The role of infection in preterm labour and delivery

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 that a of all patients with preterm labour and intact a is associated with preterm rupture of the membranes and the result from delivery because of maternal or fetal (e.g. the relationship between microbial invasion of the amniotic cavity and preterm delivery, we will review the evidence supporting an association between intrauterine infection and preterm labour or intact the results of studies in which amniocentesis was performed in women with preterm labour and intact The rate of positive amniotic fluid cultures was with positive amniotic fluid cultures generally not have clinical evidence of infection at but they were more likely to clinical chorioamnionitis vs. to be to vs. and to rupture their membranes vs. than women with amniotic fluid The the at preterm the more likely that microbial invasion of the amniotic cavity was the results of amniotic fluid cultures in women with preterm in amniotic fluid cultures were detected in of but clinical chorioamnionitis was in only of cases with microbial invasion. This is probably an of the prevalence of microbial invasion of the amniotic cavity. evidence indicates that women with and reduced of amniotic fluid have a of intra-amniotic infection than those As women with are likely to have an amniocentesis, the in these studies is to the prevalence of infection. A similar is that women with preterm in labour generally not these patients have a rate of microbial invasion of the amniotic cavity than those labour vs. Furthermore, of patients are not in labour on have a positive amniotic fluid culture at the time of the onset of Therefore, studies to women not in labour provide a lower rate of microbial invasion of the cavity than those patients in labour. We have that of patients presenting with of or more and intact membranes between and have a positive amniotic fluid culture for The of patients with microbial invasion was as they developed complications of clinical chorioamnionitis or pregnancy infection-induced abortion may be from that of an cervix. Although is a risk factor for preterm delivery, the cause of preterm delivery in this is The for the rate of preterm delivery in these has been that uterine of the for the of labour. It is also that the and that in an ascending infection and in leads to preterm labour or We found that microbial invasion of the amniotic cavity in of twin that with preterm labour and a preterm This is in to the in with preterm labour and These data that intra-amniotic infection is a possible cause of preterm labour and delivery in twin but they not support the hypothesis that intra-amniotic infection is for the rate of preterm delivery in these have confirmed that microbial invasion of the amniotic cavity in patients with and have different of the frequency of this The most and stage of ascending intrauterine infection is fetal infection (stage IV). The mortality rate of with congenital neonatal sepsis ranges between and The of these studies may represent the effect of on the of that focused on found that the mortality rate was for those infected and for et have reported that fetal bacteraemia is found in of with positive amniotic fluid culture and of those with amniotic fluid Therefore, subclinical fetal infection is more common than of the placenta and membranes is a to a of infection and of the chorioamniotic membranes has been an of amniotic fluid This view has been based upon studies have demonstrated an association between inflammatory of the placenta and the recovery of micro-organisms from the and from the chorioamniotic space. have been from the plate from of with histological evidence of Furthermore, there is a strong between positive amniotic fluid cultures for micro-organism and histological Moreover, et have reported a strong association between positive microbial cultures from material obtained from the chorioamniotic and histological studies have the prevalence of inflammation in from women preterm We have these studies Collectively, the evidence indicates that there is an association between preterm birth and the of The prevalence of is in women preterm than in those at term vs. term preterm intact vs. term intact These data an association between infection and preterm The prevalence of neonatal sepsis is per in in to per for term Furthermore, the lower the the the prevalence of sepsis for for and for The of these data is that are more to infection. The observation that at of the cases of sepsis are diagnosed after delivery, with the high of microbial invasion of the amniotic cavity in women with preterm labour and for a of this We that the of sepsis in the preterm is attributable to the of intrauterine infection in women with preterm labour. This is consistent with the observations of et using fetal blood in patients with preterm 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 that infection 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 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 labour. Therefore, 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 the 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 association between the presence of micro-organisms in the amniotic cavity and the of preterm delivery patients in preterm for not that micro-organisms were there preterm labour and that they were the cause of preterm association may be related to or may be for a and and are used to that type of are into studies which may be for of the A factor is an that 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 the and of different proposed by et These are based on a by as the of of the of in We will the in 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 Collectively, this evidence indicates that intrauterine infection or the systemic administration of bacterial products can induce 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 labour because preterm delivery can and occur any microbiological and pathological evidence of Moreover, there are limited data in to the frequency with which an intrauterine infection will lead to labour. the of patients in microbial invasion of the amniotic cavity was detected in the and were to their pregnancy patients developed either preterm or These data that the of the relationship between infection and labour is this a high of is rare in biological Although the relationship between and is for that view be because it is not in of can cause other than such as and the of and can the of In the case of labour, we have 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 labour. Although this at the of is not easy to in clinical have that microbial invasion of the amniotic cavity labour based on the observation that micro-organisms are in the amniotic fluid of patients with preterm labour. In these amniotic fluid was retrieved after labour was Therefore, it is possible that microbial invasion is the of labour than the we recently that microbial invasion of the amniotic cavity in of patients with 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 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 labour and Three of observations support the relationship between infection and preterm labour and delivery. microbial invasion of the amniotic cavity in the of pregnancy leads to either abortion or delivery. et reported a 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 abortion or a preterm delivery risk chorioamnionitis and congenital pneumonia in all cases. The between a positive amniotic fluid culture and abortion was delivery at in one case and at in the This indicates that infection is a process that preterm delivery. In a we found that patients with preterm 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 that patients with this condition have a rate of preterm delivery than patients Similarly, studies that bacterial vaginosis is a risk factor for preterm and bacterial vaginosis are labour, the of a role for these conditions in preterm labour and delivery. The by which these conditions lead to 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 that In to the the has limited for of of the 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 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 preterm It is in studies in which results were cultures for were not These studies are likely to 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 preterm labour and delivery. The the association between two the the of there a The of association is a of the relative risk and not of the A of more than is generally of a strong methods for the of an association the the or the of the for by a or a of and bacterial the is between and The of a relationship is if a can be the to be is there is a between the of the infection and the of preterm delivery. lines of evidence support the of this The of bacterial endotoxin is in patients in preterm labour than in patients not in The microbial inoculum is in patients with preterm with preterm labour than in those with preterm 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 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 studies that treatment of bacterial vaginosis can the rate of preterm labour and delivery others of clinical of antibiotic administration to patients with preterm 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 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 a syndrome by the presence of uterine and and caused by 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 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 be taken to that infection is the cause of preterm labour in all cases with microbial invasion of the amniotic cavity. We in a fraction of microbial invasion is a that after labour has if infection is it would be to that it is either or to the of that lead to preterm labour and delivery. on some women ascending infections and others on methods for the diagnosis of these and on the role of in in women with proven intrauterine infection.