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Background Vasa praevia is an obstetric condition in which the fetal vessels run through the membrane over the internal cervical os, unprotected by the placenta or umbilical cord. It is associated with perinatal mortality if not diagnosed antenatally. We investigated the incidence and outcomes of vasa praevia in the UK. Methods We conducted a population-based descriptive study using the UK Obstetric Surveillance System (UKOSS). Cases were identified prospectively through monthly UKOSS submissions form all UK hospitals with obstetrician-led maternity units. All women diagnosed with vasa praevia who gave birth between 1st December 2014 and 30th November 2015 were included. The main outcome was incidence of vasa praevia with 95% confidence intervals, using 2015 maternities as the denominator. Results Fifty-one women met the case definition. The incidence of diagnosed vasa praevia was 6.64 per 100,000 maternities (95% CI 5.05-8.73). Of 198 units, 10 (5%) had a vasa praevia screening programme; one of these 10 units identified 25% of the antenatally diagnosed cases. Among women who had vasa praevia diagnosed or suspected antenatally (n=28, 55%), there were no perinatal deaths or hypoxic ischaemic encephalopathy (HIE). Twenty-four women with antenatal diagnosis were hospitalised at a median gestation of 32 weeks and caesarean section was scheduled at a median gestation of 36 weeks. When vasa praevia was diagnosed peripartum (n=23, 45%), the perinatal mortality rate was 37.5% and 47% of survivors developed HIE. Conclusions The incidence of diagnosed vasa praevia was lower than anticipated. There was high perinatal mortality and morbidity for cases not diagnosed antenatally. The incidence of antenatally identified cases was much higher in the few centres that actively screened for this condition, and the perinatal outcomes were better. However, this group were all delivered by caesarean section and may include women who would not have experienced any adverse perinatal outcome.

BackgroundCervical 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 Methods and findingsSuPPoRT 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 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 ConclusionsIn 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 registrationEU Clinical Trials register. EudraCT Number: 2015-000456-15, clinicaltrialsregister.eu., ISRCTN Registry: ISRCTN13364447, isrctn.com.

Introduction Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.Methods and analysis BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1–5/subject) and untreated prospective controls (≤30). Infants

Abstract Background Magnetic resonance imaging (MRI) provides excellent soft tissue visualisation which may be useful in late pregnancy to predict labour outcome and maternal/neonatal birth trauma. Objective To study if MRI in late pregnancy can predict maternal and neonatal outcomes of labour and birth. Methods Systematic review of studies that performed MRI in late pregnancy or immediately postpartum. Studies were included if they imaged maternal pelvic or neonatal structures and assessed birth outcome. Meta-analysis was not performed due to the heterogeneity of studies. Results Eighteen studies were selected. Twelve studies explored the value of MRI pelvimetry measurement and its utility to predict cephalopelvic disproportion (CPD) and vaginal breech birth. Four explored cervical imaging in predicting time interval to birth. Two imaged women in active labour and assessed mouldability of the fetal skull. No marker of CPD had both high sensitivity and specificity for predicting labour outcome. The fetal pelvic index yielded sensitivities between 59 and 60%, and specificities between 34 to 64%. Similarly, although the sensitivity of the cephalopelvic disproportion index in predicting labour outcome was high (85%), specificity was only 56%. In women with breech presentation, MRI was demonstrated to reduce the rates of emergency caesarean section from 35 to 19%, and allowed better selection of vaginal breech birth. Live birth studies showed that the fetal head undergoes a substantial degree of moulding and deformation during cephalic vaginal birth, which is not considered during pelvimetry. There are conflicting studies on the role of MRI in cervical imaging and predicting time interval to birth. Conclusion MRI is a promising imaging modality to assess aspects of CPD, yet no current marker of CPD accurately predicts labour outcome. With advances in MRI, it is hoped that novel methods can be developed to better identify individuals at risk of obstructed or pathological labour. Its role in exploring fetal head moulding as a marker of CPD should be further explored.

Abstract Background Legal and social changes mean that information sharing and consent in antenatal and intrapartum settings is contentious, poorly understood and uncertain for healthcare professionals. This study aimed to investigate healthcare professionals’ views and experiences of the consent process in antenatal and intrapartum care. Methods Qualitative research performed in a large urban teaching hospital in London. Fifteen healthcare professionals (obstetricians and midwives) participated in semi-structured in-depth interviews. Data were collectively analysed to identify themes in the experiences of the consent process. Results Three themes were identified: (1) Shared decision-making and shared responsibility –engaging women in dialogue is often difficult and, even when achieved, women are not always able or do not wish to share responsibility for decisions (2) Second-guessing women – assessing what is important to a woman is inherently difficult so healthcare professionals sometimes feel forced to anticipate a woman’s views (3) Challenging professional contexts – healthcare professionals are disquieted by consent practice in the Labour ward setting which is often at odds with legal and professional guidance. Conclusions Results suggest that there is a mismatch between what is required of healthcare professionals to effect an antenatal or intrapartum consent process concordant with current legal and professional guidance and what can be achieved in practice. If consent, as currently articulated, is to remain the barometer for current practice, healthcare professionals need more support in ways of enabling women to make decisions which healthcare professionals feel confident are autonomous whatever the circumstances of the consultation.

BackgroundTimely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness.Methods and findingsPregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset.ConclusionsIn this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice.Trial registrationThe study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).

In a Perspective, Lucy Chappell and Anna David discuss ways to develop and test pharmacological treatments in pregnancy.

BACKGROUND:Research using orthotopic and transgenic models of cancer requires imaging methods to non-invasively quantify tumour burden. As the choice of appropriate imaging modality is wide-ranging, this study aimed to compare low-field (1T) magnetic resonance imaging (MRI), a novel and relatively low-cost system, against established preclinical techniques: bioluminescence imaging (BLI), ultrasound imaging (US), and high-field (9.4T) MRI. METHODS:A model of colorectal metastasis to the liver was established in eight mice, which were imaged with each modality over four weeks post-implantation. Tumour burden was assessed from manually segmented regions. RESULTS:All four imaging systems provided sufficient contrast to detect tumours in all of the mice after two weeks. No significant difference was detected between tumour doubling times estimated by low-field MRI, ultrasound imaging or high-field MRI. A strong correlation was measured between high-field MRI estimates of tumour burden and all the other modalities (p < 0.001, Pearson). CONCLUSION:These results suggest that both low-field MRI and ultrasound imaging are accurate modalities for characterising the growth of preclinical tumour models.

Congenital diseases are responsible for over a third of all pediatric hospital admissions. Advances in prenatal screening and molecular diagnosis have allowed the detection of many life-threatening genetic diseases early in gestation. In utero transplantation with stem cells (IUT) could cure affected fetuses but so far in humans, successful IUT using allogeneic haematopoietic stem cells (HSCs), has been limited to fetuses with severe immunologic defects and more recently IUT with allogeneic mesenchymal stem cell transplantation, has improved phenotype in osteogenesis imperfecta. The option of preemptive treatment of congenital diseases in utero by stem cell or gene therapy are encouraging as it changes the perspective of congenital diseases. Thus, avoiding the need for post-natal treatment and reducing future costs. AFS have been isolated and characterized in human, mice, rodents, rabbit and sheep and can be a potential source of cells for therapeutic applications in a multitude of disorders that can be treated prenatally or postnatally. These cells have demonstrated the potential of repair in a range of disease models such as neurological disorder, tracheal repair, bladder injury and diaphragmatic hernia repair in adult or neonate stage. Several groups have shown the use of AFS in in utero therapy in rodents as well as sheep models. These results have been encouraging, thus allowing us to continue with the research and optimizing the procedures and experiments so as to allow it to be translated into clinic.

OBJECTIVE: Maternal recreational drug use may be associated with the development of fetal malformations such as gastroschisis, brain and limb defects, the aetiology due to vascular disruption during organogenesis. Using forensic hair analysis we reported evidence of recreational drug use in 18% of women with a fetal gastroschisis. Here we investigate this association in a variety of fetal malformations using the same method. METHODS: In a multi-centre study, women with normal pregnancies (controls) and those with fetal abnormalities (cases) gave informed consent for hair analysis for recreational drug metabolites using mass spectrometry. Hair samples cut at the root were tested in sections corresponding to 3 month time periods (pre and periconceptual period). RESULTS: Women whose fetus had gastroschisis, compared to women with a normal control fetus, were younger (mean age 23.78 ± SD4.79 years, 18-37 vs 29.79 ± SD6 years, 18-42, p = 0.00001), were more likely to have evidence of recreational drug use (15, 25.4% vs 21, 13%, OR2.27, 95thCI 1.08-4.78, p = 0.028), and were less likely to report periconceptual folic acid use (31, 53.4% vs 124, 77.5%, OR0.33, 95thCI 0.18-0.63, p = 0.001). Age-matched normal control women were no less likely to test positive for recreational drugs than women whose fetus had gastroschisis. After accounting for all significant factors, only young maternal age remained significantly associated with gastroschisis. Women with a fetus affected by a non-neural tube central nervous system (CNS) anomaly were more likely to test positive for recreational drugs when compared to women whose fetus was normal (7, 35% vs 21, 13%, OR3.59, 95th CI1.20-10.02, p = 0.01). CONCLUSIONS: We demonstrate a significant association between non neural tube CNS anomalies and recreational drug use in the periconceptual period, first or second trimesters, but we cannot confirm this association with gastroschisis. We confirm the association of gastroschisis with young maternal age.

BACKGROUND:The normal development of the uteroplacental circulation in pregnancy depends on angiogenic and vasodilatory factors such as vascular endothelial growth factor (VEGF). Reduced uterine artery blood flow (UABF) is a common cause of fetal growth restriction; abnormalities in angiogenic factors are implicated. Previously we showed that adenovirus (Ad)-mediated VEGF-A165 expression in the pregnant sheep uterine artery (UtA) increased nitric oxide synthase (NOS) expression, altered vascular reactivity and increased UABF. VEGF-D is a VEGF family member that promotes angiogenesis and vasodilatation but, in contrast to VEGF-A, does not increase vascular permeability. Here we examined the effect of Ad.VEGF-DΔNΔC vector encoding a fully processed form of VEGF-D, on the uteroplacental circulation. METHODS:UtA transit-time flow probes and carotid artery catheters were implanted in mid-gestation pregnant sheep (n = 5) to measure baseline UABF and maternal haemodynamics respectively. 7-14 days later, after injection of Ad.VEGF-DΔNΔC vector (5×10(11) particles) into one UtA and an Ad vector encoding β-galactosidase (Ad.LacZ) contralaterally, UABF was measured daily until scheduled post-mortem examination at term. UtAs were assessed for vascular reactivity, NOS expression and endothelial cell proliferation; NOS expression was studied in ex vivo transduced UtA endothelial cells (UAECs). RESULTS:At 4 weeks post-injection, Ad.VEGF-DΔNΔC treated UtAs showed significantly lesser vasoconstriction (Emax144.0 v/s 184.2, p = 0.002). There was a tendency to higher UABF in Ad.VEGF-DΔNΔC compared to Ad.LacZ transduced UtAs (50.58% v/s 26.94%, p = 0.152). There was no significant effect on maternal haemodynamics. An increased number of proliferating endothelial cells and adventitial blood vessels were observed in immunohistochemistry. Ad.VEGF-DΔNΔC expression in cultured UAECs upregulated eNOS and iNOS expression. CONCLUSIONS:Local over-expression of VEGF-DΔNΔC in the UtAs of pregnant mid-gestation sheep reduced vasoconstriction, promoted endothelial cell proliferation and showed a trend towards increased UABF. Studies in cultured UAECs indicate that VEGF-DΔNΔC may act in part through upregulation of eNOS and iNOS.

Human mesenchymal stromal/stem cells (MSC) isolated from fetal tissues hold promise for use in tissue engineering applications and cell-based therapies, but their collection is restricted ethically and technically. In contrast, the placenta is a potential source of readily-obtainable stem cells throughout pregnancy. In fetal tissues, early gestational stem cells are known to have advantageous characteristics over neonatal and adult stem cells. Accordingly, we investigated whether early fetal placental chorionic stem cells (e-CSC) were physiologically superior to their late gestation fetal chorionic counterparts (l-CSC). We showed that e-CSC shared a common phenotype with l-CSC, differentiating down the osteogenic, adipogenic and neurogenic pathways, and containing a subset of cells endogenously expressing NANOG, SOX2, c-MYC, and KLF4, as well as an array of genes expressed in pluripotent stem cells and primordial germ cells, including CD24, NANOG, SSEA4, SSEA3, TRA-1-60, TRA-1-81, STELLA, FRAGILIS, NANOS3, DAZL and SSEA1. However, we showed that e-CSC have characteristics of an earlier state of stemness compared to l-CSC, such as smaller size, faster kinetics, uniquely expressing OCT4A variant 1 and showing higher levels of expression of NANOG, SOX2, c-MYC and KLF4 than l-CSC. Furthermore e-CSC, but not l-CSC, formed embryoid bodies containing cells from the three germ layer lineages. Finally, we showed that e-CSC demonstrate higher tissue repair in vivo; when transplanted in the osteogenesis imperfecta mice, e-CSC, but not l-CSC increased bone quality and plasticity; and when applied to a skin wound, e-CSC, but not l-CSC, accelerated healing compared to controls. Our results provide insight into the ontogeny of the stemness phenotype during fetal development and suggest that the more primitive characteristics of early compared to late gestation fetal chorionic stem cells may be translationally advantageous.