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Title: Interactions between the cervix and vaginal microbiome in pregnancy
Author: Kindinger, Lindsay
ISNI:       0000 0004 7657 4051
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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During pregnancy, the cervix protects the growing fetus and uterine cavity from risk of ascending infection. Microbial-induced inflammation has been shown to disrupt the cervical epithelial barrier, cause premature cervical ripening, and ultimately result in preterm birth; the leading cause of death in children under five. Current prediction and prevention strategies have been ineffective at managing the global dilemma of preterm birth. Prior to the work presented in this thesis, there had been no examination of the association between the cervix, as a mechanical and immunological barrier to ascending bacterial infection, and the co-existing vaginal microbiota during pregnancy. Furthermore the impact of preventative interventions, namely cervical cerclage or vaginal progesterone supplementation, had not been assessed. 16S rRNA gene sequencing techniques were employed for the longitudinal assessment of vaginal microbial profiles in pregnancy, to compare women at high- and low-risk of preterm birth. At each sampling time-point (12, 16, 22, 28 and 34 weeks gestation) a matched transvaginal ultrasound scan was performed for measurements of cervical length, volume and vascularity, using 2D and 3D/4D ultrasound technology. The interaction between cervical phenotypes and the vaginal microbiota in pregnancy were assessed with respect to subsequent gestation at birth. In this thesis I demonstrate that high abundance of L. crispatus appears to be advantageous and is associated with subsequent term birth, while L. iners is a risk factor for preterm birth. Although assessment of cervical volume and vascularity did not provide improved prediction of preterm birth over current cervical length screening, second trimester vaginal microbial composition effectively differentiated subsequent early from late preterm birth (before and after 34 weeks gestation). Additionally, vaginal microbial profiles, in conjunction with ultrasound assessment cervix, may provide future potential stratification for preterm birth risk, although larger validation studies are required. I also demonstrated that the interaction between cervical length, vaginal microbiota, and gestation at birth varies according to underlying aetiology of preterm birth. In particular, women with pre-pregnancy excisional CIN treatment displayed substantially different cervical and microbial profiles to women with a prior preterm birth. Finally I assessed the impact of cervical cerclage and suture material on vaginal microbiota in high risk pregnancies. Multifilament braided suture, the material predominantly used by obstetricians without an evidence base, was shown to induce vaginal dysbiosis, local excretion of pro-inflammatory cytokines and prematurely increased cervical vascularity. The monofilament suture alternative had minimal impact on vaginal microenvironment. Similarly vaginal progesterone supplementation administered for a shortened cervical length had minimal impact on antenatal vaginal microbiota profiles. Overall, the studies presented in this thesis provide an improved understanding of microbial-host interactions in both low- and high-risk populations for preterm birth.
Supervisor: Bennett, Phillip ; MacIntyre, David ; Marchesi, Julian Sponsor: Genesis Research Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral