Treating vaginal dysbiosis to prevent preterm birth in pregnant women
Introduction
A lot of clinical trials have been done to prevent preterm birth in pregnant women with or without risk factors for preterm birth. It is difficult to find one cause for preterm birth, since there are so many factors involved. That’s why we still have not found a golden method to prevent preterm birth. Most of the studies take risk factors for preterm birth such as short cervix [1] and investigate if hormonal, antibiotic or other treatment prevents preterm birth in two groups, the intervention group and the control group. The changes in the intervention group are compared to the control group and then the microbiotal differences and outcome, preterm birth are examined to see if there is a significant effect from the therapy. In this part of the blog we will discuss progesterone, antibiotic and lactobacilli in capsules as a treatment.
Main Therapies
One of the therapies to prevent preterm birth that is researched out nowadays is progesterone therapy. Progesterone therapy is a very peculiar therapy. Mostly because there are lot of studies contradicting each other’s results. Kindinger et al. [1] found that progesterone has no significant effect on preventing preterm birth while Hassan et al. [2] found that progesterone is a protective therapy against preterm birth.
In a prospective cohort study, Kindinger et al.[1] investigated the relationship between vaginal microbiota, cervical length in the second trimester and the impact of vaginal progesterone gel on vaginal bacterial communities in women with a short cervix. A short cervix was considered a risk for preterm birth according to Kindinger et al.[1]. Preterm birth was defined at 34 weeks before gestation in this study. During the study, multiple vaginal swabs were taken in the intervention group (n= 25) and control group (n=42). These swabs were analyzed by 16SRNA sequencing to analyze the present bacteria. According to Kindinger et al.[1] Lactobacillus iners dominance was associated with a short cervix (n=15, P<0.05) and preterm birth at 34 weeks n = 18; P < 0.01; 69% PPV). Lactobacillus crispatus dominance was predictive for term birth (n = 127, 98% PPV). The cervical shortening was not associated with vaginal dysbiosis. Neither was progesterone treatment associated with altering the vaginal bacterial communities. Progesterone did not reduce the preterm births associated with Lactobacillus iners in this study.
Hassan et al. [2] investigated the effect of vaginal gel in women with a short cervix in mid trimester of pregnancy in a large randomized double blind controlled trial. However, they did not analyze the vaginal microbiota precisely before and after the treatment. We still decided write about the outcomes of the trial, to show that progesterone could have an effect in preventing preterm birth in pregnant women.However, the mechanism behind this is still unknown. The progesterone could possibly have an effect on the vaginal microbiota and this should be researched in more detail. 458 pregnant women were randomized and included in analysis. 235 were randomized for vaginal progesterone gel and 223 for the placebo. Hassan et al. [2] used preterm birth at 33 weeks as the outcome. Women with progesterone gel had 8.9% (n=21) preterm births compared to 16.1% in the placebo group n=36. relative risk (RR), 0.55; 95% CI, 0.33-0.92; P=0.02. This resulted in a significant difference of 45% reduction of preterm birth at 33 weeks in the intervention group. According to Hassan et al. [2] the progesterone gel was a successful treatment in pregnant women with a short cervix.To asses the quality of this trial read the critical appraisal and judge for yourself if the progesterone therapy is a reliable option.
The reason I choose these studies is to show that in preterm birth a lot of factors are involved. It is not just the vaginal microbiota that can cause preterm birth. To understand how we can decrease preterm births it is important to understand and know all the different causes and risk factors of preterm birth. For example these two studies applied the same method, but they analyzed differently and had different group size. It is strange that one study has a reduction while the other does not. Either way if the progesterone therapy works on preventing preterm birth, there could be a chance it effects something other than the vaginal microbiota, since it did not change the vaginal microbiota. This should be researched further to determine the effects of the progesterone gel.
We shall move on to the next therapy: clindamycin.
A large RCT was conducted by Kekki et al. [3] to investigate the effect of vaginal 2% clindamycin cream to prevent preterm birth and peripartum infection morbidity in pregnant women with vaginal dysbiosis with no past of preterm delivery. Peripartum infection morbidity was defined as postpartum endometritis, postpartum sepsis, post cesarean wound infection, or episiotomy wound infection, necessitating antimicrobial therapy in the study.
In the study more than 5000 women were screened for vaginal dysbiosis. The screening showed only 375 women had vaginal dysbiosis and those women were randomized for clindamycin or placebo treatment. The results showed there were only small differences between the clindamycin and the placebo group. The clindamycin group had 5% preterm births and the placebo group had 4% preterm births (OR 1.3, 95% CI 0.5, 3.5). The peripartum infections morbidity was 11% in the clindamycin group and 18% in the placebo group (OR 1.6, 95% CI 0.9, 2.8). According to Kekki et al. [3] there was no significant difference of clindamycin in preventing the complications, although it was clear that the women with recurrent or persistent vaginal dysbiosis had an increased risk for preterm birth and peripartum infection morbidity. The rate of preterm births in the recurrent or persistent vaginal dysbiosis group was 15% compared to 2% in the vaginal dysbiosis negative group (OR 9.3, 95% CI 1.6, 53.5). So if we can find a way to turn the vaginal dysbiosis to a healthy vaginal microbiota, maybe we can prevent the preterm births and peripartum infection morbidity caused by the vaginal dysbiosis.
Another interesting study by Kiss et al. [4] was a retrospective cohort study in 2010, which used an antenatal screening with additional treatment if needed. In total 2986 pregnant women were enrolled in the study. 1713 Women were in the the control group and they were not screened, thus not treated.The data for the control group was taken from two years earlier. 1273 Women were screened for asymptomatic vaginal infections using gram stain. The vaginal dysbiosis was differentiated in bacterial vaginosis, vaginal candidiasis and trichomoniasis. The women who were infected received different therapies. The women with bacterial vaginosis received clindamycin 2% vaginal cream, they also received vaginal capsules containing live lactobacilli for 6 days. The candidiasis infections were treated locally with clotrimazole 0.1 g for 6 days. Trichomoniasis infections were treated locally with metronidazole 500mg for 7 days, included treatment for the partner. Follow up smears were taken 4-6 weeks. The outcome was preterm birth at 37 weeks before gestation. Both groups were comparable, although the intervention group had twice as much history of preterm birth as the control group. Even with this difference there were significantly lower incidents of preterm births in the intervention group (8,2%, table 1) compared to the control group (12.1%, p< 0.0001).
Incidents preterm birth
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Table 1 Source: Kiss et al [4] |
An interesting result in this retrospective cohort study is the difference in birth weight between the intervention and the control group (table 2). The group in 2003 was the control group and the 2005 group is the intervention group. A significant difference is found in all weight categories according to the results from Kiss et al. [4]
| Table 2: Source: Kiss et al. [4] |
Conclusion
In overall conclusion to these studies, I could say humongous parts of land remain uncovered. There is a lot of research that needs to be done on the effect of vaginal microbiota on preterm birth. It is suggested that Lactobacillus iners can increase the risk for preterm birth and that Lactobacillus crispatus can decrease the risk of preterm labour
However it is still unclear which therapies work for which patients, there could be certain bacteria involved that would make one therapy better for a specific patient. For now the most effective treatment would be to screen for infections in pregnant women and to treat those infections with the standard treatment, while adding Lactobacilli crispatus in vaginal capsules to the treatment to decrease the recurrence chance of infections and to prevent preterm births.
Sources:
[1] Kindinger LM, Bennett PR, Lee YS, Marchesi JR, Smith A, Cacciatore S, Holmes E, Nicholson JK, Teoh TG1, MacIntyre DA
The interaction between vaginal microbiota, cervical length, and vaginal progesterone treatment for preterm birth risk. Microbiome 2017 Jan 19;5(1)
[2]Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011 Jul;38(1):18-31.
[3]Kekki M1, Kurki T, Pelkonen J, Kurkinen-Räty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol. 2001 May;97(5 Pt 1):643-8.
[4]Kiss H1, Petricevic L, Martina S, Husslein P. Reducing the rate of preterm birth through a simple antenatal screen-and-treat programme: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol. 2010 Nov;153(1):38-42
Written by Damla Demir
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