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Objective Preterm prelabour rupture of membranes occurs in over one third of pregnant women with a cervical cerclage in situ. In the setting of preterm prelabour rupture of membranes, clinicians are faced with the difficult decision of the optimal timing for removing the cerclage. We compared the maternal and neonatal outcomes following immediate removal or retention of the cervical cerclage. Study design Women were retrospectively identified from St Thomas’s Hospital Preterm Surveillance clinic database. Asymptomatic women with preterm prelabour rupture of membranes were identified and separated into those that had the cerclage removed and those that had the cerclage retained within 24 h of presentation. Women who were symptomatic at presentation and who delivered within 24 h of presentation were excluded from the analysis. Maternal outcomes measured were latency between preterm prelabour rupture of membranes and delivery, gestation at delivery and maternal chorioamnionitis and infection markers. Neonatal outcomes including birthweight and Apgar scores were also measured. Results 43 women with cerclage retained for over 24 h following preterm prelabour rupture of membranes were compared to 25 women in whom the cerclage was removed. The latency between preterm prelabour rupture of membranes and delivery was on average 70.4 h longer in women who had their cerclage retained compared to the removed group (p = 0.009). Rates of chorioamnionitis, maternal blood results, neonatal birthweight and Apgar scores did not differ significantly between the two groups, however a trend towards higher rates of chorioamnionitis (60 % vs 45 %) were seen in the retained group. Conclusion Cervical cerclage retention in women following preterm prelabour rupture of membranes was associated with a longer latency period to delivery and was not significantly associated with any adverse obstetric, maternal or neonatal outcomes. Therefore, in women at risk of spontaneous preterm birth, cerclage retention may be beneficial, however these women and their babies should be monitored closely for any signs of infection. Further prospective randomised controlled studies assessing these outcomes as well as longer-term outcomes in these women and their children are needed.

Objective: Emergency cervical cerclage is often considered a controversial salvage measure for those pregnancies at high risk of mid-trimester loss or early preterm birth. To determine the efficacy and benefit of emergency cerclage insertion, we assessed the predictive value of quantitative fetal fibronectin (fFN) concentration in cervicovaginal fluid for spontaneous preterm birth in women with exposed fetal membranes prior to cerclage insertion. Study design: This was a retrospective observational study from St Thomas’ Hospital, London of a cohort of women with singleton pregnancy and exposed fetal membranes presenting between 18 and 23+6 weeks of gestation (n = 35), in the period 2015-2018. fFN concentrations in cervicovaginal fluid were measured quantitatively at presentation in all women within 24 h prior to cerclage insertion. Results: 35 eligible women with exposed fetal membranes who underwent an emergency cervical cerclage were identified. The median gestational age was 20 + 0 weeks (18 + 6−21 + 2) at presentation and 29 + 3 weeks (23 + 3−38 + 2) at delivery, with a median time from emergency cerclage to delivery of 65.5 days (17–126.5). In total, 12 women (34 %) delivered within 28 days of emergency cerclage insertion. 60 % of women with an fFN level above 500 ng/mL delivered within 28 days of cerclage insertion, and they all delivered before 37 weeks gestation. No women with fFN levels below 10 ng/mL delivered within 28 days and 75 % of these women delivered at term. Concentration of quantitative fFN at presentation correlated negatively with time to delivery (Spearman's rs = −0.52, p = 0.0016). Mann–Whitney U analysis demonstrated a significant difference in the distribution of qfFN concentrations in women who delivered preterm compared to those who did not, both within 28 days from testing (p = 0.0048) and

Funding Information: Andrew Shennan reports payment/honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Manipal India; support for attending meetings and/or travel from Hologic; leadership or fiduciary roles in the HTA Commissioning Board UK and Action on Pre‐eclampsia charity. Natalie Suff reports no conflicts of interest. Jo Leigh Simpson reports royalties from Springer and Elsevier; consulting fees from the Illumina Clinical Expert Panel 2020; payment or honoraria for lectures, presentations, speakers bureaus, or educational events from the 1 and 2 International Congresses on the Future of Women's Health, and a speaker's bureau at ASRM 2019; participation on a data safety monitoring board or advisory board for the FDA DSMB; and leadership or fiduciary roles in IFFS and PGDIS. Bo Jacobbson reports research grants from Swedish Research Council, Norwegian Research Council, March of Dimes, Burroughs Wellcome Fund and the US National Institute of Health; clinical diagnostic trials on NIPT with Ariosa (completed), Natera (ongoing), Vanadis (completed) and Hologic (ongoing) with expendidures reimbused per patient; clinical probiotic studies with product provided by FukoPharma (ongoing, no funding) and BioGaia (ongoing; also provided a research grant for the specific study); collaboration in IMPACT study where Roche, Perkin Elmer and Thermo Fisher provided reagents to PLGF analyses; coordination of scientific conferences and meetings with commercial partners as such as NNFM 2015, ESPBC 2016 and a Nordic educational meeting about NIPT and preeclampsia screening. Bo Jacobbson is also Chair of the FIGO Working Group for Preterm Birth and the European Association of Perinatal Medicine's special interest group of preterm delivery; steering group member of Genomic Medicine Sweden; chairs the Genomic Medicine Sweden complex diseases group; and is Swedish representative in the Nordic Society of Precision Medicine. Ben W. Mol reports an investigator grant from NHMRC; consultancy for ObsEva; and research funding from Guerbet, Ferring, and Merck KGaA. William A. Grobman reports no conflicts of interest. st nd

Background Full dilatation caesarean sections are associated with recurrent early spontaneous preterm birth and late miscarriage. The risk following first stage caesarean sections, are less well defined, but appears to be increased in late-first stage of labour. The mechanism for this increased risk of late miscarriage and early spontaneous preterm birth in these women is unknown and there are uncertainties with regards to clinical management. Current predictive models of preterm birth (based on transvaginal ultrasound and quantitative fetal fibronectin) have not been validated in these women and it is unknown whether the threshold to define a short cervix (≤25 mm) is reliable in predicting the risk of preterm birth. In addition the efficacy of standard treatments or whether benefit may be derived from prophylactic interventions such as a cervical cerclage is unknown. Methods There are three distinct components to the CRAFT project (CRAFT-OBS, CRAFT-RCT and CRAFT-IMG). CRAFT-OBS: Observational Study; To evaluate subsequent pregnancy risk of preterm birth in women with a prior caesarean section in established labour. This prospective study of cervical length and quantitative fetal fibronectin data will establish a predictive model of preterm birth. CRAFT-RCT: Randomised controlled trial arm; To assess treatment for short cervix in women at high risk of preterm birth following a fully dilated caesarean section. CRAFT-IMG: Imaging sub-study; To evaluate the use of MRI and transvaginal ultrasound imaging of micro and macrostructural cervical features which may predispose to preterm birth in women with a previous fully dilated caesarean section, such as scar position and niche. Discussion The CRAFT project will quantify the risk of preterm birth or late miscarriage in women with previous in-labour caesarean section, define the best management and shed light on pathological mechanisms so as to improve the care we offer to women and their babies. Trial registration CRAFT was prospectively registered on 25th November 2019 with the ISRCTN registry (10.1186/ISRCTN15068651).

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

Approximately 40% of preterm births are preceded by microbial invasion of the intrauterine space: ascent from the vagina is the most common pathway. Within the cervical canal, antimicrobial peptides and proteins (AMPs) help to constitute a barrier which prevents ascending infection. We investigated whether expression of the AMP, human β-defensin-3 (HBD3), in the cervical mucosa prevented bacterial ascent from the vagina into the uterine cavity of pregnant mice. An adeno-associated virus vector containing both the HBD3 gene and GFP transgene (AAV8 HBD3.GFP) or control (AAV8 GFP), was administered intravaginally into E13.5 pregnant mice. Ascending infection was induced at E16.5 using bioluminescent E.coli (E.coli K1 A192PP-lux2). Bioluminescence imaging showed bacterial ascent into the uterine cavity, cellular events that led to premature delivery and a reduction in pups born alive, compared with uninfected controls. In addition, a significant reduction in uterine bioluminescence in the AAV8 HBD3.GFP-treated mice was observed 24 hours post-E.coli infection, compared to AAV8 GFP treated mice, signifying reduced bacterial ascent in AAV8 HBD3.GFP-treated mice. There was also an increase in the number of living pups in AAV HBD3.GFP-treated mice. We propose that HBD3 may be considered a possible candidate for augmenting cervical innate immunity to prevent ascending infection-related preterm birth.

Preterm deliveries have multiple aetiologies and management is dependent on cause. Recent studies have shown that caesarean sections performed late in labour have been associated with recurrent, early premature births and late miscarriages (Figure 1). Both the prediction and management of these under‐recognised high‐risk cases needs to be elucidated.

Background A transabdominal cerclage has been shown in a recent randomized controlled trial to be superior to a low vaginal cerclage in reducing the risk of early preterm birth (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07–0.76; P=.01570) and fetal loss (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016–0.930) in women with a previous failed vaginal cerclage. 1 Objective We sought to create a video illustrating a transabdominal cerclage procedure for use as a teaching resource and describing this uncommon but important procedure for dissemination among clinicians. Study Design Transabdominal cerclage insertion in a non-gravid and gravid uterus (less than 14 weeks’ gestation) via laparotomy and laparoscopy was filmed with patients’ and clinicians’ consent in main theatres at St Thomas’ Hospital and University College London Hospital. The film footage was edited, and an audio narration by the surgeon was included to provide a description of the procedures. Results We developed an 8-minute video with an audio narration describing the insertion and management issues of an abdominal cerclage for free dissemination among clinicians who wish to learn how to perform this procedure. Conclusion An abdominal cerclage has been shown to significantly reduce early preterm birth and fetal loss more effectively than a low vaginal cerclage in women with a previous failed cerclage. More obstetricians and gynecologists need to be trained on how to perform the transabdominal cerclage procedure to increase its availability to suitable women. This procedure is technically straightforward and can be taught via video, which can easily be shared among clinicians at a low cost.

SUMMARY Preterm birth, defined as birth occurring prior to 37 weeks gestation, is a serious obstetric problem accounting for 11% of pregnancies worldwide. It is associated with significant neonatal morbidity and mortality. Predictive tests for preterm birth are incredibly important, given the huge personal, economic, and health impacts of preterm birth. They can provide reassurance for women who are unlikely to deliver early, but they are also important for highlighting those women at higher risk of premature delivery so that we can offer prophylactic interventions and help guide antenatal management decisions. Unfortunately, there is unlikely to be a single test for predicting preterm birth, but a combination of tests is likely to improve clinical prediction. This review explores the clinical utility of the currently marketed predictive tests for preterm birth in both singleton and multiple pregnancies, as well as discussing novel predictive tests that may be useful in the future.

We have previously designed a library of lentiviral vectors to generate somatic-transgenic rodents to monitor signalling pathways in diseased organs using whole-body bioluminescence imaging, in conscious, freely moving rodents. We have now expanded this technology to adeno-associated viral vectors. We first explored bio-distribution by assessing GFP expression after neonatal intravenous delivery of AAV8. We observed widespread gene expression in, central and peripheral nervous system, liver, kidney and skeletal muscle. Next, we selected a constitutive SFFV promoter and NFκB binding sequence for bioluminescence and biosensor evaluation.An intravenous injection of AAV8 containing firefly luciferase and eGFP under transcriptional control of either element resulted in strong and persistent widespread luciferase expression. A single dose of LPS-induced a 10-fold increase in luciferase expression in AAV8-NFκB mice and immunohistochemistry revealed GFP expression in cells of astrocytic and neuronal morphology. Importantly, whole-body bioluminescence persisted up to 240 days.To further restrict biosensor activity to the CNS, we performed intracerebroventricular injection of each vector. We observed greater restriction of bioluminescence to the head and spine with both vectors. Immunohistochemistry revealed strongest expression in cells of neuronal morphology. LPS administration stimulated a 4-fold increase over baseline bioluminescence.We have validated a novel biosensor technology in an AAV system by using an NFκB response element and revealed its potential to monitor signalling pathway in a non-invasive manner using a model of LPS-induced inflammation. This technology employs the 3R’s of biomedical animal research, complements existing germline-transgenic models and may be applicable to other rodent disease models with the use of different response elements.

Objectives Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay. Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review to quantify the non-surgical risk of brain abnormalities and of neurodevelopmental delay in infants with CHD. Methods MEDLINE, EMBASE and The Cochrane Library were searched electronically without language restrictions, utilizing combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, magnetic resonance imaging, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand-searched for additional reports. Cohort and case–control studies were included. Studies reporting neurodevelopmental outcomes and/or brain lesions on neuroimaging in infants with CHD before heart surgery were included. Cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Between-study heterogeneity was assessed using the I2 test. Results The search yielded 9129 citations. Full text was retrieved for 119 and the following were included in the review: 13 studies (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo congenital cardiac surgery and nine (n = 512 cases) reporting preoperative data on neurodevelopmental assessment. The prevalence of brain lesions on neuroimaging was 34% (95% CI, 24–46; I2 = 0%) in transposition of the great arteries, 49% (95% CI, 25–72; I2 = 65%) in left-sided heart lesions and 46% (95% CI, 40–52; I2 = 18.1%) in mixed/unspecified cardiac lesions, while the prevalence of neurodevelopmental delay was 42% (95% CI, 34–51; I2 = 68.9). Conclusions In the absence of chromosomal or genetic abnormalities, infants with CHD are at increased risk of brain lesions as revealed by neuroimaging and of neurodevelopmental delay. These findings are independent of the surgical risk, but it is unclear whether the time of onset is fetal or postnatal. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Introduction Antihypertensive drugs lower blood pressure by direct vascular effects or central vasodilatory mechanisms. Methyldopa is a commonly used in hypertensive disorders in pregnancy. Although methyldopa is effective in controlling maternal blood pressure, its effects on fetal growth and wellbeing is unknown. The aim of this study was to ascertain the effect of methyldopa on uterine artery and fetal dopplers in women with hypertensive disorders in pregnancy. Methods MEDLINE (1966 – March 2012), EMBASE (1974 - March 2012) and The Cochrane library (inception–March 2012), utilising combinations of the terms methyldopa, hypertens*, pre-eclamp*, preeclamp*, pre eclamp*, pregnan*, uterine, uteroplacental, umbilical, middle cerebral artery and doppler. Between-study heterogeneity was assessed using the I2 statistic. Results The search yielded 429 citations. Full manuscripts were retrieved for 32 and 6 were included in the review and meta-analysis. Six studies (n = 188) have reported the effect of methyldopa on uterine artery doppler pulsatility index (PI). The standardised mean difference (SMD) was –0.22 (95% CI: –0.43 to –0.02). Five studies (n = 110) were included that evaluated the effect of methyldopa on umbilical artery Doppler PI. The SMD was –0.05 (95% CI: –0.32 to 0.21). Four studies (n = 82) reported the effect of methyldopa on middle cerebral artery PI. The SMD was –0.34 (95% CI: –0.65 to 0.03). Conclusion In pregnancies complicated by hypertension, methyldopa seems to have a small favourable effect on uterine artery dopplers. These results provide reassurance that the maternal hypotensive effect of methyldopa is unlikely to have a clinically significant adverse effect on the pregnancy.

Objectives Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay, partly attributed to the risk of brain injury during cardiac surgery. However, neuroimaging studies have demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review in order to quantify the non-surgical risk of brain abnormalities and neurodevelopmental delay in fetuses/newborns with CHD. Methods MEDLINE, EMBASE and The Cochrane Library, without language restrictions were searched electronically, utilising combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, MRI, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand searched for additional reports. Cohort and case-control studies were included. Case reports and editorials were excluded. Between-study heterogeneity was assessed using the I2 statistic. Results The search yielded 9,129 citations. Full manuscripts were retrieved for 119, and 30 were included in the review and meta-analysis. 21 studies (n = 953) have reported brain abnormalities in fetuses, newborn or infants with CHD, either preoperatively or in those who did not undergo congenital cardiac surgery. The remaining 9 studies (n = 512) have reported preoperative data on neurodevelopmental assessment in newborn or infants with CHD. The prevalence of brain abnormalities was 36% (95% CI, 26%, 47%; I² = 90.5%) and of the neurodevelopmental delay 42% (95% CI, 34%, 51%; I² = 68.9%), though with heterogeneity between studies. Conclusions In the absence of chromosomal or genetic abnormalities, fetuses with CHD are at increased risk of brain abnormalities and neurodevelopmental delay, which are independent of the surgical risk.

Introduction Pre-eclampsia (PE), particularly early-onset PE (PE requiring delivery before 34 weeks), is commonly associated with fetal growth restriction (FGR). The evidence for an association between FGR and a more severe PE phenotype is controversial. Objectives The main aim of this study was to investigate whether the presence of FGR in women with early-onset PE is associated with more severe maternal disease compared to those with appropriately grown fetuses (AGA). Methods This was a retrospective cohort study of women with early-onset PE between 2001 and 2010 at University College London Hospital. The diagnosis of PE was made according to the criteria defined by the International Society of the Study of Hypertension in Pregnancy (ISSHP). PE was diagnosed when the systolic blood pressure was 140mmHg or more and/or the diastolic blood pressure 90mmHg or more on at least two occasions four hours apart developing after 20 weeks of gestation in previously normotensive women with proteinuria of 300 mg or more in 24h or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-h collection is available. FGR was defined as birthweight less than the 5th centile, with abnormal umbilical artery Doppler (raised pulsatility index, absent or reversed end-diastolic flow). Maternal, fetal and neonatal data were collected and study groups compared using Chi-square test or Fisher's exact test (categorical variables), and Mann Whitney- U test (continuous variables). Data analysis was performed using SPSS 16.0. Results In women with early-onset PE ( n =134), FGR ( n =66, 49%) was associated with significantly higher perinatal mortality ( p =0.02). Gestational age at delivery was significantly lower in the FGR group (median, IQR: 29.0 weeks, 28.0–32.8 vs 32.0, 30.0–33.2, p =0.01). However, maternal indicators of PE severity, including blood pressure 3 160mmHg systolic or 3 110mmHg diastolic, ALT>100U/L, platelet count 9 /L, use of magnesium sulphate or use of antihypertensive therapy, were similar in the two groups. Conclusion In women with early onset PE, FGR was associated with worse perinatal outcome, but was not associated with a more severe maternal PE phenotype. This may be because the presence of FGR in these women leads to earlier iatrogenic delivery, before the maternal condition deteriorates, but further studies are needed to investigate this.