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IntroductionWomen identified at risk for preterm may be vulnerable to developing mental health difficulties due to the increased likelihood of poor pregnancy outcome and uncertainty surrounding their delivery. Formal assessment of mental wellbeing in specialist preterm birth clinics is not routinely offered, but may offer the opportunity for early intervention.MethodsWe aimed to investigate if demographic characteristics and obstetric risk factors were associated with psychological wellbeing in women at risk of preterm birth. We explored associations between mental wellbeing and risk factors for preterm birth using hierarchical regression analyses.ResultsWhen demographic variables were considered alone, high body mass index (BMI) was significantly associated with anxiety (p = .026), however became non-significant when obstetric risk factors were also considered. Previous late miscarriage was associated with high anxiety (p = .049). Lower maternal age at estimated date of delivery (p = .019) and non-European ethnic heritage (p = .029) were significantly associated with depression. High maternal BMI (p

Background Arterial stiffening is believed to contribute to the worsening of insulin resistance, and factors which are associated with needing pharmacological treatment of gestational diabetes (GDM), such as maternal obesity or advanced age, are associated with impaired cardiovascular adaptation to pregnancy. In this observational study, we aimed to investigate causal relationships between maternal haemodynamics and treatment requirement amongst women with GDM.Methods We assessed maternal haemodynamics in women with GDM, comparing those who remained on dietary treatment with those who required pharmacological management. Maternal haemodynamics were assessed using the Arteriograph® (TensioMed Ltd, Budapest, Hungary) and the NICOM® non-invasive bio-reactance method (Cheetah Medical, Portland, Oregon, USA). A graphical causal inference technique was used for statistical analysis.Results 120 women with GDM were included in the analysis. Maternal booking BMI was identified as having a causative influence on treatment requirement, with each unit increase in BMI increasing the odds of needing metformin and/or insulin therapy by 12% [OR 1.12 (1.02 − 1.22)]. The raw values of maternal heart rate (87.6 ± 11.7 vs. 92.9 ± 11.90 bpm, p = 0.014) and PWV (7.8 ± 1.04 vs. 8.4 ± 1.61 m/s, p = 0.029) were both significantly higher amongst the women requiring pharmacological management, though these relationships did not remain significant in causal logistic regression.Conclusions Maternal BMI at booking has a causal, rather than simply associational, relationship on the need for pharmacological treatment of GDM. No significant causal relationships were found between maternal haemodynamics and the need for pharmacological treatment.

Problem and backgroundDuring the COVID-19 pandemic, there was substantial reconfiguration of maternity care services, affecting both users and healthcare providers (HCPs), in the United Kingdom (UK) and globally.AimTo further our understanding of the impact of maternity service reconfigurations in the UK, from the perspective of maternity HCPs.MethodsScopus, MEDLINE, EMBASE, CINAHL, PsycINFO and the Cochrane COVID Study Register were searched for relevant studies reporting qualitative data from the UK, published in English between 01 June 2021 and 30 September 2023. Qualitative data on HCPs’ experiences of maternity care reconfiguration during the pandemic were extracted from 15 studies. Data were subjected to thematic synthesis according to key service reconfigurations.ResultsNine themes were identified: Care-seeking and Care Experience: Changes to existing care, Limitations placed on the partner, Mental health and lack of support networks, and Barriers to successful implementation of reconfiguration strategies; Virtual Care: Impact on quality of care, Increased convenience and flexibility, and Digital exclusion; and Ethical Future of Maternity Care Services: Optimising patient care, and Service users and staff as the driving force for change. No studies reported on the concepts of Self-monitoring or COVID-19 vaccination.Discussion and conclusionThe review findings highlight HCPs’ views of the need for greater inclusion of partners, choice of virtual or in-person care for women and birthing people; and a need for co-designed services for future policy-making.

C-repeat binding factor (CBF) transcription factors can activate the expression of a series of cold regulation-related genes, thereby improving the cold resistance of plants. However, no detailed information is known about the biological functions of CBF proteins in yellowhorn (Xanthoceras sorbifolium). In this study, a total of 59 CBF gene family members were identified in five yellowhorn cultivars (WF18, Zhongshi 4, Jinguanxipei 2021, Zhong Guan NO.2, and XsoG11), revealing their intraspecific structural and functional diversity, with 8 core genes present in all cultivars. Phylogenetic and motif analyses highlighted conserved features and species-specific adaptations. Gene duplication events revealed that tandem duplicates are major factors involved in the expansion of this gene family in yellowhorn. Expression profiling under stress conditions demonstrated the involvement of these genes in stress responses. Of particular interest was Xg11_CBF11, which showed strong induction by low-temperature stress. Overexpression of Xg11_CBF11 in Arabidopsis thaliana was performed to validate its cold resistance function. The wild-type and T2 transgenic A. thaliana plants were subjected to low-temperature stress at 4°C for 0, 24, and 48 h, and physiological indexes related to antioxidant enzyme activity, photosynthesis, and cell membrane permeability were determined by comparative test. The results were as follows: the POD and SOD activities of transgenic lines were significantly higher than those of wild-type lines, indicating Xg11_CBF11 improved the adaptability of A. thaliana to low-temperature; The increase of relative conductivity and malondialdehyde, the decrease of chlorophyll content in transgenic lines were smaller than those of wild-type lines, indicating Xg11_CBF11 enhanced the resistance of A. thaliana to low-temperature stress. These results implied that Xg11_CBF11 has a positive regulatory effect on A. thaliana ‘s response to low-temperature stress.

Background Severe early-onset intrauterine growth restriction is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is no treatment for intrauterine growth restriction with timely delivery being the only management option. Placentas from intrauterine growth restriction pregnancies often show failure to remodel maternal spiral arteries leading to a persistent vasoactive responsiveness. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide, encouraging vasodilation of vasoactive vessels. Previous studies in animal models and humans show recovery of placental function and improvement in fetal growth. The STRIDER trial aimed to address whether treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Methods The STRIDER trial was a superiority, randomised double-blind placebo-controlled trial that was carried out in 19 fetal medicine units in the United Kingdom. Women with a singleton pregnancy between 22+0 and 29+6 weeks’ gestation, with severe early-onset intrauterine growth restriction, were asked to participate. Women were randomised (1 : 1) to receive either sildenafil 25-mg three times daily or placebo until 31+6 weeks’ gestation or delivery. Women were stratified by site and their gestational age at randomisation (before 26+0 or at 26+0 weeks or later). Severe intrauterine growth restriction was defined as a combination of estimated fetal weight or abdominal circumference below the 10th percentile and absent or reversed end-diastolic blood flow in the umbilical artery on Doppler velocimetry. The primary outcome was the time from randomisation to delivery, measured in days with a 1-week difference deemed to be clinically significant. The phase 2 study followed up all babies alive at discharge to assess for cardiovascular function and neurodevelopment at 2 years of age. Results Between 21 November 2014 and 6 July 2016, a total number of 135 women were recruited to the study, of these 70 were assigned to sildenafil and 65 to the placebo. No difference was found in the median randomisation to delivery interval between sildenafil [17 days (interquartile range 7–24)] and placebo [18 days (8–28), p = 0.23]. Live births [relative risk 1.06, 95% confidence interval 0.84 to 1.33; p = 0.62], fetal deaths (relative risk 0.89, 95% confidence interval 0.54 to 1.45; p = 0.64), neonatal deaths (relative risk 1.33, 95% confidence interval 0.54 to 3.28; p = 0.53), and birthweight [mean difference −14 g (95% confidence interval −100 to 126); p = 0.81] did not differ between the treatment arms and no differences were found for other maternal or perinatal secondary outcomes. Eight serious adverse events were reported during the study (six in the placebo group and two in the sildenafil group); none of these were attributed to sildenafil. Seventy-five babies were discharged alive from the neonatal unit and of those 61 were available for follow-up with 32 treated with sildenafil and 29 with placebo. Of those that did not have a follow-up 1 baby died (placebo) and 3 declined follow-up and 10 were uncontactable. There was no difference in neurodevelopment, or blood pressure for infants treated with sildenafil versus placebo. Infants who received sildenafil had a greater head circumference compared to those who received placebo (median difference 49.25 cm, interquartile range 46.4–50.26 vs. 47.17 cm, 95% confidence interval 44.71 to 48.95). Conclusion Sildenafil did not prolong pregnancy or improve pregnancy outcomes. There was no effect from sildenafil treatment on infant neurodevelopment. Our data show that sildenafil should not be prescribed for fetal growth restriction. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary Babies that are very small in the womb are at greater risk of a poor outcome to the pregnancy such as stillbirth and learning difficulties in surviving children. Usually, a baby grows small because the placenta, which feeds the baby, is poorly formed. The study wanted to know whether using a medication, which improves the blood supply to the placenta, will give the baby more nutrition and allow better growth. This would allow doctors to keep the baby inside the womb for longer. The study used a medication called sildenafil to improve the blood supply. To be sure if it worked, the study wanted to compare this drug against an identical looking blank tablet (placebo) so women and their healthcare professionals would not know what medication was being given. Women with very small babies and who were pregnant between 22 weeks and 0 days to 29 weeks and 6 days were asked to take part in the study. Treatment was three times a day and continued until delivery or 31 weeks and 6 days. A total of 135 women agreed to take part in the study. Seventy were given sildenafil and 65 were given placebo. A computer decided which medication would be given to which women with a 50 : 50 chance of each. Women were kept in the study until discharge of their baby from hospital. Surviving babies were seen with their mothers at 2 years of age to test for brain injury and problems with thinking, speech and language, or movement (neurodevelopment). The study showed no benefit of sildenafil when compared to placebo in helping the baby grow or in preventing early delivery. In surviving babies there was no benefit for neurodevelopment 2 years after treatment with sildenafil. The findings of our study mean that sildenafil should not be used for the treatment of small babies. Scientific summary Background Severe early-onset intrauterine growth restriction (IUGR) is associated with stillbirth, neonatal death and neurodevelopmental impairment. There is currently no treatment for IUGR with timely delivery being the only management option available. The researchers know from human placentas from IUGR pregnancies that there is often a failure to remodel the maternal spiral arteries within the uterus and myometrium. This inadequate remodelling leads to the persistence of a vasoactive responsiveness within these vessels. Sildenafil, a phosphodiesterase type 5 inhibitor, potentiates naturally occurring nitrous oxide (NO), encouraging vasodilation of vasoactive vessels. Previous studies in animal models and human ex vivo samples have shown recovery of placental function and improvement in fetal growth. Small numbers of clinical trials have also shown an increase in fetal growth or vascular flow (Doppler studies) from maternal use of sildenafil. The STRIDER trial aims to address whether maternal treatment with sildenafil is beneficial to fetal growth and perinatal and toddler outcomes. Objectives The STRIDER United Kingdom (UK) study was designed to answer the following objectives in two phases; phase 1 – recruitment to a randomised controlled trial of sildenafil versus placebo for the treatment of early-onset intrauterine fetal growth restriction, and phase 2 – follow-up at 2 years of age to assess cardiovascular and neurodevelopmental outcomes effect the surviving infants. The primary objective of the phase 1 study was to determine whether sildenafil, compared to placebo therapy, delays the need to deliver a severely growth-restricted fetus by a minimum of 1 week. The secondary objectives were as follows: To investigate impact on fetal growth and fetal well‐being by comparing differential effect on vascular resistance in the uterine arteries, umbilical, fetal middle cerebral artery and fetal ductus venosus and differences in birthweight centiles in infants treated in utero with sildenafil and placebo. To examine, through collaboration with an international consortium, the hypothesis that sildenafil therapy compared to placebo therapy increases the rate of infant survival free of major neurodisability. To report frequency of adverse and serious adverse events (SAEs) associated with sildenafil use. To investigate the impact on maternal cardiovascular parameters by measurements of maternal heart rate and peripheral blood pressure (BP) before and after administration of study medication. To elucidate the precise mechanism and location of action of sildenafil in pregnancy by investigating the effects of sildenafil therapy on omental (representative of the wider maternal systemic vasculature), myometrial (uterine vasculature) and chorionic plate artery (placental vasculature) reactivity. The objective of the phase 2 follow-up study was to examine neurodevelopmental and cardiovascular outcomes at 2 years of age in children born to mothers who received sildenafil compared with placebo during pregnancy. It was hypothesised that: STRIDER UK children whose mothers received sildenafil will have improved neurodevelopmental outcomes at age 2–3 years (corrected) compared with controls exposed to placebo. There will be no difference in BP at 2–3 years (corrected) between STRIDER UK children whose mothers received sildenafil compared with controls exposed to placebo. Methods The STRIDER study was a Phase III clinical trial to quantify the effects of administration of sildenafil on pregnancy outcome in severe early‐onset IUGR. The study was designed as a randomised double-blind, placebo-controlled trial with sildenafil or placebo prescribed orally at a dose of 25 mg three times per day. All participants recruited had a singleton pregnancy between 22+0 weeks’ gestation and 29+6 weeks’ gestation with a diagnosis of IUGR and had agreed to expectant management. For the purpose of the study, IUGR was defined as a fetus with an estimated fetal weight or abdominal circumference below the 10th centile using local charts and absent or reversed end-diastolic flow in the umbilical artery on Doppler velocimetry. All participants were recruited from one of the 19 STRIDER research sites located in the UK. All sites were leading obstetric units within the UK with a high level of fetal medicine and neonatal services provided. Gestational age was confirmed by first trimester ultrasound and in each case, the diagnosis of severe early-onset IUGR was confirmed by a fetal medicine expert having excluded fetal anatomical abnormalities. Following diagnosis and informed consent, a full history, measurements of maternal cardiovascular parameters (BP and pulse rate), fetal biometry and Doppler velocimetry were taken. Maternal venepuncture for angiogenic biomarkers was also performed. All participants had further BP and pulse rate measurements and blood sampling 2 hours after receiving the first dose of the study drug. Subsequently, participants were followed up within 3–4 days and at weekly intervals thereafter, or earlier if clinically indicated. The remainder of clinical care was at the discretion of the local fetal medicine experts and included regular ultrasound assessment of growth and Doppler blood flow and antenatal cardiotocography. Study medication was over encapsulated (Sharp Clinical Services, Crickhowell, UK) to ensure that participants, clinicians and pharmacists were masked to the study drug. Medication was dispensed in 10-day supplies with a new supply being provided weekly to ensure there was no period where medication was missed. Treatment ended at 31+6 weeks’ gestation or delivery, whichever came first. All participants were advised of the potential side effects. Data on pregnancy outcome were collected prospectively from clinical maternity notes and entered onto a secure electronic case report form (eCRF) platform at research sites. Data quality and protocol compliance were monitored regularly by central and on-site monitoring methods. All surviving infants of mothers recruited to the STRIDER study were eligible and invited for follow-up. A study invitation pack was sent to all parents/carers of surviving children. This included an invitation letter, participant information sheet and informed consent form. Participants who did not contact the research team within 2 weeks were contacted by a member of the research team. Assessments took place in a clinical research setting or in the child’s home. Informed written consent was obtained before the assessment began. All assessments were performed by a single senior research psychologist with expertise in developmental assessment techniques. This researcher was blinded to treatment allocation. Assessments included the Cognitive, Language and Motor Subscales of the Bayley Scales of Infant and Toddler Development – III (BSID-III); Hempel’s Neurological Examination for Toddler Age to identify major neurological impairment (cerebral palsy; CP) and subtle deviations from typical neurological and neuromotor function. In addition, a cardiovascular assessment was undertaken, which included brachial systolic BP and diastolic BP and arterial stiffness, assessed as aortic (central) augmentation index (AIx). Where potential participants cancelled or failed to attend follow-up appointments on more than three occasions, they were invited to participate remotely. All such participants received a Follow-up questionnaire pack, which included participant information sheet, consent form and all questionnaires detailed as part of the main study in addition to the Ages and Stages Questionnaire-3 (in place of the BSID-III, neurodevelopmental assessment). The health status classification system – preschool version (HSCS-PS) is a parental (or clinician) proxy measurement of the health status of a child. The overall health status is described as a 10-element vector consisting of one level for each domain. In this study, to facilitate comparisons between groups, a total ‘disability score’ for the overall health state of a child was calculated as the sum of the level codes for the original domains. Therefore, the range of the disability score varied from 10 (no disability on any domain) to 41 (maximum disability on all 10 domains). The child behaviour checklist (CBCL) 1.5–5 was used to assess emotional and behavioural difficulties. Raw scores are normalised into T-scores [mean: 50, standard deviation (SD): 10]. Higher T-scores represent more problematic behaviour. T-scores below 60 are in the normal range, T-scores of 60–63 (84th to 90th percentile) are in the borderline range, and T-scores above 63 (above 90th percentile) are in the clinical range. The T-scores are dichotomised into typical (scores in the normal range) and atypical (scores in the borderline and clinical range). The behaviour rating inventory of executive function – preschool version (BRIEF-P) is a parent questionnaire for early assessment of executive function to assess severity of executive dysfunction in day-to-day situations. Age-based T-scores are computed for each subscale and index, and a score of 65 or higher is considered a clinically significant problem. Results The study recruited 135 participants between 21 November 2014 and 6 July 2016. A number of 75 participants were recruited before 26+0 weeks’ gestation and 60 between 26+0 and 29+6 weeks’ gestation. A total of 70 participants were randomly assigned to receive sildenafil and 65 to placebo. None of the participants withdrew their consent nor were lost to follow-up prior to delivery, therefore, additional ‘per-protocol’ analysis was not performed. Differences at baseline were not clinically important between the sildenafil group and the placebo group. The median gestation at randomisation was 24.4 weeks [interquartile range (IQR) 24.0–27.5]. Two babies were postnatally diagnosed with Down syndrome (one sildenafil and one placebo) and two had confirmed cytomegalovirus infection (one sildenafil and one placebo); all four babies were included in the intention to treat (ITT) analysis. There was no beneficial effect on maternal cardiovascular function from treatment with sildenafil. The follow-up phase was delayed due to the impact of the COVID-19 pandemic on research staff’s availability and access to patients. Out of the 75 babies who were discharged alive from the neonatal unit, 61 babies (81.3%) were included in the follow-up phase. Of those not followed up, 1 baby died (placebo), 3 declined follow-up and 10 were uncontactable. By the nature of follow-up participants were not randomised by treatment leaving 32 mothers who had received sildenafil and 29 had received placebo. There was no difference in the sex, birthweight, gestation at delivery (median 29.2 weeks vs. 29.9 weeks), mode of delivery, or oxygen usage. The physical characteristics of the population available for follow-up showed no difference in height or weight. Head circumference was slightly larger in those treated with sildenafil (49.25, 46.43–50.26) versus placebo (47.18, 44.71–48.95). There was no difference between systolic and diastolic BP between those children treated with sildenafil or placebo. Median values were appropriate for children aged 2 years. The Bayley assessment showed no significant differences in cognitive, language (including receptive and expressive language), or motor (including fine and gross motor) subscales between children of sildenafil-and placebo-treated mothers. Total scores were somewhat lower than expected across all three domains compared with standard population norms (i.e. 100, SD = 15); however, the difference was neither clinically nor statistically significant. There was no difference between the sildenafil and placebo groups for the presence of CP reported by parents. Functional assessment with the BRIEF-P demonstrated no difference in adjusted T-scores between sildenafil and placebo for any of the assessed domains. Likewise, the median total CBCL scores and adjusted T-scores also showed no difference between babies whose mothers were treated with sildenafil versus placebo for any of the assessed domains. The HSCS scores are shown as a total score by domain and as individual components. There was no difference between infants who had received sildenafil to those who had received placebo for any of the domains assessed. It was not possible to record the HEMPEL assessments and as such neurology could not be assessed. Unfortunately, no children were able to tolerate the NICOM (Non-invasive Cardiac Output Monitor)cardiovascular test, leaving BP as the sole assessment of infant cardiovascular status. Conclusions The results of the STRIDER study demonstrated that sildenafil did not result in prolongation of pregnancy, improvements in fetal growth, or perinatal outcome when administered to pregnant women with a severely-growth restricted fetus. These results have subsequently been confirmed in a number of other studies. Our study demonstrated a lack of benefit on any neurodevelopmental, emotional or behavioural assessment from treatment with sildenafil. This study represents the first study to report to the impact of antenatal treatment of women with severe early-onset FGR on their infants’ well-being at 2 years of age. Along with the findings of no benefit on prolongation of pregnancy or perinatal outcome this study it confirms the ineffectiveness of this treatment to improve outcomes in babies with severe early-onset FGR. Further to this lack of benefit there were concerns raised during the Dutch STRIDER trial of increased perinatal mortality in the sildenafil group. Further assessment deemed this excess mortality to be predominantly due to persistent pulmonary hypertension of the neonates (PPHN), which has been proposed to be a pathophysiological mechanism of ‘rebound’ vasoconstriction after cessation of sildenafil. Both the UK and the New Zealand/Australia STRIDER Trials reviewed their data using the same criteria for PPHN as the Dutch STRIDER trial and did not find an increased mortality. The international STRIDER studies are committed to combine the study data in a prospective individual participant data (IPD) meta-analysis to look for any possible long-term effect of sildenafil, particularly on neurodevelopmental and cardiovascular outcome. On current evidence, the researchers do not believe that there is likely to be any beneficial effect on fetal growth, perinatal outcomes or neurodevelopment in this patient group and would advise that further use of sildenafil in this population should be stopped. Prior to any further studies using PDE5 inhibitors to treat FGR being performed, pharmacokinetic and pharmacodynamic experiments specific to pregnancy should be performed to establish an efficacious therapeutic dose. Therefore, the STRIDER study showed no beneficial effect for any perinatal outcome for mother or baby from treatment with 25 mg sildenafil TDS for severe early-onset FGR. The follow-up study confirmed that there was no beneficial effect from maternal treatment with sildenafil on behavioural assessment performed at 2 years of age in the surviving infants. There was also no effect on infant BP from treatment with sildenafil. Trial registration This trial is registered as ISRCTN39133303. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/62/109) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 18. See the NIHR Funding and Awards website for further award information.

Objectives Malaria and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are associated with adverse pregnancy outcomes. This study reports the prevalence and risk factors of curable STIs/RTIs, STI/RTI co-infection and STI/RTI and malaria co-infection among HIV-negative pregnant women at their first antenatal care visit in Kenya, Malawi and Tanzania.Methods HIV-negative pregnant women of all gravidae (n=4680) were screened for syphilis with point-of-care tests and treated if positive. Separately, women provided blood samples (n=4569) for rapid plasma reagin (RPR) testing; positive cases were confirmation by Treponema pallidum particle agglutination (TPPA). Women also provided dried blood spots for batch testing of malaria by retrospective polymerase chain reaction (PCR (n=4226) methods. A randomly selected subgroup of women provided vaginal swabs for chlamydia, gonorrhoea and trichomoniasis testing by retrospective PCR batch testing (n=1431), and bacterial vaginosis diagnosis by Nugent scoring (n=1402).Results Malaria prevalence was 14.6% (95% CI 13.6 to 15.7), 45.9% (43.4 to 48.4) of women were positive for at least one curable STI/RTI and 6.7% (5.5 to 8.1) were co-infected with malaria and a curable STI/RTI. Prevalence of individual STIs/RTIs ranged from 28.5% (26.2 to 30.9) for bacterial vaginosis to 14.5% (12.7 to 16.4) for trichomoniasis, 13.8% (12.1 to 15.7) for chlamydia, 2.7% (1.9 to 3.6) for gonorrhoea and 1.7% (1.4 to 2.2) for RPR/TPPA-confirmed syphilis. The prevalence of STI/RTI co-infection was 10.1% (8.7 to 11.8). Paucigravidae, at highest risk of malaria, were also at greater risk of having chlamydia, gonorrhoea and bacterial vaginosis than multigravidae.Conclusions Of women infected with malaria, 49.0% also had a curable STI/RTI and one in five women with at least one STI/RTI were co-infected with more than one STI/RTI. Current antenatal interventions that address malaria and curable STIs/RTIs remain suboptimal. New approaches to preventing and managing these infections in pregnancy are urgently needed.Trial registration number NCT03208179.

Recent months have seen an increase in pertussis cases in several countries across the Northern and Southern hemispheres. The lack of immune stimulation during the COVID-19 pandemic due to the reduced circulation of Bordetella pertussis, the pathogen responsible for pertussis, is likely to have led to increased population susceptibility which has been magnified the typical three to five yearly cyclical peaks in activity. Maternal immunization for pertussis proves highly effective in protecting infants under three months of age. It's also critical for immunizers and parents to maintain high and timely immunization uptake to ensure infants receive maximum early protection when they are most at risk of severe disease.

Background Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes fetal growth restriction defined as birthweight 32 weeks). To assess if the performance of the prediction models is generalisable for various definitions of FGR, and assess the association between various birthweight centiles calculated using customised and population-based standards and perinatal morbidity and mortality. To estimate the net benefit (clinical utility) of the developed prediction models using decision curve analysis (DCA). To assess the costs and outcomes and the potential impact of resource use of the prediction models. Methods We followed existing recommendations for prediction model development and validation and reported in line with guidelines for prognostic research and IPD meta-analysis. Our meta-analysis utilised IPD within the IPPIC Network database. IPPIC is a living data repository of cleaned and harmonised data of pregnant women from large birth or population-based cohorts, study cohort data, registries or unpublished data from hospital records. The primary outcomes were (1) FGR defined as birthweight

Introduction Selective fetal growth restriction (sFGR) in monochorionic twin pregnancy, defined as an estimated fetal weight (EFW) of one twin

Objective To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit.Design Individual participant data meta-analysis.Data sources Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset.Eligibility criteria for selecting studies Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model.Results The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, −18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of −22.3 g (Allen cohort), −33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (−154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making.Conclusions The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required.Trial registration PROSPERO CRD42019135045

Objectives As part of the FERN feasibility study, this qualitative research aimed to explore parents’ and clinicians’ views on the acceptability, feasibility and design of a randomised controlled trial (RCT) of active intervention versus expectant management in monochorionic (MC) diamniotic twin pregnancies with early-onset (prior to 24 weeks) selective fetal growth restriction (sFGR). Interventions could include laser treatment or selective termination which could lead to the death or serious disability of one or both twins.Design Qualitative semi-structured interviews with parents and clinicians. Data were analysed using reflexive thematic analysis and considered against the Principles of Biomedical Ethics.Participants and setting We interviewed 19 UK parents experiencing (six mothers, two partners) or had recently experienced (eight mothers, three partners) early-onset sFGR in MC twin pregnancy and 14 specialist clinicians from the UK and Europe.Results Participants viewed the proposed RCT as ‘ethically murky’ because they believed that the management of sFGR in MC twin pregnancy should be individualised according to the type and severity of sFGR. Clinicians prioritised the gestational age, size, decrease in growth velocity, access to the placental vessels and acceptability of intervention for parents. Discussions and decision-making about selective termination appeared to cause long-term harm (maleficence). The most important outcome for parents and clinicians was ‘live birth’. For clinicians, this was the live birth of at least one twin. For parents, this meant the live birth of both twins, even if this meant that their babies had neurodevelopmental impairment or disabilities.Conclusions All three pregnancy management approaches for sFGR in MC twin pregnancy carry risks and benefits, and the ultimate goal for parents is to receive individualised care to achieve the best possible outcome for both twins. An RCT was not acceptable to parents or clinicians or seen as ethically appropriate. Alternative study designs should be considered to answer this important research question.

Summary: SARS-CoV-2 infection during pregestational and early pregnancy periods has an unclear impact on fetal development. Although vertical transmission is rare, potential effects on the developing fetal brain are plausible. However, robust evidence linking maternal SARS-CoV-2 infection to congenital anomalies is limited due to inadequate tracking of infection history and methodological flaws in published studies. This is further complicated by limitations, such as restricted testing access and undiagnosed infections, particularly in low- and middle-income countries. Most data focus on hospitalized women near term, lacking information on first- and second-trimester infections. Thus, an accurate assessment of the impact of COVID-19 on congenital anomalies is essential. It should however be emphasised that we have robust evidence that vaccination against COVID-19 before or during early pregnancy is not associated with malformations, ruling out any role of COVID-19 vaccines in these increased rates of congenital abnormalities. This viewpoint discusses findings from surveillance registries, highlights study limitations, and offers research recommendations to inform clinical guidelines and public health strategies, aiming to mitigate the effects of viral infections on early neurodevelopment.

Abstract Objective Mothers of premature infants are more likely to develop anxiety during the first postpartum year than mothers of term infants. However, commonly used measures of anxiety were developed for general adult populations and may produce spurious, over-inflated scores when used in a postpartum context. Although perinatal-specific tools such as the Postpartum Specific Anxiety Scale [PSAS] offer a promising alternative form of measurement, it is not clear whether the measure performs similarly in mothers of premature infants as it does in mothers of term infants. The objective of the current study was to identify whether items on the Postpartum Specific Anxiety Scale - Research Short Form (PSAS-RSF) are being interpreted in the same manner in mothers of term infants and mothers of premature infants. Mothers (N = 320) participated in an international on-line survey between February 2022 and March 2023 (n = 160 mothers of premature infants, n = 160 mothers of term infants) where they completed the PSAS-RSF. Data were analysed using a measurement invariance analysis to assess whether constructs of the PSAS-RSF are performing in a similar manner across the two groups. Results Whilst the PSAS-RSF achieved configural invariance and so retains its four-factor structure, metric invariance was not reached and so items are being interpreted differently in mothers of premature infants. Items concerning infant-separation, finance, and anxieties surrounding infant health are potentially problematic. Future research must now modify the PSAS-RSF for specific use in mothers of premature infants, to ensure measurement of anxiety in this population is valid.

Abstract Objectives We aimed to investigate prenatal predictors for ambulation without assistance in children following prenatal repair of open spina bifida (OSB). Methods A systematic search was conducted in three databases until June 2022. We included articles reporting on prenatal repair of open spina bifida (OSB) and ambulation outcomes. The random‐effect model was used. Effect sizes are presented as odds ratio (OR), using the Mantel–Haenszel test, with 95% confidence interval (CI). Results Five studies encompassing 460 pregnancies that underwent prenatal repair of OSB of which a total of 234 had data on ambulation and were included. The follow‐up age for all included studies was 30 months. Two studies were open repairs, two were fetoscopic repairs, and one included both open and fetoscopic repairs. Of the 234 included population, ambulation without assistance occurred in 159/234, 68% (95% CI 58, 76), and ambulation with assistance occurred in 75/234, 32% (95% CI 23.6, 41.6). Significant prenatal preoperative predictors that are negatively associated with ambulation without assistance were lateral ventricle (LV) width ≥15 mm (OR: 0.29; 95% CI 0.12, 0.69, I2 = 0.0%; p

Background Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access. Meeting A round-table discussion, held at St George’s University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation. Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified. Conclusions With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway.

Background PRECISE-DYAD is an observational cohort study of mother-child dyads running in urban and rural communities in The Gambia and Kenya. The cohort is being followed for two years and includes uncomplicated pregnancies and those that suffered pregnancy hypertension, fetal growth restriction, preterm birth, and/or stillbirth. Methods The PRECISE-DYAD study will follow up ~4200 women and their children recruited into the original PRECISE study. The study will add to the detailed pregnancy information and samples in PRECISE, collecting additional biological samples and clinical information on both the maternal and child health. Women will be asked about both their and their child’s health, their diets as well as undertaking a basic cardiology assessment. Using a case-control approach, some mothers will be asked about their mental health, their experiences of care during labour in the healthcare facility. In a sub-group, data on financial expenditure during antenatal, intrapartum, and postnatal periods will also be collected. Child development will be assessed using a range of tools, including neurodevelopment assessments, and evaluating their home environment and quality of life. In the event developmental milestones are not met, additional assessments to assess vision and their risk of autism spectrum disorders will be conducted. Finally, a personal environmental exposure model for the full cohort will be created based on air and water quality data, combined with geographical, demographic, and behavioural variables. Conclusions The PRECISE-DYAD study will provide a greater epidemiological and mechanistic understanding of health and disease pathways in two sub-Saharan African countries, following healthy and complicated pregnancies. We are seeking additional funding to maintain this cohort and to gain an understanding of the effects of pregnancies outcome on longer-term health trajectories in mothers and their children.

Objective To assess the effects of COVID-19 vaccines in women before or during pregnancy on SARS-CoV-2 infection-related, pregnancy, offspring and reactogenicity outcomes.Design Systematic review and meta-analysis.Data sources Major databases between December 2019 and January 2023.Study selection Nine pairs of reviewers contributed to study selection. We included test-negative designs, comparative cohorts and randomised trials on effects of COVID-19 vaccines on infection-related and pregnancy outcomes. Non-comparative cohort studies reporting reactogenicity outcomes were also included.Quality assessment, data extraction and analysis Two reviewers independently assessed study quality and extracted data. We undertook random-effects meta-analysis and reported findings as HRs, risk ratios (RRs), ORs or rates with 95% CIs.Results Sixty-seven studies (1 813 947 women) were included. Overall, in test-negative design studies, pregnant women fully vaccinated with any COVID-19 vaccine had 61% reduced odds of SARS-CoV-2 infection during pregnancy (OR 0.39, 95% CI 0.21 to 0.75; 4 studies, 23 927 women; I2=87.2%) and 94% reduced odds of hospital admission (OR 0.06, 95% CI 0.01 to 0.71; 2 studies, 868 women; I2=92%). In adjusted cohort studies, the risk of hypertensive disorders in pregnancy was reduced by 12% (RR 0.88, 95% CI 0.82 to 0.92; 2 studies; 115 085 women), while caesarean section was reduced by 9% (OR 0.91, 95% CI 0.85 to 0.98; 6 studies; 30 192 women). We observed an 8% reduction in the risk of neonatal intensive care unit admission (RR 0.92, 95% CI 0.87 to 0.97; 2 studies; 54 569 women) in babies born to vaccinated versus not vaccinated women. In general, vaccination during pregnancy was not associated with increased risk of adverse pregnancy or perinatal outcomes. Pain at the injection site was the most common side effect reported (77%, 95% CI 52% to 94%; 11 studies; 27 195 women).Conclusion COVID-19 vaccines are effective in preventing SARS-CoV-2 infection and related complications in pregnant women.PROSPERO registration number CRD42020178076.

Abstract Background Despite being at higher risk of severe disease and pregnancy complications, evidence on susceptibility to SARS-CoV-2 infection in pregnancy is still limited. The aim of the study is to compare the likelihood of undergoing a SARS-CoV-2 test and testing positive for COVID-19 in pregnancy and puerperium with that of the general female population of reproductive age. Methods This is a retrospective population-based cohort study including 117,606 women of reproductive age (March 2020-September 2021) with 6608 (5.6%) women having ≥ 1 pregnancy. Women were linked to the pregnancy registry to be classified as “non-pregnant”, “pregnant”, and “puerperium”; then, according to the national case-based integrated COVID-19 surveillance system, all women undergoing a SARS-CoV-2 test during the study period were identified. The Incidence Rate Ratio was calculated to compare the likelihood of being tested for SARS-CoV-2 in pregnant, puerperium and non-pregnant women among all women included. The likelihood of having a COVID-19 diagnosis was calculated using two comparators (not-pregnant women and the person-time before/after pregnancy) by means of Cox proportional hazards models, adjusting for age and with the cluster option to control standard error calculation in repeated pregnancies. Only first infection and swabs before the first one positive were included. Results The probability of being tested for SARS-CoV-2 was 4.9 (95% CI: 4.8–5.1) and 3.6 times higher (95%CI: 3.4–3.9) in pregnancy (including spontaneous miscarriages) and in the puerperium, respectively. The Hazard Ratio (HR) of covid-19 diagnosis during pregnancy vs. non-pregnancy was 1.17 (95% CI 1.03–1.33) with similar results when comparing the risk during pregnancy with that of the same women outside pregnancy (puerperium excluded), with an HR of 1.13 (95% CI 0.96–1.33); the excess decreased when excluding the test performed at admission for delivery (HR 1.08 (95%CI 0.90–1.30). In the puerperium, the HR was 0.62 (95% CI 0.41–0.92) comparing women with ≥ 1childbirth with all other women and excluding the first two weeks of puerperium. Conclusions Women during pregnancy showed a small increase in the risk of infection, compatible with a higher likelihood of being tested. A lower probability of infection during the puerperium was observed during the entire pandemic period, suggesting likely protective behaviors which were effective in reducing their probability of infection.

Maternal vaccination during pregnancy, in general and against COVID-19 infection, offers protection to both mother and baby, but uptake remains suboptimal. This study aimed to explore the perceptions regarding COVID-19 vaccination in pregnancy, particularly for marginalised populations and those living with social or medical complexity. A total of 96 semi-structured in-depth interviews were conducted with 40 women, 15 partners, 21 HCPs, and 20 policy makers, across all four nations of the United Kingdom (UK), discussing their lived experience of utilising, delivering, or developing policy for COVID-19 vaccination in pregnancy during the pandemic. Three themes were derived: (1) historical and social context, (2) communication of information and guidance, and (3) appraisal and action. Together these captured the participants’ legacy of mistrust in drugs during pregnancy; prior positive experiences; concerns about missing information, conflicting information, or false information about COVID-19 vaccines; and confusing guidance for pregnant women. The final theme describes the participants’ behaviour and actions undertaken consequent to their experiences and the available information. The findings suggest efforts to improve COVID-19 vaccination in pregnancy may be best focused on personalised communication of information. A trusting relationship and prior positive experiences with other vaccines, both in and outside of pregnancy, positively influenced perceptions of COVID-19 vaccination.

BACKGROUND: Prepregnancy obesity and racial-ethnic disparities has been shown to be associated with meningomyelocele. OBJECTIVE: This study aimed to investigate the association of maternal periconceptional factors, including race–ethnicity and prepregnancy body mass index, with the prevalence of isolated fetal myelomeningocele. METHODS: This was a population-based cross-sectional study using Centers for Disease Control and Prevention birth data from 2016 to 2021. Major structural anomalies or chromosomal abnormalities were excluded. Race–ethnicity was classified as non-Hispanic White (reference population), non-Hispanic Black, non-Hispanic Asian, Hispanic, and others. Maternal prepregnancy body mass index was classified as underweight (

IntroductionIt is well established that a premature birth increases the likelihood of developing anxiety during the postpartum period, and that the environment of the neonatal intensive care unit (NICU) might be a contributing factor. Mothers of earlier premature infants may experience these anxieties to a higher degree compared to mothers of later premature infants. The aim of this study was to explore the association between prematurity and postpartum-specific anxiety, and the relationship between postpartum-specific anxiety and stress in the NICU.Materials and methodsMothers (N = 237) of infants aged between birth and 12 months completed an online survey containing the Postpartum Specific Anxiety Scale – Research Short Form (PSAS-RSF) and the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU). Structural equation modeling was used to analyze the relationship between gestational age and postpartum-specific anxiety, with one-way ANOVAs used to analyze this relationship with respect to categories of gestational age. Hierarchical regression models analyzed the relationship between postpartum-specific anxiety and stress in the NICU.ResultsFor the PSAS-RSF, Practical Infant Care Anxieties (p = 0.001), Maternal Competence and Attachment Anxieties (p = 0.033), and Infant Safety and Welfare Anxieties (p = 0.020) were significantly associated with week of gestation. Practical Infant Care and Infant Safety and Welfare Anxieties were significantly higher for mothers of late premature infants, compared to mothers of term infants (p < 0.001; p = 0.019). There were no significant between-group differences with respect to Maternal Competence and Attachment Anxieties. After controlling for potential confounders, Infant Safety and Welfare Anxieties were significantly associated with increased stress in the NICU (p < 0.001) as measured by the PSS:NICU.ConclusionsOur findings highlight the need for interventions for mothers with premature infants, which specifically target anxieties reflected in the PSAS-RSF, such as routine care and increasing maternal self-efficacy.

The aim of this systematic review is to report the normal cortical development of different fetal cerebral fissures on ultrasound, describe associated anomalies in fetuses with cortical malformations, and evaluate the quality of published charts of cortical fissures. The inclusion criteria were studies reporting development, anomalies, and reference charts of fetal cortical structures on ultrasound. The outcomes observed were the timing of the appearance of different cortical fissures according to different gestational age windows, associated central nervous system (CNS) and extra-CNS anomalies detected at ultrasound in fetuses with cortical malformation, and rate of fetuses with isolated anomaly. Furthermore, we performed a critical evaluation of the published reference charts for cortical development on ultrasound. Random-effect meta-analyses of proportions were used to combine the data. Twenty-seven studies (6875 fetuses) were included. Sylvian fissure was visualized on ultrasound in 97.69% (95% CI 92.0–100) of cases at 18–19, 98.17% (95% CI 94.8–99.8) at 20–21, 98.94% (95% CI 97.0–99.9) at 22–23, and in all cases from 24 weeks of gestation. Parieto-occipital fissure was visualized in 81.56% (95% CI 48.4–99.3) of cases at 18–19, 96.59% (95% CI 83.2–99.8) at 20–21, 96.85% (95% CI 88.8–100) at 22–23, and in all cases from 24 weeks of gestation, while the corresponding figures for calcarine fissure were 37.27% (95% CI 0.5–89.6), 80.42% (95% CI 50.2–98.2), 89.18% (95% CI 74.0–98.2), and 96.02% (95% CI 96.9–100). Malformations of cortical development were diagnosed as an isolated finding at ultrasound in 6.21% (95% CI 2.9–10.9) of cases, while they were associated with additional CNS anomalies in 93.79% (95% CI 89.1–97.2) of cases. These findings highlight the need for large studies specifically looking at the timing of the appearance of the different brain sulci. Standardized algorithms for prenatal assessment of fetuses at high risk of malformations of cortical development are also warranted.

COVID-19 vaccination rates are lower in women of reproductive age (WRA), including pregnant/postpartum women, despite their poorer COVID-19-related outcomes. We evaluated the vaccination experiences of 3568 U.K. WRA, including 1983 women (55.6%) experiencing a pandemic pregnancy, recruited through the ZOE COVID Symptom Study app. Two staggered online questionnaires (Oct–Dec 2021: 3453 responders; Aug–Sept 2022: 2129 responders) assessed reproductive status, COVID-19 status, vaccination, and attitudes for/against vaccination. Descriptive analyses included vaccination type(s), timing relative to age-based eligibility and reproductive status, vaccination delay (first vaccination >28 days from eligibility), and rationale, with content analysis of free-text comments. Most responders (3392/3453, 98.2%) were vaccinated by Dec 2021, motivated by altruism, vaccination supportiveness in general, low risk, and COVID-19 concerns. Few declined vaccination (by Sept/2022: 20/2129, 1.0%), citing risks (pregnancy-specific and longer-term), pre-existing immunity, and personal/philosophical reasons. Few women delayed vaccination, although pregnant/postpartum women (vs. other WRA) received vaccination later (median 3 vs. 0 days after eligibility, p < 0.0001). Despite high uptake, concerns included adverse effects, misinformation (including from healthcare providers), ever-changing government advice, and complex decision making. In summary, most women in this large WRA cohort were promptly vaccinated, including pregnant/post-partum women. Altruism and community benefit superseded personal benefit as reasons for vaccination. Nevertheless, responders experienced angst and received vaccine-related misinformation and discouragement. These findings should inform vaccination strategies in WRA.

Summary: In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international mobility continue to rise, highly infectious respiratory diseases will likely emerge more frequently and their impact is expected to be substantial. How quickly a safe and efficacious vaccine can be deployed against rising infectious respiratory diseases may be the most important challenge that humanity will face in the near future. While some organizations are engaged in addressing the World Health Organization's ''blueprint for priority diseases'', the lack of worldwide preparedness, and the uncertainty around universal vaccine availability, remain major concerns. We therefore propose the establishment of an international candidate vaccine pool repository for potential respiratory diseases, supported by multiple stakeholders and countries that contribute facilities, technologies, and other medical and financial resources. The types and categories of candidate vaccines can be determined based on information from previous pandemics and epidemics. Each participant country or region can focus on developing one or a few vaccine types or categories, together covering most if not all possible potential infectious diseases. The safety of these vaccines can be tested using animal models. Information for effective candidates that can be potentially applied to humans will then be shared across all participants. When a new pandemic arises, these pre-selected and tested vaccines can be quickly tested in RCTs for human populations.

Abstract Women of reproductive age are a group of particular concern with regards to vaccine uptake, related to their unique considerations of menstruation, fertility, and pregnancy. To obtain vaccine uptake data specific to this group, we obtained vaccine surveillance data from the Office for National Statistics, linked with COVID-19 vaccination status from the National Immunisation Management Service, England, from 8 Dec 2020 to 15 Feb 2021; data from 13,128,525 such women at population-level, were clustered by age (18–29, 30–39, and 40–49 years), self-defined ethnicity (19 UK government categories), and index of multiple deprivation (IMD, geographically-defined IMD quintiles). Here we show that among women of reproductive age, older age, White ethnicity and being in the least-deprived index of multiple deprivation are each independently associated with higher vaccine uptake, for first and second doses; however, ethnicity exerts the strongest influence (and IMD the weakest). These findings should inform future vaccination public messaging and policy.

BackgroundThe optimal approach to prevent preterm birth (PTB) in twins has not been fully established yet. Recent evidence suggests that placement of cervical cerclage in twin pregnancies with short cervical length at ultrasound or cervical dilatation at physical examination might be associated with a reduced risk of PTB. However, such evidence is based mainly on small studies thus questioning the robustness of these findings. The aim of this systematic review was to determine the role of cervical cerclage in preventing PTB and adverse maternal or perinatal outcomes in twin pregnancies.Methods and findingsKey databases searched and date of last search: MEDLINE, Embase, and CINAHL were searched electronically on 20 April 2023. Eligibility criteria: Inclusion criteria were observational studies assessing the risk of PTB among twin pregnancies undergoing cerclage versus no cerclage and randomized trials in which twin pregnancies were allocated to cerclage for the prevention of PTB or to a control group (e.g., placebo or treatment as usual). The primary outcome was PTB ConclusionsEmergency cerclage for cervical dilation or short cervical length

Abstract Background Reducing the rate of stillbirth is an international priority. At least half of babies stillborn in high-income countries are small for gestational-age (SGA). The Growth Assessment Protocol (GAP), a complex antenatal intervention that aims to increase the rate of antenatal detection of SGA, was evaluated in the DESiGN type 2 hybrid effectiveness-implementation cluster randomised trial (n = 13 clusters). In this paper, we present the trial process evaluation. Methods A mixed-methods process evaluation was conducted. Clinical leads and frontline healthcare professionals were interviewed to inform understanding of context (implementing and standard care sites) and GAP implementation (implementing sites). Thematic analysis of interview text used the context and implementation of complex interventions framework to understand acceptability, feasibility, and the impact of context. A review of implementing cluster clinical guidelines, training and maternity records was conducted to assess fidelity, dose and reach. Results Interviews were conducted with 28 clinical leads and 27 frontline healthcare professionals across 11 sites. Staff at implementing sites generally found GAP to be acceptable but raised issues of feasibility, caused by conflicting demands on resource, and variable beliefs among clinical leaders regarding the intervention value. GAP was implemented with variable fidelity (concordance of local guidelines to GAP was high at two sites, moderate at two and low at one site), all sites achieved the target to train > 75% staff using face-to-face methods, but only one site trained > 75% staff using e-learning methods; a median of 84% (range 78–87%) of women were correctly risk stratified at the five implementing sites. Most sites achieved high scores for reach (median 94%, range 62–98% of women had a customised growth chart), but generally, low scores for dose (median 31%, range 8–53% of low-risk women and median 5%, range 0–17% of high-risk women) were monitored for SGA as recommended. Conclusions Implementation of GAP was generally acceptable to staff but with issues of feasibility that are likely to have contributed to variation in implementation strength. Leadership and resourcing are fundamental to effective implementation of clinical service changes, even when such changes are well aligned to policy mandated service-change priorities. Trial registration Primary registry and trial identifying number: ISRCTN 67698474. Registered 02/11/16. https://doi.org/10.1186/ISRCTN67698474 .

In the current monkeypox outbreak, vaccination and treatment of pregnant women are recommended only if the benefits outweigh risks, but the extremely sparse data available limit evidence-based recommendations. We must facilitate a unified consensus approach to rapidly collect robust data. Two years into the COVID-19 pandemic, monkeypox has emerged as yet another challenge to the mother-fetus dyad, potentially placing both at risk, if exposed.

This recommendation document follows the mission of the World Association of Perinatal Medicine (WAPM) in collaboration with the Perinatal Medicine Foundation (PMF). We aim to bring together groups and individuals throughout the world for precise standardization to implement the ultrasound evaluation of the fetus in the first trimester of pregnancy and improve the early detection of anomalies and the clinical management of the pregnancy. The aim is to present a document that includes statements and recommendations on the standard evaluation of the fetal anatomy in the first trimester, based on quality evidence in the peer-reviewed literature as well as the experience of perinatal experts around the world.

Introduction Hypertensive disorders of pregnancy (HDP) are associated with a high incidence of maternal and perinatal morbidity and mortality. HDP, in particular pre-eclampsia, have been determined as risk factors for future cardiovascular disease. Recently, the common hypothesis of pre-eclampsia being a placental disorder was challenged as numerous studies show evidence for short-term and long-term cardiovascular changes in pregnancies affected by HDP, suggesting a cardiovascular origin of the disease. Despite new insights into the pathophysiology of HDP, concepts of therapy remain unchanged and evidence for improved maternal and neonatal outcome by using antihypertensive agents is lacking.Methods and analysis A prospective observational case–control study, including 100 women with HDP and 100 healthy controls, which will assess maternal haemodynamics using the USCOM 1A Monitor and Arteriograph along with cardiovascular markers (soluble fms-like kinase 1/placental-like growth factor, N-terminal pro-B type natriuretic peptide) in women with HDP under antihypertensive therapy, including a follow-up at 3 months and 1 year post partum, will be conducted over a 50-month period in Vienna. A prospective, longitudinal study of cardiovascular surrogate markers conducted in Oslo will serve as a comparative cohort for the Vienna cohort of haemodynamic parameters in pregnancy including a longer follow-up period of up to 3 years post partum. Each site will provide a dataset of a patient group and a control group and will be assessed for the outcome categories USCOM 1A measurements, Arteriograph measurements and Angiogenic marker measurements. To estimate the effect of antihypertensive therapy on outcome parameters, ORs with 95% CIs will be computed. Longitudinal changes of outcome parameters will be compared between normotensive and hypertensive pregnancies using mixed-effects models.Ethics and dissemination Ethical approval has been granted to all participating centres. Results will be published in international peer-reviewed journals and will be presented at national and international conferences.

BackgroundAccurate knowledge of fetal presentation at term is vital for optimal antenatal and intrapartum care. The primary objective was to compare the impact of routine third trimester ultrasound or point-of-care ultrasound (POCUS) with standard antenatal care, on the incidence of overall and proportion of all term breech presentations that were undiagnosed at term, and on the related adverse perinatal outcomes.Methods and findingsThis was a retrospective multicentre cohort study where we included data from St. George's (SGH) and Norfolk and Norwich University Hospitals (NNUH). Pregnancies were grouped according to whether they received routine third trimester scan (SGH) or POCUS (NNUH). Women with multiple pregnancy, preterm birth prior to 37 weeks, congenital abnormality, and those undergoing planned cesarean section for breech presentation were excluded. Undiagnosed breech presentation was defined as follows: (a) women presenting in labour or with ruptured membranes at term subsequently discovered to have a breech presentation; and (b) women attending for induction of labour at term found to have a breech presentation before induction. The primary outcome was the proportion of all term breech presentations that were undiagnosed. The secondary outcomes included mode of birth, gestational age at birth, birth weight, incidence of emergency cesarean section, and the following neonatal adverse outcomes: Apgar score 99.9%) of reduced rate of low Apgar score (ConclusionsIn our study, we observed that both a policy of routine facility-based third trimester ultrasound or POCUS are associated with a reduction in the proportion of term breech presentations that were undiagnosed, with an improvement in neonatal outcomes. The findings from our study support the policy of third trimester ultrasound scan for fetal presentation. Future studies should focus on exploring the cost-effectiveness of POCUS for fetal presentation.

Pregnant women have been disproportionately under-vaccinated against COVID-19, partly because they were excluded from initial trials. This systematic review and meta-analysis supports efficacy of vaccination in pregnancy, and finds no evidence of adverse maternal or perinatal outcomes.

Transmission of human cytomegalovirus (CMV), from a pregnant woman to her fetus can cause congenital CMV infection, with life-long problems in some infected children. The presence of CMV in an infected individual's bodily fluid is known as shedding. An individual can become infected with CMV through contact with another individual who is shedding CMV in their bodily fluid, and the avoidance of contact with infected fluids may reduce the risk of infection. We explored the experiences of pregnant women taking part in a study investigating CMV shedding, to identify the potential facilitators and barriers towards engaging pregnant women with CMV risk-reduction measures. Twenty pregnant women participated in semi-structured, end-of-study, telephone interviews, analysed using thematic analysis. They participated in an observational study investigating CMV shedding in pregnant women previously infected with CMV living with young children. Participating women considered that CMV testing of themselves and their newborns was a benefit of participation, without raising additional concerns. They identified that their participation was contingent on a balance of convenience and inconvenience, and benefits and risks. Participation increased their awareness of their hygiene-based practices, leading to behavioural modifications that put them in contact with urine and saliva of their children without instructions to do so. These behavioural modifications might interfere with household routines. However, they recognised it to be a time-limited risk-reduction measure, and felt empowered by the knowledge they had gained through study participation and the support they had received from their partners. Participating women gained an increased awareness of their behaviour, resulting in behavioural modification without instructions to do this, in line with previous findings that trial participation can impact on participants' thinking about their behaviour with a possibility to influence change. Maternal research and risk-reduction measures should be centred around being informative, convenient, empowering, and supportive.

Introduction The prevalence of COVID-19 and its impact varied between countries and regions. Pregnant women are at high risk of COVID-19 complications compared with non-pregnant women. The magnitude of variations, if any, in SARS-CoV-2 infection rates and its health outcomes among pregnant women by geographical regions and country’s income level is not known.Methods We performed a random-effects meta-analysis as part of the ongoing PregCOV-19 living systematic review (December 2019 to April 2021). We included cohort studies on pregnant women with COVID-19 reporting maternal (mortality, intensive care admission and preterm birth) and offspring (mortality, stillbirth, neonatal intensive care admission) outcomes and grouped them by World Bank geographical region and income level. We reported results as proportions with 95% confidence intervals (CI).Results We included 311 studies (2 003 724 pregnant women, 57 countries). The rates of SARS-CoV-2 infection in pregnant women varied significantly by region (p

Abstract Background Congenital cytomegalovirus (CMV) is the most common congenital infection globally, however information about CMV is not routinely included in antenatal education in the United Kingdom. This feasibility study aimed to gather the essential data needed to design and power a large randomised controlled trial (RCT) to investigate the efficacy of a digital intervention in reducing the risk of CMV acquisition in pregnancy. In order to do this, we carried out a single-centre RCT, which explored the knowledge, attitudes and risk reduction behaviours in women in the intervention and treatment as usual groups, pre- and post-intervention. Methods CMV seronegative women living with a child less than four years old, receiving antenatal care at a single UK tertiary centre, were randomised to the digital intervention or ‘treatment as usual’ groups. Participants completed questionnaires before the digital intervention and after and at 34 gestational weeks, and responses within groups and between groups were compared using tailored randomisation tests. CMV serology was tested in the first trimester and at the end of pregnancy. Results Of the 878 women screened, 865 samples were analysed with 43% (n = 372) being CMV seronegative and therefore eligible to take part in the RCT; of these, 103 (27.7%) women were enrolled and 87 (84%) of these completed the study. Most participants (n = 66; 64%) were unfamiliar with CMV at enrolment, however at 34 gestational weeks, women in the intervention group (n = 51) were more knowledgeable about CMV compared to the treatment as usual group (n = 52) and reported engaging in activities that may increase the risk of CMV transmission less frequently. The digital intervention was highly acceptable to pregnant women. Overall, four participants seroconverted over the course of the study: two from each study group. Conclusions A large multi-centre RCT investigating the efficacy of a CMV digital intervention is feasible in the United Kingdom; this study has generated essential data upon which to power such a study. This single-centre feasibility RCT demonstrates that a digital educational intervention is associated with increase in knowledge about CMV and can result in behaviour change which may reduce the risk of CMV acquisition in pregnancy. Trial registration Clinicaltrials.gov, NCT03511274 , Registered 27.04.18, http://www.Clinicaltrials.gov

These practice guidelines follow the mission of the World Association of Perinatal Medicine (WAPM) in collaboration with the Perinatal Medicine Foundation, bringing together groups and individuals throughout the world, with the goal of improving the ultrasound assessment of the fetal central nervous system (CNS) anatomy. In fact, this document provides further guidance for healthcare practitioners for the evaluation of the fetal CNS during the mid-trimester ultrasound scan with the aim to increase the ability in evaluating normal fetal anatomy. Therefore, it is not intended to establish a legal standard of care. This document is based on consensus among perinatal experts throughout the world, and serves as a guideline for use in clinical practice.

Abstract Background Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens). Methods This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP5-IPV (n = 77) or TdaP3-IPV (n = 77) at 28–32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum. Results Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n = 67) or TdaP3-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV- and TdaP3-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56–0.90] and 0.78 [0.61–0.98], respectively); by 13 months of age, this difference was no longer observed. Conclusion Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy. Trial registration ClinicalTrials.gov , NCT02145624 , registered 23 May 2014

Abstract Background Routine assessment in (near) term pregnancy is often inaccurate for the identification of fetuses who are mild to moderately compromised due to placental insufficiency and are at risk of adverse outcomes, especially when fetal size is seemingly within normal range for gestational age. Although biometric measurements and cardiotocography are frequently used, it is known that these techniques have low sensitivity and specificity. In clinical practice this diagnostic uncertainty results in considerable ‘over treatment’ of women with healthy fetuses whilst truly compromised fetuses remain unidentified. The CPR is the ratio of the umbilical artery pulsatility index over the middle cerebral artery pulsatility index. A low CPR reflects fetal redistribution and is thought to be indicative of placental insufficiency independent of actual fetal size, and a marker of adverse outcomes. Its utility as an indicator for delivery in women with reduced fetal movements (RFM) is unknown. The aim of this study is to assess whether expedited delivery of women with RFM identified as high risk on the basis of a low CPR improves neonatal outcomes. Secondary aims include childhood outcomes, maternal obstetric outcomes, and the predictive value of biomarkers for adverse outcomes. Methods International multicentre cluster randomised trial of women with singleton pregnancies with RFM at term, randomised to either an open or concealed arm. Only women with an estimated fetal weight ≥ 10th centile, a fetus in cephalic presentation and normal cardiotocograph are eligible and after informed consent the CPR will be measured. Expedited delivery is recommended in women with a low CPR in the open arm. Women in the concealed arm will not have their CPR results revealed and will receive routine clinical care. The intended sample size based on the primary outcome is 2160 patients. The primary outcome is a composite of: stillbirth, neonatal mortality, Apgar score

Abstract Background The use of electronic patient records for assessing outcomes in clinical trials is a methodological strategy intended to drive faster and more cost-efficient acquisition of results. The aim of this manuscript was to outline the data collection and management considerations of a maternity and perinatal clinical trial using data from electronic patient records, exemplifying the DESiGN Trial as a case study. Methods The DESiGN Trial is a cluster randomised control trial assessing the effect of a complex intervention versus standard care for identifying small for gestational age foetuses. Data on maternal/perinatal characteristics and outcomes including infants admitted to neonatal care, parameters from foetal ultrasound and details of hospital activity for health-economic evaluation were collected at two time points from four types of electronic patient records held in 22 different electronic record systems at the 13 research clusters. Data were pseudonymised on site using a bespoke Microsoft Excel macro and securely transferred to the central data store. Data quality checks were undertaken. Rules for data harmonisation of the raw data were developed and a data dictionary produced, along with rules and assumptions for data linkage of the datasets. The dictionary included descriptions of the rationale and assumptions for data harmonisation and quality checks. Results Data were collected on 182,052 babies from 178,350 pregnancies in 165,397 unique women. Data availability and completeness varied across research sites; each of eight variables which were key to calculation of the primary outcome were completely missing in median 3 (range 1–4) clusters at the time of the first data download. This improved by the second data download following clarification of instructions to the research sites (each of the eight key variables were completely missing in median 1 (range 0–1) cluster at the second time point). Common data management challenges were harmonising a single variable from multiple sources and categorising free-text data, solutions were developed for this trial. Conclusions Conduct of clinical trials which use electronic patient records for the assessment of outcomes can be time and cost-effective but still requires appropriate time and resources to maximise data quality. A difficulty for pregnancy and perinatal research in the UK is the wide variety of different systems used to collect patient data across maternity units. In this manuscript, we describe how we managed this and provide a detailed data dictionary covering the harmonisation of variable names and values that will be helpful for other researchers working with these data. Trial registration Primary registry and trial identifying number: ISRCTN 67698474 . Registered on 02/11/16.

Background Antenatal detection and management of small for gestational age (SGA) is a strategy to reduce stillbirth. Large observational studies provide conflicting results on the effect of the Growth Assessment Protocol (GAP) in relation to detection of SGA and reduction of stillbirth; to the best of our knowledge, there are no reported randomised control trials. Our aim was to determine if GAP improves antenatal detection of SGA compared to standard care. Methods and findings This was a pragmatic, superiority, 2-arm, parallel group, open, cluster randomised control trial. Maternity units in England were eligible to participate in the study, except if they had already implemented GAP. All women who gave birth in participating clusters (maternity units) during the year prior to randomisation and during the trial (November 2016 to February 2019) were included. Multiple pregnancies, fetal abnormalities or births before 24+1 weeks were excluded. Clusters were randomised to immediate implementation of GAP, an antenatal care package aimed at improving detection of SGA as a means to reduce the rate of stillbirth, or to standard care. Randomisation by random permutation was stratified by time of study inclusion and cluster size. Data were obtained from hospital electronic records for 12 months prerandomisation, the washout period (interval between randomisation and data collection of outcomes), and the outcome period (last 6 months of the study). The primary outcome was ultrasound detection of SGA (estimated fetal weight Conclusions In this study, we observed no effect of GAP on antenatal detection of SGA compared to standard care. Given variable implementation observed, future studies should incorporate standardised implementation outcomes such as those reported here to determine generalisability of our findings. Trial registration This trial is registered with the ISRCTN registry, ISRCTN67698474. Matias C Vieira and colleagues evaluate the Growth Assessment Protocol (GAP) for antenatal detection of small for gestational age in the DESiGN cluster randomised trial. Summary Why was this study done? Antenatal detection and appropriate management of small for gestational age (SGA) infants is a recognised strategy to prevent stillbirth; previous reports have suggested the rate of stillbirth is halved when SGA is antenatally detected, compared to undetected SGA. Large observational studies provide conflicting results on the effect of Growth Assessment Protocol (GAP), an antenatal care package, with both findings of increased and no difference in detection of SGA and reduction of stillbirth. The observational nature of all previous studies about GAP limits the assessment of causality in any observed associations. What did the researchers do and find? To the best of our knowledge, this is the first randomised control trial of GAP, comparing 11,096 births exposed to the intervention (5 clusters) to 13,810 exposed to standard care (6 clusters) during the outcome period. We observed no significant effect on antenatal detection of SGA compared to standard care (25.9% versus 27.7%; adjusted difference 2.2%, 95% confidence interval (CI) −6.4% to 10.7%). The lack of effect should be interpreted in the context of the variable implementation of GAP. What do these findings mean? This randomised control trial of GAP compared to standard care did not observe improvement in ultrasound detection of SGA; variable implementation of GAP was observed consistent with previous studies. It is imperative that future studies of GAP assess implementation using standardised outcomes (fidelity, reach, and dose), in order to determine generalisability of our findings, identify barriers to implementation, and hence better inform policy for improving perinatal outcomes. Use of routinely collected data is both a strength (cost-efficient) and a limitation (occurrence of missing data); the modest number of hospitals in this study limits our ability to study small differences between groups.

Disease X represents a yet unknown human pathogen which has potential to cause a serious international epidemic or pandemic. The COVID-19 pandemic has illustrated that despite being at increased risk of severe disease compared with the general population, pregnant women were left behind in the development and implementation of vaccination, resulting in conflicting communications and changing guidance about vaccine receipt in pregnancy. Based on the COVID-19 experience, the COVAX Maternal Immunization Working Group have identified three key factors and five broad focus topics for consideration when proactively planning for a disease X pandemic, including 10 criteria for evaluating pandemic vaccines for potential use in pregnant women. Prior to any disease X pandemic, collaboration and coordination are needed to close the pregnancy data gap which is currently a barrier to gender equity in health innovation, which will aid in allowing timely access to life-saving interventions including vaccines for pregnant women and their infants.

Summary: A greater proportion of pregnant women with COVID-19 have mild disease compared with their non-pregnant counterparts. Paradoxically, however, they are at higher risk of developing severe disease, requiring respiratory support and admission to intensive care. The delta SARS-Cov-2 variant is associated with increased risk of hospitalization and morbidity in unvaccinated pregnant populations. However, it is not known whether the worse pregnancy outcomes associated with the delta variant are due to a direct effect of the virus on the pregnancy, or whether this effect is mediated through more severe maternal infection. Here, we synthesize studies of COVID-19 pregnancies, focusing on the different routes of SARS-CoV-2 infection of lung and placenta, and the mechanisms of syncytial formation for each SARS-CoV-2 variant. To delineate COVID-19 complications in pregnant women, future studies should explore whether the delta variant causes greater placental infection compared to other variants and contributes to increased syncytial formation.

Abstract Amniotic fluid surrounding the developing fetus is a complex biological fluid rich in metabolically active bio‐factors. The presence of extracellular vesicles (EVs) in amniotic fluid has been mainly related to foetal urine. We here characterized EVs from term amniotic fluid in terms of surface marker expression using different orthogonal techniques. EVs appeared to be a heterogeneous population expressing markers of renal, placental, epithelial and stem cells. Moreover, we compared amniotic fluid EVs from normal pregnancies with those of preeclampsia, a hypertensive disorder affecting up to 8% of pregnancies worldwide. An increase of CD105 (endoglin) expressing EVs was observed in preeclamptic amniotic fluid by bead‐based cytofluorimetric analysis, and further confirmed using a chip‐based analysis. HLA‐G, a typical placental marker, was not co‐expressed by the majority of CD105+ EVs, in analogy with amniotic fluid stromal cell derived‐EVs. At a functional level, preeclampsia‐derived EVs, but not normal pregnancy EVs, showed an antiangiogenic effect, possibly due to the decoy effect of endoglin. Our results provide a characterization of term amniotic fluid‐EVs, supporting their origin from foetal and placental cells. In preeclampsia, the observed antiangiogenic characteristics of amniotic fluid‐EVs may reflect the hypoxic and antiangiogenic microenvironment and could possibly impact on the developing fetus or on the surrounding foetal membranes.

Abstract Background Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting. Methods IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis. Results Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model’s calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%. Conclusions The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice. Trial registration PROSPERO ID: CRD42015029349 .

Objectives To determine the feasibility and acceptability of conducting a randomised trial on the effects of myo-inositol in preventing gestational diabetes in high-risk pregnant women.Design A multicentre, double-blind, placebo-controlled, pilot randomised trial with nested qualitative evaluation.Setting Five inner city UK National Health Service hospitalsParticipants Multiethnic pregnant women at 12+0 and 15+6 weeks’ gestation with risk factors for gestational diabetes.Interventions 2 g of myo-inositol or placebo, both included 200 µg folic acid, twice daily until delivery.Primary outcome measures Rates of recruitment, randomisation, adherence and follow-up.Secondary outcome measures Glycaemic indices (including homoeostatic model assessment-insulin resistance HOMA-IR), gestational diabetes (diagnosed using oral glucose tolerance test at 28 weeks and by delivery), maternal, perinatal outcomes, acceptability of intervention and costs.Results Of the 1326 women screened, 58% (773/1326) were potentially eligible, and 27% (205/773) were recruited. We randomised 97% (198/205) of all recruited women (99 each in intervention and placebo arms) and ascertained outcomes in 90% of women (178/198) by delivery. The mean adherence was 52% (SD 44) at 28 weeks’ and 34% (SD 41) at 36 weeks’ gestation. HOMA-IR and serum insulin levels were lower in the myo-inositol vs placebo arm (mean difference −0.6, 95% CI −1.2 to 0.0 and −2.69, 95% CI −5.26 to −0.18, respectively). The study procedures were acceptable to women and healthcare professionals. Women who perceived themselves at high risk of gestational diabetes were more likely to participate and adhere to the intervention. The powder form of myo-inositol and placebo, along with nausea in pregnancy were key barriers to adherence.Conclusions A future trial on myo-inositol versus placebo to prevent gestational diabetes is feasible. The intervention will need to be delivered in a non-powder form to improve adherence. There is a signal for efficacy in reducing insulin resistance in pregnancy with myo-inositol.Trial registration number ISRCTN48872100.