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Perinatology Research Branch, National Institute of Child Health and Human Development, NIH/DHHS, Bethesda, MD 20892
2 To whom correspondence should be addressed. E-mail: warfiela{at}mail.nih.gov.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • intrauterine infection • prematurity • fetal inflammation • vitamins C and E • rupture of membranes
Intrauterine infection has emerged during the past 20 y as an important and frequent mechanism of disease responsible for spontaneous preterm birth (1– 4). It is the only pathological process for which a firm causal link with prematurity has been established and for which a defined molecular pathophysiology is known. Fetal infection and inflammation has been implicated in the genesis of fetal or neonatal injury leading to cerebral palsy and chronic lung disease. This article describes the pathways leading to intrauterine infection, as well as its staging, microbiology, frequency and clinical consequences such as the fetal inflammatory response syndrome. A possible role for two micronutrients, vitamins C and E, in the prevention of the preterm prelabor rupture of membranes (PROM) 3 and the consequences of fetal inflammation is considered.
Although systemic maternal infection (i.e., pneumonia, pyelonephritis, malaria, typhoid fever, etc.) has been associated with preterm labor and delivery, the frequency of these conditions is low in developed countries. Thus, the attributable risk of systemic infection for prematurity is small. The recent report of an association between periodontal disease and prematurity may require a reexamination of this view, particularly because some preterm neonates have evidence of a humoral immune response to microorganisms normally present in the oral cavity (5, 6).
Intrauterine infection and inflammation are frequently associated with preterm labor and delivery, and at least 40% (positive, amniotic fluid & chorioamniotic space culture) of all preterm births have been estimated to occur with mothers who have an intrauterine infection, which is largely subclinical. The lower the gestational age at delivery, the greater the frequency of intrauterine infection.
Pathways of ascending intrauterine infection
Microorganisms may gain access to the amniotic cavity and fetus through the following pathways: ascending from the vagina and cervix; hematogenous dissemination through the placenta (transplacental infection); retrograde seeding from the peritoneal cavity through the fallopian tubes; and accidental introduction at the time of invasive procedures, such as amniocentesis, percutaneous fetal blood sampling, chorionic villous sampling or shunting (4, 7– 10). The most common pathway of intrauterine infection is the ascending route (11). Evidence in support of this includes the following: histological chorioamnionitis is more common and severe at the site of membrane rupture than in other locations, such as the placental chorionic plate or umbilical cord (4); inflammation of the chorioamniotic membranes is present in virtually all cases of congenital pneumonia (stillbirths or neonatal) (7, 9, 10); bacteria identified in cases of congenital infections are similar to those found in the lower genital tract (8); and in twin gestations, histological chorioamnionitis is more common in the firstborn twin and has not been demonstrated only in the second twin. As the membranes of the first twin are generally opposed to the cervix, this is taken as evidence in favor of an ascending infection (8). This observation is consistent with those made during the course of microbiological studies of the amniotic fluid in twin gestation. When infection is present, the presenting sac is always involved (12).
Stages of ascending intrauterine infection
Ascending intrauterine infection is considered to have four stages (11) (Fig. 1). The first stage consists of a change in the vaginal and cervical microbial flora or the presence of pathological organisms (i.e., Neisseria gonorrhea) in the cervix. Some forms of bacterial vaginosis may be an early manifestation of stage I. Once microorganisms gain access to the intrauterine cavity, they reside in the decidua (stage II). A localized inflammatory reaction leads to deciduitis. Microorganisms may then reside in the chorion and amnion. The infection may invade the fetal vessels (choriovasculitis) or proceed through the amnion (amnionitis) into the amniotic cavity, leading to microbial invasion of the amniotic cavity or an intraamniotic infection (stage III). Rupture of the membranes is not a prerequisite for intraamniotic infection because microorganisms can cross intact membranes (13). Once in the amniotic cavity, the bacteria may gain access to the fetus by different ports of entry (stage IV). Aspiration of the infected fluid by the fetus may lead to congenital pneumonia. Otitis, conjunctivitis and omphalitis may occur by direct spreading of microorganisms from infected amniotic fluid. Seeding from any of these sites to the fetal circulation may result in fetal bacteremia and sepsis.
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The most common microbial isolates from the amniotic cavity from women with preterm labor and intact membranes are Ureaplasma urealyticum, Fusobacterium spp. and Mycoplasma hominis (11). Other microorganisms that have been found in the amniotic fluid include Streptococcus agalactiae, Peptostreptococcus spp., Staphylococcus aureus, Gardenerella vaginalis, Streptococcus viridans and Bacterioides spp. Occasionally, Lactobacillus spp., Escherichia coli, Enterococcus faecalis, Neisseria gonorrhea and Peptococcus spp. have been encountered. Haemophilus influenzae, Capnocytophaga spp., Stomatococcus spp. and Clostridium spp. have rarely been identified (14, 15). In patients with microbial invasion, 51% have more than one microorganism isolated from the amniotic cavity; and 71% have more than 105 colony forming units per milliliter (4). Several studies have proposed a role for Fusobacterium (16, 17) and Mycoplasma species (18) in preterm labor.
The role of Chlamydia trachomatis as an intrauterine pathogen has not been clearly elucidated. This microorganism is an important cause of cervicitis and has been isolated from amniotic fluid (19, 20). A case report of congenital pneumonia caused by C. trachomatis suggests that this microorganism can cause ascending intraamniotic infection (19). The uncertainty about the role of C. trachomatis in the etiology of microbial invasion and intrauterine infection seems related to difficulties in isolating the microorganisms from amniotic fluid with standard culture techniques (21). The use of polymerase chain reaction to detect specific sequences for this microorganism should help resolve this issue (22).
Likewise, the role of viruses in the etiology of subclinical and clinical chorioamnionitis has not been determined. Yankowitz et al. (23) performed polymerase chain reaction for the presence of adenovirus, enterovirus, respiratory syncytial virus, Epstein-Barr virus, parvovirus B–19, cytomegalovirus and herpes simplex genomic material in the amniotic fluid of 77 women undergoing midtrimester genetic amniocentesis. Amniotic fluid viral footprints were found in 6 pregnancies: 3 adenovirus, 1 parvovirus, 1 cytomegalovirus and 1 enterovirus. Of these pregnancies, there were 2 pregnancy losses: at 21 wk (adenovirus) and at 26 wk (cytomegalovirus). Wenstrom et al. (24) compared amniotic fluid samples from a group of 62 pregnancy losses after midtrimester amniocentesis with 60 controls from a population of 11,971 women. Polymerase chain reaction was performed for the presence of adenovirus, parvovirus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, ß-actin DNA, enterovirus and influenza A. No difference in the prevalence of viruses in the amniotic fluid samples was observed (8% of the cases [(5/62] vs. 15% of controls [9/60], p = 0.74). At this time, no large clinical or epidemiologic study has implicated intrauterine viral infection in the genesis of preterm delivery. However, we have observed acute fetal cytomegalovirus and herpes viral infection presenting as preterm labor.
Prevalence of intraamniotic infection in preterm gestation
Microbial invasion of the amniotic cavity and preterm delivery. Studies examining the clinical circumstances surrounding preterm delivery indicate that one-third of all patients present with preterm labor and intact membranes, one-third present with preterm PROM and one-third are the result of indicated delivery (preterm delivery that does not result from the spontaneous onset of labor but rather from delivery in response to maternal or fetal complications, such as severe preeclampsia or intrauterine growth restriction with fetal distress) (25). To determine the relationship between microbial invasion of the amniotic cavity and preterm delivery, investigators have examined the rate of positive amniotic fluid cultures for microorganisms in patients at risk for preterm delivery. This includes patients with preterm labor with intact membranes, preterm PROM, an acute cervical incompetence or twin gestation.
The mean prevalence of positive amniotic fluid cultures for microorganisms in patients with preterm labor and intact membranes is approximately 12.8% (379/2963), based on the review of 33 studies (1). The earlier the gestational age at preterm birth, the more likely that microbial invasion of the amniotic cavity was present (26). The prevalence of positive amniotic fluid cultures for microorganisms is approximately 32.4% (473/1462) in patients with preterm PROM (1).
Among women presenting with a dilated cervix in the midtrimester, the prevalence of positive amniotic fluid cultures is 51% (27). Microbial invasion of the amniotic cavity occurs in 11.9% of twin gestations presenting with preterm labor and delivering a preterm neonate (12). The prevalence of positive amniotic fluid culture in women at term is approximately 18% (1). The microbial isolates are similar to the ones observed in preterm labor. However, the frequency of histological chorioamnionitis, clinical chorioamnionitis and neonatal sepsis is substantially lower in the term than in the preterm gestations. We interpret this as indicating that microbial invasion of the amniotic cavity in patients at term is often the consequence of labor and occurs during this process.
Chorioamniotic infection, histological chorioamnionitis and preterm birth. Inflammation of the placenta and membranes is a nonspecific host response to a variety of stimuli, including infection. Traditionally, acute inflammation of the chorioamniotic membranes has been considered an indicator of amniotic fluid infection (8– 10, 28– 33). This view has been based upon indirect evidence. Several studies demonstrated an association between acute inflammatory lesions of the placenta and the recovery of microorganisms from the subchorionic plate (34, 35) and from the chorioamniotic space (36). Bacteria have been recovered from the subchorionic plate from 72% of placentae with histological evidence of chorioamnionitis (18, 35, 36). A strong correlation exists between positive amniotic fluid cultures for microorganisms and histologic chorioamnionitis (37, 38), and Cassell et al. reported a strong association between positive microbial cultures from material obtained from the chorioamniotic interface and histological chorioamnionitis (39, 40). Inflammation in the umbilical cord (funisitis) is evidence of a fetal inflammatory response. In contrast, histological chorioamnionitis reflects a maternal inflammatory response.
Several studies examined the prevalence of inflammation in placentae from women delivering preterm infants. Collectively, the evidence indicates that an association exists between preterm birth and the occurrence of acute chorioamnionitis, and that the lower the gestational age at birth, the higher the frequency of histological chorioamnionitis (18).
Fetal infection. The most advanced and serious stage of ascending intrauterine infection is fetal infection (stage IV). The overall mortality rate of neonates with congenital neonatal sepsis is between 25% and 90% (41– 45). The wide range of results may reflect the effect of gestational age on the likelihood of survival. One study of infants born before 33 wk gestation found that the mortality rate was 33% for infected and 17% for noninfected fetuses (45). Carroll et al. (46) reported that fetal bacteremia is found in 33% of fetuses with positive amniotic fluid culture and 4% of those with negative amniotic fluid culture. Therefore, subclinical fetal infection is far more common than traditionally recognized.
Intrauterine infection as a chronic process
Although intrauterine infection has been traditionally considered an acute complication of pregnancy, accumulating evidence suggests that this may be a chronic condition. Supporting evidence comes from studies of the microbiological state of the amniotic fluid, as well as the concentration of inflammatory mediators at the time of genetic amniocentesis.
Microbial invasion of the amniotic cavity at the time of genetic amniocentesis. Cassel et al. (47) were the first to report the recovery of genital Mycoplasma organisms from 6.6% (4/61) of amniotic fluid samples collected by amniocentesis at 16–21 wk gestation. Two patients had positive cultures for M. hominis and two for Ureaplasma urealyticum. Patients with M. hominis delivered at 34 and 40 wk without neonatal complications, whereas those with U. urealyticum had preterm delivery, neonatal sepsis and neonatal death at 24 and 29 wk. Subsequently, Gray et al. (48) reported a 0.37% prevalence (9/2461) of positive cultures for U. urealyticum in amniotic fluid samples obtained during second trimester genetic amniocentesis. After exclusion of one case who had a therapeutic abortion, all patients (8/8) with positive amniotic fluid cultures had either a fetal loss within 4 wk of amniocentesis (n = 6) or preterm delivery (n = 2). All had histological evidence of chorioamnionitis. These observations suggest that microbial invasion can be clinically silent in the midtrimester of pregnancy and that pregnancy loss and preterm delivery can take weeks to occur. A similar finding was reported by Horowitz et al. (49) who detected U. urealyticum in 2.8% (6/214) of amniotic fluid samples obtained at 16–20 wk gestation. The rate of adverse pregnancy outcome (fetal loss, preterm delivery and low birth weight) was significantly higher in patients with a positive amniotic fluid culture than in those with a negative culture (3/6 [(50%] vs. 15/123 [12%], p = 0.035). Of interest is that patients with a positive amniotic fluid culture were more likely to have an obstetrical history that included more than three previous abortions than those with a negative culture (33% [2/6] vs.4% [5/123], p = 0.034).
Chronic intraamniotic inflammation and preterm birth. Interleukin (IL)-6 concentrations in amniotic fluid are considered a marker of intraamniotic inflammation frequently associated with microbiological infection in the amniotic fluid or the chorioamniotic space (50– 53). Romero et al. (54) reported the results of a case-control study in which IL-6 determinations were conducted in stored fluid of patients who had a pregnancy loss after midtrimester amniocentesis and a control group of patients who delivered at term. Patients who had a pregnancy loss had a significantly higher median amniotic fluid IL-6 than those with a normal outcome. Similar findings were reported by Wenstrom et al. (55) Of note is that maternal plasma concentrations of IL-6 were not associated with adverse pregnancy outcome.
The same approach was subsequently used to test the association between markers of inflammation in midtrimester amniotic fluid of asymptomatic women and preterm delivery. The concentrations of matrix metalloproteinase–8 (56), IL-6 (57), tumor necrosis factor (TNF)-
(58) and angiogenin (59) in amniotic fluid obtained at midtrimester amniocentesis were significantly higher in patients who subsequently delivered preterm than in those who delivered at term.
Collectively, this evidence suggests that a chronic intraamniotic inflammatory process is associated with both spontaneous abortion and spontaneous preterm delivery. It remains to be determined whether intraamniotic inflammation can be detected noninvasively. Goldenberg et al. (60) showed that the maternal plasma concentration of granulocyte-colony stimulating factor at 24 and 28 wk gestation is associated with early preterm birth. To the extent that this factor may reflect an inflammatory process, this finding suggests that a chronic inflammatory process identifiable in the maternal compartment is associated with early preterm birth (birth before 32 wk gestation).
A role of proinflammatory cytokines and other inflammatory mediators in preterm labor
A considerable body of evidence supports a role for inflammatory mediators in the mechanisms of preterm labor. Major attention has been focused on the role of proinflammatory cytokines such as IL-1ß, TNF- and IL-8. However, other proinflammatory and anti-inflammatory cytokines may also play a role, as can chemokines, platelet activating factors, prostaglandins and other inflammatory mediators.
During the course of ascending intrauterine infection, microorganisms may reach the decidua, where they can stimulate a local inflammatory reaction and the production of proinflammatory cytokines and inflammatory mediators (platelet activating factor, prostaglandins, leukotrienes, reactive oxygen species, nitric oxide, etc.). If this inflammatory process is not sufficient to signal the onset of labor, microorganisms can cross intact membranes into the amniotic cavity, where they can also stimulate the production of inflammatory mediators by resident macrophages and other host cells. Microorganisms that gain access to the fetus may elicit a systemic inflammatory response syndrome, which is characterized by increased concentrations of IL-6 (61) and other cytokines (62, 63), as well as cellular evidence of neutrophil and monocyte activation (64).
Evidence for the participation of IL-1 and TNF- in preterm labor includes the following: IL-1ß and TNF- stimulate prostaglandin production by amnion, decidua and myometrium (65; R. Romero, S.K. Durum, C.A. Dinarello, J.C. Hobbins & M.D. Mitchell, SGI abstract, 1986; R. Romero, D. LaFreniere, G. Duff & S. Durum, SGI abstract, 1985); human decidua can produce IL-1ß and TNF- in response to bacterial products (66,
67; R. Romero, et al., unpublished, 1986); amniotic fluid IL-1ß and TNF- bioactivity and concentrations are elevated in women with preterm labor and intraamniotic infection (68–
71); in women with preterm PROM and intraamniotic infection, IL-1ß concentrations are higher in the presence of labor (68,
69); IL-1ß and TNF- can induce preterm parturition when administered systemically to pregnant animals (72; R.M. Silver, S. Lohner, C.L. Chen, M.D. Mitchell & D.W. Branch, SGI abstract, 1993); fetal plasma IL-1ß is dramatically elevated in the context of preterm labor with intrauterine infection (73); placental tissue obtained from patients with labor, particularly those with chorioamnionitis, produces more IL-1ß than tissue from women not in labor (74). There is considerable redundancy in the cytokine network and thus it is not clear that a particular cytokine is required to signal the onset of labor. Results of knockout animal experiments suggest that infection-induced preterm labor and delivery occurs in subjects that lack a particular cytokine (75).
The fetal inflammatory response syndrome
The fetal inflammatory response syndrome (FIRS) is a subclinical condition originally described in fetuses presenting with preterm labor and intact membranes and preterm PROM. It is operationally defined as a fetal plasma IL-6 concentration above 11 ng/L (61). IL-6 is a major mediator of the host response to infection and tissue damage and can elicit biochemical, physiological and immunological changes in the host, including stimulation of the production of C-reactive protein by liver cells, the acute phase plasma protein response and activation of T and natural killer cells. Fetuses with FIRS have a higher rate of neonatal complications and are frequently born to mothers with subclinical microbial invasion of the amniotic cavity (61). Fetal microbial invasion is believed to result in a systemic fetal inflammatory response that can progress toward multiple organ dysfunction, septic shock and death in the absence of timely delivery. Evidence of multisystemic involvement in cases of FIRS includes increased concentrations of fetal plasma matrix metalloproteinase-9 (76), an enzyme involved in the digestion of type IV collagen. These fetuses also have neutrophilia, a higher number of circulating nucleated red blood cells and higher plasma concentrations of granulocyte colony stimulating factor (62). The histological hallmark of FIRS is inflammation in the umbilical cord, or funisitis (77). Newborns with funisitis are at increased risk for neonatal sepsis (78) as well as long-term handicap, including bronchopulmonary dysplasia (79) and cerebral palsy (80, 81). 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 (82), suggesting that the human fetus plays a role in initiating the onset of labor. Fetal inflammation has been linked to the onset of labor in association with ascending intrauterine infection. Systemic fetal inflammation may occur in the absence of labor when the inflammatory process does not involve the chorioamniotic membranes and decidua, such as in the context of hematogenous viral infections or the disease processes.
Micronutrients and infection and inflammation during pregnancy
Other articles in these proceedings review the infection-related morbidity in the mother, fetus and neonate (83), and the assessment of micronutrient status in the context of inflammation (84). This section reviews the possibility that supplemental administration of two vitamins with antioxidant properties—vitamins C and E—may decrease adverse outcome, such as prelabor rupture of membranes and fetal injury.
Many of the deleterious effects of inflammation are mediated by reactive oxygen species (85– 87). Compelling experimental and clinical evidence shows that patients with systemic inflammation, including neonates, are under severe oxidative stress (88– 90). One of the maneuvers under active investigation is whether changing the redox balance by enhancing the activity or availability of antioxidants may prevent tissue damage (85, 91).
Preterm PROM has been attributed to the effects of matrix-degrading enzymes on the fetal membranes (92), and reduction-oxidation status may affect the activity of matrix metalloproteinase 9, an enzyme implicated in membrane rupture (93). Observational studies suggest that patients with PROM had lower maternal plasma concentrations of ascorbate than patients who did not have PROM (94). In vitro studies indicate that the combination of vitamins C and E can prevent tissue damage to chorioamniotic membranes inflicted by hypochlorous acid, a reactive oxygen species produced by host cells during infection and inflammation (95). Although, the observational study of Wideman et al. (94) showed the dose-response relationship between the plasma ascorbic acid concentration and prevalence of prelabor rupture of membranes, ascorbic acid concentrations may have only reflected the general nutritional status of patients. This study was conducted in a disadvantaged population and the results may not be applicable to other groups. The in vitro study of Plessinger et al. (95) focused on hypochlorous acid-induced damage, whereas in vivo infection-induced damage could occur via nonoxidative pathways (e.g., elastase, protease). Woods et al. (96) proposed that diet alone is an inadequate source of vitamins C and E during pregnancy and that supplementation may be able to reduce preterm PROM. Other agents that down-regulate the inflammatory response may also be effective (e.g., N-acetylcysteine, anticytokine agents) (93, 97).
Research needs
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FOOTNOTES |
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3 Abbreviations: FIRS, fetal inflammatory response syndrome; IL, interleukin; PROM, prelabor rupture of membranes; TNF, tumor necrosis factor.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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