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`MECHANISMS OF DISEASE
`
`Review Articles
`
`Mechanisms of Disease
`
`F
`
`R A N K L I N
`
` H. E
`
`P S T E I N
`
`, M.D.,
`
` Editor
`
`P
`
`REMATURE
`
`
` R
`OF
`UPTURE
`M
`EMBRANES
`
`
`
`THE
`
` F
`
`ETAL
`
`
`
`, M.D.,
` P
`S
`ARRY
`AMUEL
` F. S
` III, M.D., P
`TRAUSS
`EROME
`H
`
`.D.
`
`AND
`
` J
`
`T
`
`HE membranes surrounding the amniotic
`cavity are composed of the amnion and the
`chorion, which are closely adherent layers
`consisting of several cell types, including epithelial
`cells, mesenchymal cells, and trophoblast cells, em-
`bedded in a collagenous matrix. They retain amni-
`otic fluid, secrete substances both into the amniotic
`fluid and toward the uterus, and guard the fetus
`against infection ascending the reproductive tract.
`The membranes normally rupture during labor. Pre-
`mature rupture of the fetal membranes is defined as
`rupture of the membranes before the onset of labor.
`1
`Premature rupture of the membranes occurring be-
`fore 37 weeks’ gestation is usually referred to as pre-
`term premature rupture of the membranes. Despite
`advances in perinatal care, premature rupture of the
`membranes and preterm premature rupture of the
`membranes continue to be important obstetrical
`complications. At term, 8 to 10 percent of pregnant
`women present with premature rupture of the mem-
`branes; these women are at increased risk for intra-
`uterine infection when the interval between the
`membrane rupture and delivery is prolonged.
` Pre-
`1
`term premature rupture of the membranes occurs in
`approximately 1 percent of all pregnancies and is as-
`sociated with 30 to 40 percent of preterm deliveries.
`It is thus the leading identifiable cause of preterm
`delivery (after less than 37 completed weeks’ gesta-
`tion) and its complications, including respiratory
`distress syndrome, neonatal infection, and intraven-
`tricular hemorrhage.
`
`From the Department of Obstetrics and Gynecology, Center for Re-
`search on Reproduction and Women’s Health and the Division of Mater-
`nal–Fetal Medicine, 2000 Courtyard Bldg., University of Pennsylvania
`Medical Center, 3400 Spruce St., Philadelphia, PA 19104-4283, where re-
`print requests should be addressed to Dr. Parry.
`©1998, Massachusetts Medical Society.
`
`Obstetricians have traditionally attributed rupture
`of the membranes to physical stress, particularly that
`associated with labor. However, more recent evi-
`dence suggests that membrane rupture is also relat-
`ed to biochemical processes, including disruption of
`collagen within the extracellular matrix of the am-
`nion and the chorion and programmed death of
`cells in the fetal membranes. It has been proposed
`that the fetal membranes and the maternal uterine
`lining (decidua) respond to various stimuli, includ-
`ing membrane stretching and infection of the repro-
`ductive tract, by producing mediators, such as pros-
`taglandins, cytokines, and protein hormones, that
`govern the activities of matrix-degrading enzymes.
`We review here the association between the degra-
`dation of the extracellular matrix within the fetal
`membranes and premature rupture of the mem-
`branes, in an effort to understand better the patho-
`physiology of such ruptures and identify potentially
`effective interventions.
`
`STRUCTURE OF THE FETAL MEMBRANES
`The human amnion is composed of five distinct
`layers (Fig. 1).
` It contains no blood vessels or
`2
`nerves; the nutrients it requires are supplied by the
`amniotic fluid. The innermost layer, nearest the fe-
`tus, is the amniotic epithelium. Amniotic epithelial
`cells secrete collagen types III and IV and noncol-
`lagenous glycoproteins (laminin, nidogen, and fibro-
`nectin) that form the basement membrane, the next
`layer of the amnion.
`The compact layer of connective tissue adjacent to
`the basement membrane forms the main fibrous skel-
`eton of the amnion. The collagens of the compact
`layer are secreted by mesenchymal cells in the fibro-
`blast layer.
` Interstitial collagens (types I and III) pre-
`3
`dominate and form parallel bundles that maintain
`the mechanical integrity of the amnion.
` Collagen
`4
`types V and VI form filamentous connections be-
`tween the interstitial collagens and the epithelial
`basement membrane.
` There is no interposition of
`4
`amorphous ground substance between collagen fibrils
`in amniotic connective tissue at term, so the amnion
`maintains its tensile strength throughout the late
`stages of normal pregnancy.
`The fibroblast layer is the thickest of the amniotic
`layers, consisting of mesenchymal cells and macro-
`phages within an extracellular matrix.
` The collagens
`4
`in this layer form a loose network with islands of
`noncollagenous glycoproteins.
`The intermediate layer (spongy layer, or zona
`spongiosa) lies between the amnion and the chori-
`on. Its abundant content of hydrated proteoglycans
`
`Volume 338 Number 10
`
`ⴢ
`
`663
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at MOUNT SINAI SCHOOL OF MEDICINE on June 25, 2014. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`The New England Journal of Medicine
`
`and glycoproteins gives this layer its “spongy” ap-
`pearance in histologic preparations, and it contains
`a nonfibrillar meshwork of mostly type III collagen.
`The intermediate layer absorbs physical stresses by
`permitting the amnion to slide on the underlying
`chorion, which is firmly adherent to the maternal
`decidua.
`Although the chorion is thicker than the amnion,
`the amnion has greater tensile strength. The chorion
`resembles a typical epithelial membrane, with its po-
`larity directed toward the maternal decidua. As preg-
`nancy progresses, trophoblastic villi within the cho-
`rionic layer of the reflected fetal membranes (free of
`the placenta) regress. Beneath the cytotrophoblast
`layer (closer to the fetus) are the basement mem-
`brane and the chorionic connective tissue, which is
`rich in collagen fibrils.
`The fetal membranes display regional variation
`that distinguishes the membranes overlying the pla-
`centa from the reflected membranes. Although there
`is no evidence of preset weak points where the mem-
`branes break, care must be taken to avoid overlook-
`
`ing localized changes in the membrane structure
`and composition in studies of premature rupture of
`the membranes.
`
`NATURAL HISTORY AND MANAGEMENT
`OF FETAL-MEMBRANE RUPTURE
`After premature rupture of the membranes at
`term, 70 percent of women begin to labor within 24
` After pre-
`hours, and 95 percent within 72 hours.
`5
`term premature rupture of the membranes, the la-
`tency period from membrane rupture to delivery de-
`creases inversely with advancing gestational age. For
`example, at 20 to 26 weeks’ gestation, the mean la-
`tency period is 12 days; at 32 to 34 weeks’ gestation,
`
`it is only 4 days.
`6
`Given the natural history of the relatively rapid
`progression to labor after premature rupture of the
`membranes at term, the goal of management is to
`minimize the risk of intrauterine infection without
`increasing the incidence of cesarean delivery. In pub-
`lished series, the rate of neonatal sepsis after preterm
`premature rupture of the membranes ranges from
`
`Amniotic fluid
`
`Layer
`
`Amnion
`
`Epithelium
`
`Basement
`membrane
`
`Extracellular-Matrix
`Composition
`
`MMP or TIMP
`Produced
`
`MMP-1, MMP-2,
`MMP-9
`
`Collagen types III, IV, V; laminin,
`fibronectin, nidogen
`
`Compact layer
`
`Collagen types I, III, V, VI;
`fibronectin
`
`Fibroblast layer
`
`Collagen types I, III, VI; nidogen,
`laminin, fibronectin
`
`MMP-1, MMP-9,
`TIMP-1
`
`Intermediate
`(spongy) layer
`
`Collagen types I, III, IV;
`proteoglycans
`
`Chorion
`
`Reticular
`layer
`
`Basement
`membrane
`
`Trophoblasts
`
`Collagen types I, III, IV, V, VI;
`proteoglycans
`
`Collagen type IV; fibronectin,
`laminin
`
`MMP-9
`
`Maternal decidua
`
`Figure 1.
` Schematic Representation of the Structure of the Fetal Membranes at Term.
`The extracellular-matrix composition of each layer and the production sites of matrix metalloproteinases (MMP) and tissue inhib-
`itors of metalloproteinases (TIMP) are shown.
`
`664
`
`ⴢ
`
`March 5, 1998
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at MOUNT SINAI SCHOOL OF MEDICINE on June 25, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
`
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`MECHANISMS OF DISEASE
`
`2 to 20 percent, and the incidence of neonatal death
`caused by infection is approximately 5 percent. When
`the fetal membranes rupture at term or before, the
`options are expectant management (with close ob-
`servation for signs of labor, nonreassuring fetal-
`heart-rate patterns, or intrauterine infection) or in-
`duction of labor.
`
`MECHANISMS OF FETAL-MEMBRANE
`RUPTURE PRECEDING AND DURING
`LABOR
`Intrapartum rupture of the fetal membranes has
`been attributed to generalized weakening due to
`uterine contractions and repeated stretching. The
`tensile strength of the membranes is reduced in
`specimens obtained after labor as compared with
`those obtained during cesarean delivery without la-
` Generalized weakness of the membranes has
`bor.
`7
`been more difficult to establish when prematurely
`ruptured membranes have been compared with
`membranes that were artificially ruptured during la-
`bor.
` Membranes that rupture prematurely, however,
`8
`appear to be focally defective rather than generally
`weakened. The area near the rupture site has been
`described as a “restricted zone of extreme altered
`morphology” that is characterized by marked swell-
`ing and disruption of the fibrillar collagen network
`within the compact, fibroblast, and spongy layers.
`9
`Because this zone does not include the entire rup-
`ture site, it may appear before membrane rupture
`and represent the initial breakpoint.
`Despite the divergent characteristics of premature
`rupture of the membranes and intrapartum rupture
`of the membranes, there is little evidence to suggest
`that the mechanisms that predispose women to the
`former are not identical to those that normally pre-
`cede labor. This has led to the view that premature
`rupture of the membranes represents an acceleration
`or exaggeration of the processes precipitating spon-
`taneous rupture of the membranes during labor.
`Consequently, investigators have frequently com-
`bined instances of preterm premature rupture of the
`membranes, premature rupture of the membranes at
`term, and rupture of the membranes during labor
`when describing mechanisms of membrane rupture.
`This practice, however, may obscure important dif-
`ferences among these events.
`
`CHANGES IN COLLAGEN CONTENT,
`STRUCTURE, AND CATABOLISM
`The maintenance of the tensile strength of fetal
`membranes appears to involve an equilibrium be-
`tween the synthesis and the degradation of the com-
`ponents of the extracellular matrix. It has been pro-
`posed that changes in the membranes, including
`decreased collagen content, altered collagen struc-
`ture, and increased collagenolytic activity, are associ-
`ated with premature rupture of the membranes.
`
`Connective-Tissue Disorders and Nutritional Deficiencies
`as Risk Factors
`Although there are conflicting data regarding
`changes in the composition of fetal-membrane col-
`lagen in association with the length of gestation and
`membrane rupture, a decline in membrane collagen
`content or a change in collagen structure probably
`
`precedes rupture of the membranes.
`10-12
`Connective-tissue disorders are associated with
`weakened fetal membranes and an increased inci-
`dence of preterm premature rupture of the mem-
`branes. Ehlers–Danlos syndrome, a group of at least
`11 heritable disorders of connective tissue charac-
`terized by hyperelasticity of the skin and joints, is
`caused by various defects in the synthesis or struc-
`ture of collagen. Among 18 patients with Ehlers–
`Danlos syndrome whose birth histories were avail-
`able, 13 (72 percent) were delivered prematurely
`after preterm premature rupture of the membranes,
`as compared with 1 of 16 unaffected siblings, and
`this one instance occurred in a twin gestation in
`which the other twin had Ehlers–Danlos syndrome.
`13
`Thus, pregnancies in which the fetus is affected with
`Ehlers–Danlos syndrome are dramatic examples of
`preterm premature rupture of the membranes asso-
`ciated with abnormal collagen content and structure.
`Nutritional deficiencies that predispose women to
`abnormal collagen structure have also been associat-
`ed with an increased risk of preterm premature rup-
`ture of the membranes. Collagen cross-links, which
`are formed in a series of reactions initiated by lysyl
`oxidase, increase the tensile strength of fibrillar col-
`lagens. Lysyl oxidase is produced by amniotic mes-
`enchymal cells, which lay down the collagenous
`compact layer of the amnion.
` Lysyl oxidase is a
`14
`copper-dependent enzyme, and women with prema-
`ture rupture of the membranes have lower copper
`concentrations in maternal and umbilical-cord se-
`rum than women whose fetal membranes are artifi-
`cially ruptured during labor.
` Similarly, women with
`15
`low serum concentrations of ascorbic acid, which is
`required for the formation of the triple helical struc-
`ture of collagen, have a higher rate of premature
`rupture of the membranes than those with normal
`serum concentrations.
` Tobacco smoking, which in-
`16
`dependently increases the risk of preterm premature
`rupture of the membranes, has been associated with
`decreased serum concentrations of ascorbic acid.
`17
`In addition, the cadmium in tobacco has been found
`to increase the metal-binding protein metallothio-
`nein in trophoblasts, which may result in sequestra-
`tion of copper. These data suggest that the de-
`creased availability of copper and ascorbic acid may
`contribute to an abnormal structure of fetal-mem-
`brane collagen in smokers. Collectively, reduced col-
`lagen cross-linking (possibly due to dietary deficien-
`cies or behavioral activities) may predispose women
`to premature membrane rupture.
`
`Volume 338 Number 10
`
`ⴢ
`
`665
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at MOUNT SINAI SCHOOL OF MEDICINE on June 25, 2014. For personal use only. No other uses without permission.
`
` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`The New England Journal of Medicine
`
`Increased Collagen Degradation
`The degradation of collagen is mediated primarily
`by matrix metalloproteinases, which are inhibited by
`specific tissue inhibitors and other protease inhibi-
`tors. The matrix metalloproteinases are a family of
`enzymes produced by various types of cells that hy-
`drolyze at least one component of the extracellular
`matrix. Because of the various substrate specificities
`of matrix metalloproteinases, effective catabolism of
`the many component molecules in the extracellular
`matrix requires the concerted actions of several en-
`zymes. The interstitial collagenases matrix metallo-
`proteinase-1 (MMP-1) and MMP-8 cleave the triple
`helix of the fibrillar collagens (types I and III), which
`are then further degraded by the gelatinases MMP-2
`and MMP-9. These gelatinases also cleave type IV
`collagen, fibronectin, and proteoglycans. In human
`fetal membranes, MMP-1 and MMP-9 messenger
`RNA and protein have been colocalized to amniotic
` Thus,
`epithelial cells and chorionic trophoblasts.
`18,19
`the compact (collagenous) layer of the fetal mem-
`branes is sandwiched between two layers of cells that
`produce matrix metalloproteinases.
`Tissue inhibitors of metalloproteinases form 1:1
`stoichiometric complexes with matrix metallopro-
`teinases and inhibit their proteolytic activity. Tissue
`inhibitor of metalloproteinase-1 (TIMP-1) binds to
`activated MMP-1, MMP-8, and MMP-9, and TIMP-
`2 binds to latent and active forms of MMP-2. The
`more recently described TIMP-3 and TIMP-4 appear
`to inhibit matrix metalloproteinases as efficiently as
`TIMP-1. Coordinated activities of matrix metallopro-
`teinases and tissue inhibitors of matrix metallopro-
`teinases are essential to the process of extracellular-
`matrix remodeling.
`The integrity of the fetal membranes remains un-
`altered throughout most of gestation, perhaps in part
`because of a combination of low matrix-metallopro-
`teinase activity and a relatively higher concentration
`of TIMP-1.
` Near the time of delivery, however, the
`20
`balance between activated matrix metalloproteinases
`and their tissue inhibitors shifts toward proteolytic
`degradation of the extracellular matrix of the fetal
`membranes. In the amnion of rats, activities of inter-
`stitial collagenase and MMP-9 increase before the
`onset of active labor.
` In human amnion and cho-
`21,22
`rion, MMP-9 activity increases and TIMP-1 concen-
`trations decrease dramatically with labor.
` Analyses
`18,20
`of membranes collected from women at the time of
`cesarean delivery (with and without labor) and after
`spontaneous labor and delivery suggest that MMP-1
`activity increases before labor, MMP-9 and MMP-3
`activities increase during labor, and TIMP-1 concen-
` These changes may
`trations increase after delivery.
`23
`reflect a coordinated progression of events preceding
`and during parturition, resulting in the controlled
`degradation of collagen within the fetal membranes.
`
`666
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`ⴢ
`
`March 5, 1998
`
`Premature rupture of the membranes may also be
`caused by an imbalance between the activities of ma-
`trix metalloproteinases and their tissue inhibitors,
`leading to inappropriate degradation of the mem-
`branes’ extracellular matrixes. Collagenase activity is
`increased in prematurely ruptured membranes at
` Overall, protease activity is increased in mem-
`term.
`12
`branes of women with preterm premature rupture of
`the membranes, the predominant activity being that
` Furthermore, gelatinolytic activity cor-
`of MMP-9.
`24
`responding to latent and active forms of MMP-9 is in-
`creased and the concentration of TIMP-1 is low in
`amniotic fluid obtained from women whose pregnan-
`cies were complicated by preterm premature rupture
` However, because specimens in
`of the membranes.
`20
`these studies were obtained after membrane rupture,
`we cannot conclude with certainty that collagen deg-
`radation in the fetal membranes precedes membrane
`rupture.
`Other observations suggest that physiologic and
`pathologic degradation of the extracellular matrix is
`associated with labor and delivery. Interstitial-col-
`lagenase activity increases dramatically in cervical tis-
`sue during cervical dilation in human parturition.
`25
`Periodontal disease, in which there is increased ma-
`trix-metalloproteinase activity in gingival tissues, has
`been reported to be an independent risk factor for
`preterm delivery.
` This finding raises the interesting
`26
`possibility that some women have a genetic predis-
`position to extracellular-matrix degradation due to
`increased matrix-metalloproteinase activity that may
`be manifested clinically as periodontitis, premature
`cervical dilatation, or premature rupture of the mem-
`branes.
`
`CLINICAL FACTORS ASSOCIATED WITH
`COLLAGEN DEGRADATION AND
`PREMATURE RUPTURE OF THE
`MEMBRANES
`
`Infection
`Obstetricians have long debated whether intra-
`uterine infection is a cause or a consequence of pre-
`mature rupture of the fetal membranes. There is
`indirect evidence that genital tract infection precipi-
`tates rupture of the membranes in animals and hu-
`mans. In pregnant rabbits, cervical inoculation with
`
`
`Escherichia coli resulted in positive cultures for E. coli
`in the amniotic fluid and decidual tissue of 97 per-
`cent of the treated animals and preterm delivery in
`half the treated animals. In contrast, cervical inocu-
`lation with saline resulted in no infections or pre-
` The identification of pathologic mi-
`term births.
`27
`croorganisms in human vaginal flora soon after
`membrane rupture provides support for the concept
`that bacterial infection may have a role in the patho-
`genesis of premature membrane rupture.
` Epidemi-
`28
`ologic data demonstrate an association between col-
`
`The New England Journal of Medicine
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`MECHANISMS OF DISEASE
`
`onization of the genital tract by group B strepto-
`cocci,
`Chlamydia trachomatis, Neisseria gonorrhoeae,
`and the microorganisms that cause bacterial vagino-
`sis (vaginal anaerobes,
`Mobi-
`Gardnerella vaginalis,
`luncus species, and genital mycoplasmas) and an in-
`creased risk of preterm premature rupture of the
` Furthermore, in some studies treat-
`membranes.
`29-32
`ment of infected women with antibiotics decreased
`the rate of preterm premature rupture of the mem-
`
`branes.
`32,33
`Intrauterine infection may predispose women to
`rupture of the fetal membranes through any of sev-
`eral mechanisms, each of which induces degradation
`of the extracellular matrix. Several organisms that are
`commonly present in the vaginal flora, including
`group B streptococci,
`Staphylococcus aureus, Tricho-
`
`monas vaginalis, and the microorganisms that cause
`bacterial vaginosis, secrete proteases that can de-
`grade collagen and weaken the fetal membranes.
`34,35
`In an in vitro system, proteolysis of the fetal mem-
`brane matrix can be inhibited by the addition of an
`antibiotic.
`
`33
`The host inflammatory response to bacterial infec-
`tion constitutes another potential mechanism that
`may partly account for the association between bac-
`terial infection of the genital tract and premature
`rupture of the membranes. The inflammatory re-
`sponse is mediated by polymorphonuclear neutro-
`phils and macrophages that are recruited to the site
`of infection and produce cytokines, matrix metallo-
`proteinases, and prostaglandins. Inflammatory cyto-
`kines, including interleukin-1 and tumor necrosis
`factor
`, are produced by stimulated monocytes, and
`a
`these cytokines increase MMP-1 and MMP-3 ex-
`pression at the transcriptional and posttranslational
`levels in human chorionic cells.
`36,37
`Bacterial infection and the host inflammatory re-
`sponse also induce prostaglandin production by the
`fetal membranes, which is thought to increase the
`risk of preterm premature rupture of the membranes
`by causing uterine irritability and collagen degrada-
`tion within the membranes. Certain strains of vagi-
`nal bacteria produce phospholipase A
`, which releas-
`2
`es the prostaglandin precursor arachidonic acid from
`membrane phospholipids within the amnion. Fur-
`thermore, the immune response to bacterial infection
`includes the production of cytokines by activated
` produc-
`monocytes that increase prostaglandin E
`2
`tion by chorionic cells.
` Cytokine stimulation of
`37
` production by the amnion and
`prostaglandin E
`2
`chorion appears to involve induction of cyclooxy-
`genase II, the enzyme that converts arachidonic acid
` The precise regulation of pros-
`into prostaglandins.
`38
`taglandin E
` synthesis in relation to bacterial infec-
`2
`tion and the host inflammatory response is not un-
`derstood, and a direct link between prostaglandin
`production and premature rupture of the mem-
`branes has not been established. However, prosta-
`
` and prosta-
`glandins (specifically prostaglandin E
`2
`glandin F
`) are considered to be mediators of labor
`2
`a
`in all mammals, and prostaglandin E
` diminishes col-
`2
`lagen synthesis in fetal membranes and increases
`MMP-1 and MMP-3 expression in human fibro-
`
`blasts.
`39,40
`Another component of the host response to infec-
`tion is the production of glucocorticoids. In most
`tissues the antiinflammatory action of glucocorti-
`coids is mediated by suppression of prostaglandin
`production. However, in some tissues, including the
`amnion, glucocorticoids paradoxically stimulate pros-
`taglandin production. Furthermore, dexamethasone
`reduces the synthesis of fibronectin and type III col-
`lagen in primary cultures of amniotic epithelial
` These findings suggest that glucocorticoids
`cells.
`41
`produced in response to the stress of microbial in-
`fection facilitate rupture of the fetal membranes.
`Despite these findings, there has been no conclu-
`sive demonstration that infection precedes prema-
`ture rupture of the fetal membranes in humans.
`Nonetheless, microbial infection and the host in-
`flammatory response may at the very least increase
`the activity of matrix metalloproteinases in the fetal
`membranes and be involved in the pathogenesis of
`some membrane ruptures.
`
`Hormones
`Progesterone and estradiol suppress extracellular-
`matrix remodeling in reproductive tissues. Both
`hormones decrease concentrations of MMP-1 and
`MMP-3 and increase the concentrations of tissue in-
`hibitors of metalloproteinases in the cervical fibro-
`blasts of rabbits.
` High concentrations of progester-
`42
`one decrease the production of collagenase in the
`cervical fibroblasts of guinea pigs, although lower
`concentrations of progesterone and estradiol stimu-
`late the production of collagenase in pregnant guin-
`ea pigs.
` Relaxin, a protein hormone that regulates
`43
`the remodeling of connective tissues, is produced lo-
`cally in the decidua and placenta and reverses the
`inhibitory effects of estradiol and progesterone by
`increasing MMP-3 and MMP-9 activities in fetal
`membranes.
` Expression of the relaxin gene is in-
`44
`creased before labor in human fetal membranes at
`term.
` Although it is important to consider the
`23
`roles of estrogen, progesterone, and relaxin in repro-
`ductive processes, their involvement in the process
`of fetal-membrane rupture remains to be defined.
`
`Programmed Cell Death
`Programmed cell death, or apoptosis, has been
`implicated in the remodeling of various reproductive
`tissues, including those of the uterus and cervix. Ap-
`optosis is characterized by the nuclear DNA frag-
`mentation and catabolism of 28S ribosomal RNA
`subunits that are required for protein synthesis. In
`rats (which have a 21-day gestation), amniotic epi-
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`Downloaded from nejm.org at MOUNT SINAI SCHOOL OF MEDICINE on June 25, 2014. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`thelial cells undergo apoptotic cell death as labor ap-
`proaches.
` This cell death appears to follow the start
`22
`of extracellular-matrix degradation, suggesting that
`it is a consequence and not a cause of catabolism of
`the extracellular matrix of the amnion.
`Human amnion and chorion obtained at term af-
`ter premature rupture of the membranes contain
`many apoptotic cells in areas adjacent to the rupture
`site and fewer apoptotic cells in other areas of the
` Furthermore, in cases of chorioamni-
`membranes.
`45
`onitis, apoptotic amniotic epithelial cells are seen in
`conjunction with adhesive granulocytes, suggesting
`that the host immune response may accelerate cell
` Although apoptotic
`death in fetal membranes.
`45
`changes have been identified in fetal membranes im-
`mediately before delivery, the mechanisms regulat-
`ing apoptosis and the subsequent effects on the ten-
`sile strength of fetal membranes have yet to be
`elucidated.
`
`Membrane Stretch and Premature Rupture
`of the Membranes
`Uterine overdistention due to both polyhydram-
`nios and multifetal gestation induces membrane
`stretch and increases the risk of premature rupture
`of the membranes. Mechanical stretching of the fetal
`membranes up-regulates the production of several
`amniotic factors, including prostaglandin E
` and in-
`2
`terleukin-8. Stretch also increases MMP-1 activity
`within the membranes.
` As stated above, prostaglan-
`46
` increases uterine irritability, decreases synthesis
`din E
`2
`of fetal-membrane collagen, and increases production
`of MMP-1 and MMP-3 by human fibroblasts.
`39,40
`Interleukin-8, which is produced by amniotic and
`chorionic cells, is chemotactic for neutrophils and
`stimulates collagenase activity. The production of
`interleukin-8, which is present in low concentrations
`in the amniotic fluid during the second trimester
`but in much higher concentrations late in gestation,
`is inhibited by progesterone. Thus, amniotic pro-
`duction of interleukin-8 and prostaglandin E
` repre-
`2
`sents biochemical changes in the fetal membranes
`that may be initiated by physical forces (membrane
`stretch), reconciling the hypothesis of force-induced
`and biochemically induced membrane rupture.
`
`PREDICTING PRETERM PREMATURE
`RUPTURE OF THE MEMBRANES
`Markers of degradation of the extracellular matrix
`of fetal membranes could be used to identify women
`who are at risk for premature rupture of the mem-
`branes and preterm delivery. The most extensively
`studied candidate marker is fetal fibronectin, which
`is present in the extracellular matrix of fetal mem-
`branes and is structurally different from the fibro-
`nectin of adult tissues. The production of fetal fi-
`bronectin by human amniotic cells is stimulated
`by inflammatory mediators (including interleukin-1
`
`668
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`March 5, 1998
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`) that are considered im-
`and tumor necrosis factor
`a
`
`portant in initiating preterm labor.
`47
`In the second and third trimesters of pregnancy,
`the presence of fetal fibronectin in cervicovaginal se-
`cretions probably reflects degradation of the extra-
`cellular matrix at the interface of the chorionic and
`decidual layers. Measurements of fetal fibronectin in
`these secretions have been used to identify a sub-
`group of women at high risk for preterm delivery.
`48
`Fetal fibronectin is most sensitive for predicting pre-
`term birth at less than 28 weeks’ gestation (sensitiv-
`ity, 63 percent); however, the positive predictive val-
`ue for preterm birth is less than 33 percent at all
`gestational ages, and there is no evidence that this
`test can be used to predict preterm premature rup-
`ture of the membranes and reduce the rate of pre-
` Tests based on the detection of other
`term birth.
`49,50
`molecules, such as specific matrix metalloprotein-
`ases, have not yet been applied to clinical practice.
`
`PREVENTION OF PRETERM PREMATURE
`RUPTURE OF THE MEMBRANES
`There has been considerable interest in the devel-
`opment of general and specific inhibitors of matrix
`metalloproteinases for the treatment of periodontal
`disease and arthritis and for the prevention of tumor
`metastasis. These agents include tetracycline antibi-
`otics, synthetic matrix-metalloproteinase inhibitors
`such as batimastat (which selectively chelates the
`zinc atom at the active site of the enzymes), and the
`native inhibitors TIMP-1 and TIMP-2. The ability
`of such substances to prevent or retard changes in
`the extracellular matrix of fetal membranes before
`preterm premature rupture occurs has yet to be eval-
`uated.
`
`CONCLUSIONS
`The cause of premature rupture of the fetal mem-
`branes is almost certainly multifactorial (Fig. 2). Tra-
`ditionally, rupture of the fetal membranes has been
`attributed to increasing physical stresses that weaken
`the membranes. At the molecular level, premature
`rupture of the membranes appears to result from di-
`minished collagen synthesis, altered collagen struc-
`ture, and accelerated collagen degradation, possibly
`in association with concurrent cellular changes with-
`in the fetal membranes. These hypotheses are not
`mutually exclusive, and biophysical stresses may am-
`plify these biochemical changes.
`Present research priorities include elucidation of
`the normal biologic processes of the fetal mem-
`branes, including extracellular-matrix remodeling,
`programmed cell death, and the response to mem-
`brane stretch as pregnancy progresses. We need to
`learn how exogenous risk factors, including nutri-
`tional deficiencies, smoking, and infection, promote
`premature rupture of the membranes. A more thor-
`ough understanding of extracellular-matrix degrada-
`
`The New England Journal of Medicine
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`Downloaded from nejm.org at MOUNT SINAI SCHOOL OF MEDICINE on June 25, 2014. For personal use only. No other uses without permission.
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` Copyright © 1998 Massachusetts Medical Society. All rights reserved.
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`MECHANISMS OF DISEASE
`
`Generalized decreased
`tensile strength
`
`Premature Rupture
`or Preterm Premature
`Rupture of the
`Membranes
`
`Membrane stretch
`(production of
`interleukin-8)
`
`Amniotic extracellular-
`matrix (collagen)
`degradation
`(collagenase activity,
`imbalance of matrix
`metalloproteinase or
`tissue inhibitor of
`metalloproteinase)
`
`Localized defects
`
`Decreased amniotic
`collagen content.