Year: 2001
Type: article
Abstract: A strong body of evidence suggests that infection plays a role in the pathogenesis of preterm labour and delivery. Moreover, recent evidence indicates that intrauterine infection may also be involved in the genesis of significant neonatal and infant complications such as periventricular leukomalacia, bronchopulmonary dysplasia and cerebral palsy. This article reviews the evidence linking infection with pre-term delivery. Three lines of evidence support a role for infection in the onset of preterm labour: • administration of bacteria or bacterial products to animals results in either abortion or labour; • systemic maternal infections such as pyelonephritis, pneumonia, malaria, and typhoid fever are associated with the onset of labour; • intrauterine infection is associated with preterm labour and delivery. Infection-induced preterm labour and delivery in animals. Considerable evidence derived from animal experimentation indicates that administration of micro-organisms or microbial products (e.g. endotoxin) to pregnant animals can induce preterm labour and delivery.1–4 In 1943, Zahl and Bjerknes5 demonstrated that injection of Shigella and Salmonella endotoxin into mice and rabbits was capable of inducing abortion. Takeda and Tsuchiya6 confirmed this observation by administering Escherichia coli endotoxin to pregnant mice and rabbits. Furthermore, immunisation of animals with an anti-endotoxin antibody ameliorates the biological effect of endotoxin.7 Animal models of ascending intrauterine infection have been developed by placing bacteria through a hysteroscope into the uterine cavity of rabbits.8 Using this model, Dombroski et al.8 and Romero et al.9 have been able to induce preterm labour and delivery. Gravett et al.10 have also developed an animal model of infection-induced preterm labour in rhesus monkeys by administering bacteria directly into the amniotic cavity or into the decidua. Extrauterine infection and preterm labour and delivery. Systemic maternal infections such as pneumonia, pyelonephritis, malaria, and typhoid fever have been associated with preterm labour and delivery.11–22 The rate of preterm delivery associated with maternal pneumonia ranges from 15% to 48%.11–14 Although the advent of antibiotic treatment has dramatically reduced maternal mortality from this condition, it has not affected the preterm delivery rate.13,14 In the pre-antibiotic era, pyelonephritis was associated with preterm delivery. Currently, pyelonephritis is associated with preterm labour but not preterm delivery,16 probably as a result of early treatment. Similarly, typhoid fever in the pre-antibiotic era carried a 60% to 80% risk of abortion and preterm labour, but this risk decreased after the introduction of antibiotic therapy.18–20 Malaria has also been associated with a 50% rate of preterm delivery. However, chemoprophylaxis seems to protect patients from preterm delivery.21,22 Recently, periodontal infection has been reported to be a risk factor for preterm delivery (Odds ratio [OR]: 7.9; attributable risk 18.2%).23 Collectively, these data support the concept that untreated systemic maternal infection is associated with preterm labour and delivery and that treatment may decrease the rate of preterm delivery in some cases (e.g. pyelonephritis, typhoid fever) but not in others (e.g. pneumonia). Intrauterine infection and preterm labour and delivery. Although untreated systemic maternal infections confer a high relative risk (RR) of preterm labour and delivery, these conditions are rare during pregnancy; modern treatment is effective and thus their attributable risk for preterm delivery is low. On the other hand, intrauterine infection has recently been recognised as a major factor associated with preterm labour. We will review the definition, microbiology, and clinical significance of intrauterine infection. The gold standard for the diagnosis of an intrauterine infection is a positive microbiological culture for micro-organisms. Intrauterine infection can be classified according to the location of the micro-organisms into two broad categories: intra-amniotic and extra-amniotic infections. It is possible to obtain biological material for microbiological culture from the amniotic cavity (i.e. fluid) and the chorioamniotic space.24,25 It is not easy to culture material derived from human decidua. Therefore, in practice, most studies in patients with preterm labour and delivery have focused on microbial invasion of the amniotic cavity (defined as a positive amniotic fluid culture for micro-organisms when the fluid is retrieved by transabdominal amniocentesis). The amniotic cavity is normally sterile and therefore the isolation of any micro-organism from the amniotic fluid constitutes evidence of microbial invasion. This condition often exists in the absence of clinical signs and symptoms of infection.26 The method of amniotic fluid collection for microbiological studies is critical. The two techniques that have been used are transabdominal amniocentesis and transcervical retrieval, either by needle puncturing of the membranes or by aspiration through an intrauterine catheter. Transcervical amniotic fluid collection is associated with a high risk of contamination with vaginal flora. Therefore, when analysing the prevalence of microbial invasion of the amniotic cavity in preterm labour, we will only consider studies in which amniotic fluid was obtained by transabdominal amniocentesis. The term ‘clinical chorioamnionitis’ refers to the clinical syndrome associated with microbial invasion of the amniotic cavity.27 This clinical syndrome only appears in a fraction of women with microbiologically proven intra-amniotic infections. We have shown that only 12.5% of women with preterm labour and intact membranes with a positive amniotic fluid culture have clinical chorioamnionitis.28 The delay in recognising the association between intrauterine infection and preterm delivery in clinical obstetrics probably stems from the fact that most intrauterine infections during pregnancy are not associated with clinical chorioamnionitis (the relationship between clinical chorioamnionitis and preterm delivery is covered later in this article). Culture of the chorioamniotic space provides information about intrauterine extra-amniotic infections. Such studies can be conducted by separating amnion and chorion after delivery of the placenta. Surface cultures of the membranes are of limited value for intrauterine infection because positive results may represent contamination with vaginal flora as the placenta and membranes pass through the birth canal. Studies in which amniotic fluid and chorioamniotic cultures were performed in the same patient demonstrate that micro-organisms are isolated twice as frequently from the chorioamniotic space than from the amniotic fluid (20% vs. 9%).24 These observations support the view that microbial invasion of the amniotic cavity is the result of advancing disease from the extra-amniotic to the intra-amniotic space. Micro-organisms may gain access to the amniotic cavity and fetus via any of the following pathways: • ascending from the vagina and the cervix; • haematogenous dissemination through the placenta (transplacental infection); • retrograde seeding from the peritoneal cavity through the fallopian tubes; • accidental introduction at the time of invasive procedures such as amniocentesis, percutaneous fetal blood sampling, chorionic villous sampling, or shunting.28–33 The most common pathway of intrauterine infection is the ascending route (Fig. 1).26 Supporting evidence includes: The stages of ascending infection. • 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;28 • in virtually all cases of congenital pneumonia (stillbirths or neonatal), inflammation of the chorioamniotic membranes is present;29–31 • bacteria identified in cases of congenital infections are similar to those found in the lower genital tract;32 • 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 favour of an ascending infection.32 These observations are consistent with our findings of the microbiological state of the amniotic cavity in twin gestations: in 11 of our cases with microbial invasion of the amniotic cavity diagnosed by transabdominal amniocentesis, the presenting sac was involved in all cases. When both amniotic cavities were infected, the inoculum size was larger in the presenting sac.34 These two observations provide additional support for the hypothesis that the mechanism of infection is through an ascending pathway. We have proposed a four-stage process leading to intrauterine infection (Fig. 1).26 The first stage consists of an overgrowth of facultative organisms or the presence of pathological organisms (i.e. Neisseria gonorrhoeae) in the vagina and/or cervix. Bacterial vaginosis may be an early manifestation of stage I. Once micro-organisms gain access to the intrauterine cavity, they reside in the decidua (stage II). A localised inflammatory reaction leads to deciduitis and further extension to chorionitis. The infection may invade the fetal vessels (choriovasculitis) or proceed through the amnion (amnionitis) into the amniotic cavity, leading to an intra-amniotic infection (stage III). Rupture of the membranes is not a prerequisite for intra-amniotic infection, as micro-organisms are capable of crossing intact membranes.35 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 are localised infections that occur by direct invasion of micro-organisms from infected amniotic fluid. Seeding from any of these sites to the fetal circulation results in bacteraemia and sepsis. Another possible pathway for fetal sepsis is the spread of an infection located in the decidua parietalis to the decidua basalis, and from there directly to the fetal villous circulation. The most common microbial isolates from the amniotic cavity from women with preterm labour and intact membranes are Ureaplasma urealyticum, Fusobacterium species, and Mycoplasma hominis.26 Fifty per cent of patients with microbial invasion have more than one micro-organism isolated from the amniotic cavity. The inoculum size varies considerably, and in 71% of the cases more than 105 colony-forming units per millilitre (cfu/mL) are found.28 Our observations are consistent with other studies supporting a role for Fusobacterium36,37 and Mycoplasma species38 in preterm labour. The role of Chlamydia trachomatis as an intrauterine pathogen has not been clearly elucidated. This micro-organism is an important cause of cervicitis and has been recently isolated from amniotic fluid.39,40 A case of congenital pneumonia caused by C. trachomatis suggests that this micro-organism may be capable of causing ascending intra-amniotic infection.39 The uncertainty about the role of C. trachomatis in the aetiology of microbial invasion and intrauterine in-fection may be related to difficulties in isolating the micro-organisms from amniotic fluid with standard culture techniques.40 The use of polymerase chain reaction (PCR) to detect specific sequences for this micro-organism should help resolve this question.41 Estimates of the frequency and the type of micro-organisms participating in intrauterine infections based upon standard microbiological techniques (e.g. culture) are likely to change with the introduction of more sensitive methods for microbial recovery and identification. Jalava et al.42 have recently reported the use of universal primers to conserved bacterial sequences (16 s ribosomal DNA). This approach should be able to detect most, if not all, bacterial species in amniotic fluid using PCR. The role of viruses in the aetiology of subclinical and clinical chorioamnionitis remains unexplored. However, recent studies demonstrated that viral footprints can be detected in the amniotic fluid of patients with other complications of pregnancy.43 Inasmuch as viruses can cause inflammation of other body cavities (i.e. pleuritis, pericarditis, meningitis), it would be surprising if they were not involved in the aetiology of inflammation of the chorioamniotic membranes. Studies examining the clinical circumstances surrounding preterm delivery indicate that a third of all patients present with preterm labour and intact membranes, a third is associated with preterm premature rupture of the membranes (PROM), and the remaining third result from delivery because of maternal or fetal indications (e.g. pre-eclampsia, growth retardation).44 To examine the relationship between microbial invasion of the amniotic cavity and preterm delivery, we will review the evidence supporting an association between intrauterine infection and spontaneous preterm labour (with or without intact membranes). Table 1 displays the results of 33 studies in which amniocentesis was performed in women with preterm labour and intact membranes.36,45–76 The mean rate of positive amniotic fluid cultures was 12.8% (379/2963). Women with positive amniotic fluid cultures generally did not have clinical evidence of infection at presentation, but they were more likely to develop clinical chorioamnionitis (37.5%[60/160] vs. 9%[27/301]), to be refractory to tocolysis (85.3%[110/129] vs. 16.3%[8/49]), and to rupture their membranes spontaneously (40%[6/15] vs. 3.8%[2/52]) than women with negative amniotic fluid cultures. The earlier the gestational age at preterm birth, the more likely that microbial invasion of the amniotic cavity was present.77 Table 2 displays the results of amniotic fluid cultures in women with preterm PROM in 18 published studies.61,62,67,68,78–91 Positive amniotic fluid cultures were detected in 32.4% (473/1462) of patients, but clinical chorioamnionitis was present in only 29.7% (49/165) of cases with microbial invasion. This is probably an underestimation of the true prevalence of microbial invasion of the amniotic cavity. Available evidence indicates that women with PROM and severely reduced volume of amniotic fluid have a higher incidence of intra-amniotic infection than those without oligohydramnios.83 As women with oligohydramnios are less likely to have an amniocentesis, the bias in these studies is to underestimate the prevalence of infection. A similar bias is that women with preterm PROM admitted in labour generally do not undergo amniocentesis; these patients have a higher rate of microbial invasion of the amniotic cavity than those admitted without labour (39.3%[24/61] vs. 25.6%[41/160], P < 0.05). Furthermore, of patients who are not in labour on admission, 75% have a positive amniotic fluid culture at the time of the onset of labour.84 Therefore, studies restricted to women not in labour provide a lower rate of microbial invasion of the amni-otic cavity than those including patients in labour. We have determined that 51.5% of patients presenting with cervical dilatation of 2 cm or more and intact membranes between 14 and 24 weeks’ gestation have a positive amniotic fluid culture for micro-organisms.92 The outcome of patients with microbial invasion was uniformly poor as they developed subsequent complications (rupture of membranes, clinical chorioamnionitis or pregnancy loss). An infection-induced spontaneous abortion may be indistinguishable from that of an incompetent cervix. Although multiple gestation is a known risk factor for preterm delivery, the cause of preterm delivery in this setting is poorly understood. The traditional explanation for the higher rate of preterm delivery in these pregnancies has been that uterine overdistension causes premature activation of the mechanisms responsible for the initiation of labour. It is also possible, however, that the premature cervical effacement and dilatation that occurs in multiple gestations favours an ascending infection and this, in turn, leads to preterm labour or PROM. We found that microbial invasion of the amniotic cavity occurs in 11.9% of twin gestations that present with preterm labour and deliver a preterm neonate.93 This finding is in contrast to the 21.6% observed in singleton gestations with preterm labour and delivery.28 These data suggest that intra-amniotic infection is a possible cause of preterm labour and delivery in twin gestation, but they do not support the hypothesis that intra-amniotic infection is responsible for the excessive rate of preterm delivery observed in these patients. Other investigators have confirmed that microbial invasion of the amniotic cavity occurs in patients with multiple gestations and have provided different estimates of the frequency of this condition.94,95 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 ranges between 25% and 90%.96–100 The wide range of these studies may represent the effect of gestational age on the likelihood of survival. One study that focused on infants born before 33 weeks’ gestation found that the mortality rate was 33% for those infected and 17% for non-infected fetuses. Carroll et al.88 have reported that fetal bacteraemia 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 recognised. Inflammation of the placenta and membranes is a host-response to a variety of stimuli including infection and chemical injury. Traditionally, acute inflammation of the chorioamniotic membranes has been considered an indicator of amniotic fluid infection.29–33,101–104 This view has been based upon indirect evidence. Several studies have demonstrated an association between acute inflammatory lesions of the placenta and the recovery of micro-organisms from the subchorionic plate105,106 and from the chorioamniotic space. Bacteria have been recovered from the subchorionic plate from 72% of placentas with histological evidence of chorioamnionitis.38,106,107 Furthermore, there is a strong correlation between positive amniotic fluid cultures for micro-organism and histological chorioamnionitis.108,109 Moreover, Cassel et al.24,25 have reported a strong association between positive microbial cultures from material obtained from the chorioamniotic interface and histological chorioamnionitis. Several studies have examined the prevalence of inflammation in placentas from women delivering preterm infants. We have critically these studies Collectively, the evidence indicates that there is an association between preterm birth and the of acute chorioamnionitis. The prevalence of is higher in women delivering preterm than in those delivering at term vs. term P < preterm intact vs. term intact P < These data suggest an association between infection and preterm The prevalence of neonatal sepsis is per in premature in contrast to per for term Furthermore, the lower the the higher the prevalence of sepsis for for and for The of these data is that premature are more to infection. The observation that at of the cases of sepsis are diagnosed after delivery, with the high incidence of microbial invasion of the amniotic cavity in women with preterm labour and for a of this traditional We suggest that the higher incidence of sepsis in the preterm is attributable to the higher incidence of intrauterine infection in women with preterm labour. This is consistent with the observations of Carroll et using fetal blood in patients with preterm PROM infection of the amniotic cavity and fetal Furthermore, we that the onset of preterm labour in this may be of the of infection. In the we the evidence an association between clinical and subclinical infection and preterm labour and delivery. However, the of an association not mean that infection causes preterm delivery. it has been that microbial invasion of the amniotic cavity is the of or not this relationship is is and has major clinical and This will examine the evidence supporting a relationship between infection and labour. is a in clinical In it is possible to animals or to a specific (i.e. bacteria or bacterial and In a clinical is able to a in human it is not possible to pregnant women with micro-organisms to infection causes premature labour. Therefore, investigators are often to to methods to the of an of the of this in we the to the and by This reviews the methods used by clinical to examine the likelihood of When the relationship between two or the first is to or not there is an association between the However, the of a relationship (i.e. a of not provide information about or of An association between the presence of micro-organisms in the amniotic cavity and the of preterm delivery patients in preterm for not mean that micro-organisms were there before preterm labour and that they were the cause of preterm An association may be related to or may be responsible for a and and are used to that type of are into studies which may be responsible for of the A factor is an that causes change in the and that varies with the The of the effect of and is not the of but of the and of use to an association is likely to be in Table displays the and of different proposed by et These are based on a by as before the of of the of in We will the in Table to the association of preterm labour and infection. This refers to the between the cause and the effect (e.g. animal pathological We the evidence derived from animal experimentation in an earlier Collectively, this evidence indicates that intrauterine infection or the systemic administration of bacterial products can induce premature labour. This the with which the of one the of The is a a cause is both and that is when one manifestation from only one This type of is not in the of premature labour because preterm delivery can and occur without any microbiological and pathological evidence of Moreover, there are limited data in to the frequency with which an intrauterine infection will lead to premature labour. Table displays the outcome of patients in microbial invasion of the amniotic cavity was detected in the and who were to their pregnancy without patients developed either preterm or PROM. These data suggest that the of the relationship between infection and premature labour is this a high of is rare in biological Although the relationship between and is for that view be because it is not occurs in of can cause other than such as and the of and can the of In the case of premature labour, we have provided and pathological data that preterm labour is a syndrome and that infection is only one of possible a relationship to be the proposed the In our infection the onset of premature labour. Although this at the of is not easy to in clinical investigators have that microbial invasion of the amniotic cavity causes premature labour based on the observation that micro-organisms are present in the amniotic fluid of patients admitted with preterm labour. In these however, amniotic fluid was retrieved after premature labour was Therefore, it is possible that microbial invasion is the of labour than the we recently determined that microbial invasion of the amniotic cavity occurs in of patients with spontaneous labour at it may be that microbial invasion is a associated with labour per than preterm labour. Micro-organisms gain access to the sterile amniotic cavity when cervical intact membranes to the vaginal flora or after membranes invasion therefore may be the of labour than the cause of preterm labour. there evidence that infection premature labour and Three of observations support the relationship between infection and preterm labour and delivery. 1 microbial invasion of the amniotic cavity in the of pregnancy leads to either spontaneous abortion or premature delivery. et reported a study in which amniotic fluid cultures for were performed in The prevalence of positive amniotic fluid cultures was the patients with a positive amniotic fluid one a abortion and their patients a spontaneous abortion or a preterm delivery risk chorioamnionitis and congenital pneumonia in all cases. The mean between a positive amniotic fluid culture and spontaneous abortion was delivery at 24 in one case and at in the This indicates that infection is a process that preterm delivery. 2 In a we found that patients with preterm PROM with positive amniotic fluid culture for or Mycoplasma on a than those with sterile amniotic of the lower with micro-organisms is a risk factor for preterm delivery. These conditions bacterial and infection with Neisseria of the results of studies examining the relationship between and preterm delivery indicate that patients with this condition have a higher rate of preterm delivery than patients Similarly, studies that bacterial vaginosis is a risk factor for preterm and bacterial vaginosis are present before premature labour, the of a role for these conditions in preterm labour and delivery. The mechanisms by which these conditions lead to premature labour have not been We that they are for the of the to microbial in the lower there is evidence that patients with bacterial vaginosis are more likely to have microbial invasion of the amniotic cavity than those without that In contrast to the the has limited for of of the study conditions is the in clinical use different studies as a for This that similar results be obtained in studies with different and is based on the that different should similar Table 1 the frequency of microbial invasion of the amniotic cavity in preterm labour. It is that microbial invasion of the amniotic cavity is found in most studies and that patients with microbial invasion of the amniotic cavity are more likely to deliver preterm It is in studies in which negative results were cultures for were not These studies are likely to underestimate the frequency and of microbial invasion of the amniotic cavity. In the case of bacterial most studies and case support an association between that condition and subsequent preterm labour and delivery. The the association between two the higher the likelihood of there a The of association is a of the relative risk and not of the A of more than 2 is generally considered of a strong Other methods for the of an association the correlation the or the of the for by a or a of and bacterial the is between and The likelihood of a relationship is if a can be possible, the to be is there is a between the of the infection and the likelihood of preterm delivery. Several lines of evidence support the of this The of bacterial endotoxin is higher in patients in preterm labour than in patients not in The microbial inoculum is in patients with preterm PROM admitted with preterm labour than in those admitted with preterm PROM but not in the of patients with an inoculum size of 105 or was in patients with preterm labour and only 15% in patients not in labour The rate of delivery after the administration of Escherichia coli bacterial endotoxin to pregnant mice a It is not possible to induce intrauterine infection in pregnant women for and we therefore direct evidence of Several examined the effect of antibiotic treatment in patients at risk for preterm labour (i.e. those with bacterial preterm or those presenting with preterm labour. of clinical of antibiotic administration in patients with indicates that this clearly the rate of Table Several studies indicate that treatment of bacterial vaginosis can the rate of preterm labour and delivery others do of clinical of antibiotic administration to patients with preterm PROM indicates that antibiotic treatment can the of the and the rate of clinical chorioamnionitis and proven neonatal administration to patients in preterm labour with intact membranes, by not the rate of preterm delivery and not pregnancy were in the rate of preterm birth or pregnancy in patients with preterm labour with intact labour can be considered a syndrome by the presence of uterine and cervical dilatation and caused by multiple pathological infection is only one of the conditions associated with the of preterm labour. It is that antibiotic administration will be effective in the of preterm labour in patients without an The data in the provide strong evidence of association between intrauterine infection and preterm labour and delivery. In this we have a of the evidence supporting the view that this association is likely to be in This should however, be taken to indicate that infection is the cause of preterm labour in all cases with microbial invasion of the amniotic cavity. We in a fraction of patients, microbial invasion is a that occurs after labour has if infection is however, it would be to that it is either or to the of that lead to preterm labour and delivery. on some women develop ascending infections and others do on methods for the diagnosis of these and on the role of in in women with proven intrauterine infection.
Language: English
Subfield: Obstetrics and Gynecology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2056228221