Mechanisms for Integrating Real Data into Search Game Simulations: An Application to Winter Health Service Pressures and Preventative Policies.

While modelling and simulation are powerful techniques for exploring complex phenomena, if they are not coupled with suitable real-world data any results obtained are likely to require extensive validation. We consider this problem in the context of search game modelling, and suggest that both demographic and behaviour data are used to configure certain model parameters. We show this integration in practice by using a combined dataset of over 150,000 individuals to configure a specific search game model that captures the environment, population, interventions and individual behaviours relating to winter health service pressures. The presence of this data enables us to more accurately explore the potential impact of service pressure interventions, which we do across 33,000 simulations using a computational version of the model. We find government advice to be the best-performing intervention in simulation, in respect of improved health, reduced health inequalities, and thus reduced pressure on health service utilisation.

Left Atrial Mechanics Following Preeclamptic Pregnancy.

BACKGROUND: Preterm preeclampsia is a pregnancy complication associated with myocardial dysfunction and premature cardiovascular disease morbidity and mortality. Left atrial (LA) strain is a noninvasive index of left ventricular end diastolic pressure and an early marker of heart failure risk. This study aimed to evaluate LA strain during the postpartum period in participants with and without preterm preeclampsia and to assess whether this varied in the presence of hypertension and/or cardiac dysfunction. METHODS: In this longitudinal cohort study, 321 women from 28 hospitals with preterm preeclampsia (cases) underwent cardiovascular assessment 6 months postpartum. This is a secondary analysis of the PHOEBE study (ISRCTN01879376). An uncomplicated pregnancy control group (n=30) was recruited from a single center for comparison. A full cross-sectional transthoracic echocardiogram was performed, and from these images, the myocardial strain of the left atrium, including reservoir, conduit, and contractile strain, as well as LA stiffness, were calculated. RESULTS: At 6 months postpartum, compared with controls, prior preeclampsia was associated with a significantly attenuated LA reservoir, conduit, and contractile strain, as well as increased LA stiffness (all P<0.001). LA strain was further reduced in preeclamptic women who had and had not developed hypertension, systolic, or diastolic dysfunction at 6 months postpartum (all P<0.05). CONCLUSIONS: LA mechanics were significantly attenuated at 6 months postpartum in participants with preterm preeclampsia, whether or not they remained hypertensive or had evidence of ventricular dysfunction. Further studies are needed to determine whether postnatal LA strain may identify women at greater risk for future cardiovascular disease.

Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes.

BACKGROUND: The aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelines and interventions aimed at limiting GWG in women with overweight or obesity. We explored relationships between maternal BMI, total GWG (as a continuous variable and as 'excessive' GWG), and pregnancy outcomes (including infant birthweight measures and caesarean birth). METHODS: Analysis of individual participant data (IPD) from the i-WIP (International Weight Management in Pregnancy) Collaboration, from randomised trials of diet and/or physical activity interventions during pregnancy reporting GWG and maternal and neonatal outcomes. Women randomised to the control arm of 20 eligible randomised trials (4370 of 8908 participants) from the i-WIP dataset of 36 randomised trials (total 12,240 women). The main research questions were to characterise the relationship between maternal BMI and (a) total GWG, (b) the risk of 'excessive' GWG (using the Institute of Medicine's guidelines), and (c) adverse pregnancy outcomes as mediated via GWG versus other pathways to determine the extent to which the observed effect of maternal BMI on pregnancy outcomes is mediated via GWG. We utilised generalised linear models and regression-based mediation analyses within an IPD meta-analysis framework. RESULTS: Mean GWG decreased linearly as maternal BMI increased; however, the risk of 'excessive' GWG increased markedly at BMI category thresholds (i.e. between the normal and overweight BMI category threshold and between the overweight and obese BMI category threshold). Increasing maternal BMI was associated with increased risk of all pregnancy outcomes assessed; however, there was no evidence that this effect was mediated via effects on GWG. CONCLUSIONS: There is evidence of a meaningful relationship between maternal BMI and GWG and between maternal BMI and adverse pregnancy outcomes. There is no evidence that the effect of maternal BMI on outcomes is via an effect on GWG. Our analyses also cast doubt on the existence of a relationship between 'excessive' GWG and adverse pregnancy outcomes. Our findings challenge the practice of actively managing GWG throughout pregnancy.

Vitamin D status of pregnant women with obesity in the UK and its association with pregnancy outcomes: a secondary analysis of the UK Pregnancies Better Eating and Activity Trial (UPBEAT) study.

Prenatal vitamin D deficiency is widely reported and may affect perinatal outcomes. In this secondary analysis of the UK Pregnancies Better Eating and Activity Trial, we examined vitamin D status and its relationship with selected pregnancy outcomes in women with obesity (BMI ≥ 30 kg/m2) from multi-ethnic inner-city settings in the UK. Determinants of vitamin D status at a mean of 17 ± 1 weeks' gestation were assessed using multivariable linear regression and reported as percent differences in serum 25-hydroxyvitamin D (25(OH)D). Associations between 25(OH)D and clinical outcomes were examined using logistic regression. Among 1089 participants, 67 % had 25(OH)D < 50 nmol/l and 26 % had concentrations < 25 nmol/l. In fully adjusted models accounting for socio-demographic and anthropometric characteristics, 25(OH)D was lower among women of Black (% difference = -33; 95 % CI: -39, -27), Asian (% difference = -43; 95 % CI: -51, -35) and other non-White (% difference = -26; 95 % CI: -35, -14) ethnicity compared with women of White ethnicity (n 1086; P < 0·001 for all). In unadjusted analysis, risk of gestational diabetes was greater in women with 25(OH)D < 25 nmol/l compared with ≥ 50 nmol/l (OR = 1·58; 95 % CI: 1·09, 2·31), but the magnitude of effect estimates was attenuated in the multivariable model (OR = 1·33; 95 % CI: 0·88, 2·00). There were no associations between 25(OH)D and risk of preeclampsia, preterm birth or small for gestational age or large-for-gestational-age delivery. These findings demonstrate low 25(OH)D among pregnant women with obesity and highlight ethnic disparities in vitamin D status in the UK. However, evidence for a greater risk of adverse perinatal outcomes among women with vitamin D deficiency was limited.

Interventions in preconception and pregnant women at risk of gestational diabetes; a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Women at risk of gestational diabetes mellitus (GDM) need preventative interventions. OBJECTIVE: To evaluate targeted interventions before and during pregnancy for women identified as being at risk of developing GDM. METHODS: Systematic review and meta-analysis conducted following PRISMA guidelines. MEDLINE, EMBASE and the Cochrane Library in addition to reference and citation lists were searched to identify eligible randomised controlled trials (RCTs) utilising risk stratification during the preconception period or in the first/early second trimester. Screening and data extraction were carried out by the authors independently. Quality assessment was conducted based on the Cochrane risk-of-bias tool. Random effects meta-analysis and narrative synthesis were performed. RESULTS: Eighty-four RCTs were included: two during preconception and 82 in pregnancy, with a pooled sample of 22,568 women. Interventions were behavioural (n = 54), dietary supplementation (n = 19) and pharmacological (n = 11). Predictive factors for risk assessment varied; only one study utilised a validated prediction model. Gestational diabetes was reduced in diet and physical activity interventions (risk difference - 0.03, 95% CI 0.06, - 0.01; I2 58.69%), inositol (risk difference - 0.19, 95% CI 0.33, - 0.06; I2 92.19%), and vitamin D supplements (risk difference - 0.16, 95% CI 0.25, - 0.06; I2 32.27%). Subgroup analysis showed that diet and physical activity interventions were beneficial in women with ≥ 2 GDM risk factors (risk difference - 0.16, 95% CI 0.25, - 0.07; I2 11.23%) while inositol supplementation was effective in women with overweight or obesity (risk difference - 0.17, 95% CI 0.22, - 0.11; I2 0.01%). Effectiveness of all other interventions were not statistically significant. CONCLUSIONS: This review provides evidence that interventions targeted at women at risk of GDM may be an effective strategy for prevention. Further studies using validated prediction tools or multiple risk factors to target high-risk women for intervention before and during pregnancy are warranted.

Omega-3 fatty acid supply in pregnancy for risk reduction of preterm and early preterm birth.

This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations, and is based on a review of the available strong evidence from randomized clinical trials and a formal consensus process. We concluded the following. Women of childbearing age should obtain a supply of at least 250 mg/d of docosahexaenoic+eicosapentaenoic acid from diet or supplements, and in pregnancy an additional intake of ≥100 to 200 mg/d of docosahexaenoic acid. Pregnant women with a low docosahexaenoic acid intake and/or low docosahexaenoic acid blood levels have an increased risk of preterm birth and early preterm birth. Thus, they should receive a supply of approximately 600 to 1000 mg/d of docosahexaenoic+eicosapentaenoic acid, or docosahexaenoic acid alone, given that this dosage showed significant reduction of preterm birth and early preterm birth in randomized controlled trials. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation. Identification of women with inadequate omega-3 supply is achievable by a set of standardized questions on intake. Docosahexaenoic acid measurement from blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cutoff values is needed. Information on how to achieve an appropriate intake of docosahexaenoic acid or docosahexaenoic+eicosapentaenoic acid for women of childbearing age and pregnant women should be provided to women and their partners.

MAGIC (maternal glucose in pregnancy) understanding the glycemic profile of pregnancy, intensive CGM glucose profiling and its relationship to fetal growth: an observational study protocol.

BACKGROUND: Continuous glucose monitoring (CGM) provides the most objective method of assessing glucose in daily life. Although there have been small, short-term physiologic studies of glucose metabolism in 'healthy' pregnant women a comprehensive, longitudinal description of changes in glucose over the course of pregnancy and how glucose dysregulation earlier in pregnancy relates to traditional third trimester screening for gestational diabetes, fetal growth and pregnancy outcomes is lacking. This study aims to characterise longitudinal changes in glycemia across gestation using CGM, in order to understand the evolution of dysglycemia and its relationship to fetal growth. METHOD/DESIGN: A multi-centre, prospective, observational, cohort study of 500 healthy pregnant women, recruited in the first trimester of pregnancy. Masked CGM will be performed for a 14-day period on five occasions across pregnancy at ~ 10-12, 18-20, 26-28, 34-36 weeks gestation and postnatally. Routinely collected anthropometric and sociodemographic information will be recorded at each visit including: weight, height, blood pressure, current medication. Age, parity, ethnicity, smoking will be recorded. Blood samples will be taken at each visit for HbA1c and a sample stored. Details on fetal growth from ultrasound scans and the OGTT results will be recorded. Maternal and neonatal outcomes will be collected. CGM glucose profiling is the exposure of interest, and will be performed using standard summary statistics, functional data analysis and glucotyping. The primary maternal outcome is clinical diagnosis of GDM. The primary neonatal outcome is large for gestational age (LGA) (> 90th centile defined by customised birthweight centile). The relationship of glucose to key secondary maternal and neonatal outcomes will be explored. DISCUSSION: This study will ascertain the relationship of maternal dysglycemia to fetal growth and outcomes. It will explore whether CGM glucose profiling can detect GDM before the OGTT; or indeed whether CGM glucose profiling may be more useful than the OGTT at detecting LGA and other perinatal outcomes. TRIAL REGISTRATION: ISRCTN 15,706,303 https://www.isrctn.com/ISRCTN15706303 Registration date: 13th March 2023.

PREPARE: A Stepped-Wedge Cluster-Randomized Trial to Evaluate Whether Risk Stratification Can Reduce Preterm Deliveries Among Patients With Suspected or Confirmed Preterm Preeclampsia.

BACKGROUND: Early delivery in preterm preeclampsia may reduce the risks for the patient, but consequences of prematurity may be substantial for the baby. This trial evaluated whether the implementation of a risk stratification model could safely reduce prematurity. METHODS: This was a stepped-wedge cluster-randomized trial in seven clusters. Patients presenting with suspected or confirmed preeclampsia between 20+0 and 36+6 gestational weeks were considered eligible. At the start of the trial, all centers were allocated in the preintervention phase, and patients enrolled in this phase were managed according to local treatment guidance. Subsequently, every 4 months, 1 randomly allocated cluster transitioned to the intervention. Patients enrolled in the intervention phase had sFlt-1 (soluble fms-like tyrosine kinase-1)/PlGF (placental growth factor) ratio and preeclampsia integrated estimate of risk assessments performed. If sFlt-1/PlGF ≤38 and preeclampsia integrated estimate of risk <10%, patients were considered low risk and clinicians received recommendations to defer delivery. If sFlt-1/PlGF >38 and preeclampsia integrated estimate of risk ≥10%, patients were considered not low risk, and clinicians received recommendations to increase surveillance. The primary outcome was the proportion of patients with preterm preeclampsia delivered prematurely out of total deliveries. RESULTS: Between March 25, 2017 and December 24, 2019, 586 and 563 patients were analyzed in the intervention and usual care groups, respectively. The event rate was 1.09% in the intervention group, and 1.37% in the usual care group. After prespecified adjustments for variation between and within clusters over time, the adjusted risk ratio was 1.45 ([95% CI, 1.04-2.02]; P=0.029), indicating a higher risk of preterm deliveries in the intervention group. Post hoc analysis including calculation of risk differences did not show evidence of statistical differences. Abnormal sFlt-1/PlGF was associated with a higher rate of identifying preeclampsia with severe features. CONCLUSIONS: The introduction of an intervention based on biomarkers and clinical factors for risk stratification did not lead to reductions in preterm deliveries. Further training on the interpretation of disease severity in preeclampsia and the development of additional risk stratification is needed before adoption into clinical practice. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03073317.

Trends in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and vaccine antibody prevalence in a multi-ethnic inner-city antenatal population: A cross-sectional surveillance study.

OBJECTIVE: To determine severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in pregnancy in an inner-city setting and assess associations with demographic factors and vaccination timing. DESIGN: Repeated cross-sectional surveillance study. SETTING: London maternity centre. SAMPLE: A total of 906 pregnant women attending nuchal scans, July 2020-January 2022. METHODS: Blood samples were tested for IgG antibodies against SARS-CoV-2 nucleocapsid (N) and spike (S) proteins. Self-reported vaccination status and coronavirus disease 2019 (COVID-19) infection were recorded. Multivariable regression models determined demographic factors associated with seroprevalence and antibody titres. MAIN OUTCOME MEASURES: Immunoglobulin G N- and S-protein antibody titres. RESULTS: Of the 960 women, 196 (20.4%) were SARS-CoV-2 seropositive from previous infection. Of these, 70 (35.7%) self-reported previous infection. Among unvaccinated women, women of black ethnic backgrounds were most likely to be SARS-CoV-2 seropositive (versus white adjusted risk ratio [aRR] 1.88, 95% CI 1.35-2.61, p < 0.001). Women from black and mixed ethnic backgrounds were least likely to have a history of vaccination with seropositivity to S-protein (versus white aRR 0.58, 95% CI 0.40-0.84, p = 0.004; aRR 0.56, 95% CI 0.34-0.92, p = 0.021, respectively). Double vaccinated, previously infected women had higher IgG S-protein antibody titres than unvaccinated, previously infected women (mean difference 4.76 fold-change, 95% CI 2.65-6.86, p < 0.001). Vaccination timing before versus during pregnancy did not affect IgG S-antibody titres (mean difference -0.28 fold-change, 95% CI -2.61 to 2.04, p = 0.785). CONCLUSIONS: This cross-sectional study demonstrates high rates of asymptomatic SARS-CoV-2 infection with women of black ethnic backgrounds having higher infection risk and lower vaccine uptake. SARS-CoV-2 antibody titres were highest among double-vaccinated, infected women.

Normative ranges of biventricular volumes and function in healthy term newborns.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used in newborns with congenital heart disease. However, reporting on ventricular volumes and mass is hindered by an absence of normative data in this population. DESIGN/METHODS: Healthy term (37-41 weeks gestation) newborns underwent non-sedated, free-breathing CMR within the first week of life using the 'feed and wrap' technique. End-diastolic volume (EDV), end-systolic volume (ESV) stroke volume (SV) and ejection fraction (EF) were calculated for both left ventricle (LV) and right ventricle (RV). Papillary muscles were separately contoured and included in the myocardial volume. Myocardial mass was calculated by multiplying myocardial volume by 1.05 g/ml. All data were indexed to weight and body surface area (BSA). Inter-observer variability (IOV) was performed on data from 10 randomly chosen infants. RESULTS: Twenty healthy newborns (65% male) with a mean (SD) birth weight of 3.54 (0.46) kg and BSA of 0.23 (0.02) m2 were included. Normative LV parameters were indexed EDV 39.0 (4.1) ml/m2, ESV 14.5 (2.5) ml/m2 and ejection fraction (EF) 63.2 (3.4)%. Normative RV indexed EDV, ESV and EF were 47.4 (4.5) ml/m2, 22.6 (2.9) ml/m2 and 52.5 (3.3)% respectively. Mean LV and RV indexed mass were 26.4 (2.8) g/m2 and 12.5 (2.0) g/m2, respectively. There was no difference in ventricular volumes by gender. IOV was excellent with an intra-class coefficient > 0.95 except for RV mass (0.94). CONCLUSION: This study provides normative data on LV and RV parameters in healthy newborns, providing a novel resource for comparison with newborns with structural and functional heart disease.

Longitudinal dietary trajectories from pregnancy to 3 years post delivery in women with obesity: relationships with adiposity.

OBJECTIVE: The study aim was to examine the relationships between longitudinal dietary trajectories from early pregnancy to 3 years post delivery and adiposity measures in women with obesity. METHODS: The diets of 1208 women with obesity in the UPBEAT (UK Pregnancy Better Eating and Activity Trial) study were assessed using a food frequency questionnaire (FFQ) at 15+0 to 18+6 weeks' gestation (baseline), 27+0 to 28+6 weeks' gestation, and 34+0 to 36+0 weeks' gestation, as well as 6 months and 3 years post delivery. Using factor analysis of the baseline FFQ data, four dietary patterns were identified: fruit & vegetable, African/Caribbean, processed, and snacking. The baseline scoring system was applied to the FFQ data at the four subsequent time points. Group-based trajectory modeling was used to extract longitudinal dietary pattern trajectories. Using adjusted regression, associations between dietary trajectories and log-transformed/standardized adiposity measures (BMI and waist and mid-upper arm circumferences) at 3 years post delivery were examined. RESULTS: Two trajectories were found to best describe the data for the four individual dietary patterns; these were characterized as high and low adherence. A high adherence to the processed pattern was associated with a higher BMI (ß = 0.38 [95% CI: 0.06-0.69]) and higher waist (ß = 0.35 [0.03-0.67]) and mid-upper arm circumferences (ß = 0.36 [0.04-0.67]) at 3 years post delivery. CONCLUSIONS: In women with obesity, a processed dietary pattern across pregnancy and 3 years post delivery is associated with higher adiposity.

Towards Precision Medicine in Gestational Diabetes: Pathophysiology and Glycemic Patterns in Pregnant Women With Obesity.

AIMS: Precision medicine has revolutionized our understanding of type 1 diabetes and neonatal diabetes but has yet to improve insight into gestational diabetes mellitus (GDM), the most common obstetric complication and strongly linked to obesity. Here we explored if patterns of glycaemia (fasting, 1 hour, 2 hours) during the antenatal oral glucose tolerance test (OGTT), reflect distinct pathophysiological subtypes of GDM as defined by insulin secretion/sensitivity or lipid profiles. METHODS: 867 pregnant women with obesity (body mass index ≥ 30 kg/m2) from the UPBEAT trial (ISRCTN 89971375) were assessed for GDM at 28 weeks' gestation (75 g oral glucose tolerance test OGTT; World Health Organization criteria). Lipid profiling of the fasting plasma OGTT sample was undertaken using direct infusion mass spectrometry and analyzed by logistic/linear regression, with and without adjustment for confounders. Insulin secretion and sensitivity were characterized by homeostatic model assessment 2b and 2s, respectively. RESULTS: In women who developed GDM (n = 241), patterns of glycaemia were associated with distinct clinical and biochemical characteristics and changes to lipid abundance in the circulation. Severity of glucose derangement, rather than pattern of postload glycaemia, was most strongly related to insulin action and lipid abundance/profile. Unexpectedly, women with isolated postload hyperglycemia had comparable insulin secretion and sensitivity to euglycemic women, potentially indicative of a novel mechanistic pathway. CONCLUSIONS: Patterns of glycemia during the OGTT may contribute to a precision approach to GDM as assessed by differences in insulin resistance/secretion. Further research is indicated to determine if isolated postload hyperglycemia reflects a different mechanistic pathway for targeted management.

National surveillance data analysis of COVID-19 vaccine uptake in England by women of reproductive age.

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.

Pre-pregnancy health of women with pre-existing diabetes or previous gestational diabetes: Analysis of pregnancy risk factors and behavioural data from a digital tool.

AIMS: To examine health behaviours and risk factors in women with pre-existing diabetes or previous gestational diabetes mellitus who are planning pregnancy. METHODS: Health behaviour, risk factor and demographic data obtained from a digital pregnancy planning advisory tool (Tommy's charity UK) were analysed. Descriptive statistical analysis was performed, stratified by diabetes type. RESULTS: Data from 84,359 women, including 668 with type 1 diabetes, 707 with type 2 diabetes and 1785 with previous gestational diabetes obtained over a 12-month period (September 2019-September 2020) were analysed. 65%, 95%CI (61,68%) of women with type 2 diabetes and 46%, 95%CI (43,48%) with previous gestational diabetes were obese (BMI ≥30 kg/m2 ), compared with 26%, 95%CI (26,26%) without diabetes. Use of folic acid supplements was low; 41%, 95%CI (40,41%) of women without diabetes and 42%, 95%CI (40,45%) with previous gestational diabetes reported taking folic acid (any dose) while 47%, 95%CI (43.50%) women with type 1 diabetes and 44%, 95%CI (40,47%) women with type 2 diabetes respectively reported taking the recommended dose (5 mg). More women with type 1 diabetes and type 2 diabetes reported smoking (20%, 95%CI [17,23%] and 23%, 95%CI [20,26%] respectively) and taking illicit/recreational drugs (7%, 95%CI [6,10%] and 9%, 95% CI [7,11%]) compared to women without diabetes (smoking 17%, 95% CI [16,17%], drug use 5%, 95%CI [5,5%]). Alcohol consumption, low levels of physical activity and of fruit and vegetable intake were also evident. CONCLUSIONS: This study highlights the potential of online pregnancy planning advisory tools to reach high-risk women and emphasises the need to improve pre-pregnancy care for women with pre-existing diabetes and previous gestational diabetes, many of whom are actively seeking advice. It is also the first to describe pre-pregnancy health behaviours in women with previous gestational diabetes.

Micronutrient supplementation interventions in preconception and pregnant women at increased risk of developing pre-eclampsia: a systematic review and meta-analysis.

BACKGROUND: Pre-eclampsia can lead to maternal and neonatal complications and is a common cause of maternal mortality worldwide. This review has examined the effect of micronutrient supplementation interventions in women identified as having a greater risk of developing pre-eclampsia. METHODS: A systematic review was performed using the PRISMA guidelines. The electronic databases MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials were searched for relevant literature and eligible studies identified according to a pre-specified criteria. A meta-analysis of randomised controlled trials (RCTs) was conducted to examine the effect of micronutrient supplementation on pre-eclampsia in high-risk women. RESULTS: Twenty RCTs were identified and supplementation included vitamin C and E (n = 7), calcium (n = 5), vitamin D (n = 3), folic acid (n = 2), magnesium (n = 1) and multiple micronutrients (n = 2). Sample size and recruitment time point varied across studies and a variety of predictive factors were used to identify participants, with a previous history of pre-eclampsia being the most common. No studies utilised a validated prediction model. There was a reduction in pre-eclampsia with calcium (risk difference, -0.15 (-0.27, -0.03, I2 = 83.4%)), and vitamin D (risk difference, -0.09 (-0.17, -0.02, I2 = 0.0%)) supplementation. CONCLUSION: Our findings show a lower rate of pre-eclampsia with calcium and vitamin D, however, conclusions were limited by small sample sizes, methodological variability and heterogeneity between studies. Further higher quality, large-scale RCTs of calcium and vitamin D are warranted. Exploration of interventions at different time points before and during pregnancy as well as those which utilise prediction modelling methodology, would provide greater insight into the efficacy of micronutrient supplementation intervention in the prevention of pre-eclampsia in high-risk women.

Gestational diabetes in women with obesity; an analysis of clinical history and simple clinical/anthropometric measures.

AIM: We assessed clinical risk factors, anthropometric measures of adiposity and weight gain to determine associations with development of GDM in a cohort of pregnant women with obesity. METHODS: This was a secondary analysis of the UPBEAT trial of a complex lifestyle intervention in pregnant women with obesity (ISRCTN89971375). Clinical risk factors, and measures of adiposity and weight were assessed in the early 2nd trimester (mean 17 +0 weeks), and adiposity and weight repeated in the early 3rd trimester (mean 27 +5 weeks'). RESULTS: Of the 1117 women (median BMI 35.0 kg/m2) with complete data, 25.8% (n = 304) developed GDM (IADPSG criteria, OGTT 24-28weeks). Using multivariable analysis, early clinical risk factors associated with later development of GDM included age (adj OR 1.06 per year; 95% CI 1.04-1.09), previous GDM (3.27; 1.34-7.93) and systolic blood pressure (per 10mmHg, 1.34; 1.18-1.53). Anthropometric measures positively associated with GDM included second trimester (mean 17+0 weeks) subscapular skinfold thickness, (per 5mm, 1.12; 1.05-1.21), and neck circumference (per cm, 1.11; 1.05-1.18). GDM was not associated with gestational weight gain, or changes in skinfolds thicknesses or circumferences between visits. CONCLUSIONS: In this cohort of women with obesity, we confirmed clinical risk factors for GDM, (age, systolic blood pressure) previously identified in heterogeneous weight women but add to these indices of adiposity which may provide a discriminatory approach to GDM risk assessment in this group. This study also underscores the need to focus on modifiable factors pre-pregnancy as an opportunity for GDM prevention, as targeting gestational weight gain and adiposity during pregnancy is likely to be less effective.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year olds: children of the UPBEAT RCT.

BACKGROUND/OBJECTIVES: Obesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk. SUBJECTS/METHODS: Children were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram. RESULTS: Compared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS -0.03 cm (-0.05 to -0.008); PW -0.03 cm (-0.05 to -0.01); RWT -0.02 cm (-0.04 to -0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis. CONCLUSIONS: Maternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.