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.

Placental multimodal MRI prior to spontaneous preterm birth <32 weeks' gestation: An observational study.

OBJECTIVE: To utilise combined diffusion-relaxation MRI techniques to interrogate antenatal changes in the placenta prior to extreme preterm birth among both women with PPROM and membranes intact, and compare this to a control group who subsequently delivered at term. DESIGN: Observational study. SETTING: Tertiary Obstetric Unit, London, UK. POPULATION: Cases: pregnant women who subsequently spontaneously delivered a singleton pregnancy prior to 32 weeks' gestation without any other obstetric complications. CONTROLS: pregnant women who delivered an uncomplicated pregnancy at term. METHODS: All women consented to an MRI examination. A combined diffusion-relaxation MRI of the placenta was undertaken and analysed using fractional anisotropy, a combined T2*-apparent diffusion coefficient model and a combined T2*-intravoxel incoherent motion model, in order to provide a detailed placental phenotype associated with preterm birth. Subgroup analyses based on whether women in the case group had PPROM or intact membranes at time of scan, and on latency to delivery were performed. MAIN OUTCOME MEASURES: Fractional anisotropy, apparent diffusion coefficients and T2* placental values, from two models including a combined T2*-IVIM model separating fast- and slow-flowing (perfusing and diffusing) compartments. RESULTS: This study included 23 women who delivered preterm and 52 women who delivered at term. Placental T2* was lower in the T2*-apparent diffusion coefficient model (p < 0.001) and in the fast- and slow-flowing compartments (p = 0.001 and p < 0.001) of the T2*-IVIM model. This reached a higher level of significance in the preterm prelabour rupture of the membranes group than in the membranes intact group. There was a reduced perfusion fraction among the cases with impending delivery. CONCLUSIONS: Placental diffusion-relaxation reveals significant changes in the placenta prior to preterm birth with greater effect noted in cases of preterm prelabour rupture of the membranes. Application of this technique may allow clinically valuable interrogation of histopathological changes before preterm birth. In turn, this could facilitate more accurate antenatal prediction of preterm chorioamnionitis and so aid decisions around the safest time of delivery. Furthermore, this technique provides a research tool to improve understanding of the pathological mechanisms associated with preterm birth in vivo.

The Fetal Spleen in Low-Risk Pregnancies and prior to Preterm Birth: Observational Study of the Role of Anatomical and Functional Magnetic Resonance Imaging.

INTRODUCTION: Spontaneous preterm birth complicates ∼7% of pregnancies and causes morbidity and mortality. Although infection is a common etiology, our understanding of the fetal immune system in vivo is limited. This study aimed to utilize T2-weighted imaging and T2* relaxometry (which is a proxy of tissue oxygenation) of the fetal spleen in uncomplicated pregnancies and in fetuses that were subsequently delivered spontaneously prior to 32 weeks. METHODS: Women underwent imaging including T2-weighted fetal body images and multi-eco gradient echo single-shot echo planar sequences on a Phillips Achieva 3T system. Previously described postprocessing techniques were applied to obtain T2- and T2*-weighted imaging of the fetal spleen and T2-weighted fetal body volumes. RESULTS: Among 55 women with uncomplicated pregnancies, an increase in fetal splenic volume, splenic:body volume, and a decrease in splenic T2* signal intensity was demonstrated across gestation. Compared to controls, fetuses who were subsequently delivered prior to 32 weeks' gestation (n = 19) had a larger spleen when controlled for the overall size of the fetus (p = 0.027), but T2* was consistent (p = 0.76). CONCLUSION: These findings provide evidence of a replicable method of studying the fetal immune system and give novel results on the impact of impending preterm birth on the spleen. While T2* decreases prior to preterm birth in other organs, preservation demonstrated here suggests preferential sparing of the spleen.

Adrenal volumes in fetuses delivering prior to 32 weeks' gestation: An MRI pilot study.

INTRODUCTION: Spontaneous preterm birth prior to 32 weeks' gestation accounts for 1% of all deliveries and is associated with high rates of morbidity and mortality. A total of 70% are associated with chorioamnionitis which increases the incidence of morbidity, but for which there is no noninvasive antenatal test. Fetal adrenal glands produce cortisol and dehydroepiandosterone-sulphate which upregulate prior to spontaneous preterm birth. Ultrasound suggests that adrenal volumes may increase prior to preterm birth, but studies are limited. This study aimed to: (i) demonstrate reproducibility of magnetic resonance imaging (MRI) derived adrenal volumetry; (ii) derive normal ranges of total adrenal volumes, and adrenal: body volume for normal; (iii) compare with those who have spontaneous very preterm birth; and (iv) correlate with histopathological chorioamnionitis. MATERIAL AND METHODS: Patients at high risk of preterm birth prior to 32 weeks were prospectively recruited, and included if they did deliver prior to 32 weeks; a control group who delivered an uncomplicated pregnancy at term was also recruited. T2 weighted images of the entire uterus were obtained, and a deformable slice-to-volume method was used to reconstruct the fetal abdomen. Adrenal and body volumes were obtained via manual segmentation, and adrenal: body volume ratios generated. Normal ranges were created using control data. Differences between groups were investigated accounting for the effect of gestation by use of regression analysis. Placental histopathology was reviewed for pregnancies delivering preterm. RESULTS: A total of 56 controls and 26 cases were included in the analysis. Volumetry was consistent between observers. Adrenal volumes were not higher in the case group (p = 0.2); adrenal: body volume ratios were higher (p = 0.011), persisting in the presence of chorioamnionitis (p = 0.017). A cluster of three pairs of adrenal glands below the fifth centile were noted among the cases all of whom had a protracted period at risk of preterm birth prior to MRI. CONCLUSIONS: Adrenal: body volume ratios are significantly larger in fetuses who go on to deliver preterm than those delivering at term. Adrenal volumes were not significantly larger, we hypothesize that this could be due to an adrenal atrophy in fetuses with fulminating chorioamnionitis. A straightforward relationship of adrenal size being increased prior to preterm birth should not be assumed.

Outcomes following elective cerclage versus ultrasound surveillance in women with one prior preterm event.

OBJECTIVE: Preterm birth, defined as delivery before 37 weeks' gestation, is a major obstetric challenge and is associated with serious long-term complications in those infants that survive. Preventative management includes cervical cerclage, either as an elective procedure or performed following transvaginal ultrasound surveillance and shortening of the cervix (≤25 mm). Significant questions remain regarding the optimal management, target population and technique. Therefore, this study aimed to assess differences in risk factors and pregnancy outcomes for women who received an elective cerclage versus ultrasound surveillance, following one prior premature event (spontaneous preterm birth/second trimester loss). STUDY DESIGN: Women were retrospectively identified from St Thomas's Hospital Preterm Birth Clinical Network Database. Women who had one prior premature event (between 14+0 and 36+6 weeks' gestation) were included and they were separated into those that an elective cerclage and those who underwent ultrasound surveillance to assess differences in demographics, pregnancy risk factors and preterm birth outcomes. We excluded women who received other preventative therapies. We also separately analysed those women who required an ultrasound-indicated cerclage, comparing the differences between women that delivered preterm and term. RESULTS: We collected data from 1077 women who had a prior preterm event. 66 women received an elective cerclage. 11.4% of women who had ultrasound surveillance received an ultrasound indicated cerclage. Women with a prior history of mid-trimester loss, instead of preterm birth, were more likely to receive an elective cerclage. The mean gestational age of delivery was similar between those women who received an elective cerclage and those who had ultrasound surveillance with and without an ultrasound-indicated cerclage (38+1 vs 37+1), however, preterm birth rates <37 weeks' were twice as high in this ultrasound group (OR 2.3 [1.1-4.5], p = 0.02). In those women that do require an ultrasound-indicated cerclage, 50.4% deliver preterm. CONCLUSIONS: In conclusion, this study shows that in women with one prior preterm event, both history-indicated cerclage and ultrasound surveillance are appropriate management options. The majority of women undergoing ultrasound surveillance did not require a cerclage and so avoided the potential perioperative complications of cerclage insertion. However, those that did require an ultrasound-indicated cerclage were at high risk of preterm birth so should be followed up closely to enable adequate preterm birth preparation. Further prospective studies comparing history indicated cerclage and US surveillance in women with one prior preterm event are necessary.

Amniotic fluid sludge is associated with earlier preterm delivery and raised cervicovaginal interleukin 8 concentrations.

BACKGROUND: Preterm birth is the leading cause of global neonatal mortality. Amniotic fluid sludge, thought to indicate intra-amniotic infection, may have potential as a clinical biomarker of preterm birth risk. OBJECTIVE: This study aimed to analyze whether the presence of amniotic fluid sludge in pregnant participants with a known short cervical length can help improve the understanding of the etiology and guide management choice. STUDY DESIGN: This was a retrospective cohort study analyzing the effects of amniotic fluid sludge presence on the risk of preterm birth in high-risk asymptomatic pregnant participants with a short cervical length (<25 mm) at a large tertiary referral maternity center in London. Amniotic fluid sludge was detected on a routine transvaginal ultrasound scan. RESULTS: Overall, 147 pregnant participants with a short cervical length were identified, 54 of whom had amniotic fluid sludge. Compared with pregnant participants without amniotic fluid sludge, pregnant participants with amniotic fluid sludge were more likely to have a short cervical length (19 vs 14 mm, respectively; P<.0001) and increased cervicovaginal fetal fibronectin concentrations at diagnosis (125 vs 45 ng/mL, respectively; P=.0006). Pregnant participants with amniotic fluid sludge were at increased risk of midtrimester loss and delivery before 24 weeks of gestation (relative risk, 3.4; 95% confidence interval, 1.2-10.3). Furthermore, this study showed that pregnant participants with amniotic fluid sludge have increased cervicovaginal interleukin 8 concentrations, supporting the concept of amniotic fluid sludge as an indicator of an inflammatory response to microbial invasion (P=.03). Neonatal outcomes were similar between the 2 groups. CONCLUSION: In our cohort of high-risk asymptomatic pregnant participants with a short cervical length, the presence of amniotic fluid sludge is associated with an increased risk of delivery before 24 weeks of gestation. Moreover, pregnant participants with amniotic fluid sludge were more likely to have raised fetal fibronectin levels and inflammatory cytokines, particularly interleukin 8, in the cervicovaginal fluid, supporting the concept that amniotic fluid sludge is associated with an infective or inflammatory process. Future research should aim to further establish the clinical significance of amniotic fluid sludge presence and guide subsequent management.

Removal versus retention of cervical cerclage with preterm prelabor rupture of membranes: Systematic review and meta-analysis.

OBJECTIVE: To evaluate maternal and perinatal outcomes of removal versus retention of cervical cerclage after premature preterm rupture of membranes (pPROM). STUDY DESIGN: Medline, Embase and Cochrane databases were searched electronically on February 2023 utilizing combinations of the relevant medical subject heading (MeSH) terms, keywords, and word variants that were considered suitable for the topic. Either prospective or retrospective trials were considered suitable for the inclusion. The coprimary outcome of this study were pregnancy latency >7 days from pPROM and pregnancy latency >48 h from pPROM. Random effect head to-head meta-analyses were performed to directly compare each outcome, expressing the results as summary odds ratio (OR) for dichotomous outcomes and as mean difference (MD) for continuous outcomes, plus relative 95% confidence interval (CI). Quality assessment of the included studies was performed using the Newcastle-Ottawa Scale. RESULTS: Six studies involving a total of 377 women (169 in the "removal" and 208 in the "retention" group) were included. The rate of pregnancy prolongation >48 h was significantly lower in the removal compared to retention group (OR 0.15, 95% CI 0.07-0.31; p < 0.0001), as well as the rate of pregnancy prolongation >7 days (OR 0.30 95% CI 0.11-0.83; p = 0.02) and pregnancy latency expressed in days (MD -2.84 days, 95% CI -5.40 to -0.29; p = 0.03). The rate of chorioamnionitis was significantly lower in the removal compared to the retention group (OR 0.57 95% CI 0.34-0.96p = 0.03) as was the rate of Apgar score < 7 at 5 min (OR 0.22 95% CI 0.08-0.56; p = 0.002). There was no difference between removal and retention groups for all the other maternal and perinatal outcomes. CONCLUSIONS: The decision whether to remove or retain cerclage in case of pPROM should balance the prematurity-related risks with that of infectious complications, thus highlighting the need for tailored management based on gestational age at occurrence of pPROM.

Cervical cerclage technique: what do experts actually achieve?

BACKGROUND: Cervical cerclage is a recognized intervention in the management of women at risk of preterm birth and midtrimester loss. The mechanism of action of cerclage is unclear, and the technique has been poorly researched. OBJECTIVE: This study aimed to evaluate cerclage technique among experienced obstetricians, using a previously developed and evaluated cerclage simulator. STUDY DESIGN: This prospective experimental simulation and observational study used identical simulators for 28 consultant obstetricians who were asked to perform their normal cerclage. Suture type, height, knot site, and free thread length were recorded. Using computed tomography, depth of bite and tension (by reduction in area of cervix) were calculated. RESULTS: A total of 52 cervical cerclages were completed (Mersilene tape, n=20; monofilament suture, n=32). Mean suture height was 33 mm (standard deviation, 7.7 mm), greater with monofilament suture than with Mersilene tape, and associated with smaller needle size. Mean depth of bite and mean reduction of starting area did not differ by suture type. Seven procedures showed ≥1 suture bite that had entered the cervical canal once or more. CONCLUSION: This study assessed cerclage technique of experienced obstetricians using simulators and computed tomography imaging, and demonstrated wide variation in technique; this may affect the efficacy of the procedure. Further work should establish optimal technique and consensus for training and clinical practice.

Cervical cerclage training: Development and assessment of a simulator.

BACKGROUND: Cervical cerclage is a mainstay intervention for the prevention of spontaneous preterm birth in high-risk women. Simulation training facilitates high-level skill transfer in a low-consequence environment, and is being integrated into obstetrics and gynecology training. OBJECTIVE: This study aimed to develop a simulator for cervical cerclage, determine its validity as a simulator, and identify parameters suitable as proxy markers for performance. STUDY DESIGN: The 3 aims of this study were achieved, namely: (1) simulator design by obstetricians and a commercial company; (2) survey of obstetricians and gynecologists across a variety of training stages to determine need for and opinion of the simulator; and (3) comparison of novice and expert groups across a variety of proxy markers for successful cerclage insertion. RESULTS: Obstetricians and gynecologists found the simulator to be similar to clinical scenarios and suitable for skill training. Novice participants stated that the use of the simulator improved their confidence (P=.016). In a comparison between 6 expert and 8 novice surgeons, there seemed to be variations across multiple measurements of cerclage placement. CONCLUSION: Simulation is an increasingly prominent training modality for surgical skills. The simulator described herein was considered suitable for training by obstetricians and gynecologists. Further work should focus on the validations of proxy markers of successful insertion, longitudinal assessment of trainees, and correlation of training outcomes with clinical outcomes.

Successful term pregnancy following cervical cerclage for uterine atrophy secondary to childhood radiotherapy.

Pelvic radiotherapy can lead to scarring and atrophy of reproductive organs including the uterus. This may lead to complications, such as preterm birth, during pregnancy. The mechanism by which preterm birth is associated with pelvic radiation is believed to be due to inefficient uterine stretch or a deficient cervix. We report a case of cervical shortening during the second trimester in a pregnant woman with a history of pelvic radiotherapy in childhood. Ultrasound surveillance and cervical cerclage inserted in the shortening cervix successfully prevented preterm labour in this case. Cerclage insertion led to a longer cervix and lower fibronectin. Although cervical cerclage does not influence uterine stretch, it may be able to prevent cervical dilatation and therefore prevent ascending infections and subsequent inflammatory sequelae which results in preterm labour. We recommend cervical surveillance and targeted cerclage interventions to prevent preterm labour in women with prior childhood pelvic radiotherapy.

The use of fetal fibronectin and cervical length measurements in the prediction of spontaneous preterm birth in women with an Arabin pessary in situ.

OBJECTIVES: The ability to predict spontaneous PTB (sPTB) has improved greatly, allowing women at risk to be managed with prophylactic interventions such as cervical cerclage and the Arabin pessary. Cervicovaginal fetal fibronectin (qfFN) concentration and ultrasound measurement of cervical length (CL) are the two most established tools to predict sPTB. There is however limited data regarding the predictive value of qfFN and CL tests following insertion of an Arabin pessary. Our aim was therefore to determine the clinical use of qfFN and CL measurements to predict sPTB in women fitted with an Arabin pessary. STUDY DESIGN: This study is a secondary analysis on the SUPPORT trial data. Data were prospectively collected from women attending high-risk preterm surveillance clinics in 3 London centres between July 2015 and April 2020. The matched control group was pregnant women attending the same high-risk preterm surveillance clinics who had not received an Arabin pessary. Receiver operating characteristic (ROC) curves for prediction of birth by 34 and by 37 weeks' gestation were generated for qfFN and CL measurements combined for both study groups. A formal comparison of area under the curve before 34 weeks' gestation (AUC < 34 weeks) was made between the two study groups. RESULTS: At our primary endpoint of sPTB < 34 weeks' gestation, qfFN was a good predictor of sPTB in cases with an Arabin pessary in situ (AUC, 0.79, 95% CI: 0.62-0.90) and no worse than the control group who did not have an Arabin pessary, (AUC 0.74, 95% CI: 0.48-0.96). CL had good prediction for sPTB < 34 weeks' gestation in the control group (AUC 0.76, 95% CI: 0.63-0.88) but was lower and non-significant in the Arabin pessary case group (AUC 0.60, 95% CI: 0.43-0.76). CONCLUSIONS: This study showed that cervicovaginal qfFN concentration is equally reliable in the prediction of sPTB in pregnant women at increased risk of sPTB with and without an Arabin pessary in situ, and significantly better than CL measurement alone for predicting delivery before 34 weeks. This commonly used test therefore has utility in predicting sPTB in pregnant women fitted with an Arabin pessary.

Antenatal diagnosis of chorioamnionitis: A review of the potential role of fetal and placental imaging.

Chorioamnionitis is present in up to 70% of spontaneous preterm births. It is defined as an acute inflammation of the chorion, with or without involvement of the amnion, and is evidence of a maternal immunological response to infection. A fetal inflammatory response can coexist and is diagnosed on placental histopathology postnatally. Fetal inflammatory response syndrome (FIRS) is associated with poorer fetal and neonatal outcomes. The only antenatal diagnostic test is amniocentesis which carries risks of miscarriage or preterm birth. Imaging of the fetal immune system, in particular the thymus and the spleen, and the placenta may give valuable information antenatally regarding the diagnosis of fetal inflammatory response. While ultrasound is largely limited to structural information, MRI can complement this with functional information that may provide insight into the metabolic activities of the fetal immune system and placenta. This review discusses fetal and placental imaging in pregnancies complicated by chorioamnionitis and their potential future use in achieving non-invasive antenatal diagnosis.

Prior term delivery increases risk of subsequent recurrent preterm birth: An unexpected finding.

BACKGROUND: Women with a prior pregnancy at term are generally considered to be at reduced risk for subsequent spontaneous preterm birth (sPTB), whereas a previous sPTB is a major predictor for a future sPTB. AIMS: The objective of this study was to investigate the risk of recurrent sPTB in women with a prior term birth and a subsequent sPTB. MATERIALS AND METHODS: This is a retrospective cohort study conducted at St Thomas' Hospital in London, UK. There were 430 women included: 230 with a term birth (caesarean section or vaginal delivery) preceding a sPTB (term + sPTB group) and 200 with a prior sPTB only (sPTB only group). The primary outcome was sPTB, <37 weeks gestation. RESULTS: Of the term + sPTB group, 38.7% (89/230) had a recurrent sPTB compared to 20% (40/200) in the sPTB only group (P < 0.0001), with a relative risk (RR) of 1.9. Of women who had a term caesarean section and a subsequent PTB, 50% (30/60) had a further sPTB (RR 2.5 compared to the sPTB only group), while 34.7% (59/170) of women who had a term vaginal birth and subsequent sPTB, had a further sPTB (RR 1.7 compared to the sPTB only group). CONCLUSION: In women who have had a previous sPTB, the risk of a recurrence is much higher than in women with a prior term birth. The aetiology of PTB may be different in this subgroup of women and needs to be further elucidated to determine how best to identify and treat them.

Previous term emergency caesarean section is a risk factor for recurrent spontaneous preterm birth; a retrospective cohort study.

OBJECTIVES: Emergency caesarean sections (EmCS), particularly those performed in the second stage of labour, have been associated with a risk of subsequent preterm birth. More worrying is that the risk of sPTB recurrence appears to be high in women who have had a second stage EmCS and a subsequent sPTB. However, there is a paucity of evidence regarding the risk of recurrence in women who have had a prior term EmCS at any stage of labour followed by a sPTB. This study aims to investigate the relationship between all term in labour EmCS and the risk of recurrent spontaneous preterm birth (sPTB). STUDY DESIGN: This is an observational, retrospective cohort study conducted at St Thomas' Hospital, a tertiary-level maternity hospital in London, United Kingdom. 259 women were included; 59 women with a term in labour EmCS preceding a sPTB (EmCS group) and 200 women with a prior sPTB only (control group). The initial EmCS was further categorised into first stage (FS)-EmCS or second stage (SS)-EmCS. Primary outcome was sPTB in Pregnancy C < 37 weeks' gestation. Secondary outcomes included sPTB < 34 weeks' and < 24 weeks' gestation. RESULTS: 54% (32/59) of the EmCS group had a recurrent sPTB < 37 weeks compared to 20% (40/200) of the control women (p < 0.0001) with a relative risk of 2.71 [95%CI 1.87-3.87]). Of women who had a SS-EmCS and a subsequent PTB, 61.9% (13/21) had a further sPTB (RR 3.0 [95%CI, 1.8-4.5] compared to control women). In addition, there is nearly a 6-fold increased risk of a recurrent sPTB or midtrimester loss < 24 weeks' gestation in these women (RR 5.65 [95%CI2.6-12.0]). CONCLUSIONS: In women who have had a previous sPTB in which a term in labour EmCS is a risk factor, the risk of a further sPTB is much higher than in those women where a prior sPTB is the sole risk factor. Furthermore, EmCS at both the first and second stage of labour are associated with a increased risk of recurrent sPTB. Further work should ascertain which women who have had a prior term EmCS are at risk of sPTB and recurrence, and how best to identify and treat them.

FIGO good practice recommendations on progestogens for prevention of preterm delivery.

Women at high risk of preterm birth (either a previous spontaneous preterm birth and/or sonographic short cervix) with a singleton gestation should be offered daily vaginal progesterone or weekly 17-OHPC treatment to prevent preterm birth. Benefit is most significant in those with prior history of preterm birth and a short cervix. For women with a previous spontaneous preterm birth and a cervix ≥30 mm the effectiveness of progesterone is uncertain. In asymptomatic women with no prior history of previous preterm birth, no mid-trimester loss, or no short cervical length, progesterone therapy is not recommended for the prevention of preterm birth. For those with unselected multiple pregnancies, progesterone therapy is not recommended for the prevention of preterm birth. Daily vaginal progesterone or weekly 17-OHPC treatment can be used for the prevention of preterm birth. The preparation used should be decided by the woman and her clinician. There is no evidence of neurological or developmental benefit or harm in babies whose mothers use progestogens for preterm birth prevention antenatally.

In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications.

The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D-such as their cellular tropism, receptor usage, and in vivo biodistribution profile-remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)-a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism.

Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-µ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS.

Optimal timing of cervical cerclage removal following preterm premature rupture of membranes; a retrospective analysis.

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.