Mycoplasmas in pregnancy
Prof. D Taylor-Robinson, Division of Medicine, Imperial College London, St Mary’s Hospital Campus, Paddington, W2 1NY, London, UK. Email email@example.com
Please cite this paper as: Taylor-Robinson D, Lamont R. Mycoplasmas in pregnancy. BJOG 2011;118:164–174.
The genital mycoplasmas have been implicated in a number of adverse outcomes of pregnancy. Spontaneous preterm labour and preterm birth is an important contributor to perinatal mortality and morbidity. If Mycoplasma hominis plays an integral part in this problem, it is likely to contribute through its involvement with bacterial vaginosis. Ureaplasmas induce cytokines and inflammation, making a casual association compelling. The role of Mycoplasma genitalium and Mycoplasma fermentans is less clear, but M. genitalium is potentially pathogenic and should be treated if detected. There is considerable evidence for the role of M. hominis in post-partum and post-abortal sepsis, and for ureaplasmas causing chronic lung disease or death in very low birthweight infants. The role of the genital mycoplasmas in adverse outcomes of pregnancy is complicated by the presence or absence of bacterial vaginosis, and this association requires further research.
In 1937 Mycoplasma hominis was isolated from a Bartholin’s gland abscess,1 and in 1954 ureaplasmas were isolated from the male genital tract.2 Since then there have been many reports associating both mycoplasmas and ureaplasmas with known adverse outcomes of pregnancy, but their true role has remained somewhat controversial because many investigators have failed to take into account the relationship between bacterial vaginosis (BV) and genital mycoplasmas. Because this topic has been reviewed quite recently,3 reference will be made to this to avoid unnecessary repetition. The ensuing discussion updates the main issues and indicates where further research would be helpful.
Mycoplasma characteristics are detailed elsewhere.4,5 There are nearly 200 species within the class Mollicutes (soft skin), most of which belong to the genus Mycoplasma. Of the 14 Mycoplasma species that have been detected in humans, six have the genitourinary (GU)tract as their primary site of colonisation, as do the two species of the genus Ureaplasma that are human specific (Table 1). Both mycoplasmas and ureaplasmas have a trilayered external membrane, rather than a rigid cell wall, rendering them resistant to β-lactam antibiotics.
Table 1. Features of Mycoplasma and Ureaplasma species of human origin with the genital tract as the primary site of colonisation
Background to mycoplasmas under consideration
Mycoplasmas of human origin apparently of little importance
There is no obvious threat to pregnancy by Mycoplasma pirum, Mycoplasma penetrans, Mycoplasma primatum, Mycoplasma spermatophilum or Mycoplasma amphoriforme, which is the most recent mycoplasma of human origin to be identified.3
The detection of important mycoplasmas
The use of microbiological methods to diagnose and infer a relationship between mycoplasmal infections and adverse outcomes of pregnancy have been described elsewhere.4,6 For Mycoplasma hominis and the ureaplasmas, culture techniques are still valuable, but molecular-based techniques using the sensitive polymerase chain reaction (PCR) may be essential for diagnosis, and are now available for most mycoplasmal species, as well as ureaplasmal species of human origin.6Mycoplasma fermentans was thought to occur only rarely in the GU tract, but the use of PCR has shown that this species occurs frequently.7 In one study of 232 samples of amniotic fluid from women at the time of caesarean section, with singleton pregnancies and intact membranes, four were PCR-positive for M. fermentans.8 Two of these four women had histological evidence of chorioamnionitis, and their infants died. The significance of this seemingly interesting observation remains unclear some 17 years later.
Mycoplasma hominis and Ureaplasma spp. organisms (ureaplasmas) are those isolated most frequently from the human GU tract.9 Based mainly on genome size, ureaplasmas comprise two distinct species, Ureaplasma parvum and Ureaplasma urealyticum.10 It has become customary to refer to M. hominis and the Ureaplasma spp. as ‘the genital mycoplasmas’. However, the latter should now include Mycoplasma genitalium,11 a species that requires PCR technology for detection. It is one of the causes of non-gonococcal urethritis in men, and has been associated with cervicitis and pelvic inflammatory disease (PID).11 The effects that the latter four mycoplasmal species might have on the mother and fetus during pregnancy, and the mother and neonate thereafter, will be discussed.
As mentioned before,3 infection in utero with M. hominis and/or ureaplasmas is more common following membrane rupture than with intact membranes. Colonisation of infants is usually the result of contact with an infected cervix/vagina during birth, and therefore infants delivered by caesarian section are colonised less often.11 The frequency of neonatal colonisation varies according to vaginal colonisation in a given population. Vertical transmission of M. genitalium from mother to baby is uncommon, with only one case reported,12 despite the fact that this mycoplasma has been detected in the endometrium, cervix and vagina. Neonatal colonisation with M. hominis and ureaplasmas tends not to persist beyond the neonatal period, but ureaplasmas and M. hominis have been found in up to one-fifth and one-sixth of prepubertal girls, respectively.13–15 After puberty and sexual activity, colonisation with M. hominis and to a greater extent with ureaplasmas occurs,16,17 and increases according to the number of different sexual partners.
Apart from sexual contact, the prevalence of the genital mycoplasmas in a population is influenced by age, race, socio-economic status, contraception, menstruation, menopausal changes and pregnancy.18,19 In pregnancy, immunological and hormonal changes are very likely to affect colonisation. It is relevant that a powerful influence of estrogen and progesterone on the colonisation of the genital tract of female mice by different mycoplasmas, including M. hominis, ureaplasmas and M. genitalium, has been demonstrated.20 Accordingly, it is evident that determination of the precise prevalence of genital mycoplasmas in pregnant as opposed to non-pregnant women requires all the factors listed above to be considered. It is, therefore, not surprising that reliable data do not exist, although the tendency has been to recover M. hominis and ureaplasmas more often from pregnant than from non-pregnant women.19
The prevalence of M. genitalium in the community is subject to the same influences, and has not been established precisely. However, Oakeshott et al.21 found that in 2378 sexually active but non-pregnant, female students, aged <27 years, who were recruited from London universities in 2004–2006, the prevalence of M. genitalium was 3.0%. This was similar to the 2.3% prevalence found in Danish women of 21–23 years of age,22 and the 2.8% prevalence in Japanese women,23 but was higher than the 0.7% prevalence in pregnant women, of mean age 31 years, attending inner London general practices,24 or the 0.8% prevalence in young adult American women.25 In contrast, vaginal colonisation of certain groups of women, such as those presenting for termination of pregnancy, may be much higher (9%).26
Adherence of mycoplasmas to host cells is a prerequisite for pathogenicity, and mycoplasmal membrane adhesin protein, or lipoprotein, components are instrumental in bringing this about.4 These adhesins have been found in the mycoplasmas under consideration: the 140-kDa adhesin of M. genitalium is probably the most extensively characterized.27 Adhesion provides the opportunity for various metabolites of the mycoplasma to cause cell injury or otherwise interfere with host metabolism. In addition, antigenic variation in lipid-modified proteins in mycoplasma membranes enables mycoplasmas to evade the host immune response.4 Also, various mycoplasmas, their membranes or extracts, have been shown to activate macrophages and monocytes, leading to the expression and secretion of the major pro-inflammatory cytokines: specifically, tumour necrosis factor-α, interleukin (IL-1, IL-1β, IL-6, IL-8, IL-12, IL-16) and interferon-γ.4 Systemic as well as local inflammation and infection are important in inducing abnormal outcomes of pregnancy.28–35 The postulated cascade mechanism by which this occurs involves bacterial endotoxins and mycoplasma membrane lipoproteins, which activate the fetal membranes and decidua to produce some or all of the cytokines mentioned above.36 Endotoxins and cytokines stimulate the synthesis and release of prostaglandins, which results in the production of proteases and other bioactive substances that, in turn, can cause an adverse outcome of pregnancy.28,29,37
Genital mycoplasmas and adverse outcomes of pregnancy
The association between the genital mycoplasmas and ectopic pregnancy has been reviewed elsewhere.3 Previous PID, particularly if this has resulted in damage to the fallopian tubes, often leads to an ectopic pregnancy. Whereas Neisseria gonorrhoeae and Chlamydia trachomatis are the most likely causative organisms,38 the genital mycoplasmas may be responsible. There is no evidence that ureaplasmas cause PID, but there is a little evidence to suggest that M. hominis does,38–40 and more evidence that M. genitalium may be implicated.11,41,123 Thus, there is a small chance that an ectopic pregnancy could have a mycoplasmal aetiology, but formal studies to establish this need to be conducted.
Other adverse outcomes of pregnancy
Preterm birth (PTB) is often classified by clinical presentation, namely, spontaneous preterm labour (SPTL) (about 50%), preterm prelabour rupture of the membranes (PPROM) (30%) and medically induced PTB because of feto-maternal indications (20%). Although the cause is multifactorial, various microorganisms have been linked to the pathogenesis of PTB,28 by ascending from the lower genital tract and sometimes penetrating the chorioamnion,42 followed by chorioamnionitis, invasion of the amniotic cavity and fetal infection. The detection of bacteria in the amniotic fluid (AF) is significant as the AF is normally sterile in non-labouring women.43 Positive AF cultures can be found in about 13% of women who are in SPTL with intact membranes. In such women who go on to deliver preterm, positive AF cultures can be found in 22%. Of those who present with PPROM, positive cultures can be detected in 32% on admission, rising to 75% by the time of onset of labour.43 The earlier in gestation at which SPTL occurs, the higher is the frequency of positive AF cultures.44
Bacterial vaginosis (BV)
It is imperative that the existence of an abnormal vaginal flora in a poor pregnancy outcome is recognised. The abnormality is dominated by BV, although a publication by Donders et al.,45 discussed by Lamont and Taylor-Robinson,46 drew additional attention to the possible importance of aerobic bacteria and vaginal inflammation. With respect to BV, the results of a number of studies have shown that women with BV (symptomatic or asymptomatic) are significantly more likely to experience a late miscarriage or an early PTB.47–52 In otherwise normal healthy pregnant and non-pregnant women, BV occurs in approximately 20%, and the healthy lactobacillus-dominated vaginal flora is replaced by gram-negative cocco-bacilli, together with other bacteria and mycoplasmas/ureaplasmas.53 Lee et al.54 considered a high (≥8) Nugent score (indicative of BV), but not a positive culture for genital mycoplasmas (M. hominis/ureaplasmas), to be a risk factor for SPTL and PTB. They did not mention quantitation of the organisms, which is important as women with BV who are colonised by M. hominis organisms usually have much larger numbers (up to 10 000-fold) than women who do not have BV.53 In addition, if the detailed microbiology of different grades of Gram-staining is examined, it can be seen that with some micro-organisms, particularly M. hominis, greater numbers are found in the fullest manifestation of BV (Nugent score 7–10; grade-III Gram stain).53 Mycoplasmas are resistant to metronidazole, but this antibiotic is often effective in treating BV and in eliminating M. hominis.55 This may be because M. hominis prospers in the conditions created by the other bacteria, and when the latter are eradicated, it is too. In this way, it is difficult to know whether M. hominis is a pathogen in its own right, or whether it needs the presence of other BV-related bacteria to be pathogenic or is simply a bystander.
The first clue that a mycoplasma might be associated with an abnormal pregnancy outcome was an observation in 1971 that pregnant women given tetracycline had a surprisingly low incidence of low-birthweight (LBW <2500 g) infants.56 The possibility that this benefit might have resulted from the inadvertent eradication of the genital mycoplasmas was suggested. Support for this was the finding that the rate of isolation of genital mycoplasmas from the upper respiratory tract of neonates was inversely proportional to birthweight,57 and that the rate of LBW was related to the presence or absence of the genital mycoplasmas in the cervix of women at the time of their first antenatal visit.58 Although this was not accepted by all investigators,59 the results of a number of studies supported the relationship.3 In one study,60 the use of erythromycin over a 6-week period late in pregnancy resulted in a birthweight that was significantly greater than in those women given a placebo (3331 g versus 3187 g; P < 0.05). However, this was not confirmed in a subsequent large-scale trial.61
It is possible that BV rather than the genital mycoplasmas per se are responsible for the association with LBW.52,62,63 In one study,64 women with PPROM and intrauterine infection that was not specifically caused by the genital mycoplasmas, the rate of LBW was greater than for those who were not infected. It has been suggested that ureaplasmas (particularly U. urealyticum) alone, rather than M. hominis, the role of which remains unclear, have a significant association with LBW,65 especially when there is intra-amniotic infection.66 However, whether or not they require the presence of other BV-associated bacteria is unknown.52
Late miscarriage and preterm birth
These conditions are considered together because they occur on a continuum with common aetiological factors. It now seems clear that congenital fetal infection occurs more often than has been previously recognised,67 as one of every four preterm neonates of 23–32 weeks of gestation is born with bacteraemia, which is frequently caused by genital mycoplasmas, and by ureaplasmas in particular.68 In one study,69M. hominis was isolated from 17 (24%) patients with PTB, and from two (8%) of those without PTB, a difference that was not statistically significant. However, M. hominis organisms in large numbers (≥105 colour-changing units) were detected in 13 (18%) of the patients with PTB, but in none of the control patients (P < 0.05). Large numbers of these organisms are a feature of BV. As a result, although it is possible that M. hominis could have a major role in BV per se, and hence in adverse pregnancy outcomes, it remains unknown whether this is peculiar to BV, or is also applicable to other bacteria that are an integral part of BV. As it is very uncommon for large numbers of M. hominis organisms to be present in the absence of BV, it is likely that small numbers without BV are of no consequence with respect to an adverse outcome of pregnancy.
The association between ureaplasma organisms and BV is less consistent than for M. hominis, although when present in large numbers they are more common in BV than in women who have a normal vaginal flora.53 As for M. hominis, it is difficult to appreciate how the inter-relationship between ureaplasmas and BV or BV-related bacteria impacts on the adverse outcomes of pregnancy. What also remains unanswered is whether ureaplasmas alone without BV are associated with SPTL and PTB. On the one hand, some investigators have been unable to find a relationship between the presence of ureaplasmas and fetal loss,70,71 yet in other studies, the isolation of these organisms was much more common among PTBs, miscarriages and stillbirths than from healthy infants born at term or following therapeutic abortion, and was not entirely the result of superficial contamination as, in some instances, organisms were isolated from deep fetal tissues (lungs, brain, heart and viscera).3 In the case of preterm infants, taking one study as an example, ureaplasmas were isolated from 62 (86%) women who delivered after SPTL and from 12 (46%) women who delivered electively for fetomaternal indications (P < 0.01).72 Recently, Mitsunari et al.73 and Harada et al.74 reported that women in whom ureaplasmas had been detected in the cervix/vagina were more likely to deliver preterm than other women, and Abele-Horn et al.75 indicated that a large rather than a small number of U. urealyticum organisms in the vagina was the important factor. Furthermore, Namba et al.76 reported that the detection of Ureaplasma spp. in the placenta was an independent risk factor for chorioamnionitis in deliveries of <32 weeks of gestation. However, examination of AF would seem to have greater predictive possibilities. Intra-amniotic inflammation can be detected rapidly by a matrix metalloproteinase-8 test,77 and the finding of ureaplasmas in AF probably has greater significance than detecting them in the vagina/cervix. One group of investigators stated that the finding of ureaplasmas existing alone in AF at ≥34 weeks of gestation did not predict the occurrence of PTB,78 but two other groups found a significant association between ureaplasmas in AF and SPTL.79–81 In addition, an association between ureaplasmal infection and chorioamnionitis with an adverse pregnancy outcome has been seen, even when the duration of membrane rupture was taken into account.3
Such membrane inflammation is greater when there is intra-amniotic infection,82 and associated increased levels of cytokines,83–86 which are important in bringing about PPROM and a poor pregnancy outcome. The intra-amniotic inflammatory response is greater if the amnion is involved rather than there being only chorionitis.87 Nevertheless, it is often impossible to know whether fetal damage or death occurs because of organism invasion, or whether the latter is subsequent to these events. Furthermore, aetiology is often difficult to resolve because of the failure to take into consideration other microorganisms, particularly those occurring in BV, in which ureaplasmas are partially involved. Indeed, Olomu et al.88 emphasise the importance of controlling for confounding by other intrauterine organisms, and this is supported by another study in which about half of second-trimester placentas harboured various bacteria within the chorionic plate, organisms which could not be identified by PCR methods.89 In one study, however, BV was excluded and women infected apparently only with ureaplasmas were analysed.90Ureaplasma urealyticum, as opposed to U. parvum, was dominant in women who had had a miscarriage, and in those who delivered preterm. However, whether one ureaplasmal species is more important than the other needs to be resolved, because in another study the species diversity of ureaplasmas in AF was not associated with different pregnancy outcomes,65 whereas, in another study,91U. parvum was considered to be important. The latter observation is noteworthy as Moss et al.92 found that although SPTL was not a consequence of intra-amniotic colonisation in sheep experimentally infected with U. parvum, there was intrauterine inflammation and impaired fetal lung development. Further support for a role of U. parvum comes from a study in rhesus macaques, in which chorioamnionitis, PTB and fetal pneumonia were seen following intra-amniotic inoculation with this ureaplasmal species or with M. hominis.93 Antibiotic treatment of pregnant women colonised by ureaplasmas, who had a history of recurrent abortion, has been reported to have culminated in a normal outcome. However, the significance of this is not certain as specimens were not examined for other bacteria and the treatment trials were largely uncontrolled, or few individuals were studied.
Evidence for the association of M. genitalium with BV is contradictory,21,94 but it probably behaves more independently of BV than M. hominis. This should make it easier to assess its role, if any, in inducing a poor pregnancy outcome. However, in three studies,24,95,96M. genitalium was considered unlikely to be responsible for a poor outcome, whereas in a fourth it was reported to be a significant independent risk factor for SPTL and PTB.97 Clearly, further research is needed.
Postpartum and postabortal fever
This has been discussed in detail previously.3 In brief, seeking genital mycoplasmas in blood rather than the vagina is probably the best way of establishing a relationship with fever. Reports exist of women with postpartum fever, from whose blood M. hominis was isolated a day or more after delivery, often accompanied by an antibody response.98 However, an association with fever assumes that the organisms have been recovered in pure culture, otherwise a causal role is difficult to establish. The rare spread of M. hominis to an extragenital site, such as the brain or joint, causes a major problem. There is some but less evidence that ureaplasmas cause postpartum or postabortal fever. The role of M. genitalium, if any, has not been assessed.
Infection in the newborn
Evidence that M. hominis causes conjunctivitis in newborns is inconclusive. Moreover, published studies of the role of BV in conjunctivitis, with M. hominis in mind, are non-existent. The involvement of ureaplasmas has not been described, nor has that of M. genitalium, although it has been mentioned as a cause of adult conjunctivitis.99
Neonatal respiratory disease
There is unsubstantiated evidence to suggest that M. hominis might be a cause of respiratory distress syndrome,100 but the presence of M. hominis in the respiratory tract might, again, be no more than a marker for BV, with the other BV-associated bacteria being responsible, or with the mycoplasma behaving as a co-contributor.
Ureaplasmas in the lower respiratory tract of infants with a birthweight of <1000 g have been associated with congenital pneumonia, progressing to chronic lung disease of prematurity, and occasionally fetal death.3 This event is at least twice as common as that in uninfected infants of similar birthweight, or in heavier infants.101–103 There is also increasing support for an association of ureaplasmas with bronchopulmonary dysplasia.68,104,105 In addition, hyaline membrane disease in preterm infants has been simulated in infant baboons infected with ureaplasmas.106 Nevertheless, it is perhaps still too early to conclude that ureaplasmas are a definite cause of chronic lung disease of prematurity, as erythromycin failed to prevent such disease in two trials.107 However, both trials were ‘underpowered’ and further studies would not be out of place. Of some relevance is the fact that in a neonatal mouse model of ureaplasmal and oxygen-induced lung disease, azithromycin was more effective than erythromycin in improving survival and morbidity, and in decreasing lung inflammation.108
Other neonatal disease
Mycoplasma hominis and/or ureaplasmas have been isolated from the cerebrospinal fluid or from the brain of a few infants, presumably from infection in utero or colonisation at birth. An anatomical abnormality increases the chance of this occurring, and should be considered particularly if routine bacteriology fails to provide evidence of such infection. In a mouse model, antenatal exposure to U. parvum induced central microgliosis and disrupted brain development.109
Treatment and management of mycoplasmal disease in pregnancy
This is a topic that has been reviewed before.3 However, it is worth emphasising that access to mycoplasmal diagnostic facilities is often not possible, or decisions have to be made ahead of laboratory results. Consequently, management may depend on an understanding of what mycoplasmas might cause, and providing therapy empirically. Nevertheless, the mere presence in small numbers of M. hominis and/or ureaplasma organisms in the lower genital tract would not justify treatment. This may not be the case for M. genitalium, which is potentially of greater pathogenicity. More appropriate would be to treat, early in pregnancy, symptomatic/asymptomatic BV, in which M. hominis is linked, as are ureaplasmas to a lesser extent, using antibiotics active against a range of micro-organisms, including the latter two. Administration of ceftriaxone, clindamycin and erythromycin rarely eradicates intra-amniotic infection in women with PPROM,110 either because the organisms are insensitive or are partially protected by their invasion of cells,111 or by forming biofilms.112 Nevertheless, the finding of any of the genital mycoplasmas in amniotic fluid taken at amniocentesis could be regarded as acceptable grounds for treatment, and fluoroquinolones and/or clindamycin have been suggested.113 The activity of various antibiotics against genital mycoplasmas is shown in Table 2. Tetracyclines are effective against many strains of M. hominis, but some exhibit tetracycline resistance,6,114 and this, with the undesirability of giving these antibiotics in pregnancy, makes clindamycin an acceptable alternative.
Table 2. Susceptibility* of some genital mycoplasmas to various antibiotics
Antibiotic usage in pregnancy has been reviewed in detail before,115 and it is beyond our remit to discuss in any detail antibiotic trials concerned with the prevention of SPTL and PTB, and the associated deleterious effects on the fetus/neonate. Nevertheless, it is worth emphasising that a systematic review of giving clindamycin before 22 weeks of gestation to women with abnormal vaginal flora has revealed a significant reduction in the rate of PTB and LBW.116 The failure of the Overview of the Role of Antibiotics in Curtailing Labour and Early Delivery (ORACLE II) trial to affect PTB and neonatal morbidity or mortality,117 and for erythromycin to have caused functional impairment in some children when assessed 7 years later,118 has been criticised as having probably resulted from giving inappropriate antibiotics too late in pregnancy, and without evaluation of the vaginal microbial flora.119,120 The failure of erythromycin also diminishes the potential role for ureaplasmas in the aetiology of PTB.
At least 10% of ureaplasmas are resistant to tetracyclines,6,114 with a substantial proportion of these strains exhibiting cross-resistance to erythromycin,121 to which M. hominis is resistant. A combination of cefoxitin and doxycycline, a PID treatment regimen recommended by the Centers for Disease Prevention and Control,122 is ineffective for the treatment of upper genital tract infection by M. genitalium.123 Azithromycin is more active against this mycoplasma and a range of others, excepting M. hominis. Ureaplasmas are weakly affected,124 and are less susceptible than M. genitalium.6,114 Transplacental passage of erythromycin, roxithromycin and azithromycin is poor,125 but the passage of clarithromycin, to which M. hominis is not sensitive, but M. genitalium and ureaplasmas are, surpasses that of other macrolide antibiotics.126
Maternal postpartum or postabortal fever as a result of M. hominis and/or ureaplasmas often settles without treatment. If severe or persistent, similar reasoning as above applies to the administration of antibiotics. This should be guided by the results of blood cultures, not forgetting to use broad-spectrum antibiotics that are active against the bacteria found in BV, such as clindamycin, which is also active against M. hominis, and clarithromycin, which is highly active against ureaplasmas (Table 2).
For the neonate, if prophylactic antibiotics have not been given earlier in the pregnancy, treatment for respiratory disease or meningitis with the antibiotics mentioned above might be necessary, guided by the results of blood cultures.
A subjective assessment of the involvement of genital mycoplasmas in an adverse pregnancy outcome and other conditions is presented in Table 3. It is worth re-emphasising that in all the conditions considered, BV is a complicating factor that has often received insufficient attention in determining the role of the genital mycoplasmas. Treatment for some of the conditions is warranted with appropriate antibiotics. Future research should focus on: (1) the question of whether M. hominis and ureaplasmas, in the absence of BV, have a role to play in the development of preterm birth; (2) the involvement, if any, of M. genitalium and M. fermentans in inducing an adverse pregnancy outcome; (3) the extent to which the genital mycoplasmas, with or without BV, are involved in causing neonatal disease; and (4) defining which of the Ureaplasma species is most important as a cause of maternal and neonatal disease.
Table 3. Status of genital mycoplasmas with regard to an adverse pregnancy outcome and some other conditions
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Disclosure of interest
Both authors have studied BV and associated bacteria and their impact on pregnancy outcome. Otherwise no conflict of interest.
Contribution to authorship
DT-R was responsible for the first draft of the overview, after which the authors contributed equally.
Details of ethics approval
The review covers many laboratory and clinical studies, ethical approval having been granted for the latter.
DT-R was funded by the Medical Research Council for topics covered by the review.
DT-R acknowledges the Medical Research Council for financial support.