Arch Gynecol Obstet (2010) 281:589–600DOI 10.1007/s00404-009-1318-3 MATERNO-FETAL MEDICINEVaginal microbial flora and outco...
590                                                                                    Arch Gynecol Obstet (2010) 281:589–...
Arch Gynecol Obstet (2010) 281:589–600                                                                                    ...
592                                                                                    Arch Gynecol Obstet (2010) 281:589–...
Table 1 Intermediate vaginal flora and adverse pregnancy outcome: patients, method, results of individual studies      Stud...
594                                                                                    Arch Gynecol Obstet (2010) 281:589–...
Arch Gynecol Obstet (2010) 281:589–600                                                                                   5...
596                                                                                                     Arch Gynecol Obste...
Arch Gynecol Obstet (2010) 281:589–600                                                                                    ...
598                                                                                        Arch Gynecol Obstet (2010) 281:...
Arch Gynecol Obstet (2010) 281:589–600                                                                                    ...
600                                                                                                  Arch Gynecol Obstet (...
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Flora batterica vaginale ed esiti delle gravidanze

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Flora batterica vaginale ed esiti delle gravidanze

  1. 1. Arch Gynecol Obstet (2010) 281:589–600DOI 10.1007/s00404-009-1318-3 MATERNO-FETAL MEDICINEVaginal microbial flora and outcome of pregnancyLaura Donati • Augusto Di Vico • Marta Nucci • Lorena Quagliozzi •Terryann Spagnuolo • Antonietta Labianca • Marina Bracaglia •Francesca Ianniello • Alessandro Caruso • Giancarlo ParadisiReceived: 13 May 2009 / Accepted: 26 October 2009 / Published online: 5 December 2009Ó Springer-Verlag 2009Abstract Conclusions Vaginal ecosystem study with the detectionBackground The vaginal microflora of a healthy asymp- of pathogens is a key instrument in the prevention of pre-tomatic woman consists of a wide variety of anaerobic and term delivery, pPROM, chorioamnionitis, neonatal,aerobic bacterial genera and species dominated by the puerperal and maternal-fetal infections.facultative, microaerophilic, anaerobic genus Lactobacil-lus. The activity of Lactobacillus is essential to protect Keywords Vaginal flora Á Bacterial vaginosis Áwomen from genital infections and to maintain the natural Clinical diagnosis Á Pregnancyhealthy balance of the vaginal flora. Increasing evidenceassociates abnormalities in vaginal flora during pregnancywith preterm labor and delivery with potential neonatal Introductionsequelae due to prematurity and poor perinatal outcome.Although this phenomenon is relatively common, even in The vaginal microflora of healthy asymptomatic womenpopulations of women at low risk for adverse events, the consists of a wide variety of anaerobic and aerobic bacterialpathogenetic mechanism that leads to complications in genera and species dominated by the facultative, microaer-pregnancy is still poorly understood. ophilic, anaerobic genus Lactobacillus [1, 2]. LactobacilliObjective This review summarizes the current knowledge are the most well-known markers of normal vaginal flora.and uncertainties in defining alterations of vaginal flora in The activity of Lactobacillus is essential to protectnon-pregnant adult women and during pregnancy, and, in women from genital infections and to maintain the naturalparticular, investigates the issue of bacterial vaginosis and healthy balance of the vaginal flora. This role is particu-aerobic vaginitis. This could help specialists to identify larly important during pregnancy because vaginal infectionwomen amenable to treatment during pregnancy leading to has been claimed as one of the most important mechanismsthe possibility to reduce the preterm birth rate, preterm responsible for preterm birth and perinatal complications.premature rupture of membranes, chorioamnionitis, neo- In normal conditions, Lactobacillus spp. utilizing availablenatal, puerperal and maternal–fetal infectious diseases. glycogen produce lactic acid, which is able to acidify the vaginal pH to less than 4.5, inhibiting the growth of non- acid tolerant microorganisms, known as potentially path- ogenic. Moreover, Lactobacillus spp. also produce hydro-L. Donati Á A. Di Vico Á M. Nucci Á L. Quagliozzi Á gen peroxide, a potent antimicrobial molecule, toxic toT. Spagnuolo Á A. Labianca Á M. Bracaglia Á F. Ianniello Á other microorganisms [3]. There are many different strainsA. Caruso Á G. ParadisiDepartment of Obstetrics and Gynecology, Catholic University of lactobacilli present in the vagina, the most frequentof Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy being L. jensenii, L. gasseri, L. iners and L. crispatus, and there is a wide variation in species and relative numbers ofG. Paradisi (&) species according to the population studied. When ‘‘nor-Department of Obstetrics and Gynecology, Catholic Universityof Sacred Heart, Via Servilio IV 4, 00178 Rome, Italy mal’’, Bacterial flora is predominantly lactobacillary type.e-mail: giancarlo.paradisi@tin.it When ‘‘abnormal’’, the flora can be disturbed by anaerobic 123
  2. 2. 590 Arch Gynecol Obstet (2010) 281:589–600overgrowth [bacterial vaginosis (BV)] or by aerobic that of White women among subjects who were not diag-microorganisms such as Escherichia coli, group B strep- nosed as having BV [10]. Additional studies suggested thattococci, enterococci, etc. [aerobic vaginitis (AV)], or can this difference was only statistically significant amongbe a mixture of both (mixed abnormal flora). women who had abnormal, i.e., non-lactobacilli-domi- Therefore, it is clearly evident that where lactobacilli nated, vaginal microflora [11, 12].predominate, other bacteria and parasites such as Tricho- Regardless of the predominant bacterial species in themonas are not abundant. On the other hand, Lactobacillus- vagina of a healthy premenopausal woman, it appearsdeficient conditions are associated with the development of certain that lactic acid production is crucial to the main-numerous infectious conditions such as the previously tenance of a healthy vaginal ecosystem. The resultingmentioned BV and AV, and promote the transmission of acidic pH prevents the overgrowth of potentially patho-sexually transmitted diseases such as Gonorrhoea, Chla- genic microorganisms. Additional benefits for the hostmydia, Syphilis, Trichomoniasis, HIV and HPV. Normal of Lactobacillus predominance are the production ofand abnormal lactobacillary flora is divided into three or hydrogen peroxide and bacteriocins by strains of thesefour floral types also called as ‘‘Lactobacillary grades’’. microbes.Normal—grade I—flora corresponds to predominantly The composition of the vaginal ecosystem is not staticlactobacillary morphotypes, with very few coccoid bacteria but changes over time and in response to endogenous andpresent. The intermediate—grade II—flora corresponds to exogenous influences [13]. Variables include the stage ofa diminished lactobacillary flora, mixed with other bacte- the menstrual cycle, pregnancy, use of contraceptiveria. This group is subdivided into slightly disturbed, fairly agents, frequency of sexual intercourse, specific sexualnormal (IIa) and moderately disturbed, rather abnormal partners, vaginal douching, use of panty liners or vaginal(IIb) lactobacillary flora. Finally, the grossly abnormal— deodorants, and the utilization of antibiotics or othergrade III—flora consists of numerous other bacteria, with medications with immune or endocrine activities.no lactobacilli present. In order to diagnose such abnormal During the menstrual cycle, vaginal levels of hormoneslactobacillary grades, the use of the wet mount is preferred and glycogen vary and menstrual blood alters vaginal pHto the Gram stain due to its superior accuracy and better and provides a substrate for many microorganisms. Nev-correlation with vaginal lactate, accepted by most as the ertheless, levels of vaginal lactobacilli appear to remainbest functional test for lactobacillary defense function. constant throughout the cycle; non-Lactobacillus species increase during the proliferative phase, while Candida albicans concentrations are highest towards menstruationNormal vaginal flora (as determined by culture) [14].As previously stated, the dominant species of vaginal florais initially identified as Lactobacillus Acidophilus. Bacterial vaginosis In healthy women with a Lactobacillus-dominant vagi-nal microflora, the major phylotypes detected by gene Bacterial vaginosis, as previously mentioned, is charac-amplification are L. crispatus and L. iners [4–7] or L. terized by a change in vaginal microflora in which thecrispatus and L. gasseri [6]. Additional species, such as L. normally occurring lactobacilli yield to an overgrowth of ajensenii, L. gallinarum and L. vaginalis, have also been mixed anaerobic bacterial flora (Fig. 1). The most commonidentified in some women. Interestingly, apparently healthy symptom among women with BV is a thin, gray, non-vaginal ecosystems are maintained in some women in the pruritic discharge with a fishy odor, while the vagina is notabsence of a Lactobacillus-dominant vaginal microflora. red or inflamed and there is no prominent symptoms ofAtopobium, Megasphaera and Leptotrichia are all pro- burning, pain or dyspareunia. Thus, BV is usually aducers of lactic acid [4, 8] similar to the lactobacilli. polymicrobial infection, and organisms responsible forTherefore, the acidic environment of the vagina, recog- infection include: Gardnerella vaginalis, Mycoplasmanized as an important defense mechanism against the hominis, Bacteroides spp., Peptostreptococcus spp., Fuso-proliferation of different microbial pathogens, can be bacterium spp., Prevotella [15, 16].maintained by bacterial species other than the lactobacilli. A typical feature of BV is the absence of inflammation. In Possible racial/ethnic differences in the composition of BV, there is only a slight increase in interleukin I and anthe ‘‘normal’’ microflora have also not yet received ade- unexpectedly low production of interleukin 8, preventingquate research attention. The occurrence of hydrogen-per- the attraction of inflammatory cells such as macrophagesoxide-producing lactobacilli, active in antimicrobial and neutrophils. Hence, if severe inflammation is presentdefense, is lower in Black women [9]. It has also been (e.g., when more than ten leukocytes are present per epi-noted that the vaginal pH of Black women is higher than thelial cell), another diagnosis has to be considered. Indeed,123
  3. 3. Arch Gynecol Obstet (2010) 281:589–600 591 G. vaginalis on BV. However, since G. vaginalis was also detected in a minority of asymptomatic women, it is clear that its presence ‘‘per se’’ is not sufficient for the devel- opment of BV [25]. Mycoplasmas and ureaplasmas are eubacteria. They are the smallest self-replicating organisms, both in genome size and cellular dimensions. Mycoplasma and Ureaplasma species are included within the class Mollicutes. Three species in the genus Mycoplasma, M. hominis, M. genita- lium and M. fermentans, are known to occur in the female urogenital tract and have been associated with disease. However, ureaplasmas are unique among the Mollicutes in that they hydrolyze urea to generate metabolic energy. The cytadherence proteins of M. hominis and Ureaplasma spp.Fig. 1 Bacterial vaginosis are not organized into a demonstrable attachment organelle and they have not been completely characterized. Theconcomitant cervicitis, trichomoniasis, candidiasis and AV M. hominis variable adherence-associated (Vaa) antigen is aare all known to present with an increased immune response, size- and phase-variable adhesin which is highly immuno-with increased numbers of monocytes and leukocytes in the genic. The high variability of Vaa is presumably importantvast majority of cases. Recently, due to the heterogeneity of for the diversity and host adaptation of this mycoplasma.microorganisms involved in the pathogenesis and the clin- Similar to the Vaa of M. hominis, the multiple-banded (MB)ical findings, several efforts have been made to define antigen of Ureaplasma spp. is immunogenic, undergoes aunequivocally the presence of an abnormal vaginal flora and high rate of variation in vitro, may be involved in theto standardize the diagnosis and therapy. The Amsel criteria stimulation of the host inflammatory response, and is vari-and scoring of Gram-stained smears of vaginal fluid are the able in size on invasive isolates. Ureaplasmas attach to hostmost commonly used diagnostic principles for BV. The four erythrocytes, neutrophils, spermatozoa and urethral epi-Amsel criteria are usually regarded as the gold standard. thelial cells, and they can directly activate the first com-Criteria include: the presence of a thin, homogeneous dis- ponent of complement. Both M. hominis and Ureaplasmacharge, which adheres to the vaginal walls, vaginal pH spp. can induce inflammation in humans and this is a majorabove 4.5, release of fishy odor upon alkalinization with factor involved in the production and manifestation of10% potassium hydroxide and clue cells on a saline well clinical disease. Secretory products such as ammonia gen-mount. If three of these four criteria are met, the patient is erated from the metabolism of arginine by M. hominis anddiagnosed with BV [17]. However, these criteria are often urea by Ureaplasma spp. may produce a local cytotoxicmodified, as the typical homogenous discharge (the most effect. Urease production by ureaplasmas has been impli-subjective sign) is often not included. Among the organisms cated in urinary calculus production [26].responsible for infection, G. vaginalis and Mycoplasma arethe most important and the most common. In the 1950s, Leopold [18] and then Gardner and Dukes The ‘‘intermediate flora’’[19] observed abundant small, pleomorphic gram-variablerods in the genital tracts of women with BV. This organ- Ideally, the ‘‘ intermediate flora’’ state represents a turningism, first called Haemophilus vaginalis [20] and then point from a normal state into BV, or from BV to normalrepeatedly renamed, is now classified as G. vaginalis, the (Fig. 2). In reality, however, most of the women with so-sole member of the genus Gardnerella [21, 22]. Phyloge- called intermediated BV according to Nungent will neithernetic analysis based on 16S rRNA places Gardnerella in have BV nor a normal flora. It is becoming clear that thethe Gram-positive family Bifidobacteriales. An abundance intermediate group is linked to a different and usually moreof G. vaginalis and a paucity of Lactobacillus species are serious range of complications, including mid-trimestercharacteristic of a BV-associated microflora, but the rela- pregnancy loss, than the ‘‘classic’’ full-blown BV [27–29].tive contribution of G. vaginalis to the pathogenesis of BV The criteria for the diagnosis of intermediate vaginal flora isis not yet clear. Recently, in a series of clinical studies, Gram-based; there is also the definition of Spiegel et al. [30]Swidsinski et al. demonstrated that G. vaginalis has the in which the intermediate category is defined as the pres-unique characteristic to develop an adherent biofilm, spe- ence of reduced lactobacilli mixed with other morphotypescific for BV, that persists after metronidazole treatment [27] or it is defined as the presence of intermediate[23, 24]. These findings added new insight into the role of microbial flora, predominantly M. hominis, Ureaplasma 123
  4. 4. 592 Arch Gynecol Obstet (2010) 281:589–600 – Presence of parabasal epithelial cells. – The type of background flora. Parabasal cells were added because they were con- sidered to be a sign of inflammation usually not seen in uncomplicated BV, but rather in severe forms of AV, such as in desquamative inflammatory vaginitis [33]. Background flora was allocated score 0 if the back- ground flora was unremarkable or showed debris and bare nuclei from lysed epithelial cells (cytolysis) [34], score 1 if the lactobacillary morphotypes were very coarse or resembled small bacilli (other than lactobacilli), and 2 if there were prominent cocci, or chained cocci visible. A composite score of 1–2 represents normality.Fig. 2 Intermediate vaginosis A score of 3–4 corresponds to slight AV, a score of 5–6 to moderate vaginitis, and a score above 6 (to maximumurealyticum, G. vaginalis, Gram-negative anaerobic rods, 10) to severe AV. In practice, a score of 8–10 is usuallyChlamydia trachomatis and few Lactobacillus spp. [31]. identical to so-called ‘‘desquamative vaginitis’’, so that Leitich H. and Kiss H., in their meta-analysis, evaluated such a diagnosis can be seen as the most extreme formBV and intermediate vaginal flora as risk factors for of AV [33, 35].adverse pregnancy outcome (Table 1). Fourteen new The question remains if AV is an entity that really dif-studies with results for 10,286 patients are included, so the fers from BV. The pro-inflammatory cytokines produced inresults for 30,518 patients in 32 studies are available for the host’s vagina should also differ between the two enti-this meta-analysis. Intermediate vaginal flora is not sig- ties, as full-blown BV is typically devoid of any host leu-nificantly associated with any outcome included. kocytosis response, while AV is a real vaginitis. Indeed, major differences in response were seen between AV and BV. Interleukin-1-b increases in both conditions, but sig-Aerobic vaginitis nificantly more so in AV (eightfold): vaginal IL-1-b con- centrations increase as lactobacilli decrease [36]. IL-1-bIn recent years, Donders et al. [32] concentrated their tends to increase even more dramatically when theattention on women with abnormal vaginal flora with or inflammatory response of the host increases. In a study bywithout concomitant BV and described a clinical and Mattsby-Baltzer et al. [37] in women during their firstmicroscopic pattern that fits a new condition defined as trimester of pregnancy, BV was associated with IL-1-b, but‘‘AV’’, raising the possibility that there may be a degree of not with IL-6. Similarly, in another study of women inoverlap between these two entities, indicating that AV and labor, IL-1b was associated with BV, but IL-6 was not [38].BV can coexist. IL-6 remained unchanged in women with BV, when We are convinced that AV should be seen as a separate compared to women with normal flora. In women with AV,disease entity. on the other hand, IL-6 is increased fivefold. IL-6 is a well- Clinical features associated with them and the host known marker for bacterial amnionitis and imminent termresponse to AV are so specific for the conditions and differ and preterm delivery [38, 39]. IL-6 and IL-8 are knownclearly from BV. Further studies to differentiate the effects chemo-attractants and are directly linked to increasedof BV and AV on the outcome of pregnancy are therefore prostaglandin production and delivery [38]. Finally, theurgently needed, as they may hold part of the answer to the production of LIF, a relatively unknown cytokine, isquestion why some studies have found no association threefold lower in women with BV, but threefold higher inbetween BV or its treatment and pregnancy outcome, while women with AV. Even though these differences are notothers have found that restoring the flora to normal pre- quite statistically significant, vaginal LIF concentrationvented preterm birth. may be seen as a marker for AV. Diagnosis of AV is based on microscopy (Fig. 3). There is an evident correlation between AV and group BLactobacillary grades (see above) are the basis for a streptococci, S. aureus and E. coli. The more severe thecomposite score to which any of the four following vari- microscopic findings, the more likely these organisms willables is added: be cultured. Case studies have recently drawn attention to– Proportional number of leukocytes. the possibility of vaginitis due to group B streptococci [40],– Presence of toxic leukocytes. and Monif provides in vitro evidence that group B123
  5. 5. Table 1 Intermediate vaginal flora and adverse pregnancy outcome: patients, method, results of individual studies Study Patient inclusion Diagnosis of Mean gestational Outcome Patients with Patients with OR (95%CI) criteria intermediate age at BV screening intermediate normal vaginal vaginal flora (weeks) vaginal flora flora Donders et al. [66] Singleton pregnancy at Clinical criteria 9.1 Delivery 37 weeks 5/10 20/180 8.00 (2.13–30.06) 14 weeks (B Amsel criteria) and Late miscarriage 20 weeks 1/11 12/192 1.50 (0.18–12.71) abnormal vaginal Arch Gynecol Obstet (2010) 281:589–600 bacterial flora Edwards et al. [67] Singleton pregnancy at Gram stain (Nungent 28.3 Delivery 37 weeks 5/19 20/86 1.18 (0.38–3.67) 23–32 weeks and score 4–6) preterm labor Goffinet et al. [68] Pregnancy at Gram stain (Nungent 29.0 Delivery 35 weeks 21/76 50/254 1.56 (0.86–2.81) 24–34 weeks and score 4–6) Delivery 33 weeks 14/76 27/254 1.90 (0.94–3.84) preterm labor Chorioamnionitis 3/76 4/254 2.57 (0.56–11.74) Neonatal infection 6/76 13/254 1.59 (0.58–4.33) Guerra et al. [69] Singleton pregnancy at Gram stain (Nungent 8.5 Delivery 37 weeks 24/48 17/90 6.01 (2.76–13.11) 10 weeks score 4–6) Late miscarriage B25 weeks 4/52 5/95 1.50 (0.38–5.85) 25.0 Delivery 37 weeks 17/23 43/145 6.72 (2.48–18.21) Hay et al. [27] Singleton pregnancy at Gram stain (Spiegel 12.5 Delivery 37 weeks 0/19 9/380 0.0 (n.c.) 9–24 weeks definition with Late miscarriage 1/20 4/384 5.00 (0.53–46.93) addition of an At 16–24 weeks intermediate category) 16.5 Delivery 37 weeks 1/32 17/584 1.08 (0.14–8.35) Kalinka et al. [31] Singleton pregnancy at Gram stain (Spiegel 12.3 Delivery 37 weeks 8/71 6/70 1.35 (0.44–4.13) 8–16 weeks definition with addition of an intermediate category) Oakeshott et al. [70] Singleton pregnancy at Gram stain (Nungent 7.0 Delivery 37 weeks 1/39 46/746 0.40 (0.05–2.98) 10 weeks score 4–6) Late miscarriage 2/41 8/754 4.78 (0.98–23.28) At 13–23 weeks Modified from Leitich H. and Kiss H. (2007) 593123
  6. 6. 594 Arch Gynecol Obstet (2010) 281:589–600 Neisseria gonorrhoeae, C. trachomatis and Trichomonas vaginalis. Haemophilus influenzae only occasionally acts like a pathogen, being associated with preterm labor. Group B hemolytic Streptococcus can have devastating effects on the preterm or low birth weight infant. Bacterial vaginosis is a polymicrobial condition increasingly associated with adverse perinatal sequelae. No single organism causes BV; however, there appears to be an independent association between BV and G. vaginalis, Mobiluncus spp., anaerobic Gram-negative rods, and M. hominis. The exact role and significance that M. hominis and Ureaplasma spp. play in BV remain uncertain [25]. The reason why BV causes preterm birth or labor in someFig. 3 Aerobic vaginosis women, and remains practically paucisymptomatic and without any complications for pregnancy in others, is stillstreptococci inhibit the growth of lactobacilli and G. vag- poorly understood.inalis, but not S. aureus [41, 42]. Risk in pregnancyVaginal flora and pregnancy Vaginal infection represents one of the most important riskDuring physiological pregnancy, the higher levels of factors for complications of pregnancy such as prematureestrogens induce not only a better epithelial tropism but rupture of membrane, preterm labor and birth and perinatalalso a positive effect on lactobacillary activity and prolif- infection. In the following paragraph, we have tried toeration due to an increased glycogen availability. summarize recently obtained information in this field. As pregnancy advances, the genital tract flora becomesprogressively more benign, until term. It is particularly Preterm delivery and late miscarriagedifficult to define abnormal genital tract flora in pregnancy. Usui et al. [43] prospectively examined the vaginal flora Bacterial vaginosis occurs in up to 20% of pregnant womenin a sample of 1,958 pregnant women during the first and and has been associated with premature birth and sponta-second trimesters and analyzed the relative percentage of neous abortion [44]. This condition is characterized by aeach bacterial species found. Aerobic Gram-negative rods watery discharge with a fishy odor, but half of the womenand cocci, anaerobic Gram-negative rods, and lactobacilli with this infection may be asymptomatic or experiencewere analyzed using standard laboratory methods. In only mild symptoms [45]. The natural history of BV isaddition, the percentage of women with preterm birth was such that it may spontaneously resolve without treatmentanalyzed: 6% of women delivered before the 33rd week although most women identified as having BV in early(n = 118) and 11% before the 37th week (n = 224). In pregnancy are likely to not have persistent infection later inthese cohort of patients, Lactobacilli were significantly pregnancy [46]. Increasing evidences associates BV indecreased, whereas the presence of other bacteria was pregnancy with poor perinatal outcome, in particular angreater in patients with the absence of Lactobacilli. The increased risk of preterm birth with potential neonatalMycoplasmas were not influenced by the presence of sequelae due to prematurity.Lactobacilli flora. The mechanism by which BV may lead to preterm These results indicate that the element that exposes the labor/preterm birth has not yet been well defined. A pos-risk of preterm birth seems to be the absence of Lactoba- sible explanation involves alterations in the host defensecilli, rather than the presence of other microorganisms and mechanism that leads to ascending intrauterine infection.suggests that a test for determining the presence of vaginal Since individuals differ in their innate ability to mount anlactobacilli may be a clinically useful tool for identifying inflammatory response to bacterial products, it has beenwomen at risk for preterm delivery at 33 weeks of proposed that women who are immunologically hypore-gestation. sponsive may not be able to control a large bacterial attack The numerous types of organisms which can be found in and may be predisposed to ascending infection with vari-association with preterm labor and delivery can be classi- able fetal consequences [47]. On the other hand, womenfied into four main groups. There are three main pathogens: who respond to a bacterial stimulus with exaggerated123
  7. 7. Arch Gynecol Obstet (2010) 281:589–600 595cytokine production at the maternal–fetal interface may be Bacterial morphotypes and pregnancy complicationsat greater risk of preterm labor if microorganisms gainaccess to the choriodecidual space. Hillier et al. [48] Table 3 presents the data regarding the specific bacterialreported that BV was significantly associated with the morphotypes present by trimester. Consistent withisolation of microorganisms from the chorioamnion, but Waters’s findings of Nugent score by trimester, there waswas unable to determine the effects of individual bacterial an observed trend toward a Gram stain without anyspecies, or to address the question of whether BV is abnormalities as pregnancy progressed [54]. Some micro-associated with premature delivery independently of organisms, due to their higher incidence in the population,chorioamnion infection. deserve clarification: while a number of genital microor- BV more than doubled the risk of preterm delivery in ganisms such as E. coli, Listeria monocytogenes and viri-asymptomatic patients (OR 2.31, 95% CI: 1.56–3.00) and dans streptococci may be involved in chorioamnionitis,in patients with symptoms of preterm labor (OR 2.38, 95% harboring of these organisms during early- to mid-preg-CI 1.02–5.58). BV also significantly increased the risk of nancy has not been associated with an increased risk oflate miscarriages (OR 6.32, 95% CI 3.65–10.94) and preterm labor [55, 56].maternal infection (OR 2.53, 95% CI 1.26–5.08) in Mycoplasma hominis and Ureaplasma species haveasymptomatic patients (Table 2). been associated with a variety of conditions that may affect These results confirm that BV is a risk factor for preterm the gravida, the developing fetus, and the neonate. For thedelivery and maternal infectious morbidity and a strong gravida and fetus, these organisms may contribute to pre-risk factor for late miscarriage [49]. mature labor, chorioamnionitis, postpartum endometritis, Nearly one quarter of pregnant white women in a growth restriction, spontaneous abortion and stillbirth;National Health and Nutrition Examination Survey while the exposed neonate may develop pneumonia, bac-(NHANES) probability vaginal sample had Gram stains teremia, meningitis, abscesses and chronic lung disease.consistent with BV [50]. BV in pregnancy may be more Intrauterine infections may trigger premature labor andcommon among minority women, those of low socioeco- lead to preterm birth. The mechanisms by which intra-nomic status, and those who have previously delivered low uterine infections lead to preterm labor are related, asbirth weight infants. The National Institute of Child Health mentioned before, to the activation of the innate immuneand Human Development Maternal–Fetal Medicine Units system. Microorganisms are recognized by pattern-recog-Network study found that nearly 50% of pregnant African- nition receptors (e.g., Toll-like receptors), which in turnAmerican women had BV, similar to the rate found in non- elicit the release of inflammatory chemokines and cyto-pregnant African-American women in NHANES [51]. BV kines. These cytokines, elaborated at the maternal–fetalis relatively common, even in populations of women at low interface, trigger prostaglandin production in the amnion,risk of adverse events, and as it is amenable to appropriate chorion, decidua and myometrium, leading to uterinetherapy [52, 53], identification during pregnancy and contractions, cervical dilatation, membrane rupture andtreatment may theoretically represent a rare opportunity to uterine contractions which further facilitate bacterial entryreduce the preterm birth rate, resulting risk of prematurity into the uterine cavity. Intra-amniotic infection contributesto the newborn. Such treatment may also reduce other to 40% of peripartum febrile illness and is associated withadverse perinatal outcomes such as postpartum infection. at least one-third of early-onset neonatal sepsis. The inci- Moreover, BV is diagnosed mostly in the first trimester dence increases with decreasing gestational age at deliveryand the prevalence decreases in the second and third. [57]. The prevalence of positive cultures and bacterialInterestingly, only 9.4% of gravid patients have a positive DNA in choriodecidual tissues can be greater than indiagnosis for BV, according to the Nugent criteria, in all amniotic fluid, lending further support to the idea thatthree trimesters, regardless of the treatment [32]. These microorganisms ascend from the vagina through the chor-findings suggest that some BV are self-limited and com- ioamniotic space to gain access to the amniotic cavity and,plication-free. However, it is also known that 20% do not subsequently, the fetus. There is also evidence that bacte-progress to a normal Nugent score by the third trimester ria, including ureaplasmas, may colonize the endometrialand approximately 15% were persistently BV intermediate cavity prior to implantation [58]. Ureaplasma spp. are the(Nugent 4–6). microorganisms most frequently isolated from amniotic Interestingly, in the setting of BV during pregnancy, the fluid or placentae in women who deliver prematurely,incidence of different bacterial morphotypes varies either with preterm premature rupture of membranes or inbetween the three trimesters (Table 2), demonstrating a preterm labor with intact membranes [59]. These organ-dynamic phenomenon and/or different types of imbalance isms have been isolated in the amniotic fluid as early as thein vaginal bacterial flora during different phases of 16th week and can result in a clinically silent chronic andgestation. progressive infection where delivery does not occur for 123
  8. 8. 596 Arch Gynecol Obstet (2010) 281:589–600Table 2 Bacterial vaginosis and adverse pregnancy outcome: patients, methods and results of individual studiesStudy Patient inclusion Diagnosis of BV Mean Outcome Patients Patients OR (95%CI) Criteria gestational with BV without age at BV BV screening (weeks)Andrews et al. [71] Singleton pregnancy at Gram stain 23.7 Delivery 37 weeks 15/99 23/217 1.51 (0.75–3.03) (RCT) 21–25 weeks and (Nungent positive fetal score C7) fibronectin testDaskalakis et al. [72] Singleton pregnancy at Gram stain 23.5 Delivery 37 weeks 16/95 88/1102 2.33 (1.31–4.17) 22–25 weeks and no (Nungent previous preterm score C7) and delivery vaginal pH [4.5De Seta et al. [73] Singleton pregnancy at Gram stain 15.5 Delivery 37 weeks 14/95 35/503 2.31 (1.19–4.49) 13–18 weeks (Nungent score C7)Edwards et al. [67] Singleton pregnancy at Gram stain 28.3 Delivery 37 weeks 9/23 25/105 2.06 (0.80–5.32) 23–32 weeks and (Nungent preterm labor score C7)Genc et al. [74] Singleton pregnancy at Gram stain 20.0 Delivery 37 weeks 4/30 19/177 1.28 (0.40–4.06) 18–22 weeks and no (Nungent previous preterm score C7) delivery 24 weeksGoffinet et al. [68] Pregnancy at Gram stain 29.0 Delivery 35 weeks 6/24 71/330 1.22 (0.47–3.18) 24–34 weeks and (Nungent Delivery 33 weeks 6/24 41/330 2.35 (0.88–6.26) preterm labor score C 7) Chorioamnionitis 1/24 7/330 2.01 (0.24–17.01) Neonatal infection 2/24 19/330 1.49 (0.33–6.80)Goyal et al. [75] Pregnancy at Gram stain 30.2 Delivery 37 weeks 18/19 30/41 6.60 (0.79–55.48) 23–36 weeks and (Nungent preterm labor score C7)Guerra et al. [69] Singleton pregnancy at Gram stain 8.5 Delivery 37 weeks 33/72 45/138 1.75 (0.97–3.14) 10 weeks and C1 (Nungent 25.0 Late miscarriage 23/95 9/147 4.90 (2.15–11.14) previous preterm score C7) B25 weeks delivery Delivery 37 weeks 12/36 60/168 0.90 (0.42–1.93)Kalinka et al. [31] Singleton pregnancy at Gram stain 12.3 Delivery 37 weeks 9/55 14/141 1.77 (0.72–4.38) 8–16 weeks (Nungent score C7)Kalinka et al. [76] Singleton pregnancy at Gram stain 29.0 Delivery 37 weeks 5/31 10/83 1.40 (0.44–4.49) 22–34 weeks (Nungent score C7)Kiss et al. [77] (RCT) Singleton pregnancy at Gram stain 17.0 Delivery 37 weeks 10/179 116/1918 0.92 (0.47–1.79) 15–19 weeks (Nungent score C7)Oakeshott et al. [70] Singleton pregnancy at Gram stain 7.0 Delivery 37 weeks 7/112 47/785 1.05 (0.46–2.38) 10 weeks (Nungent Late miscarriage at 5/117 10/795 3.50 (1.18–10.44) score C7) 13–23 weeksPurwar et al. [78] Singleton pregnancy at Gram stain 25.5 Delivery 37 weeks 32/115 40/823 7.55 (4.50–12.66) 12–28 weeks (Nungent score C7)Thorsen et al. [79] Pregnancy at Gram stain 17.0 Delivery 37 weeks 13/401 99/2526 0.82 (0.46–1.48) 24 weeks (Nungent Delivery 34 weeks 7/401 39/2526 1.13 (0.50–2.55) score C7) Delivery 32 weeks 2/401 22/2526 0.57 (0.13–2.44)Modified from Leitich H. and Kiss H. (2007)several weeks [60]. In a recent study of 254 asymptomatic correlated with subsequent preterm labor and pretermwomen, the detection of the Ureaplasma species by PCR delivery [59]. It is correct to emphasize that physiologicalassay in second trimester amniotic fluid was highly colonization of the vagina with lactobacilli appears to play123
  9. 9. Arch Gynecol Obstet (2010) 281:589–600 597Table 3 Bacterial morphotypes by trimesterGram stain I trimester II trimester III trimester (n = 148), % (n = 148), % (n = 148), %None 26.4 48.7 50.1Lactobacillus deficient 5.4 10.1 8.1Gardnerella 5.4 0 0Bacteroides 0 0 0.7Gardnerella and Bacteroides 10.8 12.8 14.2Gardnerella and Lactobacillus deficient 1.4 0 0.7Bacteroides and Lactobacillus deficient 0.7 0 0Gardnerella, Bacteroides and Lactobacillus deficient 31.8 16.9 17.6Gardnerella, Bacteroides, Lactobacillus deficient and Mobiluncus 18.2 11.5 6.8Modified from Waters et al. (2008)an important role in preventing infection in genital sites. have found that restoring the flora to normal preventedThe inhibitory effects of lactobacilli against a variety of preterm birth.microorganisms have long been recognized. Lactobacilliare more likely to be absent from the vagina in women with Therapeutic options in pregnancyBV than in women without BV. Therefore, no vaginitissigns are present in BV. Typically, full-blown uncompli- The question of why some vaginal infection in general, andcated BV presents the absence of leukocytes on micros- BV in particular, is associated with preterm birth in somecopy, the vagina is not red or inflamed and there are no women but not in others remains still partially unansweredprominent symptoms of burning, pain or dyspareunia. By and this unavoidably leads to scarce consensus on treat-contrast, in AV, vaginal leukocytes are usually abundant ment during pregnancy. Given the large amount of evi-and their numbers as well as their appearance are part of dence that links subclinical maternal infection with pretermthe definition of the disease entity. labor, it has been postulated that the prophylactic use of Moreover, the microscopic diagnosis of AV is associ- antibiotics in pregnancy or adjunctive use of antibiotics forated with a yellow discharge in more than 70% of the preterm labor should result in an improved perinatal out-women and with vaginal dyspareunia in 12%. come. The results of published studies addressing the issue The clinical signs of vaginitis, with red inflammation of of antibiotic intervention to prolong gestation vary. In athe vagina, yellowish discharge and dyspareunia are con- recent review of 15 trials [61], the authors concluded that,sistent with the microscopy findings of decreased lactoba- despite eradication of BV in pregnancy, antibiotic treat-cilli, increased vaginal leukocytosis with toxic appearance, ment did not reduce the risk of preterm delivery. There wasparabasal type epithelial cells and increased pH. Further- no prolongation of pregnancy even in women with amore, the vaginal concentration of succinate, which is history of prior preterm birth. On the other hand, a meta-mainly produced by anaerobes, was increased in patients analysis of randomized clinical trials showed that macro-with BV, but not in those with AV. lides and clindamycin given during the second trimester However, further studies to differentiate the effects of were associated with a lower rate of preterm delivery,BV and AV on the outcome of pregnancy are urgently whereas metronidazole used alone was linked to a greaterneeded. It should also be determined whether BV can risk of preterm delivery in a high-risk population [62].evolve into AV especially in the third trimester and if Another meta-analysis confirmed that infection screeningthis transition can provide insights into the comprehen- and treatment programs in pregnant women may reducesion of complications associated with the last phase of preterm birth and preterm low birth weights [63].pregnancy. Conflicting results in the literature may be attributed to The pathogenesis of AV and its production of immense variations in study design. Among potential confoundersamounts of vaginal pro-inflammatory cytokines, in fact, are the inclusion of women with preterm contractionsmake it an ideal candidate for causing or promoting pre- without infection, administration of antibiotics at varyingterm labor, chorioamnionitis and preterm rupture of the stages of intra-uterine infection and at different dosages, ormembranes and could, moreover, help to answer, at least in trials that do not target the appropriate pathogens. Forpart, the question why some studies have found no asso- instance, metronidazole is inactive against many organismsciation between BV and pregnancy outcome, while others associated with BV and preterm labor, such as M. hominis. 123
  10. 10. 598 Arch Gynecol Obstet (2010) 281:589–600Another possible explanation could be that antibiotics may Some recent evidence associates severe forms of BV innot effectively treat chorioamnionitis or reverse the pro- pregnancy with poor perinatal outcome, increased risk ofinflammatory mediators that play a key role in the initiation preterm birth with potential neonatal sequelae due toof labor. Finally, we have to underline that many clinicians prematurity.do not distinguish between BV and AV. Given that these Vaginal ecosystem study with the detection of patho-two conditions are responsive to different antibiotic treat- gens is a key instrument in the prevention of pretermment (i.e., metronidazole does not have effects on AV, delivery, pPROM, chorioamnionitis, neonatal, puerperalwhile clindamycin does), it is difficult to compare their and maternal–fetal infections. The physiological status ofclinical effect to reduce preterm delivery if there is not a the vaginal ecosystem in pregnancy is greatly conditionedclear characterization of vaginal infection. by Lactobacilli and cell-mediated mechanisms immune of The ORACLE study [64], which evaluated the use of pregnancy.broad spectrum, antepartum antibiotics for premature rup- Further decisive clinical trials are necessary to defineture of fetal membranes, showed some benefits for the baby unanimously the need for correct diagnosis of vaginalif mothers received erythromycin. Infants of mothers infection, medical treatment during pregnancy and thetreated with erythromycin had less need for oxygen during potential therapeutic protocols.the hospital stay and a trend toward a reduction in thecomposite primary outcome of neonatal death, chronic lung Acknowledgment The authors would like to thank Tracie Dor- nbusch for revising the manuscript.disease, or major cerebral abnormality before discharge.The results from this trial suggest that early antimicrobial Conflict of interest statement None.treatment could play a role in interrupting the inflammatorycascade to improve respiratory and other outcomes. The hormonal changes of pregnancy which favor anincrease in the concentration of lactobacilli might also favor Referencesthe elimination of the BV. Secondly, BV is more commonin sexually active than non-sexually active women. A 1. 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