Reducing infection-related preterm birth
Reducing infection-related preterm birth GGG Dondersa,b,c a Femicare Clinical Research for Women, Tienen bDepartment of Ob/Gyn, University Hospital Antwerp, Antwerp c Department of Ob/Gyn H Hart Hospital Tienen, Belgium Linked article This is a mini commentary on SS Witkin et al., pp. 213–8 in this issue. To view this article visit http:// dx.doi.org/10.1111/1471-0528.13115. A myriad of research papers have indicated that abnormal vaginal flora is a risk factor for preterm delivery. The most favored hypothesis for the mechanism is through ascending infection from the vagina, causing deciduitis and chorioamnionitis, inducing the cytokine and prostaglandin cascade and hence cervical weakening and contractions. In his contribution, Steve Witkin points to the matrix metalloproteinase (MMP)-8 and its inducer extracellular MMP inducer (EMMPRIN) as a key trigger to weaken the cervix and allow ascending commensal or potential pathogenic microorganisms, most often associated with bacterial vaginosis (BV), to cause intra-amniotic infection to occur. In conjunction with the L-lactate producing vaginal epithelium, the presence of Lactobacillus crispatus, Lactobacillus jenseni, and Lactobacillus gasseri, but not the BV-associated Lactobacillus iners, contributes to the protection of the vagina against this EMMPRIN activity by producing D-lactate, which decreases its release by the epithelium. This point is well taken and his suggestion to replace antibiotic therapy by lactic acid gel application to the vagina in women living in areas with poor resources and women with signs of disturbed flora could work. However, a few details may matter. That the production of vaginal lactic acid is closely correlated with the proportional level of other bacteria replacing the lactobilli (lactobacillary grades) has been known for decades, as well as the association of the latter with vaginal pro-inflammatory cyto-
kine production, which fluctuates along the course of pregnancy. The results of Hoyme’s original observational study of self-measuring vaginal pH, followed by treatment without proper diagnostic workout may have suggested a benefit in reducing preterm births, but this was not confirmed in a subsequent population-based controlled trial following 149 048 pregnant women in the same region (Bitzer et al. Dtsch Arztebl Int 2011;108:81–6). Analysing self-measurements of vaginal pH, although well accepted in poor resource countries such as Uganda, did not reflect the presence of BV in these women, as only 34% of women with increased pH had BV, the others having aerobic vaginitis (AV), endogeneous lack of lactobacilli or other conditions influencing pH (G.G.G Donders, F. Donders, G. Bellen, C. Depuydt, N. Eggermont, T. Michiels, J. Lule, J. Byamughisa, data on file). In this study the transitional state between normal flora and BV, called partial BV, had the same increased vaginal pH as full blown BV, whereas the so-called intermediate flora, representing a Nugent score 4–6 on gram-stained specimens, was found equally frequently in all pH groups. As this ‘intermediate flora’ according to Nugent represents not only partial BV, but also AV and other abnormalities, it is not surprising that it should also be considered a risk factor for preterm labour, as AV as well as partial BV may pose a greater risk for the pregnancy than full blown BV (Donders et al. BJOG 2009;116:1315– 24). Hence it does not come as a surprise that meta-analyses have failed to show that metronidazole prevents pre-
ª 2014 Royal College of Obstetricians and Gynaecologists
term birth, as mentioned in the paper. Besides L. iners and Gardnerella vaginalis being general surrogate markers markers of BV, Mobiluncus and Atopobium vaginae are even stronger indicators of full-blown BV (Nugent score above 8), and are, remarkably, not responsive to metronidazole. Although they are notorious lactic acid producers, both organisms are independently linked to an increased preterm birth risk (Foxman et al. AJOG 2014;210:226–7). As reasoned by Dr Witkin, treatment with lactic acid in cases with a disturbed lactate D over lactate L ratio could be an option to help prevent preterm birth that requires further attention. However, preventive or curative non-antibiotic treatment options are not limited to the use of lactic acid gel and/or glycogen. Antiseptics, pH-lowering devices such as vitamin C, or probiotic agents can also restore resistant vaginal flora (Donders et al. Expert Opin Pharmacother 2014;15:645–57) and are currently being studied in low resource countries.
Disclosure of interests None.
Contribution to authorship Wrote the paper.
Details of ethics approval Not applicable.
Funding None.
Acknowledgements None. &
219
Copyright of BJOG: An International Journal of Obstetrics & Gynaecology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Reducing infection-related preterm birth GGG Dondersa,b,c a Femicare Clinical Research for Women, Tienen bDepartment of Ob/Gyn, University Hospital Antwerp, Antwerp c Department of Ob/Gyn H Hart Hospital Tienen, Belgium Linked article This is a mini commentary on SS Witkin et al., pp. 213–8 in this issue. To view this article visit http:// dx.doi.org/10.1111/1471-0528.13115. A myriad of research papers have indicated that abnormal vaginal flora is a risk factor for preterm delivery. The most favored hypothesis for the mechanism is through ascending infection from the vagina, causing deciduitis and chorioamnionitis, inducing the cytokine and prostaglandin cascade and hence cervical weakening and contractions. In his contribution, Steve Witkin points to the matrix metalloproteinase (MMP)-8 and its inducer extracellular MMP inducer (EMMPRIN) as a key trigger to weaken the cervix and allow ascending commensal or potential pathogenic microorganisms, most often associated with bacterial vaginosis (BV), to cause intra-amniotic infection to occur. In conjunction with the L-lactate producing vaginal epithelium, the presence of Lactobacillus crispatus, Lactobacillus jenseni, and Lactobacillus gasseri, but not the BV-associated Lactobacillus iners, contributes to the protection of the vagina against this EMMPRIN activity by producing D-lactate, which decreases its release by the epithelium. This point is well taken and his suggestion to replace antibiotic therapy by lactic acid gel application to the vagina in women living in areas with poor resources and women with signs of disturbed flora could work. However, a few details may matter. That the production of vaginal lactic acid is closely correlated with the proportional level of other bacteria replacing the lactobilli (lactobacillary grades) has been known for decades, as well as the association of the latter with vaginal pro-inflammatory cyto-
kine production, which fluctuates along the course of pregnancy. The results of Hoyme’s original observational study of self-measuring vaginal pH, followed by treatment without proper diagnostic workout may have suggested a benefit in reducing preterm births, but this was not confirmed in a subsequent population-based controlled trial following 149 048 pregnant women in the same region (Bitzer et al. Dtsch Arztebl Int 2011;108:81–6). Analysing self-measurements of vaginal pH, although well accepted in poor resource countries such as Uganda, did not reflect the presence of BV in these women, as only 34% of women with increased pH had BV, the others having aerobic vaginitis (AV), endogeneous lack of lactobacilli or other conditions influencing pH (G.G.G Donders, F. Donders, G. Bellen, C. Depuydt, N. Eggermont, T. Michiels, J. Lule, J. Byamughisa, data on file). In this study the transitional state between normal flora and BV, called partial BV, had the same increased vaginal pH as full blown BV, whereas the so-called intermediate flora, representing a Nugent score 4–6 on gram-stained specimens, was found equally frequently in all pH groups. As this ‘intermediate flora’ according to Nugent represents not only partial BV, but also AV and other abnormalities, it is not surprising that it should also be considered a risk factor for preterm labour, as AV as well as partial BV may pose a greater risk for the pregnancy than full blown BV (Donders et al. BJOG 2009;116:1315– 24). Hence it does not come as a surprise that meta-analyses have failed to show that metronidazole prevents pre-
ª 2014 Royal College of Obstetricians and Gynaecologists
term birth, as mentioned in the paper. Besides L. iners and Gardnerella vaginalis being general surrogate markers markers of BV, Mobiluncus and Atopobium vaginae are even stronger indicators of full-blown BV (Nugent score above 8), and are, remarkably, not responsive to metronidazole. Although they are notorious lactic acid producers, both organisms are independently linked to an increased preterm birth risk (Foxman et al. AJOG 2014;210:226–7). As reasoned by Dr Witkin, treatment with lactic acid in cases with a disturbed lactate D over lactate L ratio could be an option to help prevent preterm birth that requires further attention. However, preventive or curative non-antibiotic treatment options are not limited to the use of lactic acid gel and/or glycogen. Antiseptics, pH-lowering devices such as vitamin C, or probiotic agents can also restore resistant vaginal flora (Donders et al. Expert Opin Pharmacother 2014;15:645–57) and are currently being studied in low resource countries.
Disclosure of interests None.
Contribution to authorship Wrote the paper.
Details of ethics approval Not applicable.
Funding None.
Acknowledgements None. &
219
Copyright of BJOG: An International Journal of Obstetrics & Gynaecology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
