140 The pathophysiology of premature rupture of the membranes Thomas Kelly Department of Reproductive Medicine, University of California at San Diego Medical Center, San Diego, California, USA Premature rupture of the membranes [PROM) is the condition in which the horioamnion is disrupted before the onset of labor. This condition creates a dilesnma for the practicing obstetrician, because once the membranes have broken the risk of fetal or maternal infection, or both, increases. Pretexmn PROM adds to this management challenge, mainly because of the added problem of prematurity, Although the epidemiology of PROM has been well defined, the exact etiology has yet to be understood. However, using the associated clinical risk factors of PROM, researchers in this field have contributed to our understanding of the causes. Various mechanisms have bbeen proposed, including mechanical, as well as infectious or inflammatory processes. The purpose of this article is to review the various proposed ‘mechanisms of PROM, Maternal risk factors for PROM are presented, mainly to place into context the current literature involving both in-vitro and in-vivo Fesearch. It is apparent that a single pathophysiologic mechanism is not responsible for all cases of PROM, but rather a combination of processes is in operation. Current Opinion in Obstetics and Gynecology 1995, 7:140-145 Introducti Preterm delivery continues to be a major obstetric prob- lem, and is a significant contributor to perinatal mortal- ity. Premature rupture of the membranes (PROM) oc curs in approximately 4.5-7.6% of total deliveries and preterm PROM in 1% of all pregnancies [1], Manage- ‘ment of term and preterm PROM can be problematic for the obstetrician who must balance maternal and fetal risks. At term, these include maternal and fetal infection and cord accident in the expectantly managed patient, and filed induction requiring cesarean section in the patient in whom labor is induced [2]. The decision be- "ween expectant management and induction of labor is often made easier by the patient either having a fivor- able cervix or undergoing spontancous labor. Preterm PROM adds the clements of prematurity as well as the long-term risks of oligohydramnios (such as pulmonary hypoplasia and fetal deformation abnormalities), partic~ ularly when it occurs before the fetus is viable [3]. Preterm PROM results in approximately 10% of all peri- natal deaths [4]; 40-10% of infants delivered prematurely are secondary to preterin PROM when clective preterin deliveries, multiple gestations, and fetal demises are ex- cluded (5}. Although the latency period appears to in crease with decreasing gestational age, the majority of patients with preterm PROM will deliver within 1 week of rupture [3]. Sixty six percent of patients with preterm PROM between 20 and 32 weeks, and 80% of those at 33-36 weeks, will be in labor within 48h [6]. Vieually ‘90% of patients with PROM at term are in labor within 48h (2), The etiology of PROM appears quite varied, and is associated with certain clinical risk fictors, as well as potential underlying pathophysiology. There appear to bbe mechanical as well as infectious mediators in mem- brane rupture. The result is weakness of the chorion and ammion that allows leakage of amniotic fiuid. Clinical risk factors Clinical risk factors for PROM can be categorized into those which can be altered and those which cannot (Table 1) 7]. Remediable factors include vaginitis, in- competent cervix, smoking, and prenatal diagnostic pro- cedures. Most commonly, however, the risk factors are nonremediable and usually include 2 previous history of PROM {8} le 4s not surprising that infection has been implicated in the causation of PROM, Bacterial vaginosis and group B streptococcal colonization have been associ- ated with higher rates of membrane rupture [9-11] Trichomonas vaginalis has also been implicated, Bacteria may cause weakening of the membranes, presumably through proteolysis. Intrauterine bacteria can lead to Abbreviations interleukin; PROM—premature rupture of the membranes: TIMP tissue inhibitor of metalloproeinases; "TNF-a-—tumor necrosis factor-a. © Current Science Ltd ISSN 1040-872x.‘The pathophysiology of premature rupture of the membranes Kelly prostaglandin synthesis, primarily through macrophage activation, Subsequent increases in uterine activity can result in weakening of the fetal membranes [7 Table 1, Rsk actors for premature tpt ofthe mame emedable Norrmeditle cenacovaginns Incompetent cenie Prev PROM or rete deety resus ceva suc procedures ign smaking ‘aint bled Prenatal aprotic procedures Placental stology Choon ils sampling Pacers preva Arinacenens Pace angie cons" Marginal cord amon Mineral nd wtamin deticences thle-Danensyndome conc examination sal gender mae Thee sik ator ach conelsive cntemation. PROM, prematre supe othe mena, Adapted wth pes 7 Preterm PROM can be associated with placement of a corclage either in an elecuve fishion, of more com- monly im an emergently placed stiteh [12]. Amnio- centesis and chorionic villus samphng ako ate related to increased risks for preterm PROM [13.14], Smok- ing has been associated with increased rates of preterm PROM, with odds ratios approaching 2.1 |15,16]. The mechanism for this increase is unclear but may be re- Iated to the increased risk of abruptio placentae and chronic bleeding. Cocaine has been associated with an increased risk of preterm labor and PROM. probably because it affects the myometrium, increasing uterine ac~ tivity [17.18%]. Furthermore, the latent period is shorter and the cervix is more dilated in women who expen tence PROM with recent cocaine use than in those with PROM but without recent cocaine use [19] Maternal zine index (measurement in blood, har and colostrum) appears lower in patients with PROM than in those without [20]. However, the reasons for this find ing are unclear. Zine plays a role in cellular-mnediated immunity and the function of various proteins, Other nutritional factors include vitamin C and copper deti- ciency. However, i is unclear how socioeconomic status influences PROM [7] [Most patients who present with PROM either have a nonremediable risk factor or no previous risk, Untor- tunately, the major risk factor for PROM is a previous history of PROM: the recurrence tate approaches 21% [8). Previous preterm delivery without PROM also in- ‘creases the risk of PROM. Unexplained bleeding or pla- Cental abnormalities may precipitate membrane rupture If bleeding occurs in more than one trimester, the risk is significant, with che odds ratio approaching 7.4 [15], Diseases which impair the ability to synthesize collagen. such as Ehlers-Danlos syndrome, increase the risk. Fetal nomalies that result in polyhydramnios, such as upper gastrointestinal obstruction or anencephaly cause ter ine overdisension and Gequently result in premature riembrane rupture and labor. Inadequate prenatal care 4s associated with a thrcefold increase in PROM and 2 doubling of preterm delivery without PROM, com- pared with controls matched for medical history, so- pH 4.5), and are associated with decreased numbers of Lacobaillis species. Prophy- lactic therapy with metronidazole for bacterial vaginosis has been shown to reduce the risk of PROM in patients with a previous preterm delivery [52]. However, topical clindamycin cream, although effective in treatment of bacterial vaginosis, temporarily reducing nuucinase and Silidase activities, did not appear to reduce perinatal morbidity or significantly reduce the risks of preterm birth [53]. The authors speculated chat local treatment may not be sufficient, in that there could be upper genital tract colonization. The presence of sialidise 8 ‘weeks after treatment was associated with a higher risk of PROM (30%) than its absence, stongly suggesting that the production of this enzyme contributes to the viru- lence of the bacteria Cytokines formed by the decidua have also been shown to be increased in the amniotic fluid fiom patients with preterm labor and PROM, Tumor necrosis factor-ct (TNF-0), a monokine which can lyse malignant cells, is formed in response to bacterial toxins such as lipote- ichoic acid, and is cytostatic when exposed to amnion tissue culture cells [54,55]. Interleukin (IL)-1, IL-6 and IL-8 can be released by the activated macrophages of the decidua, IL-1 and TNF-c stimulate collagenase produc tion [54]. IL-6 is produced by many cell cypes, and ‘can induce the production of TNF-a and IL-1 by macrophages. Women with PROM have higher co: centrations and activity of IL-6 im their amniotic fluid than women with intact membranes, suggesting a role for cytokines in the pathogenesis of PROM [56]. IL-6 may also be useful in predicting intra-amniotic infection in those patients with PROM [57% Prostaglandin release leading to uterine irritability can be the result of infection, and can lead to membrane ‘weakening and PROM, Endotoxin, 2 lipopolysaccha- ride product of the Gram-negative bacterial cell wall, appears ¢o stimulate prostaglandin E2 production in the amnion [58], as well as from macrophages [59]. C bacteria produce phospholipase A2, a critical enzyme for the release of arachidonic acid (60). Cytokines TNF-a [61,62] and IL-1 [63,64] have been shown to increase prostaglandin production in the maternal decidua. Other ‘mediators may include platelet-activating factor, a potent stimulator of myometrial activity, which appears to be in- fluenced by cytokines (65]. Nitric oxide metabolites are increased in patients with PROM, which suggests a sub- clinical infectious process [66]. Ik remains uncleat whether the increased uterine activity resulting from the release of prostaglandins or the di- rect effect of bacterial-macrophage release of proteases is responsible for PROM. The mechanisms of PROM associated with infection appear to be the result of the direct effect of protease production by bacteria, initiation of the inflammatory cascade by the host with release of proteolytic enzymes and cytokines, and the release of arachidonic acid with the subsequent production of prostaglandi Conclusion PROM appears co be the resule of multiple complex: mechanisms. In identifying the previously well known risk factors, one can begin to make some sense of the various proposed pathophysiologic mechanisms. Some risks can be altered, such a5 cessation of smoking, but the majority of patients with PROM either have no previous risk, oF a nonremediable risk. The chorioan ‘ion normally provides a barrier capable of withstand: ing the pressures of the intrauterine environment, even with the associated deformities that occur with cer cal ripening and increased uterine activity. However, when PROM does occur, there is an alteration in the collagen content. This may be the result of increased trypsin activity in the amniotic fluid, and the increased production or decreased inhibition of other proteolytic enzymes such as collagenase. The resulting weakening, of the chorioamnion decreases its ability to withstand normal deformation stresses imposed by the uterus and lower uterine segment. Why the increased production of these proteolytic en- zymes occurs is unclear. However, work over the past decade has strongly suggested that a bacterial component is important, The high rate of amniotic fluid coloniza~ tion found at the time of PROM, as well as bacterial ability (o initiate the maternal inflammatory response, and the production of various mediators which stimu- late the production and activity of proteases, appear to be crucial to membrane weakening, References and recommended reading Papers of panicula interes, published within the annual period of reve; have been highlighted 1. Gis RS, Blanco jO- Premature rupture of the membranes. ‘Obstet Gynecol 1982, 6061-679, 2. Dull ® Half RW, Gibbs RS: Management of premature rupture of membranes and untavorabe cervix in term pepe fancy, Otster Gynecol 1984, 631937-702 3. Taylor |, Garte Th: Premature rupture of membranes before fetal ial. Obstet Gynecol 1986, 6415-690. 4. 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