Oral Presentations

The toolkit will be available as hard copy, or online. It is aimed at nursing management level, but also encourages the involvement of ward & community based KMC staff so ideas are pragmatic & feasible. Local staff will be able to use this toolkit, or elements of it, to identify local influences on the implementation of CKMC & changes that need to be employed in order to address these influences & achieve successful. and embedded practice.

Sixteen datasets from uncomplicated pregnancies that delivered at term and 11 from pregnancies that delivered before 32 weeks were analysed.
Mean gestation at MRI of the control group was 27.4 (SD± 3.6) and was 25.6 (SD± 3.1) for the preterm group and mean gestation at delivery (p<0.0001) was respectively 40 (SD± 1.7) for the control and 27.9 (SD± 2.6) for the preterm group. In the control population pulmonary volumes increased between 20 and 32 weeks gestation while mean pulmonary ADC and T2* values appeared constant. There was no difference in mean T2* values or ADC values between fetuses that delivered at term and those that delivered preterm but pulmonary volumes were found to be lower within the preterm cohort.

147 women with short CL were identified, 54 of whom presented with AFS. Presence of AFS was associated with reduced CL (14.06mm vs 19.39mm, p < 0.0001) and increased fFN (125.3ng/ml vs 55.39ng/ml, p = 0.038). Women presenting with AFS were also at increased risk of delivery <24 gestational weeks (17% vs 4.2% p = 0.0156) and delivered infants with a reduced mean gestational birthweight (2439g vs 2786g, p = 0.0188). However, women presenting with AFS were not significantly more likely to deliver before 34 (30% vs 19%, p = 0.1621) or 37 gestational weeks (37% vs 33%, p = 0.5886). The rates of NICU admission (22% vs 17%, p >0.999) and mean Apgar scores at five minutes (8.68 vs 8.75, p = 0.6228) were similar between infants born to women with and without AFS at all gestations. Logistic regression analysis further concluded that AFS presence was not independently associated with increased risk of PTB 24+0-36+6 weeks (aOR = 0.7710).

Mean (SD) maternal age and BMI were 32.6 (5.2) years, and 32.6 (8.1) kg/m2, respectively. 37% (24/65) of women were managed with diet alone, while 63% required both metformin and insulin.

Table 1 presents ACS exposure rates, and requirement for Variable Rate Insulin Infusion (VRII). Of 15 women with late PTB who received ACS, 60% received ACS at 35 weeks or later (n=9). 65% of women commenced VRII after ACS exposure (n=20/31), over half of whom had previously been managed by diet or metformin alone (n=11).

On unadjusted analysis, compared to non-exposure, ACS exposure was not associated with a reduction in respiratory distress syndrome (RDS) (8/31 ACS-exposed babies with RDS, 5/34 unexposed babies with RDS, Relative Risk (RR) 1.7, 95% Confidence interval (CI) 0.64-4.8), but was associated with statistically significant increased neonatal unit admission rates (22/31 ACS-exposed babies admitted, 10/34 unexposed babies admitted, RR 2.4, 95%CI 1.37-4.26).

Four (23%) of the preterm women experienced preterm prelabour rupture of membranes. None of the measured cytokines differed between the groups at GTP1. At GTP2, only TNFR1 was higher in the term compared to preterm women (p=.049) and distinguished both groups (AUC=.88, p=.005, n=12). However, when expressed as a ratio of GTP1/GTP2, only CXCL10 was higher in the preterm than term women and was predictive of sPTB (AUC=.68, p=.044, n=45). Combination of the ratios of CXCL10 and fFN improved sPTB prediction (AUC=.74, p=.007). The concentrations of CXCL11, TNF-α, Eotaxin (in all samples) and TNFR1 (in some samples) could not be determined as they were either below or above the detection limit of the CBA.

A total of 441 women were included in the multivariable analysis which demonstrated no statistically significant association between vaginal cerclage (n = 18) or Arabin pessary (n = 48) and gestation time. Progesterone (n = 57) was associated with a decreased gestation time (Est -3.15 (1.059); p-value 0.004) in women with a previous PTB, there was no association in women without a previous PTB.

We identified a total of 1842 metabolites, of these, 54 differed from GTP1 to GTP2. At GTP1 20 metabolites differed in term vs preterm. Notably, xanthosine, xanthotoxin, acacetin, athamantin, phloretin, methylglyoxal, urocanate and deoxythymidine monophosphate were higher in the preterm women. At GTP2 9 metabolites differed in term vs preterm. Notably, androsterone, dhurrin, palmitate, pantetheine and zierin were higher in the preterm women. Using an Anova, 18 metabolites were significantly different between all groups. Notably, in preterm women, putrescine, pyruvate and pantothenate significantly increased from GTP1 to GTP2. Pathway analysis showed enriched pathways with an impact score of ≥0.1 in term vs preterm. Specifically, pathways enriched were: glycolysis/gluconeogenesis, inositol phosphate metabolism, ubiquinone terpenoid-quinone in GTP1 and glycolysis/gluconeogenesis arachidonic acid in GTP2.

TLR3 (“viral”) priming prior to TLR2/6 agonist (“bacterial”) exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased mRNA expression of TLR3 and TLR2 but not TLR6.

857 cases from 407 women were included in the analysis. 470 (54.8%) cases had qfFN tests without lubricating gel, the remaining 387 (45.7%) having used lubricating gel. The mean qfFN results for these groups were 39ng/mL and 29ng/mL respectively, and the medians 4ng/mL and 5ng/mL respectively. Initial analysis with Mann-Whitney U showed the two groups had significantly different qfFN results (p=0.045) but the effect size was very small (r=0.069). Chi-square testing suggested the spread of qfFN results over 4 categories (<10, 10-49, 50-199 and ≥200 ng/mL) was the same within the gel used and the gel not used groups (p=0.056). Mann-Whitney U tests in subsets based on delivery outcomes also provided insufficient evidence to suggest statistically significantly different qfFN results between the two groups (term: p=0.077, spontaneous preterm: p=0.763, non-spontaneous preterm: p=0.203).

A total of 693 babies were born during the project. When data were compared with 2019, there were statistically significant improvements in the percentage of eligible interventions mothers/babies received (Table 1), in the proportion of mothers/babies who were fully optimised and for 10 of 11 interventions in the percentage of eligible mothers/babies who received that bundle element. Enablers to implementation included fostering a positive perinatal team dynamic, access to evidence-based adaptable resources and coaching, senior leadership and trust endorsement and appropriate project leadership. Barriers to implementation included the complexity and size of the bundle, procedural knowledge, the mental capacity of staff and limited protected time.

23 HCPs participated in interviews. Fluidity of equipoise was interpreted as one of the main themes from the QPE. This fluidity was impacted by: (1) the influence of gestation; (2) obstetric history; (3) standard site practice, and (4) HCPs previous experiences of ECC. Where there was perceived community equipoise across the clinical body, actual offering of trial entry was influenced by personal and clinical equipoise. Equipoise varied within and across study sites, and was demonstrated to be fluid at different time points (gestation at presentation) and influenced by (changing) clinical presentations of prospective participants.

CXCL10 levels did not differ between term vs preterm women. 6/9 of the preterm women had preterm premature rupture of membranes. Stages and grades of MIR and FIR correlated positively in both groups. However, a negative correlation between CXCL10 levels and both stages and grades of MIR and FIR was only observed in term women (Table 1). Moreso, there was no correlation between CXCL10 and MIR or FIR in the total cohort. Neither MIR, FIR nor CXCL10 correlated with APGAR score.

Data was obtained from 96 units (94 units that offer obstetric-led intrapartum care, and 2 units that provides maternity-led intrapartum care and/or antenatal/community care).

Asymptomatic high risk women
Overall, 78/96 units (81%) reported that they had a preterm birth prevention clinic. SBLCBv2 has had a considerable impact in the increase of preterm birth prevention clinic services, with the majority (61%) of sites reporting that the NHS England publication influenced their unit in setting up their clinic. Most sites, 65%, also felt that their referral criteria had changed because of SBLCBv2.
This questionnaire found only one common risk factor across all clinics (which was having a previous spontaneous preterm birth or mid-trimester loss). The preferred treatment for a short cervical length was a cerclage (braided suture) (38/86, 44%), followed by a cerclage (monofilament suture) (16/86, 19%).
When asked what hindered the implementation of their clinic, over half of respondents (56%, 40/72) highlighted capacity issues. These ranged from too many referrals to cope with, a lack of appropriate clinical space, a lack of staff, and/or a lack of resources. This included 19% (14/72) who specifically mentioned a lack of clinicians able to scan and/or scanning equipment.

Symptomatic women
Most sites, 69%, (64/93) utilise quantitative fetal fibronectin to assess symptomatic women at risk of preterm labour. Over half of respondents utilise the QUiPP App when assessing symptomatic women (47/93, 51%) and for 78% of these sites (36/46) it is recommended in local guidance.

296 questionnaires were completed by 168 women between 1st July and 20th September 2021. The number of visits per woman ranged from 1-6. Using data from the visit with the highest scores, screening indicated mild to very high levels of anxiety in 22% of women (37/168), and depressive symptoms in 19% (32/168). Screening indicated 8 women were experiencing “Probable major depression” and 3 reported thoughts that they “would be better off dead or…hurting [themselves]…” more than half the days (n=1) or nearly every day (n=2) (Table).

Sixty-one trials (17,273 pregnant women) contributed data to analysis for at least one outcome. The summary of findings table for the maternal outcome of PTB < 34 weeks is shown in the attached table. For the outcome of perinatal death, 30 trials (12,119 pregnant women) contributed data to the network. Vaginal progesterone (VP) was the only treatment that demonstrated clear evidence of benefit for this outcome (OR 0.66; 95% CrI 0.44-0.97, moderate certainty). In addition, 17OHPC (OR 0.78, CrI 0.50-1.21, moderate certainty of evidence), McDonald cerclage (OR 0.59, CrI 0.33-1.03, moderate certainty of evidence) and unspecified cerclage (OR 0.77, CrI 0.53-1.11, moderate certainty of evidence) may reduce perinatal death rates, but CrIs could not exclude the possibility of harm. Compared to controls, only progesterone treatments are associated with reduction in neonatal respiratory distress syndrome, neonatal sepsis, necrotising enterocolitis, and admission to NICU.

Majority of pregnant Chinese women had vaginal microbiomes dominated by Lactobacillus (2275/2646, 85.89%), specifically L. crispatus (1058/2646, 39.98%) or L. iners (952/2646, 35.98%). Women with high sialidase activity (n=36) had significantly higher proportions of Lactobacillus spp. depleted microbiomes, with enrichment of BV-associated genera including Gardnerella, Prevotella and Atopobium, compared to women with low sialidase activity (n=783, p=2.403e-13). Women with high leukocyte counts (n=572) had higher prevalence of Lactobacillus dominated microbiomes compared to women with low leukocyte counts (n=247), and this was mostly driven by significantly higher relative abundance of L. iners (p<0.01). Lactobacillus spp. depleted microbiomes, high sialidase activity and/or high leukocyte counts was not associated with increased risk of PTB.

After CTS or trauma, preterm AM showed a dense region of mesenchymal cell migration to the wound edge in CAM and PAM specimens. In wound edge preterm AM after CTS, collagen fibres were highly polarised and aligned parallel to the axis of the wound edge and the direction of applied strain, with greater Cx43 puncta preferentially expressed by mesenchymal cells (Fig. 1). In the fibroblast layer, nuclear cell contraction and myofibroblast differentiation increased in wounded CAM and PAM specimens after CTS or trauma. The mechanotransduction mechanism appeared to bring together the wound edges with greater crosslinking of collagen fibres in wounded preterm AM specimens (Fig. 1), similar to the purse string contraction model. But even after stimulation with CTS for 24 hours, the wound only partially closed. Unstrained control AM was not polarised and fibres were randomly interwoven (Fig. 1, Left panel). CTS significantly increased GAG synthesis, elastin concentration and PGE2 release when compared to unstrained control preterm AM specimens, with differences dependent on tissue region and pregnancy outcome.

Vaginal depletion of Lactobacillus species was associated with increased mannose binding lectin (MBL) (p<0.0001), IgM (p<0.0001), IgG (p<0.0001), C3b (p<0.0001), C5 (p<0.001), IL-8 (p<0.003), IL-6 (p<0.003) and IL-1β (p<0.0001) and with an increased risk of sPTB (all mediators statistically significant). In women with a diverse composition, those who went on to deliver preterm had an augmented inflammatory response compared to those who delivered at term (IL-8, IL6, IL-1β, C3b and C5 p<0.05; MBL and IgM p<0.01), supporting a dysregulated host immune response. Cervical shortening, which often precedes preterm birth, was associated with Lactobacillus iners and statistically significant elevated levels of IgM, C3b, C5, and IL-6.

Clinical data and placental pathology was collected for 613 women. Of these, 97% (592/613) of women had a WCC/CRP undertaken within 24 hours prior of their delivery. 42% (248/592) had confirmed histological chorioamnionitis. The mean NLR was raised in this group compared to those with non-inflammatory placenta (n=344), 9.8 vs 5.7. In women with placentas showing signs of histological chorioamnionitis, 56% had an NLR 6 compared to 27% in those without inflammation.

161 IUT requests were analysed. Table 1 shows the number of women transferred from/to each level of neonatal unit, suggesting that 50.37% of requests were due to uplift in care and 49.63% of requests were due to capacity issues at the woman’s booking hospital. Only 29.1% of women delivered within 48 hours of transfer, and women travelled an average of 32.5 miles away from their booking hospital. Fetal fibronectin was the most commonly used predictive biomarker, however predictive testing was used in only 28.8% of women and 10 women were still transferred despite receiving a negative predictive test result.

Pregnancy loss rates did not differ between the two groups: 4% (n=7) in the C-STICH trial participants and 3.3% (n=7) in the non-participant group (p=0.73). The median gestation at birth was 38 completed weeks in both groups. The proportion of babies born ≥37 weeks was 77% in both groups. The proportion of babies born very preterm (<32 weeks) did not differ between the two groups: 3.5% in the C-STICH group and 4.4% in the non-participant group (p=0.68). 42% of live births in the C-STICH group were delivered via caesarean section versus 45% in the non-participant group (p=0.71). There was no significant reduction in small for gestational age babies seen in the C-STICH participant group compared to the non-participant group: 10.5% and 7.5% respectively (p=0.35).

The most common single risk factors were previous cervical treatment (CT) (28.8%), previous sPTB (24.5%) and previous MTL (22.3%). 13.7% of women had more than one risk factor. Women with a previous sPTB or MTL were at higher risk of cervical shortening, PPROM and sPTB <37 weeks compared to those with CT (cervical shortening: 24.9 %, 39.6% and 19.4%, p=0.03, p<0.001;PPROM: 9.9%, 6.9% and 5.9% respectively, p=0.018, and sPTB: 28.3%, 23.5% and 13.4%, p<0.0001). The rate of sPTB following ultrasound-indicated cerclage was 23.5% for those with CT compared to 38.1% for those with previous PTB or MTL (p=0.027), supporting potentially greater benefit from cerclage for those with shortening secondary to mechanical weakness in the context of CT. Furthermore, when braided material was used for cerclages in women with a history of previous sPTB or MTL, higher rates of sPTB <34 and <37 occurred compared to those who received monofilament (p=0.03, p=0.01), a relationship not seen in women with CT.

The concentration of 113 metabolite features detected in DESI-MS negative and positive ion modes were significantly different between Lactobacillus dominated and depleted samples in independent analyses of both patient cohorts. Robust prediction of genera-level classification was observed across cohorts (VMET/VMET2; AUC 94.1/90.6; sensitivity: 62.0/54.5; specificity: 97.8/96.4). Discrimination between the major vaginal community state types (CSTs; I, III and IV) could also be achieved (VMET/VMET2; AUC 95.76 (94.3–97.7); sensitivity: 69.74(57.5–80.2); specificity 98.28 (97.7–98.9)). High vaginal diversity and instability during pregnancy, defined as shifts between Lactobacillus-dominated and Lactobacillus-depleted communities characterised by metataxonomics, were associated with an increased risk of PTB compared to those women maintaining Lactobacillus-dominance (OR 1.97, 95% CI 1.03–3.66, p= 0.04). A similar trend was observed when stability was predictive by DESI-MS but this did not reach significance (OR 1.47, 95% CI 0.75–2.78, p = 0.25).

11 women and 23 HCPs were interviewed. Three super-ordinate themes of Fluidity of Equipoise, a Complex Obstetric History, and Influence of Gestation were interpreted. Clinical expertise, standard practice and women’s and HCPs understanding around ECC varied. Women’s decision-making about trial entry was influenced by their own obstetric history. Some women preferred personalised treatment decision-making instead of random allocation. Other women accepted randomisation because they understood the uncertainty around treatment options, and had not been pre-primed. We defined pre-priming as discussion of treatment prior to discussion about the trial or the uncertainty around the evidence base.

Following simulation, a statistically significant median increase in confidence levels by 2 points was reported within the novice group in both history and ultrasound indicated cerclage and self-evaluation of cerclage placement, (p = 0.0078, p = 0.0156 and p = 0.0156). Experts recorded a median increase in confidence by at least 0.5 points following simulation, however this result was not significant (p >0.9999 and p = 0.6250). Cervical cerclage placement analysis between groups did not report any statistically significant outcomes to indicate successful stitch placement. However, despite being not statistically significant, participants within the Expert group performed better in all areas that would indicated successful stitch placement such as height and diameter of stitch compared to those within the Intermediate and Novice groups.

We identified 28% of the cohort as non-secretors with the highest proportion in Afro-Caribbean women, 34.6%. Co-occurrence networks showed contrasting patterns of interactions in the microbiota of secretors and non-secretors: Lactobacillus species, in particular L.crispatus, were observed to have a greater proportion of negative edges in the non-secretors. Regression modelling of gestational length showed that non-secretors with Lactobacillus-depleted microbiota in early pregnancy had significantly shorter pregnancies compared with Lactobacillus-dominated non-secretors (p=0.045). This difference in gestational length was not observed in the secretors (p=0.28).

Our differential gene expression (DEG), gene ontology and pathway analysis revealed several dysregulated genes including OCLN, ARF6, KRT7, SLC6A13, SLC6A17, SLC26A8, KLF8 and FOXA1 which are associated with altered trophoblast functions characterised by aberrant cell motility, differentiation and micronutrients transport. We also detected significant upregulation of pivotal Wnt ligands WNT7A and RSPO4 suggesting an augmentation of the canonical Wnt/β-catenin signalling that may have detrimental effects on trophoblast function. By conducting bioinformatics analysis on DEGs we have identified four key miRNAs, including miR-524-5p, miR-520d-5p, miR-15a-5p and miR-424-5p which were significantly downregulated in the preterm placenta as confirmed by qRT-PCR. These miRNAs may have regulatory roles on the aberrant gene expressions that we have observed. Furthermore, we have identified two potential biomarker candidates, RSPO4 and SLC26A8 that need further exploration.