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Recent advances in neonatal care have resulted in increased survival of preterm infants, including those born at the very margins of viability, albeit without a reduction in the incidence of cerebral palsy. On the other hand, modern obstetric services have not reduced the incidence of preterm delivery in the last 50 years. Bacterial vaginosis (BV) is a state of abnormal vaginal ecology in which the normal and protective lactobacilli-dominated flora is transformed by an overgrowth of vaginal anerobes and varying degrees of depletion of the lactobacilli population. The stimuli that initiate this transformation are unknown. Bacterial vaginosis is associated with subclinical intrauterine infection1,2 and confers a 2–7-fold increase in the risk of preterm delivery and mid-trimester pregnancy wastage3–5. Previously, the causes of a third of all preterm births were unknown and classified as idiopathic. Today, subclinical intrauterine infection is recognized to play a key role in the pathogenesis of labor and delivery in 30–40% of preterm births6. Decidual activation and fetal host response results in the release of pro-inflammatory cytokines, including IL-1, IL-6 and TNF-β7–10. These cytokines do not only drive the process of preterm labor but are now recognized as playing a crucial role in the pathogenesis of the long-term neurological and pulmonary morbidity previously attributed to biological immaturity11–18.

The most widely accepted route of intrauterine infection in pregnancy is the ascent of lower genital tract organisms, although pre-existing endometrial colonization and/or inflammation is probably more plausible. The BV-related micro-organisms involved are usually atypical Mycoplasmas (M. hominis and Ureaplasma urealyticum). They are non-pyrogenic, very rarely evoke systemic symptoms and as such evade routine microbiological and clinical detection.

The traditional use of demographic data to predict spontaneous preterm delivery has been unsuccessful because of its low sensitivity and specificity. Preterm labor/delivery is a syndrome produced by a wide variety of disease conditions operating through different pathways and mechanisms. Modern obstetrics, having failed in its search for reliable predictors of preterm delivery, falls back on a reactive strategy to arrest a process that is driven by an irreversible cascade mechanism. Consequently, none of the currently available interventions such as tocolysis, antibiotic therapy, bed rest and cervical cerclage have been proven beyond reasonable doubt to halt the process of preterm labor, prevent preterm delivery and reduce neonatal morbidity and mortality. In the long term, the causes of preterm labor will inevitably produce changes in the cervix as a final common pathway. One manifestation of such a change is cervical effacement, which may be detectable sonographically as cervical shortening. The competent cervix provides a mechanical resistance against preterm delivery. However, the cervix itself may become a target for cellular and biochemical modulation during pregnancy. The mucous plug provides a layer of mechanical and immunological protection against the ascent of lower vaginal organisms. The crucial question is whether these protective functions of the cervix correlate with its length; whether a shorter cervix is necessarily weaker in strength, altered in constitution and deficient in the quantity and/or quality of the mucous plug? A short cervical length < 25 mm (10th centile) clearly identifies a group of women at high risk of preterm delivery19, but how might BV affect cervical length and morphology in pregnancy?

Organisms associated with bacterial vaginosis may possess lipopolysaccharides (endotoxin), produce Phospholipases A2 and C all of which may induce prostaglandin synthesis20,21. Prostaglandins can induce myometrial contractility22 and extra-cellular matrix changes in the cervix associated with cervical ripening23. Other virulence factors such as collagenases, mucinases and sialidases produced by BV organisms5 may exert potentially lytic effects on the ground substance on the cervix. Therefore, it is plausible that these bioactive agents may act synergistically on the cervix to produce changes that lead to effacement and dilatation. Although BV is associated with preterm delivery, it is unknown whether this association is causal, and at present, there is no direct in-vivo evidence that BV shortens the cervix. In this issue of the journal Surbeck et al.24 makes this important connection and links BV with changes in cervical length and morphology in women admitted into hospital with preterm labor. Their findings are of great clinical interest and merit closer observation. What readers may find intriguing is the lack of correlation between the short cervix demonstrated in the BV-positive group and the occurrence of preterm delivery. The reasons for this paradox may well lie in the design and execution of the study.

Surbeck et al.24 defined preterm labor as ≥ 3 painful contractions in 20 min with or without cervical effacement and dilatation but did not state whether cervical assessment was performed digitally or sonographically and over two time points, since a snapshot will not define the process of effacement, dilatation or indeed labor. Where digital examination was performed, was a lubricant used? Gels and antiseptic solutions may influence the accuracy of the diagnosis of BV by Gram stain. The same question applies to the speculum examination used to obtain swabs for microbiological studies. More important, however, is the lack of report of the cultures. Did the BV-positive women have an excess of other coexisting lower genital tract infections such as chlamydia, gonorrhoea and trichomonas which may confound the contribution of BV in the process of preterm labor? Boomgaard et al. found no association between the presence of BV, vaginitis or cervicitis and cervical length in pregnancy25. In that study, an elevated pH was strongly associated with a short cervix25. An elevated pH is, however, not specific for BV and could reflect vaginitis secondary to other infections, and indeed may persist for up to 48 h after sexual intercourse or contamination with blood. If BV acts on the cervix through a raised pH, so can other causes of high vaginal pH.

Several published studies have demonstrated an inverse correlation between cervical length and the risk of preterm birth19,26,27. It seems paradoxical that BV could exert such a significant reduction in mean cervical length as demonstrated by Surbeck and colleagues24 but fail to produce preterm delivery in the same women, more so when the overall preterm delivery rate in the study is 40%. The sub population of BV-positive women who have consistently benefited from antibiotic intervention is the group with a previous history of preterm delivery28–30. These women are truly at risk of preterm delivery and failure to define them in this study may have contributed to the lack of correlation between the short cervix observed in the BV-positive group and the occurrence of preterm birth.

Between 16 and 36 weeks of gestation, a stepwise and progressive spontaneous resolution of BV occurs in up to 50% of cases31. This spontaneous resolution is, however, not associated with a reduction in the risk of preterm delivery32. It is probable therefore that a proportion of women identified as BV-negative during enrolment at 24 weeks in this study may have been BV-positive earlier in pregnancy but in whom BV has undergone spontaneous resolution. Their inclusion in the BV-negative group may have introduced bias into the study.

The observation that a short cervix correlates with the risk of preterm delivery is useful, but in the course of one ultrasound scan examination, the cervix can actively undergo dramatic changes in length and shape, even in the absence of clinically apparent contractions33. It may not be sufficient therefore to obtain a single snap shot image of the cervix in patients undergoing examination for research purposes and in those at high risk of preterm delivery. Morphological parameters of the cervix including cervical length ≤ 25 mm, percentage funnelling ≥ 40% and funnel width > 12–14 mm have all been correlated with increased risk of preterm birth34,35. The choice of 5 mm as the cut off point rather than 12 mm or 14 mm for funnel width may have limited the ability of this study to detect an increased risk of preterm delivery based on this parameter.

In conclusion, the prevention of preterm birth and its complications is a primary obstetric goal worldwide. We need better understanding of the factors that alter uterine quiescence during pregnancy and of the mechanisms of cervical ripening, effacement and dilatation in the preterm period. This will open the way for more selective and effective therapeutic interventions. Bacterial vaginosis may not be the cause of preterm delivery but a downstream marker of some other underlying pathology. This may partly explain why the vast majority of BV-positive women do not deliver prematurely and randomized comparisons of antibiotic eradication of BV in normal risk pregnant women have not shown any benefit29,36. If BV caused preterm delivery, the jury is still out on whether it exerts this effect by altering the cervical morphology in pregnancy.

References

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