Perinatal outcomes after admission with COVID-19 in pregnancy: a UK national cohort study.

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

Efficacy of decentralised home-based antihypertensive treatment in older adults with multimorbidity and polypharmacy (ATEMPT): an open-label randomised controlled pilot trial.

BACKGROUND: Older patients with multimorbidity and polypharmacy have been under-represented in clinical trials. We aimed to assess the effect of different intensities of antihypertensive treatment on changes in blood pressure, major safety outcomes, and patient-reported outcomes in this population. METHODS: ATEMPT was a decentralised, two-armed, parallel-group, open-label randomised controlled pilot trial conducted in the Thames Valley area, South East England. Individuals aged 65 years or older with multimorbidity (three or more chronic conditions) or polypharmacy (five or more types of medications) and a systolic blood pressure of 115-165 mm Hg were eligible for inclusion. Participants were identified through a search of national hospital discharge databases, identification of patients registered with an online pharmacy, and via targeted advertising on social media platforms. Participants were randomly assigned to receive up to two more classes versus up to two fewer classes of antihypertensive medications. Apart from routine home visits for conducting the baseline assessment, all communication, monitoring, and management of participants by the trial team was conducted remotely. The primary outcome was change in home-measured blood pressure. FINDINGS: Between Dec 15, 2020, and Aug 31, 2022, 230 participants were randomly assigned (n=126 to more vs n=104 to fewer antihypertensive medications). The frequency of serious adverse events was similar across both groups; no cardiovascular events occurred in the more antihypertensive drugs group, compared with six in the fewer antihypertensive drugs group, of which two were fatal. Over a 13-month follow-up period, the mean systolic blood pressure in the group allocated to receive more antihypertensive medications decreased from 134·5 mm Hg (SD 10·7) at baseline to 122·1 mm Hg (10·5). By contrast, in the group allocated to receive fewer antihypertensive medications, it remained relatively unchanged, moving from 134·8 mm Hg (SD 11·2) at baseline to 132·9 mm Hg (15·3); this corresponded to a mean difference of -10·7 mm Hg (95% CI -17·5 to -4·0). INTERPRETATION: Remotely delivered antihypertensive treatment substantially reduced systolic blood pressure in older adults who are often less represented in trials, with no increase in the risk of serious adverse events. The results of this trial will inform a larger clinical trial focusing on assessing major cardiovascular events, safety, physical functioning, and cognitive function that is currently in the planning stages. These results also underscore the efficiency of decentralised trial designs, which might be of broader interest in other settings. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Oxford Martin School.

Defining treatment success in children with surgical conditions.

OBJECTIVES: Develop a score summarising how successfully a child with any surgical condition has been treated, and test the clinical validity of the score. DESIGN: Discrete choice experiment (DCE), and secondary analysis of data from six UK-wide prospective cohort studies. PARTICIPANTS: 253 people with lived experience of childhood surgical conditions, 114 health professionals caring for children with surgical conditions and 753 members of the general population completed the DCE. Data from 1383 children with surgical conditions were used in the secondary analysis. MAIN OUTCOME MEASURES: Normalised importance value of attribute (NIVA) for number/type of operations, hospital-treated infections, quality of life and duration of survival (reference attribute). RESULTS: Quality of life and duration of survival were the most important attributes in deciding whether a child had been successfully treated. Parents, carers and previously treated adults placed equal weight on both attributes (NIVA=0.996; 0.798 to 1.194). Healthcare professionals placed more weight on quality of life (NIVA=1.469; 0.950 to 1.987). The general population placed more weight on survival (NIVA=0.823; 95% CI 0.708 to 0.938). The resulting score (the Children's Surgery Outcome Reporting (CSOR) Treatment Success Score (TSS)) has the best possible value of 1, a value of 0 describes palliation and values less than 0 describe outcomes worse than palliation. CSOR TSSs varied clinically appropriately for infants whose data were included in the UK-wide cohort studies. CONCLUSIONS: The CSOR TSS summarises how successfully children with surgical conditions have been treated, and can therefore be used to compare hospitals' observed and expected outcomes.

Frenotomy with breastfeeding support versus breastfeeding support alone for infants with tongue-tie and breastfeeding difficulties: the FROSTTIE RCT.

Background: Tongue-tie can be diagnosed in 3-11% of babies, with some studies reporting almost universal breastfeeding difficulties, and others reporting very few feeding difficulties that relate to the tongue-tie itself, instead noting that incorrect positioning and attachment are the primary reasons behind the observed breastfeeding difficulties and not the tongue-tie itself. The only existing trials of frenotomy are small and underpowered and/or include only very short-term or subjective outcomes. Objective: To investigate whether frenotomy is clinically and cost-effective to promote continuation of breastfeeding at 3 months in infants with breastfeeding difficulties diagnosed with tongue-tie. Design: A multicentre, unblinded, randomised, parallel group controlled trial. Setting: Twelve infant feeding services in the UK. Participants: Infants aged up to 10 weeks referred to an infant feeding service (by a parent, midwife or other breastfeeding support service) with breastfeeding difficulties and judged to have tongue-tie. Interventions: Infants were randomly allocated to frenotomy with standard breastfeeding support or standard breastfeeding support without frenotomy. Main outcome measures: Primary outcome was any breastmilk feeding at 3 months according to maternal self-report. Secondary outcomes included mother's pain, exclusive breastmilk feeding, exclusive direct breastfeeding, frenotomy, adverse events, maternal anxiety and depression, maternal and infant NHS health-care resource use, cost-effectiveness, and any breastmilk feeding at 6 months of age. Results: Between March 2019 and November 2020, 169 infants were randomised, 80 to the frenotomy with breastfeeding support arm and 89 to the breastfeeding support arm from a planned sample size of 870 infants. The trial was stopped in the context of the COVID-19 pandemic due to withdrawal of breastfeeding support services, slow recruitment and crossover between arms. In the frenotomy with breastfeeding support arm 74/80 infants (93%) received their allocated intervention, compared to 23/89 (26%) in the breastfeeding support arm. Primary outcome data were available for 163/169 infants (96%). There was no evidence of a difference between the arms in the rate of breastmilk feeding at 3 months, which was high in both groups (67/76, 88% vs. 75/87, 86%; adjusted risk ratio 1.02, 95% confidence interval 0.90 to 1.16). Adverse events were reported for three infants after surgery [bleeding (n = 1), salivary duct damage (n = 1), accidental cut to the tongue and salivary duct damage (n = 1)]. Cost-effectiveness could not be determined with the information available. Limitations: The statistical power of the analysis was extremely limited due to not achieving the target sample size and the high proportion of infants in the breastfeeding support arm who underwent frenotomy. Conclusions: This trial does not provide sufficient information to assess whether frenotomy in addition to breastfeeding support improves breastfeeding rates in infants diagnosed with tongue-tie. Future work: There is a clear lack of equipoise in the UK concerning the use of frenotomy, however, the effectiveness and cost-effectiveness of the procedure still need to be established. Other study designs will need to be considered to address this objective. Trial registration: This trial is registered as ISRCTN 10268851. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (project number 16/143/01) and will be published in full in Health Technology Assessment; Vol. 27, No. 11. See the NIHR Journals Library website for further project information. The funder had no role in study design or data collection, analysis and interpretation. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Many mothers and babies experience difficulties in establishing breastfeeding. In some babies it is thought that their difficulties may be linked to a condition called tongue-tie, in which a piece of skin tightly joins the middle part of the underside of the tongue to the base of the baby's mouth. This can be treated by an operation to divide the tight part/skin in the middle of the underneath of the tongue. We planned to carry out a trial of 870 babies to find out whether an operation together with breastfeeding support helps more mothers and babies with tongue-tie to continue breastfeeding until the baby is 3 months old compared to breastfeeding support on its own and whether the costs were different between the two groups of mothers and babies. We were only able to recruit 169 babies as the trial was stopped because of slow recruitment, changes to services in the COVID-19 pandemic and a high proportion of the babies in the breastfeeding support group going on to have an operation. There were no differences in the rate of breastfeeding at 3 months between the babies in the group who had an operation straightaway and those in the group that had breastfeeding support alone, or had an operation later. More than four in every five babies in both groups were still breastmilk feeding at 3 months. Three babies who had an operation, around 1 in 50 babies, had a complication of the operation (bleeding, scarring or a cut to the tube that makes saliva). Because of the small size of the study, we cannot say whether an operation to divide a tongue-tie along with breastfeeding support helps babies with tongue-tie and breastfeeding difficulties or has different costs. We will need to try different types of research to answer the question.

Variations across Europe in hospitalization and management of pregnant women with SARS-CoV-2 during the initial phase of the pandemic: Multi-national population-based cohort study using the International Network of Obstetric Survey Systems (INOSS).

INTRODUCTION: The majority of data on COVID-19 in pregnancy are not from sound population-based active surveillance systems. MATERIAL AND METHODS: We conducted a multi-national study of population-based national or regional prospective cohorts using standardized definitions within the International Network of Obstetric Survey systems (INOSS). From a source population of women giving birth between March 1 and August 31, 2020, we included pregnant women admitted to hospital with a positive SARS-CoV-2 PCR test ≤7 days prior to or during admission and up to 2 days after birth. The admissions were further categorized as COVID-19-related or non-COVID-19-related. The primary outcome of interest was incidence of COVID-19-related hospital admission. Secondary outcomes included severe maternal disease (ICU admission and mechanical ventilation) and COVID-19-directed medical treatment. RESULTS: In a source population of 816 628 maternities, a total of 2338 pregnant women were admitted with SARS-CoV-2; among them 940 (40%) were COVID-19-related admissions. The pooled incidence estimate for COVID-19-related admission was 0.59 (95% confidence interval 0.27-1.02) per 1000 maternities, with notable heterogeneity across countries (I2 = 97.3%, P = 0.00). In the COVID-19 admission group, between 8% and 17% of the women were admitted to intensive care, and 5%-13% needed mechanical ventilation. Thromboprophylaxis was the most frequent treatment given during COVID-19-related admission (range 14%-55%). Among 908 infants born to women in the COVID-19-related admission group, 5 (0.6%) stillbirths were reported. CONCLUSIONS: During the initial months of the pandemic, we found substantial variations in incidence of COVID-19-related admissions in nine European countries. Few pregnant women received COVID-19-directed medical treatment. Several barriers to rapid surveillance were identified. Investment in robust surveillance should be prioritized to prepare for future pandemics.

Mental health impact of the Middle East respiratory syndrome, SARS, and COVID-19: A comparative systematic review and meta-analysis.

BACKGROUND: Over the last few decades, 3 pathogenic pandemics have impacted the global population; severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2. The global disease burden has attributed to millions of deaths and morbidities, with the majority being attributed to SARS-CoV-2. As such, the evaluation of the mental health (MH) impact across healthcare professionals (HCPs), patients and the general public would be an important facet to evaluate to better understand short, medium and long-term exposures. AIM: To identify and report: (1) MH conditions commonly observed across all 3 pandemics; (2) Impact of MH outcomes across HCPs, patients and the general public associated with all 3 pandemics; and (3) The prevalence of the MH impact and clinical epidemiological significance. METHODS: A systematic methodology was developed and published on PROSPERO (CRD42021228697). The databases PubMed, EMBASE, ScienceDirect and the Cochrane Central Register of Controlled Trials were used as part of the data extraction process, and publications from January 1, 1990 to August 1, 2021 were searched. MeSH terms and keywords used included Mood disorders, PTSD, Anxiety, Depression, Psychological stress, Psychosis, Bipolar, Mental Health, Unipolar, Self-harm, BAME, Psychiatry disorders and Psychological distress. The terms were expanded with a 'snowballing' method. Cox-regression and the Monte-Carlo simulation method was used in addition to I 2 and Egger's tests to determine heterogeneity and publication bias. RESULTS: In comparison to MERS and SARS-CoV, it is evident SAR-CoV-2 has an ongoing MH impact, with emphasis on depression, anxiety and post-traumatic stress disorder. CONCLUSION: It was evident MH studies during MERS and SARS-CoV was limited in comparison to SARS-CoV-2, with much emphasis on reporting symptoms of depression, anxiety, stress and sleep disturbances. The lack of comprehensive studies conducted during previous pandemics have introduced limitations to the "know-how" for clinicians and researchers to better support patients and deliver care with limited healthcare resources.

Associations of Cord Blood Lipids with Childhood Adiposity at the Age of Three Years: A Prospective Birth Cohort Study.

We aimed to examine the associations between cord blood lipids and childhood adiposity and to investigate whether these associations vary across birth weight categories (small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA)) in 1306 infants in the Born in Guangzhou Cohort Study, China. Adiposity outcomes at the age of three years included z-scores of weight-for-length/height (WFLZ), body mass index (BMIZ), subscapular (SSTZ) and triceps skinfold thickness (TSTZ), and the sum of skinfold thicknesses (SSFTZ). Cord blood triglycerides (TG) levels were negatively associated with WFLZ and BMIZ, whereas high density lipoprotein (HDL) levels were positively associated with WFLZ, BMIZ, TSTZ and SSFTZ. These associations were attenuated after adjustment for birth weight. Stratified analyses revealed that total cholesterol (TC) and low-density lipoprotein (LDL) levels were positively associated with childhood adiposity indicators among AGA infants but tended to be negatively associated with the adiposity indicators among LGA infants (p values for interaction <0.05). Furthermore, TG levels appeared to be positively associated with adiposity indicators among SGA infants but negatively associated with the outcomes among LGA infants (p values for interaction <0.05). Cord blood lipids levels might be associated with childhood adiposity, and these associations appear to differ across different birth weight categories. If confirmed in future studies, our findings suggest that individualized management plans might be warranted in preventing obesity.

Targeted-BEHRT: Deep Learning for Observational Causal Inference on Longitudinal Electronic Health Records.

Observational causal inference is useful for decision-making in medicine when randomized clinical trials (RCTs) are infeasible or nongeneralizable. However, traditional approaches do not always deliver unconfounded causal conclusions in practice. The rise of "doubly robust" nonparametric tools coupled with the growth of deep learning for capturing rich representations of multimodal data offers a unique opportunity to develop and test such models for causal inference on comprehensive electronic health records (EHRs). In this article, we investigate causal modeling of an RCT-established causal association: the effect of classes of antihypertensive on incident cancer risk. We develop a transformer-based model, targeted bidirectional EHR transformer (T-BEHRT) coupled with doubly robust estimation to estimate average risk ratio (RR). We compare our model to benchmark statistical and deep learning models for causal inference in multiple experiments on semi-synthetic derivations of our dataset with various types and intensities of confounding. In order to further test the reliability of our approach, we test our model on situations of limited data. We find that our model provides more accurate estimates of relative risk least sum absolute error (SAE) from ground truth compared with benchmark estimations. Finally, our model provides an estimate of class-wise antihypertensive effect on cancer risk that is consistent with results derived from RCTs.

Placenta accreta spectrum - variations in clinical practice and maternal morbidity between the UK and France: a population-based comparative study.

OBJECTIVE: To compare the management and outcomes of women with placenta accreta spectrum (PAS) in France and the UK. DESIGN: Two population-based cohorts. SETTING: All obstetrician-led hospitals in the UK and maternity hospitals in eight French regions. POPULATION: A cohort of 219 women with PAS in France and a cohort of 154 women with PAS in the UK. METHODS: The management and outcomes of women with PAS were compared between the UK and France. MAIN OUTCOME MEASURES: Median blood loss, severe postpartum haemorrhage (≥3 l), postpartum infection and damage to surrounding organs. RESULTS: The management of PAS differed between the two countries: a larger proportion of women with PAS in the UK had a caesarean hysterectomy compared with France (43% vs 26%, p < 0.001), whereas in France a larger proportion of women with PAS received a uterus-preserving approach compared with the UK (36% vs 19%, p < 0.001). The total median blood loss in the UK was 3 l (IQR 1.7-6.5 l), compared with 1 l (IQR 0.5-2.5 l) in France; more women with PAS had a severe postpartum haemorrhage (PPH) in the UK compared with women with PAS in France (58% vs 21%, p < 0.001) [Correction added on 06 May 2022, after first online publication: '24 hour' has been changed to 'total' in the preceding sentence]. There was no difference between the UK and French populations for postpartum infection or organ damage. CONCLUSIONS: The UK and France have very different approaches to managing PAS, with more women in France receiving a uterine-conserving approach and more women in the UK undergoing caesarean hysterectomy. A life-threatening haemorrhage was more common in the UK than in France, which may be the result of differential management and/or the organisation of the healthcare systems. In women with placenta accreta spectrum, severe haemorrhage was more common in the UK than in France. TWEETABLE ABSTRACT: In women with placenta accreta spectrum, severe haemorrhage was more common in the UK than in France.

An Explainable Transformer-Based Deep Learning Model for the Prediction of Incident Heart Failure.

Predicting the incidence of complex chronic conditions such as heart failure is challenging. Deep learning models applied to rich electronic health records may improve prediction but remain unexplainable hampering their wider use in medical practice. We aimed to develop a deep-learning framework for accurate and yet explainable prediction of 6-month incident heart failure (HF). Using 100,071 patients from longitudinal linked electronic health records across the U.K., we applied a novel Transformer-based risk model using all community and hospital diagnoses and medications contextualized within the age and calendar year for each patient's clinical encounter. Feature importance was investigated with an ablation analysis to compare model performance when alternatively removing features and by comparing the variability of temporal representations. A post-hoc perturbation technique was conducted to propagate the changes in the input to the outcome for feature contribution analyses. Our model achieved 0.93 area under the receiver operator curve and 0.69 area under the precision-recall curve on internal 5-fold cross validation and outperformed existing deep learning models. Ablation analysis indicated medication is important for predicting HF risk, calendar year is more important than chronological age, which was further reinforced by temporal variability analysis. Contribution analyses identified risk factors that are closely related to HF. Many of them were consistent with existing knowledge from clinical and epidemiological research but several new associations were revealed which had not been considered in expert-driven risk prediction models. In conclusion, the results highlight that our deep learning model, in addition high predictive performance, can inform data-driven risk factor identification.

Management and implications of severe COVID-19 in pregnancy in the UK: data from the UK Obstetric Surveillance System national cohort.

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

Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomised clinical trials.

OBJECTIVE: Evidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics. METHODS: We conducted an individual patient-level data meta-analysis of 52 large-scale randomised clinical trials in the Blood Pressure Lowering Treatment Trialists' Collaboration using mixed models to examine treatment effects on BP over 4 years of mean follow-up. RESULTS: There were 363 684 participants (42% women), with baseline mean age=65 years and mean systolic/diastolic BP=152/87 mm Hg, and among whom 19% were current smokers, 49% had cardiovascular disease, 28% had diabetes and 69% were taking antihypertensive treatment at baseline. Drugs were effective in lowering BP showing maximal effect after 12 months and gradually attenuating towards later years. Based on measures taken ≥12 months postrandomisation, mean systolic/diastolic BP difference (95% CI) between more and less intense BP-lowering treatment was -11.1 (-11.3 to -10.8)/-5.6 (-5.7 to -5.4) mm Hg; between active treatment and placebo was -5.1 (-5.3 to -5.0)/-2.3 (-2.4 to -2.2) mm Hg; and between active and control arms for drug comparison trials was -1.4 (-1.5 to -1.3)/-0.6 (-0.7 to -0.6) mm Hg. BP reductions were observed across different baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes and prior antihypertensive treatment use. CONCLUSION: These findings suggest that BP-lowering pharmacotherapy is effective in lowering BP, up to 4 years on average, in people with different characteristics. Appropriate treatment strategies are needed to sustain substantive long-term BP reductions.

Characteristics Associated with Participant Attrition and Retention in a Perinatal Home Visiting Program.

Using data from the Florida Maternal, Infant, and Early Childhood Home Visiting (MIECHV) funded programs, we examined program- and participant-level characteristics associated with participant retention by time of enrollment. Analyses of data for 1,807 women enrolled in 11 sites across three years included descriptive statistics; Kaplan-Meier survival curve estimation and multilevel survival analyses using shared frailty model to assess participant- and program-level characteristics overall and by time of enrollment (during pregnancy or post-delivery). Median retention time for MIECHV participants was 462 days. The primary reason for attrition was loss-to-follow-up (59.4%) due to change of address/telephone. We found participant age > 25 years (compared to < 20 years), enrollment during pregnancy, and an average of 1.5-2.0 home visit/month to be protective, while current/history of substance abuse was a risk factor for attrition. To improve participant retention, the Florida MIECHV program may need to bolster efforts to support housing stability, increase outreach and engagement to younger women, address barriers to achieving two home visits per month throughout the program, and target differential predictors of participant attrition depending on time of enrollment.

Optimising Exome Prenatal Sequencing Services (EXPRESS): a study protocol to evaluate rapid prenatal exome sequencing in the NHS Genomic Medicine Service.

Background: Prenatal exome sequencing (ES) for the diagnosis of fetal anomalies was implemented nationally in England in October 2020 by the NHS Genomic Medicine Service (GMS). is the GMS is based around seven regional Genomic Laboratory Hubs (GLHs). Prenatal ES has the potential to significantly improve NHS prenatal diagnostic services by increasing genetic diagnoses and informing prenatal decision-making. Prenatal ES has not previously been offered routinely in a national healthcare system and there are gaps in knowledge and guidance. Methods: Our mixed-methods evaluation commenced in October 2020, aligning with the start date of the NHS prenatal ES service . Study design draws on a framework developed in previous studies of major system innovation. There are five interrelated workstreams. Workstream-1 will use interviews and surveys with professionals, non-participant observations and documentary analysis to produce in-depth case studies across all GLHs. Data collection at multiple time points will track changes over time. In Workstream-2 qualitative interviews with parents offered prenatal ES will explore experiences and establish information and support needs. Workstream-3 will analyse data from all prenatal ES tests for nine-months to establish service outcomes (e.g. diagnostic yield, referral rates, referral sources). Comparisons between GLHs will identify factors (individual or service-related) associated with any variation in outcomes. Workstream-4 will identify and analyse practical ethical problems. Requirements for an effective ethics framework for an optimal and equitable service will be determined. Workstream-5 will assess costs and cost-effectiveness of prenatal ES versus standard tests and evaluate costs of implementing an optimal prenatal ES care pathway. Integration of findings will determine key features of an optimal care pathway from a service delivery, parent and professional perspective. Discussion: The proposed formative and summative evaluation will inform the evolving prenatal ES service to ensure equity of access, high standards of care and benefits for parents across England.

BACKGROUND: Prenatal exome sequencing is a new test that is offered through the NHS Genomic Medicine Service. Prenatal exome sequencing is offered to pregnant women when ultrasound scans suggest that their baby may have a genetic condition that cannot be diagnosed using standard tests. If a genetic condition is diagnosed this can give parents important information about the outlook for their baby. It can also help with their decisions about whether to continue or end the pregnancy, pregnancy management, post-birth care and future pregnancies. STUDY METHODS: The aim of this study is to evaluate the prenatal exome sequencing service. To do this we will; 1. Study how prenatal exome sequencing is delivered across England using surveys and interviews with professionals.2. Interview parents to ask what they think of prenatal exome sequencing and how support and information could be improved3. Look at how many parents have prenatal exome sequencing and the test results. We will look carefully at who has access to the test and whether any particular groups are less likely to be offered testing.4. Conduct workshops with health professionals and parents to identify any practical or ethical problems that arise when prenatal exome sequencing is offered.5. Look at the cost of prenatal exome sequencing and compare it to the cost of other tests that are offered to diagnose genetic conditions in pregnancy.6. Gather our findings together to make recommendations for best practice. Patient and Public Involvement: A patient and public Involvement, engagement and participation (PPIEP) advisory group will work closely with the research team to design the study and develop study materials. They will also help us understand our findings to make sure the information and recommendations that come out of our research will be helpful to parents and the NHS.

Severity of maternal infection and perinatal outcomes during periods of SARS-CoV-2 wildtype, alpha, and delta variant dominance in the UK: prospective cohort study.

Objective: To compare the severity of maternal infection and perinatal outcomes during periods in which wildtype, alpha variant, and delta variant of SARS-CoV-2 were dominant in the UK. Design: Prospective cohort study. Setting: 194 obstetric units across the UK, during the following periods: between 1 March and 30 November 2020 (wildtype dominance), between 1 December 2020 and 15 May 2021 (alpha variant dominance), and between 16 May and 31 October 2021 (delta variant dominance). Participants: 4436 pregnant women admitted to hospital with covid-19 related symptoms. Main outcome measures: Moderate to severe maternal SARS-CoV-2 infection (indicated by any of the following: oxygen saturation <95% on admission, need for oxygen treatment, evidence of pneumonia on imaging, admission to intensive care, or maternal death), and pregnancy and perinatal outcomes (including mode and gestation of birth, stillbirth, live birth, admission to neonatal intensive care, and neonatal death). Results: 1387, 1613, and 1436 pregnant women were admitted to hospital with covid-19 related symptoms during the wildtype, alpha, and delta dominance periods, respectively; of these women, 340, 585, and 614 had moderate to severe infection, respectively. The proportion of pregnant women admitted with moderate to severe infection increased during the subsequent alpha and delta dominance periods, compared with the wildtype dominance period (wildtype 24.5% v alpha 36.2% (adjusted odds ratio 1.98, 95% confidence interval 1.66% to 2.37%); wildtype 24.5% v delta 42.8% (2.66, 2.21 to 3.20)). Compared with the wildtype dominance period, women admitted during the alpha dominance period were significantly more likely to have pneumonia, require respiratory support, and be admitted to intensive care; these three risks were even greater during the delta dominance period (wildtype v delta: pneumonia, adjusted odds ratio 2.52, 95% confidence interval 2.06 to 3.09; respiratory support, 1.90, 1.52 to 2.37; and intensive care, 2.71, 2.06 to 3.56). Of 1761 women whose vaccination status was known, 38 (2.2%) had one dose and 16 (1%) had two doses before their diagnosis (of whom 14 (88%) had mild infection). The proportion of women receiving drug treatment for SARS-CoV-2 management was low, but did increase between the wildtype dominance period and the alpha and delta dominance periods (10.4% wildtype v 14.9% alpha (2.74, 2.08 to 3.60); 10.4% wildtype v 13.6% delta (2.54, 1.90 to 3.38)). Conclusions: While limited by the absence of variant sequencing data, these findings suggest that during the periods when the alpha and delta variants of SARS-CoV-2 were dominant, covid-19 was associated with more severe maternal infection and worse pregnancy outcomes than during the wildtype dominance period. Most women admitted with SARS-CoV-2 related symptoms were unvaccinated. Urgent action to prioritise vaccine uptake in pregnancy is essential. Study registration: ISRCTN40092247.

Severity of maternal SARS-CoV-2 infection and perinatal outcomes of women admitted to hospital during the omicron variant dominant period using UK Obstetric Surveillance System data: prospective, national cohort study.

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

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts.

BACKGROUND: Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. METHODS: Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. RESULTS: Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10-2.58)] and subtypes ALL [1.49 (0.87-2.56)] and AML [2.70 ([0.93-7.86)], but not with any cancer [1.13 (0.85-1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06-2.34)], ALL [1.43 (0.94-2.19)], AML [2.37 (1.10-5.12)] and any cancer [1.33 (1.09-1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. CONCLUSIONS: Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Associations of Longitudinal Fetal Growth Patterns With Cardiometabolic Factors at Birth.

Background: Birth weight is associated with cardiometabolic factors at birth. However, it is unclear when these associations occur in fetal life. We aimed to investigate the associations between fetal growth in different gestational periods and cord blood cardiometabolic factors. Methods: We included 1,458 newborns from the Born in Guangzhou Cohort Study, China. Z-scores of fetal size parameters [weight, abdominal circumference (AC), and femur length (FL)] at 22 weeks and growth at 22-27, 28-36, and ≥37 weeks were calculated from multilevel linear spline models. Multiple linear regression was used to examine the associations between fetal growth variables and z-scores of cord blood cardiometabolic factors. Results: Fetal weight at each period was positively associated with insulin levels, with stronger association at 28-36 weeks (ß, 0.31; 95% CI, 0.23 to 0.39) and ≥37 weeks (ß, 0.15; 95% CI, 0.10 to 0.20) compared with earlier gestational periods. Fetal weight at 28-36 (ß, -0.32; 95% CI, -0.39 to -0.24) and ≥37 weeks (ß, -0.26; 95% CI, -0.31 to -0.21) was negatively associated with triglyceride levels, whereas weight at 28-36 weeks was positively associated with HDL levels (ß, 0.12; 95% CI, 0.04 to 0.20). Similar results were observed for AC. Fetal FL at 22 and 22-27 weeks was associated with increased levels of insulin, glucose, and HDL. Conclusions: Fetal growth at different gestational periods was associated with cardiometabolic factors at birth, suggesting that an interplay between fetal growth and cardiometabolic factors might exist early in pregnancy.