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  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Randall NJ, Bond K, Macaulay J, et al: Measuring fetal and maternal tem- perature differentials: A probe for clinical use during labour. J Biomed Eng 13:481-485, 1991. 11. Nathanielsz P, Honnebier M: Myometrial function. In Drife J, Calder A (eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992, p 161. 12. Hsu HW, Figueroa JP, Honnebier MB, et al: Power spectrum analysis of myometrial electromyogram and intrauterine pressure changes in the pregnant rhesus monkey in late gestation. Am J Obstet Gynecol 161:467- 473, 1989. 13. Taylor NF, Martin MC, Nathanielsz PW, et al: The fetus determines circa- dian oscillation of myometrial electromyographic activity in the pregnant rhesus monkey. Am J Obstet Gynecol 146:557-567, 1983. 14. Binienda Z, Rosen ED, Kelleman A, et al: Maintaining fetal normoglyce- mia prevents the increase in myometrial activity and uterine 13,14- dihydro-15-keto-prostaglandin F2 alpha production during food withdrawal in late pregnancy in the ewe. 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. Garfield RE, Hayashi RH: Appearance of gap junctions in the myome- trium of women during labor. Am J Obstet Gynecol 140:254-260, 1981. 21. Garfield RE, Puri CP, Csapo AI: Endocrine, structural, and functional changes in the uterus during premature labor. Am J Obstet Gynecol 142:21-27, 1982.
  • 13. 533CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 22. Balducci J, Risek B, Gilula NB, et al: Gap junction formation in human myometrium: A key to preterm labor? Am J Obstet Gynecol 168:1609- 1615, 1993. 23. Chow L, Lye SJ: Expression of the gap junction protein connexin-43 is increased in the human myometrium toward term and with the onset of labor. Am J Obstet Gynecol 170:788-795, 1994. 24. Lefebvre DL, Piersanti M, Bai XH, et al: Myometrial transcriptional regu- lation of the gap junction gene, connexin-43. Reprod Fertil Dev 7:603-611, 1995. 25. Orsino A, Taylor CV, Lye SJ: Connexin-26 and connexin-43 are differen- tially expressed and regulated in the rat myometrium throughout late pregnancy and with the onset of labor. Endocrinology 137:1545-1553, 1996. 26. Ou CW, Orsino A, Lye SJ: Expression of connexin-43 and connexin-26 in the rat myometrium during pregnancy and labor is differentially regulated by mechanical and hormonal signals. Endocrinology 138:5398-5407, 1997. 27. Cook JL, Zaragoza DB, Sung DH, et al: Expression of myometrial activa- tion and stimulation genes in a mouse model of preterm labor: Myome- trial activation, stimulation, and preterm labor. Endocrinology 141:1718-1728, 2000. 28. Lye SJ, Nicholson BJ, Mascarenhas M, et al: Increased expression of con- nexin-43 in the rat myometrium during labor is associated with an increase in the plasma estrogen:progesterone ratio. Endocrinology 132:2380-2386, 1993. 29. Petrocelli T, Lye SJ: Regulation of transcripts encoding the myometrial gap junction protein, connexin-43, by estrogen and progesterone. Endocrinol- ogy 133:284-290, 1993. 30. Lye SJ: The initiation and inhibition of labour: Towards a molecular understanding. Semin Reprod Endocrinol 12:284-294, 1994. 31. Lye SJ, Mitchell J, Nashman N, et al: Role of mechanical signals in the onset of term and preterm labor. Front Horm Res 27:165-178, 2001. 32. Lye S, Tsui P, Dorogin A, et al: Myometrial programmning: A new concept underlying the mainteinance of pregnancy and the initiation of labor. In VIIth International Conference on the Extracelullar Matrix of the Female Reproductive Tract and Simpson Symposia, Centre for Reproductive Biology, University of Edinburgh, 2004. 33. Csapo AI: The “see-saw” theory of parturition. Ciba Found Symp (47):159- 210, 1977. 34. Chan EC, Fraser S, Yin S, et al: Human myometrial genes are differentially expressed in labor: A suppression subtractive hybridization study. J Clin Endocrinol Metab 87:2435-2441, 2002. 35. Word RA, Li XH, Hnat M, et al: Dynamics of cervical remodeling during pregnancy and parturition: Mechanisms and current concepts. Semin Reprod Med 25:69-79, 2007. 36. Winkler M, Rath W: Changes in the cervical extracellular matrix during pregnancy and parturition. J Perinat Med 27:45-60, 1999. 37. Ludmir J, Sehdev HM: Anatomy and physiology of the uterine cervix. Clin Obstet Gynecol 43:433-439, 2000. 38. Westergren-Thorsson G, Norman M, Bjornsson S, et al: Differential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution. Biochim Biophys Acta 1406:203-213, 1998. 39. Leppert PC: Anatomy and physiology of cervical ripening. Clin Obstet Gynecol 38:267-279, 1995. 40. Straach KJ, Shelton JM, Richardson JA, et al: Regulation of hyaluronan expression during cervical ripening. Glycobiology 15:55-65, 2005. 41. Obara M, Hirano H, Ogawa M, et al: Changes in molecular weight of hyaluronan and hyaluronidase activity in uterine cervical mucus in cervi- cal ripening. Acta Obstet Gynecol Scand 80:492-496, 2001. 42. Sakamoto Y, Moran P, Bulmer JN, et al: Macrophages and not granulo- cytes are involved in cervical ripening. J Reprod Immunol 66:161-173, 2005. 43. Hassan SS, Romero R, Haddad R, et al: The transcriptome of the uterine cervix before and after spontaneous term parturition. Am J Obstet Gynecol 195:778-786, 2006. 44. Liggins G: Cervical ripening as an inflammatory reaction. In Ellwood D, Anderson A (eds): The Cervix in Pregnancy and Labour: Clinical and Biochemical Investigations. Edinburgh: Churchill Livingstone, 1981. 45. Sennstrom MK, Brauner A, Lu Y, et al: Interleukin-8 is a mediator of the final cervical ripening in humans. Eur J Obstet Gynecol Reprod Biol 74:89- 92, 1997. 46. Sakamoto Y, Moran P, Searle RF, et al: Interleukin-8 is involved in cervical dilatation but not in prelabour cervical ripening. Clin Exp Immunol 138:151-157, 2004. 47. Maradny EE, Kanayama N, Halim A, et al: Effects of neutrophil chemo- tactic factors on cervical ripening. Clin Exp Obstet Gynecol 22:76-85, 1995. 48. Osmers RG, Blaser J, Kuhn W, et al: Interleukin-8 synthesis and the onset of labor. Obstet Gynecol 86:223-229, 1995. 49. Tornblom SA, Klimaviciute A, Bystrom B, et al: Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endocrinol 3:39, 2005. 50. Roth J, Vogl T, Sorg C, et al: Phagocyte-specific S100 proteins: A novel group of proinflammatory molecules. Trends Immunol 24:155-158, 2003. 51. HavelockJC,KellerP,MulebaN,etal:Humanmyometrialgeneexpression before and during parturition. Biol Reprod 72:707-719, 2005. 52. Ito A, Hiro D, Ojima Y, et al: Spontaneous production of interleukin-1-like factors from pregnant rabbit uterine cervix. Am J Obstet Gynecol 159:261- 265, 1988. 53. Ito A, Leppert PC, Mori Y: Human recombinant interleukin-1 alpha increases elastase-like enzyme in human uterine cervical fibroblasts. Gynecol Obstet Invest 30:239-241, 1990. 54. Kelly RW: Inflammatory mediators and cervical ripening. J Reprod Immunol 57:217-224, 2002. 55. VanderBurgB,VanderSaagPT:Nuclearfactor-kappa-B/steroidhormone receptor interactions as a functional basis of anti-inflammatory action of steroids in reproductive organs. Mol Hum Reprod 2:433-438, 1996. 56. Chwalisz K, Shi Shao O, Neff G, et al: The effect of antigestagen ZK 98, 199 on the uterine cervix. Acta Endocrinol 283:113, 1987. 57. Elliott CL, Brennand JE, Calder AA: The effects of mifepristone on cervical ripening and labor induction in primigravidae. Obstet Gynecol 92:804- 809, 1998. 58. Giacalone PL, Daures JP, Faure JM, et al: The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns. Eur J Obstet Gynecol Reprod Biol 97:30-34, 2001. 59. Norman J: Antiprogesterones. Br J Hosp Med 45:372-375, 1991. 60. Stenlund PM, Ekman G, Aedo AR, et al: Induction of labor with mifepris- tone: A randomized, double-blind study versus placebo. Acta Obstet Gynecol Scand 78:793-798, 1999. 61. Chwalisz K, Shao-Qing S, Garfield RE, et al: Cervical ripening in guinea- pigs after a local application of nitric oxide. Hum Reprod 12:2093-2101, 1997. 62. Hegele-Hartung C, Chwalisz K, Beier HM, et al: Ripening of the uterine cervix of the guinea-pig after treatment with the progesterone antagonist onapristone (ZK 98.299): An electron microscopic study. Hum Reprod 4:369-377, 1989. 63. Wolf JP, Sinosich M, Anderson TL, et al: Progesterone antagonist (RU 486) for cervical dilation, labor induction, and delivery in monkeys: Effective- ness in combination with oxytocin. Am J Obstet Gynecol 160:45-47, 1989. 64. Stys SJ, Clewell WH, Meschia G: Changes in cervical compliance at par- turition independent of uterine activity. Am J Obstet Gynecol 130:414- 418, 1978. 65. Chwalisz K: The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery. Hum Reprod (9 Suppl 1):131-161, 1994. 66. DeFranco EA, O’Brien JM, Adair CD, et al: Vaginal progesterone is associ- ated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: A secondary analysis from a randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 30:697-705, 2007.
  • 14. 534 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 67. Meis PJ, Klebanoff M, Thom E, et al: Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 348:2379-2385, 2003. 68. Fonseca EB, Celik E, Parra M, et al: Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 357:462-469, 2007. 69. Facchinetti F, Paganelli S, Comitini G, et al: Cervical length changes during preterm cervical ripening: Effects of 17-alpha-hydroxyprogesterone cap- roate. Am J Obstet Gynecol 196:453-454, 2007. 70. Lockwood CJ, Senyei AE, Dische MR, et al: Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 325:669-674, 1991. 71. Iams JD, Casal D, McGregor JA, et al: Fetal fibronectin improves the accu- racy of diagnosis of preterm labor. Am J Obstet Gynecol 173:141-145, 1995. 72. Nageotte MP, Casal D, Senyei AE: Fetal fibronectin in patients at increased risk for premature birth. Am J Obstet Gynecol 170:20-25, 1994. 73. Oshiro B, Edwin S, Silver R: Human fibronectin and human tenascin production in human amnion cells. J Soc Gynecol Invest 3:351A, 1996. 74. Bell SC, Meade EA: Fetal membrane rupture. In Critchley H, Bennett P, Thornton S (eds): Preterm Birth. London: RCOG Press, 2004, pp 195-212. 75. King L, MacDonald P, Casey ML: Regulation of tissue inhibitor of metal- loproteinase-1 (TIMP-1) in human amnion. J Soc Gynecol Invest 3:232A, 1996. 76. Romero R, Gomez R, Helming R, et al: Amniotic fluid elastase and secre- tory leukocyte protease natural inhibitor during labor, rupture of mem- branes and intrauterine infection. 41st Annual Meeting of the Society for Gynecologic Investigation, Chicago, 1994. Abstract O183, p 183. 77. Vadillo-Ortega F, Hernandez A, Gonzalez-Avila G, et al: Increased matrix metalloproteinase activity and reduced tissue inhibitor of metalloprotein- ases-1 levels in amniotic fluids from pregnancies complicated by premature rupture of membranes. Am J Obstet Gynecol 174:1371-1376, 1996. 78. Skinner SJ, Liggins GC: Glycosaminoglycans and collagen in human amnion from pregnancies with and without premature rupture of the membranes. J Dev Physiol 3:111-121, 1981. 79. Malak TM, Bell SC: Structural characteristics of term human fetal mem- branes: A novel zone of extreme morphological alteration within the rupture site. BJOG 101:375-386, 1994. 80. McLaren J, Malak TM, Bell SC: Structural characteristics of term human fetal membranes prior to labour: Identification of an area of altered mor- phology overlying the cervix. Hum Reprod 14:237-241, 1999. 81. Bell SC, Pringle JH, Taylor DJ, et al: Alternatively spliced tenascin-C mRNA isoforms in human fetal membranes. Mol Hum Reprod 5:1066- 1076, 1999. 82. Malak TM, Mulholland G, Bell SC: Morphometric characteristics of the decidua, cytotrophoblast, and connective tissue of the prelabor ruptured fetal membranes. Ann N Y Acad Sci 734:430-432, 1994. 83. Maymon E, Romero R, Pacora P, et al: Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes. Am J Obstet Gynecol 183:914-920, 2000. 84. Maymon E, Romero R, Pacora P, et al: Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection. Am J Obstet Gynecol 183:94-99, 2000. 85. Athayde N, Edwin SS, Romero R, et al: A role for matrix metalloprotein- ase-9 in spontaneous rupture of the fetal membranes. Am J Obstet Gynecol 79:1248-1253, 1998. 86. Helmig BR, Romero R, Espinoza J, et al: Neutrophil elastase and secretory leukocyte protease inhibitor in prelabor rupture of membranes, parturi- tion and intra-amniotic infection. J Matern Fetal Neonatal Med 12:237- 246, 2002. 87. Everts V, van der ZE, Creemers L, Beertsen W: Phagocytosis and intracel- lular digestion of collagen, its role in turnover and remodelling. Histo- chem J 28:229-245, 1996. 88. Fortunato SJ, Menon R: Screening of novel matrix metalloproteinases (MMPs) in human fetal membranes. J Assist Reprod Genet 19:483-486, 2002. 89. Reboul P, Pelletier JP, Tardif G, et al: The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synovio- cytes: A role in osteoarthritis. J Clin Invest 97:2011-2019, 1996. 90. Velasco G, Pendas AM, Fueyo A, et al: Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem 274:4570-4576, 1999. 91. Maymon E, Romero R, Pacora P, et al: A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection. J Perinat Med 29:308- 316, 2001. 92. Bennett PR, Elder MG, Myatt L: The effects of lipoxygenase metabolites of arachidonic acid on human myometrial contractility. Prostaglandins 33:837-844, 1987. 93. Bleasdale JE, Johnston JM: Prostaglandins and human parturition: regula- tion of arachidonic acid mobilization. Rev Perinat Med 5:151, 1985. 94. Calder A: Pharmacological management of the unripe cervix in the human. In Naftolin F, Stubblefield P (eds): Dilatation of the Uterine Cervix. New York: Raven Press, 1980, p 317. 95. Calder AA, Greer IA: Pharmacological modulation of cervical compliance in the first and second trimesters of pregnancy. Semin Perinatol 15:162- 172, 1991. 96. Carraher R, Hahn DW, Ritchie DM, et al: Involvement of lipoxygenase products in myometrial contractions. Prostaglandins 26:23-32, 1983. 97. Challis JRG: Endocrine control of parturition. Physiol Rev 59:863, 1979. 98. Challis JR, Olson D: Parturition. In Knobil E, Neill J (eds): The Physiology of Reproduction. New York: Raven Press, 1988, p 2177. 99. Ellwood DA, Mitchell MD, Anderson AB, et al: The in vitro production of prostanoids by the human cervix during pregnancy: Preliminary observa- tions. BJOG 87:210-214, 1980. 100. Greer I: Cervical ripening. In Drife J, Calder A (eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992, p 191. 101. MacDonald PC, Schultz FM, Duenhoelter JH, et al: Initiation of human parturition. I: Mechanism of action of arachidonic acid. Obstet Gynecol 44:629-636, 1980. 102. Mitchell MD: The mechanism(s) of human parturition. J Dev Physiol 6:107-118, 1984. 103. Novy MJ, Liggins GC: Role of prostaglandins, prostacyclin, and throm- boxanes in the physiologic control of the uterus and in parturition. Semin Perinatol 4:45-66, 1980. 104. Rajabi M, Solomon S, Poole AR: Hormonal regulation of interstitial col- lagenase in the uterine cervix of the pregnant guinea pig. Endocrinology 128:863-871, 1991. 105. Ritchie DM, Hahn DW, McGuire JL: Smooth muscle contraction as a model to study the mediator role of endogenous lipoxygenase products of arachidonic acid. Life Sci 34:509-513, 1984. 106. Thorburn GD, Challis JR: Endocrine control of parturition. Physiol Rev 59:863-918, 1979. 107. Wiqvist N, Lindblom B, Wikland M, et al: Prostaglandins and uterine contractility. Acta Obstet Gynecol Scand Suppl 113:23-29, 1983. 108. Ekman G, Forman A, Marsal K, et al: Intravaginal versus intracervical application of prostaglandin E2 in viscous gel for cervical priming and induction of labor at term in patients with an unfavorable cervical state. Am J Obstet Gynecol 147:657-661, 1983. 109. Embrey MP: Induction of abortion by prostaglandins E1 and E2. BMJ 1:258-260, 1970. 110. Gordon-Wright AP, Elder MG: Prostaglandin E2 tablets used intravagi- nally for the induction of labour. BJOG 86:32-36, 1979. 111. Husslein P: Use of prostaglandins for induction of labor. Semin Perinatol 15:173-181, 1991. 112. Husslein P: Prostaglandins for induction of labour. In Drife J, Calder A (eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992. 113. Karim SM, Filshie GM: Therapeutic abortion using prostaglandin F2alpha. Lancet 1:157-159, 1970.
  • 15. 535CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 114. Macer J, Buchanan D, Yonekura ML: Induction of labor with prostaglan- din E2 vaginal suppositories. Obstet Gynecol 63:664-668, 1984. 115. MacKenzie IZ: Prostaglandins and midtrimester abortion. In Drife J, Calder A (eds): Prostaglandins and the Uterus. London: Springer-Verlag, 1992, p 119. 116. World Health Organization Task Force: Repeated vaginal administration of 15-methyl pgf2 alpha for termination of pregnancy in the 13th to 20th week of gestation. Contraception 16:175, 1977. 117. World Health Organization Task Force: Comparison of intra-amniotic prostaglandin f2 alpha and hypertonic saline for second trimester abor- tion. BMJ 1:1373, 1976. 118. World Health Organization Task Force: Termination of second trimester pregnancy by intramuscular injection of 16-phenoxy-w-17, 18, 19, 20- tetranor PGE methyl sulfanilamide. Int J Gynaecol Obstet 16:175, 1982. 119. Giri SN, Stabenfeldt GH, Moseley TA, et al: Role of eicosanoids in abortion and its prevention by treatment with flunixin meglumine in cows during the first trimester of pregnancy. Zentralbl Veterinarmed A 38:445-459, 1991. 120. Harper MJ, Skarnes RC: Inhibition of abortion and fetal death produced by endotoxin or prostaglandin F2alpha. Prostaglandins 2:295-309, 1972. 121. Keirse MJ: Eicosanoids in human pregnancy and parturition. In Mitchell M (ed): Eicosanoids in Reproduction. Boca Raton, FL: CRC Press, 1990, p 199. 122. Skarnes RC, Harper MJ: Relationship between endotoxin-induced abor- tion and the synthesis of prostaglandin F. Prostaglandins 1:191-203, 1972. 123. Keirse MJ: Endogenous prostaglandins in human parturition. In Keirse MA, Gravenhorst J (eds): Human Parturition. The Hague, Netherlands: Nijhoff Publishers, 1979, p 101. 124. Romero R, Emamian M, Quintero R, et al: Amniotic fluid prostaglandin levels and intra-amniotic infections. Lancet 1:1380, 1986. 125. Romero R, Emamian M, Wan M, et al: Increased concentrations of arachidonic acid lipoxygenase metabolites in amniotic fluid during par- turition. Obstet Gynecol 70:849-851, 1987. 126. Romero R, Emamian M, Wan M, et al: Prostaglandin concentrations in amniotic fluid of women with intra-amniotic infection and preterm labor. Am J Obstet Gynecol 157:1461-1467, 1987. 127. Romero R, Wu YK, Mazor M, et al: Amniotic fluid prostaglandin E2 in preterm labor. Prostaglandins Leukot Essent Fatty Acids 34:141-145, 1988. 128. Romero R, Wu YK, Mazor M, et al: Increased amniotic fluid leukotriene C4 concentration in term human parturition. Am J Obstet Gynecol 159:655-657, 1988. 129. Romero R, Wu YK, Sirtori M, et al: Amniotic fluid concentrations of prostaglandin F2 alpha, 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) and 11-deoxy-13,14-dihydro-15-keto-11, 16-cyclo-prostaglan- din E2 (PGEM-LL) in preterm labor. Prostaglandins 37:149-161, 1989. 130. Sellers SM, Mitchell MD, Anderson AB, et al: The relation between the release of prostaglandins at amniotomy and the subsequent onset of labour. BJOG 88:1211-1216, 1981. 131. Romero R, Baumann P, Gonzalez R, et al: Amniotic fluid prostanoid con- centrations increase early during the course of spontaneous labor at term. Am J Obstet Gynecol 171:1613-1620, 1994. 132. Brodt-Eppley J, Myatt L: Prostaglandin receptors in lower segment myo- metrium during gestation and labor. Obstet Gynecol 93:89-93, 1999. 133. Matsumoto T, Sagawa N, Yoshida M, et al: The prostaglandin E2 and F2 alpha receptor genes are expressed in human myometrium and are down- regulated during pregnancy. Biochem Biophys Res Commun 238:838-841, 1997. 134. Mohan AR, Loudon JA, Bennett PR: Molecular and biochemical mecha- nisms of preterm labour. Semin Fetal Neonatal Med 9:437-444, 2004. 135. Myatt L, Lye SJ: Expression, localization and function of prostaglandin receptors in myometrium. Prostaglandins Leukot Essent Fatty Acids 70:137-148, 2004. 136. Olson DM: The role of prostaglandins in the initiation of parturition. Best Pract Res Clin Obstet Gynaecol 17:717-730, 2003. 137. Denison FC, Calder AA, Kelly RW: The action of prostaglandin E2 on the human cervix: Stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor. Am J Obstet Gynecol 180:614-620, 1999. 138. Yoshida M, Sagawa N, Itoh H, et al: Prostaglandin F(2alpha), cytokines and cyclic mechanical stretch augment matrix metalloproteinase-1 secre- tion from cultured human uterine cervical fibroblast cells. Mol Hum Reprod 8:681-687, 2002. 139. Madsen G, Zakar T, Ku CY, et al: Prostaglandins differentially modulate progesterone receptor-A and -B expression in human myometrial cells: Evidence for prostaglandin-induced functional progesterone withdrawal. J Clin Endocrinol Metab 89:1010-1013, 2004. 140. Romero R, Espinoza J, Mazor M, et al: The preterm parturition syndrome. In Critchely H, Bennett P, Thornton S (eds): Preterm Birth. London: RCOG Press, 2004, pp 28-60. 141. Elovitz MA, Mrinalini C: Animal models of preterm birth. Trends Endo- crinol.Metab 15:479-487, 2004. 142. Fidel PL Jr, Romero R, Wolf N, et al: Systemic and local cytokine profiles in endotoxin-induced preterm parturition in mice. Am J Obstet Gynecol 170:1467-1475, 1994. 143. Gravett MG, Witkin SS, Haluska GJ, et al: An experimental model for intraamniotic infection and preterm labor in rhesus monkeys. Am J Obstet Gynecol 171:1660-1667, 1994. 144. Hirsch E, Saotome I, Hirsh D: A model of intrauterine infection and preterm delivery in mice. Am J Obstet Gynecol 172:1598-1603, 1995. 145. Kullander S: Fever and parturition: An experimental study in rabbits. Acta Obstet Gynecol Scand Suppl 66:77-85, 1977. 146. McDuffie RS Jr, Sherman MP, Gibbs RS: Amniotic fluid tumor necrosis factor-alpha and interleukin-1 in a rabbit model of bacterially induced preterm pregnancy loss. Am J Obstet Gynecol 167:1583-1588, 1992. 147. McKay DG, Wong TC: The effect of bacterial endotoxin on the placenta of the rat. Am J Pathol 42:357-377, 1963. 148. Romero R, Mazor M, Wu YK, et al: Infection in the pathogenesis of preterm labor. Semin Perinatol 12:262-279, 1988. 149. Romero R, Munoz H, Gomez R, et al: Antibiotic therapy reduces the rate of infection-induced preterm delivery and perinatal mortality. Am J Obstet Gynecol 170:390, 1994. 150. Takeda Y, Tsuchiya I: Studies on the pathological changes caused by the injection of the Shwartzman filtrate and the endotoxin into pregnant rabbits. Jap J Exp Med 21:9-16, 1953. 151. Wang H, Hirsch E: Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: The role of toll- like receptor 4. Biol Reprod 69:1957-1963, 2003. 152. Zahl PA, Bjerknes C: Induction of decidua-placental hemorrhage in mice by the endotoxins of certain gram-negative bacteria. Proc Soc Exp Biol Med 54:329-332, 1943. 153. Gibbs RS, McDuffie RS Jr, Kunze M, et al: Experimental intrauterine infec- tion with Prevotella bivia in New Zealand White rabbits. Am J Obstet Gynecol 190:1082-1086, 2004. 154. Gilles HM, Lawson JB, Sibelas M, et al: Malaria, anaemia and pregnancy. Ann Trop Med Parasitol 63:245-263, 1969. 155. Herd N, Jordan T: An investigtion of malaria during pregnancy in Zim- babwe. Afr J Med 27:62, 1981. 156. Hibbard L, Thrupp L, Summeril S, et al: Treatment of pyelonephritis in pregnancy. Am J Obstet Gynecol 98:609-615, 1967. 157. Patrick MJ: Influence of maternal renal infection on the foetus and infant. Arch Dis Child 42:208-213, 1967. 158. Wren BG: Subclinical renal infection and prematurity. Med J Aust 2:596- 600, 1969. 159. Cunningham FG, Morris GB, Mickal A: Acute pyelonephritis of preg- nancy: A clinical review. Obstet Gynecol 42:112-117, 1973. 160. Kaul AK, Khan S, Martens MG, et al: Experimental gestational pyelone- phritis induces preterm births and low birth weights in C3H/HeJ mice. Infect Immun 67:5958-5966, 1999. 161. Benedetti TJ, Valle R, Ledger WJ: Antepartum pneumonia in pregnancy. Am J Obstet Gynecol 144:413-417, 1982.
  • 16. 536 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 162. Madinger NE, Greenspoon JS, Ellrodt AG: Pneumonia during pregnancy: Has modern technology improved maternal and fetal outcome? Am J Obstet Gynecol 161:657-662, 1989. 163. Munn MB, Groome LJ, Atterbury JL, et al: Pneumonia as a complication of pregnancy. J Matern Fetal Med 8:151-154, 1999. 164. Goepfert AR, Jeffcoat MK, Andrews WW, et al: Periodontal disease and upper genital tract inflammation in early spontaneous preterm birth. Obstet Gynecol 104:777-783, 2004. 165. Jarjoura K, Devine PC, Perez-Delboy A, et al: Markers of periodontal infection and preterm birth. Am J Obstet Gynecol 192:513-519, 2005. 166. Jeffcoat MK, Geurs NC, Reddy MS, et al: Current evidence regarding periodontal disease as a risk factor in preterm birth. Ann Periodontol 6:183-188, 2001. 167. Offenbacher S, Boggess KA, Murtha AP, et al: Progressive periodontal disease and risk of very preterm delivery. Obstet Gynecol 107:29-36, 2006. 168. Xiong X, Buekens P, Fraser WD, et al: Periodontal disease and adverse pregnancy outcomes: A systematic review. BJOG 113:135-143, 2006. 169. Offenbacher S: Maternal periodontal infections, prematurity, and growth restriction. Clin Obstet Gynecol 47:808-821, 2004. 170. Gomez R, Ghezzi F, Romero R, et al: Premature labor and intra-amniotic infection: Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clin Perinatol 22:281-342, 1995. 171. Cassell GH, Davis RO, Waites KB, et al: Isolation of Mycoplasma hominis and Ureaplasma urealyticum from amniotic fluid at 16-20 weeks of gesta- tion: Potential effect on outcome of pregnancy. Sex Transm Dis 10:294- 302, 1983. 172. Gray DJ, Robinson HB, Malone J, et al: Adverse outcome in pregnancy following amniotic fluid isolation of Ureaplasma urealyticum. Prenat Diagn 12:111-117, 1992. 173. Horowitz S, Mazor M, Romero R, et al: Infection of the amniotic cavity with Ureaplasma urealyticum in the midtrimester of pregnancy. J Reprod Med 40:375-379, 1995. 174. Romero R, Munoz H, Gomez R, et al: Two thirds of spontaneous abor- tion/fetal deaths after genetic amniocentesis are the result of a pre-existing sub-clinical inflammatory process of the amniotic cavity. Am J Obstet Gynecol 172:S261, 1995. 175. Wenstrom KD, Andrews WW, Hauth JC, et al: Elevated second-trimester amniotic fluid interleukin-6 levels predict preterm delivery. Am J Obstet Gynecol 178:546-550, 1998. 176. Yoon BH, Oh SY, Romero R, et al: An elevated amniotic fluid matrix metalloproteinase-8 level at the time of mid-trimester genetic amniocen- tesis is a risk factor for spontaneous preterm delivery. Am J Obstet Gynecol 185:1162-1167, 2001. 177. Fidel P, Ghezzi F, Romero R, et al: The effect of antibiotic therapy on intrauterine infection-induced preterm parturition in rabbits. J Matern Fetal Neonatal Med 14:57-64, 2003. 178. Romero R, Oyarzun E, Mazor M, et al: Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 73:576-582, 1989. 179. Smaill F: Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev (2);CD000490, 2001. 180. Goncalves LF, Chaiworapongsa T, Romero R: Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev 8:3-13, 2002. 181. Romero R, Salafia CM, Athanassiadis AP, et al: The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. Am J Obstet Gynecol 166:1382-1388, 1992. 182. Mays JK, Figueroa R, Shah J, et al: Amniocentesis for selection before rescue cerclage. Obstet Gynecol 95:652-655, 2000. 183. Romero R, Gonzalez R, Sepulveda W, et al: Infection and labor: VIII. Microbial invasion of the amniotic cavity in patients with suspected cervi- cal incompetence: Prevalence and clinical significance. Am J Obstet Gynecol 167:1086-1091, 1992. 184. Romero R, Espinoza J, Chaiworapongsa T, et al: Infection and prematurity and the role of preventive strategies. Semin Neonatol 7:259-274, 2002. 185. Romero R, Sirtori M, Oyarzun E, et al: Infection and labor: V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol 161:817-824, 1989. 186. Romero R, Mazor M, Morrotti R, et al: Infection and labor: VII. Microbial invasion of the amniotic cavity in spontaneous rupture of membranes at term. Am J Obstet Gynecol 166:129-133, 1992. 187. Andrews WW, Hauth JC, Goldenberg RL, et al: Amniotic fluid interleukin- 6: Correlation with upper genital tract microbial colonization and gesta- tional age in women delivered after spontaneous labor versus indicated delivery. Am J Obstet Gynecol 173:606-612, 1995. 188. Watts DH, Krohn MA, Hillier SL, Eschenbach DA: The association of occult amniotic fluid infection with gestational age and neonatal outcome among women in preterm labor. Obstet Gynecol 79:351-357, 1992. 189. Romero R, Kadar N, Hobbins JC, et al: Infection and labor: The detection of endotoxin in amniotic fluid. Am J Obstet Gynecol 157:815-819, 1987. 190. Romero R, Roslansky P, Oyarzun E, et al: Labor and infection: II. Bacterial endotoxin in amniotic fluid and its relationship to the onset of preterm labor. Am J Obstet Gynecol 158:1044-1049, 1988. 191. Grigsby PL, Hirst JJ, Scheerlinck JP, et al: Fetal responses to maternal and intra-amniotic lipopolysaccharide administration in sheep. Biol Reprod 68:1695-1702, 2003. 192. Jobe AH, Newnham JP, Willet KE, et al: Effects of antenatal endotoxin and glucocorticoids on the lungs of preterm lambs. Am J Obstet Gynecol 182:401-408, 2000. 193. Jobe AH, Newnham JP, Willet KE, et al: Endotoxin-induced lung matura- tion in preterm lambs is not mediated by cortisol. Am J Respir Crit Care Med 162:1656-1661, 2000. 194. Janeway C, Travers P, Walport M, et al: Innate immunity. In Janeway C, Travers P, Walport M, Schlomchik M (eds): Immunobiology. New York: Garland Science Publishing, 2005, pp 37-102. 195. Hargreaves DC, Medzhitov R: Innate sensors of microbial infection. J Clin Immunol 25:503-510, 2005. 196. Elovitz MA, Wang Z, Chien EK, et al: A new model for inflammation- induced preterm birth: The role of platelet-activating factor and toll-like receptor-4. Am J Pathol 163:2103-2111, 2003. 197. Kim YM, Romero R, Chaiworapongsa T, et al: Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol 191:1346-1355, 2004. 198. Krikun G, Lockwood CJ, Abrahams VM, et al: Expression of toll-like receptors in the human decidua. Histol Histopathol 22:847-854, 2007. 199. Romero R, Durum SK, Dinarello CA, et al: Interleukin-1: A signal for the initiation of labor in chorioamnionitis. 33rd Annual Meeting for the Society for Gynecologic Investigation, Toronto, Ontario, 1986. 200. Romero R, Wu YK, Brody DT, et al: Human decidua: A source of inter- leukin-1. Obstet Gynecol 73:31-34, 1989. 201. Romero R, Durum S, Dinarello CA, et al: Interleukin-1 stimulates prostaglandin biosynthesis by human amnion. Prostaglandins 37:13-22, 1989. 202. Romero R, Brody DT, Oyarzun E, et al: Infection and labor: III. Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol 1989;160:1117-1123. 203. Sadowsky DW, Novy MJ, Witkin SS, et al: Dexamethasone or interleukin- 10 blocks interleukin-1beta-induced uterine contractions in pregnant rhesus monkeys. Am J Obstet Gynecol 188:252-263, 2003. 204. Romero R, Mazor M, Tartakovsky B: Systemic administration of interleu- kin-1 induces preterm parturition in mice. Am J Obstet Gynecol 165:969- 971, 1991. 205. Romero R, Tartakovsky B: The natural interleukin-1 receptor antagonist prevents interleukin-1-induced preterm delivery in mice. Am J Obstet Gynecol 167:1041-1045, 1992. 206. Casey ML, Cox SM, Beutler B, et al: Cachectin/tumor necrosis factor-alpha formation in human decidua: Potential role of cytokines in infection- induced preterm labor. J Clin Invest 83:430-436, 1989. 207. Romero R, Mazor M, Manogue K, et al: Human decidua: A source of cachectin-tumor necrosis factor. Eur J Obstet Gynecol Reprod Biol 41:123- 127, 1991.
  • 17. 537CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 208. Romero R, Manogue KR, Mitchell MD, et al: Infection and labor: IV. Cachectin-tumor necrosis factor in the amniotic fluid of women with intraamniotic infection and preterm labor. Am J Obstet Gynecol 161:336- 341, 1989. 209. Fortunato SJ, Menon R, Lombardi SJ: Role of tumor necrosis factor- [alpha] in the premature rupture of membranes and preterm labor path- ways. Am J Obstet Gynecol 187:1159-1162, 2002. 210. Watari M, Watari H, DiSanto ME, et al: Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. Am J Pathol ;54:1755-1762, 1999. 211. Maymon E, Romero R, Pacora P, et al: Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intra-amniotic infection. Am J Obstet Gynecol 183:887-894, 2000. 212. Romero R, Chaiworapongsa T, Espinoza J, et al: Fetal plasma MMP-9 concentrations are elevated in preterm premature rupture of the mem- branes. Am J Obstet Gynecol 187:1125-1130, 2002. 213. Chwalisz K, Benson M, Scholz P, et al: Cervical ripening with the cytokines interleukin 8, interleukin 1 beta and tumour necrosis factor alpha in guinea-pigs. Hum Reprod 9:2173-2181, 1994. 214. Kajikawa S, Kaga N, Futamura Y, et al: Lipoteichoic acid induces preterm delivery in mice. J Pharmacol Toxicol.Methods 39:147-154, 1998. 215. Hirsch E, Filipovich Y, Mahendroo M: Signaling via the type I IL-1 and TNF receptors is necessary for bacterially induced preterm labor in a murine model. Am J Obstet Gynecol 194:1334-1340, 2006. 216. Lockwood CJ, Arcuri F, Toti P, et al: Tumor necrosis factor-alpha and interleukin-1beta regulate interleukin-8 expression in third trimester decidual cells: Implications for the genesis of chorioamnionitis. Am J Pathol 169:1294-1302, 2006. 217. Cox SM, King MR, Casey ML, et al: Interleukin-1 beta, -1 alpha, and -6 and prostaglandins in vaginal/cervical fluids of pregnant women before and during labor. J Clin Endocrinol Metab 77:805-815, 1993. 218. Gomez R, Romero R, Galasso M, et al: The value of amniotic fluid inter- leukin-6, white blood cell count, and gram stain in the diagnosis of micro- bial invasion of the amniotic cavity in patients at term. Am J Reprod Immunol 32:200-210, 1994. 219. Hillier SL, Witkin SS, Krohn MA, et al: NB, Eschenbach DA. The relation- ship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection. Obstet Gynecol 81:941-948, 1993. 220. Messer J, Eyer D, Donato L, et al: Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infec- tion. J Pediatr 129:574-580, 1996. 221. Romero R, Avila C, Santhanam U, et al: Amniotic fluid interleukin 6 in preterm labor: Association with infection. J Clin Invest 85:1392-1400, 1990. 222. Hanna N, Hanna I, Hleb M, et al: Gestational age-dependent expression of IL-10 and its receptor in human placental tissues and isolated cytotro- phoblasts. J Immunol 164:5721-5728, 2000. 223. Hanna N, Bonifacio L, Weinberger B, et al: Evidence for interleukin-10- mediated inhibition of cyclo- oxygenase-2 expression and prostaglandin production in preterm human placenta. Am J Reprod Immunol 55:19-27, 2006. 224. Athayde N, Romero R, Maymon E, et al: Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and microbial invasion of the amniotic cavity. Am J Obstet Gynecol 182:135-141, 2000. 225. Pacora P, Romero R, Maymon E, et al: Participation of the novel cytokine interleukin 18 in the host response to intra-amniotic infection. Am J Obstet Gynecol 183:1138-1143, 2000. 226. Goldenberg RL, Andrews WW, Mercer BM, et al: The preterm prediction study: Granulocyte colony-stimulating factor and spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 182:625- 630, 2000. 227. Saito S, Kato Y, Ishihara Y, et al: Amniotic fluid granulocyte colony-stimu- lating factor in preterm and term labor. Clin Chim Acta 208:105-109, 1992. 228. Saito S, Kasahara T, Kato Y, et al: Elevation of amniotic fluid interleukin 6 (IL-6), IL-8 and granulocyte colony stimulating factor (G-CSF) in term and preterm parturition. Cytokine 5:81-88, 1993. 229. Chaiworapongsa T, Romero R, Espinoza J, et al: Macrophage migration inhibitory factor in patients with preterm parturition and microbial inva- sion of the amniotic cavity. J Matern Fetal Neonatal Med 18:405-416, 2005. 230. Ghezzi F, Gomez R, Romero R, et al: Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia. Eur J Obstet Gynecol Reprod Biol 78:5-10, 1998. 231. Romero R, Ceska M, Avila C, et al: Neutrophil attractant/activating peptide-1/interleukin-8 in term and preterm parturition. Am J Obstet Gynecol 165:813-820, 1991. 232. Yoon BH, Romero R, Jun JK, et al: Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 177:825-830, 1997. 233. Cherouny PH, Pankuch GA, Romero R, et al: Neutrophil attractant/acti- vating peptide-1/interleukin-8: Association with histologic chorioamnio- nitis, preterm delivery, and bioactive amniotic fluid leukoattractants. Am J Obstet Gynecol 169:1299-1303, 1993. 234. Gonzalez BE, Ferrer I, Valls C, et al: The value of interleukin-8, interleu- kin-6 and interleukin-1beta in vaginal wash as predictors of preterm deliv- ery. Gynecol Obstet Invest 59:175-178, 2005. 235. Esplin MS, Romero R, Chaiworapongsa T, et al: Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection. J Matern Fetal Neonatal Med 17:365-373, 2005. 236. Keelan JA, Yang J, Romero RJ, et al: Epithelial cell-derived neutrophil- activating peptide-78 is present in fetal membranes and amniotic fluid at increased concentrations with intra-amniotic infection and preterm deliv- ery. Biol Reprod 70:253-259, 2004. 237. Athayde N, Romero R, Maymon E, et al: A role for the novel cytokine RANTES in pregnancy and parturition. Am J Obstet Gynecol 181:989-994, 1999. 238. Hirsch E, Muhle RA, Mussalli GM, et al: Bacterially induced preterm labor in the mouse does not require maternal interleukin-1 signaling. Am J Obstet Gynecol 186:523-530, 2002. 239. Krasnow JS, Tollerud DJ, Naus G, et al: Endometrial Th2 cytokine expres- sion throughout the menstrual cycle and early pregnancy. Hum Reprod 11:1747-1754, 1996. 240. Lidstrom C, Matthiesen L, Berg G, et al: Cytokine secretion patterns of NK cells and macrophages in early human pregnancy decidua and blood: Implications for suppressor macrophages in decidua. Am J Reprod Immunol 50:444-452, 2003. 241. Ekerfelt C, Lidstrom C, Matthiesen L, et al: Spontaneous secretion of interleukin-4, interleukin-10 and interferon-gamma by first trimester decidual mononuclear cells. Am J Reprod Immunol 47:159-166, 2002. 242. Greig PC, Herbert WN, Robinette BL, et al: Amniotic fluid interleukin-10 concentrations increase through pregnancy and are elevated in patients with preterm labor associated with intrauterine infection. Am J Obstet Gynecol 173:1223-1227, 1995. 243. Moore KW, de Waal MR, Coffman RL, et al: Interleukin-10 and the inter- leukin-10 receptor. Annu Rev Immunol 19:683-765, 2001. 244. Murray PJ: Understanding and exploiting the endogenous interleukin- 10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6:379-386, 2006. 245. Trinchieri G: Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med 204:239-243, 2007. 246. Berg DJ, Kuhn R, Rajewsky K, et al: Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest 96:2339- 2347, 1995. 247. Howard M, Muchamuel T, Andrade S, et al: Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 177:1205-1208, 1993.
  • 18. 538 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 248. Lang R, Rutschman RL, Greaves DR, et al: Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter. J Immunol 168:3402-3411, 2002. 249. Rodts-Palenik S, Wyatt-Ashmead J, Pang Y, et al: Maternal infection- induced white matter injury is reduced by treatment with interleukin-10. Am J Obstet Gynecol 191:1387-1392, 2004. 250. Chernoff AE, Granowitz EV, Shapiro L, et al: A randomized, controlled trial of IL-10 in humans: Inhibition of inflammatory cytokine production and immune responses. J Immunol 154:5492-5499, 1995. 251. Huhn RD, Radwanski E, Gallo J, et al: Pharmacodynamics of subcutane- ous recombinant human interleukin-10 in healthy volunteers. Clin Phar- macol Ther 62:171-180, 1997. 252. Pajkrt D, Camoglio L, Tiel-van Buul MC, et al: Attenuation of proinflam- matory response by recombinant human IL-10 in human endotoxemia: Effect of timing of recombinant human IL-10 administration. J Immunol 158:3971-3977, 1997. 253. Chakraborty A, Blum RA, Mis SM, et al: Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers. J Clin Phar- macol 39:624-635, 1999. 254. Wolfberg AJ, Dammann O, Gressens P: Anti-inflammatory and immuno- modulatory strategies to protect the perinatal brain. Semin Fetal Neonatal Med 12:296-302, 2007. 255. Terrone DA, Rinehart BK, Granger JP, et al: Interleukin-10 administration and bacterial endotoxin-induced preterm birth in a rat model. Obstet Gynecol 98:476-480, 2001. 256. Carroll SG, Nicolaides KH: Fetal haematological response to intra-uterine infection in preterm prelabour amniorrhexis. Fetal Diagn Ther 10:279- 285, 1995. 257. Goldenberg RL, Andrews WW, Goepfert AR, et al: The Alabama Preterm Birth Study: Umbilical cord blood Ureaplasma urealyticum and Myco- plasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol 198:43-45, 2008. 258. Gomez R, Romero R, Ghezzi F, et al: The fetal inflammatory response syndrome. Am J Obstet Gynecol 179:194-202, 1998. 259. 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. 260. Chaiworapongsa T, Romero R, Kim JC, et al: Evidence for fetal involve- ment in the pathologic process of clinical chorioamnionitis. Am J Obstet Gynecol 186:1178-1182, 2002. 261. Witt A, Berger A, Gruber CJ, et al: IL-8 concentrations in maternal serum, amniotic fluid and cord blood in relation to different pathogens within the amniotic cavity. J Perinat Med 33:22-26, 2005. 262. Yoon BH, Romero R, Kim KS, et al: A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 181:773-779, 1999. 263. Pacora P, Chaiworapongsa T, Maymon E, et al: Funisitis and chorionic vasculitis: The histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Med 11:18-25, 2002. 264. Yoon BH, Romero R, Shim JY, et al: C-reactive protein in umbilical cord blood: A simple and widely available clinical method to assess the risk of amniotic fluid infection and funisitis. J Matern Fetal Neonatal Med 14:85- 90, 2003. 265. Gomez R, Berry S, Yoon BH, et al: The hematologic profile of the fetus with systemic inflammatory response syndrome. Am J Obstet Gynecol 178:S202, 1998. 266. Yoon BH, Romero R, Jun JK, et al: An increase in fetal plasma cortisol but not dehydroepiandrosterone sulfate is followed by the onset of preterm labor in patients with preterm premature rupture of the membranes. Am J Obstet Gynecol 179:1107-1114, 1998. 267. Kim YM, Romero R, Chaiworapongsa T, et al: Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of toll-like receptors in epidermal keratinocytes. Histopathology 49:506- 514, 2006. 268. Romero R, Espinoza J, Goncalves LF, et al: Fetal cardiac dysfunction in preterm premature rupture of membranes. J Matern Fetal Neonatal Med 16:146-157, 2004. 269. Di Naro E, Cromi A, Ghezzi F, et al: Fetal thymic involution: A sono- graphic marker of the fetal inflammatory response syndrome. Am J Obstet Gynecol 194:153-159, 2006. 270. Jobe AH: Antenatal associations with lung maturation and infection. J Perinatol 25(Suppl 2):S31-S35, 2005. 271. Speer CP: New insights into the pathogenesis of pulmonary inflammation in preterm infants. Biol Neonate 79:205-209, 2001. 272. Speer CP: Inflammation and bronchopulmonary dysplasia. Semin Neo- natol 8:29-38, 2003. 273. Watterberg KL, Demers LM, Scott SM, et al: Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 97:210-215, 1996. 274. Yoon BH, Romero R, Shim JY, et al: “Atypical” chronic lung disease of the newborn is linked to fetal systemic inflammation. Am J Obstet Gynecol 187:S129, 2002. 275. Alexander JM, Gilstrap LC, Cox SM, et al: Clinical chorioamnionitis and the prognosis for very low birth weight infants. Obstet Gynecol 91:725- 729, 1998. 276. Bejar R, Wozniak P, Allard M, et al: Antenatal origin of neurologic damage in newborn infants: I. Preterm infants. Am J Obstet Gynecol 159:357-363, 1988. 277. Dammann O, Leviton A: Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant. Semin Pediatr Neurol 5:190-201, 1998. 278. Dammann O, Leviton A: Role of the fetus in perinatal infection and neo- natal brain damage. Curr Opin Pediatr 12:99-104, 2000. 279. Dammann O, Kuban KC, Leviton A: Perinatal infection, fetal inflamma- tory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 8:46-50, 2002. 280. Dammann O, Leviton A, Gappa M, et al: Lung and brain damage in preterm newborns, and their association with gestational age, prematurity subgroup, infection/inflammation and long term outcome. BJOG 112(Suppl 1):4-9, 2005. 281. Grether JK, Nelson KB: Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278:207-211, 1997. 282. Nelson KB, Dambrosia JM, Grether JK, et al: Neonatal cytokines and coagulation factors in children with cerebral palsy. Ann Neurol 44:665- 675, 1998. 283. Eastman NJ, DeLeon M: The etiology of cerebral palsy. Am J Obstet Gynecol 69:950-961, 1955. 284. Grether JK, Nelson KB, Dambrosia JM, et al: Interferons and cerebral palsy. J Pediatr 134:324-332, 1999. 285. Hagberg B, Hagberg G, Olow I, et al: The changing panorama of cerebral palsy in Sweden: V. The birth year period 1979-82. Acta Paediatr Scand 78:283-290, 1989. 286. Leviton A: Preterm birth and cerebral palsy: Is tumor necrosis factor the missing link? Dev Med Child Neurol 35:553-558, 1993. 287. Leviton A, Paneth N, Reuss ML, et al: Maternal infection, fetal inflamma- tory response, and brain damage in very low birth weight infants. Devel- opmental Epidemiology Network Investigators. Pediatr Res 46:566-575, 1999. 288. Murphy DJ, Sellers S, MacKenzie IZ, et al: Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 346:1449-1454, 1995. 289. Nelson KB, Ellenberg JH: Epidemiology of cerebral palsy. Adv Neurol 19:421-435, 1978. 290. Nelson KB: Can we prevent cerebral palsy? N Engl J Med 349:1765-1769, 2003. 291. O’Shea TM, Klinepeter KL, Dillard RG: Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol 147:362- 369, 1998. 292. Redline RW: Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 192:452-457, 2005. 293. Verma U, Tejani N, Klein S, et al: Obstetric antecedents of intraventricular hemorrhage and periventricular leukomalacia in the low-birth-weight neonate. Am J Obstet Gynecol 176:275-281, 1997.
  • 19. 539CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 294. Wharton KN, Pinar H, Stonestreet BS, et al: Severe umbilical cord inflam- mation: A predictor of periventricular leukomalacia in very low birth weight infants. Early Hum Dev 77:77-87, 2004. 295. Yoon BH, Romero R, Yang SH, et al: Interleukin-6 concentrations in umbilical cord plasma are elevated in neonates with white matter lesions associated with periventricular leukomalacia. Am J Obstet Gynecol 174:1433-1440, 1996. 296. Yoon BH, Jun JK, Romero R, et al: Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neo- natal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 177:19-26, 1997. 297. Hagberg B, Hagberg G, Beckung E, et al: Changing panorama of cerebral palsy in Sweden: VIII. Prevalence and origin in the birth year period 1991- 94. Acta Paediatr 90:271-277, 2001. 298. Hagberg H, Peebles D, Mallard C: Models of white matter injury: Com- parison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 8:30-38, 2002. 299. Hagberg H, Mallard C: Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 18:117-123, 2005. 300. Kaukola T, Satyaraj E, Patel DD, et al: Cerebral palsy is characterized by protein mediators in cord serum. Ann Neurol 55:186-194, 2004. 301. Mallard C, Welin AK, Peebles D, et al: White matter injury following sys- temic endotoxemia or asphyxia in the fetal sheep. Neurochem Res 28:215- 223, 2003. 302. Moon JB, Kim JC, Yoon BH, et al: Amniotic fluid matrix metalloproteinase-8 and the development of cerebral palsy. J Perinat Med 30:301-306, 2002. 303. Yoon BH, Romero R, Kim CJ, et al: High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 177:406-411, 1997. 304. Grether JK, Nelson KB, Emery ES III, et al: Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr 128:407-414, 1996. 305. Gotsch F, Romero R, Kusanovic JP, et al: The fetal inflammatory response syndrome. Clin Obstet Gynecol 50:652-683, 2007. 306. Clayton D, McKeigue PM: Epidemiological methods for studying genes and environmental factors in complex diseases. Lancet 358:1356-1360, 2001. 307. Tiret L: Gene-environment interaction: A central concept in multifactorial diseases. Proc Nutr Soc 61:457-463, 2002. 308. Macones GA, Parry S, Elkousy M, et al: A polymorphism in the promoter region of TNF and bacterial vaginosis: Preliminary evidence of gene- environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 190:1504-1508, 2004. 309. Roberts AK, Monzon-Bordonaba F, Van Deerlin PG, et al: Association of polymorphism within the promoter of the tumor necrosis factor alpha gene with increased risk of preterm premature rupture of the fetal mem- branes. Am J Obstet Gynecol 180:1297-1302, 1999. 310. Romero R, Chaiworapongsa T, Kuivaniemi H, et al: Bacterial vaginosis, the inflammatory response and the risk of preterm birth: A role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol 190:1509-1519, 2004. 311. Williams MA, Mittendorf R, Lieberman E, et al: Adverse infant outcomes associated with first-trimester vaginal bleeding. Obstet Gynecol 78:14-18, 1991. 312. Harger JH, Hsing AW, Tuomala RE, et al: Risk factors for preterm prema- ture rupture of fetal membranes: A multicenter case-control study. Am J Obstet Gynecol 163:130-137, 1990. 313. Strobino B, Pantel-Silverman J: Gestational vaginal bleeding and preg- nancy outcome. Am J Epidemiol 129:806-815, 1989. 314. Arias F: Placental insufficiency: An important cause of preterm labor and preterm premature ruptured membranes. 10th Annual Meeting of the Society of Perinatal Obstetricians, Houston, Texas, 1990. Abstract 144. 315. Arias F, Rodriquez L, Rayne SC, et al: Maternal placental vasculopathy and infection: Two distinct subgroups among patients with preterm labor and preterm ruptured membranes. Am J Obstet Gynecol 168:585-591, 1993. 316. Major C, Nageotte M., Lewis D: Preterm premature rupture of membranes and placental abruption: Is there an association between these pregnancy complications? Am J Obstet Gynecol 164:381, 1991. 317. Moretti M, Sibai BM: Maternal and perinatal outcome of expectant man- agement of premature rupture of membranes in the midtrimester. Am J Obstet Gynecol 159:390-396, 1988. 318. Vintzileos AM, Campbell WA, Nochimson DJ, et al: Preterm premature rupture of the membranes: A risk factor for the development of abruptio placentae. Am J Obstet Gynecol 156:1235-1238, 1987. 319. Bukowski R, Gahn D, Denning J, et al: Impairment of growth in fetuses destined to deliver preterm. Am J Obstet Gynecol 185:463-467, 2001. 320. MacGregor SN, Sabbagha RE, Tamura RK, et al: Differing fetal growth patterns in pregnancies complicated by preterm labor. Obstet Gynecol 72:834-837, 1988. 321. Morken NH, Kallen K, Jacobsson B: Fetal growth and onset of delivery: A nationwide population-based study of preterm infants. Am J Obstet Gynecol 195:154-161, 2006. 322. Ott WJ: Intrauterine growth retardation and preterm delivery. Am J Obstet Gynecol 168:1710-1715, 1993. 323. Weiner CP, Sabbagha RE, Vaisrub N, et al: A hypothetical model suggest- ing suboptimal intrauterine growth in infants delivered preterm. Obstet Gynecol 65:323-326, 1985. 324. Zeitlin J, Ancel PY, Saurel-Cubizolles MJ, et al: The relationship between intrauterine growth restriction and preterm delivery: An empirical approach using data from a European case-control study. BJOG 107:750- 758, 2000. 325. Kim YM, Chaiworapongsa T, Gomez R, et al: Failure of physiologic transformation of the spiral arteries in the placental bed in preterm pre- mature rupture of membranes. Am J Obstet Gynecol 187:1137-1142, 2002. 326. Kim YM, Bujold E, Chaiworapongsa T, et al: Failure of physiologic trans- formation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 189:1063-1069, 2003. 327. Salafia CM, Lopez-Zeno JA, Sherer DM, et al: Histologic evidence of old intrauterine bleeding is more frequent in prematurity. Am J Obstet Gynecol 173:1065-1070, 1995. 328. Brar HS, Medearis AL, DeVore GR, et al: Maternal and fetal blood flow velocity waveforms in patients with preterm labor: prediction of successful tocolysis. Am J Obstet Gynecol 159:947-950, 1988. 329. Brar HS, Medearis AL, De Vore GR, et al: Maternal and fetal blood flow velocity waveforms in patients with preterm labor: Relationship to outcome. Am J Obstet Gynecol 161:1519-1522, 1989. 330. Strigini FA, Lencioni G, De Luca G, et al: Uterine artery velocimetry and spontaneous preterm delivery. Obstet Gynecol 85:374-377, 1995. 331. Romero R, Espinoza J, Kusanovic JP, et al: The preterm parturition syn- drome. BJOG 113(Suppl 3):17-42, 2006. 332. Lockwood CJ, Krikun G, Papp C, et al: The role of progestationally regu- lated stromal cell tissue factor and type-1 plasminogen activator inhibitor (PAI-1) in endometrial hemostasis and menstruation. Ann N Y Acad Sci 734:57-79, 1994. 333. Elovitz MA, Saunders T, Ascher-Landsberg J, et al: Effects of thrombin on myometrial contractions in vitro and in vivo. Am J Obstet Gynecol 183:799-804, 2000. 334. Rosen T, Schatz F, Kuczynski E, et al: Thrombin-enhanced matrix metal- loproteinase-1 expression: A mechanism linking placental abruption with premature rupture of the membranes. J Matern Fetal Neonatal Med 11:11- 17, 2002. 335. Lockwood CJ, Krikun G, Aigner S, et al: Effects of thrombin on steroid- modulated cultured endometrial stromal cell fibrinolytic potential. J Clin Endocrinol.Metab 81:107-112, 1996. 336. Lijnen HR: Matrix metalloproteinases and cellular fibrinolytic activity. Biochemistry (Mosc) 67:92-98, 2002. 337. Aplin JD, Campbell S, Allen TD: The extracellular matrix of human amni- otic epithelium: Ultrastructure, composition and deposition. J Cell Sci 79:119-136, 1985.
  • 20. 540 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 338. Chaiworapongsa T, Espinoza J, Yoshimatsu J, et al: Activation of coagula- tion system in preterm labor and preterm premature rupture of mem- branes. J Matern Fetal Neonatal Med 11:368-373, 2002. 339. Gomez R, Athayde N, Pacora P, et al: Increased thrombin in intrauterine inflammation. Am J Obstet Gynecol 178:S62, 1998. 340. Rosen T, Kuczynski E, O’Neill LM, et al: Plasma levels of thrombin- antithrombin complexes predict preterm premature rupture of the fetal membranes. J Matern Fetal Med 10:297-300, 2001. 341. Nagy S, Bush M, Stone J, et al: Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol 102:94-100, 2003. 342. Mackenzie AP, Schatz F, Krikun G, et al: Mechanisms of abruption- induced premature rupture of the fetal membranes: Thrombin enhanced decidual matrix metalloproteinase-3 (stromelysin-1) expression. Am J Obstet Gynecol 191:1996-2001, 2004. 343. Darby MJ, Caritis SN, Shen-Schwarz S: Placental abruption in the preterm gestation: An association with chorioamnionitis. Obstet Gynecol 74:88- 92, 1989. 344. Lockwood CJ, Toti P, Arcuri F, et al: Mechanisms of abruption-induced premature rupture of the fetal membranes: Thrombin-enhanced interleukin-8 expression in term decidua. Am J Pathol 167:1443-1449, 2005. 345. Lathbury LJ, Salamonsen LA: In-vitro studies of the potential role of neutrophils in the process of menstruation. Mol Hum Reprod 6:899-906, 2000. 346. Karlsson A, Dahlgren C: Assembly and activation of the neutrophil NADPH oxidase in granule membranes. Antioxid Redox Signal 4:49-60, 2002. 347. Britigan BE, Cohen MS, Rosen GM: Detection of the production of oxygen-centered free radicals by human neutrophils using spin trapping techniques: A critical perspective. J Leukoc Biol 41:349-362, 1987. 348. McCord JM, Fridovich I: The biology and pathology of oxygen radicals. Ann Intern Med 89:122-127, 1978. 349. Cakmak H, Schatz F, Huang ST, et al: Progestin suppresses thrombin- and interleukin-1beta-induced interleukin-11 production in term decidual cells: Implications for preterm delivery. J Clin Endocrinol Metab 90:5279- 5286, 2005. 350. Lockwood CJ: Stress-associated preterm delivery: The role of corticotro- pin-releasing hormone. Am J Obstet Gynecol 180:S264-S266, 1999. 351. Wadhwa PD, Culhane JF, Rauh V, et al: Stress, infection and preterm birth: A biobehavioural perspective. Paediatr Perinat Epidemiol 15(Suppl 2):17- 29, 2001. 352. Wadhwa PD, Culhane JF, Rauh V, et al: Stress and preterm birth: Neuro- endocrine, immune/inflammatory, and vascular mechanisms. Matern Child Health J 5:119-125, 2001. 353. Challis JR, Smith SK: Fetal endocrine signals and preterm labor. Biol Neonate 79:163-167, 2001. 354. Hobel CJ: Stress and preterm birth. Clin Obstet Gynecol 47:856-880, 2004. 355. Mozurkewich EL, Luke B, Avni M, Wolf FM: Working conditions and adverse pregnancy outcome: A meta-analysis. Obstet Gynecol 95:623-635, 2000. 356. Copper RL, Goldenberg RL, Das A, et al: The preterm prediction study: Maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks’ gestation. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am J Obstet Gynecol 175:1286-1292, 1996. 357. Orr ST, James SA, Blackmore PC: Maternal prenatal depressive symptoms and spontaneous preterm births among African-American women in Bal- timore, Maryland. Am J Epidemiol 156:797-802, 2002. 358. Bloomfield FH, Oliver MH, Hawkins P, et al: A periconceptional nutri- tional origin for noninfectious preterm birth. Science 300:606, 2003. 359. Challis JR, Lye SJ, Gibb W, et al: Understanding preterm labor. Ann N Y Acad Sci 943:225-234, 2001. 360. McLean M, Bisits A, Davies J, et al: A placental clock controlling the length of human pregnancy. Nat Med 1:460-463, 1995. 361. Smith R, Nicholson RC: Corticotrophin releasing hormone and the timing of birth. Front Biosci 12:912-918, 2007. 362. Jones SA, Brooks AN, Challis JR: Steroids modulate corticotropin-releas- ing hormone production in human fetal membranes and placenta. J Clin Endocrinol Metab 68:825-830. 363. Jones SA, Challis JR: Steroid, corticotrophin-releasing hormone, ACTH and prostaglandin interactions in the amnion and placenta of early preg- nancy in man. J Endocrinol 125:153-159, 1990. 364. Jones SA, Challis JR: Effects of corticotropin-releasing hormone and adre- nocorticotropin on prostaglandin output by human placenta and fetal membranes. Gynecol Obstet Invest 29:165-168, 1990. 365. Li W, Challis JR: Corticotropin-releasing hormone and urocortin induce secretion of matrix metalloproteinase-9 (MMP-9) without change in tissue inhibitors of MMP-1 by cultured cells from human placenta and fetal membranes. J Clin Endocrinol Metab 90:6569-6574, 2005. 366. Lockwood CJ, Radunovic N, Nastic D, et al: Corticotropin-releasing hormone and related pituitary-adrenal axis hormones in fetal and mater- nal blood during the second half of pregnancy. J Perinat Med 24:243-251, 1996. 367. Mastorakos G, Ilias I: Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann N Y Acad Sci 997:136-149, 2003. 368. Parker CR Jr, Stankovic AM, Goland RS: Corticotropin-releasing hormone stimulates steroidogenesis in cultured human adrenal cells. Mol Cell Endocrinol 155:19-25, 1999. 369. Chakravorty A, Mesiano S, Jaffe RB: Corticotropin-releasing hormone stimulates P450 17alpha-hydroxylase/17,20-lyase in human fetal adrenal cells via protein kinase C. J Clin Endocrinol Metab 84:3732-3438, 1999. 370. Wu WX, Ma XH, Zhang Q, et al: Regulation of prostaglandin endoperox- ide H synthase 1 and 2 by estradiol and progesterone in nonpregnant ovine myometrium and endometrium in vivo. Endocrinology 138:4005- 4012, 1997. 371. Di WL, Lachelin GC, McGarrigle HH, et al: Oestriol and oestradiol increase cell to cell communication and connexin43 protein expression in human myometrium. Mol Hum Reprod 7:671-679, 2001. 372. Geimonen E, Boylston E, Royek A, et al: Elevated connexin-43 expression in term human myometrium correlates with elevated c-Jun expression and is independent of myometrial estrogen receptors. J Clin Endocrinol Metab 83:1177-1185, 1998. 373. Kimura T, Takemura M, Nomura S, et al: Expression of oxytocin receptor in human pregnant myometrium. Endocrinology 137:780-785, 1996. 374. Richter ON, Kubler K, Schmolling J, et al: Oxytocin receptor gene expression of estrogen-stimulated human myometrium in extracor- poreally perfused non-pregnant uteri. Mol Hum Reprod 10:339-346, 2004. 375. Wu WX, Ma XH, Zhang Q, et al: Characterization of topology-, gestation- and labor-related changes of a cassette of myometrial contraction-associ- ated protein mRNA in the pregnant baboon myometrium. J Endocrinol 171:445-453, 2001. 376. Helguera G, Olcese R, Song M, et al: Tissue-specific regulation of Ca(2+) channel protein expression by sex hormones. Biochim Biophys Acta 1569:59-66, 2002. 377. Matsui K, Higashi K, Fukunaga K, et al: Hormone treatments and preg- nancy alter myosin light chain kinase and calmodulin levels in rabbit myometrium. J Endocrinol 97:11-19, 1983. 378. Economopoulos P, Sun M, Purgina B, et al: Glucocorticoids stimulate prostaglandin H synthase type-2 (PGHS-2) in the fibroblast cells in human amnion cultures. Mol Cell Endocrinol 117:141-147, 1996. 379. Patel FA, Clifton VL, Chwalisz K, Challis JR: Steroid regulation of prosta- glandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labor. J Clin Endocrinol Metab 84:291- 299, 1999. 380. Zakar T, Hirst JJ, Mijovic JE, et al: Glucocorticoids stimulate the expres- sion of prostaglandin endoperoxide H synthase-2 in amnion cells. Endo- crinology 136:1610-1619, 1995.
  • 21. 541CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 381. Sun K, Ma R, Cui X, et al: Glucocorticoids induce cytosolic phospholipase A2 and prostaglandin H synthase type 2 but not microsomal prostaglan- din E synthase (PGES) and cytosolic PGES expression in cultured primary human amnion cells. J Clin Endocrinol Metab 88:5564-5571, 2003. 382. Yang R, You X, Tang X, et al: Corticotropin-releasing hormone inhibits progesterone production in cultured human placental trophoblasts. J Mol Endocrinol 37:533-540, 2006. 383. Ludmir J, Samuels P, Brooks S, et al: Pregnancy outcome of patients with uncorrected uterine anomalies managed in a high-risk obstetric setting. Obstet Gynecol 75:906-910, 1990. 384. Hill LM, Breckle R, Thomas ML, et al: Polyhydramnios: Ultrasonically detected prevalence and neonatal outcome. Obstet Gynecol 69:21-25, 1987. 385. Phelan JP, Park YW, Ahn MO, et al: Polyhydramnios and perinatal outcome. J Perinatol 10:347-350, 1990. 386. Besinger R, Carlson N: The physiology of preterm labor. In Keith L, Papiernik E, Keith D, Luke B (eds): Multiple Pregnancy: Epidemiology, Gestation and Perinatal Outcome. London: Parthenon Publishing, 1995, p 415. 387. Levy R, Kanengiser B, Furman B, et al: A randomized trial comparing a 30-mL and an 80-mL Foley catheter balloon for preinduction cervical ripening. Am J Obstet Gynecol 191:1632-1636, 2004. 388. Fisk NM, Ronderos-Dumit D, Tannirandorn Y, et al: Normal amniotic pressure throughout gestation. BJOG 99:18-22, 1992. 389. Sideris IG, Nicolaides KH: Amniotic fluid pressure during pregnancy. Fetal Diagn Ther 5:104-108, 1990. 390. Speroff L, Glass RH, Kase NG: The endocrinology of pregnancy. In Mitch- ell C (ed): Clinical Gynecologic Endocrinology and Infertility. Baltimore: Williams & Wilkins, 1994, p 251-290. 391. Sladek SM, Westerhausen-Larson A, Roberts JM: Endogenous nitric oxide suppresses rat myometrial connexin 43 gap junction protein expression during pregnancy. Biol Reprod 61:8-13, 1999. 392. LaudanskiT,RockiW:TheeffectsonstretchingandprostaglandinF2alpha on the contractile and bioelectric activity of the uterus in rat. Acta Physiol Pol 26:385-393, 1975. 393. Kloeck FK, Jung H: In vitro release of prostaglandins from the human myometrium under the influence of stretching. Am J Obstet Gynecol 115:1066-1069, 1973. 394. Ou CW, Chen ZQ, Qi S, et al: Increased expression of the rat myometrial oxytocin receptor messenger ribonucleic acid during labor requires both mechanical and hormonal signals. Biol Reprod 59:1055-1061, 1998. 395. Tzima E, del Pozo MA, Shattil SJ, et al: Activation of integrins in endothe- lial cells by fluid shear stress mediates Rho-dependent cytoskeletal align- ment. EMBO J 20:4639-4647, 2001. 396. Farrugia G, Holm AN, Rich A, et al: A mechanosensitive calcium channel in human intestinal smooth muscle cells. Gastroenterology 117:900-905, 1999. 397. Holm AN, Rich A, Sarr MG, et al: Whole cell current and membrane potential regulation by a human smooth muscle mechanosensitive calcium channel. Am J Physiol Gastrointest Liver Physiol 279:G1155-G1161, 2000. 398. Hu Y, Bock G, Wick G, Xu Q: Activation of PDGF receptor alpha in vas- cular smooth muscle cells by mechanical stress. FASEB J 12:1135-1142, 1998. 399. Li C, Xu Q: Mechanical stress-initiated signal transductions in vascular smooth muscle cells. Cell Signal 12:435-445, 2000. 400. Mitchell JA, Lye SJ: Regulation of connexin43 expression by c-fos and c-jun in myometrial cells. Cell Commun Adhes 8:299-302, 2001. 401. Mitchell JA, Lye SJ: Differential expression of activator protein-1 tran- scription factors in pregnant rat myometrium. Biol Reprod 67:240-246, 2002. 402. Oldenhof AD, Shynlova OP, Liu M, et al: Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells. Am J Physiol Cell Physiol 283:C1530-C1539, 2002. 403. Piersanti M, Lye SJ: Increase in messenger ribonucleic acid encoding the myometrial gap junction protein, connexin-43, requires protein synthesis and is associated with increased expression of the activator protein-1, c- fos. Endocrinology 136:3571-3578, 1995. 404. Shynlova OP, Oldenhof AD, Liu M, et al: Regulation of c-fos expression by static stretch in rat myometrial smooth muscle cells. Am J Obstet Gynecol 186:1358-1365, 2002. 405. Millar LK, Stollberg J, DeBuque L, et al: Fetal membrane distention: Determination of the intrauterine surface area and distention of the fetal membranes preterm and at term. Am J Obstet Gynecol 182:128-134, 2000. 406. Maehara K, Kanayama N, Maradny EE, et al: Mechanical stretching induces interleukin-8 gene expression in fetal membranes: A possible role for the initiation of human parturition. Eur J Obstet Gynecol Reprod Biol 70:191-196, 1996. 407. Maradny EE, Kanayama N, Halim A, et al: Stretching of fetal membranes increases the concentration of interleukin-8 and collagenase activity. Am J Obstet Gynecol 174:843-849, 1996. 408. Kanayama N, Fukamizu H: Mechanical stretching increases prostaglandin E2 in cultured human amnion cells. Gynecol Obstet Invest 28:123-126, 1989. 409. Nemeth E, Tashima LS, Yu Z, et al: Fetal membrane distention: I. Differen- tially expressed genes regulated by acute distention in amniotic epithelial (WISH) cells. Am J Obstet Gynecol 182:50-59, 2000. 410. Nemeth E, Millar LK, Bryant-Greenwood G: Fetal membrane distention: II. Differentially expressed genes regulated by acute distention in vitro. Am J Obstet Gynecol 182:60-67, 2000. 411. Barclay CG, Brennand JE, Kelly RW, et al: Interleukin-8 production by the human cervix. Am J Obstet Gynecol 169:625-632, 1993. 412. el Maradny E, Kanayama N, Halim A, et al: Interleukin-8 induces cervical ripening in rabbits. Am J Obstet Gynecol 171:77-83, 1994. 413. Calder AA: Prostaglandins and biological control of cervical function. Aust N Z J Obstet Gynaecol 34:347-351, 1994. 414. Stjernholm YM, Sahlin L, Eriksson HA, et al: Cervical ripening after treat- ment with prostaglandin E2 or antiprogestin (RU486): Possible mecha- nisms in relation to gonadal steroids. Eur J Obstet Gynecol Reprod Biol 84:83-88, 1999. 415. Ekerhovd E, Weijdegard B, Brannstrom M, et al: Nitric oxide induced cervical ripening in the human: Involvement of cyclic guanosine mono- phosphate, prostaglandin F(2 alpha), and prostaglandin E(2). Am J Obstet Gynecol 186:745-750, 2002. 416. Mazor M, Hershkovitz R, Ghezzi F, et al: Intraamniotic infection in patients with preterm labor and twin pregnancies. Acta Obstet Gynecol Scand 75:624-627, 1996. 417. Romero R, Shamma F, Avila C, et al: Infection and labor: VI. Prevalence, microbiology, and clinical significance of intraamniotic infection in twin gestations with preterm labor. Am J Obstet Gynecol 163:757-761, 1990. 418. Yoon BH, Park KH, Koo JN, et al: Intra-amniotic infection of twin pregnancies with preterm labor. Am J Obstet Gynecol 176:535. 1997. 419. Romero R, Mazor M, Avila C, et al: Uterine “allergy”: A novel mechanism for preterm labor. Am J Obstet Gynecol 164:375. 1991. 420. Holgate ST: The epidemic of allergy and asthma. Nature 402:B2-B4, 1999. 421. Corry DB, Kheradmand F: Induction and regulation of the IgE response. Nature 402:B18-B23, 1999. 422. Holloway JA, Warner JO, Vance GH, et al: Detection of house-dust-mite allergen in amniotic fluid and umbilical-cord blood. Lancet 356:1900- 1902, 2000. 423. Jones AC, Miles EA, Warner JO, et al: Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation. Pediatr Allergy Immunol 7:109-116, 1996. 424. Rudolph MI, Reinicke K, Cruz MA, et al: Distribution of mast cells and the effect of their mediators on contractility in human myometrium. BJOG 100:1125-1130, 1993.
  • 22. 542 CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 425. Padilla L, Reinicke K, Montesino H, et al: Histamine content and mast cells distribution in mouse uterus: The effect of sexual hormones, gesta- tion and labor. Cell Mol Biol 36:93-100, 1990. 426. Rudolph MI, Bardisa L, Cruz MA, et al: Mast cells mediators evoke con- tractility and potentiate each other in mouse uterine horns. Gen Pharma- col 23:833-836, 1992. 427. Bytautiene E, Vedernikov YP, Saade GR, et al: Endogenous mast cell degranulation modulates cervical contractility in the guinea pig. Am J Obstet Gynecol 186:438-445, 2002. 428. Garfield RE, Bytautiene E, Vedernikov YP, et al: Modulation of rat uterine contractility by mast cells and their mediators. Am J Obstet Gynecol 183:118-125, 2000. 429. Shingai Y, Nakagawa K, Kato T, et al: Severe allergy in a pregnant woman after vaginal examination with a latex glove. Gynecol Obstet Invest 54:183- 184, 2002. 430. Bulmer JN, Pace D, Ritson A: Immunoregulatory cells in human decidua: Morphology, immunohistochemistry and function. Reprod Nutr Dev 28:1599-1613, 1988. 431. Lachapelle MH, Miron P, Hemmings R, et al: Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion: Altered profile and pregnancy outcome. J Immunol 156:4027-4034, 1996. 432. Kammerer U, Schoppet M, McLellan AD, et al: Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol 157:159- 169, 2000. 433. Bytautiene E, Romero R, Vedernikov YP, et al: Induction of premature labor and delivery by allergic reaction and prevention by histamine H1 receptor antagonist. Am J Obstet Gynecol 191:1356-1361, 2004. 434. Iams JD, Johnson FF, Sonek J, et al: Cervical competence as a continuum: A study of ultrasonographic cervical length and obstetric performance. Am J Obstet Gynecol 172:1097-1103, 1995. 435. Romero R, Mazor M, Gomez R: Cervix, incompetence and premature labor. Fetus 3:1, 1993. 436. Romero R, Espinoza J, Erez O, et al: The role of cervical cerclage in obstet- ric practice: Can the patient who could benefit from this procedure be identified? Am J Obstet Gynecol 194:1-9, 2006. 437. Mesiano S: Roles of estrogen and progesterone in human parturition. Front Horm Res 27:86-104, 2001. 438. Stjernholm Y, Sahlin L, Akerberg S, et al: Cervical ripening in humans: Potential roles of estrogen, progesterone, and insulin-like growth factor-I. Am J Obstet Gynecol 174:1065-1071, 1996. 439. Gorodeski IG, Geier A, Lunenfeld B, et al: Progesterone (P) receptor dynamics in estrogen primed normal human cervix following P injection. Fertil Steril 47:108-113, 1987. 440. Kelly RW, Leask R, Calder AA: Choriodecidual production of interleukin-8 and mechanism of parturition. Lancet 339:776-777, 1992. 441. Puri CP, Patil RK, Elger WA, et al: Effects of progesterone antagonist ZK 98.299 on early pregnancy and foetal outcome in bonnet monkeys. Con- traception 41:197-205, 1990. 442. Bernal AL: Overview of current research in parturition. Exp Physiol 86:213-222, 2001. 443. Young IR: The comparative physiology of parturition in mammals. In Smith R (ed): The enodocrinology of parturition. Basel: Reinhardt Druck, 2001, p 10-30. 444. Schwarz BE, Milewich L, Johnston JM, et al: Initiation of human parturi- tion: V. Progesterone binding substance in fetal membranes. Obstet Gynecol 48:685-689, 1976. 445. Westphal U, Stroupe SD, Cheng SL: Progesterone binding to serum pro- teins. Ann N Y Acad Sci 286:10-28, 1977. 446. Karalis K, Goodwin G, Majzoub JA: Cortisol blockade of progesterone: A possible molecular mechanism involved in the initiation of human labor. Nat Med 2:556-660, 1996. 447. Milewich L, Gant NF, Schwarz BE, et al: Initiation of human parturition: VIII. Metabolism of progesterone by fetal membranes of early and late human gestation. Obstet Gynecol 50:45-48, 1977. 448. Mitchell BF, Wong S: Changes in 17 beta,20 alpha-hydroxysteroid dehy- drogenase activity supporting an increase in the estrogen/progesterone ratio of human fetal membranes at parturition. Am J Obstet Gynecol 168:1377-1385, 1993. 449. How H, Huang ZH, Zuo J, et al: Myometrial estradiol and progesterone receptor changes in preterm and term pregnancies. Obstet Gynecol 86:936-940, 1995. 450. Mesiano S, Chan EC, Fitter JT, et al: Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J Clin Endocrinol Metab 87:2924-2930, 2002. 451. Pieber D, Allport VC, Hills F, et al: Interactions between progesterone receptor isoforms in myometrial cells in human labour. Mol Hum Reprod 7:875-879, 2001. 452. Condon JC, Hardy DB, Kovaric K, et al: Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol 20:764-775, 2006. 453. Zakar T, Hertelendy F: Progesterone withdrawal: key to parturition. Am J Obstet Gynecol 196:289-296, 2007. 454. Allport VC, Pieber D, Slater DM, et al: Human labour is associated with nuclear factor-kappaB activity which mediates cyclo-oxygenase-2 expres- sion and is involved with the “functional progesterone withdrawal.” Mol Hum Reprod 7:581-586, 2001. 455. Belt AR, Baldassare JJ, Molnar M, et al: The nuclear transcription factor NF-kappaB mediates interleukin-1beta-induced expression of cyclooxy- genase-2 in human myometrial cells. Am J Obstet Gynecol 181:359-366, 1999. 456. Kalkhoven E, Wissink S, Van der Saag PT, et al: Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J Biol Chem 271:6217-6224, 1996. 457. Merlino AA, Welsh TN, Tan H, et al: Nuclear progesterone receptors in the human pregnancy myometrium: Evidence that parturition involves functional progesterone withdrawal mediated by increased expression of progesterone receptor-A. J Clin Endocrinol Metab 92:1927-1933, 2007. 458. Karteris E, Zervou S, Pang Y, et al: Progesterone signaling in human myo- metrium through two novel membrane G protein-coupled receptors: Potential role in functional progesterone withdrawal at term. Mol Endo- crinol 20:1519-1534, 2006. 459. Oh SY, Kim CJ, Park I, et al: Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition. Am J Obstet Gynecol 193:1156-1160, 2005. 460. Sheehan PM, Rice GE, Moses EK, et al: 5-Beta-dihydroprogesterone and steroid 5 beta-reductase decrease in association with human parturi- tion at term. Mol Hum Reprod 11:495-501, 2005. 461. Word RA, Landrum CP, Timmons BC, et al: Transgene insertion on mouse chromosome 6 impairs function of the uterine cervix and causes failure of parturition. Biol Reprod 73:1046-1056, 2005. 462. Dong X, Shylnova O, Challis JR, et al: Identification and characterization of the protein-associated splicing factor as a negative co-regulator of the progesterone receptor. J Biol Chem 280:13329-13340, 2005. 463. Brown AG, Leite RS, Strauss JF III: Mechanisms underlying “functional” progesterone withdrawal at parturition. Ann N Y Acad Sci 1034:36-49, 2004. 464. Mesiano S: Myometrial progesterone responsiveness and the control of human parturition. J Soc Gynecol Investig 11:193-202, 2004. 465. Garfield RE, Puri CP, Csapo AI: Endocrine, structural, and functional changes in the uterus during premature labor. Am J Obstet Gynecol 142:21-27, 1982. 466. Condon JC, Jeyasuria P, Faust JM, et al: A decline in the levels of proges- terone receptor coactivators in the pregnant uterus at term may antago- nize progesterone receptor function and contribute to the initiation of parturition. Proc Natl Acad Sci U S A 100:9518-9523, 2003. 467. Stjernholm-Vladic Y, Wang H, Stygar D, et al: Differential regulation of the progesterone receptor A and B in the human uterine cervix at parturi- tion. Gynecol Endocrinol 18:41-46, 2004. 468. Bethin KE, Nagai Y, Sladek R, et al: Microarray analysis of uterine gene expression in mouse and human pregnancy. Mol Endocrinol 17:1454- 1469, 2003.
  • 23. 543CHAPTER 28 Pathogenesis of Spontaneous Preterm Labor 469. Haluska GJ, Wells TR, Hirst JJ, et al: Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: Evidence for functional progesterone withdrawal at parturi- tion. J Soc Gynecol Investig 9:125-136, 2002. 470. Romero R: Prevention of spontaneous preterm birth: The role of sonographic cervical length in identifying patients who may benefit from progesterone treatment. Ultrasound Obstet Gynecol 30:675-686, 2007. 471. da Fonseca EB, Bittar RE, Carvalho MH, et al: Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spon- taneous preterm birth in women at increased risk: A randomized placebo- controlled double-blind study. Am J Obstet Gynecol 188:419-424, 2003. 472. O’Brien JM, Adair CD, Lewis DF, et al: Progesterone vaginal gel for the reduction of recurrent preterm birth: Primary results from a randomized, double-blind,placebo-controlledtrial.UltrasoundObstetGynecol30:687- 696, 2007.