BACKGROUND:Vaginal cervical cerclage and progesterone are established treatments for prevention of pregnancy loss and prematurity. There is limited data to assess the effect of these treatments in combination. The objective of this study was to investigate the association between progesterone and no progesterone treatment on pregnancy outcomes in women at high risk of preterm birth who had received a vaginal cervical cerclage. METHODS AND FINDINGS:This is a secondary post-hoc analysis of women recruited to the C-STICH randomised controlled trial, which recruited in 75 obstetric units in the UK between 2015 and 2021. In the C-STICH trial, women with a singleton pregnancy, receiving a vaginal cervical cerclage due to a history of pregnancy loss or premature birth, or if indicated by ultrasound, were randomised to cerclage with braided or monofilament suture, with a primary outcome of pregnancy loss, defined as miscarriage, stillbirth, or neonatal death in the first week of life. In this secondary analysis, the primary outcome was pregnancy loss, defined as miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life. Secondary maternal outcomes included miscarriage and previable neonatal death; stillbirth; gestational age at delivery; preterm pre labour rupture of membranes, and sepsis. Secondary neonatal outcomes included early/late neonatal death and sepsis. For each outcome, regression models were fitted adjusting for prespecified prognostic variables. From the 2,048 women recruited to C-STICH, 1943 (95%) women had a vaginal cerclage placed and available progesterone data. Of these, 834 (43%) women received progesterone and 1,109 (57%) did not receive progesterone. In women with primary outcome data available, in our predefined analysis pregnancy loss occurred in 49 (5.9%) of 832 women who received progesterone and 91 (8.3%) of 1,103 women who did not receive progesterone (adjusted* risk ratio 0.70 (95% confidence interval (CI) [0.50, 0.99]); adjusted risk difference -0.02 (95% CI [-0.04, -0.001], *adjusted for indication, obstetric history, surgical technique, and maternal age). Further exploratory analysis excluding women who had termination of pregnancy for foetal anomaly demonstrated a nonsignificant reduction in the risk of pregnancy loss. Key limitations of this study include a nonrandomised trial design and unknown confounding relating to variation in progesterone use. CONCLUSION:In women with a vaginal cervical cerclage and concomitant progesterone there appears to be an association with a reduced risk of pregnancy loss. This combination therapy may be an important opportunity to further reduce the risk of pregnancy loss in this high-risk cohort.

This study investigated morphometric differences in placentas from gestational diabetes mellitus (GDM) pregnancies by integrating deep learning with quantitative statistical analysis. Whole slide images (WSIs) of placentas from four pathological groups: small-for-gestational-age (SGA), appropriate-for-gestational-age (AGA), large-for-gestational-age (LGA), and non-GDM pregnancies were analyzed to evaluate cell type distributions, morphology, and connectivity. A state-of-the-art benchmark model was used for comparison. This pipeline produced plausible cell maps and revealed significant cell-type-specific differences across groups. SGA placentas showed reduced vascular myocyte connectivity, and AGA placentas maintained robust cellular interactions. LGA and non-GDM placentas showed intermediate or compensatory remodeling patterns. These results highlight the potential of morphometric analysis as a biomarker discovery tool for placental dysfunction and suggest that deep learning-based cellular mapping can provide clinically relevant insights into pregnancy outcomes.

Background Approximately 5% of women will be affected by fetal malposition at full cervical dilatation, with the occiput in transverse or posterior positions. These women are more likely to require assistance to give birth to their babies with either rotational vaginal birth or cesarean birth at full dilatation. Three different rotational methods can be used: rotational (Kielland) forceps, rotational vacuum, and manual rotation. Current evidence supporting the use of the 3 rotational methods is only from observational data. To date, no randomized controlled trial (RCT) of rotational methods has been completed. Objective This study aimed to evaluate whether manual rotation of the fetal head in persistent malposition at full cervical dilatation reduces the risk of severe maternal perineal trauma without substantially increasing the risk of cesarean birth, compared with instrumental rotation. Methods ROTATE is a pragmatic, multicenter, 2-arm parallel group, open-label RCT of manual versus instrumental rotation of the fetal head in malposition at birth with an internal pilot and an embedded qualitative process evaluation. The primary outcome is to evaluate whether manual versus instrumental rotation at full cervical dilatation reduces the risk of severe perineal trauma (superiority outcome), defined as a third- or fourth-degree tear, without substantially increasing the risk of cesarean birth at full dilatation (noninferiority coprimary outcome). A sample size calculation found that 4988 participants are required to detect a clinically meaningful reduction of third- or fourth-degree tears from 6% to 4% with 90% power (α=.05). A total sample size of 5200 participants from approximately 40 sites is anticipated, as loss to follow-up is expected to be about 4%. Neonatal trauma, a composite of potential outcomes relating to intrapartum hypoxia and physical trauma, is a safety signal. The setting is National Health Service consultant–led maternity units across the United Kingdom. Randomization is performed after eligibility has been confirmed and verbal consent has been obtained. Randomization is undertaken via a 24-hour telephone service or web-based system. Participants are randomized at an individual level on a 1:1 ratio to manual or instrumental (forceps or vacuum) rotation. Written consent is sought postnatally. Results Data collection took place between September 9, 2022, and November 5, 2024. The total number of recruits is 321. The data analysis of primary and secondary outcomes is ongoing at the time of submission. Conclusions A multicenter RCT of rotational methods has been conducted in the United Kingdom. Although the trial was closed early due to challenges in meeting recruitment targets, the results are still highly anticipated. Trial Registration ISRCTN ISRCTN10193017; https://www.isrctn.com/ISRCTN10193017 International Registered Report Identifier (IRRID) DERR1-10.2196/72505

Objective: This study aimed to increase understanding of the signs and symptoms that lead pregnant people to seek hospital care in the second trimester of pregnancy. In addition, we aimed to describe management and follow up, to record pregnancy outcomes, and to gather information about symptoms and signs related to second trimester pregnancy loss. Methods: This prospective audit in seven geographically dispersed sites across the UK collected data over two weeks (7th March-20th March 2022 inclusive) on all unscheduled secondary care attendances between 14 and 21 completed weeks' gestation. Data on the number of patients booked at each unit within this 8-week second trimester gestational age range were collected. Descriptive analyses identified common patterns and associations with second trimester pregnancy loss. Results: Of 8,585 patients in the second trimester of their pregnancy, 283 presented acutely at least once over the two-week period (3.3 %) Of these, 19 patients experienced a second trimester pregnancy loss (7 % of those presenting in the second trimester). There were a broad range of presentations and diagnoses and a lack of standardisation of investigation and management of patients. Logistic regression identified associations between previous first trimester miscarriage (OR 2.95 95 % CI 1.15, 7.60), previous first trimester termination of pregnancy (OR 7.00 95 % CI 2.45, 19.98), and presentation with increased vaginal discharge (OR 3.82 CI 1.24, 11.7) with second trimester pregnancy loss. Conclusions: This study has identified that a significant number of pregnant people attend hospital and reattend in the second trimester of pregnancy, with a worrying lack of standardisation of both investigation and management, and a broad range of presenting symptoms and diagnoses. Patients who present in the second trimester have a high rate of second trimester pregnancy loss and the preliminary associations identified would benefit from further research in a larger scale study.

Mid‐trimester pregnancy loss (MTL), defined as a pregnancy loss occurring between 14 + 0 and 21 + 6 weeks of gestation, causes significant physical and emotional distress to women and presents clinical challenges to healthcare professionals. It is acknowledged that in low‐resource settings, this guideline might be applicable to births up to 28 weeks or babies weighing less than 1 kg. Risk factors for MTL include advanced maternal age, previous history of MTL, women of Black ethnicity, smoking, excessive alcohol consumption, obesity, and anatomical factors such as a short cervix, congenital uterine anomalies, and myomas. Medical risk factors include previous cervical trauma from loop electrosurgical excision procedure or Cesarean section in labor, placental dysfunction, infections, thrombophilias, endocrine disorders such as thyroid disease and polycystic ovary syndrome, and fetal chromosomal abnormalities. Early assessment and accurate diagnosis are fundamental to managing threatened and confirmed mid‐trimester pregnancy loss. Our guideline emphasizes the importance of maternal vital signs monitoring, laboratory investigations, and ultrasound imaging to identify and manage those with threatened or confirmed mid‐trimester pregnancy loss, as well as address potential maternal complications, including infection or hemorrhage. A multidisciplinary approach involving obstetricians, gynecologists, maternal‐fetal medicine specialists, nurses, midwives, psychologists, and social workers is important for providing comprehensive care. The guideline advocates for personalized management plans tailored to individual women's preferences, medical history, and gestational age. Care for threatened MTL should be targeted to the likely cause and might include cervical cerclage, progesterone, and management of risk factors, for example antibiotics for urinary tract infections. Care for confirmed MTL might include expectant management, medical induction of labor, or surgical intervention such as dilation and evacuation. Acknowledging the profound emotional impact of mid‐trimester pregnancy loss, our guideline underscores the importance of offering compassionate and culturally sensitive psychosocial support to women and their families. This includes providing access to bereavement care, counseling services, support groups, and resources for coping with grief and loss. Continued monitoring and follow‐up care are essential components of managing mid‐trimester pregnancy loss. Our guideline recommends regular postpartum assessments to evaluate physical recovery and emotional well‐being and to address any ongoing medical or psychological concerns. Contraceptive counseling and future pregnancy planning should also be discussed as part of comprehensive care. It is important that, where possible, women receive continuity of care from healthcare professionals to help the coordination and provision of holistic and comprehensive care. Further research is needed to enhance our understanding of the etiology, risk factors, and optimal management strategies for threatened mid‐trimester pregnancy loss. Additionally, education and training initiatives should be implemented to ensure healthcare professionals are equipped with the knowledge and skills necessary to deliver high‐quality, woman‐centered care to individuals and families experiencing this complication. Mid‐trimester pregnancy loss represents a complex clinical scenario necessitating a holistic and compassionate approach to care. By adhering to the recommendations outlined in this clinical guideline, healthcare providers can strive to optimize outcomes and support individuals and their families through this challenging experience.

Objective Type 2 diabetes (T2D) now accounts for the majority of pre-existing diabetes affecting pregnancy in the UK. Our aim was to determine its impact on pregnancy outcomes compared to type 1 diabetes (T1D), gestational diabetes (GDM) and non-diabetes pregnancies. Data Sources PubMed was searched 1 January 2009-2024. Study Eligibility Criteria Cohort observational studies reporting original data on at least one of the primary outcomes in ten or more T2D pregnancies were eligible for inclusion. Comparative diabetes and non-diabetes pregnancies were also collected. Study Appraisal and Synthesis Methods Primary outcomes included congenital anomalies, stillbirths, neonatal and perinatal mortality, birthweight, rates of large for gestational age (LGA), small for gestational age (SGA) and macrosomia.PROSPERO ID CRD42023411057. Results 47 studies were analysed. The number of pregnancies in each analysis varied depending on the available data from the outcome being analysed but ranged from 723 to 4,469,053 pregnancies.When compared with T1D pregnancies, T2D were more likely to have SGA babies as well as greater neonatal and perinatal mortality (OR 2.29, 95% CI 1.12 – 4.67; OR 1.53 95% CI 1.20 to 1.94 and OR 1.31 95% CI 1.07 to 1.61 respectively).When compared with GDM, T2D were more likely to have babies with congenital anomalies (OR 1.91, 95% CI 1.04 – 3.50), LGA (OR 3.49, 95% CI 2.49 to 4.89), neonatal mortality (OR 3.96, 95% CI 3.38 to 4.64) and stillbirth (OR 16.55, 95% CI 5.69 to 48.11).In comparison to non-diabetic pregnancy, T2D were more likely to have babies with congenital anomalies (OR 1.76, 95% CI 1.11 – 2.79), LGA (OR 2.79, 95% CI 1.93 to 4.04), perinatal mortality (OR 4.18, 95% CI 2.91 to 6.01) and stillbirth (OR 7.27, 95% CI 3.01 to 17.53). Conclusions T2D pregnancies are associated with a greater perinatal mortality than other forms of diabetes in pregnancy. Given its increasing prevenance, greater awareness of the adverse pregnancy outcomes associated with T2D is needed, by both healthcare providers and policy makers, to improve care.

Introduction In the UK, 1600 babies die every year before, during or immediately after birth at 20–28 weeks’ gestation. This bereavement has a similar impact on parental physical and psychological well-being to late stillbirth (>28 weeks’ gestation). Improved understanding of potentially modifiable risk factors for late stillbirth (including supine going-to-sleep position) has influenced international clinical practice. Information is now urgently required to similarly inform clinical practice and aid decision-making by expectant mothers/parents, addressing inequalities in pregnancy loss between 20 and 28 weeks.Methods and analysis This study focuses on what portion of risk of pregnancy loss 20–28 weeks’ gestation is associated with exposures amenable to public health campaigns/antenatal care adaptation. A case–control study of non-anomalous singleton baby loss (via miscarriage, stillbirth or early neonatal death) 20+0 to 27+6 (n=316) and randomly selected control pregnancies (2:1 ratio; n=632) at group-matched gestations will be conducted. Data is collected via participant recall (researcher-administered questionnaire) and extraction from contemporaneous medical records. Unadjusted/confounder-adjusted ORs will be calculated. Exposures associated with early stillbirth at OR≥1.5 will be detectable (p<0.05, β>0.80) assuming exposure prevalence of 30%–60%.Ethics and dissemination NHS research ethical approval has been obtained from the London—Seasonal research ethics committee (23/LO/0622). The results will be presented at international conferences and published in peer-reviewed open-access journals. Information from this study will enable development of antenatal care and education for healthcare professionals and pregnant people to reduce risk of early stillbirth.Trial registration number NCT06005272.

Background Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage. Design Superiority open randomised controlled trial. Setting Seventy-five maternity sites across the UK. Participants Women experiencing a singleton pregnancy requiring a cervical cerclage. Interventions Monofilament suture or braided suture. Main outcome measures The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth. Methods Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit. Results A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: −0.02 to 0.03). Limitations The trial did not collect long-term paediatric outcomes. There were no safety concerns. Conclusions There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture. Future work Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information.

There are few population-based studies of sufficient size and follow-up duration to have reliably assessed perinatal outcomes for pregnant women hospitalised with SARS-CoV-2 infection. The United Kingdom Obstetric Surveillance System (UKOSS) covers all 194 consultant-led UK maternity units and included all pregnant women admitted to hospital with an ongoing SARS-CoV-2 infection. Here we show that in this large national cohort comprising two years' active surveillance over four SARS-CoV-2 variant periods and with near complete follow-up of pregnancy outcomes for 16,627 included women, severe perinatal outcomes were more common in women with moderate to severe COVID-19, during the delta dominant period and among unvaccinated women. We provide strong evidence to recommend continuous surveillance of pregnancy outcomes in future pandemics and to continue to recommend SARS-CoV-2 vaccination in pregnancy to protect both mothers and babies.

We tested the hypothesis that conserved placental mammal-specific microRNAs and their targets facilitate endometrial receptivity to implantation. Expression of miR-340-5p, -542-3p, and -671-5p was regulated by exposure of endometrial epithelial cells to progesterone (10 μg/ml) for 24 h coordinate with 1,713 of their predicted targets. Proteomic analysis of cells transfected with miRNA mimic/inhibitor (48 h: n = 3) revealed 1,745 proteins altered by miR-340-5p (mimic; 1,369, inhibitor; 376) of which 171 were predicted targets and P4-regulated. MiR-542-3p altered 2,353 (mimic; 1,378, inhibitor; 975) 100 which were mirDB predicted, including 46 P4-regulated. MiR-671-5p altered 1,744 proteins (mimic; 1,252, inhibitor; 492) 95 of which were predicted targets and 46 P4-regulated. All miRNAs were detected in luteal phase endometrial biopsies, irrespective of pregnancy outcomes. miR-340-5p expression increased in biopsies from individuals suffering previous and subsequent miscarriage compared to those with subsequent live birth. Dysfunction of these miRNAs and their targets contribute to endometrial-derived recurrent pregnancy loss.

Chorioamnionitis is present in up to 70% of spontaneous preterm births and is associated with poor maternal, fetal and neonatal outcomes. Objective: To explore the relationship between the neutrophil-to-lymphocyte ratio and histological chorioamnionitis in women who delivered preterm with no clinical signs or symptoms of infection. Study design: This was a retrospective analysis of a cohort of women who delivered spontaneously between 16 and 36(+6) weeks at a tertiary UK hospital. Only women with placental histology and no signs of clinical infection were included. The neutrophil-to-lymphocyte ratio was calculated from a full blood count sample taken routinely within 24 h of delivery. The neutrophil-to-lymphocyte ratio was also calculated from first trimester booking bloods (<13 + 6 weeks) in a subgroup. Placental histopathology was categorised as either inflammatory (i.e. histologic chorioamnionitis, with or without evidence of fetal inflammatory response) or non-inflammatory (vascular pathology or a normal placenta). Results: 169 women had available placental pathology and were included in the analysis. 70 % (118/169) had confirmed placental inflammation. The mean neutrophil-to-lymphocyte ratio was significantly raised in this group compared to those with normal (n = 24) or vascular (n = 27) pathology (inflammatory neutrophil-to-lymphocyte ratio 9.81 vs non-inflammatory neutrophil-to-lymphocyte ratio 6.53, p = 0.002. The delivery neutrophil-to-lymphocyte ratio had an area under the receiver operating characteristic curve of 0.69 (0.60 to 0.78) for predicting placental inflammation. A raised neutrophil-to-lymphocyte ratio (>6) was associated with an odds ratio of 5.2 (95 % CI 2.55 to 10.56) for histological chorioamnionitis, with a sensitivity of 80 % and negative predictive value of 86 %. A higher cut-off of 9 had a negative predictive value of 79 % for fetal inflammatory response. Conclusions: A raised neutrophil-to-lymphocyte ratio is associated with a 5-fold increased risk of histological chorioamnionitis in women who delivered early without signs or symptoms of infection. It was also raised at the time of preterm labour compared to the first trimester. A full blood count is an almost universal investigation in women admitted in preterm labour, often repeated, making this inexpensive and non-invasive ratio a useful additional antenatal biomarker in women admitted in spontaneous preterm labour at risk of subclinical chorioamnionitis and its associated poor outcomes.

ABSTRACT Preterm birth complicates approximately 10% of pregnancies worldwide. It can lead to neonatal mortality or lifelong complications for those babies who survive. One cause of preterm birth is cervical insufficiency, which affects up to 1% of pregnant women and can be treated with the placement of vaginal cervical cerclage. There are 2 techniques for cervical cerclage: the modified Shirodkar cerclage, which involves dissecting the bladder and placing a suture around the supravaginal cervix with the suture thread buried, and the McDonald cerclage, which involves inserting the suture thread as high as possible around the upper section of the cervix. The effectiveness of either technique is dependent on perioperative decisions, such as suture thread choice. One UK survey found that 87% of clinicians prefer to use braided thread, with 13% preferring monofilament thread. The preference for braided thread was due to its easy handling and concerns that monofilament thread is difficult to remove if it becomes embedded in the cervix. However, an observational, nonrandomized systemic review suggested that monofilament thread was better than braided thread to prevent pregnancy loss (7% vs 18.9%; risk ratio [RR], 0.34; 95% confidence interval [CI], 0.18–0.63). Additional evidence suggests that monofilament thread is superior because braided thread could serve as a reservoir for bacteria, causing vaginal dysbiosis and increasing the risk of pregnancy loss. There are no randomized clinical trials to inform the choice of suture thread to prevent pregnancy loss. The aim of this study was to compare the effectiveness of monofilament suture thread to braided suture thread on pregnancy loss in women undergoing cervical cerclage. This was a superiority randomized clinical trial, conducted at 75 obstetric units in the United Kingdom between August 21, 2015, and January 28, 2021. Included were women aged 18 years and older with singleton pregnancies, who required vaginal cervical cerclage. Excluded were women who required emergency or rescue cerclage, needed immediate suture insertion, or had ruptured or visible membranes, as well as those who did not have a cerclage placed vaginally. Eligible women were randomized to receive either monofilament thread or braided thread. Women were followed up until 28 days postdelivery or hospital discharge, whichever came first. Preterm neonates were followed up until delivery or discharge, and babies born at term were followed up 28 days postdelivery or hospital discharge, whichever came first. A total of 2049 women were randomized to the monofilament suture thread group (n = 1025) or the braided suture thread group (1024). The intention-to-treat analysis included 1003 women in the monofilament group and 993 women in the braided group. No significant differences were observed in the rate of pregnancy loss between the monofilament group and braided group (8% vs 7.6%, respectively; RR, 1.05; 95% CI, 0.79–1.40; adjusted risk difference, 0.002; 95% CI, −0.02 to 0.03; P = 0.73). Insertion complications occurred in 4% of women in the monofilament group and 3% in the braided suture group. Women in the monofilament group experienced more removal complications than the braided group (RR, 1.25; 95% CI, 1.15–1.36). No significant differences were observed in maternal secondary outcomes or neonatal outcomes. In conclusion, there was no difference in the rate of pregnancy loss when using monofilament suture thread or braided suture thread in women undergoing cervical cerclage.

Hypoxic-ischaemic encephalopathy (HIE) in the newborn baby is a major contributor to neonatal mortality and morbidity across the world. Therapeutic hypothermia (TH) is the current standard treatment for moderate to severe HIE, but not all babies benefit. Potential neuroprotective actions of progesterone (PROG) include anti-apoptotic, anti-inflammatory, and anti-oxidative effects and reduction of energy depletion, tissue/cellular oedema, and excitotoxicity. In pre-clinical studies of neonatal HIE, PROG has neuroprotective properties but has not been the subject of systematic review. Here, our objective was to evaluate the evidence base for PROG as a potential therapeutic agent in HIE. The PICO framework was used to define the following inclusion criteria. Population: human neonates with HIE/animal models of HIE; intervention: PROG +/− other agents; comparison: V.S. control; outcome: pathological, neurobehavioural, and mechanistic outcome measures. Medline, EMBASE, and CINHAL were then searched between August to October 2018 using pre-defined medical subject heading and keywords. Study inclusion, data extraction, and risk of bias (ROB) analysis using the SYRCLE ROB tool were carried out by two authors. 14 studies were included in the review. They typically displayed a high ROB. This systematic review suggests that PROG reduced neuropathology and reduced neurobehavioural deficits post-hypoxic-ischaemic (HI) insult in 8 and 3 studies, respectively. However, there was sex dimorphism in the effects of PROG. In addition, there are limitations and biases in these studies, and there remains a need for well-designed large pre-clinical studies with greater methodological quality to further inform the efficacy, safety, dose, timing, and frequency of PROG administration. With such data, large animal studies could be planned combining PROG administration with and without TH.

Lay summary Friction caused by blood flowing across cells that line blood vessels (endothelial cells) activates sensors of mechanical force. This produces nitric oxide (NO) which widens placental blood vessels, enabling more blood flow to the baby. This study sought to determine whether the mechanical sensor, Piezo1, is important for NO production in fetoplacental endothelial cells (FpECs) and whether the steps in this pathway are different in small for gestational age (SGA) babies, where placental blood flow is often altered. We showed that in healthy FpECs, blood flow increased NO signalling. We suggest that in SGA babies, FpECs have an increase in baseline levels of NO signalling, suggestive of a compensatory drive. Treating healthy and SGA cells with a Piezo1 chemical activator, Yoda1, upregulated NO signalling. This shows that Piezo1 is linked to NO and that in SGA, FpECs have the capacity to further increase NO. Further research will establish whether Piezo1 enhancement leads to increased blood flow in the placenta. If so, Piezo1 could be a new target for developing treatments to prevent poor growth of babies in the womb.

There is a lack of population level data on risk factors and impact of severe COVID-19 in pregnancy. The aims of this study were to determine the characteristics, and maternal and perinatal outcomes associated with severe COVID-19 in pregnancy compared with those with mild and moderate COVID-19 and to explore the impact of timing of birth. This was a secondary analysis of a national, prospective cohort study. All pregnant women admitted to hospital in the UK with symptomatic SARS-CoV-2 from March 1, 2020 to October 31, 2021 were included. The severity of maternal infection (need for high flow or invasive ventilation, intensive care admission or died), pregnancy and perinatal outcomes, and the impact of timing of birth were analyzed using multivariable logistic regression. Of 4436 pregnant women, 13.9% ( n  = 616) had severe infection. Women with severe infection were more likely to be aged ≥30 years (adjusted odds ratio [aOR] aged 30–39 1.48, 95% confidence interval [CI] 1.20–1.83), be overweight or obese (aOR 1.73, 95% CI 1.34–2.25 and aOR 2.52 95% CI 1.97–3.23, respectively), be of mixed ethnicity (aOR 1.93, 95% CI 1.17–3.21) or have gestational diabetes (aOR 1.43, 95% CI 1.09–1.87) compared with those with mild or moderate infection. Women with severe infection were more likely to have a pre-labor cesarean birth (aOR 8.84, 95% CI 6.61–11.83), a very or extreme preterm birth (28–31+ weeks’ gestation, aOR 18.97, 95% CI 7.78–14.85; <28 weeks’ gestation, aOR 12.35, 95% CI 6.34–24.05) and their babies were more likely to be stillborn (aOR 2.51, 95% CI 1.35–4.66) or admitted to a neonatal unit (aOR 11.61, 95% CI 9.28–14.52). Of 112 women with severe infection who were discharged and gave birth at a later admission, the majority gave birth ≥36 weeks (85.7%), noting that three women in this group (2.7%) had a stillbirth. Severe COVID-19 in pregnancy increases the risk of adverse outcomes. Information to promote uptake of vaccination should specifically target those at greatest risk of severe outcomes. Decisions about timing of birth should be informed by multidisciplinary team discussion; however, our data suggest that women with severe infection who do not require early delivery have mostly good outcomes but that those with severe infection at term may warrant rapid delivery.

Objectives:To describe the severity of maternal infection when the omicron SARS-CoV-2 variant (B.1.1.529) was dominant (15 December 2021 to 14 March 2022) and describe outcomes by symptoms and vaccination status. Design:Prospective, national cohort study using the UK Obstetric Surveillance System. Setting:94 hospitals in the UK with a consultant led maternity unit. Participants:Pregnant women admitted to hospital for any cause with a positive SARS-CoV-2 test. Main outcome measures:Symptomatic or asymptomatic infection, vaccination status by doses before admission, and severity of maternal infection (moderate or severe infection according to modified World Health Organization's criteria). Results:Of 3699 women who were admitted to hospital, 986 (26.7%, 95% confidence interval 25.3% to 28.1%) had symptoms; of these, 144 (14.6%, 12.5% to 17.0%) had a moderate to severe infection, 99 (10.4%, 8.6% to 12.5%) of 953 received respiratory support, and 30 (3.0%, 2.1% to 4.3%) were admitted to an intensive care unit. Covid-19 specific drug treatment was given to 13 (43.3%) of the 30 women in intensive care. Four women with symptoms died (0.4%, 0.1% to 1.1%). Vaccination status was known for 845 (85.6%) women with symptoms; 489 (58.9%) were unvaccinated and only 55 (6.5%) had three doses. Moderate to severe infection was reported for 93 (19.0%) of 489 unvaccinated women with symptoms, decreasing to three (5.5%) of 55 after three doses. Among the 30 women with symptoms who were admitted to intensive care, 23 (76.7%) were unvaccinated and none had received three doses. Conclusion:Most women with severe covid-19 disease were unvaccinated and vaccine coverage among pregnant women admitted to hospital with SARS-CoV-2 was low. Ongoing action to prioritise and advocate for vaccine uptake in pregnancy is essential. A better understanding of the persistent low use of drug treatments is an urgent priority. Trial registration:ISRCTN 40092247.

As major immune responsive cells in the central nervous system (CNS), activated microglia can present pro-inflammatory M1 phenotype aggravating the neuronal injury or anti-inflammatory M2 phenotype providing neuroprotection and promoting neuronal survival in neurodegenerative diseases. In this study, we demonstrated that a compound, 4R-cembranoid (4R, 1S, 2E, 4R, 6R,−7E, 11E-2, 7, 11-cembratriene-4, 6-diol cembranoids) promoted M2 phenotype while attenuated M1 phenotype in N9 cells, a microglial cell line. Following Lipopolysaccharides (LPS) or Oxygen-glucose deprivation (OGD) treatment, the N9 cells treated by 1 µM 4R showed an increased Arginase-1 (Arg1, a M2 marker) expression and a reduced inducible nitric oxide synthase (iNOS, M1 marker) expression. In addition, the conditioned medium of 4R-treated post-OGD N9 cells protected neuro2a cells, a neuronal cell line, from OGD-induced injury. The viability of neuro2a cells in OGD condition was increased by 54.5% after treated with the conditioned medium of 4R-treated post-OGD N9 cells. Furthermore, we demonstrated the protective mechanism of 4R was associated with a decreased TNF-α release and an increased IL-10 release from N9 cells. In conclusion, our study demonstrated that the neuroprotective effects of 4R were through the regulation of microglial activation by promoting the protective M2 activation and inhibiting the damaging M1 activation. Therefore, the findings of this study suggest that 4R could be a promising lead structure for the development of drugs for the treatment of ischemic stroke and other neurodegenerative diseases with an inflammatory component involved.

This article explores the complexities of diagnosing and managing preterm labour and highlights the importance of tailoring labour and delivery care to the individual, based on gestation and neonatal prognosis. Available diagnostic criteria and interventions to optimize the preterm infant are discussed, and the limitations of evidence to inform current practice described. The benefit of national improvement drives in the quality and consistency of preterm labour care is introduced to encourage local education and clinical training to combat the harmful sequelae of preterm birth.