition. COX2, cyclooxygenase- 2; CRH, corticotropin-releasing hormone; IL-1β, interleukin-1β; MMPs, matrix metalloproteinases; PGDH, prostaglandin dehydrogenase; PPROM, preterm premature rupture of membranes; PR-B, progesterone receptor type B; PTL, preterm labor; TNF-α, tumor necrosis factor-α. III IV II I FIGURE 28-6 The pathway of ascending intrauterine infection. Stage I refers to a change in microbial flora in the vagina and/or cervix. In Stage II, microorganisms are located between the amnion and chorion. Stage III represents intra-amniotic infection, and Stage IV is fetal invasion. The most common sites for microbial attack are the skin and the fetal respiratory tract. (Reproduced with permission from Romero R, Mazor M: Infection and preterm labor. Clin Obstet Gynecol 31:553-584, 1988.)
  6. 6. 526 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor Microorganisms are “sensed” by the innate components of the immune system,194 which include (1) the soluble pattern recognition receptors (PRRs), lectin, and C-reactive protein; (2) transmembrane PRRs, which include scavenger receptors, C-type lectins, and Toll-like receptors (TLRs); and (3) intracellular PRRs, including Nod1 and Nod2, retinoic-induced gene type 1, and melanoma differentiation associated protein 5, which mediate recognition of intracellular patho- gens (e.g., viruses).195 The best-studied PRRs are the TLRs.194 Ligation of TLR results in activation of NF-κB, which, in turn, leads to the production of cytokines, chemokines, and antimicrobial peptides.194 Because TLRs are crucial for the recognition of microorganisms, it could be anticipated that defective signaling through this pathway would impair bacteria-induced preterm labor. Consistent with this thesis, a strain of mice bearing a spontaneous mutation for TLR-4 was less likely to deliver preterm after intrauterine inoculation of heat- killed bacteria or administration of lipopolysaccharide than wild-type mice.151,196 In pregnant women, TLR-2 and TLR-4 are expressed in the amniotic epithelium197 as well as in decidua.198 Moreover, spontaneous labor that occurs at term or preterm and is complicated by histologic evidence of chorioamnionitis, regardless of the membrane status (intact or ruptured), is associated with increased mRNA expression of TLR-2 and TLR-4 in the chorioamniotic membranes.197 These observa- tions suggest that the innate immune system plays a role in parturition. The Role of Proinflammatory Cytokines Inflammation and its mediators, chemokines such as IL-8, the proin- flammatory cytokines (IL-1β, TNF-α), and other mediators (e.g., platelet activating factor, prostaglandins) are central to preterm partu- rition induced by infection. IL-1 was the first cytokine implicated in the onset of preterm labor associated with infection.199 Evidence in support of this concept includes the following: (1) IL-1 is produced by human decidua in response to bacterial products200 ; (2) IL-1α and IL- 1β stimulate prostaglandin production by human amnion and decidua201 ; (3) IL-1α and IL-1β concentrations and IL-1–like bioactiv- ity are increased in the amniotic fluid of women with preterm labor and infection202 ; (4) intravenous IL-1β stimulates uterine contrac- tions203 ; and (5) administration of IL-1 to pregnant animals induces preterm labor and delivery,204 and this effect can be blocked by the administration of its natural antagonist, the IL-1 receptor antagonist (IL-1ra).205 Evidence supporting the role of TNF-α in the mechanisms of preterm parturition is similar and includes the following: (1) TNF-α stimulates prostaglandin production by amnion, decidua, and myome- trium148 ; (2) human decidua can produce TNF-α in response to bacte- rial products206,207 ; (3) amniotic fluid TNF-α bioactivity and immunoreactive concentrations are elevated in women with preterm labor and intra-amniotic infection208 ; (4) in women with preterm PROM and intra-amniotic infection, TNF-α concentrations are higher in the presence of labor208 ; (5) TNF-α can stimulate the production of MMPs,209,210 which have been implicated in membrane rupture85,211,212 ; (6) TNF-α application to the cervix induces changes that resemble cervical ripening213 ; (7) TNF-α can induce preterm parturition when administered systemically to pregnant animals214,215 ; and (8) TNF-α and IL-1β enhance IL-8 expression by decidual cells, and this chemo- kine is strongly expressed by term decidual cells in the presence of chorioamnionitis.216 Figure 28-7 displays the mechanisms involved in preterm parturition in the setting of infection. Other cytokines and chemokines (IL-6,187,217-221 IL-10,203,222,223 IL- 16,224 IL-18,225 colony-stimulating factors,226-228 macrophage migration inhibitory factor,229 IL-8,228,230-234 monocyte chemotactic protein-1,235 epithelial cell–derived neutrophil-activating peptide-78,236 and, regu- lated on activation, normal T-cell expressed and secreted (RANTES)237 ) have also been implicated in infection-induced preterm delivery. The redundancy of the cytokine network implicated in parturition is such that blockade of a single cytokine is insufficient to prevent preterm delivery in the context of infection. For example, preterm labor after exposure to infection can occur in knockout mice for the IL-1 type I receptor, suggesting that IL-1 is sufficient, but not necessary, for the onset of parturition in the context of intra-amniotic infection/inflam- IL-1 IL-1 TNF TNF PAF PG PG PG Amnioticfluid AmnionChorion Decidua Myometrium Deciduitis FIGURE 28-7 Cellular and biochemical mechanisms involved in initiation of preterm labor in cases of intrauterine infection. IL-1, interleukin-1; TNF, tumor necrosis factor/cachectin; PG, prostaglandins; PAF, platelet activating factor. (Reproduced with permission from Romero R, Mazor M: Infection and preterm labor. Clin Obstet Gynecol 31:553-584, 1988.)
  7. 7. 527CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor mation.238 However, blockade of both signaling pathways (i.e., for IL-1 and TNF-α) in a double-knockout mice model was associated with a decreased rate of preterm birth after the administration of microorganisms.215 Anti-inflammatory Cytokines and Preterm Labor IL-10 is thought to be a key cytokine for the maintenance of preg- nancy.239-241 Its concentrations are increased in intra-amniotic inflam- mation,242 suggesting that IL-10 may play a role in dampening the inflammatory response243-248 and may have therapeutic value.249-254 In a nonhuman primate model of intrauterine infection, pregnant rhesus monkeys (n = 13) were allocated to one of three interventional groups: (1) intra-amniotic IL-1β infusion with maternal dexamethasone intra- venously (n = 4); (2) intra-amniotic IL-1β + IL-10 (n = 5); or (3) intra-amniotic IL-1β administered alone (n = 5). Dexamethasone and IL-10 treatment significantly reduced IL-1β–induced uterine contrac- tility (P < .05). The amniotic fluid concentrations of TNF-α and leu- kocyte counts were also decreased by IL-10 treatment (P < .05).203 Furthermore, the administration of IL-10 in animal models of infec- tion has been associated with improved pregnancy outcome.249,255 Fetal Involvement in Intrauterine Infection Carroll and Nicolaides256 found fetal bacteremia in 33% of fetuses with positive amniotic fluid cultures and in 4% of those with negative amniotic fluid cultures in the context of preterm PROM. Therefore, subclinical fetal infection is far more common than traditionally rec- ognized. Recently, Goldenberg and colleagues257 reported that 23% of neonates born between 23 and 32 weeks of gestation had positive umbilical blood cultures for genital mycoplasmas. Inflammation and Fetal Injury: The Fetal Inflammatory Response Syndrome The fetal inflammatory response syndrome (FIRS) was initially described in pregnancies complicated by preterm labor and preterm PROM.258,259 It was defined as a fetal plasma concentration of IL-6 greater than 11 pg/mL.258 Fetuses with an elevated plasma IL-6 concen- tration had a higher rate of severe neonatal morbidity and a shorter cordocentesis-to-delivery interval than those with an IL-6 concentra- tion lower than 11 pg/mL.259 These original findings were subsequently confirmed.259-262 The histopathologic landmarks of FIRS are funisitis and chorionic vasculitis.263 The disorder can also be diagnosed by measurement of C-reactive protein concentrations in umbilical cord blood.264 Fetuses with FIRS have more systemic involvement, including hematologic abnormalities (neutrophilia), and a higher median nucle- ated red blood cell count than those without elevated IL-6.265 In addi- tion, they have evidence of fetal stress, as determined by the fetal plasma ratio of cortisol to dehydroepiandrosterone sulfate (DHEAS),266 congenital fetal dermatitis,267 fetal cardiac dysfunction,268 involution of the thymus,269 and abnormalities of the fetal lung230,232,262,270-274 and brain.275-304 Among patients with preterm PROM, elevated fetal plasma IL-6 is associated with the impending onset of preterm labor, regardless of the inflammatory state of the amniotic fluid (Fig. 28-8).258 This suggests that the human fetus plays a role in initiating the onset of labor. However, maternal-fetal cooperation must occur for parturition to be completed. Fetal inflammation has been linked to the onset of labor in association with ascending intrauterine infection. However, systemic fetal inflammation may occur in the absence of labor if the inflamma- tory process does not involve the chorioamniotic membranes and decidua. Such instances may take place in the context of hema- togenous viral infections or other disease processes (e.g., rhesus alloimmunization).305 Gene-Environment Interaction A gene-environment interaction is said to be present when the risk of a disease (occurrence or severity) among individuals exposed to both the genotype and an environmental factor is either more severe or less severe than that which is predicted from the presence of either the genotype or the environmental exposure alone.306,307 Evidence in support of a gene-environment interaction in infection-related prema- ture labor was reported by Macones and coworkers308 in a case-control study in which cases were defined as patients who had a spontaneous preterm delivery (<37 weeks) and controls as women who delivered after 37 weeks. The environmental exposure was clinically diagnosed bacterial vaginosis (symptomatic vaginal discharge, a positive whiff test, and clue cells on a wet preparation). The genotype of interest was TNF-α allele 2, given that carriage of this genotype had been demon- strated by the authors to be associated with spontaneous preterm birth in previous studies.309 The key observation was that patients with both bacterial vaginosis and the TNF-α allele 2 had an odds ratio of 6.1 (95% confidence interval [CI], 1.9 to 21) for spontaneous preterm delivery and that this odds ratio was higher than for patients with either bacterial vaginosis or carriage of the TNF-α allele alone, sug- gesting that a gene-environment interaction predisposes to preterm birth.308,310 Similar interactions may determine the susceptibility to intrauterine infection, microbial invasion of the fetus, and the likeli- hood of fetal injury. Uteroplacental Vascular Disease and Decidual Hemorrhage Vaginal bleeding in the first or second trimester is a risk factor for preterm birth. Bleeding in the first trimester alone is associated with an adjusted risk ratio of 2 (95% CI, 1.6 to 2.5) for preterm delivery.311 If vaginal bleeding is present in more than one trimester, the odds ratio for preterm PROM is 7.4 (95% CI, 2.2 to 25.6).312 Therefore, a disorder of uterine hemostasis that manifests clinically as bleeding places the patient at risk for preterm birth. The location of bleeding could be the decidua, specifically the interface between decidual parietalis and chorion or between the basal plate of the placenta and the decidua. The latter, when large enough, is known as abruptio placenta. The typical patient with vaginal bleeding who delivers preterm is a privately insured, white, older, parous, and college-educated patient.313 The evidence in support of spiral artery vasculopathy and decidual hemorrhage as a mechanism of disease in spontaneous preterm deliv- ery is the following: (1) abruptio placenta, a lesion of uteroplacental vascular origin is more frequent in women who deliver preterm with intact membranes314,315 or with PROM than in those who deliver at term316-318 ; (2) the frequency of SGA infants is increased in women who deliver after preterm labor with intact membranes and preterm PROM319-324 (SGA has generally been attributed to a problem with the uterine vascular supply line, and this could account for both IUGR and abruption-associated preterm parturition); (3) vascular lesions in decidual vessels attached to the placenta have been reported in 34% of women with preterm labor and intact membranes and in 35% of those with PROM, but only in 12% of control patients (term gestations without complications) (such vascular lesions are associated with a mean odds ratio of 3.8 for preterm labor with intact membranes and 4 for PROM)315 ; (4) women with preterm labor and intact membranes and those with preterm PROM have a higher percentage of failure of physiologic transformation in the myometrial segment of the spiral
  8. 8. 528 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor arteries than women who deliver at term325,326 ; (5) decidual hemosid- erin deposition and retrochorionic hematoma formation is present in 37.5% of patients who deliver preterm after PROM (between 22 and 32 weeks of gestation) than in those who deliver at term (0.8%)327 (patients with preterm deliveries with intact membranes had decidual hemosiderin in 36% of cases); and (6) patients presenting with preterm labor and intact membranes who go on to have a preterm delivery are more likely to have an abnormal uterine artery velocimetry than patients with an episode of preterm labor who deliver at term.328-330 The mechanisms by which uteroplacental ischemia, decidual hem- orrhage, or both may activate the common pathway of parturition include the generation of thrombin. Evidence in support of this mech- anism has been summarized elsewhere331 and includes the following: (1) because decidua is a rich source of tissue factor, the primary initia- tor of coagulation, hemorrhage into the decidua would generate sub- stantial quantities of thrombin, explaining the strong association between abruption and disseminated intravascular coagulation332 ; (2) intrauterine administration of whole blood to pregnant rats stimulates myometrial contractility,333 but administration of heparinized blood does not (heparin blocks the generation of thrombin)333 ; (3) fresh whole blood stimulates myometrial contractility in vitro, and this effect is partially blunted by incubation with hirudin, a thrombin inhibitor333 ; (4) thrombin stimulates myometrial contractility in a dose-dependent manner333 ; (5) thrombin stimulates the production of MMP-1,334 urokinase-type plasminogen activator (uPA), and tissue- type plasminogen activator (tPA) by decidualized endometrial stromal cells in culture335 (MMP-1 can digest collagen directly, whereas uPA and tPA catalyze the transformation of plasminogen into plasmin, which in turn can degrade type III collagen and fibronectin,336 impor- tant components of the extracellular matrix of the chorioamniotic membranes and decidua337 ); (6) thrombin/antithrombin (TAT) com- plexes, a marker of in vivo generation of thrombin, are increased in the plasma338 and amniotic fluid339 of patients with preterm labor and preterm PROM; (7) an elevation of plasma TAT complex concentra- tion in the second trimester is associated with subsequent preterm PROM340 ; and (8) the presence of retroplacental hematoma detected by ultrasound examination in the first trimester is associated with adverse pregnancy outcomes, including preterm delivery and fetal growth restriction.341 Additional evidence providing biologic plausibility for a role of thrombin is that the production of MMP-3 mRNA and protein by term decidual cells is normally inhibited by progestins. However, thrombin reverses this inhibition by interacting with the protease-activated receptor type 1 (PAR-1).342 This is important, because MMP-3 can degrade extracellular matrix located in the decidua and fetal mem- branes, but it can also activate MMP-1 and MMP-9, which can degrade, respectively, fibrillar collagen and gelatin. Thrombin also binds to PARs and increases expression of MMP-1 mRNA and proteins by decidual cells.334 Histologic examination of placentas with abruption frequently show evidence of inflammation.343,344 Neutrophils in the decidua colo- calize with areas of fibrin deposition, suggesting a link between inflam- n Procedure-to-delivery interval (median, range, days) I 14 5 (0.2–33.6) AF IL-6 ≤7.9 ng/mL FP IL-6 ≤11 pg/mL II 5 7 (1.5–32) AF IL-6 >7.9 ng/mL FP IL-6 ≤11 pg/mL III 6 1.2 (0.25–2) AF IL-6 >7.9 ng/mL FP IL-6 >11 pg/mL IV 5 0.75 (0.13–1) AF IL-6 ≤7.9 ng/mL FP IL-6 >11 pg/mL FIGURE 28-8 Classification and procedure-to-delivery intervals of patients according to amniotic fluid (AF) and fetal plasma (FP) concentrations of interleukin-6 (IL-6). In the FP, the white color indicates a low concentration of IL-6, and the dark red color represents a high concentration. Likewise, the white color in the AF compartment indicates a low concentration of IL-6, and the gray color indicates a high concentration. (Reproduced with permission from Romero R, Gomez R, Ghezzi F, et al: A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol 179:186-193, 1998.)
  9. 9. 529CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor mation and thrombin generation. Thrombin increases IL-8 mRNA and protein expression by decidual cells. IL-8 is a potent neutrophil che- mokine that is capable of attracting neutrophils to the areas of bleed- ing.344 Inasmuch as neutrophils are a rich source of MMP-8, MMP-9, elastase,345 and reactive oxygen radicals,346-348 these products can con- tribute to extracellular matrix degradation in the decidual/membrane interface and to membrane rupture. IL-11 has been demonstrated in the decidua of patients with abrup- tion and preterm PROM. Thrombin induces IL-11 production (mRNA and protein) by decidual cells,349 and IL-11 can induce PGE2 produc- tion.349 Therefore, this cytokine provides a link between thrombin generation, inflammation, activation of PARs, and the common pathway of parturition. Figures 28-9 and 28-10 describe the molecular mechanisms implicated in hemorrhage- or vascular-induced preterm labor. Maternal and Fetal Stress Maternal stress of exogenous or endogenous origin is modestly associ- ated with an increased risk for preterm delivery.350-354 The nature and timing of the stressful stimuli can range from a heavy workload to anxiety and depression.355,356 African-American women with elevated scores for depression have an adjusted odds ratio for preterm delivery of 1.96 (95% CI, 1.04 to 3.72).357 The absence of similar findings in Hispanic and non-Hispanic white populations suggests an ethnic dis- parity in the effect of stress in the United States. The stressful insult could occur in the pre-conceptional period or during pregnancy. Starvation before pregnancy leads to spontaneous preterm delivery in sheep.358 The precise mechanism whereby stress induces parturition is not known. However, a role for CRH has been proposed. This hormone was originally identified in the hypothalamus but is expressed by the placenta.359 The maternal plasma CRH concen- trations increase during the second half of pregnancy and peak during labor, whereas serum concentrations of the CRH binding protein decline during the third trimester.360,361 Smith and colleagues360,361 demonstrated that the trajectory of CRH serum concentration changes identify women destined for preterm, term, and post-term delivery. The mechanisms regulating the serum concentration and trajectory of CRH have been described as “a pla- cental clock.” Because CRH maternal plasma concentrations are ele- vated in both term and preterm parturition, it would appear that CRH is part of the common pathway of labor. The mechanisms through which CRH activates the common pathway of parturition include the following: (1) increased production of PGE2 by amnion, chorion, and placental cells, but not by decidual cells362-364 ; (2) increased production of PGF2α by amnion, decidua, and placental cells, but not by chorion362-364 ; (3) increased expression of MMP-9 by chorion and amnion365 ; (4) stimulation of the release of adrenocorticotropin (ACTH) from the pituitary gland to drive fetal cortisol production366 (this establishes a feed-forward cycle, because cortisol stimulates production of CRH by the placenta and fetal mem- branes)359 ; (5) induction of the synthesis of fetal DHEAS by the fetal adrenal zone367-369 (DHEAS serves as a source for estrogens,367 which in turn enhance the expression of the oxytocin receptor, COX-2, pros- taglandin receptors, and connexin-43)370-377 ; (6) cortisol produced in response to CRH can increase amnion COX-2 expression while inhib- iting chorionic PGDH expression378-381 (resulting in a net bioavailabil- ity of prostaglandins); and (7) CRH inhibits progesterone production by the placenta.382 Figures 28-11 and 28-12 illustrate the molecular mechanisms for stress-associated preterm labor. As noted, CRH has been implicated in the mechanisms of sponta- neous parturition at term. Therefore, this specific pathway may operate in normal term labor as well as in preterm labor. In the former case, placental CRH expression reflects maturation of the fetal hypotha- lamic-pituitary-adrenal axis; in the latter, it reflects physiologically stressful events occurring at later gestational ages. It may be surmised that some cases of preterm labor occurring close to term resort to the physiologic mechanisms used in term labor after fetal maturation has been accelerated by stressful stimuli. Uterine Overdistention Patients with müllerian duct abnormalities,383 polyhydramnios,384,385 or multiple gestations386 are at increased risk for spontaneous preterm labor and delivery. The frequency of preterm delivery in multifetal gestations is 17%, and the mean gestational age at delivery decreases as a function of the number of fetuses: 35.3 weeks for twins, 32.2 weeks for triplets, and 29.9 weeks for quadruplets.4 Myometrial stretch has been implicated as a key mechanism driving these preterm deliveries. IX X Xa ؉ VaX Tissue Factor Prothrombin IXa ؉ Vllla ؉ VII or VIIa Thrombin Fibrinogen Fibrin FIGURE 28-9 Tissue factor generates thrombin. The decidua is a rich source of tissue factor, the primary initiator of clotting. Disruption of spiral arteries and/or arterioles permits factor X or IX to be activated by the action of factor VII when complexed with tissue factor. Factor IXa combines with its cofactor VIIa to generate factor Xa indirectly. In either case, Xa binds to its cofactor to convert prothrombin to thrombin, which cleaves fibrinogen to fibrin. Decidual Hemorrhage Thrombin PARs Myometrium Contractions MMPs and IL-8 PTL ؉/؊ PPROM Decidua amniochorion FIGURE 28-10 Mechanisms implicated in abruption-associated preterm labor and delivery. IL-8, interleukin 8; MMPs, matrix metalloproteinases; PARs, protease-activated receptors; PTL, preterm labor; PPROM, preterm premature rupture of membranes.
  10. 10. 530 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor However, the importance of stretch as a mechanism of activation of the common pathway of parturition is not restricted to the myome- trium. Indeed, stretch may play a role in cervical remodeling and membrane rupture.387 How does stretch activate the common pathway of parturition? Intra-amniotic pressure remains relatively constant during gestation, despite the continued growth of the fetus, placenta, and uterus.388,389 This stability of pressure has been attributed to progressive myometrial relaxation caused by the effects of progesterone390 and nitric oxide.391 Stretch, however, can induce increased myometrial contractility,392 prostaglandin release,393 expression of connexin-43,26 and increased oxytocin receptors in pregnant and nonpregnant human myome- trium.394 The gene expression of these stretch-induced contraction- associated proteins (CAPs) during pregnancy is inhibited by progesterone.26 Mechanical stress in smooth muscle induces activation of integrin receptors395 and stretch-activated calcium channels,396,397 phosphoryla- tion of platelet-derived growth factor receptor,398 and activation of G proteins.398,399 Mechanical force, once sensed, leads to activation of protein kinase C and mitogen activated protein kinases, increased gene expression of FOS (c-fos) and JUN (c-jun), and enhanced binding activity of transcription factor AP-1, which drives transcription of multiple parturition-associated genes.24,400-404 Other effects of physical forces relevant to myometrium include increased expression of COX-2, superoxide dismutase, and nitric oxide synthase. The precise nature of the sensing mechanisms of pressure/tension in the myometrium is yet to be determined. Stretch can also affect the chorioamniotic membranes, which are distended by 40% at 25 to 29 weeks, 60% at 30 to 34 weeks, and 70% at term.405 Stretching of the membranes in vitro induces histologic changes characterized by elongation of the amnion cells and increased production of collagenase activity and IL-8,406,407 and stretching of amnion cells in culture results in increased production of PGE2.408 Studies using an in vitro cell culture model for fetal membrane disten- tion revealed upregulation of proinflammatory genes, including IL-8 and pre–B-cell colony-enhancing factor (visfatin).409 Distention of fetal membrane in vitro results in overexpression of four genes, namely IL-8, interleukin enhancer binding factor 2 (ILF2), huntingtin- interacting protein 2, and an interferon-stimulated gene encoding a 54-kDaprotein.410 Collectively,theseobservationssuggestthatmechan- ical forces associated with uterine overdistention may result in activa- tion of mechanisms leading to membrane rupture. Premature cervical ripening is also a feature of patients with mul- tiple gestations, as well as those with certain müllerian duct anomalies (e.g., incompetent cervix in diethylstilbestrol [DES]-exposed daugh- ters). IL-8,45,411,412 MMP-1,104 prostaglandins,137,413,414 and nitric oxide415 have been implicated in the control of cervical ripening. Inasmuch as these mediators are produced in response to membrane stretch, they may exert part of their biologic effects in parturition by stimulating extracellular matrix degradation of the cervix. Figure 28-13 describes the mechanisms by which stretch may acti- vate the common pathway of parturition. It is possible, however, that patients with multiple gestations represent a heterogeneous group. Maternal stress Activation of fetal HPA axis Placental insufficiency Cortisol CRH E1-E3 PG Cervical change Preterm PROM Contractions Myometrial (PR-A/B, and ER-␣) enhances c-jun causing increase in CAPs, FP, EP1, EP3 Placenta, membranes and decidua (؉) CRH ACTH Fetal adrenal zone DHEA/16-OH DHEA Placental sulfatases ؉ FIGURE 28-12 Proposed pathways by which stress can induce preterm labor. ACTH, corticotropin; CAPs, contraction-associated proteins; CRH, corticotropin-releasing hormone; DHEA, dehydroepiandrosterone; E1-E3, estrone, estradiol, and estriol; EP1 and EP3, prostaglandin E receptors types 1 and 3; ER-α, estrogen receptor-α; FP, prostaglandin F receptor; HPA, hypophysis-pituitary- adrenal; PG, prostaglandins; PR, prostaglandin receptor; PROM, premature rupture of membranes. ؉ ؉ Stress Hypothalamus Pituitary CRH ACTH Cortisol Placenta, decidua and amniochorion Adrenal gland (؊) (؊) FIGURE 28-11 The fetal hypophysis-pituitary-adrenal-placental axis in pregnancy. ACTH, corticotropin; CRH, corticotropin-releasing hormone.
  11. 11. 531CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor Some such patients have preterm labor associated with infection.416-418 Others have abnormalities of trophoblast invasion leading to vascular pathology, with or without fetal growth disorders, causing stress or decidual hemorrhage–mediated preterm deliveries. These separate mechanisms of disease may operate alone or in conjunction with uterine overdistention to activate the components of the common pathway. Allergic Phenomena Another potential mechanism of disease in preterm labor is an immu- nologically mediated phenomenon induced by an allergic mechanism. We have previously proposed that an allergic-like immune response (type I hypersensitivity) may be associated with preterm labor.419 The term “allergy” refers to disorders caused by the response of the immune system to an otherwise innocuous antigen.420 This “allergen” cross- links immunoglobulin E (IgE) bound to high-affinity receptors on uterine mast cells, causing degranulation of these cells. The products of degranulation initiate inflammation.421 Evidence in support of the possibility that an allergic-like phenom- enon may operate in preterm labor includes the following: (1) the human fetus is exposed to common allergens such as house-dust mite, which has been detected in amniotic fluid in the mid-trimester of pregnancy and in umbilical cord blood422 ; (2) allergen-specific reactiv- ity has been shown in umbilical cord blood at birth and as early as 23 weeks of gestation423 ; (3) pregnancy is traditionally regarded as a T helper 2 (TH2) state that favors the production of IgE; (4) the human uterus contains mast cells, the effector cells of allergy424 ; (5) products of mast cell degranulation (i.e., histamine and prostaglandins) may induce myometrial contractility425,426 ; (6) pharmacologic degranulation of mast cells induces myometrial and cervical contractility427,428 ; (7) incubation of myometrial strips from sensitized and nonsensitized animals with an anti-IgE antibody increases myometrial contractil- ity428 ; (8) human myometrial strips obtained from women known to be allergic to ragweed demonstrate increased myometrial contractility when challenged in vitro by the allergen, and, moreover, the sensitivity of the myometrial strips of nonallergic women can be transferred passively by preincubation of the strips with human serum (Robert Garfield, University of Texas, Galveston, personal communication); (9) nonpregnant guinea pigs sensitized with ovalbumin and then chal- lenged with this antigen demonstrate increased uterine tone428 ; (10) traditional descriptions of animals dying of anaphylactic shock have demonstrated enhanced uterine contractility when autopsy was per- formed immediately after death; (11) severe latex allergy in a pregnant woman after vaginal examination with a latex glove was followed by regular uterine contractions429 ; (12) human decidua contains immune cells capable of identifying local foreign antigens, including macro- phages, B cells, T cells,430,431 and dendritic cells432 ; and (13) we have identified a subgroup of patients with preterm labor who have eosino- phils in the amniotic fluid as the predominant white blood cell419 (under normal circumstances, white blood cells are not present in amniotic fluid; the presence of eosinophils therefore suggests an abnor- mal immune response, and perhaps they are the markers of an allergic- like response in preterm labor). The antigen eliciting an abnormal immunologic response remains to be identified. Recent evidence sug- gests that administration of ovalbumin to sensitized pregnant guinea pigs can induce preterm labor and delivery and that this phenomenon can be prevented with treatment with either cromolyn sodium or antihistaminics.433 Cervical Disorders Cervical insufficiency is traditionally considered a cause of mid- trimester abortion. However, accumulating evidence suggests that it can produce a wide spectrum of disease,434 including the well- recognized recurrent pregnancy loss in the mid-trimester, some forms of preterm labor (presenting with bulging membranes in the absence of significant uterine contractility or rupture of membrane), and prob- ably precipitous labor at term. Cervical disease may be the result of a congenital disorder (i.e., hypoplastic cervix or DES exposure in utero), surgical trauma (i.e., conization resulting in substantial loss of connec- tive tissue) or traumatic damage of the structural integrity of the cervix (i.e., repeated cervical dilation).435 Cervical insufficiency in the mid-trimester can be considered an example of asynchronous activation of the mechanisms that induce cervical remodeling. Indeed, it is likely that most cases of “cervical insufficiency” reflect not primary cervical disease leading to premature remodeling but other pathologic processes, such as infection, which has been reported in 50% of patients presenting with acute cervical insufficiency,183 or recurrent decidual hemorrhage. The reader is referred to a detailed review of this condition and the role of cervical cerclage in the prevention of preterm birth.436 Hormonal Disorders: Suspension of Progesterone Action Progesterone has been considered central to pregnancy maintenance.437 Progesterone promotes myometrial quiescence, downregulates gap junction formation, inhibits cervical ripening, and decreases the pro- duction of chemokines (i.e., IL-8) by the chorioamniotic membranes, which is thought to impede decidual/membrane activation.65,438-440 Pro- gesterone is considered important for pregnancy maintenance in humans, because inhibition of progesterone action can result in partu- rition. Administration of progesterone receptor antagonists (i.e., mife- pristone or onapristone) to pregnant women, nonhuman primates,441 and guinea pigs65 can induce labor or cervical change or both.437 There- fore, a suspension of progesterone action is believed to be important for the onset of parturition in humans. In many species, a progesterone withdrawal (a drop in serum progesterone concentration) occurs before spontaneous labor.442 Rapid increases in myometrial stretch due to polyhydramnios, multifetal gestations or uterine anatomic abnormalities Integrin-MAPK signaling PG, oxytocin receptors, IL-8 MMPs PG IL-8 IL-8 PG Cervix PTL ؉/؊ PPROM Myometrium Amniochorion Contractions ECM degradation FIGURE 28-13 Proposed mechanisms by which stretch can induce preterm labor. ECM, extracellular matrix; IL-8, interleukin 8; MAPK, mitogen-activated protein kinase; MMPs, matrix metalloproteinases; PG, prostaglandins; PTL, preterm labor; PPROM, preterm premature rupture of membranes.
  12. 12. 532 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor However, in humans, nonhuman primates, and guinea pigs, a pro- gesterone withdrawal has not been demonstrated (see Young443 for a description of the comparative physiology of parturition in mammals). The mechanism by which, in humans, progesterone action is sus- pended in the setting of sustained high circulating concentrations of progesterone has eluded discovery. Six potential mechanisms have been posited to explain this paradox: (1) reduced bioavailability of progesterone by binding to a high-affinity protein444,445 ; (2) increased cortisol concentration in late pregnancy, which may compete with progesterone for binding to the glucocorticoid receptor446 ; (3) conver- sion of progesterone to an inactive form within the target cell before it interacts with its receptor447,448 ; (4) quantitative and qualitative changes in progesterone receptor isoforms (PR-A, PR-B, PR-C)449-452 ; (5) changes in progesterone receptor coregulators453 ; and (6) a func- tional progesterone withdrawal through NF-κB.454-456 Progesterone’s actions are mediated by multiprotein complexes, including progesterone receptors, modifying factors (co-regulators and adaptors), and effector proteins (RNA-polymerase, chromatin- remodeling proteins, and RNA-processing factors). In addition, non- genomic mechanisms have recently been proposed.453 There is evidence supporting the view that a “functional progester- one withdrawal” occurs locally in intrauterine tissues during human parturition in both term and preterm gestation.453,457-463 The changes in the ratio of estrogen and progesterone activity could activate the three tissue components of the common pathway of parturition, including myometrium, cervix, and decidual-amniochorionic mem- branes directly or indirectly through prostaglandin or oxytocin and its receptor systems.437,450,451,453,457-469 However, the signal eliciting the onset of these hormonal functional changes in human parturition remains to be determined. The interest in progestins to prevent preterm delivery has been rekindled by several randomized clinical trials, suggesting that proges- tins may prevent preterm delivery.470 The initial trials were conducted in women with a previous preterm delivery and used either vaginal progesterone471 or 17α-hydroxyprogesterone caproate.67 Subsequently, vaginal progesterone was reported to reduce the rate of preterm birth by 40% in women with a short cervix (≤15 mm).68 A post hoc analysis of another trial was supportive of this concept.66,472 The precise mecha- nisms by which exogenous progestins reduce the rate of preterm birth are unknown. It is possible that exogenous progesterone inhibits cervi- cal remodeling in the mid-trimester of pregnancy through the mecha- nisms outlined earlier in this chapter. Summary It is becoming increasingly evident that preterm labor, preterm PROM, and cervical insufficiency are syndromes caused by multiple pathologic processes leading to increased myometrial contractility, cervical remodeling, and/or membrane activation. The clinical pre- sentation depends on the nature and timing of the insults affecting the various components of the uterine common pathway of parturi- tion. This view has important implications for understanding the biology of preterm parturition, as well as its diagnosis, treatment, and prevention. Acknowledgment This work was funded in part by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH). References 1. Mazaki-Tovi S, Romero R, Kusanovic JP, et al: Recurrent preterm birth. Semin Perinatol 31:142-158, 2007. 2. Parry S, Strauss JF III: Premature rupture of the fetal membranes. N Engl J Med 338:663-670, 1998. 3. Moutquin JM: Classification and heterogeneity of preterm birth. BJOG 110(Suppl 20):30-33, 2003. 4. Martin JA, Hamilton BE, Sutton PD, et al: Births: Final data for 2002. Natl Vital Stat Rep 52:1-113, 2003. 5. Romero R, Mazor M, Munoz H, et al: The preterm labor syndrome. Ann N Y Acad Sci 734:414-429, 1994. 6. Romero R, Gomez R, Mazor M, et al: The preterm labor syndrome. In Elder MG, Romero R, Lamont RF (eds). Preterm Labor. New York: Churchill Livingstone, 1997, pp 29-49. 7. Genazzani AR, Petraglia F, Facchinetti F, et al: Lack of beta-endorphin plasma level rise in oxytocin-induced labor. Gynecol Obstet Invest 19:130- 34, 1985. 8. Ohrlander S, Gennser G, Eneroth P: Plasma cortisol levels in human fetus during parturition. Obstet Gynecol 48:381-387, 1976. 9. Petraglia F, Giardino L, Coukos G, et al: Corticotropin-releasing factor and parturition: Plasma and amniotic fluid levels and placental binding sites. Obstet Gynecol 75:784-789, 1990. 10. 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Endocrinology 127:3047-3051, 1990. 15. Nathanielsz P, Poore E, Brodie A, et al: Update on molecular events of myometrial activity during pregnancy. In Nathanielsz P, Parer J (eds): Research in Perinatal Medicine. Ithaca, NY: Perinatology, 1987, p 111. 16. Romero R, Avila C, Sepulveda W, et al: The role of systemic and intrauter- ine infection in preterm labor. In Fuchs A, Fuchs F, Stubblefield P (eds): PretermBirth:Causes,Prevention,andManagement.NewYork:McGraw- Hill, 1993. 17. Cole WC, Garfield RE, Kirkaldy JS: Gap junctions and direct intercellular communication between rat uterine smooth muscle cells. Am J Physiol 249:C20-C31, 1985. 18. Garfield RE, Sims S, Daniel EE: Gap junctions: Their presence and necessity in myometrium during parturition. Science 198:958-960, 1977. 19. Garfield RE, Sims SM, Kannan MS, et al: Possible role of gap junctions in activation of myometrium during parturition. Am J Physiol 235:C168- C179, 1978. 20. 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