Comparing cervical cerclage, pessary and vaginal progesterone for prevention of preterm birth in women with a short cervix (SuPPoRT): A multicentre randomised controlled trial.

BACKGROUND: Cervical cerclage, cervical pessary, and vaginal progesterone have each been shown to reduce preterm birth (PTB) in high-risk women, but to our knowledge, there has been no randomised comparison of the 3 interventions. The SuPPoRT "Stitch, Pessary, or Progesterone Randomised Trial" was designed to compare the rate of PTB <37 weeks between each intervention in women who develop a short cervix in pregnancy. METHODS AND FINDINGS: SuPPoRT was a multicentre, open label 3-arm randomised controlled trial designed to demonstrate equivalence (equivalence margin 20%) conducted from 1 July 2015 to 1 July 2021 in 19 obstetric units in the United Kingdom. Asymptomatic women with singleton pregnancies with transvaginal ultrasound cervical lengths measuring <25 mm between 14+0 and 23+6 weeks' gestation were eligible for randomisation (1:1:1) to receive either vaginal cervical cerclage (n = 128), cervical pessary (n = 126), or vaginal progesterone (n = 132). Minimisation variables were gestation at recruitment, body mass index (BMI), and risk factor for PTB. The primary outcome was PTB <37 weeks' gestation. Secondary outcomes included PTB <34 weeks', <30 weeks', and adverse perinatal outcome. Analysis was by intention to treat. A total of 386 pregnant women between 14+0 and 23+6 weeks' gestation with a cervical length <25 mm were randomised to one of the 3 interventions. About 67% were of white ethnicity, 18% black ethnicity, and 7.5% Asian ethnicity. Mean BMI was 25.6. Around 85% of women had prior risk factors for PTB; 39.1% had experienced a spontaneous PTB or midtrimester loss (>14 weeks gestation); and 45.8% had prior cervical surgery. Data from 381 women were available for outcome analysis. Using binary regression, randomised therapies (cerclage versus pessary versus vaginal progesterone) were found to have similar effects on the primary outcome PTB <37 weeks (39/127 versus 38/122 versus 32/132, p = 0.4, cerclage versus pessary risk difference (RD) -0.7% [-12.1 to 10.7], cerclage versus progesterone RD 6.2% [-5.0 to 17.0], and progesterone versus pessary RD -6.9% [-17.9 to 4.1]). Similarly, no difference was seen for PTB <34 and 30 weeks, nor adverse perinatal outcome. There were some differences in the mild side effect profile between interventions (vaginal discharge and bleeding) and women randomised to progesterone reported more severe abdominal pain. A small proportion of women did not receive the intervention as per protocol; however, per-protocol and as-treated analyses showed similar results. The main study limitation was that the trial was underpowered for neonatal outcomes and was stopped early due to the COVID-19 pandemic. CONCLUSIONS: In this study, we found that for women who develop a short cervix, cerclage, pessary, and vaginal progesterone were equally efficacious at preventing PTB, as judged with a 20% equivalence margin. Commencing with any of the therapies would be reasonable clinical management. These results can be used as a counselling tool for clinicians when managing women with a short cervix. TRIAL REGISTRATION: EU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Evaluating the use of the QUiPP app and its impact on the management of threatened preterm labour: A cluster randomised trial.

BACKGROUND: Preterm delivery (before 37 weeks of gestation) is the single most important contributor to neonatal death and morbidity, with lifelong repercussions. However, the majority of women who present with preterm labour (PTL) symptoms do not deliver imminently. Accurate prediction of PTL is needed in order ensure correct management of those most at risk of preterm birth (PTB) and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the majority. The QUantitative Innovation in Predicting Preterm birth (QUIPP) app aims to support clinical decision-making about women in threatened preterm labour (TPTL) by combining quantitative fetal fibronectin (qfFN) values, cervical length (CL), and significant PTB risk factors to create an individualised percentage risk of delivery. METHODS AND FINDINGS: EQUIPTT was a multi-centre cluster randomised controlled trial (RCT) involving 13 maternity units in South and Eastern England (United Kingdom) between March 2018 and February 2019. Pregnant women (n = 1,872) between 23+0 and 34+6 weeks' gestation with symptoms of PTL in the analysis period were assigned to either the intervention (762) or control (1,111). The mean age of the study population was 30.2 (+/- SD 5.93). A total of 56.0% were white, 19.6% were black, 14.2% were Asian, and 10.2% were of other ethnicities. The intervention was the use of the QUiPP app with admission, antenatal corticosteroids (ACSs), and transfer advised for women with a QUiPP risk of delivery >5% within 7 days. Control sites continued with their conventional management of TPTL. Unnecessary management for TPTL was a composite primary outcome defined by the sum of unnecessary admission decisions (admitted and delivery interval >7 days or not admitted and delivery interval ≤7 days) and the number of unnecessary in utero transfer (IUT) decisions/actions (IUT that occurred or were attempted >7 days prior to delivery) and ex utero transfers (EUTs) that should have been in utero (attempted and not attempted). Unnecessary management of TPTL was 11.3% (84/741) at the intervention sites versus 11.5% (126/1094) at control sites (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.66-1.42, p = 0.883). Control sites frequently used qfFN and did not follow UK national guidance, which recommends routine treatment below 30 weeks without testing. Unnecessary management largely consisted of unnecessary admissions which were similar at intervention and control sites (10.7% versus 10.8% of all visits). In terms of adverse outcomes for women in TPTL <36 weeks, 4 women from the intervention sites and 12 from the control sites did not receive recommended management. If the QUiPP percentage risk was used as per protocol, unnecessary management would have been 7.4% (43/578) versus 9.9% (134/1,351) (OR 0.72, 95% CI 0.45-1.16). Our external validation of the QUiPP app confirmed that it was highly predictive of delivery in 7 days; receiver operating curve area was 0.90 (95% CI 0.85-0.95) for symptomatic women. Study limitations included a lack of compliance with national guidance at the control sites and difficulties in implementation of the QUiPP app. CONCLUSIONS: This cluster randomised trial did not demonstrate that the use of the QUiPP app reduced unnecessary management of TPTL compared to current management but would safely improve the management recommended by the National Institute for Health and Care Excellence (NICE). Interpretation of qfFN, with or without the QUiPP app, is a safe and accurate method for identifying women most likely to benefit from PTL interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN17846337.

Development and rapid rollout of The QUiPP App Toolkit for women who arrive in threatened preterm labour.

BACKGROUND: Often the first opportunity for clinicians to assess risk of preterm birth is when women present with threatened preterm labour symptoms (such as period-like pain, tightening's or back ache). However, threatened preterm labour symptoms are not a strong predictor of imminent birth. Clinicians are then faced with a complex clinical dilemma, the need to ameliorate the consequences of preterm birth requires consideration with the side-effects and costs. The QUiPP app is a validated app which can aid clinicians when they triage a women who is in threatened preterm labour. AIM: Our aim was to produce a toolkit to promote a best practice pathway for women who arrive in threatened preterm labour. METHODS: We worked with two hospitals in South London. This included the aid of a toolkit midwife at each hospital. We also undertook stakeholder focus groups and worked with two Maternity Voice Partnership groups to ensure a diverse range of voices was heard in the toolkit development. While we aimed to produce the toolkit in September 2020, we rapidly rolled out and produced the first version of the toolkit in April 2020 due to COVID-19. As the QUiPP app can reduce admissions and hospital transfers, there was a need to enable all hospitals in England to have access to the toolkit as soon as possible. RESULTS: While the rapid rollout of The QUiPP App Toolkit due to COVID-19 was not planned, it has demonstrated that toolkits to improve clinical practice can be produced promptly. Through actively welcoming continued feedback meant the initial version of the toolkit could be continually and iteratively refined. The toolkit has been recommended nationally, with National Health Service England recommending the app and toolkit in their COVID-19 update to the Saving Babies Lives Care Bundle and in the British Association of Perinatal Medicine Antenatal Optimisation Toolkit.

All the right moves: why in utero transfer is both important for the baby and difficult to achieve and new strategies for change.

The best way to ensure that preterm infants benefit from relevant neonatal expertise as soon as they are born is to transfer the mother and baby to an appropriately specialised neonatal facility before birth (" in utero"). This review explores the evidence surrounding the importance of being born in the right unit, the advantages of in utero transfers compared to ex utero transfers, and how to accurately assess which women are at most risk of delivering early and the challenges of in utero transfers. Accurate identification of the women most at risk of preterm birth is key to prioritising who to transfer antenatally, but the administrative burden and pathway variation of in utero transfer in the UK are likely to compromise optimal clinical care. Women reported the impact that in utero transfers have on them, including the emotional and financial burdens of being transferred and the anxiety surrounding domestic and logistical concerns related to being away from home. The final section of the review explores new approaches to reforming the in utero transfer process, including learning from outside the UK and changing policy and guidelines. Examples of collaborative regional guidance include the recent Pan-London guidance on in utero transfers. Reforming the transfer process can also be aided through technology, such as utilising the CotFinder app. In utero transfer is an unavoidable aspect of maternity and neonatal care, and the burden will increase if preterm birth rates continue to rise in association with increased rates of multiple pregnancy, advancing maternal age, assisted reproductive technologies, and obstetric interventions. As funding and capacity pressures on health services increase because of the COVID-19 pandemic, better prioritisation and sustained multi-disciplinary commitment are essential to maximise better outcomes for babies born too soon.

Efficacy of transvaginal cervical cerclage in women at risk of preterm birth following previous emergency cesarean section.

INTRODUCTION: Emergency cesarean sections (EMCS) are associated with subsequent preterm birth, particularly at full dilation (FDCS), which is a cause of both second trimester miscarriages and early, recurrent spontaneous preterm birth (sPTB). The optimal management for these women in subsequent pregnancies is currently unknown. This study aims to assess efficacy of transvaginal cervical cerclage (TVC) in prevention of preterm birth among women who have had an EMCS followed by a subsequent late miscarriage or sPTB. MATERIAL AND METHODS: A historical cohort study was performed assessing outcomes of women attending the Preterm Surveillance Clinic at St Thomas' Hospital, London, who received TVC, with a history of EMCS (pregnancy A) followed by a sPTB/late miscarriage (pregnancy B) and a subsequent pregnancy (pregnancy C). A historical reference group managed in the same clinic was identified comprising women with any risk factor for sPTB, who required TVC. Incidence of delivery >24 to <30 weeks' gestation was compared with relative risk and 95% confidence intervals (CI). Subgroup analysis was carried out assessing women who had a previous FDCS. RESULTS: 209 women with a previous EMCS during labor (50 with FDCS), followed by sPTB/late miscarriage were identified. 178 progressed beyond 24 weeks; of these, 56 received TVC and formed the study group. 905 high-risk women were identified; of these, 154 received TVC and formed the reference group. Despite TVC treatment, 17/56 (30%) of the study group delivered <30 weeks' gestation compared with 5/154 (3%) of the reference group (RR 9.4, 95% CI 3.6-24.2, P < .001). In the subset of 17 women in the study group with a previous FDCS, followed by sPTB/late miscarriage, 6/17 (35%) delivered <30 weeks' gestation, significantly higher than the reference group (P < .001) but similar to EMCS at less than full dilation (35% vs 28%, P = .596). Overall, 33/72 (46%) women receiving cerclage with prior EMCS had either a mid-trimester loss or delivery <30 weeks. CONCLUSIONS: Transvaginal cervical cerclage appears less effective in preventing preterm birth among pregnant women who have had an EMCS followed by a sPTB/late miscarriage compared with other high-risk women. The lack of efficacy in the subgroup with an FDCS was similar.

The role of medical smartphone apps in clinical decision-support: A literature review.

INTRODUCTION: The now ubiquitous smartphone has huge potential to assist clinical decision-making across the globe. However, the rapid pace of digitalisation contrasts starkly with the slower rate of medical research and publication. This review explores the evidence base that exists to validate and evaluate the use of medical decision-support apps. The resultant findings will inform appropriate and pragmatic evaluation strategies for future clinical app developers and provide a scientific and cultural context for research priorities in this field. METHOD: Medline, Embase and Cochrane databases were searched for clinical trials concerning decision support and smart phones from 2007 (introduction of first smartphone iPhone) until January 2019. RESULTS: Following exclusions, 48 trials and one Cochrane review were included for final analysis. Whilst diagnostic accuracy studies are plentiful, clinical trials are scarce. App research methodology was further interrogated according to setting and decision-support modality: e.g. camera-based, guideline-based, predictive models. Description of app development pathways and regulation were highly varied. Global health emerged as an early adopter of decision-support apps and this field is leading implementation and evaluation. CONCLUSION: Clinical decision-support apps have considerable potential to enhance access to care and quality of care, but the medical community must rise to the challenge of modernising its approach if it is truly committed to capitalising on the opportunities of digitalisation.

EQUIPTT: The Evaluation of the QUiPP app for Triage and Transfer protocol for a cluster randomised trial to evaluate the impact of the QUiPP app on inappropriate management for threatened preterm labour.

BACKGROUND: Accurate diagnosis of preterm labour is needed to ensure correct management of those most at risk of preterm birth and to prevent the maternal and fetal risks incurred by unnecessary interventions given to the large majority of women, who do not deliver within a week of presentation. Intervention "just-in-case" results in many avoidable admissions, women being transferred out of their local hospital unnecessarily and most women receiving unwarranted drugs, such as steroids and tocolytics. It also precludes appropriate transfers for others as neonatal cots are blocked pre-emptively, resulting in more dangerous ex-utero transfers. We have developed the QUiPP App which is a clinical decision-making aid based on previous outcomes of women, quantitative fetal fibronectin (qfFN) values and cervical length. It is hypothesised that using the QUiPP app will reduce inappropriate admissions and transfers. METHODS: A multi-site cluster randomised trial will evaluate whether the QUiPP app reduces inappropriate management for threatened preterm labour. The 13 participating centres will be randomly allocated to receive either intervention or control. If the QUiPP app calculates risk of delivery within 7 days to be is less than 5%, clinicians are advised that interventions may be withheld. Women's experience of threatened preterm labour assessment will be explored using self-completed questionnaires, with a subset of participants being invited to semi-structured interview. A health economics analysis is also planned. DISCUSSION: We hypothesise that the QUiPP app will improve identification of the most appropriate women for admission and transfer and ensure that therapies known to reduce risk of preterm neonatal morbidities are offered to those who need them. We will determine which women do not require these therapies, thereby reducing over-medicalisation and the associated maternal and fetal risks for these women. The findings will inform future national guidelines on threatened preterm labour. Beyond obstetrics, evaluating the impact of an app in an emergency setting, and our emphasis on balancing harms of over-treatment as well as under-treatment, make EQUIPTT a valuable contribution to translational medicine. TRIAL REGISTRATION: The EQUIPTT trial was prospectively registered on 16th January 2018 with the ISRCTN registry (no. 17846337 ).

Full dilation cesarean section: a risk factor for recurrent second-trimester loss and preterm birth.

INTRODUCTION: A previous cesarean section at full dilation (FDCS) is a risk factor for preterm birth. To provide insight into the risk to subsequent pregnancies, this cohort study compares the outcomes of pregnant women with a previous preterm birth associated with either a prior FDCS or a prior term vaginal delivery. MATERIAL AND METHODS: We identified women attending two inner-city preterm surveillance clinics (Guy's and St Thomas Hospital and University College London Hospital, London, UK) who had a spontaneous late miscarriage (14+0 -23+6 weeks) or spontaneous preterm birth (sPTB; <37 weeks' gestation) following a term pregnancy, and then a further pregnancy for analysis. Cases were those with a prior term FDCS, whereas controls had a prior term vaginal birth; both before the late miscarriage/sPTB. Main outcomes were gestational age at delivery and delivery at <30 weeks in the next (third) pregnancy. RESULTS: Over the study period, 66 women were identified who had a term delivery followed by a late miscarriage or sPTB, and a subsequent pregnancy. Recurrent sPTB <30 weeks was more common in cases than in controls (12/29, vs. 5/37, p = 0.02, Fisher's exact test, RR 3.06, 95% CI 1.22-7.71). Median gestation at delivery was significantly lower [249 days (IQR 154, 267) vs. 280 days (IQR 259, 280) p < 0.001]. Eleven women in the FDCS group received vaginal cerclage, five of whom delivered <37 weeks. CONCLUSION: In this cohort study we observed that women with a term FDCS and subsequent late miscarriage/sPTB have a higher risk of recurrent sPTB compared with women whose first term delivery was vaginal.

Rationale and design of SuPPoRT: a multi-centre randomised controlled trial to compare three treatments: cervical cerclage, cervical pessary and vaginal progesterone, for the prevention of preterm birth in women who develop a short cervix.

BACKGROUND: Clinically, once a woman has been identified as being at risk of spontaneous preterm birth (sPTB) due to a short cervical length, a decision regarding prophylactic treatment must be made. Three interventions have the potential to improve outcomes: cervical cerclage (stitch), vaginal progesterone and cervical pessary. Each has been shown to have similar benefit in reduction of sPTB, but there have been no randomised control trials (RCTs) to compare them. METHODS: This open label multi-centre UK RCT trial, will evaluate whether the three interventions are equally efficacious to prevent premature birth in women who develop a short cervix (<25 mm on transvaginal ultrasound). Participants will be asymptomatic and between 14+0 and 23+6 weeks' gestation in singleton pregnancies. Eligible women will be randomised to cervical cerclage, Arabin pessary or vaginal progesterone (200 mg once daily) (n = 170 women per group). The obstetric endpoints are premature birth rate <37 weeks' of gestation (primary), 34 weeks and 30 weeks (secondary outcomes) and short-term neonatal outcomes (a composite of death and major morbidity). It will also explore whether intervention success can be predicted by pre-intervention biomarker status. DISCUSSION: Preterm birth is the leading cause of perinatal morbidity and mortality and a short cervix is a useful way of identifying those most at risk. However, best management of these women has presented a clinical conundrum for decades. Given the promise offered by cerclage, Arabin pessary and vaginal progesterone for prevention of preterm birth in individual trials, direct comparison of these prophylactic interventions is now essential to establish whether one treatment is superior. If, as we hypothesise, the three interventions are equally efficacious, this study will empower women to make a choice of treatments based on personal preference and quality of life issues also explored by the study. Our exploratory analysis into whether the response to intervention is related to the pre-intervention biomarker status further our understanding of the pathophysiology of spontaneous preterm birth and help focus future research questions. TRIAL REGISTRATION: EudraCT Number: 2015-000456-15 . Registered 11th March 2015.

A case report of urethral prolapse in a 38 year old female with 46XY karyotype.

A 38-year old female presented with the acute onset of a vulval mass associated with pain and vaginal bleeding. She is female phenotype but has 46XY karyotype and Complete Androgen Insensitivity Syndrome (CAIS). At 15 years old she had a laparotomy and bilateral orchidectomy. Following admission, an examination under anaesthesia and cystoscopy was performed. A diagnosis of strangulated complete urethral prolapse was made. The lesion was excised with diathermy and the meatal skin was reanastomosed to the urethra. At follow-up, the urethra was well healed. The patient now attends Menopause Clinic for oestrogen-replacement therapy. We hope this case raises awareness of the possibility of urethral prolapse in younger women who are oestrogen deficient. It provides further incentive for compliance with hormone replacement therapy for patients with CAIS following gonadectomy, or other women with premature menopause.