Intra-amniotic infection in patients with preterm prelabor rupture of membranes: Pathophysiology, detection, and management

PRELABOR RUPTURE OF MEMBRANES

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INTRA-AMNIOTIC INFECTION IN PATIENTS WITH PRETERM PRELABOR RUPTURE OF MEMBRANES Pathophysiology, Detection, and Management Tamerou Asrat, MD

Intrauterine infection diagnosed in conjunction with prelabor rupture of the membranes (PROM) has traditionally been called chorioamnionitis. There has always been considerable confusion over this term, however, because there is both a clinical and a histopathologic definition. This is further clouded by the evolution of understanding that in many cases a deciduitis may precede inflammation of the chorion; that intraamniotic colonization may occur before local or systemic inflammatory response; and even that fetal infection can occasionally precede any evidence of maternal or chorioamniotic infection. Most recently, the term intra-amniotic infection has been proposed to encompass all of these entities. From a practical standpoint the diagnosis of clinical chorioamnionitis, which virtually always demands immediate delivery, includes a clinical picture of both intra-amniotic infection and a maternal systemic inflammatory response. The classic definition of clinical chorioamnionitis in the setting of PROM includes a maternal temperature elevation to 38C or higher plus at least two of the following signs: uterine tenderness, foul-smelling amniotic fluid, increasing white blood cell count (WBC), and maternal or fetal tachycardia. Fever alone in the patient with PROM generally makes the clinical diagnosis, unless another source of fever can be identified.

From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of California Irvine, Orange; and Department of Maternal Fetal Medicine, Women’s Hospital, Long Beach Memorial Medical Center, Long Beach, California

CLINICS IN PERINATOLOGY VOLUME 28 • NUMBER 4 • DECEMBER 2001

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Clinical chorioamnionitis has the potential to cause serious complications in both mother and fetus. With PROM, chorioamnionitis is more common the earlier in pregnancy membrane rupture occurs, with rates of 5% at term, 20% at 26 to 35 weeks, and more than 40% at less than 24 weeks. The consequences to mother, especially if delivery is delayed or an unusually virulent organisms is encountered, include those that may occur with any serious bacterial sepsis: shock, disseminated intravascular coagulation, adult respiratory distress syndrome, renal failure, and even death. For the fetus-neonate, once clinical chorioamnionitis occurs in the premature gestation, rates of sepsis, pneumonia, respiratory distress syndrome, and death all increase by twofold to fourfold and long-term neurologic injury is substantially more likely to occur. A discussion of the mechanisms of infection, the pathophysiologic relationships between infection and PROM, the options for detecting infection, and the management of patients with PROM once clinical chorioamnionitis is diagnosed are all critical to a complete understanding of PROM. EVIDENCE FOR AN INFECTIOUS CAUSE OF PRETERM PRELABOR RUPTURE OF MEMBRANES Both premature labor and preterm PROM (PPROM) are often associated with infection, and often the infection precedes the onset of either. Epidemiologic studies have identified several risk factors, such as genital tract infections, colonization with various microorganisms, coitus, low socioeconomic status, poor nutrition, smoking, and bleeding, to be associated with both spontaneous preterm births and an increased risk of PPROM.16, 37, 38, 61, 92 A growing body of both animal and human data supports a mechanism whereby various genital microorganisms gain access to the choriodecidual interface and initiate an inflammatory response, which ultimately results in preterm labor or PPROM.1, 2, 14, 25, 33, 35, 56, 73, 75, 82, 88, 89, 90 Theoretically, microorganisms may gain access to the choriodecidual layer and the amniotic cavity in one of several ways: by the transcervical route, hematogenously through the placenta, iatrogenically at the time of amniocentesis or other invasive fetal procedures, or by seeding from the peritoneal cavity through the fallopian tubes. There is even some evidence to suggest that the endometrium may be colonized before conception in certain cases.5, 51 The most common pathway of intrauterine infection seems to be the ascending route. This view is supported by clinical and histologic evidence. Histologic evidence of chorioamnionitis is more common and more severe at the site of membrane rupture than in other locations. In general, the isolates from congenital infections are similar to those normally found in the lower genital tract. Carroll et al8 examined the relationship between genital tract flora and organisms in amniotic fluid and fetal blood in patients with PPROM. In 76% of cases the organisms isolated from the amniotic cavity were the same as those retrieved from the vagina and endocervix.5, 8, 41

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To understand whether bacterial invasion of the amniotic cavity causes PPROM or is the consequence of PPROM, it is important to look at the body of evidence that has attempted to clarify the pathophysiology of membrane rupture. Knox and Hoerner50 and Benirschke and Clifford6 were first to observe and suggest a primary role in the cause of PPROM. Subsequently, several investigators have shown that histologic chorioamnionitis precedes rather than follows PPROM.77, 91 Naeye and Peters64 reported that patients with PPROM 1 to 4 hours before the onset of labor had a higher prevalence of histologic chorioamnionitis than patients who delivered preterm without PROM. Similarly Cederquist et al9 showed a bimodal distribution of clinical and immunologic evidence of infection in neonates born prematurely following PPROM. They demonstrated that IgA and IgM levels and clinical symptoms peaked between 1 and 12 hours after PPROM and again at about 72 hours after PPROM, suggesting that some infections precede PPROM and others occur after membrane integrity is disrupted. Identification of signs and symptoms of infection among newborns at birth and shortly after PPROM suggests that infection frequently occurs before PPROM.9 The bacteria invading the choriodecidual interface release endotoxins and exotoxins, which activate the decidua and the fetal membranes. Several investigators have shown that bacterial products contain phospholipase A2 and C, lipopolysaccharide (endotoxin) that are capable of stimulating production of prostaglandins by the amnion and decidua in vitro. Substantial evidence supports a critical role for products of arachidonic acid metabolism in the physiology of human labor, both term and preterm. The enzymes phospholipase A2 acts to cleave and release free arachidonic acid. Arachidonic acid can then be metabolized in one of three different pathways, which results in the formation of prostaglandins, leukotrienes, and epoxides. Intrauterine prostaglandins can induce myometrial contractility, changes in extracellular matrix metabolism associated with cervical ripening, and are believed to participate in decidual and fetal membrane activation.53, 62 Infection is believed to increase prostaglandin production by amnion, chorion, or decidua through the activity of bacterial products, cytokinesis, growth factors, and other inflammatory mediators.32, 47 Indeed, amniotic fluid levels of prostaglandin E2 are significantly elevated in patients with bacterial invasion of the amniotic cavity.28, 79 The amnion obtained from patients with histologic chorioamnionitis produces higher amounts of prostaglandins than those from patients without documented chorioamnionitis.55 Until recently, the bacteria alone were believed to be responsible for the various clinical and metabolic derangements seen with infection. It is now well established, however, that the host immune responses and endogenous products precipitated by bacterial endotoxins are in a large part responsible for the deleterious effects of the infection. There is a growing body of evidence that indicates that preterm birth in the presence of bacterial invasion or infection may be caused by the hostmediated response through activation of the macrophage-monocyte system by bacterial products and tissue injury. On activation of these cells

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by microbial products proinflammatory cytokines and chemokines are released, including interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-8, tumor necrosis factor, and granulocyte colony-stimulating factor.* The release of these proinflammatory cytokines and chemokines along with the microbial endotoxins and exotoxins create essentially a ‘‘positive feedback loop,’’ which recruits more monocytes and macrophages to the infected area, sustaining this host-mediated response. There are several lines of evidence that support a role for IL-1, IL-6, and tumor necrosis factor in infection-associated PPROM. The bioactivity and concentrations of these proinflammatory cytokines are elevated in amniotic fluid of women with PPROM and intra-amniotic infection.73–76 Cells from the human decidua can produce these proinflammatory cytokines in response to bacterial products or other cytokines.20, 71 These cytokines have been shown to stimulate production of prostaglandins by the human chorion, amnion decidua cells, and myometrium leading to preterm parturition.71, 72 IL-8 or neutrophil attractant activating peptide, is a cytokine that47 promotes recruitment and activation of granulocytes and is present in elevated concentrations in patients with PPROM and microbial invasion of the amniotic cavity. IL-8 can induce neutrophils to release leukocyte elastase, a serine protease capable of degrading components of the extracellular matrix. Studies have shown an increased concentration of leukocyte elastase in amniotic fluid of patients with PPROM and bacterial infection.20 Recent evidence suggests that in many cases the infection may actually start or occur coincidentally in the fetus. The fetus may also participate in a host-mediated response involving the fetus. Romero et al34, 70 coined the term fetal inflammatory response defined by elevated fetal plasma IL-6 obtained by cordocentesis. They discovered this condition frequently in fetuses with PPROM, preterm labor with intact membranes, and with microbial invasion of the amniotic cavity. The authors also demonstrated that fetuses with fetal inflammatory response have a higher perinatal morbidity and are more likely to deliver prematurely than fetuses without an inflammatory response. Bacteria are also a known source of a variety of proteases, including several types of collagenases that can weaken the fetal membranes and lead to PPROM.* Recent data strongly support a role for increased proteolytic activity in patients with PPROM. The fetal membranes are formed by the apposition of the amnion and chorion cells. The amnion, chorion, and decidua are a source of metalloproteinases (MMPs). MMPs are proteolytic enzymes that degrade extracellular matrix macromolecules and are considered to play a significant role in morphogenesis, ovulation, embryo implantation, menstruation angiogenesis, wound healing, cell invasion, and metastasis.44, 58, 99 MMPs and their inhibitors seem to be regulated by inflammatory cytokines and certain growth factors.86, 99 Several investigators have reported an increased expression of MMPs, particularly MMP-9, in the *References 2, 13, 14, 25, 33, 35, 56, 59, 67, 75, 82–85, 88, 89, 90.

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chorion-decidua, myometrium, and amniotic fluid, both in term and preterm labor with PPROM.57 It seems that MMPs may be involved in collagen degradation of the amnion, leading to PPROM, and remodeling of the collagen of the cervix, softening it, resulting in preterm birth.21, 93 Another proteolytic enzyme, leukocyte elastase, a serine protease capable of degrading most components of the extracellular matrix, has been isolated in human cervical mucus and is believed to play a role in the pathogenesis of rupture of membrane.42, 46 Another group of cytokines that may be important in the pathogenesis of preterm birth in patients with PPROM and microbial invasion of the amniotic cavity are the colony-stimulating factors (CSF). CSFs belongs to a group of glycoprotein growth factors that regulate the survival, multiplication, and differentiation of hematopoietic cells. Several investigators have documented statistically significant increases in the concentrations of CSFs in patients with chorioamnionitis and those with PPROM and microbial invasion of the amniotic cavity.33, 82

ORGANISMS CAUSING INTRAUTERINE INFECTION IN PATIENTS WITH PRETERM PRELABOR RUPTURE OF MEMBRANES The most commonly identified isolated microorganisms from the amniotic cavity of patients with PPROM are Ureaplasma urealyticum; Mycoplasma hominis; Streptococcus agalactiae (group B streptococcus); fusobacterium; and Gardnerella vaginalis. Table 1 depicts the results of 18 studies, which were done to establish the rate of positive amniotic fluid cultures in patients with PPROM. The overall prevalence of a positive amniotic fluid culture is 36%.* This number is probably an underestimate of the true prevalence of microbial invasion of the amniotic cavity in patients with PPROM. Women with PPROM and oligohydramnios and those in labor are less likely to undergo an amniocentesis. Available evidence indicates, however, that these patients are more likely to have microbial invasion of the amniotic cavity than those with PPROM not in labor and without oligohydramnios.

DETECTION OF INTRA-AMNIOTIC INFECTION There are many tests available to detect intra-amniotic infection. It is theoretically important to make an early diagnosis of infection in patients with PPROM because, as previously mentioned, there is a twofold to fourfold increase in perinatal morbidity and mortality once fever is present. More important, antepartum treatment of maternal amnionitis clearly decreases the incidence of neonatal sepsis.29, 30, 87 *References 4, 7, 10, 11, 15, 17, 19, 23, 24, 26, 27, 40, 65, 80, 97, 103.

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Table 1. BACTERIAL COLONIZATION OF AMNIOTIC FLUID IN WOMEN WITH PPROM AND SUCCESS RATE OF AMNIOCENTESIS First Author

Year

No. of Patients

Positive Culture

Success Rate (%)

Garite Garite Cotton Zlatnik Broelzhuizen Vintzileos Feinstein Romero O’Brien Dudley Gauthier Coultrip Gauthier Romero Font Averbuch Hazan Carroll

1979 1982 1984 1984 1985 1986 1986 1988 1990 1991 1991 1992 1992 1993 1995 1995 1995 1996

59 207 61 63 79 54 73 230 27 81 91 29 117 110 74 90 35 97

9/30 20/86 6/41 9/29 15/53 12/54 12/50 65/221 10/27 29/79 49/91 12/29 56/117 42/110 21/37 32/90 20/35 30/82 449/1252

51 49 69 66 67 NA 68 96 NA NA NA NA NA NA NA NA NA 85 36

TOTAL

NA  Not available.

Maternal Blood Tests White blood cell counts are currently suggested by many as a means of identifying infection before it becomes clinically obvious. In patients with PPROM, sensitivities as high as 81% have been reported in the literature.36 Yoon et al101 evaluated WBC counts over 13,000 and correlated them with positive amniotic fluid cultures. They found a sensitivity of only 32% with a positive predictive value of 40%, both inadequate for clinical use. Specificities, however, have averaged in the 80th percentile range in most of the studies to date.36 Disappointing sensitivities and positive predictive values suggest that WBC counts are not clinically useful. The significance of C-reactive protein has been extensively evaluated in PPROM. Many studies have correlated high levels with histologic chorioamnionitis, but few studies have evaluated this test with clinical findings. Yoon et al101 found a sensitivity of 56% and a positive predictive value of 83% in 90 patients when positive amniotic fluid cultures were used as the outcome variable. Romem and Artal,69 in a small series, found that a 30% rise over baseline level of C-reactive protein predicted amniotic infection with 100% sensitivity, specifically, and positive and negative predictive values. This series, however, only included 16 patients. Overall, C-reactive protein seems to lack the sensitivity for clinical use, although these sensitivities have varied widely (37% to 100%) in the studies to date.

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Erythrocyte sedimentation rate has also been evaluated as a way of identifying infections in this group of patients. Hawrylyshyn et al39 found high specificities (100%) and fair sensitivities (65%) when evaluating the ability of erythrocyte sedimentation to predict histologic chorioamnionitis. An elevated erythrocyte sedimentation has rarely been used to identify infections in pregnancy, however, because of the known elevations that occur with high fibrinogen concentrations associated with pregnancy. Its use as a diagnostic test in patients with PPROM needs further evaluation. Maternal serum IL-6 has been suggested as a way to predict infectious morbidity in patients with PPROM. Murtha et al63 demonstrated elevated IL-6 concentrations (8 pg/dL) to have a 96% positive predictive value at predicting clinical and histologic chorioamnionitis. Lewis et al54 found that high maternal serum concentrations of IL-6 in PPROM patients predicted infectious complications and neonatal morbidities. With a sensitivity of 88.9% for predicting neonatal components and 75% for infectious components in this study, IL-6 was a better predictor of neonatal complications than infectious complications. Preliminary data have shown promise in its clinical use; however, this test is still limited to the research laboratory and is not widely clinically available. Amniocentesis Garite et al24 were the first to propose the use of amniocentesis in the evaluation of the microbial flora of the amniotic cavity in PPROM patients. Successful retrieval rates by transabdominal amniocentesis in published reports range between 49% and 96%. Yeast et al,100 who reviewed charts from 138 patients with PPROM at 28 to 34 weeks’ gestation who were not in labor or clinically infected, addressed the issue of safety of the procedure. Amniocentesis was performed in 91 women compared with 46 women who could not have an amniocentesis because of technical difficulties. There was no difference in time to onset of labor between the two groups. There was no evidence of fetal injury from the amniocentesis needle. A hematoma of the broad ligament was noted in one patient, who ended up having a cesarean section for an unrelated indication. Another review of the safety of amniocentesis reports the risk of fetal injury to be between 0.6% and 2% and that of placenta and cord injury to be 0.3% to 1.1%.22 Once the amniotic fluid has been retrieved there is a veritable plethora of tests than can be ordered. Table 2 depicts the tests available that may be ordered to diagnose intra-amniotic infection. Ohlsson and Wang66 in their meta-analysis reviewed tests to detect intrauterine infection. Amniotic fluid Gram stains have a sensitivity of 36% to 80% and a specificity of 80% to 97%. Approximately 105 organisms per mL are needed before a Gram stain is positive. In addition, Gram stain does not identify Mycoplasma because of a lack of a defined cell wall complex. Not all culture-positive fluids have a positive Gram stain, although

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Table 2. MARKERS OF INTRAUTERINE INFECTION IN WOMEN PRESENTING WITH PPROM Amniotic Fluid Bacteria (Gram stain and culture) Low glucose High white cell count High G-CSF High TNF-2 High IL-1 High IL-6 High MMP-9

Maternal Serum High High High High

G-CSF IL-6 TNF-2 C-reactive protein

G-CSF  Granulocyte colony–stimulating factor; TNF  tumor necrosis factor; IL  interleukin; MMP  matrix metalloproteinase.

virtually all positive Gram stain results have positive cultures.66 Amniotic fluid glucose levels have been proposed to detect amnionitis. The mechanism for low glucose values probably involves glucose metabolism by both microorganisms and polymorphonuclear leukocytes, similar to the presumed pathophysiologic mechanism of decreased glucose levels in other body fluids, such as cerebrospinal fluid.103 Romero et al,80 using an amniotic fluid glucose level of less than 14 mg/dL and a positive amniotic fluid culture as the outcome variable found an 87% sensitivity compared with 65% for Gram stain alone. Using a cutoff of less than 10 mg/dL and a positive amniotic fluid culture combined with histologic chorioamnionitis Kirshon et al49 reported 100% sensitivity compared with 66% sensitivity for the Gram stains alone.87 Passing mention is made here about amniotic fluid IL-6 levels, primarily because this test is not yet clinically available in most centers. Romero et al80 compared various diagnostic tests and their predictive values in the detection of positive amniotic fluid cultures in patients with PPROM. IL-6 by itself in their study performed best in detecting microbial invasion of the amniotic cavity and had a sensitivity of 79% and a specificity of 100% for diagnosing acute histologic chorioamnionitis at concentration levels greater than 17 mg/mL. Noninvasive Evaluation of the Fetus to Detect Intraamniotic Infections. Several investigators have observed that the fetus residing in a colonized amniotic cavity has an abnormal biophysical behavior, such as a nonreactive nonstress test (NST) or a low score on the biophysical profile (BPP). Overall, most studies support an association between a nonreactive NST and infectious outcome. The sensitivity ranges between 36% and 84%, with a positive predictive value of 14% to 75% and a negative predictive value of 18% to 100%.12, 96 A significant limitation of these studies is the various indices used to define an infection. There

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seems to be no standard definition of what constitutes a clinically relevant perinatal infection. Although NSTs for patients with PPROM are widely and properly used for fetal well-being and cord compression, their high false-positive rates make them inappropriate for clinical decisions. Several studies have examined the relationship between oligohydramnios and PPROM. Collectively these data indicate that there is an association between the severity of amniotic fluid volume reduction and maternal or neonatal infection. Jackson et al45 noted that the amniotic fluid index in PPROM patients remains stable after the membranes rupture with the mean amniotic fluid index on admission being 5.9 and on the day of delivery 5.4.52 Vintzileos et al95 reported vertical pockets greater than 2 cm in 65.5% of their patients with PPROM; 15.5% had a vertical pocket between 1 and 2 cm; and only 19% had vertical pockets of less than 1 cm (i.e., oligohydramnios). The reason for the high rate of infection in patients with PPROM and oligohydramnios is unknown. One possible explanation may be that a decreased amniotic fluid volume may deprive patients of the antimicrobial properties of the normal amniotic fluid. The relationship between the BPP either in whole or its components and infection-related outcome in PPROM has also been studied extensively. There is compelling evidence that a low BPP is associated with the subsequent development of clinical infection and associated morbidity.68, 81, 96, 98, 102 Much like the limitations of NSTs in predicting infections in PPROM patients, the numerous definitions of infections used by the various investigators, such as possible-probable neonatal sepsis-infection, microbial invasion of the amniotic fluid, and so forth, make it difficult to understand clearly the relationship between infection and a low BPP. Vintzileos et al96 were the first to document an association between infection and infection-related morbidity (defined as maternal chorioamnionitis, possible neonatal sepsis, and proved neonatal sepsis). In their first study, using a scoring scheme of 12 (plus two for placental grade) they found that a BPP of 7 or lower, done 24 hours before delivery, had a sensitivity of 94%, specificity of 97%, positive predictive value of 94%, and negative value of 97% in predicting infection in a population with an infection-related outcome prevalence of 30%. In subsequent studies Vintzileos et al94 used daily BPPs to manage patients with PPROM. An abnormal BPP (defined as a score of 7 or less, and with a nonreactive NST and absent fetal breathing movements) on two examinations 2 hours apart was an indication for delivery. They reported that the patients managed with daily BPPs had a lower overall neonatal sepsis (suspected or proved) than did patients in the control and amniocentesis group. The study failed, however, to report on other indices of neonatal morbidity (respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, and so forth) in the different groups. Furthermore, 14 patients born with a low BPP showed no evidence of neonatal sepsis. Subsequent to Vintzileos’ studies three other studies reported an

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association between the results of the BPP and an infection-related outcome.18, 31, 60 Two other studies were unable to corroborate such an association.62, 102 Goldstein et al31 demonstrated that if fetal breathing was absent or lasted less than 30 seconds, and if body movements were decreased (less than 50 seconds) microbial invasion of the amniotic cavity was documented in all cases. Conversely the presence of fetal breathing movements of 30 seconds or more ruled out intra-amniotic infection. What is clear from all of these studies, and is intuitively correct, is that the abnormal BPP correlates better with fetal as opposed to maternal infection. Furthermore, as with newborns, the signs of sepsis in a fetus are very nonspecific until the fetus is quite sick. What is also clear from those studies where the individual data are available, is that virtually all babies with abnormal BPPs also had a nonreactive NST. The question arises: can the NST be used as the initial screen, reserving the remainder of the BPP as a back-up for those nonreactive fetuses only? The only prospective randomized trial to compare daily nonstressing with biophysical profile was published by Lewis et al.53 They found that neither a daily NST nor BPP had good sensitivities at predicting infectious complications (39.1% and 25%, respectively). Good specificities were noted for both tests with a NST having 84.6% and the BPP 92.6%. They concluded that neither test predicted infectious complications well, but that the NST was needed as a daily screening test for variable decelerations and umbilical cord compression. The NST serves double duty, because when it is nonreactive and the BPP is abnormal, a sufficient specificity does exist to warrant further investigation or delivery. DETECTION OF INTRA-AMNIOTIC INFECTION: CLINICAL APPLICATIONS There are several different clinical circumstances in the setting of PROM where the need to assess the patient carefully for intra-amniotic infection comes into play. Obviously, because infection is both a potential cause and a possible consequence of amniorrhexis, every patient who presents, regardless of gestational age needs careful evaluation to rule out intra-amniotic infection. The clinical picture of fever, maternal and fetal tachycardia, foul-smelling amniotic fluid in the vagina, and a tender uterus in the setting or PROM is characteristic of advanced chorioamnionitis. Many patients, however, fortunately present much earlier in the course of such infection and the diagnosis may not be quite as obvious. Fever (temperature ⬎ 38oC) in the patient with PROM without another apparent source in and of itself is usually the criteria used to make the diagnosis of chorioamnionitis. Gibbs et al28 demonstrated in term patients that virtually all such patients have confirmation of the diagnosis by amniotic fluid culture and subsequent histopathology. Even fever, however, may be a relatively late finding in the progression of intraamniotic infection. At earlier times during the evolution of this infection

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and before the appearance of fever, there may be other signs that suggest that the patient is, or is becoming, infected. Such signs as fetal tachycardia and a nonreactive NST have been shown by Asrat et al3 to correlate independently with a high rate of positive amniotic fluid cultures on amniocentesis. Even labor may be an early sign of infection in PPROM. Studies of amniocentesis in patients with PPROM and not in labor have shown that the onset of labor occurs significantly sooner in those with positive Gram stains and or cultures.24, 43 It is important to point out that, whereas generally maternal infection precedes fetal infection, and for that reason maternal infection usually is present without fetal infection, this is not always the case. Recent evidence from several studies by Romero et al34, 70 show that in some cases fetal infection may precede any evidence of maternal inflammatory response to colonization and may have caused fetal damage long before the clinical appearance of chorioamnionitis. In evaluating the patient who presents with PROM at all gestational ages it is imperative that a careful assessment of mother and fetus be carried out. Clinical history and physical examination begins the process and if infection is not obvious, additional tests are warranted. A complete blood count is virtually always obtained on admission, and many clinicians often repeat this serially, often on a daily basis. As previously noted, however, only in extremes is the WBC of clear value. The patient without clinical or laboratory signs of infection must be re-evaluated on at least a daily basis, and sooner if she or the nurse reports any suspicious change in her condition. The fetus can be surveyed for possible infection in one of several ways. As previously discussed, a daily NST is of value in evaluating the fetus for more common signs of cord compression. If a nonreactive NST persists, a BPP is warranted and the fetus with a low BPP (0 to 2) requires further evaluation or more likely immediate delivery. Amniocentesis correlates better with the subsequent development of maternal rather that fetal infection. This is true for at least two reasons. First maternal infection is more common. Second the evolution of infection probably occurs most frequently from decidual colonization to amniotic colonization, especially in the preterm patient when infection often precedes membrane rupture. In this situation the amniotic fluid reflects the maternal compartment. The place for amniocentesis in the evaluation of the patient with PROM is not clear and certainly there is little agreement, especially on its routine use. In those patients who are undergoing amniocentesis to assess fetal lung maturity, Gram stain and glucose concentration should be performed. Obviously, since one has already done the invasive test, additional valuable information should be sought. Secondly, in the gestational ages where one is most likely to be performing amniocentesis to assess lung maturity (e.g., 32 to 34 weeks), the benefit of earlier diagnosis of infection and potentially delivery before the fetus becomes infected probably outweighs the risk of prematurity in this group. The argument for the routine use of amniocentesis in patients with PPROM is much

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less clear. The question is: does the benefit of knowing that the patient is very likely to develop infection soon justify the risk of amniocentesis? Because intrauterine treatment is not an option and the only viable option is delivery, the benefits of early delivery must be established before subjecting the fetus, especially at very early gestational ages, to the complications of prematurity. No comparative studies are available to answer this question and most clinicians do not perform amniocentesis routinely for this purpose. One situation where amniocentesis is likely to be a very useful option is in the patient with suspicious findings, but without a clear-cut diagnosis of chorioamnionitis. Such patients might include those with PPROM and a low-grade fever, an intermediate BPP score, an moderately high WBC, or an unexplained fetal tachycardia. Usually time alone resolves the question, but often in waiting the mother becomes seriously infected or the fetus can sustain much more serious insults. In such patients, an amniocentesis can be extremely useful in resolving whether or not there is infection. SUMMARY The recent increase in knowledge about infection and preterm delivery has engendered many new questions and should make us rethink our long held beliefs and management strategies. Although this article focused primarily on infection as an important factor in the pathogenesis of PPROM, multiple other causes do exist. The various serologic and amniotic fluid assays that can identify activation of the host immune and inflammatory responses as a consequence of the microbial invasion of the amniotic cavity detailed in the preceding paragraphs are very promising but not yet available for clinical use. These tests identify the fetus in the early stages of an infectious process, before the full clinical manifestations of chorioamnionitis. Should such fetuses be treated with antibiotics in an effort to sterilize the amniotic cavity? Should patients with documented microbial invasion be delivered immediately or is there room for a more conservative management with aggressive antibiotic in utero treatment, altering the natural course of PPROM, avoiding extremely preterm deliveries? Certainly many questions remain unanswered. Continuing the search for information on the relationship between infection and PPROM can only add hope to one day finding an option for prevention, because many and probably most cases of PPROM are apparently caused by infection, and the opportunity for preventing this problem most probably lies here. References 1. Andrews WW, Hauth JC, Goldenberg RL, et al: Amniotic fluid interleukin-6: Correlation with upper genital tract microbial colonization and gestational age in women

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2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

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