Title: Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. One Sentence Summary



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Title: Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage.
One Sentence Summary: Cervical cerclage using braided suture material disrupts vaginal microbial stability and increases inflammation.
Authors: Lindsay M. Kindinger1,2,3, David A. MacIntyre1*, Yun S Lee1, Julian R. Marchesi4,5, Ann Smith5, Julie A. K. McDonald4, Vasso Terzidou1,6, Joanna R. Cook1, Christoph Lees1,2, Fidan Israfil-Bayli7, Yazmin Faiza8, Philip Toozs-Hobson7, Mark Slack8, Stefano Cacciatore1, Elaine Holmes4,9, Jeremy K. Nicholson4,9, TG Teoh3 and Phillip R. Bennett1,2*.

Affiliations:

1 Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, W12 0NN, UK

2 Queen Charlotte’s Hospital, Imperial College Healthcare NHS Trust, London, W12 0HS, UK

3 St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, W2 1NY, UK

4 Centre for Digestive and Gut Health, Imperial College London, W2 1NY, UK

5 School of Biosciences, Cardiff University, CF103AX, UK

6 Chelsea & Westminster Hospital, Imperial College Healthcare NHS Trust, London, SW10 9NH, UK

7 Birmingham Women’s Hospital NHS Foundation Trust, Edgbaston, Birmingham, B15 2TG, UK

8 Urogynaecology Department, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

9 Division of Computational Systems Medicine, Department of Surgery and Cancer, Imperial College London, SW7 2AZ, UK


*Corresponding authors:

Dr David MacIntyre (d.macintyre@imperial.ac.uk) and Prof Phillip Bennett (p.bennett@imperial.ac.uk)

Imperial College Parturition Research Group, Division of the Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, W12 0NN, UK.

Abstract:

Preterm birth, the leading cause of death in children under five, may be caused by inflammation triggered by ascending vaginal infection. About two million cervical cerclages are performed annually to prevent preterm birth. The procedure is thought to provide structural support and maintain the endocervical mucus plug as a barrier to ascending infection. Two types of suture material are used for cerclage: monofilament or multifilament braided. Braided sutures are most frequently used, though no evidence exists to favor them over monofilament sutures. In this study we assessed birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in 5 UK university hospitals and showed that braided cerclage was associated with increased intrauterine death (15% v 5%, P = 0.0001) and preterm birth (28% v 17%, P = 0.0006) compared to monofilament suture. To understand the potential underlying mechanism, we performed a prospective, longitudinal study of the vaginal microbiome in women at risk of preterm birth because of short cervical length (≤25 mm) who received braided (n=25) or monofilament (n=24) cerclage under otherwise comparable circumstances. Braided suture induced a persistent shift towards vaginal microbiome dysbiosis characterized by reduced Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the vaginal microbiome and its interactions with the host. These data provide in vivo evidence that a dynamic shift of the human vaginal microbiome toward dysbiosis correlates with preterm birth.



Main Text:

Introduction

Each year, preterm birth (PTB, defined as delivery before 37 weeks of gestation) causes over one million deaths worldwide (1). Although preterm birth has multiple etiologies, infection is thought to be a causal mechanism in up to 50% of cases (2). It has been postulated that microbiota may spread hematogenously (3), or ascend from the vagina along mucosal surfaces. During a healthy pregnancy, the uterus and fetus are protected from ascending infection from the vagina by the cervix, which acts as a functional and physical barrier to bacteria and pathogens (4). In the vagina, Lactobacillus spp. stability and dominance are central to reproductive health. Pregnancy induces a shift in the vaginal microbiome from a temporally dynamic community structure in non-pregnant women (5) towards stable, Lactobacillus spp. dominance that inhibits growth of pathobionts (6, 7). The vaginal microbiome at delivery also acts as an important source of pioneering microbiota for the neonatal gut microbiome, thus implicating it in long-term health outcomes (8, 9). An association between vaginal dysbiosis during pregnancy, characterized by reduced quantities of Lactobacillus spp., and preterm birth has long been recognized (2, 10); women diagnosed with bacterial vaginosis have a 2- and 6-fold increased risk of preterm birth and late miscarriage, respectively (10). Recent analyses of the vaginal microbiome in pregnancy using culture-independent methods lend further support to associate vaginal dysbiosis and preterm birth (11).



Cervical cerclage (12, 13) and progesterone supplementation (14) are the only widely used clinical strategies for the prevention of preterm birth, with an estimated two million cerclage procedures performed annually (15). Cervical cerclage reduces the risk of preterm birth by approximately 20% in women with a history of spontaneous preterm birth and/or a short cervical length (16, 17), and its use in these circumstances is recommended by both the American and the UK Royal College of Obstetricians and Gynecologists (12, 13). Its mechanisms of action are uncertain, but it is thought to provide mechanical support to a weakened cervix (18) as well as to support the cervical mucosal plug as a barrier to ascending infection (4). However, cervical cerclage is associated with increased risk of infection (17, 19). The procedure involves placing a purse-string stitch around the cervix with or without a dissection of the bladder away from the cervix although there is no evidence for a benefit of bladder dissection (20). Two different suture materials, braided or monofilament, are used for the procedure, with braided preferred by 80% of surgeons without an evidence base (21, 22). Braided suture is composed of non-absorbable polyester ethylene terephthalate fibers braided together to form a 5 mm wide mesh tape. The tape is characteristically high in tensile strength and is thought to provide a secure structural support to a weakened cervix because of its high coefficient of friction (18). Monofilament sutures are made of a single strand of non-absorbable polyamide polymer and because of their simple structure, they provide less mechanical resistance when passed through tissue. As a result, they have a tendency to slip and therefore require a greater number of throws to secure the knot than a braided suture (18), which is why braided suture is usually preferred.
However, an association between braided suture use and increased risk of infection in other disciplines (23, 24) has informed the hypothesis that pregnancy outcome after cervical cerclage may be influenced by suture material (15). Aiming to assess the impact of cerclage suture on vaginal microbiota, we hypothesized that the braided suture material promotes pathobiont colonization of the vagina, resulting in activation of inflammatory parturition pathways and premature cervical ripening. In this study we have undertaken a retrospective analysis of pregnancy outcomes in women receiving a clinically indicated cervical cerclage over a ten-year period across five university hospitals in England (UK). After this, a prospective cohort of women at risk of preterm birth were randomized to either braided or monofilament suture material. Longitudinal profiling of their vaginal microbiome in the context of cerclage insertion was undertaken using 16S rRNA gene sequencing. Cytokine expression profiling of matched cervico-vaginal fluid samples and cervical vascular assessment by 4-D ultrasound were concurrently performed as measures of physiological responses to cerclage insertion and changing microbial composition.


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